The international generalisability of evidence for health policy: A cross country comparison of medication adherence following policy change.

PubMed

Sinnott, Sarah-Jo; Whelton, Helen; Franklin, Jessica Myers; Polinski, Jennifer Milan

2017-01-01

Copayments for prescriptions may increase morbidity and mortality via reductions in adherence to medications. Relevant data can inform policy to minimise such unintended effects. We explored the generalisability of evidence for copayments by comparing two international copayment polices, one in Massachusetts and one in Ireland, to assess whether effects on medication adherence were comparable. We used national prescription data for public health insurance programmes in Ireland and Medicaid data in the U.S. New users of oral anti-hypertensive, anti-hyperlipidaemic and diabetic drugs were included (total n=14,259 in U.S. and n=43,843 in Ireland). We examined changes in adherence in intervention and comparator groups in each setting using segmented linear regression with generalised estimating equations. In Massachusetts, a gradual decrease in adherence to anti-hypertensive medications of -1% per month following the policy occurred. In contrast, the response in Ireland was confined to a -2.9% decrease in adherence immediately following the policy, with no further decrease over the 8 month follow-up. Reductions in adherence to oral diabetes drugs were larger in the U.S. group in comparison to the Irish group. No difference in adherence changes between the two settings for anti-hyperlipidaemic drugs occurred. Evidence on cost-sharing for prescription medicines is not 'one size fits all'. Time since policy implementation and structural differences between health systems may influence the differential impact of copayment policies in international settings. Copyright © 2016. Published by Elsevier Ireland Ltd.

Orally Administered Baker's Yeast β-Glucan Promotes Glucose and Lipid Homeostasis in the Livers of Obesity and Diabetes Model Mice.

PubMed

Cao, Yan; Sun, Ying; Zou, Siwei; Li, Mengxia; Xu, Xiaojuan

2017-11-08

Baker's yeast glucan (BYG) has been reported to be an anti-diabetic agent. In the work described herein, further study on the effect of orally administered BYG on glucose and lipid homeostasis in the livers of ob/ob mice was performed. It was found that BYG decreased the blood glucose and the hepatic glucose and lipid disorders. Western blotting analysis revealed that BYG up-regulated p-AKT and p-AMPK, and down-regulated p-Acc in the liver. Furthermore, RNA-Seq analysis indicated that BYG down-regulated genes responsible for gluconeogenesis (G6pase and Got1), fatty acid biosynthesis (Acly, Acc, Fas, etc.), glycerolipid synthesis (Gpam and Lipin1/2), and cholesterol synthesis (Hmgcr, Fdps, etc.). Additionally, BYG decreased glucose transporters SGLT1 and GLUT2, fat emulsification, and adipogenic genes/proteins in the intestine to decrease glucose and lipid absorption. All these findings demonstrated that BYG is beneficial for regulating glucose and lipid homeostasis in diabetic mice, and thus has potential applications in anti-diabetic foods or drugs.

Improved glycemic control in patients with advanced type 2 diabetes mellitus taking Urtica dioica leaf extract: a randomized double-blind placebo-controlled clinical trial.

PubMed

Kianbakht, Saeed; Khalighi-Sigaroodi, Farahnaz; Dabaghian, Fataneh Hashem

2013-01-01

Advanced type 2 diabetes mellitus (T2DM) needing insulin therapy is common. Most conventional anti-hyperglycemic drugs have limited efficacies and significant side effects, so that better anti-hyperglycemic agents are needed. Urtica dioica L. (nettle) leaves have insulin secretagogue, PPARgamma agonistic, and alpha-glucosidase inhibitory effects. Moreover, nettle leaves are used in traditional medicine as an anti-hyperglycemic agent to treat diabetes mellitus. Thus, efficacy and safety of nettle in the treatment of patients with advanced type 2 diabetes mellitus needing insulin were studied. In this randomized double-blind placebo-controlled clinical trial, we evaluated the effects of taking nettle leaf extract (one 500 mg capsule every 8 hours for 3 months) combined with the conventional oral anti-hyperglycemic drugs on the blood levels of fasting glucose, postprandial glucose, glycosylated hemoglobin (HbA1c), creatinine and liver enzymes SGOT and SGPT, and systolic and diastolic blood pressures in 46 patients and compared with the placebo group (n = 46). At the endpoint, the extract lowered the blood levels of fasting glucose, 2 hours postprandial glucose, and HbA1c significantly (p < 0.001, p = 0.009, and p = 0.006, respectively) without any significant effects on the other parameters (p > 0.05) compared with placebo. Nettle may safely improve glycemic control in type 2 diabetic patients needing insulin therapy.

Glycaemic control and hypoglycaemia with insulin glargine 300 U/mL compared with glargine 100 U/mL in Japanese adults with type 2 diabetes using basal insulin plus oral anti-hyperglycaemic drugs (EDITION JP 2 randomised 12-month trial including 6-month extension).

PubMed

Terauchi, Y; Koyama, M; Cheng, X; Sumi, M; Riddle, M C; Bolli, G B; Hirose, T

2017-10-01

To compare insulin glargine 300 U/mL (Gla-300) with glargine 100 U/mL (Gla-100) in Japanese adults with uncontrolled type 2 diabetes on basal insulin and oral anti-hyperglycaemic drugs over 12 months. EDITION JP 2 was a randomised, open-label, phase 3 study. Following a 6-month treatment period, participants continued receiving previously assigned once daily Gla-300 or Gla-100, plus oral anti-hyperglycaemic drugs, in a 6-month extension period. Glycaemic control, hypoglycaemia and adverse events were assessed. The 12-month completion rate was 88% for Gla-300 and 96% for Gla-100, with comparable reasons for discontinuation. Mean HbA 1c decrease from baseline to month 12 was 0.3% in both groups. Annualised rates of confirmed (≤3.9mmol/L [≤70mg/dL]) or severe hypoglycaemia were lower with Gla-300 than Gla-100 (nocturnal [00:00-05:59h]: rate ratio 0.41; 95% confidence interval: 0.18 to 0.92; anytime [24h]: rate ratio 0.64; 95% confidence interval: 0.44 to 0.94). Cumulative number of hypoglycaemic events was lower with Gla-300 than Gla-100. Adverse event profiles were comparable between treatments. Over 12 months, Gla-300-treated participants achieved sustained glycaemic control and experienced less hypoglycaemia, particularly at night, versus Gla-100, supporting 6-month results. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Repaglinide, but not nateglinide administered supraspinally and spinally exerts an anti-diabetic action in d-glucose fed and streptozotocin-treated mouse models.

PubMed

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi; Suh, Hong-Won

2013-12-01

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 µg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models.

Repaglinide, but Not Nateglinide Administered Supraspinally and Spinally Exerts an Anti-Diabetic Action in D-Glucose Fed and Streptozotocin-Treated Mouse Models

PubMed Central

Sim, Yun-Beom; Park, Soo-Hyun; Kang, Yu-Jung; Kim, Sung-Su; Kim, Chea-Ha; Kim, Su-Jin; Lim, Su-Min; Jung, Jun-Sub; Ryu, Ohk-Hyun; Choi, Moon-Gi

2013-01-01

We have recently demonstrated that some anti-diabetic drugs such as biguanide and thizolidinediones administered centrally modulate the blood glucose level, suggesting that orally administered anti-diabetic drugs may modulate the blood glucose level by acting on central nervous system. The present study was designed to explore the possible action of another class of anti-diabetic drugs, glinidies, administered centrally on the blood glucose level in ICR mice. Mice were administered intracerebroventricularly (i.c.v.) or intrathecally (i.t.) with 5 to 30 µg of repaglinide or nateglinide in D-glucose-fed and streptozotocin (STZ)-treated models. We found that i.c.v. or i.t. injection with repaglinide dose-dependently attenuated the blood glucose level in D-glucose-fed model, whereas i.c.v. or i.t. injection with nateglinide showed no modulatory action on the blood glucose level in D-glucose-fed model. Furthermore, the effect of repaglinide administered i.c.v. or i.t. on the blood glucose level in STZ-treated model was studied. We found that repaglinide administered i.c.v. slightly enhanced the blood glucose level in STZ-treated model. On the other hand, i.t. injection with repaglinide attenuated the blood glucose level in STZ-treated model. The plasma insulin level was enhanced by repaglinide in D-glucose-fed model, but repaglinide did not affect the plasma insulin level in STZ-treated model. In addition, nateglinide did not alter the plasma insulin level in both D-glucose-fed and STZ-treated models. These results suggest that the anti-diabetic action of repaglinide appears to be, at least, mediated via the brain and the spinal cord as revealed in both D-glucose fed and STZ-treated models. PMID:24381497

Metformin - a Future Therapy for Neurodegenerative Diseases : Theme: Drug Discovery, Development and Delivery in Alzheimer's Disease Guest Editor: Davide Brambilla.

PubMed

Markowicz-Piasecka, Magdalena; Sikora, Joanna; Szydłowska, Aleksandra; Skupień, Agata; Mikiciuk-Olasik, Elżbieta; Huttunen, Kristiina M

2017-12-01

Type 2 diabetes mellitus (T2DM) is a complex, chronic and progressive metabolic disease, which is characterized by relative insulin deficiency, insulin resistance, and high glucose levels in blood. Esteemed published articles and epidemiological data exhibit an increased risk of developing Alzheimer's disease (AD) in diabetic pateints. Metformin is the most frequently used oral anti-diabetic drug, which apart from hypoglycaemic activity, improves serum lipid profiles, positively influences the process of haemostasis, and possesses anti-inflammatory properties. Recently, scientists have put their efforts in establishing metformin's role in the treatment of neurodegenerative diseases, such as AD, amnestic mild cognitive impairment and Parkinson's disease. Results of several clinical studies confirm that long term use of metformin in diabetic patients contributes to better cognitive function, compared to participants using other anti-diabetic drugs. The exact mechanism of metformin's advantageous activity in AD is not fully understood, but scientists claim that activation of AMPK-dependent pathways in human neural stem cells might be responsible for the neuroprotective activity of metformin. Metformin was also found to markedly decease Beta-secretase 1 (BACE1) protein expression and activity in cell culture models and in vivo, thereby reducing BACE1 cleavage products and the production of Aβ (β-amyloid). Furthermore, there is also some evidence that metformin decreases the activity of acetylcholinesterase (AChE), which is responsible for the degradation of acetylcholine (Ach), a neurotransmitter involved in the process of learning and memory. In regard to the beneficial effects of metformin, its anti-inflammatory and anti-oxidative properties cannot be omitted. Numerous in vitro and in vivo studies have confirmed that metformin ameliorates oxidative damage.

Zinc complexes developed as metallopharmaceutics for treating diabetes mellitus based on the bio-medicinal inorganic chemistry.

PubMed

Yoshikawa, Yutaka; Yasui, Hiroyuki

2012-01-01

Biological trace metals such as iron, zinc, copper, and manganese are essential to life and health of humans, and the success of platinum drugs in the cancer chemotherapy has rapidly grown interest in developing inorganic pharmaceutical agents in medicinal chemistry, that is, medicinal inorganic chemistry, using essential elements and other biological trace metals. Transition metal complexes with unique chemical structures may be useful alternatives to the drugs available to address some of the incurable diseases. In this review, we emphasize that metal complexes are an expanding of interest in the research field of treatment of diabetes mellitus. Especially, orally active anti-diabetic and anti-metabolic syndrome zinc complexes have been developed and progressed since the discovery in 2001, where several highly potent anti-diabetic zinc complexes with different coordination structures have quite recently been disclosed, using experimental diabetic animals. In all of the complexes discussed, zinc is found to be biologically active and function by interacting with some target proteins related with diabetes mellitus. The design and screening of zinc complexes with higher activity is not efficient without consideration of the translational research. For the development of a clinically useful metallopharmaceutics, the research of zinc complexes on the long-term toxicity including side effects, clear-cut evidence of target molecule for the in vivo pharmacological action, and good pharmacokinetic property are essential in the current and future studies.

Anti-diabetic activity of traditional Indian gold containing preparation: Shadguna Balijarita Makaradhwaja on streptozotocin induced diabetic rats.

PubMed

Khedekar, Sanjay; Rukkudin, Galib; Ravishankar, Basavaiah; Prajapati, Pradeepkumar

2016-01-01

Makaradhwaja a gold containing mercurial preparation used for diabetes mellitus in indigenous system of medicine. It is a popular aphrodisiac and rejuvenator traditional medicine. It is prepared by using processed gold, mercury and sulfur in different ratios by applying intermittent heating pattern in Valuka Yantra. The aim of the study was to evaluate anti-diabetic effect of Shadguna Balijarita Makaradhwaja (SBM) on streptozotocin (STZ) induced diabetic rats. Diabetes was induced to normal rats by injecting STZ in dose 40 mg/kg. Powdered SBM and dried extract of Tinospora cordifolia were mixed with honey and administered orally for 20 days at dose 2.63 mg/kg and 42.34 mg/kg body weight, respectively. The effects of treatment on body weight changes and blood glucose levels were quantified on day 1, 5, 10, 15 and 21 of the experiments. On the 21(st) day, animals were sacrificed and gross histopathological changes in liver, kidney and pancreas were illustrated. Blood sugar level, glyacated hemoglobin, blood urea, serum cholesterol, serum creatinine, serum triglyceride and serum protein were estimated with standard methods. The study was conducted in the year 2011. Test drug observed significant decrease (P < 0.001) in glyacated hemoglobin level compared to diabetic control rats. Blood sugar level of test drug group shown a significant decrease (279.11 ± 57.95) compared with diabetic rats. The present study demonstrates that SBM and dried extract of T. cordifolia with honey significantly reduces the blood glucose level and shows anti-diabetic effect.

Anti-diabetic activity of traditional Indian gold containing preparation: Shadguna Balijarita Makaradhwaja on streptozotocin induced diabetic rats

PubMed Central

Khedekar, Sanjay; Rukkudin, Galib; Ravishankar, Basavaiah; Prajapati, Pradeepkumar

2016-01-01

Background: Makaradhwaja a gold containing mercurial preparation used for diabetes mellitus in indigenous system of medicine. It is a popular aphrodisiac and rejuvenator traditional medicine. It is prepared by using processed gold, mercury and sulfur in different ratios by applying intermittent heating pattern in Valuka Yantra. Objectives: The aim of the study was to evaluate anti-diabetic effect of Shadguna Balijarita Makaradhwaja (SBM) on streptozotocin (STZ) induced diabetic rats. Materials and Methods: Diabetes was induced to normal rats by injecting STZ in dose 40 mg/kg. Powdered SBM and dried extract of Tinospora cordifolia were mixed with honey and administered orally for 20 days at dose 2.63 mg/kg and 42.34 mg/kg body weight, respectively. The effects of treatment on body weight changes and blood glucose levels were quantified on day 1, 5, 10, 15 and 21 of the experiments. On the 21st day, animals were sacrificed and gross histopathological changes in liver, kidney and pancreas were illustrated. Blood sugar level, glyacated hemoglobin, blood urea, serum cholesterol, serum creatinine, serum triglyceride and serum protein were estimated with standard methods. The study was conducted in the year 2011. Results: Test drug observed significant decrease (P < 0.001) in glyacated hemoglobin level compared to diabetic control rats. Blood sugar level of test drug group shown a significant decrease (279.11 ± 57.95) compared with diabetic rats. Conclusion: The present study demonstrates that SBM and dried extract of T. cordifolia with honey significantly reduces the blood glucose level and shows anti-diabetic effect. PMID:27104037

Myopic and Forward Looking Behavior in Branded Oral Anti-Diabetic Medication Consumption: An Example from Medicare Part D.

PubMed

Sacks, Naomi C; Burgess, James F; Cabral, Howard J; Pizer, Steven D

2017-06-01

We evaluate consumption responses to the non-linear Medicare Part D prescription drug benefit. We compare propensity-matched older patients with diabetes and Part D Standard or low-income-subsidy (LIS) coverage. We evaluate monthly adherence to branded oral anti-diabetics, with high end-of-year donut hole prices (>$200) for Standard patients and consistent, low (≤$6) prices for LIS. As an additional control, we examine adherence to generic anti-diabetics, with relatively low, consistent prices for Standard patients. If Standard patients are forward looking, they will reduce branded adherence in January, and LIS-Standard differences will be constant through the year. Contrary to this expectation, branded adherence is lower for Standard patients in January and diverges from LIS as the coverage year progresses. Standard-LIS generic adherence differences are minimal. Our findings suggest that seniors with chronic conditions respond myopically to the nonlinear Part D benefit, reducing consumption in response to high deductible, initial coverage and gap prices. Thus, when the gap is fully phased out in 2020, cost-related nonadherence will likely remain in the face of higher spot prices for more costly branded medications. These results contribute to studies of Part D plan choice and medication adherence that suggest that seniors may not make optimal healthcare decisions. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Navel orange peel hydroethanolic extract, naringin and naringenin have anti-diabetic potentials in type 2 diabetic rats.

PubMed

Ahmed, Osama M; Hassan, Mohamed A; Abdel-Twab, Sanaa M; Abdel Azeem, Manal N

2017-10-01

The therapy of Type 2 Diabetes Mellitus (T2DM) stays a challenging issue. During the last decade, there has been an interest in the expansion of anti-diabetic drugs especially those of natural sources. Thus, the aim of this study was to assess the anti-hyperglycemic and the anti-hyperlipidemic effects as well as the anti-oxidant activities of navel orange hydroethanolic extract and its constituting flavonoids naringin and naringenin on nicotineamide (NA)/streptozotocin (STZ)-induced type 2 diabetic rats. To induce T2DM, 16h-fasted rats were intraperitoneally injected with STZ at dose of 50mg/kg body weight (b. w.), 15min after the intraperitoneal administration of NA (120mg/kg b. w.). The NA/STZ-induced type 2 diabetic rats were orally treated with navel orange peel hydroethanolic extract, naringin and narengenin at dose level of 100mg/kg b. w./day for 4 weeks. The treatments with navel orange peel hydroethanolic extract, naringin and narengenin potentially alleviated the lowered serum insulin and C-peptide levels, the depleted liver glycogen content, the elevated liver glucose-6-phosphatase and glycogen phosphorylase activities, the deteriorated serum lipid profile, and the suppressed liver antioxidant defense system of NA/STZ-induced type 2 diabetic rats. The treatments also enhanced the mRNA expression of insulin receptor β-subunit, GLUT4 and adiponectin in adipose tissue of STZ/NA-induced type 2 diabetic rats. In conclusion, the navel orange peel hydroethanolic extract, naringin and naringenin have potent anti-diabetic effects in NA/STZ-induced type 2 diabetic rats via their insulinotropic effects and insulin improving action which in turn may be mediated through enhancing insulin receptor, GLUT4 and adiponectin expression in adipose tissue. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Pharmacy Use and Costs in Employer-Provided Health Plans. Insights for TRICARE Benefit Design from the Private Sector

DTIC Science & Technology

2005-01-01

non - steroidal anti - inflammatory drugs ( NSAIDs ), oral antihistamines, gastrointestinal agents, and oral...National Defense Authorization Act NSAID non - steroidal anti - inflammatory drug OLS ordinary least squares p-value probability value P&T Pharmacy...antihypertensives, non - steroidal anti - inflammatory drugs ( NSAIDs ), oral antihistamines, gastrointestinal agents, and oral hy-

The efficacy of oral non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy: a systematic review and meta-analysis.

PubMed

Boudreault, Jennifer; Desmeules, François; Roy, Jean-Sébastien; Dionne, Clermont; Frémont, Pierre; Macdermid, Joy C

2014-04-01

To conduct a systematic review and meta-analysis on the efficacy of oral non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy. Systematic review. A literature search was conducted in 4 databases for randomized controlled trials published until 05/2013, comparing the efficacy of oral anti-inflammatory drugs to any other intervention. Studies characteristics were extracted using a standardized form and the methodological quality was evaluated. Results were summarized qualitatively or quantitatively. The mean methodological score of the 12 included studies was 53.6 ± 8.8%. The majority of studies included acute cases and were underpowered to detect differences in adverse events. Compared to a placebo, oral non-steroidal anti-inflammatory drugs were found to provide short-term pain relief (pooled mean difference: -2.69; 95% confidence interval: -1.96 to -3.41) but not function. Oral anti-inflammatory- drugs and corticosteroids injections have similar short-term efficacy in terms of pain reduction as well as in function (pooled standardized mean difference: 0.09; 95% confidence interval: -0.25 to 0.44). Low to moderate grade evidence exists regarding the efficacy of non-steroidal anti-inflammatory drugs for rotator cuff tendinopathy. Oral anti-inflammatory drugs are effective in reducing short-term pain but not function. In terms of pain and function, oral anti-inflammatory drugs in the short term are as effective as corticosteroid injections.

In-silico analysis of gymnemagenin from Gymnema sylvestre (Retz.) R.Br. with targets related to diabetes.

PubMed

Rathore, Poonam K; Arathy, V; Attimarad, Vijaylaxmi S; Kumar, Pramod; Roy, Subarna

2016-02-21

Diabetes is a metabolic disorder characterized by higher than normal glucose in the blood. Most oral hypoglycemic drugs available in market produce adverse side effects which have resulted in continued search for new therapeutic agents with little or no side effects. Herbal drugs are considered relatively safer alternatives and Gymnema sylvestre is one of the most well established natural remedy for diabetes and is traded worldwide under several brands. In the present study an attempt has been made to use in silico techniques to understand and predict the drug likeliness of gymnemagenin, one of the key constituents of G. sylvestre against 15 proteins having key role in carbohydrate metabolism. Gymnemagenin was found to dock well with crystallographic structures of 7 of the 15 selected targets and was found even better than the two known clinically used antidiabetic compounds, repaglinide and sitagliptin taken in the study for comparison. Gymnemagenin therefore can be considered further for development into a potent anti-diabetic drug. Copyright © 2015 Elsevier Ltd. All rights reserved.

Oral anti-diabetics in Ramadan.

PubMed

Islam, Najmul

2015-05-01

A large proportion of Muslim patients with type 2 diabetes fast during the month of Ramadan worldwide. Hypoglycaemia is one of the major complications associated with long periods without food during the fasting hours. There is also a risk of hyperglycaemia due to over indulgence in food during the two main meals of Suhur and Iftar. Healthcare providers need to be cognizant of the risk of fasting and be competent to provide Ramadan adjusted diabetes care particularly adjustment of oral anti diabetics. This review article has taken into consideration observational studies, randomized trial data, pathophysiology and practical experience in recommending adjustment in oral anti-diabetics during fasting in type-2 diabetics. Metformin and Thiazolidinediones (TZD'S) being insulin sensitizers need minimum adjustment with low risk of hypoglycaemia. Older generation Sulphonylureas (SU) pose a high risk of hypoglycaemia but the newer generations of Sulphonylureas have a reasonable safety profile. Alpha- Glucosidase inhibitors are safe during fasting but their use is limited due to the side effects.

Transient B-Cell Depletion with Anti-CD20 in Combination with Proinsulin DNA Vaccine or Oral Insulin: Immunologic Effects and Efficacy in NOD Mice

PubMed Central

Sarikonda, Ghanashyam; Sachithanantham, Sowbarnika; Manenkova, Yulia; Kupfer, Tinalyn; Posgai, Amanda; Wasserfall, Clive; Bernstein, Philip; Straub, Laura; Pagni, Philippe P.; Schneider, Darius; Calvo, Teresa Rodriguez; Coulombe, Marilyne; Herold, Kevan; Gill, Ronald G.; Atkinson, Mark; Nepom, Gerald; Ehlers, Mario; Staeva, Teodora; Garren, Hideki; Steinman, Lawrence; Chan, Andrew C.; von Herrath, Matthias

2013-01-01

A recent type 1 diabetes (T1D) clinical trial of rituximab (a B cell-depleting anti-CD20 antibody) achieved some therapeutic benefit in preserving C-peptide for a period of approximately nine months in patients with recently diagnosed diabetes. Our previous data in the NOD mouse demonstrated that co-administration of antigen (insulin) with anti-CD3 antibody (a T cell-directed immunomodulator) offers better protection than either entity alone, indicating that novel combination therapies that include a T1D-related autoantigen are possible. To accelerate the identification and development of novel combination therapies that can be advanced into the clinic, we have evaluated the combination of a mouse anti-CD20 antibody with either oral insulin or a proinsulin-expressing DNA vaccine. Anti-CD20 alone, given once or on 4 consecutive days, produced transient B cell depletion but did not prevent or reverse T1D in the NOD mouse. Oral insulin alone (twice weekly for 6 weeks) was also ineffective, while proinsulin DNA (weekly for up to 12 weeks) showed a trend toward modest efficacy. Combination of anti-CD20 with oral insulin was ineffective in reversing diabetes in NOD mice whose glycemia was controlled with SC insulin pellets; these experiments were performed in three independent labs. Combination of anti-CD20 with proinsulin DNA was also ineffective in diabetes reversal, but did show modest efficacy in diabetes prevention (p = 0.04). In the prevention studies, anti-CD20 plus proinsulin resulted in modest increases in Tregs in pancreatic lymph nodes and elevated levels of proinsulin-specific CD4+ T-cells that produced IL-4. Thus, combination therapy with anti-CD20 and either oral insulin or proinsulin does not protect hyperglycemic NOD mice, but the combination with proinsulin offers limited efficacy in T1D prevention, potentially by augmentation of proinsulin-specific IL-4 production. PMID:23405091

Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice.

PubMed

Qiu, Guizhen; Tian, Wei; Huan, Mei; Chen, Jinlong; Fu, Haitao

2017-01-01

The aim of this study was to investigate the anti-hyperglycemic activity and mechanism of formononetin in alloxan-induced type 1 diabetic mice by determining its effect on some diabetes-related indices as described below. Body weight, fasting blood glucose, hepatic glycogen, serum insulin, and serum glucagon were determined by electronic scales, glucometer, and ELISA kits. Fas, Caspase-3, pancreatic and duodenal homeobox-1 , insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase and glucose-6-phosphatase mRNA, and proteins levels in liver tissue were detected by fluorogenic quantitative-polymerase chain reaction and Western blot assays. The results indicated that formononetin (5, 10, and 20 mg/kg; oral administration) reversed the alloxan-induced increase of some indices (fasting blood glucose level and Fas and Caspase-3 mRNA and proteins levels in pancreas tissue) and reduction of some indices (body weight gain, oral glucose tolerance, insulin activity, hepatic glycogen level, pancreatic and duodenal homeobox-1, insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase mRNA and protein levels in liver tissue). The glucagon level and glucose-6-phosphatase mRNA and protein levels in liver tissue were not affected by the drugs administration. In conclusion, formononetin exhibited anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice by inhibiting islet B cell apoptosis and promoting islet B cell regeneration, insulin secretion, hepatic glycogen synthesis, and hepatic glycolysis.

Dipeptidyl peptidase-4 inhibitor ameliorates early renal injury through its anti-inflammatory action in a rat model of type 1 diabetes

DOE Office of Scientific and Technical Information (OSTI.GOV)

Kodera, Ryo, E-mail: kodera@cc.okayama-u.ac.jp; Shikata, Kenichi; Department of Medicine and Clinical Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 2-5-1 Shikata-cho, Kita-ku, Okayama 700-8558

Highlights: •DPP-4 inhibitor decreased urinary albumin excretion in a rat of type 1 diabetes. •DPP-4 inhibitor ameliorated histlogical changes of diabetic nephropathy. •DPP-4 inhibitor has reno-protective effects through anti-inflammatory action. •DPP-4 inhibitor is beneficial on diabetic nephropathy besides lowering blood glucose. -- Abstract: Introduction: Dipeptidyl peptidase-4 (DPP-4) inhibitors are incretin-based drugs in patients with type 2 diabetes. In our previous study, we showed that glucagon-like peptide-1 (GLP-1) receptor agonist has reno-protective effects through anti-inflammatory action. The mechanism of action of DPP-4 inhibitor is different from that of GLP-1 receptor agonists. It is not obvious whether DPP-4 inhibitor prevents the exacerbationmore » of diabetic nephropathy through anti-inflammatory effects besides lowering blood glucose or not. The purpose of this study is to clarify the reno-protective effects of DPP-4 inhibitor through anti-inflammatory actions in the early diabetic nephropathy. Materials and methods: Five-week-old male Sprague–Dawley (SD) rats were divided into three groups; non-diabetes, diabetes and diabetes treated with DPP-4 inhibitor (PKF275-055; 3 mg/kg/day). PKF275-055 was administered orally for 8 weeks. Results: PKF275-055 increased the serum active GLP-1 concentration and the production of urinary cyclic AMP. PKF275-055 decreased urinary albumin excretion and ameliorated histological change of diabetic nephropathy. Macrophage infiltration was inhibited, and inflammatory molecules were down-regulated by PKF275-055 in the glomeruli. In addition, nuclear factor-κB (NF-κB) activity was suppressed in the kidney. Conclusions: These results indicate that DPP-4 inhibitor, PKF275-055, have reno-protective effects through anti-inflammatory action in the early stage of diabetic nephropathy. The endogenous biological active GLP-1 might be beneficial on diabetic nephropathy besides lowering blood glucose.« less

Evaluation of Antidiabetic and Antihyperlipidemic Effects of Hydroalcoholic Extract of Leaves of Ocimum tenuiflorum (Lamiaceae) and Prediction of Biological Activity of its Phytoconstituents

PubMed Central

Parasuraman, Subramani; Balamurugan, Subramani; Christapher, Parayil Varghese; Petchi, Rajendran Ramesh; Yeng, Wong Yeng; Sujithra, Jeyabalan; Vijaya, Chockalingam

2015-01-01

Objective: The aim was to evaluate the anti-diabetic and anti-hyperlipidemic effects of hydroalcoholic extract of leaves of Ocimum tenuiflorum (Lamiaceae) and prediction of biological activities of its phytoconstituents using in vivo anti-diabetic model and in silico analysis respectively. Materials and Methods: The leaves of O. tenuiflorum were extracted with 60% ethanol, and the extract was used for further pharmacological screening. The acute toxicity of the extract was evaluated as per the guidelines set by the Organization for Economic Co-operation and Development, revised draft guidelines 423. The oral anti-diabetic activity of the hydroalcoholic extract of O. tenuiflorum (125, 250 and 500 mg/kg) was studied against streptozotocin (STZ) (50 mg/kg; i.p.) + nicotinamide (120 mg/kg; i.p.) induced diabetes mellitus. The animals were treated with the investigational plant extract and standard drug (glibenclamide) for 21 consecutive days and the effect of hydroalcoholic extract of O. tenuiflorum on blood glucose levels was measured at regular intervals. At the end of the study, blood samples were collected from all the animals for biochemical estimation, then the animals were sacrificed and the liver and kidney were collected for organ weight analysis. Prediction for pharmacological and toxicological properties of phytoconstituents of O. tenuiflorum was carried out using online web tools such as online pass prediction and lazar toxicity prediction. Results: The hydroalcoholic extract of O. tenuiflorum showed significant anti-diabetic and anti-hyperlipidemic activity at 250 and 500 mg/kg, and this effect was comparable with that of glibenclamide. Predicted biological activities of phytoconstituents of O. tenuiflorum showed presence of various pharmacological actions, which includes anti-diabetic and anti-hyperlipidemic activities. Prediction of toxicological properties of phytoconstituents of O. tenuiflorum did not show any major toxic effects. Conclusion: The hydroalcoholic extract of O. tenuiflorum showed significant anti-diabetic and anti-hyperlipidemic activity against STZ + nicotinamide induced diabetes mellitus in rats. Further studies are required to confirm the anti-diabetic and anti-hyperlipidemic activities of individual phytoconstituents of O. tenuiflorum. PMID:25829789

Drug development from the bench to the pharmacy: with special reference to dipeptidyl peptidase-4 inhibitor development.

PubMed

Carr, R D

2016-06-01

The dipeptidyl peptidase-4 (DPP-4) inhibitor concept is an example of prospective drug design and development based upon a distinct endocrine hypothesis. The design of enzyme inhibitors is a pragmatic approach to drug design; being compatible with the identification and optimization of small molecules that have properties commensurate with oral administration, as well as acceptable drug metabolism, distribution and elimination characteristics. Glucagon-like peptide 1 (GLP-1), a hormone with a spectrum of favourable metabolic actions, including glucose-dependent stimulation of insulin and inhibition of glucagon secretion, provided the endocrine basis from which the idea of using DPP-4 inhibitors as anti-diabetic agents was developed. The origin of the DPP-4 inhibitor concept was inspired by the angiotensin-converting enzyme inhibitor approach, which succeeded in establishing a class of extensively used therapeutic agents for the treatment of cardiovascular disorders. © 2016 Diabetes UK.

Indexing Natural Products for Their Potential Anti-Diabetic Activity: Filtering and Mapping Discriminative Physicochemical Properties.

PubMed

Zeidan, Mouhammad; Rayan, Mahmoud; Zeidan, Nuha; Falah, Mizied; Rayan, Anwar

2017-09-17

Diabetes mellitus (DM) poses a major health problem, for which there is an unmet need to develop novel drugs. The application of in silico techniques and optimization algorithms is instrumental to achieving this goal. A set of 97 approved anti-diabetic drugs, representing the active domain, and a set of 2892 natural products, representing the inactive domain, were used to construct predictive models and to index anti-diabetic bioactivity. Our recently-developed approach of 'iterative stochastic elimination' was utilized. This article describes a highly discriminative and robust model, with an area under the curve above 0.96. Using the indexing model and a mix ratio of 1:1000 (active/inactive), 65% of the anti-diabetic drugs in the sample were captured in the top 1% of the screened compounds, compared to 1% in the random model. Some of the natural products that scored highly as potential anti-diabetic drug candidates are disclosed. One of those natural products is caffeine, which is noted in the scientific literature as having the capability to decrease blood glucose levels. The other nine phytochemicals await evaluation in a wet lab for their anti-diabetic activity. The indexing model proposed herein is useful for the virtual screening of large chemical databases and for the construction of anti-diabetes focused libraries.

[EFFICACY OF CYTOFLAVIN IN COMPLEX TREATMENT OF DIABETIC FOOT SYNDROME].

PubMed

Skrypko, V; Kovalenko, A; Zaplutanov, V; Kharitonova, T; Myhaloyko, I

2017-04-01

The study involved 97 patients with severe diabetic foot syndrome (DFS) subcompensated type 2 diabetes. All patients were available mediacalcification foot and lower leg arteries of different severity. Depending on the treatment, all patients were divided into 2 groups by stratified randomization. The І group received standard therapy, which is indicated for the DFS. A ІІ group of patients additionally received basic therapy drug Cytoflavin 10 ml 0,9% NaCl 200 ml for 10 days, followed by transfer to tablet form Cytoflavin 2 tablets 2 times per day orally for one month. We noted a positive trend of treatment of patients who, in addition to standard therapy received the drug Cytoflavin. Thus, the use of complex surgical treatment of patients with mixed form of DFS Cytoflavin reduces the severity of distal polyneuropathy, improves oxygenation of tissues and restores the enzyme activity of antioxidant system, that manifested neuroprotective, antioxidant and anti-hypoxic effects of drugs, which substantiates the indications for its use in the this pathology.

In-vivo study for anti-hyperglycemic potential of aqueous extract of Basil seeds (Ocimum basilicum Linn) and its influence on biochemical parameters, serum electrolytes and haematological indices.

PubMed

Chaudhary, Sachin; Semwal, Amit; Kumar, Hitesh; Verma, Harish Chandra; Kumar, Amit

2016-12-01

The study introduced anti-hyperglycemic influence of aqueous extract of Ocimum basilicum seeds (AEOBS) in Streptozotocin (STZ) induced diabetic rats and estimating its potential to ameliorate altered level of biochemical parameters, serum electrolytes level and haematological indices along with its effect on body weight of treated rats. The albino rats were selected to observe oral glucose tolerance test by oral intake of aq. glucose solution (4g/kg, body weight) in normal rats and estimation of blood glucose level after administration of AEOBS at 250mg/kg, 500mg/kg and standard drug glibenclamide at 0.6mg/kg, body weight. Antidiabetic activity was evaluated in chronic study models by STZ induced diabetes in rats followed by blood glucose estimation. Chronic study model was selected to carry out further studies to evaluate the effect of AEOBS at 250mg/kg, 500mg/kg and standard drug on body weight, alterations in biochemical parameters including AST, ALT, ALP, total bilirubin and total protein, alterations in serum electrolytes like Na + , K + , Cl - , HCO 3 - along with estimation of haematological indices like red blood cells (RBC), white blood cells (WBC), hemoglobin (Hb), lymphocytes, neutrophils, eosinophils, monocytes and basophils. AEOBS significantly reduced the blood glucose level of diabetic rats at both doses. Body weight was also improved significantly. Similarly, the levels of biochemical parameters, serum electrolytes, and haematological indices were significantly ameliorated at both doses of AEOBS. The histopathological results revealed reconstitution of pancreatic islets towards normal cellular architecture in rats treated with AEOBS. The results illustrated that AEOBS have eminent antidiabetic potential in STZ effectuated diabetes in rats and can be extensively used for the treatment of diabetes mellitus-II and its associated complications including anaemia, diabetic nephropathy, liver dysfunction, and immunosuppression. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Formononetin exhibits anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice

PubMed Central

Qiu, Guizhen; Tian, Wei; Huan, Mei; Chen, Jinlong

2016-01-01

The aim of this study was to investigate the anti-hyperglycemic activity and mechanism of formononetin in alloxan-induced type 1 diabetic mice by determining its effect on some diabetes-related indices as described below. Body weight, fasting blood glucose, hepatic glycogen, serum insulin, and serum glucagon were determined by electronic scales, glucometer, and ELISA kits. Fas, Caspase-3, pancreatic and duodenal homeobox-1 , insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase and glucose-6-phosphatase mRNA, and proteins levels in liver tissue were detected by fluorogenic quantitative-polymerase chain reaction and Western blot assays. The results indicated that formononetin (5, 10, and 20 mg/kg; oral administration) reversed the alloxan-induced increase of some indices (fasting blood glucose level and Fas and Caspase-3 mRNA and proteins levels in pancreas tissue) and reduction of some indices (body weight gain, oral glucose tolerance, insulin activity, hepatic glycogen level, pancreatic and duodenal homeobox-1, insulin receptor substrate 2, glucokinase and glucose transporter 2, mRNA and proteins levels in pancreas tissue, and glucokinase mRNA and protein levels in liver tissue). The glucagon level and glucose-6-phosphatase mRNA and protein levels in liver tissue were not affected by the drugs administration. In conclusion, formononetin exhibited anti-hyperglycemic activity in alloxan-induced type 1 diabetic mice by inhibiting islet B cell apoptosis and promoting islet B cell regeneration, insulin secretion, hepatic glycogen synthesis, and hepatic glycolysis. PMID:27412955

Evaluation of anti-diabetic and anti-tumoral activities of bioactive compounds from Phoenix dactylifera L's leaf: In vitro and in vivo approach.

PubMed

Chakroun, Mouna; Khemakhem, Bassem; Mabrouk, Hazem Ben; El Abed, Hanen; Makni, Mohamed; Bouaziz, Mohamed; Drira, Noureddine; Marrakchi, Naziha; Mejdoub, Hafedh

2016-12-01

Among various chronic disorders, cancer and diabetes mellitus are the most common disorders. This study was designed to evaluate the effectiveness of hydroalcoholic extract of Phoenix dactylifera L. leaves (HEPdL) in animal models of type II diabetes in vitro/in vivo and in a human melanoma-derived cell line (IGR-39). A liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis was also performed to determine the amount of phenolic and flavonoid compounds in this plant. The physicochemical results by LC-MS/MS analysis of HEPdL showed the presence of 10 phenolic compounds. The in vitro study showed that the extract exhibited a more specific and potent inhibitor of α-glucosidase than α-amylase with an IC 50 value of 20±1μg/mL and 30±0.8μg/mL, respectively. More importantly, the in vivo study of the postprandial hyperglycemia activity with (20mg/kg) of HEPdL showed a decrease in plasma glucose levels after 60min in resemblance to the glucor (acarbose) (50mg/kg) effect. The oral administration of HEPdL (20mg/kg) in alloxan-induced diabetic mices for 28days showed a more significant anti-diabetic activity than that of the drug (50mg/kg). Moreover, cytotoxicity effects of HEPdL in IGR-39 cancer cell lines were tested by MTT assay. This extract was effective in inhibiting cancer cells growth (IGR-39) at dose 35 and 75μg/mL. These results confirm ethnopharmacological significance of the plant and could be taken further for the development of an effective pharmaceutical drug against diabetes and cancer. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Glycaemic control and antidiabetic therapy in patients with diabetes mellitus and chronic kidney disease - cross-sectional data from the German Chronic Kidney Disease (GCKD) cohort.

PubMed

Busch, Martin; Nadal, Jennifer; Schmid, Matthias; Paul, Katharina; Titze, Stephanie; Hübner, Silvia; Köttgen, Anna; Schultheiss, Ulla T; Baid-Agrawal, Seema; Lorenzen, Johan; Schlieper, Georg; Sommerer, Claudia; Krane, Vera; Hilge, Robert; Kielstein, Jan T; Kronenberg, Florian; Wanner, Christoph; Eckardt, Kai-Uwe; Wolf, Gunter

2016-06-11

Diabetes mellitus (DM) is the leading cause of end-stage renal disease. Little is known about practice patterns of anti-diabetic therapy in the presence of chronic kidney disease (CKD) and correlates with glycaemic control. We therefore aimed to analyze current antidiabetic treatment and correlates of metabolic control in a large contemporary prospective cohort of patients with diabetes and CKD. The German Chronic Kidney Disease (GCKD) study enrolled 5217 patients aged 18-74 years with an estimated glomerular filtration rate (eGFR) between 30-60 mL/min/1.73 m(2) or proteinuria >0.5 g/d. The use of diet prescription, oral anti-diabetic medication, and insulin was assessed at baseline. HbA1c, measured centrally, was the main outcome measure. At baseline, DM was present in 1842 patients (35 %) and the median HbA1C was 7.0 % (25(th)-75(th) percentile: 6.8-7.9 %), equalling 53 mmol/mol (51, 63); 24.2 % of patients received dietary treatment only, 25.5 % oral antidiabetic drugs but not insulin, 8.4 % oral antidiabetic drugs with insulin, and 41.8 % insulin alone. Metformin was used by 18.8 %. Factors associated with an HbA1C level >7.0 % (53 mmol/mol) were higher BMI (OR = 1.04 per increase of 1 kg/m(2), 95 % CI 1.02-1.06), hemoglobin (OR = 1.11 per increase of 1 g/dL, 95 % CI 1.04-1.18), treatment with insulin alone (OR = 5.63, 95 % CI 4.26-7.45) or in combination with oral antidiabetic agents (OR = 4.23, 95 % CI 2.77-6.46) but not monotherapy with metformin, DPP-4 inhibitors, or glinides. Within the GCKD cohort of patients with CKD stage 3 or overt proteinuria, antidiabetic treatment patterns were highly variable with a remarkably high proportion of more than 50 % receiving insulin-based therapies. Metabolic control was overall satisfactory, but insulin use was associated with higher HbA1C levels.

Open randomised prospective comparative multi-centre intervention study of patients with cystic fibrosis and early diagnosed diabetes mellitus

PubMed Central

2014-01-01

Background Diabetes mellitus may be present in patients with cystic fibrosis starting in the second decade of life. The prevalence increases rapidly with increasing age. As life-expectancy increases in cystic fibrosis, cystic fibrosis related diabetes will be diagnosed more frequently in the future. Up to date, no data are available to answer the question if cystic fibrosis related diabetes should always initially be treated by insulin therapy. Missing data regarding oral antidiabetic treatment of newly diagnosed cystic fibrosis related diabetes are an important reason to recommend insulin treatment. Several centres report the successful management of cystic fibrosis related diabetes using oral anti-diabetic drugs at least for some years. Oral therapies would be less invasive for a patient group which is highly traumatized by a very demanding therapy. Based on an initiative of the German Mukoviszidosis-Foundation, the present study tries to answer the question, whether oral therapy with repaglinide is as effective as insulin therapy in cystic fibrosis patients with early diagnosed diabetes mellitus. Methods/Design In all cystic fibrosis patients with an age of 10 years or older, an oral glucose tolerance test is recommended. The result of this test is classified according to the WHO cut off values. It is required to have two diabetes positive oral glucose tolerance tests for the diagnosis of diabetes mellitus. This study is a multi-national, multicentre, open labelled, randomized and prospective controlled parallel group’s trial, with 24 months treatment. The primary objective of this trial is to compare the glycaemic control of oral therapy with Repaglinide with insulin injections in patients with cystic fibrosis related diabetes after 2 years of treatment. The trial should include 74 subjects showing cystic fibrosis related diabetes newly diagnosed by oral glucose tolerance test during annual screening for cystic fibrosis related diabetes. Patients are randomised by central fax randomisation. Primary endpoint is mean HbA1c after 24 months of treatment. Secondary endpoints are change in FEV1% predicted and change in BMI-Z-score. Discussion There is only one prospective study comparing oral antidiabetic drugs to insulin in the treatment of CFRD without fasting hyperglycaemia. The results regarding BMI after 6 months and 12 months showed an improvement for the insulin treated patients and were inconsistent for those treated with repaglinide. HbA1c and lung function (FEV1%pred) were unchanged for either group. The authors compared the changes -12 months to baseline and baseline to +12 months separately for each group. Therefore a direct comparison of the effect of repaglinide versus insulin on BMI, HbA1c and FEV1%pred was not presented. According to our protocol, we will directly compare treatment effects (HbA1c, BMI, FEV1%pred) in between both groups. The actual Cochrane report regarding “Insulin and oral agents for managing CFRD” stated that further studies are needed to establish whether there is clear benefit for hypoglycemic agents. We expect that the results of our study will help to address this clinical need. Trial registration ClinicalTrials.gov Identifier: NCT00662714 PMID:24620855

A Mechanistic Review on Medicinal Plants Used for Diabetes Mellitus in Traditional Persian Medicine

PubMed Central

Farzaei, Fatemeh; Morovati, Mohammad Reza; Farjadmand, Fatemeh; Farzaei, Mohammad Hosein

2017-01-01

Diabetes mellitus is the most common endocrine disorder and a major cause of morbidity and mortality. Traditional medicines worldwide suggest a wide range of natural remedies for the prevention and treatment of chronic disorders, including diabetes mellitus. This mechanistic review aims to highlight the significance of medicinal plants traditionally used as dietary supplements in Persian medicine in adjunct with restricted conventional drugs for the prevention and treatment of diabetes mellitus. Mounting evidence suggests that these natural agents perform their protective and therapeutic effect on diabetes mellitus via several cellular mechanisms, including regeneration of pancreatic β cell, limitation of glycogen degradation and gluconeogenesis, anti-inflammatory, immunoregulatory, antiapoptosis, antioxidative stress, as well as modulation of intracellular signaling transduction pathways. In conclusion, traditional medicinal plants used in Persian medicine can be considered as dietary supplements with therapeutic potential for diabetes mellitus and maybe potential sources of new orally active agent(s). PMID:29228789

Nanotechnology based approaches for anti-diabetic drugs delivery.

PubMed

Kesharwani, Prashant; Gorain, Bapi; Low, Siew Yeng; Tan, Siew Ann; Ling, Emily Chai Siaw; Lim, Yin Khai; Chin, Chuan Ming; Lee, Pei Yee; Lee, Chun Mey; Ooi, Chun Haw; Choudhury, Hira; Pandey, Manisha

2018-02-01

Nanotechnology science has been diverged its application in several fields with the advantages to operate with nanometric range of objects. Emerging field of nanotechnology has been also being approached and applied in medical biology for improved efficacy and safety. Increased success in therapeutic field has focused several approaches in the treatment of the common metabolic disorder, diabetes. The development of nanocarriers for improved delivery of different oral hypoglycemic agents compared to conventional therapies includes nanoparticles (NPs), liposomes, dendrimer, niosomes and micelles, which produces great control over the increased blood glucose level and thus becoming an eye catching and most promising technology now-a-days. Besides, embellishment of nanocarriers with several ligands makes it more targeted delivery with the protection of entrapped hypoglycaemic agents against degradation, thereby optimizing prolonged blood glucose lowering effect. Thus, nanocarriers of hypoglycemic agents provide the aim towards improved diabetes management with minimized risk of acute and chronic complications. In this review, we provide an overview on distinctive features of each nano-based drug delivery system for diabetic treatment and current NPs applications in diabetes management. Copyright © 2017 Elsevier B.V. All rights reserved.

Drug usage patterns and treatment costs in newly-diagnosed type 2 diabetes mellitus cases, 2007 vs 2012: findings from a large US healthcare claims database analysis.

PubMed

Weng, W; Liang, Y; Kimball, E S; Hobbs, T; Kong, S; Sakurada, B; Bouchard, J

2016-07-01

Objective To explore trends in demographics, comorbidities, anti-diabetic drug usage, and healthcare utilization costs in patients with newly-diagnosed type 2 diabetes mellitus (T2DM) using a large US claims database. Methods For the years 2007 and 2012, Truven Health Marketscan Research Databases were used to identify adults with newly-diagnosed T2DM and continuous 12-month enrollment with prescription benefits. Variables examined included patient demographics, comorbidities, inpatient utilization patterns, healthcare costs (inpatient and outpatient), drug costs, and diabetes drug claim patterns. Results Despite an increase in the overall database population between 2007-2012, the incidence of newly-diagnosed T2DM decreased from 1.1% (2007) to 0.65% (2012). Hyperlipidemia and hypertension were the most common comorbidities and increased in prevalence from 2007 to 2012. In 2007, 48.3% of newly-diagnosed T2DM patients had no claims for diabetes medications, compared with 36.2% of patients in 2012. The use of a single oral anti-diabetic drug (OAD) was the most common diabetes medication-related claim (46.2% of patients in 2007; 56.7% of patients in 2012). Among OAD monotherapy users, metformin was the most commonly used and increased from 2007 (74.7% of OAD monotherapy users) to 2012 (90.8%). Decreases were observed for sulfonylureas (14.1% to 6.2%) and thiazolidinediones (7.3% to 0.6%). Insulin, predominantly basal insulin, was used by 3.9% of patients in 2007 and 5.3% of patients in 2012. Mean total annual healthcare costs increased from $13,744 in 2007 to $15,175 in 2012, driven largely by outpatient services, although costs in all individual categories of healthcare services (inpatient and outpatient) increased. Conversely, total drug costs per patient were lower in 2012 compared with 2007. Conclusions Despite a drop in the rate of newly-diagnosed T2DM from 2007 to 2012 in the US, increased total medical costs and comorbidities per individual patient suggest that the clinical and economic trends for T2DM are not declining.

Antioxidant activity of Albizzia lebbeck (Linn.) Benth. in alloxan diabetic rats.

PubMed

Resmi, C R; Venukumar, M R; Latha, M S

2006-01-01

There is an increasing demand for natural anti-diabetic drugs, as continuous oral administration of insulin can culminate in many side effects and toxicity. In our endeavour to formulate some cost-effective herbal medicines for diabetes, we undertook this study to evaluate the antioxidant potential of aqueous extract of Albizzia lebbeck (ALL) in diabetic rats. The oxidative stress in alloxan-induced diabetic rats was determined by estimating the levels of thiobarbituric acid reactive substances (TBARS), conjugated dienes (CD) and reduced glutathione (GSH) in liver and kidneys. Activities of antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPX) and glutathione S transferase (GST) were assessed in diabetic as well as rats co-administered with ALL. Oxidative damage in the liver and kidneys of diabetic rats as evidenced by a marked increment in the levels of TBARS and CD, and also a distinct diminution in GSH content was nullified by ALL, as these parameters showed a tendency to retrieve towards normalcy on co-administration of the herbal drug. The antioxidant enzymes registered a decline in activity in diabetic rats thus revealing the damaging effects of free radicals generated due to alloxan exposure. The activities of these enzymes returned to normalcy in ALL-administered rats indicating the antioxidant efficacy of the drug in resisting oxidative insult. The findings provide a rationale for further studies on isolation of active principles and pharmacological evaluation.

Comparative effectiveness of vildagliptin in combination with other oral anti-diabetes agents in usual-care conditions: the EDGE-Latin America study.

PubMed

Mendivil, Carlos O; Márquez-Rodríguez, Eduardo; Angel, Iván D; Paz, Gustavo; Rodríguez, Cruz; Almada, Jorge; Szyskowsky, Ofelia

2014-09-01

To assess the proportion of patients on vildagliptin add-on dual therapy who respond to treatment over a 12 month follow-up, relative to comparator oral anti-diabetes dual therapy, in a usual care setting. Participants were patients with type 2 diabetes (T2DM) aged 18 years and older from 311 centers in Argentina, Colombia, Ecuador, Mexico and Venezuela. Patients were taking monotherapy with an oral anti-diabetes drug (OAD), and were prescribed a new add-on OAD based on the judgment of their personal physician. According to this choice, patients were assigned to one of the two cohorts: vildagliptin or comparator OADs. The primary endpoint was the proportion of patients achieving an A1c drop >0.3% without edema, hypoglycemia, weight gain or discontinuation due to gastrointestinal (GI) events. The secondary endpoint was the proportion of patients with baseline A1c ≥7% who reached the goal of an A1c <7% without hypoglycemia or weight gain. The per-protocol population (a subset of the intention-to-treat population that excluded patients with pre-specified protocol deviations) comprised 3773 patients, 3002 in the vildagliptin cohort and 771 in the comparator cohort. The proportion of patients reaching the primary endpoint was higher in the vildagliptin cohort (60.3%) than the comparator cohort (50.7%), OR 1.48 (95% CI: 1.25-1.73). The same was observed for the secondary endpoint (44.8 versus 33.1%) OR 1.64 (95% CI: 1.37-1.98). The incidence of adverse events was low and similar between treatment cohorts. In a usual care setting, patients treated with a vildagliptin combination succeeded in lowering A1c to <7%, without weight gain, hypoglycemia or peripheral edema more often than patients treated with comparator combinations, without increased risk of adverse events. Key limitations are the observational nature of the study and its relatively limited 12 month timeframe.

Management of diabetic complications through fruit flavonoids as a natural remedy.

PubMed

Tanveer, Amna; Akram, Kashif; Farooq, Umar; Hayat, Zafar; Shafi, Afshan

2017-05-03

Diabetes mellitus is a global disorder, and a major issue for health care systems. The current review outlooks the use of fruit flavonoids as natural remedy in the prevention of diabetes mellitus. The onset of diabetes mainly depends upon genetics and lifestyle issues. Currently used therapeutic options for the control of diabetes, like dietary amendments, oral hypoglycemic drugs, and insulin, have their own limitations. Fruit flavonoids possess various antidiabetic, anti-inflammatory, and antioxidant potentials and act on various cellular signaling pathways in pancreas, white adipose tissue, skeletal muscle, and liver function, which in result induces antidiabetic effects. Recently, antidiabetic effect of fruit flavonoids has been studied using various animal models and clinical trials. Research studies revealed a statistically significant potential of fruit flavonoids in managing the altered glucose and oxidative metabolisms in diabetes. Unlike synthetic antidiabetic agents, fruit flavonoids manage diabetes without compromising cellular homeostasis thereby posing no side effects. Further studies are required in purification and characterization of different fruit flavonoids with respect to their beneficial effect for diabetic patients.

Primary care physicians' practice regarding diabetes mellitus diagnosis, evaluation and management in the West region of Cameroon.

PubMed

Jingi, Ahmadou M; Nansseu, Jobert Richie N; Noubiap, Jean Jacques N

2015-04-04

Primary care physicians (PCPs) are the main providers of diabetes care especially in resource-limited countries which experience extreme shortage of specialists. The present study aimed to evaluate PCPs' approach towards diabetes mellitus (DM) diagnosis, evaluation and management in Cameroon. We carried-out a cross-sectional survey in February 2012 in the West Region of Cameroon. Using a structured pretested questionnaire, we interviewed all PCPs working in the region who were present at their working place when the investigators visited, and volunteered to be enrolled in the study. Sixty-six PCPs were interviewed. Their ages ranged from 24 to 56 years (mean 38.3, standard deviation 9.2 years). The levels of knowledge of PCPs regarding DM diagnosis were: 72.7%, 37.9%, 19.7% and 32.8% respectively obtained when using fasting plasma glucose, post-prandial glycemia, random glycemia and glycated hemoglobin as diagnostic tools. Only 6 PCPs (9.9%) prescribed the correct minimal work-up to evaluate diabetes patients at diagnosis. PCPs advised lifestyle modifications in 92.4% of cases, and thirty nine (53.1%) PCP's used to prescribe both generic and specialty oral anti-diabetic drugs in case of uncomplicated type 2 DM management. The two main classes of anti-diabetic drugs prescribed were biguanides (77.3%) and sulfonamides (60.6%). Nearly all PCPs (97%) used to give frequent follow-up appointments to their patients. Ninety eight point five percent of participants were willing to receive any further continuous training on DM management. PCPs knowledge and practices towards diabetes mellitus diagnosis, evaluation and management were not optimal, stressing the need to improve their capacities regarding diabetes care. As such, more educational initiatives should be taken on, alongside regular upgrade and dissemination of clinical guidelines.

Association between payments from manufacturers of pharmaceuticals to physicians and regional prescribing: cross sectional ecological study.

PubMed

Fleischman, William; Agrawal, Shantanu; King, Marissa; Venkatesh, Arjun K; Krumholz, Harlan M; McKee, Douglas; Brown, Douglas; Ross, Joseph S

2016-08-18

 To examine the association between payments made by the manufacturers of pharmaceuticals to physicians and prescribing by physicians within hospital referral regions.  Cross sectional analysis of 2013 and 2014 Open Payments and Medicare Part D prescribing data for two classes of commonly prescribed, commonly marketed drugs: oral anticoagulants and non-insulin diabetes drugs, overall and stratified by physician and payment type.  306 hospital referral regions, United States.  45 949 454 Medicare Part D prescriptions written by 623 886 physicians to 10 513 173 patients for two drug classes: oral anticoagulants and non-insulin diabetes drugs.  Proportion, or market share, of marketed oral anticoagulants and non-insulin diabetes drugs prescribed by physicians among all drugs in each class and within hospital referral regions.  Among 306 hospital referral regions, there were 977 407 payments to physicians totaling $61 026 140 (£46 174 600; €54 632 500) related to oral anticoagulants, and 1 787 884 payments totaling $108 417 616 related to non-insulin diabetes drugs. The median market share of the hospital referral regions was 21.6% for marketed oral anticoagulants and 12.6% for marketed non-insulin diabetes drugs. Among hospital referral regions, one additional payment (median value $13, interquartile range, $10-$18) was associated with 94 (95% confidence interval 76 to 112) additional days filled of marketed oral anticoagulants and 107 (89 to 125) additional days filled of marketed non-insulin diabetes drugs (P<0.001). Payments to specialists were associated with greater prescribing of marketed drugs than payments to non-specialists (212 v 100 additional days filled per payment of marketed oral anticoagulants, 331 v 114 for marketed non-insulin diabetes drugs, P<0.001). Payments for speaker and consulting fees for non-insulin diabetes drugs were associated with greater prescribing of marketed drugs than payments for food and beverages or educational materials (484 v 110, P<0.001).  Payments by the manufacturers of pharmaceuticals to physicians were associated with greater regional prescribing of marketed drugs among Medicare Part D beneficiaries. Payments to specialists and payments for speaker and consulting fees were predominantly associated with greater regional prescribing of marketed drugs than payments to non-specialists or payments for food and beverages, gifts, or educational materials. As a cross sectional, ecological study, we cannot prove causation between payments to physicians and increased prescribing. Furthermore, our findings should be interpreted only at the regional level. Our study is limited to prescribing by physicians and the two drug classes studied. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

Association Of Serum Total Bilirubin Level With Diabetic Retinopathy In Type 2 Diabetes Mellitus.

PubMed

Ghaffar, Tahir; Marwat, Zahid Irfan; Ullah, Fahim; Khan, Salman; Hassan Aamir, Aziz Ul

2016-01-01

Serum bilirubin has anti-inflammatory, antioxidant and immunological properties. It is considered a protective substance against atherosclerotic and microvascular complications of diabetes mellitus (DM). This study was designed to find the association between total serum bilirubin concentration and diabetic retinopathy (DR). This case control study was conducted in the Department of Endocrinology, Diabetes and Metabolic Diseases, Hayatabad Medical Complex, Peshawar. Type-2 DM patients more than 18 years of age of either gender with duration of T2DM more than 6 months were included and sub categorized in two groups. Cases (DM with DR) and Controls (DM without DR) while patients with acute and chronic liver diseases, haemolytic anaemia, history of chronic alcohol consumption, use of hepatotoxic drugs (anti-tuberculous, anti-epileptic), women on oral contraceptive pills were excluded. All participants underwent ophthalmic examination at diabetic retinopathy screening clinic followed by pre designed set of investigations. A total of 152 patients, 76 cases and 76 controls were included. Serum bilirubin concentration was found inversely and independently (p 0.000) associated and inversely co related (r -0.345and p 0.000) with prevalence of DR. Cases were concentrated in the lower quartiles of serum bilirubin concentration and vice versa. Low haemoglobin (p 0.00) and longer duration of DM (0.003) were independently and directly associated with prevalence of DR. Serum bilirubin concentration is inversely and independently associated and inversely correlated with the prevalence of DR and may predict progression of DR over time.

In vitro and in vivo α-amylase and α-glucosidase inhibiting activities of the protein extracts from two varieties of bitter gourd (Momordica charantia L.).

PubMed

Poovitha, Sundar; Parani, Madasamy

2016-07-18

α-amylase and α-glucosidase digest the carbohydrates and increase the postprandial glucose level in diabetic patients. Inhibiting the activity of these two enzymes can control postprandial hyperglycemia, and reduce the risk of developing diabetes. Bitter gourd or balsam pear is one of the important medicinal plants used for controlling postprandial hyperglycemia in diabetes patients. However, there is limited information available on the presence of α-amylase and α-glucosidase inhibiting compounds. In the current study, the protein extracts from the fruits of M. charantia var. charantia (MCC) and M. charantia var. muricata (MCM) were tested for α-amylase and α-glucosidase inhibiting activities in vitro, and glucose lowering activity after oral administration in vivo. The protein extract from both MCC and MCM inhibited the activity of α-amylase and α-glucosidase through competitive inhibition, which was on par with Acarbose as indicated by in vitro percentage of inhibition (66 to 69 %) and IC50 (0.26 to 0.29 mg/ml). Both the protein extracts significantly reduced peak blood glucose and area under the curve in Streptozotocin-induced diabetic rats, which were orally challenged with starch and sucrose. Protein extracts from the fruits of the two varieties of bitter gourd inhibited α-amylase and α-glucosidase in vitro and lowered the blood glucose level in vivo on par with Acarbose when orally administrated to Streptozotocin-induced diabetic rats. Further studies on mechanism of action and methods of safe and biologically active delivery will help to develop an anti-diabetic oral protein drug from these plants.

Multi-country retrospective observational study of the management and outcomes of patients with Type 2 diabetes during Ramadan in 2010 (CREED).

PubMed

Babineaux, S M; Toaima, D; Boye, K S; Zagar, A; Tahbaz, A; Jabbar, A; Hassanein, M

2015-06-01

To describe the characteristics and management of patients with diabetes who chose to fast during Ramadan in 2010. This was a multi-country, retrospective, observational study, supplemented with physician and patient questionnaires, with data captured before, during and after Ramadan. A total of 508 physicians in 13 countries enrolled 3777 patients and a total of 3394 evaluable cases were analysed. We report on the subset of patients with Type 2 diabetes, which included 3250 patients (95.8%). Oral anti-hyperglycaemic therapy was the predominant pre-Ramadan therapy for most patients (76.6%). The treatment regimen was modified before Ramadan for 39.3% of all patients (34.9% for patients on oral drugs alone, 47.1% for patients on injectable drugs alone). Almost all physicians (96.2%) reported providing fasting-specific advice to patients and 62.6% report using guidelines or recommendations for the management of diabetes during Ramadan. In all, 64% of patients reported fasting everyday of Ramadan and 94.2% fasted for at least 15 days. Physicians have increasingly adopted multiple approaches to the management of fasting during Ramadan, including the adoption of international and/or national guidelines, providing fasting-specific advice and adjusting treatment regimens, such that patients are able to fast for a greater number of days without acute complications. Additional research is needed to explore physician and patient beliefs and practices to inform the evidence-based management of diabetes while fasting, both during and outside of Ramadan, and to identify and address barriers to the universal uptake of techniques to facilitate that management. © 2015 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.

Evaluation of the influence of blood glucose level on oral candidal colonization in complete denture wearers with Type-II Diabetes Mellitus: An in vivo Study.

PubMed

Ganapathy, Dhanraj Muthuveera; Joseph, Sajeesh; Ariga, Padma; Selvaraj, Anand

2013-01-01

Candidal colonization in complete denture wearers is a commonly encountered condition that worsens in the presence of untreated Diabetes Mellitus. The aim of this study was to evaluate the correlation between oral candidiasis in denture-bearing mucosa and elevated blood glucose levels in complete denture wearers and to evaluate the effect of oral hypoglycemic drug therapy in controlling oral candidal colonization in denture-bearing mucosa of complete denture wearers with Type II Diabetes Mellitus. This prospective observational study involved the participation of 15 complete denture wearers with Type II Diabetes Mellitus. The sample collection was made prior and after oral hypoglycaemic drug intervention, by swabbing the rugal surfaces of palatal mucosa, cultured and the density of the candidal colony formed was analyzed and interpreted as colony forming units (CFU) per mL. The candidal samples CFU and corresponding pre- and post-prandial blood glucose levels were estimated, analyzed and compared using Karl Pearson correlation analysis and paired t-test (α = 0.05). The Karl Pearson correlation analysis showed that there was a positive correlation between the blood glucose levels (PPS and FBS) and the candidal colonization (CFU) (P < 0.05). The mean values of all the variables were analyzed using the paired t-test. There was significant reduction in the mean values of blood glucose levels (P < 0.001) and the mean values of the CFU (P < 0.001) following oral hypoglycemic drug therapy. Positive correlation was observed between oral candidiasis in complete denture-bearing mucosa and elevated blood glucose levels and oral hypoglycemic drug therapy has a positive effect in controlling oral candidal colonization in complete denture wearers with Type II Diabetes Mellitus.

Nutritional status, glycemic control and its associated risk factors among a sample of type 2 diabetic individuals, a pilot study.

PubMed

Firouzi, Somayyeh; Barakatun-Nisak, Mohd Yusof; Azmi, Kamaruddin Nor

2015-01-01

The prevalence of type 2 diabetes is increasing in Malaysia, with most patients poorly controlled. Hence, this study aimed to determine nutritional and metabolic status as well as blood pressure of Malaysian patients with type 2 diabetes mellitus and identify associated risk factors for poor glycemic control. A total of 104 type 2 diabetic patients were recruited and completed a questionnaire covering socio-demographic status, 3-day diet records, and physical activity. Anthropometry and glycemic control parameters, lipid profile and blood pressure were also measured. Subjects were on average 56.7±9.9 years old with a mean duration of diabetes of 6.5 ± 5.0 years. The mean hemoglobin A1c of the subjects was 7.6% ± 1.4%, with only 20.2% achieving the target goal of <6.5% with no significant differences between genders. The mean body mass index was 26.9 ± 4.7 kg/m(2), with 86.5% either were overweight or obese. Only 10.6% of the subjects exercised daily. The proportions of macronutrients relative to total energy intake were consistent with the recommendations of most diabetes associations. The adjusted odds of having poor glycemic control were 3.235 (1.043-10.397) (P < 0.05) higher among those who had high density lipoprotein cholesterol levels below the normal range. Those taking one or two types of oral anti-diabetic drugs had 19.9 (2.959-87.391) (P < 0.01) and 14.3 (2.647-77.500) (P < 0.01) higher odds of poor glycemic control respectively compared to those who were being treated by diet alone. Poor glycemic control was prevalent among Malaysian diabetic patients, and this could be associated with low levels of HDL and being treated with oral anti-diabetes agents.

Nutritional status, glycemic control and its associated risk factors among a sample of type 2 diabetic individuals, a pilot study

PubMed Central

Firouzi, Somayyeh; Barakatun-Nisak, Mohd Yusof; Azmi, Kamaruddin Nor

2015-01-01

Background: The prevalence of type 2 diabetes is increasing in Malaysia, with most patients poorly controlled. Hence, this study aimed to determine nutritional and metabolic status as well as blood pressure of Malaysian patients with type 2 diabetes mellitus and identify associated risk factors for poor glycemic control. Materials and Methods: A total of 104 type 2 diabetic patients were recruited and completed a questionnaire covering socio-demographic status, 3-day diet records, and physical activity. Anthropometry and glycemic control parameters, lipid profile and blood pressure were also measured. Results: Subjects were on average 56.7±9.9 years old with a mean duration of diabetes of 6.5 ± 5.0 years. The mean hemoglobin A1c of the subjects was 7.6% ± 1.4%, with only 20.2% achieving the target goal of <6.5% with no significant differences between genders. The mean body mass index was 26.9 ± 4.7 kg/m2, with 86.5% either were overweight or obese. Only 10.6% of the subjects exercised daily. The proportions of macronutrients relative to total energy intake were consistent with the recommendations of most diabetes associations. The adjusted odds of having poor glycemic control were 3.235 (1.043-10.397) (P < 0.05) higher among those who had high density lipoprotein cholesterol levels below the normal range. Those taking one or two types of oral anti-diabetic drugs had 19.9 (2.959-87.391) (P < 0.01) and 14.3 (2.647-77.500) (P < 0.01) higher odds of poor glycemic control respectively compared to those who were being treated by diet alone. Conclusion: Poor glycemic control was prevalent among Malaysian diabetic patients, and this could be associated with low levels of HDL and being treated with oral anti-diabetes agents. PMID:25767521

Semen Cassiae Extract Improves Glucose Metabolism by Promoting GlUT4 Translocation in the Skeletal Muscle of Diabetic Rats

PubMed Central

Zhang, Meiling; Li, Xin; Liang, Hangfei; Cai, Huqiang; Hu, Xueling; Bian, Yu; Dong, Lei; Ding, Lili; Wang, Libo; Yu, Bo; Zhang, Yan; Zhang, Yao

2018-01-01

Diabetes mellitus is a clinical syndrome characterised by hyperglycaemia; its complications lead to disability and even death. Semen Cassiae is a traditional Chinese medicine, which has anti-hypertensive, anti-hyperlipidaemia, anti-oxidation, and anti-ageing properties. Our study was designed to evaluate the action of total anthraquinones of Semen Cassiae extract (SCE) on the improvement of glucose metabolism in diabetic rats and to elucidate the underlying mechanism. First, we evaluated the effect of SCE on normal rats. Next, we observed the effect of SCE using a rat model of diabetes, which was established by feeding rats with high-energy diet for 4 weeks and a single intraperitoneal injection of streptozotocin (STZ; 30 mg/kg) 3 weeks after starting the high-energy diet. Rats in different SCE groups (administered 54, 108, and 324 mg/kg/day of SCE) and metformin group (162 mg/kg/day, positive control drug) were treated with the corresponding drugs 1 week before starting high-energy diet and treatment continued for 5 weeks; meanwhile, rats in the control group were administered the same volume of sodium carboxymethyl cellulose solution (vehicle solution). One week after STZ injection, fasting blood glucose (FBG), oral glucose tolerance (OGT), fasting serum insulin (FSI) and serum lipids were quantified. Finally, the expression of proteins in the phosphatidylinositol-3-kinase (PI3K)–Akt–AS160–glucose transporter isoform 4 (GLUT4) signalling pathway was detected by western blotting. The data indicated that the levels of FBG and serum lipids were significantly lowered, and OGT and FSI were markedly increased in diabetic rats treated with SCE (108 mg/kg/day); however, SCE did not cause hypoglycaemia in normal rats. The molecular mechanisms were explored in the skeletal muscle. SCE markedly restored the decreased translocation of GLUT4 in diabetic rats. Moreover, the protein expressions of phosphorylated-AS160 (Thr642), phosphorylated-Akt (Ser473) and PI3K were significantly increased after SCE treatment in the skeletal muscle. These results indicate that SCE exerts an anti-hyperglycaemic effect by promoting GLUT4 translocation through the activation of the PI3K–Akt–AS160 signalling pathway. Our findings suggest that treatment with SCE, containing anthraquinones, could be an effective approach to enhance diabetes therapy. PMID:29670524

Antidiabetic and antihyperlipidemic activity of Piper longum root aqueous extract in STZ induced diabetic rats

PubMed Central

2013-01-01

Background The available drugs for diabetes, Insulin or Oral hypoglycemic agents have one or more side effects. Search for new antidiabetic drugs with minimal or no side effects from medicinal plants is a challenge according to WHO recommendations. In this aspect, the present study was undertaken to evaluate the antihyperglycemic and antihyperlipidemic effects of Piper longum root aqueous extract (PlrAqe) in streptozotocin (STZ) induced diabetic rats. Methods Diabetes was induced in male Wister albino rats by intraperitoneal administration of STZ (50 mg/kg.b.w). Fasting blood glucose (FBG) levels were measured by glucose-oxidase & peroxidase reactive strips. Serum biochemical parameters such as glycosylated hemoglobin (HbA1c), total cholesterol (TC), triglycerides (TG), very low density lipoprotein (VLDL), low density lipoprotein (LDL) and high density lipoprotein (HDL) cholesterol were estimated. The activities of liver and kidney functional markers were measured. The statistical analysis of results was carried out using Student t-test and one-way analysis (ANOVA) followed by DMRT. Results During the short term study the aqueous extract at a dosage of 200 mg/kg.b.w was found to possess significant antidiabetic activity after 6 h of the treatment. The administration of aqueous extract at the same dose for 30 days in STZ induced diabetic rats resulted in a significant decrease in FBG levels with the corrections of diabetic dyslipidemia compared to untreated diabetic rats. There was a significant decrease in the activities of liver and renal functional markers in diabetic treated rats compared to untreated diabetic rats indicating the protective role of the aqueous extract against liver and kidney damage and its non-toxic property. Conclusions From the above results it is concluded that the plant extract is capable of managing hyperglycemia and complications of diabetes in STZ induced diabetic rats. Hence this plant may be considered as one of the potential sources for the isolation of new oral anti hypoglycemic agent(s). PMID:23414307

Determinants of saxagliptin use among patients with type 2 diabetes mellitus treated with oral anti-diabetic drugs.

PubMed

Saine, M Elle; Carbonari, Dena M; Newcomb, Craig W; Nezamzadeh, Melissa S; Haynes, Kevin; Roy, Jason A; Cardillo, Serena; Hennessy, Sean; Holick, Crystal N; Esposito, Daina B; Gallagher, Arlene M; Bhullar, Harshvinder; Strom, Brian L; Lo Re, Vincent

2015-04-02

The patterns and determinants of saxagliptin use among patients with type 2 diabetes mellitus (T2DM) are unknown in real-world settings. We compared the characteristics of T2DM patients who were new initiators of saxagliptin to those who were new initiators of non-dipeptidyl peptidase-4 (DPP-4) inhibitor oral anti-diabetic drugs (OADs) and identified factors associated with saxagliptin use. We conducted a cross-sectional study within the Clinical Practice Research Datalink (CPRD), The Health Improvement Network (THIN), US Medicare, and the HealthCore Integrated Research Database (HIRD(SM)) across the first 36 months of saxagliptin availability (29 months for US Medicare). Patients were included if they were: 1) ≥18 years old, 2) newly prescribed saxagliptin or a non-DPP-4 inhibitor OAD, and 3) enrolled in their respective database for 180 days. For each saxagliptin initiator, we randomly selected up to ten non-DPP-4 inhibitor OAD initiators matched on age, sex, and geographic region. Conditional logistic regression was used to identify determinants of saxagliptin use. We identified 64,079 saxagliptin initiators (CPRD: 1,962; THIN: 2,084; US Medicare: 51,976; HIRD(SM): 8,057) and 610,660 non-DPP-4 inhibitor OAD initiators (CPRD: 19,484; THIN: 19,936; US Medicare: 493,432; HIRD(SM): 77,808). Across all four data sources, prior OAD use, hypertension, and hyperlipidemia were associated with saxagliptin use. Saxagliptin initiation was also associated with hemoglobin A1c results >8% within the UK data sources, and a greater number of hemoglobin A1c measurements in the US data sources. In these UK and US data sources, initiation of saxagliptin was associated with prior poor glycemic control, prior OAD use, and diagnoses of hypertension and hyperlipidemia. ClinicalTrials.gov identifiers NCT01086280 , NCT01086293 , NCT01086319 , NCT01086306 , and NCT01377935.

Diabetes mellitus: Exploring the challenges in the drug development process.

PubMed

Vaz, Julius A; Patnaik, Ashis

2012-07-01

Diabetes mellitus has reached epidemic proportions and continues to be a major burden on society globally. The International Diabetes Federation (IDF) estimated the global burden of diabetes to be 366 million in 2011 and predicted that by 2030 this will have risen to 552 million. In spite of newer and effective treatment options, newer delivery and diagnostic devices, stricter glycaemic targets, better treatment guidelines and increased awareness of the disease, baseline glycosylated hemoglobin remains relatively high in subjects diagnosed and treated with type 2 diabetes. The search continues for an ideal anti diabetic drug that will not only normalize blood glucose but also provide beta cell rest and possibly restoration of beta cell function. The development of anti diabetic drugs is riddled with fundamental challenges. The concept of beta cell rest and restoration is yet to be completely understood and proven on a long term. The ideal therapeutic approach to treating type 2 diabetes is not yet determined. Our understanding of drug safety in early clinical development is primarily limited to "Type A" reactions. Until marketing authorization most drugs are approved based on the principle of confirming non-inferiority with an existing gold standard or determining superiority to a placebo. The need to obtain robust pharmaco-economic data prior to marketing authorization in order to determine appropriate pricing of a new drug remains a major challenge. The present review outlines some of the challenges in drug development of anti-diabetic drugs citing examples of pulmonary insulin, insulin analogues, thiazolidinediones and the GLP1 analogues.

Family Physician Clinical Inertia in Glycemic Control among Patients with Type 2 Diabetes

PubMed Central

Lang, Valerija Bralić; Marković, Biserka Bergman; Kranjčević, Ksenija

2015-01-01

Background Many patients with diabetes do not achieve target values. One of the reasons for this is clinical inertia. The correct explanation of clinical inertia requires a conjunction of patient with physician and health care system factors. Our aim was to determine the rate of clinical inertia in treating diabetes in primary care and association of patient, physician, and health care setting factors with clinical inertia. Material/Methods This was a national, multicenter, observational, cross-sectional study in primary care in Croatia. Each family physician (FP) provided professional data and collected clinical data on 15–25 type 2 diabetes (T2DM) patients. Clinical inertia was defined as a consultation in which treatment change based on glycated hemoglobin (HbA1c) levels was indicated but did not occur. Results A total of 449 FPs (response rate 89.8%) collected data on 10275 patients. Mean clinical inertia per FP was 55.6% (SD ±26.17) of consultations. All of the FPs were clinically inert with some patients, and 9% of the FPs were clinically inert with all patients. The main factors associated with clinical inertia were: higher percentage of HbA1c, oral anti-diabetic drug initiated by diabetologist, increased postprandial glycemia and total cholesterol, physical inactivity of patient, and administration of drugs other than oral antidiabetics. Conclusions Clinical inertia in treating patients with T2DM is a serious problem. Patients with worse glycemic control and those whose therapy was initiated by a diabetologist experience more clinical inertia. More research on causes of clinical inertia in treating patients with T2DM should be conducted to help achieve more effective diabetes control. PMID:25652941

Family physician clinical inertia in glycemic control among patients with type 2 diabetes.

PubMed

Bralić Lang, Valerija; Bergman Marković, Biserka; Kranjčević, Ksenija

2015-02-05

Many patients with diabetes do not achieve target values. One of the reasons for this is clinical inertia. The correct explanation of clinical inertia requires a conjunction of patient with physician and health care system factors. Our aim was to determine the rate of clinical inertia in treating diabetes in primary care and association of patient, physician, and health care setting factors with clinical inertia. This was a national, multicenter, observational, cross-sectional study in primary care in Croatia. Each family physician (FP) provided professional data and collected clinical data on 15-25 type 2 diabetes (T2DM) patients. Clinical inertia was defined as a consultation in which treatment change based on glycated hemoglobin (HbA1c) levels was indicated but did not occur. A total of 449 FPs (response rate 89.8%) collected data on 10275 patients. Mean clinical inertia per FP was 55.6% (SD ±26.17) of consultations. All of the FPs were clinically inert with some patients, and 9% of the FPs were clinically inert with all patients. The main factors associated with clinical inertia were: higher percentage of HbA1c, oral anti-diabetic drug initiated by diabetologist, increased postprandial glycemia and total cholesterol, physical inactivity of patient, and administration of drugs other than oral antidiabetics. Clinical inertia in treating patients with T2DM is a serious problem. Patients with worse glycemic control and those whose therapy was initiated by a diabetologist experience more clinical inertia. More research on causes of clinical inertia in treating patients with T2DM should be conducted to help achieve more effective diabetes control.

Two cases of corneal perforation after oral administration of nonsteroidal anti-inflammatory drugs: oral NSAID-induced corneal damage.

PubMed

Masuda, Ikuya; Matsuo, Toshihiko; Okamoto, Kazuo; Matsushita, Kyoko; Ohtsuki, Hiroshi

2010-01-01

To report 2 cases of corneal perforation associated with the use of oral nonsteroidal anti-inflammatory drugs (NSAIDs). In a 62-year-old woman and a 79-year-old woman, corneal perforation occurred after 7 days and 5 months of oral NSAIDs administration, respectively. After NSAIDs were discontinued, the cornea epithelialized and the anterior chamber formed within 14 and 10 days, respectively. It is well known that topical NSAIDs cause corneal perforation. Observations in the present cases suggest that the oral administration of NSAIDs may also cause corneal damage, and hence, medical professionals should consider the risk of damage to the cornea when administering these drugs orally.

Insulin for the treatment of women with gestational diabetes.

PubMed

Brown, Julie; Grzeskowiak, Luke; Williamson, Kathryn; Downie, Michelle R; Crowther, Caroline A

2017-11-05

Gestational diabetes mellitus (GDM) is associated with short- and long-term complications for the mother and her infant. Women who are unable to maintain their blood glucose concentration within pre-specified treatment targets with diet and lifestyle interventions will require anti-diabetic pharmacological therapies. This review explores the safety and effectiveness of insulin compared with oral anti-diabetic pharmacological therapies, non-pharmacological interventions and insulin regimens. To evaluate the effects of insulin in treating women with gestational diabetes. We searched Pregnancy and Childbirth's Trials Register (1 May 2017), ClinicalTrials.gov, WHO International Clinical Trials Registry Platform (ICTRP) (1 May 2017) and reference lists of retrieved studies. We included randomised controlled trials (including those published in abstract form) comparing:a) insulin with an oral anti-diabetic pharmacological therapy;b) with a non-pharmacological intervention;c) different insulin analogues;d) different insulin regimens for treating women with diagnosed with GDM.We excluded quasi-randomised and trials including women with pre-existing type 1 or type 2 diabetes. Cross-over trials were not eligible for inclusion. Two review authors independently assessed study eligibility, risk of bias, and extracted data. Data were checked for accuracy. We included 53 relevant studies (103 publications), reporting data for 7381 women. Forty-six of these studies reported data for 6435 infants but our analyses were based on fewer number of studies/participants.Overall, the risk of bias was unclear; 40 of the 53 included trials were not blinded. Overall, the quality of the evidence ranged from moderate to very low quality. The primary reasons for downgrading evidence were imprecision, risk of bias and inconsistency. We report the results for our maternal and infant GRADE outcomes for the main comparison. Insulin versus oral anti-diabetic pharmacological therapyFor the mother, insulin was associated with an increased risk for hypertensive disorders of pregnancy (not defined) compared to oral anti-diabetic pharmacological therapy (risk ratio (RR) 1.89, 95% confidence interval (CI) 1.14 to 3.12; four studies, 1214 women; moderate-quality evidence). There was no clear evidence of a difference between those who had been treated with insulin and those who had been treated with an oral anti-diabetic pharmacological therapy for the risk of pre-eclampsia (RR 1.14, 95% CI 0.86 to 1.52; 10 studies, 2060 women; moderate-quality evidence); the risk of birth by caesarean section (RR 1.03, 95% CI 0.93 to 1.14; 17 studies, 1988 women; moderate-quality evidence); or the risk of developing type 2 diabetes (metformin only) (RR 1.39, 95% CI 0.80 to 2.44; two studies, 754 women; moderate-quality evidence). The risk of undergoing induction of labour for those treated with insulin compared with oral anti-diabetic pharmacological therapy may possibly be increased, although the evidence was not clear (average RR 1.30, 95% CI 0.96 to 1.75; three studies, 348 women; I² = 32%; moderate-quality of evidence). There was no clear evidence of difference in postnatal weight retention between women treated with insulin and those treated with oral anti-diabetic pharmacological therapy (metformin) at six to eight weeks postpartum (MD -1.60 kg, 95% CI -6.34 to 3.14; one study, 167 women; low-quality evidence) or one year postpartum (MD -3.70, 95% CI -8.50 to 1.10; one study, 176 women; low-quality evidence). The outcomes of perineal trauma/tearing or postnatal depression were not reported in the included studies.For the infant, there was no evidence of a clear difference between those whose mothers had been treated with insulin and those treated with oral anti-diabetic pharmacological therapies for the risk of being born large-for-gestational age (average RR 1.01, 95% CI 0.76 to 1.35; 13 studies, 2352 infants; moderate-quality evidence); the risk of perinatal (fetal and neonatal death) mortality (RR 0.85; 95% CI 0.29 to 2.49; 10 studies, 1463 infants; low-quality evidence);, for the risk of death or serious morbidity composite (RR 1.03, 95% CI 0.84 to 1.26; two studies, 760 infants; moderate-quality evidence); the risk of neonatal hypoglycaemia (average RR 1.14, 95% CI 0.85 to 1.52; 24 studies, 3892 infants; low-quality evidence); neonatal adiposity at birth (% fat mass) (mean difference (MD) 1.6%, 95% CI -3.77 to 0.57; one study, 82 infants; moderate-quality evidence); neonatal adiposity at birth (skinfold sum/mm) (MD 0.8 mm, 95% CI -2.33 to 0.73; random-effects; one study, 82 infants; very low-quality evidence); or childhood adiposity (total percentage fat mass) (MD 0.5%; 95% CI -0.49 to 1.49; one study, 318 children; low-quality evidence). Low-quality evidence also found no clear differences between groups for rates of neurosensory disabilities in later childhood: hearing impairment (RR 0.31, 95% CI 0.01 to 7.49; one study, 93 children), visual impairment (RR 0.31, 95% CI 0.03 to 2.90; one study, 93 children), or any mild developmental delay (RR 1.07, 95% CI 0.33 to 3.44; one study, 93 children). Later infant mortality, and childhood diabetes were not reported as outcomes in the included studies.We also looked at comparisons for regular human insulin versus other insulin analogues, insulin versus diet/standard care, insulin versus exercise and comparisons of insulin regimens, however there was insufficient evidence to determine any differences for many of the key health outcomes. Please refer to the main results for more information about these comparisons. The main comparison in this review is insulin versus oral anti-diabetic pharmacological therapies. Insulin and oral anti-diabetic pharmacological therapies have similar effects on key health outcomes. The quality of the evidence ranged from very low to moderate, with downgrading decisions due to imprecision, risk of bias and inconsistency.For the other comparisons of this review (insulin compared with non-pharmacological interventions, different insulin analogies or different insulin regimens), there is insufficient volume of high-quality evidence to determine differences for key health outcomes.Long-term maternal and neonatal outcomes were poorly reported for all comparisons.The evidence suggests that there are minimal harms associated with the effects of treatment with either insulin or oral anti-diabetic pharmacological therapies. The choice to use one or the other may be down to physician or maternal preference, availability or severity of GDM. Further research is needed to explore optimal insulin regimens. Further research could aim to report data for standardised GDM outcomes.

Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug

PubMed Central

Dang, Tram T.; Thai, Anh V.; Cohen, Joshua; Slosberg, Jeremy E.; Siniakowicz, Karolina; Doloff, Joshua C.; Ma, Minglin; Hollister-Lock, Jennifer; Tang, Katherine; Gu, Zhen; Cheng, Hao; Weir, Gordon C.; Langer, Robert; Anderson, Daniel G.

2013-01-01

Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology towards a long-term cure for type I diabetes. PMID:23660251

Anti-diabetic activity of methanolic extract of Alpinia galanga Linn. aerial parts in streptozotocin induced diabetic rats

PubMed Central

Verma, Ramesh Kumar; Mishra, Garima; Singh, Pradeep; Jha, Keshri K.; Khosa, Ratan L.

2015-01-01

Introduction: Alpinia galanga Linn. belongs to the family Zingiberaceae has been used as a traditional medicine in China for relieving stomach ache, treating cold, invigorating the circulatory systems, diabetes, and reducing swelling. Aim: To evaluate the antidiabetic activity of methanolic extract of A. galanga aerial parts on streptozotocin (STZ) induced diabetic rats. Materials and Methods: Diabetes was induced by single intraperitoneal injection of STZ at a dose of 60 mg/kg bodyweight. Test drug methanolic extract of A. galanga (200 and 400 mg/kg b.w.) and glibenclamide (10 mg/kg b.w.) as standard drug was administered orally for 21 consecutive days in STZ-induced diabetic rats. Fasting blood glucose level, serum lipid profiles, as well as initial and final changes in body weight were assessed along with histopathology. All the parameters were statistically analyzed by using one-way ANOVA followed by Bonferroni t-test. Results: Experimental findings showed significant dose dependent antidiabetic potential of methanolic extract in terms of reduction of fasting blood glucose level and various biochemical parameters in diabetic rats when compared with that of the diabetic control group, which might be due to the stimulatory effect of methanolic extracts on the regenerating β-cells and also on the surviving β-cells. Conclusion: Methanolic extract of aerial parts of A. galanga was effective in controlling blood glucose level and improve lipid profile in euglycemic as well as diabetic rats. PMID:26730146

Bartter's syndrome with type 2 diabetes mellitus.

PubMed

See, Ting-Ting; Lee, Siu-Pak

2009-02-01

We report a rare case of Bartter's syndrome in a 35-year-old woman with type 2 diabetes mellitus. The patient presented with leg weakness, fatigue, polyuria and polydipsia. Hypokalemia, metabolic alkalosis, and high renin and aldosterone concentrations were present, but the patient was normotensive. Gitelman's syndrome was excluded because of the presence of hypercalciuria, secondary hyperparathyroidism and bilateral nephrocalcinosis. The patients condition improved upon administration of a prostaglandin synthetase inhibitor (acemetacin), oral potassium chloride and potassium-sparing diuretics. Five months later, the patient discontinued acemetacin because of epigastric discomfort; at the same time, severe hypokalemia and hyperglycemia developed. Glucagon stimulation and water deprivation tests were performed. Type 2 diabetes mellitus with nephrogenic diabetes insipidus was diagnosed. To avoid further gastrointestinal complications, the patient was treated with celecoxib, a selective cyclooxygenase 2 inhibitor. This case serves as a reminder that Bartter's syndrome is associated with various metabolic derangements including nephrogenic diabetes insipidus, nephrocalcinosis and diabetes mellitus. When treating Bartter's syndrome, it is also prudent to remember that the long-term use of nonsteroidal anti-inflammatory drugs and potassium-sparing diuretics may result in serious adverse reactions.

State-of-the-Art: Hypo-responsiveness to oral antiplatelet therapy in patients with type 2 diabetes mellitus.

PubMed

Kumbhani, Dharam J; Marso, Steven P; Alvarez, Carlos A; McGuire, Darren K

2015-01-01

Diabetes mellitus is a global pandemic, associated with a high burden of cardiovascular disease. There are multiple platelet derangements in patients with diabetes, and antiplatelet drugs remain the first-line agents for secondary prevention as well as for high-risk primary prevention among patients with diabetes. This review provides a summary of oral antiplatelet drug hypo-responsiveness in patients with diabetes, specifically aspirin and Clopidogrel resistance. Topics discussed include antiplatelet testing, definitions used to define hypo-response and resistance, its prevalence, association with clinical outcomes and strategies to mitigate resistance. The role of prasugrel and ticagrelor, as well as investigational agents, is also discussed.

Promising anti-diabetes mellitus activity in rats of β-amyrin palmitate isolated from Hemidesmus indicus roots.

PubMed

Nair, S Ajikumaran; Sabulal, B; Radhika, J; Arunkumar, R; Subramoniam, A

2014-07-05

While evaluating the toxicity of the tuberous root extracts of Hemidesmus indicus, a traditional medicinal plant, the glucose lowering property of the root was observed by the investigators. Therefore, it was thought of interest to isolate the anti-hyperglycemic principle from the root and determine its utility to develop an anti-diabetes mellitus medicine. The active principle was isolated from H. indicus root extract by anti-hyperglycemic activity guided chromatographic techniques. Glucose tolerance test in rats was used to evaluate the anti-hyperglycenic property. Anti-diabetes mellitus property was evaluated in alloxan-induced diabetic rats as well as streptozotocin-induced (type-2 model) diabetic rats. The active principle was isolated and identified with spectral data as β-amyrin palmitate. Although it is a known compound, its presence in H. indicus is not known previously. It was observed for the first time that β-amyrin palmitate has remarkable anti-hyperglycemic activity in orally glucose loaded rats. Further, interestingly, it exhibited excellent anti-diabetes mellitus activity in both alloxan-diabetic and streptozotocin-diabetic rats at a very low concentration (50µg/kg body weight). One of the mechanisms of action of β-amyrin palmitate appears to be blocking the entry of glucose from the intestine. β-Amyrin palmitate is very promising to develop a medicine for diabetes for combination therapy and/or mono-therapy. Copyright © 2014 Elsevier B.V. All rights reserved.

Past and current perspective on new therapeutic targets for Type-II diabetes.

PubMed

Patil, Pradip D; Mahajan, Umesh B; Patil, Kalpesh R; Chaudhari, Sandip; Patil, Chandragouda R; Agrawal, Yogeeta O; Ojha, Shreesh; Goyal, Sameer N

2017-01-01

Loss of pancreatic β-cell function is a hallmark of Type-II diabetes mellitus (DM). It is a chronic metabolic disorder that results from defects in both insulin secretion and insulin action. Recently, United Kingdom Prospective Diabetes Study reported that Type-II DM is a progressive disorder. Although, DM can be treated initially by monotherapy with oral agent; eventually, it may require multiple drugs. Additionally, insulin therapy is needed in many patients to achieve glycemic control. Pharmacological approaches are unsatisfactory in improving the consequences of insulin resistance. Single therapeutic approach in the treatment of Type-II DM is unsuccessful and usually a combination therapy is adopted. Increased understanding of biochemical, cellular and pathological alterations in Type-II DM has provided new insight in the management of Type-II DM. Knowledge of underlying mechanisms of Type-II DM development is essential for the exploration of novel therapeutic targets. Present review provides an insight into therapeutic targets of Type-II DM and their role in the development of insulin resistance. An overview of important signaling pathways and mechanisms in Type-II DM is provided for the better understanding of disease pathology. This review includes case studies of drugs that are withdrawn from the market. The experience gathered from previous studies and knowledge of Type-II DM pathways can guide the anti-diabetic drug development toward the discovery of clinically viable drugs that are useful in Type-II DM.

Effect of bromocriptine-QR on glycemic control in subjects with uncontrolled hyperglycemia on one or two oral anti-diabetes agents.

PubMed

Vinik, Aaron I; Cincotta, Anthony H; Scranton, Richard E; Bohannon, Nancy; Ezrokhi, Michael; Gaziano, J Michael

2012-01-01

To investigate the effect of Bromocriptine-QR on glycemic control in patients with type 2 diabetes whose glycemia is poorly controlled on one or two oral anti-diabetes agents. Five hundred fifteen Type 2 Diabetes Mellitus (T2DM) subjects (ages 18 to 80 and average body mass index [BMI] of 32.7) with baseline HbA1c ≥ 7.5 and on one or two oral anti-diabetes (OAD) medications (metformin, sulfonylurea, and/or thiazolidinediones) were randomized 2:1 to bromocriptine-QR (1.6 to 4.8 mg/day) or placebo for a 24 week treatment period. Study investigators were allowed to adjust, if necessary, subject anti-diabetes medications during the study to attempt to achieve glycemic control in case of glycemic deterioration. The impact of bromocriptine-QR treatment intervention on glycemic control was assessed in subjects on any one or two OADs (ALL treatment category) (N = 515), or on metformin with or without another OAD (Met/OAD treatment category) (N = 356), or on metformin plus a sulfonylurea (Met/SU treatment category) (N = 245) 1) by examining the between group difference in change from baseline a) concomitant OAD medication changes during the study, and b) HbA1c and 2) by determining the odds of reaching HbA1c of ≤ 7.0% on bromocriptine-QR versus placebo. Significantly more patients (approximately 1.5 to 2-fold more; P<.05) intensified concomitant anti-diabetes medication therapy during the study in the placebo versus the bromocriptine-QR arm. In subjects that did not change the intensity of the baseline diabetes therapy (72%), and that were on any one or two OADs (ALL), or on metformin with or without another OAD (Met/OAD), or on metformin plus sulfonylurea (Met/SU), the HbA1c change for bromocriptine-QR versus placebo was -0.47 versus +0.22 (between group delta of -0.69, P<.0001), -0.55 versus +0.26 (between group delta of -0.81, P<.0001) and -0.63 versus +0.20 (between group delta of -0.83, P<.0001) respectively, after 24 weeks on therapy. The odds ratio of reaching HbA1c of ≤ 7.0% was 6.50, 12.03 and 11.45 (P<.0002) for these three groups, respectively. In T2DM subjects whose hyperglycemia is poorly controlled on one or two oral agents, bromocriptine-QR therapy for 24 weeks can provide significant added improvement in glycemic control relative to adding placebo.

Enhanced function of immuno-isolated islets in diabetes therapy by co-encapsulation with an anti-inflammatory drug.

PubMed

Dang, Tram T; Thai, Anh V; Cohen, Joshua; Slosberg, Jeremy E; Siniakowicz, Karolina; Doloff, Joshua C; Ma, Minglin; Hollister-Lock, Jennifer; Tang, Katherine M; Gu, Zhen; Cheng, Hao; Weir, Gordon C; Langer, Robert; Anderson, Daniel G

2013-07-01

Immuno-isolation of islets has the potential to enable the replacement of pancreatic function in diabetic patients. However, host response to the encapsulated islets frequently leads to fibrotic overgrowth with subsequent impairment of the transplanted grafts. Here, we identified and incorporated anti-inflammatory agents into islet-containing microcapsules to address this challenge. In vivo subcutaneous screening of 16 small molecule anti-inflammatory drugs was performed to identify promising compounds that could minimize the formation of fibrotic cell layers. Using parallel non-invasive fluorescent and bioluminescent imaging, we identified dexamethasone and curcumin as the most effective drugs in inhibiting the activities of inflammatory proteases and reactive oxygen species in the host response to subcutaneously injected biomaterials. Next, we demonstrated that co-encapsulating curcumin with pancreatic rat islets in alginate microcapsules reduced fibrotic overgrowth and improved glycemic control in a mouse model of chemically-induced type I diabetes. These results showed that localized administration of anti-inflammatory drug can improve the longevity of encapsulated islets and may facilitate the translation of this technology toward a long-term cure for type I diabetes. Published by Elsevier Ltd.

An invertebrate hyperglycemic model for the identification of anti-diabetic drugs.

PubMed

Matsumoto, Yasuhiko; Sumiya, Eriko; Sugita, Takuya; Sekimizu, Kazuhisa

2011-03-30

The number of individuals diagnosed with type 2 diabetes mellitus, which is caused by insulin resistance and/or abnormal insulin secretion, is increasing worldwide, creating a strong demand for the development of more effective anti-diabetic drugs. However, animal-based screening for anti-diabetic compounds requires sacrifice of a large number of diabetic animals, which presents issues in terms of animal welfare. Here, we established a method for evaluating the anti-diabetic effects of compounds using an invertebrate animal, the silkworm, Bombyx mori. Sugar levels in silkworm hemolymph increased immediately after feeding silkworms a high glucose-containing diet, resulting in impaired growth. Human insulin and 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR), an AMP-activated protein kinase (AMPK) activator, decreased the hemolymph sugar levels of the hyperglycemic silkworms and restored growth. Treatment of the isolated fat body with human insulin in an in vitro culture system increased total sugar in the fat body and stimulated Akt phosphorylation. These responses were inhibited by wortmannin, an inhibitor of phosphoinositide 3 kinase. Moreover, AICAR stimulated AMPK phosphorylation in the silkworm fat body. Administration of aminoguanidine, a Maillard reaction inhibitor, repressed the accumulation of Maillard reaction products (advanced glycation end-products; AGEs) in the hyperglycemic silkworms and restored growth, suggesting that the growth defect of hyperglycemic silkworms is caused by AGE accumulation in the hemolymph. Furthermore, we identified galactose as a hypoglycemic compound in jiou, an herbal medicine for diabetes, by monitoring its hypoglycemic activity in hyperglycemic silkworms. These results suggest that the hyperglycemic silkworm model is useful for identifying anti-diabetic drugs that show therapeutic effects in mammals.

The metabolic score: A decision making tool in diabetes care.

PubMed

Kalra, Sanjay; Gupta, Yashdeep

2015-11-01

The heterogeneity of diabetes mellitus, and the various metabolic abnormalities associated with it, are well known. Current management guidelines used to help choose glucose-lowering drugs in diabetes mellitus describe various drug classes in detail, but do not take the overall metabolic profile into consideration. To help physicians choose appropriate oral therapy, we propose a discrete metabolic score, based upon the presence and absence of metabolic comorbidities included in the definition of metabolic syndrome. This communication describes how to choose an appropriate oral antidiabetic drug using such a score. The metabolic score based decision making aid should be able to prove its utility in all health care settings, especially resource constrained societies.

Spices in the management of diabetes mellitus.

PubMed

Bi, Xinyan; Lim, Joseph; Henry, Christiani Jeyakumar

2017-02-15

Diabetes mellitus (DM) remains a major health care problem worldwide both in developing and developed countries. Many factors, including age, obesity, sex, and diet, are involved in the etiology of DM. Nowadays, drug and dietetic therapies are the two major approaches used for prevention and control of DM. Compared to drug therapy, a resurgence of interest in using diet to manage and treat DM has emerged in recent years. Conventional dietary methods to treat DM include the use of culinary herbs and/or spices. Spices have long been known for their antioxidant, anti-inflammatory, and anti-diabetic properties. This review explores the anti-diabetic properties of commonly used spices, such as cinnamon, ginger, turmeric, and cumin, and the use of these spices for prevention and management of diabetes and associated complications. Copyright © 2016 Elsevier Ltd. All rights reserved.

Stabilities and Biological Activities of Vanadium Drugs: What is the Nature of the Active Species?

PubMed

Levina, Aviva; Lay, Peter A

2017-07-18

Diverse biological activities of vanadium(V) drugs mainly arise from their abilities to inhibit phosphatase enzymes and to alter cell signaling. Initial interest focused on anti-diabetic activities but has shifted to anti-cancer and anti-parasitic drugs. V-based anti-diabetics are pro-drugs that release active components (e.g., H 2 VO 4 - ) in biological media. By contrast, V anti-cancer drugs are generally assumed to enter cells intact; however, speciation studies indicate that nearly all drugs are likely to react in cell culture media during in vitro assays and the same would apply in vivo. The biological activities are due to V V and/or V IV reaction products with cell culture media, or the release of ligands (e.g., aromatic diimines, 8-hydroxyquinolines or thiosemicarbazones) that bind to essential metal ions in the media. Careful consideration of the stability and speciation of V complexes in cell culture media and in biological fluids is essential to design targeted V-based anti-cancer therapies. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Platelets, diabetes and myocardial ischemia/reperfusion injury.

PubMed

Russo, Isabella; Penna, Claudia; Musso, Tiziana; Popara, Jasmin; Alloatti, Giuseppe; Cavalot, Franco; Pagliaro, Pasquale

2017-05-31

Mechanisms underlying the pathogenesis of ischemia/reperfusion injury are particularly complex, multifactorial and highly interconnected. A complex and entangled interaction is also emerging between platelet function, antiplatelet drugs, coronary diseases and ischemia/reperfusion injury, especially in diabetic conditions. Here we briefly summarize features of antiplatelet therapy in type 2 diabetes (T2DM). We also treat the influence of T2DM on ischemia/reperfusion injury and how anti-platelet therapies affect post-ischemic myocardial damage through pleiotropic properties not related to their anti-aggregating effects. miRNA-based signature associated with T2DM and its cardiovascular disease complications are also briefly considered. Influence of anti-platelet therapies and different effects of healthy and diabetic platelets on ischemia/reperfusion injury need to be further clarified in order to enhance patient benefits from antiplatelet therapy and revascularization. Here we provide insight on the difficulty to reduce the cardiovascular risk in diabetic patients and report novel information on the cardioprotective role of widely used anti-aggregant drugs.

Anti-hyperglycemic effect and glucose tolerance of guajava (Psidium guajava L.) leaf ethanol extract in diabetic rats

NASA Astrophysics Data System (ADS)

Yanis Musdja, Muhammad; Mahendra, Feizar; Musir, Ahmad

2017-12-01

Traditionally guava (Psidium guajava L) leaf is used for treatment of various ailments like diarrhea, wounds, rheumatism, anti-allergy, ant-spasmodic, etc, as folk medicine. The aim of this research is to know the effect of hypoglycemia and glucose tolerance of ethanol extract of guava leaf against male white rat. The guajava leaf was obtained from Balitro Bogor. Preparation of guajava leaf extract was done by cold maceration extraction technique using ethanol 70%. Male albino rats were made into diabetics using the alloxan method. Rats were divided into 6 groups, as a comparative drug for anti-hyperglycemic used glibenclamid and as a comparative drug for glucose tolerance used acarbose. The result of blood glucometer test showed that ethanol extract 70% of guajava leaf had effect as anti-hyperglycemic and glucose tolerance with no significant difference with glibenclamid drug as anti-hyperglycemic and acarbose as glucose tolerance drug.

Glimepiride attenuates Aβ production via suppressing BACE1 activity in cortical neurons.

PubMed

Liu, Feiyang; Wang, Yijin; Yan, Ming; Zhang, Luyong; Pang, Tao; Liao, Hong

2013-12-17

Numerous lines of evidence suggest a strong link between diabetes mellitus and Alzheimer's disease (AD). Impaired insulin signaling and insulin resistance occur not only in diabetes but also in the brain of AD. Recent evidence has indicated that peroxisome proliferator-activated receptor γ (PPARγ) agonists thiazolidinediones (TZDs) can decrease β-amyloid peptide (Aβ) deposition, which is the core component of senile plaques in AD, but the underlying mechanisms still remain unclear. In this study, we investigated whether glimepiride with PPARγ-stimulating activity, an oral anti-diabetic drug, has similar effects on Aβ production in primary cortical neurons. We demonstrated that glimepiride decreased extracellular Aβ40 and Aβ42 levels. The effect of glimepiride on reduction of Aβ40 generation was mediated by downregulation of β-site APP-cleaving enzyme 1 (BACE1) mRNA and protein expression, and by suppression of BACE1 activity. In addition, we found that high glucose condition enhanced Aβ40 production and glimepiride significantly decreased high glucose-induced Aβ40 production. Finally, a specific PPARγ antagonist GW9662 reversed glimepiride inhibitory effect on Aβ40 generation, suggesting a PPARγ-dependent mechanism may be involved. Our data indicated that glimepiride may serve as a promising drug for the treatment of AD associated with diabetes. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Anti-Emetic Drug Effects on Pilot Performance, Phase 2: Simulation Test.

DTIC Science & Technology

1996-04-01

The objectives of this study were to evaluate the effects of two anti-emetic drugs, granisetron (2 mg oral dose) and ondansetron (8 mg oral dose), on...and preduce no cognitive, psychomotor or subjective state changes. In this study, there was no evidence of performance degradation caused by either granisetron or ondansetron when tested in a complex military task environment.

DIABETES PREVENTION PROGRAM

EPA Science Inventory

The Diabetes Prevention Program (DPP) was a major clinical trial, or research study, aimed at discovering whether either diet and exercise or the oral diabetes drug metformin (Glucophage) could prevent or delay the onset of type 2 diabetes in people with impaired glucose toleranc...

Diabetes therapies in hemodialysis patients: Dipeptidase-4 inhibitors

PubMed Central

Nakamura, Yuya; Hasegawa, Hitomi; Tsuji, Mayumi; Udaka, Yuko; Mihara, Masatomo; Shimizu, Tatsuo; Inoue, Michiyasu; Goto, Yoshikazu; Gotoh, Hiromichi; Inagaki, Masahiro; Oguchi, Katsuji

2015-01-01

Although several previous studies have been published on the effects of dipeptidase-4 (DPP-4) inhibitors in diabetic hemodialysis (HD) patients, the findings have yet to be reviewed comprehensively. Eyesight failure caused by diabetic retinopathy and aging-related dementia make multiple daily insulin injections difficult for HD patients. Therefore, we reviewed the effects of DPP-4 inhibitors with a focus on oral antidiabetic drugs as a new treatment strategy in HD patients with diabetes. The following 7 DPP-4 inhibitors are available worldwide: sitagliptin, vildagliptin, alogliptin, linagliptin, teneligliptin, anagliptin, and saxagliptin. All of these are administered once daily with dose adjustments in HD patients. Four types of oral antidiabetic drugs can be administered for combination oral therapy with DPP-4 inhibitors, including sulfonylureas, meglitinide, thiazolidinediones, and alpha-glucosidase inhibitor. Nine studies examined the antidiabetic effects in HD patients. Treatments decreased hemoglobin A1c and glycated albumin levels by 0.3% to 1.3% and 1.7% to 4.9%, respectively. The efficacy of DPP-4 inhibitor treatment is high among HD patients, and no patients exhibited significant severe adverse effects such as hypoglycemia and liver dysfunction. DPP-4 inhibitors are key drugs in new treatment strategies for HD patients with diabetes and with limited choices for diabetes treatment. PMID:26131325

Micro-Environmental Signature of The Interactions between Druggable Target Protein, Dipeptidyl Peptidase-IV, and Anti-Diabetic Drugs.

PubMed

Chakraborty, Chiranjib; Mallick, Bidyut; Sharma, Ashish Ranjan; Sharma, Garima; Jagga, Supriya; Doss, C George Priya; Nam, Ju-Suk; Lee, Sang-Soo

2017-01-01

Druggability of a target protein depends on the interacting micro-environment between the target protein and drugs. Therefore, a precise knowledge of the interacting micro-environment between the target protein and drugs is requisite for drug discovery process. To understand such micro-environment, we performed in silico interaction analysis between a human target protein, Dipeptidyl Peptidase-IV (DPP-4), and three anti-diabetic drugs (saxagliptin, linagliptin and vildagliptin). During the theoretical and bioinformatics analysis of micro-environmental properties, we performed drug-likeness study, protein active site predictions, docking analysis and residual interactions with the protein-drug interface. Micro-environmental landscape properties were evaluated through various parameters such as binding energy, intermolecular energy, electrostatic energy, van der Waals'+H-bond+desolvo energy (E VHD ) and ligand efficiency (LE) using different in silico methods. For this study, we have used several servers and software, such as Molsoft prediction server, CASTp server, AutoDock software and LIGPLOT server. Through micro-environmental study, highest log P value was observed for linagliptin (1.07). Lowest binding energy was also observed for linagliptin with DPP-4 in the binding plot. We also identified the number of H-bonds and residues involved in the hydrophobic interactions between the DPP-4 and the anti-diabetic drugs. During interaction, two H-bonds and nine residues, two H-bonds and eleven residues as well as four H-bonds and nine residues were found between the saxagliptin, linagliptin as well as vildagliptin cases and DPP-4, respectively. Our in silico data obtained for drug-target interactions and micro-environmental signature demonstrates linagliptin as the most stable interacting drug among the tested anti-diabetic medicines.

The mechanism of hypoglycemic action of the semi-purified fractions of Averrhoa bilimbi in streptozotocin-diabetic rats.

PubMed

Pushparaj, P N; Tan, B K; Tan, C H

2001-12-21

In the present study, we have examined the possible mechanism of the hypoglycemic action of the semi-purified fractions of an ethanolic extract of Averrhoa bilimbi Linn (Oxalidaceae) leaves (ABe) in streptozotocin-diabetic male Sprague-Dawley (SD) rats. The ABe was partitioned with water and butanol to yield a butanol-soluble fraction (BuF) and a water-soluble fraction (AF). The AF was further partitioned with ethyl acetate and hexane to obtain ethyl acetate (EF) and hexane (HF) soluble fractions. The hypoglycemic property of each fraction was assessed by the oral glucose tolerance test (OGTT) at a dose of 125-mg/kg-body weight in streptozotocin (STZ)-diabetic rats (STZ 60 mg/kg i.p.). Fractions AF, BuF and the reference drug metformin (500 mg/kg body weight), produced significant blood glucose-lowering effect in the diabetic rats when compared to the vehicle (distilled water). In the long-term study, the diabetic rats were randomly divided into 4 groups and treated orally by gavage with vehicle, AF (125 mg/kg body weight), BuF (125 mg/kg body weight), and metformin (500 mg/kg body weight) respectively twice a day for 14 days. On day 7 and day 14, AF and BuF, like the reference drug, metformin, lowered the fasting blood glucose concentration significantly (P < 0.05) when compared with the vehicle. The serum insulin level was significantly increased in the AF-treated rats only on day 14 when compared to that in the vehicle-treated rats on day zero (P < 0.05). The serum insulin level in BuF-treated rats was also significantly higher (P < 0.05) on both day 7 and day 14 compared to that on day zero. Hepatic glucose-6-phosphatase activity was significantly lower (P<0.05) in AF- and metformin-treated groups, but not in BuF-treated groups, compared to that in vehicle-treated group. However, there was no change in hepatic glycogen content in AF-, BuF- and metformin-treated group compared to the vehicle-treated group. These results indicate that AF is more potent than BuF in the amelioration of hyperglycemia in STZ-diabetic rats and is a potential source for the isolation of new orally active agent(s) for anti-diabetic therapy.

Use of demographic and pharmacy data to identify patients included within both the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN).

PubMed

Carbonari, Dena M; Saine, M Elle; Newcomb, Craig W; Blak, Betina; Roy, Jason A; Haynes, Kevin; Wood, Jennifer; Gallagher, Arlene M; Bhullar, Harshvinder; Cardillo, Serena; Hennessy, Sean; Strom, Brian L; Lo Re, Vincent

2015-09-01

Pharmacoepidemiology researchers often utilize data from two UK electronic medical record databases, the Clinical Practice Research Datalink (CPRD) and The Health Improvement Network (THIN), and may choose to combine the two in an effort to increase sample size. To minimize duplication of data, previous studies examined the practice-level overlap between these databases. However, the proportion of overlapping patients remains unknown. We developed a method using demographic and pharmacy variables to identify patients included in both CPRD and THIN, and applied this method to measure the proportion of overlapping patients who initiated the oral anti-diabetic drug saxagliptin. We conducted a cross-sectional study among patients initiating saxagliptin in CPRD and THIN between October 2009 and September 2012. Within both databases, we identified patients: (i) ≥18 years, (ii) newly prescribed saxagliptin, and (iii) with ≥180 days enrollment prior to saxagliptin initiation. Demographic data (birth year, sex, patient registration date, family number, and marital status) and prescriptions (including dates) for the first two oral anti-diabetic drugs prescribed within the study period were used to identify matching patients. Among 4202 CPRD and 3641 THIN patients initiating saxagliptin, 2574 overlapping patients (61% of CPRD saxagliptin initiators; 71% of THIN saxagliptin initiators) were identified. Among these patients, 2474 patients (96%) perfectly matched on all demographic and prescription data. Within each database, over 60% of patients initiating saxagliptin were included within both CPRD and THIN. Combined demographic and prescription data can be used to identify patients included in both CPRD and THIN. Copyright © 2015 John Wiley & Sons, Ltd.

A comprehensive review of the pharmacodynamics of the SGLT2 inhibitor empagliflozin in animals and humans

PubMed Central

Michel, Martin C.

2018-01-01

Empagliflozin (formerly known as BI 10773) is a potent, competitive, and selective inhibitor of the sodium glucose transporter SGLT2, which mediates glucose reabsorption in the early proximal tubule and most of the glucose reabsorption by the kidney, overall. Accordingly, empagliflozin treatment increased urinary glucose excretion. This has been observed across multiple species including humans and was reported under euglycemic conditions, in obesity and, most importantly, in type 2 diabetic patients and multiple animal models of type 2 diabetes and of type 1 diabetes. This led to a reduction in blood glucose, smaller blood glucose excursions during oral glucose tolerance tests, and, upon chronic treatment, a reduction in HbA1c in animal models and patients. In rodents, such effects were observed in early and late phases of experimental diabetes and were associated with preservation of pancreatic β-cell function. Combination studies in animals demonstrated that beneficial metabolic effects of empagliflozin may also manifest when added to other types of anti-hyperglycemic treatments including linagliptin and pioglitazone. While some anti-hyperglycemic drugs lead to weight gain, empagliflozin treatment was associated with reduced body weight in normoglycemic obese and non-obese animals despite an increased food intake, largely due to a loss of adipose tissue; on the other hand, empagliflozin preserved body weight in models of type 1 diabetes. Empagliflozin improved endothelial dysfunction in diabetic rats and arterial stiffness, reduced blood pressure in diabetic patients, and attenuated early signs of nephropathy in diabetic animal models. Taken together, the SGLT2 inhibitor empagliflozin improves glucose metabolism by enhancing urinary glucose excretion; upon chronic administration, at least in animal models, the reductions in blood glucose levels are associated with beneficial effects on cardiovascular and renal complications of diabetes. PMID:26108304

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model.

PubMed

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2015-10-01

Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6-8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) was orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20 μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. Copyright © 2015 Elsevier B.V. All rights reserved.

An endostatin-derived peptide orally exerts anti-fibrotic activity in a murine pulmonary fibrosis model

PubMed Central

Nishimoto, Tetsuya; Mlakar, Logan; Takihara, Takahisa; Feghali-Bostwick, Carol

2016-01-01

Objective Pulmonary fibrosis causes high morbidity and mortality in affected individuals. Recently, we showed that parenteral or intratracheal administration of a peptide derived from endostatin, called E4, prevents and ameliorates fibrosis using different models of dermal and pulmonary disease. No marketed orally delivered peptide drugs are currently available for progressive pulmonary fibrosis; however oral delivery of drugs is the preferred route for treating most chronic diseases. Thus, we investigated whether oral administration of E4 peptide exerted anti-fibrotic activity in a murine pulmonary fibrosis model. Methods Bleomycin (1.2mU/g body weight) was intratracheally administrated to male 6–8-week-old C57BL/6J mice. E4 peptide (20, 10, 5, and 1 μg/mouse) or scrambled control peptide (20 μg/mouse) were orally administered on the same day as bleomycin. In some experiments, E4 peptide (10 and 5 μg/mouse) was orally administered three times on days 0, 3, and 6 post-bleomycin treatment. Lungs were harvested on day 21 for histological analysis and hydroxyproline assay. Results Histological analysis and hydroxyproline assay revealed that bleomycin successfully induced pulmonary fibrosis, and that 20μg of oral E4 peptide ameliorated the fibrosis. The lower doses of E4 peptide (10, 5, and 1 μg) were insufficient to exert anti-fibrotic activity when given as a single dose. Multiple doses of E4 peptide efficiently exerted anti-fibrotic activity even at lower doses. Conclusion E4 peptide shows oral bioavailability and exerts anti-fibrotic activity in a bleomycin-induced pulmonary fibrosis model. We suggest that E4 peptide is a novel oral drug for fibroproliferative disorders. PMID:26315492

Who continues to stock oral artemisinin monotherapy? Results of a provider survey in Myanmar.

PubMed

Thein, Si Thu; Sudhinaraset, May; Khin, Hnin Su Su; McFarland, Willi; Aung, Tin

2016-06-22

Artemisinin-based combination therapy (ACT) is a key strategy for global malaria elimination efforts. However, the development of artemisinin-resistant malaria parasites threatens progress and continued usage of oral artemisinin monotherapies (AMT) predisposes the selection of drug resistant strains. This is particularly a problem along the Myanmar/Thailand border. The artemisinin monotherapy replacement programme (AMTR) was established in 2012 to remove oral AMT from stocks in Myanmar, specifically by replacing oral AMT with quality-assured ACT and conducting behavioural change communication activities to the outlets dispensing anti-malarial medications. This study attempts to quantify the characteristics of outlet providers who continue to stock oral AMT despite these concerted efforts. A cross-sectional survey of all types of private sector outlets that were stocking anti-malarial drugs in 13 townships of Eastern Myanmar was implemented from July to August 2014. A total of 573 outlets were included. Bivariate and multivariable logistic regressions were conducted to assess outlet and provider-level characteristics associated with stocking oral AMT. In total, 2939 outlets in Eastern Myanmar were screened for presence of any anti-malarial drugs in August 2014. The study found that 573 (19.5 %) had some kind of oral anti-malarial drug in stock at the time of survey and among them, 96 (16.8 %) stocked oral AMT. In bivariate analyses, compared to health care facilities, itinerant drug vendors, retailers and health workers were less likely to stock oral AMT (33.3 vs 12.9, 10.0, 8.1 %, OR = 0.30, 0.22, 0.18, respectively). Providers who cut blister pack or sell partial courses (40.6 vs 11.7 %, OR 5.18, CI 3.18-8.44) and those who based their stock decision on consumer demand (32.8 vs 12.1 %, OR 3.54, CI 2.21-5.63) were more likely to stock oAMT. Multivariate logistic regressions produced similar significant associations. Private healthcare facilities and drug shops and providers who prioritize consumers' demand instead of recommended practices were more likely to stock oral AMT. Malaria elimination strategies should include targeted interventions to effectively reach those outlets.

Anti hyperglycaemic study of natural inhibitors for Insulin receptor

PubMed Central

Chatterjee, Subhojyoti; Narasimhaiah, Akshaya Lakshmi; Kundu, Sanjay; Anand, Santosh

2012-01-01

Diabetes is a metabolic disorder associated with either improper functioning of the beta-cells or wherein cells fail to use insulin properly. Insulin, the principal hormone regulates uptake of glucose from the blood into most of the cells except central nervous system. Therefore, deficiency of insulin or the insensitivity of its receptors plays a key role in all forms of diabetes. In the present work, attempt has been made to find out plant sources which show anti hyperglycaemic activity (AhG) (i.e. compounds that bring down the blood glucose level in the body). Ayurvedic plants showing AhG activity formed the basis of our study by using the platform of Computer Aided Drug Designing (CADD). Among 600 plants showing AhG activity, 500 compounds were selected and screened, out of which 243 compounds showed drug likeness property that can be used as therapeutic ligand/drug. Initial screening of such compounds was done based on their drug likeness or biochemical properties. Dynamic interaction of these molecules was captured through Protein-Ligand study. It also gave an insight of the binding pockets involved. Bench marking of all the parameters were done using the diabetic inhibitor drug, Glipizide. Pharmacokinetic studies of the compounds such as Aloins, Capparisine, Funiculosin and Rhein exhibited less toxicity on various levels of the body. As a conclusion these ligands can lay a foundation for a better anti-diabetic therapy. Abbreviations AhG - Anti hyperglycaemic, CADD - Computer Aided Drug Designing. PMID:23275719

Anti hyperglycaemic study of natural inhibitors for Insulin receptor.

PubMed

Chatterjee, Subhojyoti; Narasimhaiah, Akshaya Lakshmi; Kundu, Sanjay; Anand, Santosh

2012-01-01

Diabetes is a metabolic disorder associated with either improper functioning of the beta-cells or wherein cells fail to use insulin properly. Insulin, the principal hormone regulates uptake of glucose from the blood into most of the cells except central nervous system. Therefore, deficiency of insulin or the insensitivity of its receptors plays a key role in all forms of diabetes. In the present work, attempt has been made to find out plant sources which show anti hyperglycaemic activity (AhG) (i.e. compounds that bring down the blood glucose level in the body). Ayurvedic plants showing AhG activity formed the basis of our study by using the platform of Computer Aided Drug Designing (CADD). Among 600 plants showing AhG activity, 500 compounds were selected and screened, out of which 243 compounds showed drug likeness property that can be used as therapeutic ligand/drug. Initial screening of such compounds was done based on their drug likeness or biochemical properties. Dynamic interaction of these molecules was captured through Protein-Ligand study. It also gave an insight of the binding pockets involved. Bench marking of all the parameters were done using the diabetic inhibitor drug, Glipizide. Pharmacokinetic studies of the compounds such as Aloins, Capparisine, Funiculosin and Rhein exhibited less toxicity on various levels of the body. As a conclusion these ligands can lay a foundation for a better anti-diabetic therapy. AhG - Anti hyperglycaemic, CADD - Computer Aided Drug Designing.

Rationale and trial design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON).

PubMed

de Zeeuw, Dick; Akizawa, Tadao; Agarwal, Rajiv; Audhya, Paul; Bakris, George L; Chin, Melanie; Krauth, Melissa; Lambers Heerspink, Hiddo J; Meyer, Colin J; McMurray, John J; Parving, Hans-Henrik; Pergola, Pablo E; Remuzzi, Giuseppe; Toto, Robert D; Vaziri, Nosratola D; Wanner, Christoph; Warnock, David G; Wittes, Janet; Chertow, Glenn M

2013-01-01

Chronic kidney disease (CKD) associated with type 2 diabetes mellitus constitutes a global epidemic complicated by considerable renal and cardiovascular morbidity and mortality, despite the provision of inhibitors of the renin-angiotensin-aldosterone system (RAAS). Bardoxolone methyl, a synthetic triterpenoid that reduces oxidative stress and inflammation through Nrf2 activation and inhibition of NF-κB was previously shown to increase estimated glomerular filtration rate (eGFR) in patients with CKD associated with type 2 diabetes mellitus. To date, no antioxidant or anti-inflammatory therapy has proved successful at slowing the progression of CKD. Herein, we describe the design of Bardoxolone Methyl Evaluation in Patients with Chronic Kidney Disease and Type 2 Diabetes: the Occurrence of Renal Events (BEACON) trial, a multinational, multicenter, double-blind, randomized, placebo-controlled Phase 3 trial designed to determine whether long-term administration of bardoxolone methyl (on a background of standard therapy, including RAAS inhibitors) safely reduces renal and cardiac morbidity and mortality. The primary composite endpoint is time-to-first occurrence of either end-stage renal disease or cardiovascular death. Secondary endpoints include the change in eGFR and time to occurrence of cardiovascular events. BEACON will be the first event-driven trial to evaluate the effect of an oral antioxidant and anti-inflammatory drug in advanced CKD. Copyright © 2013 S. Karger AG, Basel.

Metformin: an old but still the best treatment for type 2 diabetes

PubMed Central

2013-01-01

The management of T2DM requires aggressive treatment to achieve glycemic and cardiovascular risk factor goals. In this setting, metformin, an old and widely accepted first line agent, stands out not only for its antihyperglycemic properties but also for its effects beyond glycemic control such as improvements in endothelial dysfunction, hemostasis and oxidative stress, insulin resistance, lipid profiles, and fat redistribution. These properties may have contributed to the decrease of adverse cardiovascular outcomes otherwise not attributable to metformin’s mere antihyperglycemic effects. Several other classes of oral antidiabetic agents have been recently launched, introducing the need to evaluate the role of metformin as initial therapy and in combination with these newer drugs. There is increasing evidence from in vivo and in vitro studies supporting its anti-proliferative role in cancer and possibly a neuroprotective effect. Metformin’s negligible risk of hypoglycemia in monotherapy and few drug interactions of clinical relevance give this drug a high safety profile. The tolerability of metformin may be improved by using an appropiate dose titration, starting with low doses, so that side-effects can be minimized or by switching to an extended release form. We reviewed the role of metformin in the treatment of patients with type 2 diabetes and describe the additional benefits beyond its glycemic effect. We also discuss its potential role for a variety of insulin resistant and pre-diabetic states, obesity, metabolic abnormalities associated with HIV disease, gestational diabetes, cancer, and neuroprotection. PMID:23415113

New Therapeutic Approaches in Diabetic Retinopathy

PubMed Central

Vaziri, Kamyar; Schwartz, Stephen G.; Relhan, Nidhi; Kishor, Krishna S.; Flynn Jr, Harry W.

2015-01-01

Diabetic retinopathy is a common microvascular complication of diabetes mellitus. It affects a substantial proportion of US adults over age 40. The condition is a leading cause of visual loss. Much attention has been given to expanding the role of current treatments along with investigating various novel therapies and drug delivery methods. In the treatment of diabetic macular edema (DME), intravitreal pharmacotherapies, especially anti-vascular endothelial growth factor (anti-VEGF) agents, have gained popularity. Currently, anti-VEGF agents are often used as first-line agents in center-involved DME, with recent data suggesting that among these agents, aflibercept leads to better visual outcomes in patients with worse baseline visual acuities. While photocoagulation remains the standard treatment for proliferative diabetic retinopathy (PDR), recent FDA approvals of ranibizumab and aflibercept in the management of diabetic retinopathy associated with DME may suggest a potential for pharmacologic treatments of PDR as well. Novel therapies, including small interfering RNAs, chemokines, kallikrein-kinin inhibitors, and various anti-angiogenic agents, are currently being evaluated for the management of diabetic retinopathy and DME. In addition to these strategies, novel drug delivery methods such as sustained-release implants and refillable reservoir implants are either under active evaluation or have recently gained FDA approval. This review provides an update on the novel developments in the treatment of diabetic retinopathy. PMID:26676668

Thiazolidine-2,4-dione derivatives: programmed chemical weapons for key protein targets of various pathological conditions.

PubMed

Chadha, Navriti; Bahia, Malkeet Singh; Kaur, Maninder; Silakari, Om

2015-07-01

Thiazolidine-2,4-dione is an extensively explored heterocyclic nucleus for designing of novel agents implicated for a wide variety of pathophysiological conditions, that is, diabetes, diabetic complications, cancer, arthritis, inflammation, microbial infection, and melanoma, etc. The current paradigm of drug development has shifted to the structure-based drug design, since high-throughput screenings have continued to generate disappointing results. The gap between hit generation and drug establishment can be narrowed down by investigation of ligand interactions with its receptor protein. Therefore, it would always be highly beneficial to gain knowledge of molecular level interactions between specific protein target and developed ligands; since this information can be maneuvered to design new molecules with improved protein fitting. Thus, considering this aspect, we have corroborated the information about molecular (target) level implementations of thiazolidine-2,4-diones (TZD) derivatives having therapeutic implementations such as, but not limited to, anti-diabetic (glitazones), anti-cancer, anti-arthritic, anti-inflammatory, anti-oxidant and anti-microbial, etc. The structure based SAR of TZD derivatives for various protein targets would serve as a benchmark for the alteration of existing ligands to design new ones with better binding interactions. Copyright © 2015 Elsevier Ltd. All rights reserved.

The Interaction of Anti-diabetic α-Glucosidase Inhibitors and Gut Bacteria α-Glucosidase.

PubMed

Tan, Kemin; Tesar, Christine; Wilton, Rosemarie; Jedrzejczak, Robert P; Joachimiak, Andrzej

2018-05-15

Carbohydrate hydrolyzing α-glucosidases are commonly found in microorganisms present in the human intestine microbiome. We have previously reported crystal structures of an α-glucosidase from the human gut bacterium Blaubia (Ruminococcus) obeum (Ro-αG1) and its substrate preference/specificity switch. This novel member of the GH31 family is a structural homolog of human intestinal maltase-glucoamylase (MGAM) and sucrase-isomaltase (SI) with a highly conserved active site that is predicted to be common in Ro-αG1 homologs among other species that colonize the human gut. In this report, we present structures of Ro-αG1 in complex with the anti-diabetic α-glucosidase inhibitors voglibose, miglitol and acarbose and supporting binding data. The in vitro binding of these anti-diabetic drugs to Ro-αG1 suggests the potential for unintended in vivo cross-reaction of the α-glucosidase inhibitors to bacterial α-glucosidases that are present in gut microorganism communities. Moreover, analysis of these drug-bound enzyme structures could benefit further anti-diabetic drug development. This article is protected by copyright. All rights reserved. © 2018 The Protein Society.

Assessment of Knowledge of Self Blood Glucose Monitoring and Extent of Self Titration of Anti-Diabetic Drugs among Diabetes Mellitus Patients - A Cross Sectional, Community Based Study.

PubMed

Krishnan, V; Thirunavukkarasu, J

2016-03-01

Self blood glucose monitoring is an important context of self care in the management of diabetes mellitus. All the guidelines must be followed while performing self blood glucose monitoring and tracking of values is essential to facilitate the physician while titrating the drugs and /or doses of anti diabetes medication. Self titration by patients following self monitoring must be discouraged. To assess the knowledge and practice of self blood glucose monitoring among diabetes patients and extent of self titration of anti diabetes medicines among diabetes patients based on self blood glucose monitoring. This pilot, cross-sectional, observational study was conducted using a validated questionnaire among adult male and female diabetes patients performing self blood glucose monitoring at home. Diabetes patients with complications and juvenile diabetes patients were excluded. Out of 153 patients surveyed, only 37 (24.1%) (20 males, 17 females) patients were aware and have been following self blood glucose monitoring appropriately. About 116 (75.8%) (64 males, 52 females) of patients were devoid of adequate knowledge and did not practice self blood glucose monitoring in a proper way. Ninety eight (64.05%) accepted that they self titrate their anti diabetic medicines based on self monitoring. Self monitoring of blood glucose should be encouraged and patients should be taught importance of following correct steps and tracking of self monitoring by physician or diabetes educator.

Comparing anti-hyperglycemic activity and acute oral toxicity of three different trivalent chromium complexes in mice.

PubMed

Li, Fang; Wu, Xiangyang; Zou, Yanmin; Zhao, Ting; Zhang, Min; Feng, Weiwei; Yang, Liuqing

2012-05-01

Three different ligands (rutin, folate and stachyose) of chromium(III) complexes were compared to examine whether they have similar effect on anti-hyperglycemic activity as well as the acute toxicity status. Anti-hyperglycemic activities of chromium rutin complex (CrRC), chromium folate complex (CrFC) and chromium stachyose complex (CrSC) were examined in alloxan-induced diabetic mice with daily oral gavage for a period of 2 weeks at the dose of 0.5-3.0 mg Cr/kg. Acute toxicities of CrRC and CrFC were tested using ICR mice at the dose of 1.0-5.0 g/kg with a single oral gavage and observed for a period of 2 weeks. Biological activities results indicated that only CrRC and CrFC could decrease blood glucose level, reduce the activities of aspartate transaminase, alanine transaminase, alkaline phosphatase, and increase liver glycogen level. In acute toxicity study, LD(50) values for both CrRC and CrFC were above 5.0 g/kg. The minimum lethal dose for CrFC was above 5.0 g/kg, while that for CrRC was 1.0 g/kg. Anti-diabetic activity of those chromium complexes was not similar and their acute toxicities were also different. CrFC represent an optimal chromium supplement among those chromium complexes with potential therapeutic value to control blood glucose in diabetes and non-toxicity in acute toxicity. Copyright © 2012 Elsevier Ltd. All rights reserved.

Anti-diabetic potential of peptides: Future prospects as therapeutic agents.

PubMed

Marya; Khan, Haroon; Nabavi, Seyed Mohammad; Habtemariam, Solomon

2018-01-15

Diabetes mellitus is a metabolic disorder in which the glucose level in blood exceeds beyond the normal level. Persistent hyperglycemia leads to diabetes late complication and obviously account for a large number of morbidity and mortality worldwide. Numerous therapeutic options are available for the treatment of diabetes including insulin for type I and oral tablets for type II, but its effective management is still a dream. To date, several options are under investigation in various research laboratories for efficacious and safer agents. Of them, peptides are currently amongst the most widely investigated potential therapeutic agents whose design and optimal uses are under development. A number of natural and synthetic peptides have so far been found with outstanding antidiabetic effect mediated through diverse mechanisms. The applications of new emerging techniques and drug delivery systems further offer opportunities to achieve the desired target outcomes. Some outstanding peptides in preclinical and clinical studies with better efficacy and safety profile have already been identified. Further detail studies on these peptides may therefore lead to significant clinically useful antidiabetic agents. Copyright © 2017. Published by Elsevier Inc.

[A 50-year history of new drugs in Japan-the development and progress of anti-diabetic drugs and the epidemiological aspects of diabetes mellitus].

PubMed

Ozawa, Hikaru; Murai, Yuriko; Ozawa, Terutaka

2003-01-01

The development and progress of antidiabetic drugs (e.g., insulin preparations and hypoglycemic drugs) are retrospectively investigated in Japan. Their influences on the treatment of diabetes mellitus (DM) and its epidemiological aspects are also discussed. 1) Insulin preparations: Insulin was introduced for DM therapy in 1925, two or three years after its discovery in Canada. The preparations were raw extracts of bovine or porcine pancreas. These did not prevail widely in Japan because of the low incidence of DM before World Wan II. After the war, a shortage of mammalian materials compelled the use of fish pancreatic tissues such as bonito and/or tuna for insulin production. Insulin infection, so-called regular insulin, was first promoted in the 6th "Pharmacopoeia Japonica" (JP6) in 1951 and has been maintained to the present edition (JP14, 2001). Although depot-type insulin preparations were developed in the USA and Europe during the war, the introduction of those preparations to Japan was delayed until 1951, when Protamine zinc insulin appeared. Globin zinc insulin and Isophane insulin were introduced for clinical use in 1952 and 1955, respectively. These were also adopted for JP7 (1961). Biphasic-type insulin, which has a rapid onset and long duration of activity, appeared in 1965. Purified preparations from bovine or porcine sources have been available since 1980, which might be a strong reason for the decrease in insulin allergy. Insulin from animal origin has been supplied for almost 60 years since its discovery. Amino acid sequences of insulins from various species of animals were determined by the pioneering studies of Sanger and his associates. Human insulin, which differs from porcine insulin by only one amino acid, was produced by Novo researchers in 1982 using a semi-synthetic method. Then the Lilly group soon succeeded in obtaining human insulin by recombinant DNA technology in the same year. Both products were introduced to Japan in 1985, and the recombinant products prevailed throughout the 1990s. Human insulin analogues (i.e., Insulin lispro and Insulin aspart) appeared in 2001. These are applied for after-meal glycosmia owing to their ultrarapid onset of activity. Self-injection by DM patients was legalized in 1981. To make the infection technique sure and easy, cartridge (pen-type) and disposable kit-type needles were devised in the 1990s. 2) Oral hypoglycemic drugs: Instead of the exclusive parenteral usage of insulins, there was also demand for oral dosage forms. The first of the sulfonyrlurea (SU) group, BZ-55, was used for DM clinically in 1955 in Germany. But it was soon withdrawn because of its antibacterial action. This led to the development of various SU groups. Tolbutamide (1956), chlorpropamide (1959), acetohexamide (1964) and tolazamide (1961) were introduced to Japan as first-generation SUs. Then glyclopyramide (Kyorin, 1965), glybenclamide (1971), gliclazide (1984) and glimepiride (1999) appeared as the second-generation SUs. These were used orally for Type 2 diabetes. Biguanide (BG) group, phenformin HC1 (1959), metformin HC1 (1961) and buformin HC1 (1961) had also been in use by oral treatment of Type 2 diabetes. SU appears to act by increasing the sensitivity of b-cells, which secrete insulin. BG probably exerts by increasing glucose transport across the membranes of target organs. 3) New types of antidiabetic drugs: a-Glucosidase inhibitors (i.e., acarbose: Bayer, 1993; and voglibose: Takeda, 1994) act on hyperglycemia after meals by decreasing glucose absorption. Thiazolidinedione compounds, such as troglitazone (Sankyo, 1995) and pioglitazone HC1 (Takeda, 1994) act by increasing the insulin sensitivity of the target tissues. These are useful for Type 2 DM patients when SUs are ineffective. Nevertheless, troglitazone was discontinued in 2000 due to severe liver damage. Nateglinide (Ajinomoto Co., 1999), which is a D-phenylalanine derivative acting similar to SUs, is useful orally for after-meal hyperglycemia of Type 2 diabetes. Epalrestat (Ono Yakuhin Co., 1992) is effective for diabetic neuropathy by reducing the formation of sorbitol. These anti-DM drugs were recently studied and developed in Japan. 4) The Japan Diabetes Society proposed a guideline on diagnostic criteria and treatment of diabetes mellitus (DM) in 1999 and revised it in 2002. DM is classified as insulin-dependent DM (Type l) and non-insulin dependent DM (Type 2). Type 1, juvenile onset DM, requires insulin therapy to prevent ketosis and to sustain life. Treatment of type 2, adult onset DM, is recommended as a step-by-step method, starting with dietary-exercise therapy, followed by oral hypoglycemic drugs and then insulin therapy. DM patients with complications should have a therapy devised to match their circumstances. 5) Epidemiological aspects: The mortality rate of DM compared to the time of drug appearance was traced from 1920 to 2000. The curve goes down slowly in the time frame of World War II, but rises from 1950 to 1970. The elevation could not be suppressed by the appearance of SUs, BGs or improved insulin preparations. The curve runs flat from 1980 to 1990, which might be related to the use of purified insulin or human insulin therapy. The mortality rate of DM indicates that death by hyperglycemic coma and other deaths resulting from complications are excluded. The survey of the principal cause of death by DM during the period of 1981-1990 indicates that the death rate due to hyperglycemic coma is only 1.7% of the total deaths caused by DM. The effect of drug therapy on all of the death resulting from DM is not detected. Hospital visitation and admission rates of the DM patients have been recorded since 1952 in Japan. This curve is rising continuously, and none of the antidiabetic drugs has been able to suppress it. These data show that the antidiabetic drugs relieve DM symptoms through their effective hypoglycemic actions, but that they cannot suppress the mortality rate of DM. It is possible that none of the drugs currently available can suppress the increasing tendency of DM patients.

Cardiovascular effects of anti-diabetes drugs

PubMed Central

Younk, Lisa M.; Lamos, Elizabeth M.

2016-01-01

Introduction Cardiovascular disease remains the major contributor to morbidity and mortality in diabetes. From the need to reduce cardiovascular risk in diabetes and to ensure that such risk is not exacerbated by drug treatments, governmental regulators and drug manufacturers have focused on clinical trials evaluating cardiovascular outcomes. Areas covered Findings from mechanistic and clinical trials of biguanides, sulfonylureas, thiazolidinediones, dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists, and sodium-glucose transporter 2 (SGLT-2) inhibitors will be reviewed. These drug classes will be compared within the context of available cardiovascular outcomes data. Clinical implications of new study regulations will be examined. Expert opinion Recent cardiovascular studies provide a more comprehensive evaluation of specific anti-diabetes therapy in individuals with high cardiovascular risk. Long-term effects of anti-hyperglycemic agents in patients with lower cardiovascular risk are still speculative. Historical data supports continued use of metformin as a first-line agent. DPP-4 inhibitors and GLP-1 receptor agonists appear to have neutral effects on cardiovascular outcomes. The significantly decreased cardiovascular risk associated with empagliflozin SGLT-2 inhibitor therapy is impressive and may change how practitioners prescribe add-on therapy to metformin. PMID:27268470

The complexities of obesity, diabetes, and the development and progression of pancreatic cancer

PubMed Central

Bao, Bin; Wang, Zhiwei; Li, Yiwei; Kong, Dejuan; Ali, Shadan; Banerjee, Sanjeev; Ahmad, Aamir; Sarkar, Fazlul H.

2011-01-01

Pancreatic cancer (PC) is one of the most lethal malignant diseases with the worst prognosis. It is ranked as the fourth leading cause of cancer-related deaths in the United States. Many risk factors have been associated with PC. Interestingly, large numbers of epidemiological studies suggest that obesity and diabetes, especially type-2 diabetes, are positively associated with increased risk of PC. Similarly, these chronic diseases (obesity, diabetes and cancer) are also a major public health concern. In the U.S. population, 50 percent are overweight, 30 percent are medically obese and 10 percent have diabetes mellitus (DM). Therefore, obesity and DM have been considered as potential risk factors for cancers; however, the focus of this article is restricted to PC. Although the mechanisms responsible for the development of these chronic diseases leading to the development of PC are not fully understood, the biological importance of the activation of insulin, insulin like growth factor-1 (IGF-1) and its receptor (IGF-1R) signaling pathways in insulin resistance mechanism and subsequent induction of compensatory hyperinsulinemia has been proposed. Therefore, targeting insulin/IGF-1 signaling with anti-diabetic drugs for lowering blood insulin levels and reversal of insulin-resistance could be useful strategy for the prevention and/or treatment of PC. A large number of studies have demonstrated that the administration of anti-diabetic drugs such as metformin and thiazolidinediones (TZD) class of PPAR-γ agonists decreases the risk of cancers, suggesting that these agents might be useful anti-tumor agents for the treatment of PC. In this review article, we will discuss the potential roles of metformin and TZD anti-diabetic drugs as anti-tumor agents in the context of PC, and will further discuss the complexities and the possible roles of microRNAs (miRNAs) in the pathogenesis of obesity, diabetes and PC. PMID:21129444

Anti-diabetic medications and risk of primary liver cancer in persons with type II diabetes.

PubMed

Hagberg, K W; McGlynn, K A; Sahasrabuddhe, V V; Jick, S

2014-10-28

Type II diabetes increases liver cancer risk but the risk may be mitigated by anti-diabetic medications. However, choice of medications is correlated with diabetes duration and severity, leading to confounding by indication. To address this association, we conducted a nested case-control study among persons with type II diabetes in the Clinical Practice Research Datalink. Cases had primary liver cancer and controls were matched on age, sex, practice, calendar time, and number of years in the database. Exposure was classified by type and combination of anti-diabetic prescribed and compared to non-use. Odds ratios (ORs) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression. In 305 cases of liver cancer and 1151 controls, there was no association between liver cancer and anti-diabetic medication use compared to non-use (OR=0.74 (95% CI=0.45-1.20) for metformin-only, 1.10 (95% CI=0.66-1.84) for other oral hypoglycaemic (OH)-only, 0.89 (95% CI=0.58-1.37) for metformin+other OH, 1.11 (95% CI=0.60-2.05) for metformin+insulin, 0.81 (95% CI=0.23-2.85) for other OH+insulin, and 0.72 (95% CI=0.18-2.84) for insulin-only). Stratification by duration of diabetes did not alter the results. Use of any anti-diabetic medications in patients with type II diabetes was not associated with liver cancer, though there was a suggestion of a small protective effect for metformin.

42 CFR 414.701 - Purpose.

Code of Federal Regulations, 2013 CFR

2013-10-01

...; statutorily covered drugs, for example, influenza, pneumococcal and hepatitis vaccines, antigens, hemophilia blood clotting factor, immunosuppressive drugs and certain oral anti-cancer drugs. ...

42 CFR 414.701 - Purpose.

Code of Federal Regulations, 2014 CFR

2014-10-01

...; statutorily covered drugs, for example, influenza, pneumococcal and hepatitis vaccines, antigens, hemophilia blood clotting factor, immunosuppressive drugs and certain oral anti-cancer drugs. ...

42 CFR 414.701 - Purpose.

Code of Federal Regulations, 2012 CFR

2012-10-01

...; statutorily covered drugs, for example, influenza, pneumococcal and hepatitis vaccines, antigens, hemophilia blood clotting factor, immunosuppressive drugs and certain oral anti-cancer drugs. ...

Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery.

PubMed

Date, Abhijit A; Vador, Nimish; Jagtap, Aarti; Nagarsenker, Mangal S

2011-07-08

To evaluate the ability of Gelucire 50/13 (an amphiphilic lipid excipient) to act as a stabilizer for lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and to establish the ability of Gelucire 50/13 based lipid nanocarriers to improve oral delivery of hydrophobic drugs using repaglinide (RPG) as a model drug. The ability of Gelucire 50/13 to nanosize various solid lipids was evaluated. The ability of Gelucire 50/13 to yield NLC was evaluated by using Precirol ATO 5 as a model solid lipid and various liquid lipids (oils). Gelucire 50/13 based NLC (GeluPearl) were evaluated for their ability to improve the efficacy of RPG on oral administration in comparison to RPG tablets. The short term stability of RPG-GeluPearl was evaluated at 25 °C/60% RH. Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month.

Lipid nanocarriers (GeluPearl) containing amphiphilic lipid Gelucire 50/13 as a novel stabilizer: fabrication, characterization and evaluation for oral drug delivery

NASA Astrophysics Data System (ADS)

Date, Abhijit A.; Vador, Nimish; Jagtap, Aarti; Nagarsenker, Mangal S.

2011-07-01

Purpose. To evaluate the ability of Gelucire 50/13 (an amphiphilic lipid excipient) to act as a stabilizer for lipid nanocarriers such as solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) and to establish the ability of Gelucire 50/13 based lipid nanocarriers to improve oral delivery of hydrophobic drugs using repaglinide (RPG) as a model drug. Methods. The ability of Gelucire 50/13 to nanosize various solid lipids was evaluated. The ability of Gelucire 50/13 to yield NLC was evaluated by using Precirol ATO 5 as a model solid lipid and various liquid lipids (oils). Gelucire 50/13 based NLC (GeluPearl) were evaluated for their ability to improve the efficacy of RPG on oral administration in comparison to RPG tablets. The short term stability of RPG-GeluPearl was evaluated at 25 °C/60% RH. Results. Gelucire 50/13 could successfully yield SLN and NLC of various solid lipids, demonstrating its potential to act as a novel stabilizer. DSC studies indicated that Gelucire 50/13 interacts with Precirol ATO 5 and this interaction suppresses polymorphic transitions of both the components. RPG-GeluPearl exhibited significantly higher anti-diabetic activity compared to marketed RPG tablets. RPG-GeluPearl demonstrated good colloidal and chemical stability at the end of 1 month. Indian patent application number 2167/MUM/2008.

Insulin sparing action of adenovirus 36 and its E4orf1 protein.

PubMed

Dhurandhar, Nikhil V

2013-01-01

Additional drugs are required to effectively manage diabetes and its complications. Recent studies have revealed protective effects of Ad36, a human adenovirus, and its E4orf1 protein on glucose disposal, which may be creatively harnessed to develop novel anti-diabetic agents. Experimental Ad36 infection improves hyperglycemia in animal models and natural Ad36 infection in humans is associated with better glycemic control. Available data indicate distinctive advantages for a drug that may mimic the action of Ad36/E4orf1. The key features of such a potential drug include the ability to increase glucose uptake by adipose tissue and skeletal muscle, to reduce hepatic glucose output independent of proximal insulin signaling, and to up-regulate adiponectin and its hepatic action. The effect of Ad36/E4orf1 on hepatocyte metabolism suggests a role for treating hepatic steatosis. Despite these potential advantages, considerable research is required before such a drug is developed. The in vivo efficacy and safety of E4orf1 in improving hyperglycemia remain unknown, and an appropriate drug delivery system is required. Nonetheless, Ad36 E4orf1 offers a research opportunity to develop a new anti-diabetic agent with multiple potential advantages and conceptually advances the use of a rather unconventional source, microbial proteins, for anti-diabetic drug development. Copyright © 2013 Elsevier Inc. All rights reserved.

Anti-diabetic and anti-inflammatory effect of a novel selective 11β-HSD1 inhibitor in the diet-induced obese mice.

PubMed

Park, Sung Bum; Jung, Won Hoon; Kang, Nam Sook; Park, Ji Seon; Bae, Gyu Hwan; Kim, Hee Youn; Rhee, Sang Dal; Kang, Seung Kyu; Ahn, Jin Hee; Jeong, Hye Gwang; Kim, Ki Young

2013-12-05

It has been reported that the selective inhibitors of 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) have considerable potential for treating type 2 diabetes mellitus, metabolic syndrome and inflammation. In the present study, we investigated the anti-diabetic and anti-inflammatory effects of N-(5-carbamoyladamantan-2-yl)-3-((2-fluorophenyl) sulfonyl)thiazolidine-2-carboxamide (KR-67105), a novel 11β-HSD1 inhibitor, in diabetic mice model and preadipocyte model. KR-67105 concentration dependently inhibited 11β-HSD1 activity in human and mouse 11β-HSD1 overexpressing cells and mouse 3T3-L1 adipocytes. Furthermore, KR-67105 concentration-dependently inhibited 11β-HSD1 activity in the ex vivo assay of C57BL/6 mice. In the study with diet-induced obese (DIO) mice, the administration of KR-67105 (100mg/kg/day, orally for 28 days) improved the glucose tolerance and insulin sensitivity as determined by the oral glucose tolerance test and the insulin tolerance test. Anti-diabetic effect by KR-67105 was associated with the suppression of diabetic related genes expression in liver and fat. Furthermore, KR-67105 suppressed 11β-HSD1 activity in liver and fat of diabetic mice, but showed no effect on adrenal grand weight/body weight ratio and plasma corticosterone concentration in diabetic mice. In 3T3-L1 preadipocytes, cortisone induced the mRNA of inflammatory cytokines and 11β-HSD1 and reactive oxygen species formation. This effect was abolished by co-incubation with KR-67105 in a concentration-dependent manner. Moreover, KR-67105 attenuated cortisone induced iNOS expression and phosphorylation of NF-κB p65, p38 MAPK, and ERK1/2 in preadipocytes. Taken together, it is concluded that a selective 11β-HSD1 inhibitor, KR-67105, may provide a new therapeutic window in the prevention and treatment of type 2 diabetes with chronic inflammation without toxicity. © 2013 Elsevier B.V. All rights reserved.

Identification of trans-tiliroside as active principle with anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects from Potentilla chinesis.

PubMed

Qiao, Wei; Zhao, Chuan; Qin, Nan; Zhai, Hui Yuan; Duan, Hong Quan

2011-05-17

The present study was carried out to isolate and identify trans-tiliroside as principal compound with anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects from Potentilla chinesis. A bioactive compound, trans-tiliroside was isolated from the ethanol extract of Potentilla chinesis and its administration dose was optimized and patented. The normal, alloxan-induced diabetic mice and streptozotocin-induced diabetic rats were used to evaluate the anti-hyperglycemic, anti-hyperlipidemic and antioxidant effects of trans-tiliroside from Potentilla chinesis. Biochemical parameters were assayed in blood samples of different groups of alloxan-induced diabetic mice and streptozotocin-induced diabetic rats. The level of fasting serum glucose levels, triglycerides (TG) and total cholesterol (TC) in alloxan-induced diabetic mice were significantly decrease after daily oral administration of trans-tiliroside in normal and diabetic mice at doses of 0.4, 0.8 and 1.6 mg/kg/day, for 15 days. Blood glucose level was significant decrease in STZ induced diabetic rats by trans-tiliroside (1.2 and 0.3mg/kg body weight for 10 weeks). The content of TC, low density lipoprotein (LDL-C) and TG levels were decreased and high density lipoprotein (HDL-C) content was increased, so lipid metabolism was improved. Moreover, trans-tiliroside revealed antioxidant activity as shown by increased activities of superoxide dismutase (SOD), decreased level of malondialdehyde (MDA) in diabetic rats. Histological morphology examination showed that the trans-tiliroside restored the damage of pancreas tissues in rats with diabetes mellitus. Trans-tiliroside, a constituent from Potentilla chinesis, revealed significant anti-hyperglycemic, anti-hyperlipidemic and antioxidant activities. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Application of Raman spectroscopy in type 2 diabetes screening in blood using leucine and isoleucine amino-acids as biomarkers and in comparative anti-diabetic drugs efficacy studies.

PubMed

Birech, Zephania; Mwangi, Peter Waweru; Bukachi, Fredrick; Mandela, Keith Makori

2017-01-01

Diabetes is an irreversible condition characterized by elevated blood glucose levels. Currently, there are no predictive biomarkers for this disease and the existing ones such as hemoglobin A1c and fasting blood glucose are used only when diabetes symptoms are noticed. The objective of this work was first to explore the potential of leucine and isoleucine amino acids as diabetes type 2 biomarkers using their Raman spectroscopic signatures. Secondly, we wanted to explore whether Raman spectroscopy can be applied in comparative efficacy studies between commercially available anti-diabetic drug pioglitazone and the locally used anti-diabetic herbal extract Momordica spinosa (Gilg.)Chiov. Sprague Dawley (SD) rat's blood was used and were pipetted onto Raman substrates prepared from conductive silver paste smeared glass slides. Prominent Raman bands associated with glucose (926, 1302, 1125 cm-1), leucine (1106, 1248, 1302, 1395 cm-1) and isolecucine (1108, 1248, 1437 and 1585 cm-1) were observed. The Raman bands centered at 1125 cm-1, 1395 cm-1 and 1437 cm-1 associated respectively to glucose, leucine and isoleucine were chosen as biomarker Raman peaks for diabetes type 2. These Raman bands displayed decreased intensities in blood from diabetic SD rats administered antidiabetic drugs pioglitazone and herbal extract Momordica spinosa (Gilg.)Chiov. The intensity decrease indicated reduced concentration levels of the respective biomarker molecules: glucose (1125 cm-1), leucine (1395 cm-1) and isoleucine (1437 cm-1) in blood. The results displayed the power and potential of Raman spectroscopy in rapid (10 seconds) diabetes and pre-diabetes screening in blood (human or rat's) with not only glucose acting as a biomarker but also leucine and isoleucine amino-acids where intensities of respectively assigned bands act as references. It also showed that using Raman spectroscopic signatures of the chosen biomarkers, the method can be an alternative for performing comparative efficacy studies between known and new anti-diabetic drugs. Reports on use of Raman spectroscopy in type 2 diabetes mellitus screening with Raman bands associated with leucine and isoleucine molecules acting as reference is rare in literature. The use of Raman spectroscopy in pre-diabetes screening of blood for changes in levels of leucine and isoleucine amino acids is particularly interesting as once elevated levels are noticed, necessary interventions to prevent diabetes development can be initiated.

Disordered haematopoiesis and athero-thrombosis

PubMed Central

Murphy, Andrew J.; Tall, Alan R.

2016-01-01

Abstract Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium arteries. Increased production and activation of monocytes, neutrophils, and platelets, driven by hypercholesterolaemia and defective high-density lipoproteins-mediated cholesterol efflux, tissue necrosis and cytokine production after myocardial infarction, or metabolic abnormalities associated with diabetes, contribute to atherogenesis and athero-thrombosis. This suggests that in addition to traditional approaches of low-density lipoproteins lowering and anti-platelet drugs, therapies directed at abnormal haematopoiesis, including anti-inflammatory agents, drugs that suppress myelopoiesis, and excessive platelet production, rHDL infusions and anti-obesity and anti-diabetic agents, may help to prevent athero-thrombosis. PMID:26869607

Effect of strawberry (Fragaria × ananassa) leaf extract on diabetic nephropathy in rats

PubMed Central

Ibrahim, Doaa S; Abd El-Maksoud, Marwa A E

2015-01-01

Diabetic nephropathy is a clinical syndrome characterized by albuminuria, hypertension and progressive renal insufficiency. The aim of this study was to investigate the effect of strawberry (Fragaria × ananassa) leaf extract on diabetic nephropathy in rats. Streptozotocin (STZ) diabetic rats were orally treated with three doses (50, 100 and 200 mg/kg) of strawberry leaf extract for 30 days. Nephropathy biomarkers in plasma and kidney were examined at the end of the experiment. The three doses of strawberry leaf extract significantly decreased the levels of blood glucose, urea nitrogen, plasma creatinine, kidney injury molecule (Kim)-1, renal malondialdehyde (MDA), tumour necrosis factor alpha (TNF-α), interleukin (IL)- 6 and caspase-3 in diabetic rats. Meanwhile, the levels of plasma insulin, albumin, uric acid, renal catalase (CAT), superoxide dismutase (SOD) and vascular endothelial growth factor A (VEGF-A) were significantly elevated in diabetic rats treated with strawberry leaf extract. These results indicate the role of strawberry leaves extract as anti-diabetic, antioxidant, anti-inflammatory and anti-apoptosis in diabetic nephropathy. PMID:25645466

Designing Decision Support System to Detect Drug Interactions Type 2 Diabetes

PubMed Central

Rasoolimoghadam, Mehdi; Safdari, Reza; Ghazisaeidi, Marjan; Maharanitehrani, MohammadReza; Tahmasebiyan, Shahram

2015-01-01

Background and Aim: Type II Diabetes is the most common diseases of metabolic disorders and the treatment of oral anti-diabetic drug use takes place But The problem of using multi-drug and interactions at the same time is an issue that has always been a major challenge And diagnosis of drug interactions, particularly in Diabetic patients due to the problem with the disease is very important. The purpose of this studying is, to design a clinical assistant decided to use this approach to determine the type II diabetes drug interactions this makes it easy for those who are active in the field. Materials and Methods: Study is Developmental that to determine the content of the system a self-made checklist was used. Checklist Validity and reliability has been confirmed by four professors. The Research community to determine the content of the system was country endocrine that are 124 people. The sample size was calculated using Cochran that was 57 people. The Score of checklist was calculated in SPSS version 20 .finally, the checklist was approved by at least 70% points. The system by using Microsoft SQL server 2008 and visual Studio 2012 development environment was designed in C#.net. In the end, In order to evaluate the software to determine the level of satisfaction, usability and ease of use, designed systems sharing with all Medical Informatics students of Tehran University of Medical Sciences. For this purpose a self-made questionnaire was used. Questionnaire Validity has been confirmed by four professors and reliability was assessed by Cronbach method. Results: The results of the survey are showing that the majority of students found out and believed the software is useful and easy to use and generally expressed their satisfaction software. Conclusions: The methodology provides a suitable approach for analysis and modeling of data in the medical field and the performance is good. PMID:26862240

Drug-Induced Hyperglycaemia and Diabetes.

PubMed

Fathallah, Neila; Slim, Raoudha; Larif, Sofien; Hmouda, Houssem; Ben Salem, Chaker

2015-12-01

Drug-induced hyperglycaemia and diabetes is a global issue. It may be a serious problem, as it increases the risk of microvascular and macrovascular complications, infections, metabolic coma and even death. Drugs may induce hyperglycaemia through a variety of mechanisms, including alterations in insulin secretion and sensitivity, direct cytotoxic effects on pancreatic cells and increases in glucose production. Antihypertensive drugs are not equally implicated in increasing serum glucose levels. Glycaemic adverse events occur more frequently with thiazide diuretics and with certain beta-blocking agents than with calcium-channel blockers and inhibitors of the renin-angiotensin system. Lipid-modifying agents may also induce hyperglycaemia, and the diabetogenic effect seems to differ between the different types and daily doses of statins. Nicotinic acid may also alter glycaemic control. Among the anti-infectives, severe life-threatening events have been reported with fluoroquinolones, especially when high doses are used. Protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors have been reported to induce alterations in glucose metabolism. Pentamidine-induced hyperglycaemia seems to be related to direct dysfunction in pancreatic cells. Phenytoin and valproic acid may also induce hyperglycaemia. The mechanisms of second-generation antipsychotic-associated hyperglycaemia, diabetes mellitus and ketoacidosis are complex and are mainly due to insulin resistance. Antidepressant agents with high daily doses seem to be more frequently associated with an increased risk of diabetes. Ketoacidosis may occur in patients receiving beta-adrenergic stimulants, and theophylline may also induce hyperglycaemia. Steroid diabetes is more frequently associated with high doses of glucocorticoids. Some chemotherapeutic agents carry a higher risk of hyperglycaemia, and calcineurin inhibitor-induced hyperglycaemia is mainly due to a decrease in insulin secretion. Hyperglycaemia has been associated with oral contraceptives containing high doses of oestrogen. Growth hormone therapy and somatostatin analogues may also induce hyperglycaemia. Clinicians should be aware of medications that may alter glycaemia. Efforts should be made to identify and closely monitor patients receiving drugs that are known to induce hyperglycaemia.

Designing Decision Support System to Detect Drug Interactions Type 2 Diabetes.

PubMed

Rasoolimoghadam, Mehdi; Safdari, Reza; Ghazisaeidi, Marjan; Maharanitehrani, MohammadReza; Tahmasebiyan, Shahram

2015-12-01

Type II Diabetes is the most common diseases of metabolic disorders and the treatment of oral anti-diabetic drug use takes place But The problem of using multi-drug and interactions at the same time is an issue that has always been a major challenge And diagnosis of drug interactions, particularly in Diabetic patients due to the problem with the disease is very important. The purpose of this studying is, to design a clinical assistant decided to use this approach to determine the type II diabetes drug interactions this makes it easy for those who are active in the field. Study is Developmental that to determine the content of the system a self-made checklist was used. Checklist Validity and reliability has been confirmed by four professors. The Research community to determine the content of the system was country endocrine that are 124 people. The sample size was calculated using Cochran that was 57 people. The Score of checklist was calculated in SPSS version 20 .finally, the checklist was approved by at least 70% points. The system by using Microsoft SQL server 2008 and visual Studio 2012 development environment was designed in C#.net. In the end, In order to evaluate the software to determine the level of satisfaction, usability and ease of use, designed systems sharing with all Medical Informatics students of Tehran University of Medical Sciences. For this purpose a self-made questionnaire was used. Questionnaire Validity has been confirmed by four professors and reliability was assessed by Cronbach method. The results of the survey are showing that the majority of students found out and believed the software is useful and easy to use and generally expressed their satisfaction software. The methodology provides a suitable approach for analysis and modeling of data in the medical field and the performance is good.

Comparative Long-Term Effect of Three Anti-P2Y12 Drugs after Percutaneous Angioplasty: An Observational Study Based on Electronic Drug Adherence Monitoring

PubMed Central

Forni Ogna, Valentina; Bassi, Isabelle; Menetrey, Isabelle; Muller, Olivier; Tousset, Eric; Fontana, Pierre; Eeckhout, Eric; Eap, Chin B.; Vrijens, Bernard; Burnier, Michel; Wuerzner, Grégoire

2017-01-01

Aims: Dual platelet inhibition using anti-P2Y12 drugs and aspirin is the standard of care in patients after percutaneous coronary interventions (PCI). Prasugrel and ticagrelor have been shown to be more potent than clopidogrel with less high on-treatment platelet reactivity. Whether differences in long-term adherence to these drugs can partly explain different antiplatelet efficacy has not been studied so far. The objective was to compare the long-term P2Y12 receptor inhibition and drug adherence to different anti-P2Y12 drugs, and to assess the impact of adherence on the pharmacodynamic effect. Methods: Monocentric, prospective, observational study. Stable outpatients treated with clopidogrel 75 mg once daily, prasugrel 10 mg once daily or ticagrelor 90 mg twice daily after PCI with stent implantation were included. Drug adherence was recorded during 6 months using electronic monitoring. Platelet responsiveness was assessed with the vasodilator-stimulated phosphoprotein platelet reactivity index (VASP-PRI) at inclusion, 3 and 6 months. Results: 120 patients had VASP-PRI and adherence data available. At 6-months, mean VASP-PRI (±SD) was 17.7 ± 11.0% with ticagrelor, 29.2 ± 15.5% with prasugrel and 47.2 ± 17.6% with clopidogrel (ANOVA, P < 0.0001). Median [IQR] taking adherence was 96 [82–100]% with ticagrelor, 100 [97–101]% with prasugrel and 100 [99–101]% with clopidogrel (p = 0.0001). Median [IQR] correct dosing was 88 [73–95]% with ticagrelor, 97 [92.5–98]% with prasugrel and 98 [96–99]% with clopidogrel (p = 0.0001). Anti-P2Y12 drug (p ≤ 0.001) and diabetes (p = 0.014) emerged as predictors of poor antiplatelet response after adjusting for age, BMI, sex, and CYP2C19∗2 carriers status. Conclusion: Drug adherence to anti-P2Y12 drugs assessed with electronic monitoring was very high. However, anti-P2Y12 drugs showed significant differences in antiplatelet activity, with newer anti-P2Y12 drugs ticagrelor and prasugrel exerting a stronger P2Y12 receptor inhibition. These data suggest that pharmacokinetic-pharmacodynamic differences between oral anti-P2Y12 drugs are more important than adherence in determining antiplatelet efficacy when adherence to prescription is high. The study was registered (Current Controlled Trials ISRCTN85949729). PMID:29118712

Biomarkers in Diabetic Retinopathy

PubMed Central

Jenkins, Alicia J.; Joglekar, Mugdha V.; Hardikar, Anandwardhan A.; Keech, Anthony C.; O'Neal, David N.; Januszewski, Andrzej S.

2015-01-01

There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy. PMID:26676667

Biomarkers in Diabetic Retinopathy.

PubMed

Jenkins, Alicia J; Joglekar, Mugdha V; Hardikar, Anandwardhan A; Keech, Anthony C; O'Neal, David N; Januszewski, Andrzej S

2015-01-01

There is a global diabetes epidemic correlating with an increase in obesity. This coincidence may lead to a rise in the prevalence of type 2 diabetes. There is also an as yet unexplained increase in the incidence of type 1 diabetes, which is not related to adiposity. Whilst improved diabetes care has substantially improved diabetes outcomes, the disease remains a common cause of working age adult-onset blindness. Diabetic retinopathy is the most frequently occurring complication of diabetes; it is greatly feared by many diabetes patients. There are multiple risk factors and markers for the onset and progression of diabetic retinopathy, yet residual risk remains. Screening for diabetic retinopathy is recommended to facilitate early detection and treatment. Common biomarkers of diabetic retinopathy and its risk in clinical practice today relate to the visualization of the retinal vasculature and measures of glycemia, lipids, blood pressure, body weight, smoking, and pregnancy status. Greater knowledge of novel biomarkers and mediators of diabetic retinopathy, such as those related to inflammation and angiogenesis, has contributed to the development of additional therapeutics, in particular for late-stage retinopathy, including intra-ocular corticosteroids and intravitreal vascular endothelial growth factor inhibitors ('anti-VEGFs') agents. Unfortunately, in spite of a range of treatments (including laser photocoagulation, intraocular steroids, and anti-VEGF agents, and more recently oral fenofibrate, a PPAR-alpha agonist lipid-lowering drug), many patients with diabetic retinopathy do not respond well to current therapeutics. Therefore, more effective treatments for diabetic retinopathy are necessary. New analytical techniques, in particular those related to molecular markers, are accelerating progress in diabetic retinopathy research. Given the increasing incidence and prevalence of diabetes, and the limited capacity of healthcare systems to screen and treat diabetic retinopathy, there is need to reliably identify and triage people with diabetes. Biomarkers may facilitate a better understanding of diabetic retinopathy, and contribute to the development of novel treatments and new clinical strategies to prevent vision loss in people with diabetes. This article reviews key aspects related to biomarker research, and focuses on some specific biomarkers relevant to diabetic retinopathy.

Safety and efficacy of skin patches containing loxoprofen sodium in diabetic patients with overt nephropathy.

PubMed

Araki, Hisazumi; Kuwagata, Shogo; Soumura, Mariko; Yamahara, Kosuke; Morita, Yoshikata; Kume, Shinji; Isshiki, Keiji; Araki, Shin-ichi; Kashiwagi, Atsunori; Maegawa, Hiroshi; Uzu, Takashi

2014-06-01

Because oral nonsteroidal anti-inflammatory drugs (NSAIDs) have adverse effects on kidney function, patients with kidney diseases are administered these drugs as transdermal patches. Little is known about the effects of NSAID patches on renal function. We therefore assessed the effects of topical loxoprofen sodium on kidney function in type 2 diabetic patients with overt nephropathy. Twenty patients with type 2 diabetes and overt proteinuria and with knee and/or low back pain were treated with skin patches containing 100 mg loxoprofen on the knee or back for 24 h per day for 5 consecutive days. The degree of pain was assessed using a visual analogue scale (VAS). Blood and 24-h urine samples were obtained at baseline and at the end of the study. Glomerular filtration rate (GFR) was estimated from serum creatinine and cystatin C concentrations. The 20 patients consisted of 11 males and 9 females, of mean age 61.6 ± 13.9 years. Loxoprofen-containing patches significantly reduced VAS pain without affecting blood pressure, GFR or urinary prostaglandin E2 concentration. Serum concentrations of loxoprofen and its active trans-OH metabolite did not correlate with GFR. Loxoprofen-containing patches do not affect renal function in type 2 diabetic patients with overt nephropathy over a short-term period. Long-term studies are needed to clarify the safety of loxoprofen-containing patches in patients with chronic kidney diseases.

Drug repurposing: In-vitro anti-glycation properties of 18 common drugs

PubMed Central

Rasheed, Saima; Sánchez, Sara S.; Yousuf, Sammer; Honoré, Stella M.; Choudhary, M. Iqbal

2018-01-01

Drug repositioning or repurposing, i.e. identifying new indications for existing drugs, has gained increasing attention in the recent years. This approach enables the scientists to discover “new targets” for known drugs in a cost and time efficient manner. Glycation, the non-enzymatic reaction of sugars with proteins or nucleic acids to form early glycation (Amadori or fructosamine) products, is a key molecular basis of diabetic complications. Inhibiting the process of non-enzymatic protein glycation is one of the key strategies to prevent glycation-mediated diabetic complications. The present study focuses on the anti-glycation activity of 18 drugs, commonly used for the treatment of gastrointestinal, central nervous system, inflammatory diseases, bacterial infections, and gout. This study was carried out by using two in-vitro protein anti-glycation assay models. Results revealed that nimesulide (3), a non-steroidal anti-inflammatory drug, possesses a good anti-glycation activity in in-vitro BSA-MG and BSA-glucose glycation models with IC50 values of 330.56 ± 2.90, and 145.46 ± 16.35 μM, respectively. Phloroglucinol dihydrate (11), a drug used for the treatment of gastrointestinal diseases, showed a weak activity in BSA-MG glycation model (IC50 = 654.89 ± 2.50 μM), while it showed a good activity in BSA-glucose assay (IC50 = 148.23 ± 0.15 μM). Trimethylphloroglucinol (9), a drug used for the treatment of pain related to functional disorders of the digestive and biliary tracts, also showed a good antiglycation activity in BSA-MG model (IC50 = 321.15 ± 1.26 μM), while it was found to be inactive in in-vitro BSA-glucose assay (IC50 = 12.95% inhibition). These activities of drugs were compared with the anti-glycation activity of the standard, rutin (IC50 = 294.5 ± 1.50 μM in BSA-MG glycation model, and IC50 = 86.94 ± 0.24 μM in BSA- glucose model). Rest of the drugs exhibited a relatively weak antiglycation activity. This study identifies nimesulide (3), and phloroglucinol dihydrate (11) as new inhibitors of in-vitro protein glycation for further investigations as potential anti-diabetic agents. PMID:29300762

Natural Phyto-Bioactive Compounds for the Treatment of Type 2 Diabetes: Inflammation as a Target

PubMed Central

Gothai, Sivapragasam; Ganesan, Palanivel; Park, Shin-Young; Fakurazi, Sharida; Choi, Dong-Kug; Arulselvan, Palanisamy

2016-01-01

Diabetes is a metabolic, endocrine disorder which is characterized by hyperglycemia and glucose intolerance due to insulin resistance. Extensive research has confirmed that inflammation is closely involved in the pathogenesis of diabetes and its complications. Patients with diabetes display typical features of an inflammatory process characterized by the presence of cytokines, immune cell infiltration, impaired function and tissue destruction. Numerous anti-diabetic drugs are often prescribed to diabetic patients, to reduce the risk of diabetes through modulation of inflammation. However, those anti-diabetic drugs are often not successful as a result of side effects; therefore, researchers are searching for efficient natural therapeutic targets with less or no side effects. Natural products’ derived bioactive molecules have been proven to improve insulin resistance and associated complications through suppression of inflammatory signaling pathways. In this review article, we described the extraction, isolation and identification of bioactive compounds and its molecular mechanisms in the prevention of diabetes associated complications. PMID:27527213

Comparative Efficacy and Acceptability of Anti-Diabetic Agents for Alzheimer's Disease and Mild Cognitive Impairment: A Systematic Review and Network Meta-analysis.

PubMed

Cao, Bing; Rosenblat, Joshua D; Brietzke, Elisa; Park, Caroline; Lee, Yena; Musial, Natalie; Pan, Zihang; Mansur, Rodrigo B; McIntyre, Roger S

2018-05-23

The current meta-analysis compares the efficacy (i.e., pro-cognitive effects) and acceptability of anti-diabetic agents for Alzheimer's disease (AD) and mild cognitive impairment (MCI). Cochrane Library (CENTRAL), PubMed/MEDLINE, EMBASE and PsycINFO were searched from inception to January 15, 2018 for randomized controlled trials (RCTs) comparing anti-diabetic agents with placebo and/or another active anti-diabetic agent for the treatment of AD or MCI. Nineteen eligible studies (n = 4,855) evaluating the effects of six different anti-diabetic drugs (i.e., intranasal insulin, pioglitazone, rosiglitazone, metformin, sitagliptin and liraglutide) were included. The results of 29 pairwise comparisons indicated that cognition was significantly improved in subjects treated with anti-diabetic agents compared to placebo. Pioglitazone 15-30 mg demonstrated the greatest efficacy compared to placebo in network meta-analysis. No significant differences in acceptability were identified when comparing agents with each other and with placebo. The current findings indicate a pro-cognitive class effect of anti-diabetic agents in AD/MCI. Other anti-diabetic agents should also be investigated in future studies. This study is registered with PROSPERO (CRD42018085967). This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Anti-depressant effect of hesperidin in diabetic rats.

PubMed

El-Marasy, Salma A; Abdallah, Heba M I; El-Shenawy, Siham M; El-Khatib, Aiman S; El-Shabrawy, Osama A; Kenawy, Sanaa A

2014-11-01

This study aimed to investigate the anti-depressant effect of hesperidin (Hsp) in streptozotocin (STZ)-induced diabetic rats. Additionally, the effect of Hsp on hyperglycaemia, oxidative stress, inflammation, brain-derived neurotrophic factor (BDNF), and brain monoamines in diabetic rats was also assessed. The Wistar rats in the experimental groups were rendered hyperglycaemic with a single dose of STZ (52.5 mg·(kg body mass)(-1), by intraperitoneal injection). The normal group received the vehicle only. Hyperglycaemic rats were treated with Hsp (25.0, 50.0, or 100.0 mg·(kg body mass)(-1)·day(-1), per oral) and fluoxetine (Flu) (5.0 mg·(kg body mass)(-1)·day(-1), per oral) 48 h after the STZ injection, for 21 consecutive days. The normal and STZ control groups received the vehicle (distilled water). Behavioral and biochemical parameters were then assessed. When Hsp was administered to the STZ-treated rats, this reversed the STZ-induced increase in immobility duration in the forced swimming test (FST) and attenuated hyperglycaemia, decreased malondialdehyde (MDA), increased reduced glutathione (GSH) decreased interleukin-6 (IL-6), and increased BDNF levels in the brain. Treatment with Hsp attenuated STZ-induced neurochemical alterations, as indicated by increased levels of monoamines in the brain, namely, norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine; 5-HT). All of these effects of Hsp were similar to those observed with the established anti-depressant Flu. This study shows that Hsp exerted anti-depressant effect in diabetic rats, which may have been partly mediated by its amelioration of hyperglycaemia as well as its anti-oxidant and anti-inflammatory activities, the enhancement of neurogenesis, and changes in the levels of monoamines in the brain.

Novel pharmacotherapies in diabetic retinopathy: Current status and what's in the horizon?

PubMed Central

Das, Arup; McGuire, Paul G; Monickaraj, Finny

2016-01-01

The blood–retinal barrier (BRB) alteration is the hallmark feature of diabetic retinopathy. Vascular endothelial growth factor (VEGF) is a potent vasopermeability factor that has been implicated in the pathogenesis of BRB alteration. Inflammation also plays a crucial role in this process with involvement of several chemokines and cytokines. Multiple anti-VEGF drugs are widely used as in the treatment of diabetic macular edema (DME) as well as proliferative diabetic retinopathy. Several clinical trials have proved the beneficial effects of these drugs in improvement of vision and prevention of vision loss. However, the response to anti-VEGF drugs in DME is not complete in a significant number of patients. The effect seems transient in this latter group, and many patients do not show complete resolution of fluid. Potential novel therapies targeting molecules beyond VEGF are being developed and examined in clinical trials. PMID:26953018

Incidence of Depression and Associated Factors in Patients With Type 2 Diabetes in Quebec, Canada: A Population-Based Cohort Study.

PubMed

Lunghi, Carlotta; Moisan, Jocelyne; Grégoire, Jean-Pierre; Guénette, Line

2016-05-01

It has been reported that the risk of depression is higher among people with type 2 diabetes compared with a nondiabetic population. Among diabetic patients, depression has been associated with worse self-care behaviors, poor glycemic control, and an increased risk of diabetes complications. Identifying factors associated with the occurrence of depression may help physicians identify earlier diabetic patients at a high risk of developing depression, improve prevention, and accelerate proper treatment. To our knowledge, very few population-based studies have reported on the incidence of clinically diagnosed depression as a consequence of type 2 diabetes over a long follow-up period. The objective of this study was to estimate the incidence of clinically diagnosed depression among type 2 diabetic patients newly treated with oral antidiabetic drugs (ADs) and to identify factors associated with the occurrence of depression.Administrative claims data from the public health insurance plan were used to identify a cohort of new oral AD users aged ≥18 years between 2000 and 2006. Patients were followed from oral AD treatment initiation until the diagnosis of depression, ineligibility for the public drug plan, death, or the end of the study, whichever came first. Incidence rates were determined using person-time analysis. Factors associated with depression were identified using multivariable Cox regression analysis.We identified 114,366 new oral AD users, of which 4808 had a diagnosis of depression. The overall incidence rate of depression was 9.47/1000 person-years (PYs) (10.72/1000 PYs for women and 8.27/1000 PYs for men). The incidence of depression was higher during the year after oral AD treatment initiation. Independent factors associated with depression included having had mental disorders other than depression, hospitalization, a higher number of different drugs taken and of physicians visited during the year before oral AD initiation. Moreover, we observed a statistically significant age-by-socioeconomic status interaction.The incidence of diagnosed depression is higher during the first year after oral AD treatment initiation. Clinicians could pay particular attention to women, patients starting an AD at a young age, those with a low socioeconomic status, and especially those with a history of anxiety or dementia.

Compound 49b Reduces Inflammatory Markers and Apoptosis after Ocular Blast Injury

DTIC Science & Technology

2014-09-01

drug, Compound 49b, have anti-apoptotic and anti-inflammatory properties in retinal endothelial cells and in a diabetic retinopathy model [7, 10...plays an important role in the development of early diabetic retinopathy and long-term histopathological alterations. Mol Vis, 2009; 15: 1418-28. 12...in other retinal damage models, specifically the streptozotocin- induced type 1 diabetic retinopathy model and retinal endothelial cells cultured in

Argpyrimidine-tagged rutin-encapsulated biocompatible (ethylene glycol dimers) nanoparticles: Synthesis, characterization and evaluation for targeted drug delivery.

PubMed

Bhattacherjee, Abhishek; Dhara, Kaliprasanna; Chakraborti, Abhay Sankar

2016-07-25

Diabetes mellitus represents a major metabolic disorder affecting millions of people all over the world. Currently available therapeutic treatments are not good enough to control the long-term complications of diabetes. Active targeting via inclusion of a specific ligand on the nanoparticles provides effective therapeutic approach in different diseases. However, such specific drug delivery systems have not been explored much in diabetes due to lack of suitable biological targets in this disorder. Our objective is to synthesize a ligand-tagged drug-loaded nanoparticle for delivery of the drug at specific sites to enhance its therapeutic efficiency in diabetic condition. The nanoparticles have been prepared by using biocompatible ethylene glycol-bis (succinic acid N-hydroxysuccinimide ester) dimers. Although advanced glycation end products (AGEs) are the root causes of diabetic complications, argpyrimidine, an AGE, possesses antioxidant and reducing activities. AGE interacts selectively with its cell surface receptors (RAGE), which are significantly increased in diabetic condition. We have selected RAGE as the target of argpyrimidine, which is tagged on the nanoparticles as a ligand. Rutin, having anti-hyperglycemic and anti-glycating activities, has been used for nanoencapsulation. Rutin-loaded argpyrimidine-tagged nanoparticles have been synthesized and characterized. We have demonstrated the drug releasing capacity and target specificity of the synthesised drug delivery system under ex vivo and in vivo conditions. Copyright © 2016 Elsevier B.V. All rights reserved.

Anti-diabetic effect of pyroglutamic acid in type 2 diabetic Goto-Kakizaki rats and KK-Ay mice.

PubMed

Yoshinari, Orie; Igarashi, Kiharu

2011-10-01

With the rapidly increasing prevalence of type 2 diabetes mellitus (T2DM), specific dietary components with anti-diabetic efficacy could be one strategy with therapeutic potential. In the present study, the anti-diabetic effects of an amino acid, pyroglutamic acid (PA), found in vegetables and fruits were investigated in T2DM models using Goto-Kakizaki (GK) rats and KK-Ay mice by measuring glucose tolerance and other markers of diabetes. Moreover, the effect of PA on gene expression in GK rats was measured by DNA microarray analysis. Oral glucose tolerance and serum insulin levels were reduced by PA in both animal models. Serum and liver total cholesterol levels were also improved by PA. Expression of genes involved with gluconeogenesis and those involved with its related transcription factor were down-regulated by feeding PA. In KK-Ay mice, the glucokinase:glucose-6-phosphatase (G6Pase) activity ratio increased. From these results, it is suggested that dietary PA beneficially modifies glucose and lipid metabolism in diabetic animals, and can potentially contribute to the mitigation of T2DM.

Dental caries and salivary alterations in Type I Diabetes.

PubMed

Rai, K; Hegde, A M; Kamath, A; Shetty, S

2011-01-01

Insulin dependent diabetes mellitus is a severe disease that raises blood glucose levels because of hyperglycemia and insulinopenia. Fluctuations in water and electrolyte levels may result in xerostomia and other changes in the salivary composition. Since diabetes has an influence on oral health, it is important for the dentist to be aware of newer advances in the field of diabetes and to recognize specific oral problems related to diabetes. Thus, the dentist becomes an important part of the health care team for the patients with diabetes. The present study correlated salivary flow rate, salivary pH and total salivary antioxidant levels and dental caries in type I diabetic patients. A total of 200 children that included 100 known diabetic children (study group) and 100 healthy children (controls) of both the sexes and from similar socioeconomic backgrounds formed the part of this study. Dental caries was assessed using DMFT index. The salivary total anti-oxidant level was estimated using phospho molybdic acid using spectrophotometric method. The salivary flow rate was recorded using the Zunt method and the salivary pH using the pH indicating paper. The results were statistically analyzed using t-test. The analyzed parameters showed increase in salivary anti-oxidant levels, reduced salivary flow rate, increase incidence of dental caries, salivary pH was decreased when compared to the control group.

Repaglinide: a review of its use in type 2 diabetes mellitus.

PubMed

Scott, Lesley J

2012-01-22

Oral repaglinide (GlucoNorm®; NovoNorm®; Prandin®; Surepost®) is a rapid-acting insulin secretagogue that lowers postprandial glucose (PPG) excursions by targeting early-phase insulin release, with reductions in PPG considered to be important in reducing long-term cardiovascular complications of diabetes mellitus. Repaglinide, a carbamoylbenzoic acid derivative, is chemically related to the meglitinide class of insulin secretagogues, but unrelated to the sulfonylurea insulin secretagogues. Meglitinides, including repaglinide, have a distinct binding site at the β-cell membrane, which differs from that of sulfonylureas, and corresponds to greater insulinotropic effects with repaglinide than with glibenclamide and/or glimepiride and a more rapid onset of action in in vitro and in vivo studies. This article reviews the clinical efficacy and tolerability of oral repaglinide in the treatment of patients with type 2 diabetes and provides an overview of its pharmacological properties. In well designed clinical trials of up to 52 weeks' duration and in the clinical practice setting, recommended dosages of repaglinide (0.5-4 mg three times daily up to 30 minutes prior to a meal) provided effective glycaemic control and were generally well tolerated in treatment-naive or -experienced adult patients with type 2 diabetes, including elderly patients and those with renal impairment. Furthermore, as monotherapy or in combination with other oral antihyperglycaemic drugs, repaglinide was at least as effective as other oral antihyperglycaemic drugs at improving or maintaining glycaemic control, with a tolerability profile that was generally similar to that of sulfonylurea drugs and nateglinide. Thus, repaglinide remains an effective option for the management of patients with type 2 diabetes.

Effects of Gymnema sylvestre extract on the pharmacokinetics and pharmacodynamics of glimepiride in streptozotocin induced diabetic rats.

PubMed

Kamble, Bhagyashree; Gupta, Ankur; Moothedath, Ismail; Khatal, Laxman; Janrao, Shirish; Jadhav, Amol; Duraiswamy, B

2016-02-05

Gymnema sylvestre, important Indian traditional herbal medicine has been used for diabetes from several years and marketed as single or multi-herb formulations globally. People are consuming G. sylvestre along with conventional hypoglycemic drugs. Therefore, there is need of evidence based assessment of risk versus benefits when G. sylvestre co-administered with conventional oral hypoglycemic drugs. In present investigation, pharmacodynamics and pharmacokinetic interactions with oral hypoglycemic drug, glimepiride (GLM) was studied in streptozotocin (STZ) induced diabetic rats. A specific and rapid HPLC-ESI-MS/MS method was established for simultaneous quantification of GLM and gymnemagenin (GMG) in rat plasma. Pharmacokinetic and pharmacodynamic interaction studies were carried out in STZ induced diabetic rats after concomitant administration of 400 mg/kg of G. sylvestre extract and 0.8 mg/kg of GLM for 28 days. The developed HPLC-ESI-MS/MS method was rapid, specific, and precise. Con-comitant oral administration of G. sylvestre extract (400 mg/kg) and GLM (0.8 mg/kg) in diabetic rats for 28 days showed beneficial pharmacodynamic interactions whereas no major alterations in the pharmacokinetics parameters of GLM and GMG were observed. This interaction demonstrated in animal model implies that significant clinical outcome might occur during concomitant administration of G. sylvestre extract and GLM especially in diabetic patients and warrants further studies in the same set up. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Rapid identification of illegal synthetic adulterants in herbal anti-diabetic medicines using near infrared spectroscopy

NASA Astrophysics Data System (ADS)

Feng, Yanchun; Lei, Deqing; Hu, Changqin

We created a rapid detection procedure for identifying herbal medicines illegally adulterated with synthetic drugs using near infrared spectroscopy. This procedure includes a reverse correlation coefficient method (RCCM) and comparison of characteristic peaks. Moreover, we made improvements to the RCCM based on new strategies for threshold settings. Any tested herbal medicine must meet two criteria to be identified with our procedure as adulterated. First, the correlation coefficient between the tested sample and the reference must be greater than the RCCM threshold. Next, the NIR spectrum of the tested sample must contain the same characteristic peaks as the reference. In this study, four pure synthetic anti-diabetic drugs (i.e., metformin, gliclazide, glibenclamide and glimepiride), 174 batches of laboratory samples and 127 batches of herbal anti-diabetic medicines were used to construct and validate the procedure. The accuracy of this procedure was greater than 80%. Our data suggest that this protocol is a rapid screening tool to identify synthetic drug adulterants in herbal medicines on the market.

Sodium glucose CoTransporter 2 (SGLT2) inhibitors: Current status and future perspective.

PubMed

Madaan, Tushar; Akhtar, Mohd; Najmi, Abul Kalam

2016-10-10

Diabetes mellitus is a disease that affects millions of people worldwide and its prevalence is estimated to rise in the future. Billions of dollars are spent each year around the world in health expenditure related to diabetes. There are several anti-diabetic drugs in the market for the treatment of non-insulin dependent diabetes mellitus. In this article, we will be talking about a relatively new class of anti-diabetic drugs called sodium glucose co-transporter 2 (SGLT2) inhibitors. This class of drugs has a unique mechanism of action focusing on inhibition of glucose reabsorption that separates it from other classes. This article covers the mechanism of glucose reabsorption in the kidneys, the mechanism of action of SGLT2 inhibitors, several SGLT2 inhibitors currently available in the market as well as those in various phases of development, their individual pharmacokinetics as well as the discussion about the future role of SGLT2 inhibitors, not only for the treatment of diabetes, but also for various other diseases like obesity, hepatic steatosis, and cardiovascular disorders. Copyright © 2016 Elsevier B.V. All rights reserved.

SGLT2 inhibitors: a promising new therapeutic option for treatment of type 2 diabetes mellitus.

PubMed

Misra, Monika

2013-03-01

Hyperglycemia is an important pathogenic component in the development of microvascular and macrovascular complications in type 2 diabetes mellitus. Inhibition of renal tubular glucose reabsorption that leads to glycosuria has been proposed as a new mechanism to attain normoglycemia and thus prevent and diminish these complications. Sodium glucose cotransporter 2 (SGLT2) has a key role in reabsorption of glucose in kidney. Competitive inhibitors of SGLT2 have been discovered and a few of them have also been advanced in clinical trials for the treatment of diabetes. To discuss the therapeutic potential of SGLT2 inhibitors currently in clinical development. A number of preclinical and clinical studies of SGLT2 inhibitors have demonstrated a good safety profile and beneficial effects in lowering plasma glucose levels, diminishing glucotoxicity, improving glycemic control and reducing weight in diabetes. Of all the SGLT2 inhibitors, dapagliflozin is a relatively advanced compound with regards to clinical development. SGLT2 inhibitors are emerging as a promising therapeutic option for the treatment of diabetes. Their unique mechanism of action offers them the potential to be used in combination with other oral anti-diabetic drugs as well as with insulin. © 2012 The Author. JPP © 2012 Royal Pharmaceutical Society.

Synergistic effects of acarbose and an Oroxylum indicum seed extract in streptozotocin and high-fat-diet induced prediabetic mice.

PubMed

Sun, Wenlong; Sang, Yuanbin; Zhang, Bowei; Yu, Xiaoxia; Xu, Qinmin; Xiu, Zhilong; Dong, Yuesheng

2017-03-01

Prediabetes is defined as blood glucose levels above normal but below diabetes thresholds, and up to 70% of individuals with prediabetes will eventually develop diabetes if left untreated. Acarbose, the first FDA approved anti-prediabetes agent, has some disadvantages, such as reducing the risk of diabetes by only 36%, side effects and limited effects on complications. The aim of this study is to develop a new agent to treat prediabetes and to investigate the anti-prediabetes effects and mechanisms of acarbose and an Oroxylum indicum seed extract (OISE) in prediabetic mice. The combined drugs can reduce the dose of acarbose by 80% and reduce the risk of diabetes by 75%, which is one fold higher than acarbose monotherapy. The combined drugs showed synergistic anti-prediabetes effects and could be effective in preventing the complications of prediabetes. The combined drugs could improve glucose tolerance, improve lipid metabolism and reduce oxidative stress and tissue damage. For the mechanisms, the combined drugs can reduce synergistically postprandial hyperglycaemia by inhibiting α-glucosidase. Furthermore, baicalein in OISE was demonstrated to be a major component in reducing oxidative stress and chrysin was the primary compound that activated PPARγ. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Glycemic control parameters in insulin-naïve patients with uncontrolled type 2 diabetes referred to endocrinologists, and degree of implementation of the national Spanish consensus for the management of hyperglycemia.

PubMed

Azriel, Sharona; Casal, Florentino; Dalama, Belén; Varillas, Francisco; Villarroel, África; Soto, Alfonso; Barberá, Gloria

2014-12-01

To assess blood glucose in patients with uncontrolled type 2 diabetes mellitus treated with oral antidiabetic drugs in primary care at the time of referral to specialized endocrinologists, and the degree of implementation of the national consensus guidelines of the Spanish Society of Diabetes by evaluating steps one (S1), two (S2), and three (S3) of the escalating therapy. Retrospective, observational study where 81 endocrinologists evaluated patients ≥40 years of age referred from primary care between July 2012 and July 2013, treated with 1 to 2 oral antidiabetic drugs but no insulin therapy, and with glycosylated hemoglobin (HbA(1c)) levels ≥6.5%. Patients also had to have HbA(1c) levels and both fasting and postprandial plasma glucose measurements from the previous three months. A total of 285 patients (57.6% males) were assessed. Mean (SD) age was 63.1 (9.7) years, mean HbA1c was 8.5 (1.2) %, mean FPG was 171.7 (43) mg/dL, and mean postprandial plasma glucose was 206.8 (50) mg/dL. In primary care, 26.0% of patients were at S1 and 74.0% were at S2. After referral to the endocrinologist, 9.8% of patients moved onto S1, 42.8% onto S2, and 47.4% onto S3. Oral antidiabetic drugs most commonly prescribed in primary care were metformin (90.2%), DPP-4 inhibitors (34.4%), and sulfonylureas (30.5%), while drugs most commonly used in the specialized endocrinology setting were metformin (86%), insulin (56.8%), and DPP-4 inhibitors (49.8%). The most commonly followed guidelines were those of the American Diabetes Association and the consensus guidelines of the Spanish Society of Diabetes, in 77% and 45% of cases respectively. Approximately half the patients treated with oral antidiabetic drugs in primary care are prescribed insulin after referral to an endocrinology specialist. The most commonly followed guidelines in specialized care are the American Diabetes Association guidelines. Copyright © 2014 SEEN. Published by Elsevier Espana. All rights reserved.

Analyzing the Chinese landscape in anti-diabetic drug research: leading knowledge production institutions and thematic communities.

PubMed

Deng, Junling; Sitou, Kaweng; Zhang, Yongping; Yan, Ru; Hu, Yuanjia

2016-01-01

The discovery of anti-diabetic drugs is an active Chinese medicine research area. This study aims to map out anti-diabetic drug research in China using a network-based systemic approach based on co-authorship of academic publications. We focused on identifying leading knowledge production institutions, analyzing interactions among them, detecting communities with high internal associations, and exploring future research directions. Target articles published in 2009-2013 under the topic "diabetes" and subject category "pharmacology & pharmacy," with "China," "Taiwan," "Hong Kong," or "Macao" (or "Macau") in the authors' address field were retrieved from the science citation index expanded database and their bibliographic information (e.g., article title, authors, keywords, and authors' affiliation addresses) analyzed. A social network approach was used to construct an institutional collaboration network based on co-publications. Gephi software was used to visualize the network and relationships among institutes were analyzed using centrality measurements. Thematic analysis based on article keywords and R sc value was applied to reveal the research hotspots and directions of network communities. The top 50 institutions were identified; these included Shanghai Jiao Tong University, National Taiwan University, Peking University, and China Pharmaceutical University. Institutes from Taiwan tended to cooperate with institutes outside Taiwan, but those from mainland China showed low interest in external collaboration. Fourteen thematic communities were detected with the Louvain algorithm and further labeled by their high-frequency and characteristic keywords, such as Chinese medicines, diabetic complications, oxidative stress, pharmacokinetics, and insulin resistance. The keyword Chinese medicines comprised a range of Chinese medicine-related topics, including berberine, flavonoids, Astragalus polysaccharide, emodin, and ginsenoside. These keywords suggest potential fields for further anti-diabetic drug research. The correlation of -0.641 (P = 0.013) between degree centrality and the R sc value of non-core keywords indicates that communities concentrating on rare research fields are usually isolated by others and have a lower chance of collaboration. With a better understanding of the Chinese landscape in anti-diabetic drug research, researchers and scholars looking for experts and institutions in a specific research area can rapidly spot their target community, then select the most appropriate potential collaborator and suggest preferential research directions for future studies.

Azadirachta indica: A herbal panacea in dentistry – An update

PubMed Central

Lakshmi, T.; Krishnan, Vidya; Rajendran, R; Madhusudhanan, N.

2015-01-01

Azadirachta indica commonly known as Neem, is an evergreen tree. Since time immemorial it has been used by Indian people for treatment of various diseases due to its medicinal properties. It possesses anti-bacterial, anti-cariogenic, anti-helminthic, anti-diabetic, anti-oxidant, astringent, anti-viral, cytotoxic, and anti-inflammatory activity. Nimbidin, Azadirachtin and nimbinin are active compounds present in Neem which are responsible for antibacterial activity. Neem bark is used as an active ingredient in a number of toothpastes and toothpowders. Neem bark has anti-bacterial properties, it is quite useful in dentistry for curing gingival problems and maintaining oral health in a natural way. Neem twigs are used as oral deodorant, toothache reliever and for cleaning of teeth. The objective of this article is to focus on the various aspects of Azadirachta indica in dentistry in order to provide a tool for future research. PMID:26009692

Azadirachta indica: A herbal panacea in dentistry - An update.

PubMed

Lakshmi, T; Krishnan, Vidya; Rajendran, R; Madhusudhanan, N

2015-01-01

Azadirachta indica commonly known as Neem, is an evergreen tree. Since time immemorial it has been used by Indian people for treatment of various diseases due to its medicinal properties. It possesses anti-bacterial, anti-cariogenic, anti-helminthic, anti-diabetic, anti-oxidant, astringent, anti-viral, cytotoxic, and anti-inflammatory activity. Nimbidin, Azadirachtin and nimbinin are active compounds present in Neem which are responsible for antibacterial activity. Neem bark is used as an active ingredient in a number of toothpastes and toothpowders. Neem bark has anti-bacterial properties, it is quite useful in dentistry for curing gingival problems and maintaining oral health in a natural way. Neem twigs are used as oral deodorant, toothache reliever and for cleaning of teeth. The objective of this article is to focus on the various aspects of Azadirachta indica in dentistry in order to provide a tool for future research.

Depression can be prevented by astaxanthin through inhibition of hippocampal inflammation in diabetic mice.

PubMed

Zhou, Xiao-Yan; Zhang, Fang; Hu, Xiao-Tong; Chen, Jing; Tang, Ren-Xian; Zheng, Kui-Yang; Song, Yuan-Jian

2017-02-15

The critical factor considered in a depression induced by diabetes is the inflammation eliciting hippocampal, amygdala and thalamic neuronal injury. Therefore, inhibiting inflammatory reactions in the brain and reducing neuronal injury can alleviate depression in rodents suffering from diabetes mellitus. The oral administration of astaxanthin has been employed in emotional disorders and diabetic complications due to its anti-depressant, anti-inflammatory and anti-apoptotic functions. However, it has not been reported whether astaxanthin can improve diabetes-related depression-like behavior, and its potential mechanisms have not been elucidated. The objective of the present study is to elucidate the effect of astaxanthin on depression in diabetic mice and to understand the underlying molecular mechanisms. In this study, experimental diabetic mice were given a single intraperitoneal injection of streptozotocin (STZ, 150mg/kg, dissolved in citrate buffer) after fasting for 12h. The diabetic model was assessed 72h after STZ injection, and mice with a fasting blood glucose level more than or equal to 16.7mmol/L were used in this study, and oral astaxanthin (25mg/kg) was provided uninterrupted for ten weeks. Depression-like behavior was evaluated by the tail suspension test (TST) and forced swimming test (FST). The glial fibrillary acidic protein (GFAP) and cleaved caspase-3-positive cells were measured by immunohistochemistry, and the western blotting was used to test the protein levels of interleukin-6 (IL-6), interleukin-1β (IL-1β) and cyclooxygenase (COX-2). The results showed that astaxanthin had an anti-depressant effect on diabetic mice. Furthermore, we observed that astaxanthin significantly reduced the number of GFAP-positive cells in the hippocampus and hypothalamus, and also the expression of cleaved caspase-3 in the hippocampus, amygdala and hypothalamus was decreased as well. Moreover, astaxanthin could down-regulate the expression of IL-6, IL-1β and COX-2 in the hippocampus. These findings suggest that the mechanism of astaxanthin in preventing depression in diabetic mice involves the inhibition of inflammation/inflammation inhibition, thereby protecting neurons in hippocampus, amygdala and hypothalamus against hyperglycemic damage. Copyright © 2016 Elsevier B.V. All rights reserved.

A water-soluble extract from cultured medium of Ganoderma lucidum (Reishi) mycelia attenuates the small intestinal injury induced by anti-cancer drugs

PubMed Central

KASHIMOTO, NAOKI; ISHII, SATOMI; MYOJIN, YUKI; USHIJIMA, MITSUYASU; HAYAMA, MINORU; WATANABE, HIROMITSU

2010-01-01

The present study investigated whether a water-soluble extract from the culture medium of Ganoderma lucidum (Reishi) mycelia (MAK) is able to protect the small intestine against damage induced by anti-cancer drugs. Six-week-old male B6C3F1/Crlj mice were fed a basal diet (MF) alone or with various doses of MAK or Agarics blazei Murrill (AGA) beginning one week before treatment with the anti-cancer drugs. Mice were sacrificed 3.5 days after injection of the anti-cancer drug, the small intestine was removed and tissue specimens were examined for the regeneration of small intestinal crypts. In experiment 1, the number of regenerative crypts after the administration of 5-fluorouracil (5FU) intravenously (250 mg/kg) or intraperitoneally (250 or 500 mg/kg) was compared after treatment with MAK or AGA. MAK protected against 5FU-induced small intestinal injury whereas AGA did not. In experiment 2, we investigated the protective effect of MAK against small intestinal injury induced by the anti-cancer drugs: UFT (tegafur with uracil; 1,000 mg/kg, orally), cisplatin (CDDP; 12.5 and 25 mg/kg, intraperitoneally), cyclophosphamide (CPA; 250 mg/kg, orally) and gefitinib (Iressa; 2,000 and 4,000 mg/kg, orally). UFT and CDDP decreased the number of regenerative crypts, but treatment with MAK attenuated the extent of UFT- or CDDP-induced small intestinal injury. CPA or Iressa plus MAK up-regulated crypt regeneration. The present results indicate that MAK ameliorates the small intestinal injury caused by several anti-cancer drugs, suggesting that MAK is a potential preventive agent against this common adverse effect of chemotherapy. PMID:22966257

Hypoglycemic effect of Mucuna pruriens seed extract on normal and streptozotocin-diabetic rats.

PubMed

Bhaskar, Anusha; Vidhya, V G; Ramya, M

2008-12-01

The hypoglycemic effect of the aqueous extract of the seeds of Mucuna pruriens was investigated in normal, glucose load conditions and streptozotocin (STZ)-induced diabetic rats. In normal rats, the aqueous extract of the seeds of Mucuna pririens (100 and 200 mg/kg body weight) significantly (P<0.001) reduced the blood glucose levels after an oral glucose load from 127.5+/-3.2 to 75.6+/-4.8 mg% 2 h after oral administration of seed extract. It also significantly lowered the blood glucose in STZ diabetic rats from 240.5+/-7.2 to 90.6+/-5.6 mg% after 21 days of daily oral administration of the extract (P<0.001). Thus, this study shows that M. pruriens has an anti-hyperglycemic action and it could be a source of hypoglycemic compounds.

Polysaccharide-based micro/nanocarriers for oral colon-targeted drug delivery.

PubMed

Zhang, Lin; Sang, Yuan; Feng, Jing; Li, Zhaoming; Zhao, Aili

2016-08-01

Oral colon-targeted drug delivery has attracted many researchers because of its distinct advantages of increasing the bioavailability of the drug at the target site and reducing the side effects. Polysaccharides that are precisely activated by the physiological environment of the colon hold greater promise for colon targeting. Considerable research efforts have been directed towards developing polysaccharide-based micro/nanocarriers. Types of polysaccharides for colon targeting and in vitro/in vivo assessments of polysaccharide-based carriers for oral colon-targeted drug delivery are summarised. Polysaccharide-based microspheres have gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon (colon cancer, inflammatory bowel disease (IBD), amoebiasis and irritable bowel syndrome (IBS)), but also for it's potential for the delivery of anti-rheumatoid arthritis and anti-chronic stable angina drugs. Besides, Polysaccharide-based micro/nanocarriers such as microbeads, microcapsules, microparticles, nanoparticles, nanogels and nanospheres are also introduced in this review.

Long-term safety and efficacy of a novel once-weekly oral trelagliptin as monotherapy or in combination with an existing oral antidiabetic drug in patients with type 2 diabetes mellitus: A 52-week open-label, phase 3 study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2016-09-01

Trelagliptin is a novel once-weekly oral dipeptidyl peptidase-4 inhibitor for type 2 diabetes mellitus that was first approved in Japan. We evaluated long-term safety and efficacy of trelagliptin in Japanese patients with type 2 diabetes mellitus. This was a phase 3, multicenter, open-label study to evaluate long-term safety and efficacy of trelagliptin. Patients with type 2 diabetes mellitus inadequately controlled despite diet/exercise or treatment with one of the existing oral antidiabetic drugs along with diet/exercise received trelagliptin 100 mg orally once weekly for 52 weeks as monotherapy or combination therapies. The primary end-points were the safety variables, and the secondary end-points were glycosylated hemoglobin and fasting plasma glucose. A total of 680 patients received the following antidiabetic therapies: trelagliptin monotherapy (n = 248), combination with a sulfonylurea (n = 158), a glinide (n = 67), an α-glucosidase inhibitor (n = 65), a biguanide (n = 70), or a thiazolidinedione (n = 72). During the study, 79.8% of the patients experienced at least one adverse event for monotherapy, 87.3% for combination with a sulfonylurea, 77.6% for a glinide, 81.5% for an α-glucosidase inhibitor, 64.3% for a biguanide, and 84.7% for a thiazolidinedione, respectively. Most of the adverse events were mild or moderate. The change in glycosylated hemoglobin from baseline at the end of the treatment period was -0.74 to -0.25% for each therapy. Once-weekly oral trelagliptin provides well-tolerated long-term safety and efficacy in both monotherapy and combination therapies in Japanese patients with type 2 diabetes mellitus. © 2016 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Osteoarthritis guidelines: a progressive role for topical nonsteroidal anti-inflammatory drugs

PubMed Central

Stanos, Steven P

2013-01-01

Current treatment guidelines for the treatment of chronic pain associated with osteoarthritis reflect the collective clinical knowledge of international experts in weighing the benefits of pharmacologic therapy options while striving to minimize the negative effects associated with them. Consideration of disease progression, pattern of flares, level of functional impairment or disability, response to treatment, coexisting conditions such as cardiovascular disease or gastrointestinal disorders, and concomitant prescription medication use should be considered when creating a therapeutic plan for a patient with osteoarthritis. Although topical nonsteroidal anti-inflammatory drugs historically have not been prevalent in many of the guidelines for osteoarthritis treatment, recent evidence-based medicine and new guidelines now support their use as a viable option for the clinician seeking alternatives to typical oral formulations. This article provides a qualitative review of these treatment guidelines and the emerging role of topical nonsteroidal anti-inflammatory drugs as a therapy option for patients with localized symptoms of osteoarthritis who may be at risk for oral nonsteroidal anti-inflammatory drug-related serious adverse events. PMID:23589694

Osteoarthritis guidelines: a progressive role for topical nonsteroidal anti-inflammatory drugs.

PubMed

Stanos, Steven P

2013-01-01

Current treatment guidelines for the treatment of chronic pain associated with osteoarthritis reflect the collective clinical knowledge of international experts in weighing the benefits of pharmacologic therapy options while striving to minimize the negative effects associated with them. Consideration of disease progression, pattern of flares, level of functional impairment or disability, response to treatment, coexisting conditions such as cardiovascular disease or gastrointestinal disorders, and concomitant prescription medication use should be considered when creating a therapeutic plan for a patient with osteoarthritis. Although topical nonsteroidal anti-inflammatory drugs historically have not been prevalent in many of the guidelines for osteoarthritis treatment, recent evidence-based medicine and new guidelines now support their use as a viable option for the clinician seeking alternatives to typical oral formulations. This article provides a qualitative review of these treatment guidelines and the emerging role of topical nonsteroidal anti-inflammatory drugs as a therapy option for patients with localized symptoms of osteoarthritis who may be at risk for oral nonsteroidal anti-inflammatory drug-related serious adverse events.

Application of Raman spectroscopy in type 2 diabetes screening in blood using leucine and isoleucine amino-acids as biomarkers and in comparative anti-diabetic drugs efficacy studies

PubMed Central

Mwangi, Peter Waweru; Bukachi, Fredrick; Mandela, Keith Makori

2017-01-01

Diabetes is an irreversible condition characterized by elevated blood glucose levels. Currently, there are no predictive biomarkers for this disease and the existing ones such as hemoglobin A1c and fasting blood glucose are used only when diabetes symptoms are noticed. The objective of this work was first to explore the potential of leucine and isoleucine amino acids as diabetes type 2 biomarkers using their Raman spectroscopic signatures. Secondly, we wanted to explore whether Raman spectroscopy can be applied in comparative efficacy studies between commercially available anti-diabetic drug pioglitazone and the locally used anti-diabetic herbal extract Momordica spinosa (Gilg.)Chiov. Sprague Dawley (SD) rat’s blood was used and were pipetted onto Raman substrates prepared from conductive silver paste smeared glass slides. Prominent Raman bands associated with glucose (926, 1302, 1125 cm−1), leucine (1106, 1248, 1302, 1395 cm−1) and isolecucine (1108, 1248, 1437 and 1585 cm−1) were observed. The Raman bands centered at 1125 cm−1, 1395 cm−1 and 1437 cm−1 associated respectively to glucose, leucine and isoleucine were chosen as biomarker Raman peaks for diabetes type 2. These Raman bands displayed decreased intensities in blood from diabetic SD rats administered antidiabetic drugs pioglitazone and herbal extract Momordica spinosa (Gilg.)Chiov. The intensity decrease indicated reduced concentration levels of the respective biomarker molecules: glucose (1125 cm−1), leucine (1395 cm−1) and isoleucine (1437 cm−1) in blood. The results displayed the power and potential of Raman spectroscopy in rapid (10 seconds) diabetes and pre-diabetes screening in blood (human or rat’s) with not only glucose acting as a biomarker but also leucine and isoleucine amino-acids where intensities of respectively assigned bands act as references. It also showed that using Raman spectroscopic signatures of the chosen biomarkers, the method can be an alternative for performing comparative efficacy studies between known and new anti-diabetic drugs. Reports on use of Raman spectroscopy in type 2 diabetes mellitus screening with Raman bands associated with leucine and isoleucine molecules acting as reference is rare in literature. The use of Raman spectroscopy in pre-diabetes screening of blood for changes in levels of leucine and isoleucine amino acids is particularly interesting as once elevated levels are noticed, necessary interventions to prevent diabetes development can be initiated. PMID:28926628

Metformin downregulates the insulin/IGF-I signaling pathway and inhibits different uterine serous carcinoma (USC) cells proliferation and migration in p53-dependent or -independent manners.

PubMed

Sarfstein, Rive; Friedman, Yael; Attias-Geva, Zohar; Fishman, Ami; Bruchim, Ilan; Werner, Haim

2013-01-01

Accumulating epidemiological evidence shows that obesity is associated with an increased risk of several types of adult cancers, including endometrial cancer. Chronic hyperinsulinemia, a typical hallmark of diabetes, is one of the leading factors responsible for the obesity-cancer connection. Numerous cellular and circulating factors are involved in the biochemical chain of events leading from hyperinsulinemia and insulin resistance to increased cancer risk and, eventually, tumor development. Metformin is an oral anti-diabetic drug of the biguanide family used for treatment of type 2 diabetes. Recently, metformin was shown to exhibit anti-proliferative effects in ovarian and Type I endometrial cancer, although the mechanisms responsible for this non-classical metformin action remain unclear. The insulin-like growth factors (IGFs) play a prominent role in cancer biology and their mechanisms of action are tightly interconnected with the insulin signaling pathways. Given the cross-talk between the insulin and IGF signaling pathways, the aim of this study was to examine the hypothesis that the anti-proliferative actions of metformin in uterine serous carcinoma (USC) are potentially mediated via suppression of the IGF-I receptor (IGF-IR) pathway. Our results show that metformin interacts with the IGF pathway, and induces apoptosis and inhibition of proliferation and migration of USC cell lines with both wild type and mutant p53. Taken together, our results suggest that metformin therapy could be a novel and attractive therapeutic approach for human USC, a highly aggressive variant of endometrial cancer.

Progress of Oral Insulin and Related Drug Delivery Systems and their Pharmacokinetics.

PubMed

Chen, Jingjing; Liu, Rui; Liu, Changxiao; Jin, Xin; Zhang, Qinghua; Wang, Jialu; Zhao, Fang; Wang, Ze; Qiu, Haiyan; Li, Yazhuo; Yi, Xiulin

2018-05-22

As society has developed and living standards have improved, diabetes has become a severe public health issue. Insulin plays a crucial role in managing hyperglycemia caused by type I diabetes and particular type II diabetes. Many researchers are seeking alternative, more acceptable methods of insulin delivery, such as oral insulin. An oral formulation has become a new goal for insulin delivery in recent years. The PubMed and CNKI databases were searched for "oral insulin, " "drug delivery systems, " and "pharmacokinetics, " and 85 relevant articles were selected from the results as material for this review. These papers were authoritative and had a higher number of citations. Oral insulin would be highly advantageous but is poorly absorbed. The main reason for low absorptivity is the hydrolysis of insulin by enzymes in the gastrointestinal tract. Lack of active transport vectors that pass through the intestinal epithelium is also a non-negligible problem. Additional issues need to be considered to facilitate appropriate research, such as long-term efficacy and safety, clinical data, and toxicological characteristics. This review summarized recent advances in oral insulin and the pharmacokinetic profile of the suitable delivery system, providing valuable reference material for future research. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

A review of the efficacy and safety of oral antidiabetic drugs

PubMed Central

Stein, Stephanie Aleskow; Lamos, Elizabeth Mary; Davis, Stephen N

2014-01-01

Introduction Additional oral antidiabetic agents to metformin, sulfonylureas (SU) and thiazolidinediones (TZD) are approved for the treatment of type 2 diabetes. Areas covered The efficacy and safety of metformin, SUs, TZDs, dipeptidyl peptidase-IV (DPP-4) inhibitors, meglitinide analogs, α-glucosidase inhibitors (AGIs), bile-acid sequestrants (BAS) and bromocriptine will be reviewed. Expert opinion Several new oral agents have been approved for type 2 diabetes management in recent years. It is important to understand the efficacy and safety of these medications in addition to the older agents to best maximize oral drug therapy for diabetes. Of the recently introduced oral hypoglycemic/antihyperglycemic agents, the DPP-4 inhibitors are moderately efficacious compared with mainstay treatment with metformin with a low side-effect profile and have good efficacy in combination with other oral agents and insulin. They are a recommended alternative when metformin use is limited by gastrointestinal (GI) side effects or when SU treatment results in significant hypoglycemia or weight gain. Meglitinide analogs are limited by their frequent dosing, expense and hypoglycemia (repaglinide > nateglinide), while AGIs are also limited by their dosing schedule and GI side-effect profile. BAS and bromocriptine have the lowest efficacy with regard to HbA1c reduction, also are plagued by GI adverse reactions, but have a low risk of hypoglycemia. PMID:23241069

Preoperative Beta Cell Function Is Predictive of Diabetes Remission After Bariatric Surgery.

PubMed

Souteiro, Pedro; Belo, Sandra; Neves, João Sérgio; Magalhães, Daniela; Silva, Rita Bettencourt; Oliveira, Sofia Castro; Costa, Maria Manuel; Saavedra, Ana; Oliveira, Joana; Cunha, Filipe; Lau, Eva; Esteves, César; Freitas, Paula; Varela, Ana; Queirós, Joana; Carvalho, Davide

2017-02-01

Bariatric surgery can improve glucose metabolism in obese patients with diabetes, but the factors that can predict diabetes remission are still under discussion. The present study aims to examine the impact of preoperative beta cell function on diabetes remission following surgery. We investigated a cohort of 363 obese diabetic patients who underwent bariatric surgery. The impact of several preoperative beta cell function indexes on diabetes remission was explored through bivariate logistic regression models. Postoperative diabetes remission was achieved in 39.9 % of patients. Younger patients (p < 0.001) and those with lower HbA1c (p = 0.001) at the baseline evaluation had higher odds of diabetes remission. Use of oral anti-diabetics and insulin therapy did not reach statistical significance when they were adjusted for age and HbA1c. Among the evaluated indexes of beta cell function, higher values of insulinogenix index, Stumvoll first- and second-phase indexes, fasting C-peptide, C-peptide area under the curve (AUC), C-peptide/glucose AUC, ISR (insulin secretion rate) AUC, and ISR/glucose AUC predicted diabetes remission even after adjustment for age and HbA1c. Among them, C-peptide AUC had the higher discriminative power (AUC 0.76; p < 0.001). Patients' age and preoperative HbA1c can forecast diabetes remission following surgery. Unlike other studies, our group found that the use of oral anti-diabetics and insulin therapy were not independent predictors of postoperative diabetes status. Preoperative beta cell function, mainly C-peptide AUC, is useful in predicting diabetes remission, and it should be assessed in all obese diabetic patients before bariatric or metabolic surgery.

Drug–drug Interaction between Pravastatin and Gemfibrozil (Antihyperlipidemic) with Gliclazide (Antidiabetic) in Rats

PubMed Central

Sultanpur, CM; Satyanarayana, S; Reddy, NS; Kumar, KE; Kumar, S

2010-01-01

Diabetes mellitus is a condition of increased blood glucose level in the body. Antihyperlipidemic drugs like statins and fibrates are widely used for prophylactic treatment in dyslipideamia and atherosclerosis. Diabetic dislipidemia exists with increased triglycerides, low HDL and high LDL levels. Hence, with oral hypoglycemic drugs, the addition of a lipid-lowering drug is necessary for controlling dislipidemia. In such a situation, there may be chances of drug–drug interactions between antidiabetic and antihyperlipidemic drugs. The present study is planned to evaluate the safety of gliclazide (antidiabetic) in the presence of pravastatin and gemfibrozil (antihyperlpidemic) in rats. Studies in normal and alloxan-induced diabetic rats were conducted with oral doses of gliclazide and their combination with pravastatin and gemfibrozil, with an adequate washout period in between the treatments. Blood samples were collected in rats by retroorbital puncture at 0, 1, 2, 3, 4, 6, 8, 10 and 12 h. All the blood samples were analyzed for glucose by GOD –POD. Gliclazide (½ TD) produced hypoglycemic activity in normal and diabetic rats, with peak activity at 2 and 8 h. Pravastatin (TD) + gemfibrozil (TD) combination treatment increased the hypoglycemic effect of gliclazide in normal rats or diabetic rats when administered together. The interaction observed due to inhibition of both the enzymes (CYP 450 2C9 and CYP 450 3A4) responsible for the metabolism of gliclazide showed increased half-life, which was seen in the present study. Because concomitant administration of gliclazide with provastatin and gemfibrozil in diabetes is associated with atherosclerosis, it should be contraindicated or used with caution. PMID:21264118

[Type 2 diabetes mellitus and obesity: should we treat the obesity or the diabetes?].

PubMed

García, Santiago Durán; Sanz, Santiago Durán; Sanz, Alejandro Durán

2013-09-01

In this article, we review the results that can be expected after significant weight loss in patients with type 2 diabetes mellitus. We provide consensus-based documentation supported by the American Diabetes Association, the European Association for the Study of Diabetes, and the International Diabetes Federation on the importance of physical exercise, metabolic-bariatric surgery, and drug therapy. Lastly, we report the results of studies published in the last few years on glucagon-like peptide-1 analogs and the new family of oral drugs known as gliflozins, specifically studies published on dapagliflozin. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Nanoparticle-encapsulated emodin decreases diabetic neuropathic pain probably via a mechanism involving P2X3 receptor in the dorsal root ganglia.

PubMed

Li, Lin; Sheng, Xuan; Zhao, Shanhong; Zou, Lifang; Han, Xinyao; Gong, Yingxin; Yuan, Huilong; Shi, Liran; Guo, Lili; Jia, Tianyu; Liu, Shuangmei; Wu, Bing; Yi, Zhihua; Liu, Hui; Gao, Yun; Li, Guilin; Li, Guodong; Zhang, Chunping; Xu, Hong; Liang, Shangdong

2017-12-01

Diabetic peripheral neuropathy (DPN) is the most common complication of diabetes mellitus (DM). More than 90% of all cases of DM belong to type 2 diabetes mellitus (T2DM). Emodin is the main active component of Radix et rhizoma rhei and has anti-bacterial, anti-viral, anti-ulcerogenic, anti-inflammatory, and anti-cancer effects. Nanoparticle encapsulation of drugs is beneficial for drug targeting and bioavailability as well as for lowering drug toxicity side effects. The aim of this study was to investigate the effects of nanoparticle-encapsulated emodin (nano emodin) on diabetic neuropathic pain (DNP) mediated by the Purin 2X3 (P2X3) receptor in the dorsal root ganglia (DRG). Mechanical withdrawal threshold (MWT) and thermal withdrawal latency (TWL) values in T2DM rats were lower than those of control rats. MWT and TWL in T2DM rats treated with nano emodin were higher compared with those in T2DM rats. Expression levels of P2X3 protein and messenger RNA (mRNA) in the DRG of T2DM rats were higher than those of controls, while levels in T2DM rats treated with nano emodin were significantly lower than those of the T2DM rats. Phosphorylation and activation of ERK1/2 in the T2DM DRG were decreased by nano emodin treatment. Nano emodin significantly inhibited currents activated by the P2X3 agonist α,β-meATP in HEK293 cells transfected with the P2X3 receptor. Therefore, nano emodin treatment may relieve DNP by decreasing excitatory transmission mediated by the DRG P2X3 receptor in T2DM rats.

Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase.

PubMed

Hogan, Shelly; Zhang, Lei; Li, Jianrong; Sun, Shi; Canning, Corene; Zhou, Kequan

2010-08-27

Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo. The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases. The red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge. This is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes.

Antioxidant rich grape pomace extract suppresses postprandial hyperglycemia in diabetic mice by specifically inhibiting alpha-glucosidase

PubMed Central

2010-01-01

Background Postprandial hyperglycemia is an early defect of type 2 diabetes and one of primary anti-diabetic targets. Treatment of postprandial hyperglycemia can be achieved by inhibiting intestinal α-glucosidase, the key enzyme for oligosaccharide digestion and further glucose absorption. Grape pomace is winemaking byproduct rich in bioactive food compounds such as phenolic antioxidants. This study evaluated the anti-diabetic potential of two specific grape pomace extracts by determining their antioxidant and anti-postprandial hyperglycemic activities in vitro and in vivo. Methods The extracts of red wine grape pomace (Cabernet Franc) and white wine grape pomace (Chardonnay) were prepared in 80% ethanol. An extract of red apple pomace was included as a comparison. The radical scavenging activities and phenolic profiles of the pomace extracts were determined through the measurement of oxygen radical absorbance capacity, DPPH radical scavenging activity, total phenolic content and flavonoids. The inhibitory effects of the pomace extracts on yeast and rat intestinal α-glucosidases were determined. Male 6-week old C57BLKS/6NCr mice were treated with streptozocin to induce diabetes. The diabetic mice were then treated with vehicle or the grape pomace extract to determine whether the oral intake of the extract can suppress postprandial hyperglycemia through the inhibition of intestinal α-glucosidases. Results The red grape pomace extract contained significantly higher amounts of flavonoids and phenolic compounds and exerted stronger oxygen radical absorbance capacity than the red apple pomace extract. Both the grape pomace extracts but not the apple pomace extract exerted significant inhibition on intestinal α-glucosidases and the inhibition appears to be specific. In the animal study, the oral intake of the grape pomace extract (400 mg/kg body weight) significantly suppressed the postprandial hyperglycemia by 35% in streptozocin-induced diabetic mice following starch challenge. Conclusion This is the first report that the grape pomace extracts selectively and significantly inhibits intestinal α-glucosidase and suppresses postprandial hyperglycemia in diabetic mice. The antioxidant and anti-postprandial hyperglycemic activities demonstrated on the tested grape pomace extract therefore suggest a potential for utilizing grape pomace-derived bioactive compounds in management of diabetes. PMID:20799969

Disordered haematopoiesis and athero-thrombosis.

PubMed

Murphy, Andrew J; Tall, Alan R

2016-04-07

Atherosclerosis, the major underlying cause of cardiovascular disease, is characterized by a lipid-driven infiltration of inflammatory cells in large and medium arteries. Increased production and activation of monocytes, neutrophils, and platelets, driven by hypercholesterolaemia and defective high-density lipoproteins-mediated cholesterol efflux, tissue necrosis and cytokine production after myocardial infarction, or metabolic abnormalities associated with diabetes, contribute to atherogenesis and athero-thrombosis. This suggests that in addition to traditional approaches of low-density lipoproteins lowering and anti-platelet drugs, therapies directed at abnormal haematopoiesis, including anti-inflammatory agents, drugs that suppress myelopoiesis, and excessive platelet production, rHDL infusions and anti-obesity and anti-diabetic agents, may help to prevent athero-thrombosis. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2016. For permissions please email: journals.permissions@oup.com.

Discovery and structure-activity relationships study of thieno[2,3-b]pyridine analogues as hepatic gluconeogenesis inhibitors.

PubMed

Ma, Fei; Liu, Jian; Zhou, Tingting; Lei, Min; Chen, Jing; Wang, Xiachang; Zhang, Yinan; Shen, Xu; Hu, Lihong

2018-05-25

Type 2 diabetes mellitus (T2DM) is a chronic, complex and multifactorial metabolic disorder, and targeting gluconeogenesis inhibition is a promising strategy for anti-diabetic drug discovery. This study discovered a new class of thieno[2,3-b]pyridine derivatives as hepatic gluconeogenesis inhibitors. First, a hit compound (DMT: IC 50  = 33.8 μM) characterized by a thienopyridine core was identified in a cell-based screening of our privileged small molecule library. Structure activity relationships (SARs) study showed that replaced the CF 3 in the thienopyridine core could improve the potency and led to the discovery of 8e (IC 50  = 16.8 μM) and 9d (IC 50  = 12.3 μM) with potent inhibition of hepatic glucose production and good drug-like properties. Furthermore, the mechanism of 8e for the inhibition of hepatic glucose production was also identified, which could be effective through the reductive expression of the mRNA transcription level of gluconeogenic genes, including glucose-6-phosphatase (G6Pase) and hepatic phosphoenolpyruvate carboxykinase (PEPCK). Additionally, 8e could also reduce the fasting blood glucose and improve the oral glucose tolerance and pyruvate tolerance in db/db mice. The optimization of this class of derivatives had provided us a start point to develop new anti-hepatic gluconeogenesis agents. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Curine inhibits eosinophil activation and airway hyper-responsiveness in a mouse model of allergic asthma

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ribeiro-Filho, Jaime; Laboratório de Imunofarmacologia, Departamento de Fisiologia e Patologia, UFPB, João Pessoa, Paraíba; Calheiros, Andrea Surrage

Allergic asthma is a chronic inflammatory airway disease with increasing prevalence around the world. Current asthma therapy includes drugs that usually cause significant side effects, justifying the search for new anti-asthmatic drugs. Curine is a bisbenzylisoquinoline alkaloid that modulates calcium influx in many cell types; however, its anti-allergic and putative toxic effects remain to be elucidated. Our aim was to investigate the effects of curine on eosinophil activation and airway hyper-responsiveness (AHR) and to characterize its potential toxic effects. We used a mouse model of allergic asthma induced by sensitization and challenge with ovalbumin (OVA) to evaluate the anti-allergic effectsmore » of oral treatment with curine. The oral administration of curine significantly inhibited eosinophilic inflammation, eosinophil lipid body formation and AHR in animals challenged with OVA compared with animals in the untreated group. The curine treatment also reduced eotaxin and IL-13 production triggered by OVA. Verapamil, a calcium channel antagonist, had similar anti-allergic properties, and curine pre-treatment inhibited the calcium-induced tracheal contractile response ex-vivo, suggesting that the mechanism by which curine exerts its effects is through the inhibition of a calcium-dependent response. A toxicological evaluation showed that orally administered curine did not significantly alter the biochemical, hematological, behavioral and physical parameters measured in the experimental animals compared with saline-treated animals. In conclusion, curine showed anti-allergic activity through mechanisms that involve inhibition of IL-13 and eotaxin and of Ca{sup ++} influx, without inducing evident toxicity and as such, has the potential for the development of anti-asthmatic drugs. - Highlights: • Curine is a bisbenzylisoquinoline alkaloid from Chondrodendron platyphyllum. • Curine inhibits eosinophil influx and activation and airway hyper-responsiveness. • Curine mechanisms involve inhibition of Ca{sup 2+} influx, and IL-13 and eotaxin secretion. • No significant toxicity was observed in mice orally treated with curine for 7 days. • Curine has the potential for the development of anti-asthmatic drugs.« less

Metformin: Candidate host-directed therapy for tuberculosis in diabetes and non-diabetes patients.

PubMed

Restrepo, Blanca I

2016-12-01

Despite major advances in tuberculosis (TB) control, TB continues to be a leading cause of death worldwide. The discovery of new anti-TB treatment drugs and regimens that target drug-sensitive and drug-resistant TB are being complemented with a search for adjunct host-directed therapies that synergize for Mycobacterium tuberculosis (Mtb) elimination. The goal of host-directed therapies is to boost immune mechanisms that diminish excess inflammation to reduce lung tissue damage and limit Mtb growth. Metformin is the most commonly-used medication for type 2 diabetes, and a candidate for host-directed therapy for TB. Preliminary data suggests metformin may be beneficial for TB control by reducing the deleterious inflammation associated with immune pathology and enhancing the anti-mycobacterial activity of immune cells. In this review I summarize current findings, knowledge gaps and the potential benefits as well as points of caution for using metformin as adjunct therapy for TB in patients with and without type 2 diabetes. Copyright © 2016 Elsevier Ltd. All rights reserved.

Impact of insulin treatment in diabetic macular edema therapy in type 2 diabetes.

PubMed

Matsuda, Simone; Tam, Tiffany; Singh, Rishi P; Kaiser, Peter K; Petkovsek, Daniel; Zanella, Maria Teresa; Ehlers, Justis P

2015-02-01

To evaluate the impact of insulin therapy on the outcomes of diabetic macular edema (DME) treatment with vascular endothelial growth factor (VEGF) inhibitors in people with type 2 diabetes. A retrospective consecutive case series of 95 patients with type 2 diabetes and DME who were treated with anti-VEGF therapy. We examined 2 cohorts: patients taking only oral antidiabetic agents and patients on insulin therapy. The main outcome measures were change in visual acuity and change in central subfield macular thickness measured by spectral-domain optical coherence tomography. The additional variables analyzed included glycated hemoglobin (A1C), creatinine, blood pressure and body mass index and their correlations with clinical findings. Both groups had a statistically significant improvement in visual acuity (oral antidiabetic agents group: 20/61 to 20/49, p=0.003; insulin therapy group: 20/76 to 20/56, p=0.005). There was no difference between groups at initial or 12-month examination (p=0.239 and p=0.489, respectively). From an anatomic standpoint, central subfield macular thickness also improved significantly in both groups: from 454.7 μm to 354.9 μm (p<0.001) in the oral antidiabetic agents group and from 471.5 μm to 368.4 μm (p<0.001) in the insulin therapy group. Again, there was no significant difference between groups at initial or 12-month follow-up examinations (p=0.586 and p=0.591, respectively). Mean A1C levels remained relatively stable during the follow up in both groups. Anti-VEGF therapy is a useful treatment for DME. This study suggests that chronic insulin therapy, compared with oral antidiabetic agents, does not modify the anatomic or functional effectiveness of DME treatment. Copyright © 2015 Canadian Diabetes Association. Published by Elsevier Inc. All rights reserved.

Control of risk factors for cardiovascular disease among adults with previously diagnosed type 2 diabetes mellitus: a descriptive study from a middle eastern arab population.

PubMed

Al-Lawati, Jawad A; N Barakat, Mohammed; Al-Zakwani, Ibrahim; Elsayed, Medhat K; Al-Maskari, Masoud; M Al-Lawati, Nawar; Mohammed, Ali Jaffer

2012-01-01

Despite the high burden of type 2 diabetes mellitus (T2DM) in Oman, there are scarce data from a nationally representative sample on the level of glycaemia and other cardiovascular (CVD) risk factor control. To estimate the proportion of patients with T2DM at goal for glycaemia and CVD risk factors using the National Diabetes Guidelines (NDG) and the American Diabetes Association (ADA) clinical care guidelines; and to assess the quality of selected services provided to patients with T2DM. A sample of 2,551 patients (47% men) aged ≥20 years with T2DM treated at primary health care centers was selected. Patient characteristics, medical history and treatment were collected from case notes, Diabetes Registers and computer frameworks including the use of the last 3 laboratory investigations results and blood pressure (BP) readings recorded in 2007. The overall mean age of the cohort was 54±13 years with an average median duration of diabetes of 4 (range 2 to 6) years. Over 80% of patients were overweight or obese (body mass index (BMI) of ≥25 Kg/m(2)). Sixty-nine percent were on oral anti-diabetic medication, 52% on anti-hypertensives and 40% on lipid lowering drugs. Thirty percent of patients were at goal for glycosylated haemoglobin level (<7%), 26% for BP (systolic/diastolic <130/80 mmHg), 55% for total cholesterol (<5.2 mmol/l), 4.5% for low-density lipoprotein cholesterol (<1.8 mmol/l), 52% for high-density lipoprotein cholesterol (>1 mmol/l for men, >1.3 mmol/l for women), and 61% for triglycerides (<1.7 mmol/l). Over 37% had micro-albuminuria and 5% had diabetic nephropathy. Control of hyperglycaemia and other CVD risk factor appears to be suboptimal in Omani patients with T2DM and need to be addressed in the triad of patient, physician and health system.

Type 2 diabetes and obesity in adults.

PubMed

Whitmore, Catherine

There are approximately 2.5 million people in the UK with diabetes; 85-95% of whom have type 2 diabetes. Type 2 diabetes mellitus is characterized by insulin resistance and impaired insulin secretion. As approximately 90% of people with type 2 diabetes are overweight or obese, obesity is seen as a significant contributory factor in its development. This article aims to examine some of the physiological mechanisms by which overweight and obesity contribute to the development of type 2 diabetes, and review some of the approaches to managing overweight and obesity in the person with established type 2 diabetes, including dietary management, the use of reduced carbohydrate diets on glycamic control, anti-diabetes and anti-obesity drugs both in use and in development, and bariatric surgery.

Managing chronic inflammation in the aging diabetic patient with CKD by diet or sevelamer carbonate: a modern paradigm shift.

PubMed

Vlassara, H; Cai, W; Chen, X; Serrano, E J; Shobha, M S; Uribarri, J; Woodward, M; Striker, G E

2012-12-01

The maintenance of normal metabolism and body defenses depends on the balance between cellular antioxidant and anti-inflammatory factors. This balance can be disrupted by agents/mechanisms in the extracellular milieu that induce excess reactive oxygen species (ROS) and inflammation. Cytopathic advanced glycation endproducts, present in ever increasing amounts in the modern diet, are one of the major environmental factors that cause excess ROS and/or inflammation at all ages and induce complications in aging, such as chronic kidney disease (CKD) and type 2 diabetes. Increased ROS and/or inflammation are present in both aging and CKD, and are associated with reduced cellular defenses against ROS and/or inflammation. Affected individuals have reduced defenses against further stress and are predisposed to organ failure, now a well-known phenomenon in aging. Thus, new methods are urgently needed to safely reduce ROS and/or inflammation in the aging type 2 diabetes patient with CKD. Studies of both normal aging and diabetic patients with kidney disease underline the fact that increased ROS and/or inflammation can be managed in these conditions by economical, safe, and effective interventions that reduce the uptake of advanced glycation endproducts by either modifying preparation of food or an oral drug. This communication reviews these data and adds new information on the efficacy of a drug, sevelamer carbonate, required to reduce ROS and/or inflammation in the aging type 2 diabetes patient complicated by CKD. If larger and longer studies confirm the hypothesis that one or both of these interventions reduce progression of CKD, it could represent a new paradigm in the management of complications in the type 2 diabetes patient with CKD.

Microparticles, microcapsules and microspheres: A review of recent developments and prospects for oral delivery of insulin.

PubMed

Wong, Chun Y; Al-Salami, Hani; Dass, Crispin R

2018-02-15

Diabetes mellitus is a chronic metabolic health disease affecting the homeostasis of blood sugar levels. However, subcutaneous injection of insulin can lead to patient non-compliance, discomfort, pain and local infection. Sub-micron sized drug delivery systems have gained attention in oral delivery of insulin for diabetes treatment. In most of the recent literature, the terms "microparticles" and "nanoparticle" refer to particles where the dimensions of the particle are measured in micrometers and nanometers respectively. For instance, insulin-loaded particles are defined as microparticles with size larger than 1 μm by most of the research groups. The size difference between nanoparticles and microparticles proffers numerous effects on the drug loading efficiency, aggregation, permeability across the biological membranes, cell entry and tissue retention. For instance, microparticulate drug delivery systems have demonstrated a number of advantages including protective effect against enzymatic degradation, enhancement of peptide stability, site-specific and controlled drug release. Compared to nanoparticulate drug delivery systems, microparticulate formulations can facilitate oral absorption of insulin by paracellular, transcellular and lymphatic routes. In this article, we review the current status of microparticles, microcapsules and microspheres for oral administration of insulin. A number of novel techniques including layer-by-layer coating, self-polymerisation of shell, nanocomposite microparticulate drug delivery system seem to be promising for enhancing the oral bioavailability of insulin. This review draws several conclusions for future directions and challenges to be addressed for optimising the properties of microparticulate drug formulations and enhancing their hypoglycaemic effects. Copyright © 2017 Elsevier B.V. All rights reserved.

Granulated colloidal silicon dioxide-based self-microemulsifying tablets, as a versatile approach in enhancement of solubility and therapeutic potential of anti-diabetic agent: formulation design and in vitro/in vivo evaluation.

PubMed

Pandey, Vikas; Gilhotra, Ritu M; Kohli, Seema

2017-06-01

The current research work was executed with an aim to explore and promote the potential of self-microemusifying drug delivery systems (SMEDDS) in the form of tablets, in order to enhance solubility and oral bioavailability of poorly aqueous soluble drug Repaglinide (RPG). RPG-loaded liquid SMEDDS were developed consisting Labrafil M 1944CS, Kolliphor EL and Propylene glycol, which were then characterized on various parameters. After characterization and optimization, liquid SMEDDS were converted into solid form by adsorbing on Aeroperl® 300 pharma and polyplasdone TM XL. Further, selection of suitable excipients was done and mixed with prepared solidified SMEDDS powder followed by the preparation of self-microemulsifying tablets (SMET's) wet granulation-compression method. SMET's were subjected to differential scanning calorimetry (DSC) and particle X-ray diffraction (RXRD) studies, results of which indicated transformation of crystalline structure of RPG because of dispersion of RPG at molecular level in liquid SMEDDS. This was further assured by micrographs obtained from scanning electron microscope. SMET's shown more than 85% (30 min) of in vitro drug release in contrast to conventional marketed tablets (13.2%) and pure RPG drug (3.2%). Results of in vivo studies furnished that SMET's had shown marked decrease in the blood glucose level and prolonged duration of action (up to 8 h) in comparison with conventional marketed tablets and pure RPG drug. In conclusion, SMET's serves as a promising tool for successful oral delivery of poorly aqueous soluble drug(s) such as RPG.

Nano-preparation of Andrographis paniculata extract by casein micelle for antidiabetic agent

NASA Astrophysics Data System (ADS)

Arbianti, Rita; Dewi, Veronica; Imansari, Farisa; Hermansyah, Heri; Sahlan, Muhamad

2017-02-01

Side effects caused by oral medications for person with diabetic are the background of the development of alternative treatments by traditional medicine, herbs. Andrographis paniculata (AP) is one of the herbs that is potent to be anti-diabetic agent. The active compound of AP, andrographolide have been examined to have anti-diabetic activity as α-glucosidase enzyme inhibitor. This research aims to encapsulate sambiloto's extract with casein micelle and produce nanoparticles which have anti-diabetic activity as α-glucosidase inhibitor. Extract of AP is encapsulated by casein micelle and made into nano size using sonicator. The dominant active compounds in AP extract coated by casein are andrographolide, neoandrographolide, 14-deoxy-11,12didehydroandrographolide with encapsulation efficiency of 68.83%, 89.15% and 81.69%, the average diameter of the particles is about 120.57 nm and its loading capacity is 28.85%. AP's extract has antidiabetic activity as α-glucosidase inhibitor with percent inhibition of 95%. The morphology of nanoencapsulated AP's extract analyzed by FE-SEM, were similar with casein micelle.

Comparing the risks of hospitalized heart failure associated with glinide, sulfonylurea, and acarbose use in type 2 diabetes: A nationwide study.

PubMed

Lee, Yen-Chieh; Chang, Chia-Hsuin; Dong, Yaa-Hui; Lin, Jou-Wei; Wu, Li-Chiu; Hwang, Jing-Shiang; Chuang, Lee-Ming

2017-02-01

Increasing evidence suggests that certain newer anti-diabetic drugs are associated with an increased risk of hospitalized heart failure (HHF). However, the potential risks associated with the use of sulfonylurea and glinide have not been carefully evaluated. A retrospective cohort study using the Taiwan National Health Insurance claims database was conducted to examine the risks of HHF among newly diagnosed type 2 diabetic patients who initiated glinide, sulfonylurea, or acarbose therapy during 2006-2012. The outcome of interest was hospitalization due to heart failure after treatment initiation, defined by ICD-9-CM code. A Cox proportional hazard regression model was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) using acarbose as the reference group. A total of 25,638 glinide, 272,140 sulfonylurea, and 29,376 acarbose initiators were included in the analysis. Patients who initiated glinide had the highest crude HHF incidence. In the analysis adjusted for baseline differences, a significantly higher risk of HHF was found for glinide (adjusted HR, 1.53; 95% CI, 1.24-1.88), but not for sulfonylurea (adjusted HR, 0.94; 95% CI, 0.80-1.11), as compared with acarbose. The elevated risk remained consistent across different subgroups of patients as well as several sensitivity analyses including exploring the impact of potential unmeasured confounding. These findings indicated that, as compared with acarbose, glinide may be associated with a higher risk of HHF for type 2 diabetic patients. Further researchis needed to fully evaluate the risks and benefits of glinide therapy relative to other oral anti-diabetic agents. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Dietary supplementation during diabetes therapy and the potential risk of interactions.

PubMed

Zabłocka-Słowińska, Katarzyna; Dzielska, Ewelina; Gryszkin, Iwona; Grajeta, Halina

2014-01-01

The classification of dietary supplements as foodstuffs promotes widespread access to them and increases the possibility of patients using them without being monitored. Unreasonable or excessive consumption of these preparations poses risks to type-2 diabetes mellitus (T2DM) patients (among others) because it may induce disturbances in glycemic control. The aim of this study was to assess the frequency of dietary supplementation among patients using anti-diabetic drugs and such patients' nutrient intake in order to evaluate the potential risk of interactions. The study participants were 150 diabetic patients who were asked about the type of pharmacotherapy and dietary supplementation they used. The intake of minerals, vitamins, dietary fiber and long-chain polyunsaturated fatty acids (LC-PUFAs) from the patients' diets were also assessed, using the 24-h dietary recall method. The highest percentage of patients taking individual anti-diabetic drugs used supplements containing magnesium and herbs. They also often took antioxidant vitamins, B-group vitamins and omega-3 fatty acids. In the majority of patients (both those using supplements and those not), the dietary recall showed insufficient intake of potassium, calcium and magnesium, as well as of vitamin E, folic acid, vitamin D and LC-PUFAs. In addition, their diets provided high median amounts of iron, copper, vitamin A and β-carotene. The level of dietary supplementation and the ill-balanced diets reported by the majority of the recruited T2DM patients indicate a high possible risk of interactions with the anti-diabetic drugs. Therefore, patients should always consult their physicians regarding dietary supplementation, and medically trained staff should routinely assess dietary intake to avoid hazardous changes in the activity of drugs.

Zingiber officinale attenuates retinal microvascular changes in diabetic rats via anti-inflammatory and antiangiogenic mechanisms

PubMed Central

Dongare, Shirish; Mathur, Rajani; Saxena, Rohit; Mathur, Sandeep; Agarwal, Renu; Nag, Tapas C.; Srivastava, Sushma; Kumar, Pankaj

2016-01-01

Purpose Diabetic retinopathy is a common microvascular complication of long-standing diabetes. Several complex interconnecting biochemical pathways are activated in response to hyperglycemia. These pathways culminate into proinflammatory and angiogenic effects that bring about structural and functional damage to the retinal vasculature. Since Zingiber officinale (ginger) is known for its anti-inflammatory and antiangiogenic properties, we investigated the effects of its extract standardized to 5% 6-gingerol, the major active constituent of ginger, in attenuating retinal microvascular changes in rats with streptozotocin-induced diabetes. Methods Diabetic rats were treated orally with the vehicle or the ginger extract (75 mg/kg/day) over a period of 24 weeks along with regular monitoring of bodyweight and blood glucose and weekly fundus photography. At the end of the 24-week treatment, the retinas were isolated for histopathological examination under a light microscope, transmission electron microscopy, and determination of the retinal tumor necrosis factor-α (TNF-α), nuclear factor-kappa B (NF-κB), and vascular endothelial growth factor (VEGF) levels. Results Oral administration of the ginger extract resulted in significant reduction of hyperglycemia, the diameter of the retinal vessels, and vascular basement membrane thickness. Improvement in the architecture of the retinal vasculature was associated with significantly reduced expression of NF-κB and reduced activity of TNF-α and VEGF in the retinal tissue in the ginger extract–treated group compared to the vehicle-treated group. Conclusions The current study showed that ginger extract containing 5% of 6-gingerol attenuates the retinal microvascular changes in rats with streptozotocin-induced diabetes through anti-inflammatory and antiangiogenic actions. Although precise molecular targets remain to be determined, 6-gingerol seems to be a potential candidate for further investigation. PMID:27293376

[Drug-induced oral ulcerations].

PubMed

Madinier, I; Berry, N; Chichmanian, R M

2000-06-01

Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine).

Diffusion patterns of new anti-diabetic drugs into hospitals in Taiwan: the case of Thiazolidinediones for diabetes

PubMed Central

2011-01-01

Background Diffusion of new drugs in the health care market affects patients' access to new treatment options and health care expenditures. We examined how a new drug class for diabetes mellitus, thiazolidinediones (TZDs), diffused in the health care market in Taiwan. Methods Assuming that monthly hospital prescriptions of TZDs could serve as a micro-market to perform drug penetration studies, we retrieved monthly TZD prescription data for 580 hospitals in Taiwan from Taiwan's National Health Insurance Research Database for the period between March 1, 2001 and December 31, 2005. Three diffusion parameters, time to adoption, speed of penetration (monthly growth on prescriptions), and peak penetration (maximum monthly prescription) were evaluated. Cox proportional hazards model and quantile regressions were estimated for analyses on the diffusion parameters. Results Prior hospital-level pharmaceutical prescription concentration significantly deterred the adoption of the new drug class (HR: 0.02, 95%CI = 0.01 to 0.04). Adoption of TZDs was slower in district hospitals (HR = 0.43, 95%CI = 0.24 to 0.75) than medical centers and faster in non-profit hospitals than public hospitals (HR = 1.79, 95%CI = 1.23 to 2.61). Quantile regression showed that penetration speed was associated with a hospital's prior anti-diabetic prescriptions (25%Q: 18.29; 50%Q: 25.57; 75%Q: 30.97). Higher peaks were found in hospitals that had adopted TZD early (25%Q: -40.33; 50%Q: -38.65; 75%Q: -32.29) and in hospitals in which the drugs penetrated more quickly (25%Q: 16.53; 50%Q: 24.91; 75%Q: 31.50). Conclusions Medical centers began to prescribe TZDs earlier, and they prescribed more TZDs at a faster pace. The TZD diffusion patterns varied among hospitals depending accreditation level, ownership type, and prescription volume of Anti-diabetic drugs. PMID:21281475

Effects of Averrhoa bilimbi leaf extract on blood glucose and lipids in streptozotocin-diabetic rats.

PubMed

Pushparaj, P; Tan, C H; Tan, B K

2000-09-01

The present study was designed to investigate the hypoglycemic and hypolipidemic activities of an ethanolic extract of Averrhoa bilimbi Linn. leaves (Oxalidaceae, Common name: Bilimbi) in streptozotocin (STZ)-diabetic rats. The optimal hypoglycemic dose (125 mg kg(-1)) was determined by performing the oral glucose tolerance test (OGTT) in both normal and STZ-diabetic rats. To investigate the effect of repeated administration of an ethanolic extract of Averrhoa bilimbi (ABe) leaves, diabetic rats were treated with vehicle (distilled water), ABe (125 mg kg(-1)) or metformin (500 mg kg(-1)) twice a day for 2 weeks. Like metformin, ABe significantly lowered blood glucose by 50% and blood triglyceride by 130% when compared with the vehicle. ABe also significantly increased the HDL-cholesterol concentrations by 60% compared with the vehicle. ABe thus significantly increased the anti-atherogenic index and HDL-cholesterol/total cholesterol ratio. However, like metformin, ABe did not affect total cholesterol and LDL-cholesterol concentrations, but significantly reduced the kidney lipid peroxidation level. These data show that ABe has hypoglycemic, hypotriglyceridemic, anti-lipid peroxidative and anti-atherogenic properties in STZ-diabetic rats.

Targeting inflammation in diabetes: Newer therapeutic options

PubMed Central

Agrawal, Neeraj Kumar; Kant, Saket

2014-01-01

Inflammation has been recognised to both decrease beta cell insulin secretion and increase insulin resistance. Circulating cytokines can affect beta cell function directly leading to secretory dysfunction and increased apoptosis. These cytokines can also indirectly affect beta cell function by increasing adipocyte inflammation.The resulting glucotoxicity and lipotoxicity further enhance the inflammatory process resulting in a vicious cycle. Weight reduction and drugs such as metformin have been shown to decrease the levels of C-Reactive Protein by 31% and 13%, respectively. Pioglitazone, insulin and statins have anti-inflammatory effects. Interleukin 1 and tumor necrosis factor-α antagonists are in trials and NSAIDs such as salsalate have shown an improvement in insulin sensitivity. Inhibition of 12-lipo-oxygenase, histone de-acetylases, and activation of sirtuin-1 are upcoming molecular targets to reduce inflammation. These therapies have also been shown to decrease the conversion of pre-diabetes state to diabetes. Drugs like glicazide, troglitazone, N-acetylcysteine and selective COX-2 inhibitors have shown benefit in diabetic neuropathy by decreasing inflammatory markers. Retinopathy drugs are used to target vascular endothelial growth factor, angiopoietin-2, various proteinases and chemokines. Drugs targeting the proteinases and various chemokines are pentoxifylline, inhibitors of nuclear factor-kappa B and mammalian target of rapamycin and are in clinical trials for diabetic nephropathy. Commonly used drugs such as insulin, metformin, peroxisome proliferator-activated receptors, glucagon like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors also decrease inflammation. Anti-inflammatory therapies represent a potential approach for the therapy of diabetes and its complications. PMID:25317247

Acute and chronic animal models for the evaluation of anti-diabetic agents

PubMed Central

2012-01-01

Diabetes mellitus is a potentially morbid condition with high prevalence worldwide thus being a major medical concern. Experimental induction of diabetes mellitus in animal models is essential for the advancement of our knowledge and understanding of the various aspects of its pathogenesis and ultimately finding new therapies and cure. Experimental diabetes mellitus is generally induced in laboratory animals by several methods that include: chemical, surgical and genetic (immunological) manipulations. Most of the experiments in diabetes are carried out in rodents, although some studies are still performed in larger animals. The present review highlights the various methods of inducing diabetes in experimental animals in order to test the newer drugs for their anti-diabetic potential. PMID:22257465

Effect of Sclerocarya birrea (Anacardiaceae) stem bark methylene chloride/methanol extract on streptozotocin-diabetic rats.

PubMed

Dimo, Théophile; Rakotonirina, Silvere V; Tan, Paul V; Azay, Jacqueline; Dongo, Etienne; Kamtchouing, Pierre; Cros, Gérard

2007-04-04

Sclerocarya birrea (Anacardiaceae) is used as a traditional treatment of diabetes in Cameroon. In this study, we investigated the possible antidiabetic effect of the stem bark extract in diabetic rats. Diabetes was induced by intravenous injection of streptozotocin (STZ, 55 mg/kg) to male Wistar rats. Experimental animals (six per group), were treated by oral administration of plant extract (150 and 300 mg/kg body weight) and metformin (500 mg/kg; reference drug) for comparison, during 21 days. The stem bark methanol/methylene chloride extract of Sclerocarya birrea exhibited at termination, a significant reduction in blood glucose and increased plasma insulin levels in diabetic rats. The extract also prevented body weight loss in diabetic rats. The effective dose of the plant extract (300 mg/kg) tended to reduce plasma cholesterol, triglyceride and urea levels toward the normal levels. Four days after diabetes induction, an oral glucose tolerance test (OGTT) was also performed in experimental diabetic rats. The results showed a significant improvement in glucose tolerance in rats treated with Sclerocarya birrea extract. Metformin, a known antidiabetic drug (500 mg/kg), significantly decreased the integrated area under the glucose curve. These data indicate that Sclerocarya birrea treatment may improve glucose homeostasis in STZ-induced diabetes which could be associated with stimulation of insulin secretion.

[Antineoplastic oral agents and drug-nutrient interactions: a sistematic review].

PubMed

Jiménez Torres, N V; Romero Crespo, I; Ballester Solaz, M; Albert Marí, A; Jiménez Arenas, V

2009-01-01

Studies on bioavailability are part of the clinical development of drugs for oral use in order to identify potential drug-food interactions. For oral antitumor drugs, their clinical importance is currently recognized although regrettably the information available presents variability concerning the scientific evidence. To review the available scientific evidence about oral anti-tumor medications and establish the recommendations for their administration with foods. We carried out a bibliographic search in Medline and The Cochrane Library for the period January of 1966 to March of 2008, focused on identifying those publications about drug-food interactions with oral antitumor medications. The bibliographical analysis was made in two steps. During the first phase, we excluded those articles in which the title or their content did not correspond with the objective settled; during the second phase, we deleted all the references duplicated in both databases. The inclusion criteria to select the articles were: design (systematic reviews, meta-analysis, Phase I and Phase II randomized clinical trials), population (adult patients; >19 years of age), intervention evaluated (administration of oral anti-tumor drugs under fasting conditions or with food) and measurement of the iFA results (calculation of the 90% CI of the odds ratio between the geometric mean of the values under the curve of the plasma concentrations (ABC) or the maximal plasma concentration (Cmax) with and without foods). We excluded those publications that did not make reference to the bioequivalence dictamen established by the Food and Drugs Administration (FDA) in their outcomes measurement. A critical appraisal of the selected articles was done according to the recommendations that the FDA established to be met by these studies. At the initial search we obtained 850 references (98.5% Medline + and 1.4% Cochrane). During the first phase, we excluded 87.7% (746) of the articles, 100% of them corresponding to the search in Medline. During the second phase, 40 studies remained (5.2% of the initial ones) for full-text critical appraisal, to which four studies were added not indexed in Medline. From the critical appraisal of the 44 final articles, 25 were excluded (20 original articles, 4 short communications, and 1 meta-analysis) because they did not include as an outcome measure the bioequivalence dictamen. The 19 (2.2%) remaining articles provided information on 19 oral anti-tumor drugs in 210 patients and 146 healthy volunteers. Of these 19 drugs, 63% did not present drug-food interactions, with the possibility of administering them either with or without food; 21% have to be administered with foods and only 16% present drug-food interactions, so they have to be administered without foods. Currently, the clinical importance of drug-food interactions with oral anti-tumor drugs is identified more directly with the patient's safety than with the efficacy of the therapy. Given the development of these oral agents, their incorporation into the oncologic strategy displacing parenteral therapy, with monthly costs of thousands of Euros, it is necessary to perform well-designed studies on pharmacokinetics and pharmacodynamics. Their goal has to be comparing their bioavailability in the presence or absence of foods with the clinical response. In the meanwhile, to establish recommendations for their administration in relation to foods is inconsistent for some of these drugs and their results is uncertain given the lack of studies based on the FDA bioequivalence dictamen.

New orally active DNA minor groove binding small molecule CT-1 acts against breast cancer by targeting tumor DNA damage leading to p53-dependent apoptosis.

PubMed

Saini, Karan Singh; Hamidullah; Ashraf, Raghib; Mandalapu, Dhanaraju; Das, Sharmistha; Siddiqui, Mohd Quadir; Dwivedi, Sonam; Sarkar, Jayanta; Sharma, Vishnu Lal; Konwar, Rituraj

2017-04-01

Targeting tumor DNA damage and p53 pathway is a clinically established strategy in the development of cancer chemotherapeutics. Majority of anti-cancer drugs are delivered through parenteral route for reasons like severe toxicity, lack of stability, and poor enteral absorption. Current DNA targeting drugs in clinical like anthracycline suffers from major drawbacks like cardiotoxicity. Here, we report identification of a new orally active small molecule curcumin-triazole conjugate (CT-1) with significant anti-breast cancer activity in vitro and in vivo. CT-1 selectively and significantly inhibits viability of breast cancer cell lines; retards cells cycle progression at S phase and induce mitochondrial-mediated cell apoptosis. CT-1 selectively binds to minor groove of DNA and induces DNA damage leading to increase in p53 along with decrease in its ubiquitination. Inhibition of p53 with pharmacological inhibitor as well as siRNA revealed the necessity of p53 in CT-1-mediated anti-cancer effects in breast cancer cells. Studies using several other intact p53 and deficient p53 cancer cell lines further confirmed necessity of p53 in CT-1-mediated anti-cancer response. Pharmacological inhibition of pan-caspase showed CT-1 induces caspase-dependent cell death in breast cancer cells. Most interestingly, oral administration of CT-1 induces significant inhibition of tumor growth in LA-7 syngeneic orthotropic rat mammary tumor model. CT-1 treated mammary tumor shows enhancement in DNA damage, p53 upregulation, and apoptosis. Collectively, CT-1 exhibits potent anti-cancer effect both in vitro and in vivo and could serve as a safe orally active lead for anti-cancer drug development. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Isoquercetin ameliorates hyperglycemia and regulates key enzymes of glucose metabolism via insulin signaling pathway in streptozotocin-induced diabetic rats.

PubMed

Jayachandran, Muthukumaran; Zhang, Tongze; Ganesan, Kumar; Xu, Baojun; Chung, Stephen Sum Man

2018-06-15

Among the foremost common flavonoids within the human diet, quercetin glycosides possess neuroprotective, cardioprotective, anti-oxidative, chemopreventive, and anti-allergic properties. Isoquercetin is one such promising candidate with anti-diabetic potential. However, complete studies of its molecular action on insulin signaling pathway and carbohydrate metabolizing enzymes remain unclear. Hence, we have designed this study to accumulate the experimental evidence in support of anti-diabetic effects of isoquercetin. Male albino Wistar rats were divided into seven groups. Rats (Groups 3-7) were administered a single intraperitoneal injection of streptozotocin (STZ; 40 mg/kg b.w) to induce diabetes mellitus. As an extension, STZ rats received isoquercetin at three different doses (20, 40 and 80 mg/kg b.w), and Group 7 rats received glibenclamide (standard drug) (600 μg/kg b.w). The results showed that STZ exaggerated blood sugar, decreased insulin, altered metabolizing enzymes, and impaired the mRNA expression of insulin signaling genes and carbohydrate metabolizing enzyme genes. Supplementation with isoquercetin significantly normalized blood sugar levels, insulin and regulated the mRNA expression of insulin signaling genes and carbohydrate metabolizing enzyme genes. The results achieved with isoquercetin are similar to that of standard drug glibenclamide. The findings suggest isoquercetin could be a possible therapeutic agent for treating diabetes mellitus in the near future. Copyright © 2018 Elsevier B.V. All rights reserved.

Use of Fixed Dose Combination (FDC) Drugs in India: Central Regulatory Approval and Sales of FDCs Containing Non-Steroidal Anti-Inflammatory Drugs (NSAIDs), Metformin, or Psychotropic Drugs

PubMed Central

McGettigan, Patricia; Roderick, Peter; Mahajan, Rushikesh; Kadam, Abhay; Pollock, Allyson M.

2015-01-01

Background In 2012, an Indian parliamentary committee reported that manufacturing licenses for large numbers of fixed dose combination (FDC) drugs had been issued by state authorities without prior approval of the Central Drugs Standard Control Organization (CDSCO) in violation of rules, and considered that some ambiguity until 1 May 2002 about states’ powers might have contributed. To our knowledge, no systematic enquiry has been undertaken to determine if evidence existed to support these findings. We investigated CDSCO approvals for and availability of oral FDC drugs in four therapeutic areas: analgesia (non-steroidal anti-inflammatory drugs [NSAIDs]), diabetes (metformin), depression/anxiety (anti-depressants/benzodiazepines), and psychosis (anti-psychotics). Methods and Findings This was an ecologic study with a time-trend analysis of FDC sales volumes (2007–2012) and a cross-sectional examination of 2011–2012 data to establish the numbers of formulations on the market with and without a record of CDSCO approval (“approved” and “unapproved”), their branded products, and sales volumes. Data from the CDSCO on approved FDC formulations were compared with sales data from PharmaTrac, a database of national drug sales. We determined the proportions of FDC sales volumes (2011–2012) arising from centrally approved and unapproved formulations and from formulations including drugs banned/restricted internationally. We also determined the proportions of centrally approved and unapproved formulations marketed before and after 1 May 2002, when amendments were made to the drug rules. FDC approvals in India, the United Kingdom (UK), and United States of America (US) were compared. For NSAID FDCs, 124 formulations were marketed, of which 34 (27%) were centrally approved and 90 (73%) were unapproved; metformin: 25 formulations, 20 (80%) approved, five (20%) unapproved; anti-depressants/benzodiazepines: 16 formulations, three (19%) approved, 13 (81%) unapproved; anti-psychotics: ten formulations, three (30%) approved, seven (70%) unapproved. After 1 May 2002, the proportions of approved FDC formulations increased for NSAIDs (26%/28%) and anti-psychotics (0%/38%) and decreased for metformin (100%/75%) and anti-depressants/benzodiazepines (20%/18%), and the overall proportion approved remained similar before and after that date. FDC formulations gave rise to multiple branded products, ranging from 211 anti-psychotic FDC products from ten formulations to 2,739 NSAID FDC products from 124 formulations. The proportions of FDC sales volumes arising from unapproved formulations were as follows: anti-depressants/benzodiazepines, 69%; anti-psychotics, 43%; NSAIDs, 28%; and metformin, 0.4%. Formulations including drugs banned/restricted internationally comprised over 12% of NSAID FDC sales and 53% of anti-psychotic FDC sales. Across the four therapeutic areas, 14 FDC formulations were approved in the UK and 22 in the US. Conclusions There was evidence supporting concerns about FDCs. Metformin excepted, substantial numbers of centrally unapproved formulations for NSAID, anti-depressant/benzodiazepine, and anti-psychotic FDCs were marketed; sales volumes were high. The legal need for central approval of new drugs before manufacture has been in place continuously since 1961, including for FDCs meeting the applicable legal test. Proportions of centrally unapproved formulations after 1 May 2002 did not decrease overall, and no ambiguity was found about states’ licensing powers. Unapproved formulations should be banned immediately, prioritising those withdrawn/banned internationally and undertaking a review of benefits and risks for patients in ceasing or switching to other medicines. Drug laws need to be amended to ensure the safety and effectiveness of medicines marketed in India. PMID:25965416

CREED study: Hypoglycaemia during Ramadan in individuals with Type 2 diabetes mellitus from three continents.

PubMed

Jabbar, Abdul; Hassanein, Mohamed; Beshyah, Salem A; Boye, Kristina S; Yu, Maria; Babineaux, Steven M

2017-10-01

To describe diabetes treatment and hypoglycaemia in individuals with Type 2 diabetes mellitus during Ramadan. A multi-country, retrospective, observational study with data captured before, during, and after Ramadan. We report on a cohort of people (N=3250) with Type 2 diabetes mellitus in four culturally distinct regions: Asia, North Africa, Europe, and the Middle East. During Ramadan, the proportion of participants on oral anti-diabetic medication alone ranged from 68.4% (Middle East) to 80.5% (Asia); the proportion on insulin alone ranged from 3.7% (Middle East) to 8.6% (Europe). The average number of days fasted for individuals with an American Diabetes Association (ADA) risk status of very high was 27 (Middle East), 25.7 (Asia), 25.4 (North Africa), and 21 (Europe). The incidence of hypoglycaemia according to an ADA risk status of very high was 5.6% (n=1/18, Europe), 6.1% (n=2/33, Middle East), 8.7% (n=4/46, Asia), and 38% (n=10/26, North Africa). The incidence of hypoglycaemia, during Ramadan, for the entire cohort was 16.8% with insulin treatment and 5.3% with oral anti-diabetic medication. Having an episode of hypoglycaemia before Ramadan was associated with hypoglycaemia during Ramadan (odds ratio 7.80; 95% confidence interval 5.31-11.45). Approaches to the management of Type 2 diabetes mellitus during Ramadan varied across regions. Episodes of hypoglycaemia and insulin therapy predicted risk of hypoglycaemia during Ramadan and identified individuals who required Ramadan-specific education. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Therapeutic Phytogenic Compounds for Obesity and Diabetes

PubMed Central

Jung, Hee Soong; Lim, Yun; Kim, Eun-Kyoung

2014-01-01

Natural compounds have been used to develop drugs for many decades. Vast diversities and minimum side effects make natural compounds a good source for drug development. However, the composition and concentrations of natural compounds can vary. Despite this inconsistency, half of the Food and Drug Administration (FDA)-approved pharmaceuticals are natural compounds or their derivatives. Therefore, it is essential to continuously investigate natural compounds as sources of new pharmaceuticals. This review provides comprehensive information and analysis on natural compounds from plants (phytogenic compounds) that may serve as anti-obesity and/or anti-diabetes therapeutics. Our growing understanding and further exploration of the mechanisms of action of the phytogenic compounds may afford opportunities for development of therapeutic interventions in metabolic diseases. PMID:25421245

DOE Office of Scientific and Technical Information (OSTI.GOV)

Nagamatsu, Shinya, E-mail: shinya@ks.kyorin-u.ac.jp; Ohara-Imaizumi, Mica; Nakamichi, Yoko

Highlights: {yields} Anti-diabetic new drug, DPP-4 inhibitor, can affect the insulin exocytosis. {yields} DPP-4 inhibitor treatment altered syntaxin 1 expression. {yields} Treatment of db/db mice with DPP-4 inhibitor increased insulin release. -- Abstract: Incretin promotes insulin secretion acutely. Recently, orally-administered DPP-4 inhibitors represent a new class of anti-hyperglycemic agents. Indeed, inhibitors of dipeptidyl peptidase-IV (DPP-4), sitagliptin, has just begun to be widely used as therapeutics for type 2 diabetes. However, the effects of sitagliptin-treatment on insulin exocytosis from single {beta}-cells are yet unknown. We therefore investigated how sitagliptin-treatment in db/db mice affects insulin exocytosis by treating db/db mice with des-F-sitagliptinmore » for 2 weeks. Perfusion studies showed that 2 weeks-sitagliptin treatment potentiated insulin secretion. We then analyzed insulin granule motion and SNARE protein, syntaxin 1, by TIRF imaging system. TIRF imaging of insulin exocytosis showed the increased number of docked insulin granules and increased fusion events from them during first-phase release. In accord with insulin exocytosis data, des-F-sitagliptin-treatment increased the number of syntaxin 1 clusters on the plasma membrane. Thus, our data demonstrated that 2-weeks des-F-sitagliptin-treatment increased the fusion events of insulin granules, probably via increased number of docked insulin granules and that of syntaxin 1 clusters.« less

The enhancement of oxidative DNA damage by anti-diabetic metformin, buformin, and phenformin, via nitrogen-centered radicals.

PubMed

Ohnishi, Shiho; Mizutani, Hideki; Kawanishi, Shosuke

2016-08-01

Metformin (N,N-dimethylbiguanide), buformin (1-butylbiguanide), and phenformin (1-phenethylbiguanide) are anti-diabetic biguanide drugs, expected to having anti-cancer effect. The mechanism of anti-cancer effect by these drugs is not completely understood. In this study, we demonstrated that these drugs dramatically enhanced oxidative DNA damage under oxidative condition. Metformin, buformin, and phenformin enhanced generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in isolated DNA reacted with hydrogen peroxide (H2O2) and Cu(II), although these drugs did not form 8-oxodG in the absence of H2O2 or Cu(II). An electron paramagnetic resonance (EPR) study, utilizing alpha-(4-pyridyl-1-oxide)-N-tert-butylnitrone and 3,3,5,5-tetramethyl-1-pyrroline-N-oxide as spin trapping agents, showed that nitrogen-centered radicals were generated from biguanides in the presence of Cu(II) and H2O2, and that these radicals were decreased by the addition of DNA. These results suggest that biguanides enhance Cu(II)/H2O2-mediated 8-oxodG generation via nitrogen-centered radical formation. The enhancing effect on oxidative DNA damage may play a role on anti-cancer activity.

Real-life efficacy and safety of vildagliptin compared with sulfonylureas as add-on to metformin in patients with type 2 diabetes mellitus in Germany.

PubMed

Göke, R; Gruenberger, J B; Bader, G; Dworak, M

2014-05-01

Metformin is an established first-line treatment for type 2 diabetes mellitus (T2DM) patients, but intensification of oral anti-diabetes therapy is usually required over time. A large observational study of 45,868 T2DM patients in 27 countries (EDGE) was conducted to compare the effectiveness and safety of vildagliptin as add-on therapy to another oral anti-diabetes drug (OAD) vs other dual OAD combinations. This report presents results from a post-hoc analysis of patients in Germany who received vildagliptin or a sulfonylurea (SU) in combination with metformin. Patients inadequately controlled with monotherapy became eligible only after the add-on treatment was finalized. Patients included were assigned to receive either vildagliptin or another OAD (SUs, thiazolidinediones, glinides, α-glucosidase inhibitors, or metformin; DPP-4 inhibitors or glucagon-like peptide-1 [GLP-1] mimetics/analogs were excluded). The primary end-point was the proportion of patients achieving a reduction in HbA1c >0.3% without peripheral edema, hypoglycemia, discontinuation due to gastrointestinal event, or weight gain ≥5%. Of 8887 patients enrolled in Germany, 6439 received vildagliptin and 971 received SUs as add-on to metformin. The primary end-point was reached in 34.9% and 29.6% of patients in the vildagliptin and SU groups, respectively, with an unadjusted odds ratio of 1.27 (95% CI = 1.09, 1.47; p = 0.001). HbA1c decreased in both cohorts from baseline (-0.7% with vildagliptin vs -0.5% with SUs), with a mean between-group difference of -0.2% (95% CI = -0.22, -0.09). The number of hypoglycemic events was 4-fold higher in the SU group than in the vildagliptin group (vildagliptin = 0.11%; SU = 0.41%). In a real-life setting, vildagliptin was associated with a numerically greater reduction in HbA1c, less hypoglycemia, and more patients reaching target HbA1c without hypoglycemia or weight gain compared with SUs. Open-label design and under reporting of adverse events are limitations of this post hoc analysis.

Synthesis, Characterisation, Molecular Docking, Anti-microbial and Anti-diabetic Screening of Substituted 4-indolylphenyl-6-arylpyrimidine-2-imine Derivatives.

PubMed

Ramya, Veerasamy; Vembu, Santhirakasu; Ariharasivakumar, Ganesan; Gopalakrishnan, Manathusamy

2017-09-01

The purpose of the research is to synthesise a novel series of (E)-2-(4-(1H-indol-3-yl)-6-p-substituted phenylpyrimidin-2-yl)dimethylguanidine derivatives since 3-(1H-indol-3-yl)-1-p-substituted phenylprop-2-en-1-one and evaluate their molecular docking studies, antimicrobial, and anti-diabetic activities. Among all the synthesized compounds ( 11a-g ), compound 11a exhibits excellent CDOCKER energy (-11.36 kcal/mol). The entire compounds ( 11a-g ) confirm very good antimicrobial activity towards the tested microorganisms. In the in vitro anti-diabetic studies, compounds (11a, 11c, and 11g) confirm higher alpha-amylase and alpha-glucosidase inhibition activity. In the in vivo anti-diabetic activities, the synthesized compounds (11a-g) (10 mg/kg, p.o.) investigated by the streptozotocin (60 mg/kg, ip) -nicotinamide (120 mg/kg, p.o.) - induced model in adult male albino Wistar rat and these derivatives show considerable fasting blood glucose level when compared to metformin hydrochloride a potent and well-known anti-diabetic drug as a reference. © Georg Thieme Verlag KG Stuttgart · New York.

Antidiabetic activity of the mangrove species Ceriops decandra in alloxan-induced diabetic rats.

PubMed

Nabeel, Mannalamkunnath Alikunhi; Kathiresan, Kandasamy; Manivannan, Subramanian

2010-06-01

Diabetes is a series of disorders characterized by increased fasting and postprandial glucose concentration and insulin deficiency and/or decreased insulin action. Although there are a number of commercially available drugs for the treatment of diabetes, their long-term use may cause unwanted side effects. Consequently, many studies are underway to find natural remedies that can effectively reduce the intensity of diabetes. The aim of the present study was to evaluate the antidiabetic activity of the mangrove species Ceriops decandra. The effects of daily oral administration of an ethanolic extract from the leaves of C. decandra (30, 60, 120 mg/kg) for 30 days on blood glucose, hemoglobin (Hb), HbA1c, liver glycogen and some carbohydrate metabolic enzymes were evaluated in normal and alloxan-induced diabetic rats. The effects of these extracts were compared with the effect of 30-days treatment with 0.1 mg/kg, p.o., glibenclamide, a commercially available drug commonly used in the treatment of diabetes. Oral administration of 120 mg/kg extract modulated all the parameters evaluated to levels seen in control rats. The effects of 120 mg/kg extract were comparable to those of glibenclamide. The extract of the mangrove plant C. decandra exhibited promising antidiabetic activity and could be considered for further evaluation in clinical studies and drug development. © 2010 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and Blackwell Publishing Asia Pty Ltd.

Could simvastatin be considered as a potential therapy for chronic lung diseases? A debate on the pros and cons.

PubMed

Tulbah, Alaa S; Ong, Hui Xin; Colombo, Paolo; Young, Paul M; Traini, Daniela

2016-10-01

Simvastatin (SV) is a drug from the statin class, currently used orally as an anti-cholesterolemic drug. It inhibits the 3-hydroxy-3-methyl-glutaryl-Coenzyme A (HMG-CoA) reductase to reduce cholesterol synthesis. Recently, it has been found that SV also has several other protective pharmacological actions unrelated to its anti-cholesterol effects that might be beneficial in the treatment of chronic airway diseases. This review summarizes the evidence relating to SV as a potential anti-inflammatory, anti-oxidant and muco-inhibitory agent, administered both orally and via pulmonary inhalation, and discusses its pro and cons. Evidence could potentially be used to support the delivery of SV as inhaled formulation for the treatment of chronic respiratory diseases. The use of SV as anti-inflammatory, anti-oxidant and muco-inhibitory agent for drug delivery to the lung is promising. Inhaled SV formulations could allow the delivery profile to be customized and optimized to take advantage of the rapid onset of action, low systemic side effect and improved physico-chemical stability. This treatment could potentially to be used clinically for the localized treatment of lung diseases where inflammation and oxidative stress production is present.

Pharmacologic Approaches Against Advanced Glycation End Products (AGEs) in Diabetic Cardiovascular Disease.

PubMed

Nenna, Antonio; Nappi, Francesco; Avtaar Singh, Sanjeet Singh; Sutherland, Fraser W; Di Domenico, Fabio; Chello, Massimo; Spadaccio, Cristiano

2015-05-01

Advanced Glycation End-Products (AGEs) are signaling proteins associated to several vascular and neurological complications in diabetic and non-diabetic patients. AGEs proved to be a marker of negative outcome in both diabetes management and surgical procedures in these patients. The reported role of AGEs prompted the development of pharmacological inhibitors of their effects, giving rise to a number of both preclinical and clinical studies. Clinical trials with anti-AGEs drugs have been gradually developed and this review aimed to summarize most relevant reports. Evidence acquisition process was performed using PubMed and ClinicalTrials.gov with manually checked articles. Pharmacological approaches in humans include aminoguanidine, pyridoxamine, benfotiamine, angiotensin converting enzyme inhibitors, angiotensin receptor blockers, statin, ALT-711 (alagebrium) and thiazolidinediones. The most recent promising anti-AGEs agents are statins, alagebrium and thiazolidinediones. The role of AGEs in disease and new compounds interfering with their effects are currently under investigation in preclinical settings and these newer anti-AGEs drugs would undergo clinical evaluation in the next years. Compounds with anti-AGEs activity but still not available for clinical scenarios are ALT-946, OPB-9195, tenilsetam, LR-90, TM2002, sRAGE and PEDF. Despite most studies confirm the efficacy of these pharmacological approaches, other reports produced conflicting evidences; in almost any case, these drugs were well tolerated. At present, AGEs measurement has still not taken a precise role in clinical practice, but its relevance as a marker of disease has been widely shown; therefore, it is important for clinicians to understand the value of new cardiovascular risk factors. Findings from the current and future clinical trials may help in determining the role of AGEs and the benefits of anti-AGEs treatment in cardiovascular disease.

Suicide attempt by an overdose of sitagliptin, an oral hypoglycemic agent: a case report and a review of the literature.

PubMed

Furukawa, Shinya; Kumagi, Teru; Miyake, Teruki; Ueda, Teruhisa; Niiya, Tetsuji; Nishino, Keiichiro; Murakami, Shigeto; Murakami, Masato; Matsuura, Bunzo; Onji, Morikazu

2012-01-01

Dipeptidyl peptidase-4 (DPP-4) inhibitors are a newer class of oral hypoglycemic agents for the management of diabetes that elevate the plasma concentration of active glucagon-like peptide-1 via inhibition of DPP-4. They effectively lower not only glycosylated hemoglobin levels, but also fasting and postprandial plasma glucose levels. Patients with diabetes occasionally consume an overdose of oral hypoglycemic agents in suicide attempts: the prevalence of depression is high in patients with diabetes, and depression is a strong risk factor for suicide. We encountered an 86-year-old woman with type 2 diabetes and depression, who was transferred to the emergency room 4h after ingestion of 1,700 mg of the DPP-4 inhibitor sitagliptin (1,700 mg is 17 times greater than the approved maximum dose). Upon arrival, she was fully conscious, plasma glucose was 124 mg/dL, and serum immunoreactive insulin level was 5.81 µU/mL. Thereafter, the plasma concentration of sitagliptin rose to 3,793 nM, which is 4.5 times higher than the value found under regular treatment with the maximum dose. The patient did not suffer from hypoglycemia, suggesting that a single oral overdose of sitagliptin is unlikely to cause hypoglycemia. A literature review of oral anti-diabetic agents revealed that overdose of biguanides is occasionally fatal when immediate intensive care is not provided. In summary, sitagliptin is a good treatment option for diabetic elderly patients or patients with psychiatric disorders who are suicidal and do not require insulin.

Structural investigation of chitosan-based microspheres with some anti-inflammatory drugs

NASA Astrophysics Data System (ADS)

Dreve, Simina; Kacso, Iren; Popa, Adriana; Raita, Oana; Dragan, Felicia; Bende, A.; Borodi, Gh.; Bratu, I.

2011-06-01

The use of chitosan as an excipient in oral formulations, as a drug delivery vehicle for ulcerogenic anti-inflammatory drugs and as base in polyelectrolyte complex systems, to prepare solid release systems as sponges was investigated. The preparation by double emulsification of chitosan hydrogels carrying diclofenac, acetyl-salycilic acid and hydrocortisone acetate as anti-inflammatory drugs is reported. The concentration of anti-inflammatory drug in the chitosan hydrogel generating the sponges was 0.08 mmol. Chitosan-drug loaded sponges with anti-inflammatory drugs were prepared by freeze-drying at -60 °C and 0.009 atm. Structural investigations of the solid formulations were done by Fourier-transformed infrared and ultraviolet-visible spectroscopy, spectrofluorimetry, differential scanning calorimetry and X-ray diffractometry. The results indicated that the drug molecules are forming temporary chelates in chitosan hydrogels and sponges. Electron paramagnetic resonance demonstrates the presence of free radicals in a wide range and the antioxidant activity for chitosan-drug supramolecular cross-linked assemblies.

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2013 CFR

2013-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2012 CFR

2012-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

42 CFR 414.900 - Basis and scope.

Code of Federal Regulations, 2014 CFR

2014-10-01

...— (i) Influenza. (ii) Pneumococcal and Hepatitis B vaccines. (iii) Antigens. (iv) Hemophilia blood clotting factor. (v) Immunosuppressive drugs. (vi) Certain oral anti-cancer drugs. [69 FR 66424, Nov. 15...

Discovery of specific ligands for oral squamous carcinoma to develop anti-cancer drug loaded precise targeting nanotherapeutics.

PubMed

Yang, Fan; Liu, Ruiwu; Kramer, Randall; Xiao, Wenwu; Jordan, Richard; Lam, Kit S

2012-12-01

Oral squamous cell carcinoma has a low five-year survival rate, which may be due to late detection and a lack of effective tumor-specific therapies. Using a high throughput drug discovery strategy termed one-bead one-compound combinatorial library, the authors identified six compounds with high binding affinity to different human oral squamous cell carcinoma cell lines but not to normal cells. Current work is under way to develop these ligands to oral squamous cell carcinoma specific imaging probes or therapeutic agents.

Anti-diabetic activity of extract from Persea americana Mill. leaf via the activation of protein kinase B (PKB/Akt) in streptozotocin-induced diabetic rats.

PubMed

Lima, C R; Vasconcelos, C F B; Costa-Silva, J H; Maranhão, C A; Costa, J; Batista, T M; Carneiro, E M; Soares, L A L; Ferreira, F; Wanderley, A G

2012-05-07

The leaves of Persea americana Mill. (Lauraceae) have been popularly used in the treatment of diabetes in countries in Latin America and Africa. To investigate the hypoglycaemic properties and to determine the molecular mechanism by which the hydroalcoholic extract of the leaves of Persea americana reduce blood glucose levels in streptozotocin (STZ)-induced diabetes in rats via the enzymatic pathway of protein kinase B (PKB/Akt). The hydroalcoholic extract of the leaves of Persea americana (0.15 and 0.3g/kg/day), vehicle and metformin (0.5g/kg/day) were administered orally to STZ-diabetic rats (n=7/group) for 4 weeks. Changes in body weight, food and water intake, fasting glucose levels and oral glucose tolerance were evaluated. Phosphorylation and the expression of PKB in the liver and soleus muscle were determined by Western blot. The hydroalcoholic extract of the leaves of Persea americana reduced blood glucose levels and improved the metabolic state of the animals. Additionally, PKB activation was observed in the liver and skeletal muscle of treated rats when compared with untreated rats. The results indicate that the hydroalcoholic extract of the leaves of Persea americana has anti-diabetic properties and possibly acts to regulate glucose uptake in liver and muscles by way of PKB/Akt activation, restoring the intracellular energy balance. Copyright © 2012. Published by Elsevier Ireland Ltd.

Over-the-Counter Medicines and Diabetes Care.

PubMed

Taylor, Jeff

2017-12-01

People with diabetes turn to over-the-counter (OTC) medicines for many ailments. The focus of this brief review is the impact common OTC medicines might have on this group of patients. Three types of OTC medicines were selected as most deserving of attention: 3 herbal agents, nonsteroidal anti-inflammatory drugs (NSAIDs) and cough/cold products. Existing literature was used to determine precautions that might be in order. Herbal/natural agents with the potential to impact blood sugar have been identified in various reports. In discussing 3, glucosamine and cinnamon (at doses recommended on commercial products) should have minimal impact on diabetic management, whereas St. John's wort is a concern involving potential drug interactions. For colds, of about 11 active ingredients, only decongestants (primarily oral) need be considered for their possible effects on blood sugar. Finally, NSAIDs (even at OTC doses) must be used with caution, given their cardiovascular, renal and gastrointestinal risks. Care guidelines do encourage patients to take ownership of their condition. Yet the ability to self-medicate safely is not a certainty. In spite of easy access and a reasonable level of safety, OTC medicines still can negatively impact a user. NSAIDs available without prescription continue to cause concern. Before the use of any medicine, a person must ensure it will be safe. A health-care provider can be asked for assistance, but that option may not always be employed. Package information is there to provide critical information in lieu of that, something the self-medicating patient will, it is hoped, embrace. Copyright © 2017 Diabetes Canada. Published by Elsevier Inc. All rights reserved.

Experimental study on effect of hydroalcoholic extract of Emblica officinalis fruits on glucose homeostasis and metabolic parameters

PubMed Central

Patel, Snehal S.; Goyal, Ramesh K.; Shah, Rajendra S.; Tirgar, Pravin R.; Jadav, Pinakin D.

2013-01-01

Polyphenols from natural source are potential therapeutics that act alone or supplement anti-diabetic drugs in the prevention and treatment of diabetes. The present investigation was undertaken to study the effect of hydroalcoholic extract (HE) of fruits of Emblica officinalis on type 1 diabetic rats. Diabetes was induced by streptozotocin (STZ) (45 mg/kg i.v.). HE (100 mg/kg, p.o.) was administered for 4 weeks and at the end of treatment, blood samples were collected and analyzed for various biochemical parameters. STZ produced a diabetic state exhibiting all the cardinal symptoms such as loss of body weight, polydipsia, polyuria, glucosuria, polyphagia, hypoinsulinemia, and hyperglycemia associated with hypercholesterolemia and hypertriglyceridemia. Treatment with HE prevented cardinal symptoms and caused significant decrease in fasting serum glucose, AUCglucose, cholesterol, triglyceride, low-density lipoprotein (LDL) and very LDL in diabetic rats. However, insulin, AUCinsulin, and serum high-density lipoprotein level were not significantly altered by treatment. Treatment also reduced lipid peroxidation and increased anti-oxidant parameters in the liver homogenates of diabetic rats. Polyphenol enriched fraction of HE significantly improved disarranged carbohydrate and lipid metabolism of chemically induced diabetes in rats. The mechanism of its anti-diabetic activity appears to be either improvement in peripheral glucose utilization, increased insulin sensitivity, or anti-oxidant property. PMID:24696584

Economic implications of type 2 diabetes management.

PubMed

McAdam Marx, Carrie

2013-06-01

Diabetes mellitus (DM) is a complex and progressive disease associated with significant morbidity and mortality. Both the prevalence and economic burden associated with DM have been steadily increasing and are projected to continue to increase. A series of cost reports published by the American Diabetes Association (ADA) between 1997 and 2012 have suggested that direct medical costs are the primary cost driver in DM. Direct costs have increased over 5-fold during this time frame, from $44 billion to $176 billion annually, likely due to both the increased prevalence of DM and increased costs of providing DM-related care. Trends in anti-diabetic medication usage as reported by Centers for Disease Control data from 1997 to 2011 have found that the proportion of diagnosed patients treated for DM has remained fairly stable. However, there has been an increase in the use of oral agents alone, a decrease in patients on insulin only, and a relatively small increase in the percentage of patients using both insulin and oral agents, suggesting stagnation regarding the uptake of insulin use. In parallel, the ADA cost and utilization data suggest that use of medications to treat DM-related comorbidities and complications has risen, which contributes to the risk of medication errors, avoidable adverse drug events, and noncompliance. These data highlight a few of the challenges involved in managing a population of patients with DM. A comprehensive assessment of unmet needs for the population with DM is essential for effective population management. An approach that strives to identify and reduce barriers to patients receiving optimal care and being active participants in their DM management will facilitate systemwide efforts to improve DM outcomes.

Pattern of pharmaceutical retailing of anti-diabetic products in Ibadan, Nigeria.

PubMed

Famuyiwa, O O

1991-01-01

Twenty-four pharmacists in the city of Ibadan were surveyed through a self-administered structured questionnaire as to the extent of their involvement in the pharmaceutical retailing of antidiabetic products and their cost. Oral hypoglycemic agents especially, chlorpropamide (Diabenese) and glibenclamide (Daonil) were the most readily available drugs being obtainable from 21 (87.5%) pharmacies. Insulin was stocked regularly by only 14 (58.3%) of the pharmacists and insulin syringes and needles could be obtained from only 10 (41.6%) of the pharmacies. Among materials for urine testing, clinistix strip was the most readily available and fully one-third of the pharmacies did not stock any such material. The prices of all the products were disturbingly high and between 1983 and 1986 when retail prices were re-assessed, the cost of some materials had escalated by as much as 400%. Scarcity of antidiabetic products and their high cost pose serious challenges for those involved in the care of diabetic patients in Nigeria. Some suggestions have been made as to what steps both the government and the pharmaceutical industry can take in ensuring the availability of these life sustaining products for the increasingly large Nigerian diabetic population.

Improvement of diabetes, obesity and hypertension in type 2 diabetic KKA{sup y} mice by bis(allixinato)oxovanadium(IV) complex

DOE Office of Scientific and Technical Information (OSTI.GOV)

Adachi, Yusuke; Yoshikawa, Yutaka; Yoshida, Jiro

Previously, we found that bis(allixinato)oxovanadium(IV) (VO(alx){sub 2}) exhibits a potent hypoglycemic activity in type 1-like diabetic mice. Since the enhancement of insulin sensitivity is involved in one of the mechanisms by which vanadium exerts its anti-diabetic effects, VO(alx){sub 2} was further tested in type 2 diabetes with low insulin sensitivity. The effect of oral administration of VO(alx){sub 2} was examined in obesity-linked type 2 diabetic KKA{sup y} mice. Treatment of VO(alx){sub 2} for 4 weeks normalized hyperglycemia, glucose intolerance, hyperinsulinemia, hypercholesterolemia and hypertension in KKA{sup y} mice; however, it had no effect on hypoadiponectinemia. VO(alx){sub 2} also improved hyperleptinemia, followingmore » attenuation of obesity in KKA{sup y} mice. This is the first example in which a vanadium compound improved leptin resistance in type 2 diabetes by oral administration. On the basis of these results, VO(alx){sub 2} is proposed to enhance not only insulin sensitivity but also leptin sensitivity, which in turn improves diabetes, obesity and hypertension in an obesity-linked type 2 diabetic animal.« less

Wound healing activity of Argyreia nervosa leaves extract

PubMed Central

Singhal, AK; Gupta, H; Bhati, VS

2011-01-01

Background: Argyreia nervosa (Convolvulaceae) plant is an example of hallucinogenic plant. The antiseptic, anti-inflammatory, antispasmodic, antibacterial, antiviral, antifungal, anticonvulsant, nootropic, antifertility and aphrodisiac properties have already been reported for this plant. Aim: The aim of present work was to evaluate the wound healing property in normal and diabetic animals by oral and topical administration of ethanolic extract of leaves. Materials and Methods: Phytochemical investigations showed the presence of various biochemicals (alkaloids, flavonoids, carbohydrates, triterpenoids, proteins, saponins, steroids, tannins). A single injection of alloxan monohydrate (120 mg/kg, i.p.) prepared in citrate buffer (0.1 M, pH 4.5) was administered to produce diabetes in rats and mice, after overnight fasting. Excision wounds (sized 300 mm2 and of 2 mm depth) were used for the study of rate of contraction of wound and epithelization. The means of wound area measurement between groups at different time intervalswere compared using one-way analysis of variance (ANOVA), followed by Dunnet's test. Results: Extracts of A. nervosa showed significant wound healing effect in normal (topically treated) and diabetic (both topically and orally treated) rats. In diabetic rats, the topically treated group showed more significant effect than the orally treated groups. Conclusion: The present study demonstrates that A. nervosa leaves extract applied topically promotes healing of wounds more significantly as compared to oral application, in both normal rats and alloxan induced diabetic rats, where healing is otherwise delayed. PMID:23776770

Effect of troxerutin on insulin signaling molecules in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic adult male rat.

PubMed

Sampath, Sathish; Karundevi, Balasubramanian

2014-10-01

Troxerutin is a trihydroxyethylated derivative of the flavonoid, rutin. It has been reported to possess the hepatoprotective, nephroprotective, antioxidant, anti-inflammatory, and antihyperlipidemic activities. Troxerutin treatment reduced the blood glucose and glycosylated hemoglobin levels in high-cholesterol-induced insulin-resistant mice and in type-2 diabetic patients. However, the mechanism by which it exhibits antidiabetic property was unknown. Therefore, the present study was designed to evaluate the effect of troxerutin on insulin signaling molecules in gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic rats. Wistar male albino rats were selected and divided into five groups. Group I: Control. Group II: High fat and sucrose-induced type-2 diabetic rats. Group III: Type-2 diabetic rats treated with troxerutin (150 mg/kg body weight/day orally). Group IV: Type-2 diabetic rats treated with metformin (50 mg/kg body weight/day orally). Group V: Normal rats treated with troxerutin (150 mg/kg body weight/day orally). After 30 days of treatment, fasting blood glucose, oral glucose tolerance, serum lipid profile, and the levels of insulin signaling molecules, glycogen, glucose uptake, and oxidation in gastrocnemius muscle were assessed. Diabetic rats showed impairment in insulin signaling molecules (IR, p-IRS-1(Tyr632), p-Akt(Ser473), β-arrestin-2, c-Src, p-AS160(Thr642), and GLUT4 proteins), glycogen concentration, glucose uptake, and oxidation. Oral administration of troxerutin showed near normal levels of blood glucose, serum insulin, lipid profile, and insulin signaling molecules as well as GLUT4 proteins in type-2 diabetic rats. It is concluded from the present study that troxerutin may play a significant role in the management of type-2 diabetes mellitus, by improving the insulin signaling molecules and glucose utilization in the skeletal muscle.

Antiobesity Pharmacotherapy for Patients with Type 2 Diabetes: Focus on Long-Term Management

PubMed Central

Jeon, Won Seon

2014-01-01

Type 2 diabetes and obesity have a complex relationship; obesity is linked to insulin resistance, the precursor to type 2 diabetes. The management of obesity is an important method to delay onset of diabetes and improve the glycemic durability of antidiabetic agents. However, insulin and some of the oral hypoglycemic agents used to treat diabetes cause significant weight gain, and it is difficult for patients with diabetes to reduce and maintain their weight by life-style changes alone. Thus, antiobesity medications or bariatric surgery may be a necessary adjunct for certain obese patients with diabetes. In 2012, the U.S. Food and Drug Administration (FDA) approved lorcaserin and phentermine/topiramate extended-release for the management of chronic weight, and approval for naltrexone/bupropion sustained-release as an adjunct to exercise and reduced caloric intake followed in 2014. Liraglutide is pending FDA approval for antiobesity drug. Here we review the efficacy of approved and new promising drugs for the management of obesity. PMID:25559569

Long-Term Cost-Effectiveness of Insulin Glargine Versus Neutral Protamine Hagedorn Insulin for Type 2 Diabetes in Thailand.

PubMed

Permsuwan, Unchalee; Chaiyakunapruk, Nathorn; Dilokthornsakul, Piyameth; Thavorn, Kednapa; Saokaew, Surasak

2016-06-01

Even though Insulin glargine (IGlar) has been available and used in other countries for more than a decade, it has not been adopted into Thai national formulary. This study aimed to evaluate the long-term cost effectiveness of IGlar versus neutral protamine Hagedorn (NPH) insulin in type 2 diabetes from the perspective of Thai Health Care System. A validated computer simulation model (the IMS CORE Diabetes Model) was used to estimate the long-term projection of costs and clinical outcomes. The model was populated with published characteristics of Thai patients with type 2 diabetes. Baseline risk factors were obtained from Thai cohort studies, while relative risk reduction was derived from a meta-analysis study conducted by the Canadian Agency for Drugs and Technology in Health. Only direct costs were taken into account. Costs of diabetes management and complications were obtained from hospital databases in Thailand. Both costs and outcomes were discounted at 3 % per annum and presented in US dollars in terms of 2014 dollar value. Incremental cost-effectiveness ratio (ICER) was calculated. One-way and probabilistic sensitivity analyses were also performed. IGlar is associated with a slight gain in quality-adjusted life years (0.488 QALYs), an additional life expectancy (0.677 life years), and an incremental cost of THB119,543 (US$3522.19) compared with NPH insulin. The ICERs were THB244,915/QALY (US$7216.12/QALY) and THB176,525/life-year gained (LYG) (US$5201.09/LYG). The ICER was sensitive to discount rates and IGlar cost. At the acceptable willingness to pay of THB160,000/QALY (US$4714.20/QALY), the probability that IGlar was cost effective was less than 20 %. Compared to treatment with NPH insulin, treatment with IGlar in type 2 diabetes patients who had uncontrolled blood glucose with oral anti-diabetic drugs did not represent good value for money at the acceptable threshold in Thailand.

Regulation of diet-induced adipose tissue and systemic inflammation by salicylates and pioglitazone.

PubMed

Kim, Myung-Sunny; Yamamoto, Yasuhiko; Kim, Kyungjin; Kamei, Nozomu; Shimada, Takeshi; Liu, Libin; Moore, Kristin; Woo, Ju Rang; Shoelson, Steven E; Lee, Jongsoon

2013-01-01

It is increasingly accepted that chronic inflammation participates in obesity-induced insulin resistance and type 2 diabetes (T2D). Salicylates and thiazolidinediones (TZDs) both have anti-inflammatory and anti-hyperglycemic properties. The present study compared the effects of these drugs on obesity-induced inflammation in adipose tissue (AT) and AT macrophages (ATMs), as well as the metabolic and immunological phenotypes of the animal models. Both drugs improved high fat diet (HFD)-induced insulin resistance. However, salicylates did not affect AT and ATM inflammation, whereas Pioglitazone improved these parameters. Interestingly, HFD and the drug treatments all modulated systemic inflammation as assessed by changes in circulating immune cell numbers and activation states. HFD increased the numbers of circulating white blood cells, neutrophils, and a pro-inflammatory monocyte subpopulation (Ly6C(hi)), whereas salicylates and Pioglitazone normalized these cell numbers. The drug treatments also decreased circulating lymphocyte numbers. These data suggest that obesity induces systemic inflammation by regulating circulating immune cell phenotypes and that anti-diabetic interventions suppress systemic inflammation by normalizing circulating immune phenotypes.

Novel PLGA-based nanoparticles for the oral delivery of insulin.

PubMed

Malathi, Sampath; Nandhakumar, Perumal; Pandiyan, Velayudham; Webster, Thomas J; Balasubramanian, Sengottuvelan

2015-01-01

Insulin is the drug therapy for patients with insulin-dependent diabetes mellitus. A number of attempts have been made in the past to overcome the problems associated with the oral delivery of insulin, but with little success. Orally administered insulin has encountered with many difficulties such as rapid degradation and poor intestinal absorption. The potential use of D-α-tocopherol poly(ethylene glycol) 1000 succinate (TPGS)-emulsified poly(ethylene glycol) (PEG)-capped poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was investigated for sustained delivery of insulin (IS). To investigate the efficacy of TPGS-emulsified PEG-capped PLGA NPs (TPPLG NPs) as a potential drug carrier for the oral delivery of insulin. A series of biodegradable low-molecular-weight PLGA (80/20 [PLG4] and 70/30 [PLG6]) copolymers were synthesized by melt polycondensation. The commercial insulin-loaded TPGS-emulsified PEG-capped PLGA NPs (ISTPPLG NPs) were synthesized by water-oil-water emulsion solvent evaporation method. The physical and chemical properties of PLGA copolymers, particle size, zeta potential, and morphology of the NPs were examined. The in vivo studies of ISTPPLG NPs were carried out in diabetic rats by oral administration. The maximum encapsulation efficiency of ISTPPLG6 NPs was 78.6% ± 1.2%, and the mean diameter of the NPs was 180 ± 20 nm. The serum glucose level was significantly (twofold) decreased on treatment with ISTPPLG NPs, and there was a threefold decrease with insulin-loaded PLGA (70/30) NPs when compared to that of free insulin-treated diabetic rats. The results show that the oral administration of ISTPPLG6 NPs is an effective method of reducing serum glucose level for a period of 24 hours. Histopathological studies reveal that ISTPPLG NPs could restore the damage caused by streptozotocin in the liver, kidneys, and pancreas, indicating its biocompatibility and regenerative effects. ISTPPLG6 NPs can act as potential drug carriers for the oral delivery of insulin.

Novel PLGA-based nanoparticles for the oral delivery of insulin

PubMed Central

Malathi, Sampath; Nandhakumar, Perumal; Pandiyan, Velayudham; Webster, Thomas J; Balasubramanian, Sengottuvelan

2015-01-01

Background Insulin is the drug therapy for patients with insulin-dependent diabetes mellitus. A number of attempts have been made in the past to overcome the problems associated with the oral delivery of insulin, but with little success. Orally administered insulin has encountered with many difficulties such as rapid degradation and poor intestinal absorption. The potential use of D-α-tocopherol poly(ethylene glycol) 1000 succinate (TPGS)-emulsified poly(ethylene glycol) (PEG)-capped poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) was investigated for sustained delivery of insulin (IS). Objective To investigate the efficacy of TPGS-emulsified PEG-capped PLGA NPs (TPPLG NPs) as a potential drug carrier for the oral delivery of insulin. Methods A series of biodegradable low-molecular-weight PLGA (80/20 [PLG4] and 70/30 [PLG6]) copolymers were synthesized by melt polycondensation. The commercial insulin-loaded TPGS-emulsified PEG-capped PLGA NPs (ISTPPLG NPs) were synthesized by water–oil–water emulsion solvent evaporation method. The physical and chemical properties of PLGA copolymers, particle size, zeta potential, and morphology of the NPs were examined. The in vivo studies of ISTPPLG NPs were carried out in diabetic rats by oral administration. Results The maximum encapsulation efficiency of ISTPPLG6 NPs was 78.6%±1.2%, and the mean diameter of the NPs was 180±20 nm. The serum glucose level was significantly (twofold) decreased on treatment with ISTPPLG NPs, and there was a threefold decrease with insulin-loaded PLGA (70/30) NPs when compared to that of free insulin-treated diabetic rats. The results show that the oral administration of ISTPPLG6 NPs is an effective method of reducing serum glucose level for a period of 24 hours. Histopathological studies reveal that ISTPPLG NPs could restore the damage caused by streptozotocin in the liver, kidneys, and pancreas, indicating its biocompatibility and regenerative effects. Conclusion ISTPPLG6 NPs can act as potential drug carriers for the oral delivery of insulin. PMID:25848248

Pharmacokinetic and pharmacodynamic herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide with etoricoxib after oral administration in rats.

PubMed

Balap, Aishwarya; Atre, Bhagyashri; Lohidasan, Sathiyanarayanan; Sinnathambi, Arulmozhi; Mahadik, Kakasaheb

2016-05-13

Andrographis paniculata Nees (Acanthacae) is commonly used medicinal plant in the traditional. Unani and Ayurvedic medicinal systems. It has broad range of pharmacological effects such as hepatoprotective, antioxidant, antivenom, antifertility, inhibition of replication of the HIV virus, antimalarial, antifungal, antibacterial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug To evaluate the pharmacokinetic and pharmacodynamic (anti-arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with etoricoxib (ETO) after oral co-administration in wistar rats. After oral co-administration of APE (200mg/Kg) and AN (60mg/kg) with ETO (10mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of Cmax, tmax, t1/2, MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. Co-administration of ETO with APE and pure AN decreased systemic exposure level of each compound in vivo. The Cmax, AUC, t1/2 of ETO was decreased whereas Vd and CL of ETO was increased significantly after co-administration of ETO with pure AN and APE. In pharmacodynamic study, ETO alone and ETO+APE (10+200mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups ETO+AN, APE and AN alone. The results obtained from this study suggested that ETO, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. Physicians and patients using A. paniculata should have the knowledge about its possible herb-drug interaction with ETO. Copyright © 2016. Published by Elsevier Ireland Ltd.

Scopoletin protects against methylglyoxal-induced hyperglycemia and insulin resistance mediated by suppression of advanced glycation endproducts (AGEs) generation and anti-glycation.

PubMed

Chang, Wen-Chang; Wu, Shinn-Chih; Xu, Kun-Di; Liao, Bo-Chieh; Wu, Jia-Feng; Cheng, An-Sheng

2015-02-09

Recently, several types of foods and drinks, including coffee, cream, and cake, have been found to result in high methylglyoxal (MG) levels in the plasma, thus causing both nutritional and health concerns. MG can be metabolized by phase-II enzymes in liver through the positive regulation of nuclear factor-erythroid 2-related factor 2 (Nrf2). In this study, we investigated the ability of scopoletin (SP) to protect against MG-induced hyperglycemia and insulin resistance. Recently, SP was shown to be a peroxisome proliferator-activated receptor-γ activator to elevate insulin sensitivity. We investigated the effects of oral administration of SP on the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats to understand the potential mechanism of scopoletin for diabetes protection. Our results suggested that SP activated Nrf2 by Ser40 phosphorylation, resulting in the metabolism of MG into d-lactic acid and the inhibition of AGEs generation, which reduced the accumulation of AGEs in the livers of MG-induced rats. In this manner, SP improved the results of the oral glucose tolerance test and dyslipidemia. Moreover, SP also increased the plasma translocation of glucose transporter-2 and promoted Akt phosphorylation caused by insulin treatment in MG-treated FL83B hepatocytes. In contrast, SP effectively suppressed protein tyrosine phosphatase 1B (PTP1B) expression, thereby alleviating insulin resistance. These findings suggest that SP acts as an anti-glycation and anti-diabetic agent, and thus has therapeutic potential for the prevention of diabetes.

In vivo dual-delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 (DPP4) inhibitor through composites prepared by microfluidics for diabetes therapy

NASA Astrophysics Data System (ADS)

Araújo, F.; Shrestha, N.; Gomes, M. J.; Herranz-Blanco, B.; Liu, D.; Hirvonen, J. J.; Granja, P. L.; Santos, H. A.; Sarmento, B.

2016-05-01

Oral delivery of proteins is still a challenge in the pharmaceutical field. Nanoparticles are among the most promising carrier systems for the oral delivery of proteins by increasing their oral bioavailability. However, most of the existent data regarding nanosystems for oral protein delivery is from in vitro studies, lacking in vivo experiments to evaluate the efficacy of these systems. Herein, a multifunctional composite system, tailored by droplet microfluidics, was used for dual delivery of glucagon like peptide-1 (GLP-1) and dipeptidyl peptidase-4 inhibitor (iDPP4) in vivo. Oral delivery of GLP-1 with nano- or micro-systems has been studied before, but the simultaneous nanodelivery of GLP-1 with iDPP4 is a novel strategy presented here. The type 2 diabetes mellitus (T2DM) rat model, induced through the combined administration of streptozotocin and nicotinamide, a non-obese model of T2DM, was used. The combination of both drugs resulted in an increase in the hypoglycemic effects in a sustained, but prolonged manner, where the iDPP4 improved the therapeutic efficacy of GLP-1. Four hours after the oral administration of the system, blood glucose levels were decreased by 44%, and were constant for another 4 h, representing half of the glucose area under the curve when compared to the control. An enhancement of the plasmatic insulin levels was also observed 6 h after the oral administration of the dual-drug composite system and, although no statistically significant differences existed, the amount of pancreatic insulin was also higher. These are promising results for the oral delivery of GLP-1 to be pursued further in a chronic diabetic model study.

Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension.

PubMed

Lan, Jiarong; Zhao, Yanyun; Dong, Feixia; Yan, Ziyou; Zheng, Wenjie; Fan, Jinping; Sun, Guoli

2015-02-23

Berberine, extracted from Coptis Root and Phellodendron Chinese, has been frequently used for the adjuvant treatment of type 2 diabetes mellitus, hyperlipidemia, and hypertension in China. Safety and efficacy studies in terms of evidence-based medical practice have become more prevalent in application to Chinese Herbal Medicine. It is necessary to assess the efficacy and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipidemia and hypertension by conducting a systematic review and meta-analysis of available clinical data. We searched the English databases PubMed, ScienceDirect, Cochrane library, EMbase, etc., and Chinese databases including China biomedical literature database (CBM), Chinese Technology Journal Full-text Database, Chinese journal full text database (CNKI), and Wanfang digital periodical full text database. Relevant studies were selected based on the inclusion and exclusion criteria. Meta-analysis was performed with RevMan5.0 software after data extraction and the quality of studies assessment. Twenty-seven randomized controlled clinical trials were included with 2569 patients. There are seven subgroups in our meta-analysis: berberine versus placebo or berberine with intensive lifestyle intervention versus intensive lifestyle intervention alone; berberine combined with oral hypoglycemic versus hypoglycemic alone; berberine versus oral hypoglycemic; berberine combined with oral lipid lowering drugs versus lipid lowering drugs alone; berberine versus oral lipid lowering drugs; berberine combined with oral hypotensor versus hypotensive medications; berberine versus oral hypotensive medications. In the treatment of type 2 diabetes mellitus, we found that berberine with lifestyle intervention tended to lower the level of FPG, PPG and HbA1c than lifestyle intervention alone or placebo; the same as berberine combined with oral hypoglycaemics to the same hypoglycaemics; but there was no statistical significance between berberine and oral hypoglycaemics. As for the treatment of hyperlipidemia, berberine with lifestyle intervention was better than lifestyle intervention, berberine with oral lipid lowering drugs was better than lipid lowering drugs alone in reducing the level of TC and LDL-C, and raising the level of HDL-C. In the comparative study between berberine and oral lipid lowering drugs, there was no statistical significance in reducing the level of TC and LDL-C, but berberine shows better effect in lowering the level of TG and raising the level of HDL-C. In the treatment of hypertension, berberine with lifestyle intervention tended to lower the level of blood pressure more than the lifestyle intervention alone or placebo did; The same occurred when berberine combined with oral hypotensor was compared to the same hypotensor. Notably, no serious adverse reaction was reported in the 27 experiments. This study indicates that berberine has comparable therapeutic effect on type 2 DM, hyperlipidemia and hypertension with no serious side effect. Considering the relatively low cost compared with other first-line medicine and treatment, berberine might be a good alternative for low socioeconomic status patients to treat type 2 DM, hyperlipidemia, hypertension over long time period. Due to overall limited quality of the included studies, the therapeutic benefit of berberine can be substantiated to a limited degree. Better methodological quality, large controlled trials using standardized preparation are expected to further quantify the therapeutic effect of berberine. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The impact of antihypertensives on kidney disease

PubMed Central

Marquez, Diego F; Ruiz-Hurtado, Gema; Ruilope, Luis

2017-01-01

Arterial hypertension and chronic kidney disease (CKD) are intimately related. The control of blood pressure (BP) levels is strongly recommended in patients with CKD in order to protect the kidney against the accompanying elevation in global cardiovascular (CV) risk. Actually, the goal BP in patients with CKD involves attaining values <140/90 mmHg except if albuminuria is present. In this case, it is often recommended to attain values <130/80 mmHg, although some guidelines still recommend <140/90 mmHg. Strict BP control to values of systolic BP around 120 mmHg was recently shown to be safe in CKD according to data from the SPRINT trial, albeit more data confirming this benefit are required. Usually, combination therapy initiated with an angiotensin receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACEi) and commonly followed by the addition of a calcium channel blocker and a diuretic is needed. Further studies are required as well as new drugs in particular after the positive data obtained from new oral anti-diabetic drugs. PMID:28529721

Research progress on berberine with a special focus on its oral bioavailability.

PubMed

Liu, Chang-Shun; Zheng, Yu-Rong; Zhang, Ying-Feng; Long, Xiao-Ying

2016-03-01

The natural product berberine (BBR) has become a potential drug in the treatment of diabetes, hyperlipidemia, and cancer. However, the oral delivery of BBR is challenged by its poor bioavailability. It is necessary to improve the oral bioavailability of BBR before it can be used in many clinical applications. Understanding the pharmacokinetic characteristics of BBR will enable the development of suitable formulas that have improved oral bioavailability. The key considerations for BBR are how to enhance the drug absorption and to avoid the intestinal first-pass effect. This review summarizes the pharmacological activities of BBR and analyzes the factors that lead to its poor oral bioavailability. In particular, the therapeutic potential of BBR in new indications from the aspect of oral bioavailability is discussed. In conclusion, BBR is a promising drug candidate for metabolic disorders and cancer but faces considerable challenges due to its poor oral bioavailability. Copyright © 2016 Elsevier B.V. All rights reserved.

Non-coding RNAs and Berberine: A new mechanism of its anti-diabetic activities.

PubMed

Chang, Wenguang

2017-01-15

Type 2 Diabetes (T2D) is a metabolic disease with high mortality and morbidity. Non-coding RNAs, including small and long non-coding RNAs, are a novel class of functional RNA molecules that regulate multiple biological functions through diverse mechanisms. Studies in the last decade have demonstrated that non-coding RNAs may represent compelling therapeutic targets and play important roles in regulating the course of insulin resistance and T2D. Berberine, a plant-based alkaloid, has shown promise as an anti-hyperglycaemic, anti-hyperlipidaemic agent against T2D. Previous studies have primarily focused on a diverse array of efficacy end points of berberine in the pathogenesis of metabolic syndromes and inflammation or oxidative stress. Currently, an increasing number of studies have revealed the importance of non-coding RNAs as regulators of the anti-diabetic effects of berberine. The regulation of non-coding RNAs has been associated with several therapeutic actions of berberine in T2D progression. Thus, this review summarizes the anti-diabetic mechanisms of berberine by focusing on its role in regulating non-coding RNA, thus demonstrating that berberine exerts global anti-diabetic effects by targeting non-coding RNAs and that these effects involve several miRNAs, lncRNAs and multiple signal pathways, which may enhance the current understanding of the anti-diabetic mechanism actions of berberine and provide new pathological targets for the development of berberine-related drugs. Copyright © 2016 Elsevier B.V. All rights reserved.

Preparation and evaluation of a controlled drug release of repaglinide through matrix pellets: in vitro and in vivo studies.

PubMed

Tavakoli, Naser; Minaiyan, Mohsen; Tabbakhian, Majid; Pendar, Yaqub

2014-01-01

Repaglinide, an oral antidiabetic agent, has a rapid onset of action and short half-life of approximately 1 h. Designing a controlled release dosage form of the drug is required to maintain its therapeutic blood level and to eliminate its adverse effects, particularly the hypoglycaemia. Repaglinide sustained release matrix pellets consisting of Avicel, lactose and different polymers were prepared using extrusion-spheronisation method. The effect of different formulation components on in vitro drug release were evaluated using USP apparatus (paddle) for 12 h in phosphate buffer. The optimised formulation was orally administrated to normal and STZ induced diabetic rats. Most pellet formulations had acceptable physical properties with regard to size distribution, flowability and friability. Repaglinide pellets comprising Avicel 50%, lactose 47% and SLS 1% were released 94% of its drug content after 12 h. The optimised formulation was able to decrease blood glucose level in normal rats and those with diabetes throughout 8-12 h.

Targeting inflammation in the treatment of type 2 diabetes: time to start.

PubMed

Donath, Marc Y

2014-06-01

The role of inflammation in the pathogenesis of type 2 diabetes and associated complications is now well established. Several conditions that are driven by inflammatory processes are also associated with diabetes, including rheumatoid arthritis, gout, psoriasis and Crohn's disease, and various anti-inflammatory drugs have been approved or are in late stages of development for the treatment of these conditions. This review discusses the rationale for the use of some of these anti-inflammatory treatments in patients with diabetes and what we could expect from their use. Future immunomodulatory treatments may not target a specific disease, but could instead act on a dysfunctional pathway that causes several conditions associated with the metabolic syndrome.

Metformin and Anti-Cancer Therapeutics: Hopes for a More Enhanced Armamentarium Against Human Neoplasias?

PubMed

Christodoulou, Maria-Ioanna; Scorilas, Andreas

2017-01-01

Metformin, a natural product from Galega officinalis, is an oral drug, now in the forefront of the therapeutic management of type-2 diabetes mellitus. A series of clinical observations of the last decades, support that metformin may contribute to lowering the risk of cancer development in diabetic patients, and also to improvement of response-to-therapy and survival in individuals with certain types of malignancies. Moreover, several preclinical in vitro and in vivo data indicate that metformin indeed exerts anti-proliferative capacities upon tumor cells mediated through a variety of mechanisms. Interestingly, metformin has been shown to act in synergy with certain anti-cancer agents and also to overcome chemo- and/or radio-resistance of various types of tumors, providing a hopeful rationale for novel therapeutic strategies against cancer development and progression. However, this remains an issue of controversy, since significant contradictions exist among the available data. Limitations of preclinical studies and caveats of epidemiological works, together with significant variances among the several types of cancer and the fact that the mode of metformin's action is largely unknown, make longitudinal surveys urgently needed. Now, a plethora of large clinical trials are active worldwide, aiming at determining the effect of metformin in the prevention or prognosis of a variety of human cancers. If encouraging results arise, metformin will be an attractive candidate adjuvant in the management of human neoplasias, due to its safety, tolerability and low-cost, expected to mitigate adverse effects and no-response parameters of current anti-cancer therapeutics, thus improving the quality of life and survival of cancer patients. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Protective effects of Cynara scolymus leaves extract on metabolic disorders and oxidative stress in alloxan-diabetic rats.

PubMed

Ben Salem, Maryem; Ben Abdallah Kolsi, Rihab; Dhouibi, Raouia; Ksouda, Kamilia; Charfi, Slim; Yaich, Mahdi; Hammami, Serria; Sahnoun, Zouheir; Zeghal, Khaled Mounir; Jamoussi, Kamel; Affes, Hanen

2017-06-19

Diabetes mellitus (DM) is associated with hyperglycemia, inflammatory disorders and abnormal lipid profiles, currently the extracts from leaves of cynara scolymus has been discovered to treat metabolic disorders and has been stated by multitudinous scientists according to a good source of polyphenols compounds. The present study aimed to evaluate the protective effect of the ethanol leaves extract of C. scolymus in alloxan induced stress oxidant, hepatic-kidney dysfunction and histological changes in liver, kidney and pancreas of different experimental groups of rats. We determinate the antioxidant activity by ABTS .+ and antioxidant total capacity (TAC) of all extracts of C. scolymus leaves, the inhibition of α-amylase activity in vitro was also investigated. Forty male Wistar rats were induced to diabetes with a single dose intraperitoneal injection (i.p.) of alloxan (150 mg/kg body weight (b.w.)). Diabetic rats were orally and daily administrated of ethanol extract from C. scolymus at two doses (200-400 mg/kg, b.w) or (12 mg/kg, b.w) with anti-diabetic reference drug, Acarbose for one month. Ethanol extract of C. scolymus effect was confirmed by biochemical analysis, antioxidant activity and histological study. The results indicated that the ethanol extract from leaves of C. scolymus showed the highest antioxidant activity by ABTS .+ (499.43g± 39.72 Trolox/g dry extract) and (128.75 ± 8.45 mg VC /g dry extract) for TAC and endowed the powerful inhibition in vitro of α-amylase activity with IC50=72,22 ug/uL. In vivo, the results showed that ethanol extract from the leaves of C. scolymus (200-400 mg/kg) decreased significantly (p < 0.001) the α-amylase levels in serum of diabetic rats, respectively associated with significant reduction (p < 0.001) in blood glucose rate of 42,84% and 37,91% compared to diabetic groups after 28 days of treatment, a significant lowered of plasma total cholesterol (T-Ch) by 18,11% and triglyceride (TG) by 60,47%, significantly and low-density lipoproteins (LDL-C) by 37,77%, compared to diabetic rats, moreover, the administration of ethanol extract appears to exert anti-oxidative activity demonstrated by the increase of CAT, SOD and GSH activities in liver, kidney and pancreas of diabetic rats. This positive effect of the ethanol extract from C. scolymus was confirmed by histological study. These observed strongly suggest that ethanol extract from the leaves of C. scolymus has anti-hyperglycemic properties, at least partly mediated by antioxidant and hypolipidemic effects.

Non-haemodynamic anti-anginal agents in the management of patients with stable coronary artery disease and diabetes: A review of the evidence.

PubMed

Ambrosio, Giuseppe; Tamargo, Juan; Grant, Peter J

2016-03-01

Patients with coronary artery disease and concomitant diabetes mellitus tend to have more extensive vessel disease than non-diabetes mellitus coronary artery disease patients, are at high risk of adverse cardiovascular events and suffer from a great anginal burden. Very few trials have specifically addressed the issue of optimal anti-anginal therapy in coronary artery disease patients who also have diabetes mellitus. Among 'classical' anti-anginal agents, recent guidelines do not specifically recommend any molecule over others; however, European Society of Cardiology guidelines acknowledge that favourable data in patients with concomitant diabetes mellitus and coronary artery disease are available for trimetazidine and ranolazine, two anti-anginal agents with a non-haemodynamic mechanism of action. The aim of this article is to review available evidence supporting the anti-anginal efficacy of these two drugs in the difficult-to-treat population of diabetes mellitus patients, including their effects on glycated haemoglobin (HbA1c), a measure of medium-term glycaemic control. Although direct head-to-head comparisons have not been performed, available evidence favours ranolazine as an effective anti-anginal agent over trimetazidine in this population. In addition, ranolazine lowers HbA1c, indicating that it may improve glycaemic control in patients with diabetes mellitus. Conversely, scanty data are available on the metabolic effects of trimetazidine in this cohort of patients. Thus, ranolazine may represent a valuable therapeutic option in stable coronary artery disease patients with diabetes mellitus. © The Author(s) 2015.

Access to artemisinin-based combination therapies and other anti-malarial drugs in Kinshasa.

PubMed

Nkoli Mandoko, P; Sinou, V; Moke Mbongi, D; Ngoyi Mumba, D; Kahunu Mesia, G; Losimba Likwela, J; Bi Shamamba Karhemere, S; Muepu Tshilolo, L; Tamfum Muyembe, J-J; Parzy, D

2018-06-01

Artemisinin-based combination therapies have been available since 2005 in the Democratic Republic of the Congo to treat malaria and to overcome the challenge of anti-malarial drug resistance as well as to improve access to effective treatments. The private sector is the primary distribution source for anti-malarial drugs and thus, has a key position among the supply chain actors for a rational and proper use of anti-malarial drugs. We aimed to assess access to nationally recommended anti-malarial drugs in private sector pharmacies of the capital-city of Kinshasa. We performed a cross-sectional survey of 404 pharmacies. Anti-malarial drugs were stocked in all surveyed pharmacies. Non-artemisinin-based anti-malarial therapies such as quinine or sulfadoxine-pyrimethamine, were the most frequently stocked drugs (93.8% of pharmacies). Artemisinin-based combination therapies were stocked in 88% of pharmacies. Artemether-lumefantrine combinations were the most frequently dispensed drugs (93% of pharmacies), but less than 3% were quality-assured products. Other non-officially recommended artemisinin-based therapies including oral monotherapies were widely available. Artemisinin-based combination therapies were widely available in the private pharmacies of Kinshasa. However, the private sector does not guarantee the use of nationally recommended anti-malarial drugs nor does it give priority to quality-assured anti-malarial drugs. These practices contribute to the risk of emergence and spread of resistance to anti-malarial drugs and to increasing treatment costs. Copyright © 2018 Elsevier Masson SAS. All rights reserved.

Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety.

PubMed

Roth, Sanford H

2011-01-01

Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis.

Nonsteroidal anti-inflammatory drug gastropathy: new avenues for safety

PubMed Central

Roth, Sanford H

2011-01-01

Chronic oral or systemic nonselective nonsteroidal anti-inflammatory drug (NSAID) therapy, ubiquitously used by physicians to treat osteoarthritis-associated pain, is associated with a wide range of symptomatic adverse events, the most frequent and serious of which is gastropathy. Although cardiovascular and renal problems are a very real concern, they are significantly less frequent. These complications can be life-threatening in at-risk populations such as older adults, who are common users of long-term oral systemic NSAID therapy. Topical NSAID formulations deliver effective doses of analgesics directly to the affected joints, thereby limiting systemic exposure and potentially the risk of systemic adverse events, such as gastropathy and serious cardiovascular events. There are currently two topical NSAIDs approved by the US Food and Drug Administration for osteoarthritis-associated pain, as well as for the signs and symptoms of osteoarthritis. This review discusses the relative safety, and the gastrointestinal, cardiovascular, and renal risks of chronic oral or systemic NSAID therapy and topical NSAID formulations in patients with osteoarthritis. PMID:21753867

Effect of novel water soluble curcumin derivative on experimental type- 1 diabetes mellitus (short term study)

PubMed Central

2012-01-01

Background Diabetes mellitus type 1 is an autoimmune disorder caused by lymphocytic infiltration and beta cells destruction. Curcumin has been identified as a potent inducer of heme-oxygenase-1 (HO-1), a redoxsensitive inducible protein that provides protection against various forms of stress. A novel water soluble curcumin derivative (NCD) has been developed to overcome low in vivo bioavailability of curcumin. The aim of the present work is to evaluate the anti diabetic effects of the “NCD” and its effects on diabetes-induced ROS generation and lipid peroxidation in experimental type- 1 diabetes mellitus. We also examine whether the up regulation of HO-1 accompanied by increased HO activity mediates these antidiabetic and anti oxidant actions. Materials and methods Rats were divided into control group, control group receiving curcumin derivative, diabetic group, diabetic group receiving curcumin derivative and diabetic group receiving curcumin derivative and HO inhibitor ZnPP. Type-1 diabetes was induced by intraperitoneal injection of streptozotocin. Curcumin derivative was given orally for 45 days. At the planned sacrification time (after 45 days), fasting blood samples were withdrawn for estimation of plasma glucose, plasma insulin and lipid profile . Animals were sacrificed; pancreas, aorta and liver were excised for the heme oxygenase - 1 expression, activity and malondialdehyde estimation. Results NCD supplementation to diabetic rats significantly lowered the plasma glucose by 27.5% and increased plasma insulin by 66.67%. On the other hand, the mean plasma glucose level in the control group showed no significant difference compared to the control group receiving the oral NCD whereas, NCD supplementation to the control rats significantly increased the plasma insulin by 47.13% compared to the control. NCD decreased total cholesterol, triglycerides, LDL cholesterol and increased HDL cholesterol levels. Also, it decreased lipid peroxides (malondialdehyde) in the pancreas, aorta and liver. Conclusion The (NCD) by its small dose possesses antidiabetic actions and that heme oxygenase induction seems to play an important role in its anti-diabetic effects. NCD also improves the lipid profile and oxidative status directly, proved by decreasing lipid peroxides (malondialdehyde) in pancreas, liver & aorta. The new water soluble curcumin derivative still retains the essential potencies of natural curcumin. PMID:22762693

Safety and efficacy of tinea pedis and onychomycosis treatment in people with diabetes: a systematic review.

PubMed

Matricciani, Lisa; Talbot, Kerwin; Jones, Sara

2011-12-04

Effective treatment of tinea pedis and onychomycosis is crucial for patients with diabetes as these infections may lead to foot ulcers and secondary bacterial infections resulting in eventual lower limb amputation. Although numerous studies have assessed the effectiveness of antifungal drug and treatment regimens, most exclude patients with diabetes and examine otherwise healthy individuals. While these studies are useful, results cannot necessarily be extrapolated to patients with diabetes. The purpose of this study was to therefore identify the best evidence-based treatment interventions for tinea pedis or onychomycosis in people with diabetes. The question for this systemic review was: 'what evidence is there for the safety and/or efficacy of all treatment interventions for adults with tinea pedis and/or onychomycosis in people with diabetes'? A systematic literature search of four electronic databases (Scopus, EbscoHost, Ovid, Web of Science) was undertaken (6/1/11). The primary outcome measure for safety was self-reported adverse events likely to be drug-related, while the primary outcome measures assessed for 'efficacy' were mycological, clinical and complete cure. The systematic review identified six studies that examined the safety and/or efficacy of treatment interventions for onychomycosis in people with diabetes. No studies were identified that examined treatment for tinea pedis. Of the studies identified, two were randomised controlled trials (RCTs) and four were case series. Based on the best available evidence identified, it can be suggested that oral terbinafine is as safe and effective as oral itraconazole therapy for the treatment of onychomycosis in people with diabetes. However, efficacy results were found to be poor. This review indicates that there is good evidence (Level II) to suggest oral terbinafine is as safe and effective as itraconazole therapy for the treatment of onychomycosis in people with diabetes. Further research is needed to establish the evidence for other treatment modalities and treatment for tinea pedis for people with diabetes. Future efforts are needed to improve the efficacy of treatment intervention.

Drug-related problems in type 2 diabetes mellitus patients with dyslipidemia

PubMed Central

2013-01-01

Background Drug-Related Problems (DRPs) commonly occur among type 2 diabetes mellitus (T2DM) patients. However, few studies have been performed on T2DM patients with dyslipidemia. This purpose of this study was to assess drug-related problems (DRPs) and factors associated with its occurrence. Methods The retrospective study involved 208 T2DM in-patients and out-patients with dyslipidemia, and was conducted at a tertiary hospital in Malaysia from January 2009 to December 2011. The identification and assessment of DRPs were based on the Pharmaceutical Care Network Europe (PCNE) tool version 5.01. The potentially inappropriate medication use in older adults was assessed based on the American Geriatrics Society updated Beers Criteria. Results A total of 406 DRPs were identified. Among these patients, 91.8% had at least one DRP, averaging 1.94 ± 1.10 problems per patient. The majority of T2DM patients with dyslipidemia (91.8%) had at least one DRP. The most frequent types of DRP were potential drug-drug interaction (18.0%), drug not taken or administered (14.3%) and insufficient awareness of health and diseases (11.8%). Anti-hypertensive, lipid-modifying and anti-diabetic agents were the drug classes that were most likely to be associated with DRPs. Male gender, renal impairment, polypharmacy and poor lipid control were factors that were significantly associated with DRP in diabetic dyslipidemia patients. Conclusion Early identification of DRPs and factors associated with them are essential to prevent and resolve DRPs in T2DM patients with dyslipidemia. PMID:24341672

Difference between observed and predicted glycated hemoglobin at baseline and treatment response to vildagliptin-based dual oral therapy in patients with type 2 diabetes.

PubMed

Wang, Jun-Sing; Hung, Yi-Jen; Lu, Yung-Chuan; Tsai, Cheng-Lin; Yang, Wei-Shiung; Lee, Ting-I; Hsiao, Ya-Chun; Sheu, Wayne Huey-Herng

2018-04-01

We aimed to investigate the association of difference between observed and predicted glycated hemoglobin (dopHbA1c) and HbA1c reduction after vildagliptin-based oral therapy in patients with type 2 diabetes (T2D). This was a prospective observational study. Adults ≥ 20 years old with T2D and HbA1c ≧7% treated with oral anti-diabetic drugs (OADs) were eligible if their OADs were shifted to vildagliptin-based dual oral therapy. Fasting plasma glucose (FPG) and HbA1c were recorded at baseline, week 12, and week 24. To determine baseline dopHbA1c, a predicted HbA1c was calculated by inserting baseline FPG into a regression equation (HbA1c = FPG ∗ 0.0225 + 4.3806) developed from linear relationship between HbA1c and FPG in an independent cohort of 3239 outpatients with T2D (dopHbA1c = observed HbA1c - predicted HbA1c). Patients were assigned to low (≦0) or high (>0) dopHbA1c group according to their baseline dopHbA1c levels. The study endpoint was changes from baseline to week 24 in HbA1c levels. A total of 1224 patients were enrolled. Patients with a dopHbA1c >0 had a greater HbA1c reduction after vildagliptin-based dual oral therapy than those with a dopHbA1c ≦0 (-1.5 ± 2.0 vs. -0.4 ± 1.0%, p < 0.001). Baseline dopHbA1c was positively associated with HbA1c reduction from baseline to week 24 (β coefficient 0.883, 95% CI 0.811 to 0.955, p < 0.001), and the association remained significant after adjustment for confounders. In T2D patients with an HbA1c ≧7%, a higher baseline dopHbA1c was associated with a greater HbA1c reduction after shifting to vildagliptin-based dual oral therapy. Copyright © 2018 Elsevier B.V. All rights reserved.

The opposite effect of isotype-selective monoamine oxidase inhibitors on adipogenesis in human bone marrow mesenchymal stem cells.

PubMed

Byun, Youngjoo; Park, Jongho; Hong, Soo Hyun; Han, Mi Hwa; Park, Suzie; Jung, Hyo-Il; Noh, Minsoo

2013-06-01

Adiponectin production during adipocyte differentiation of human bone marrow mesenchymal stem cells (hBM-MSCs) can be used to evaluate the pharmacological activity of anti-diabetic drugs to improve insulin sensitivity. Monoamine oxidase (MAO) inhibitors such as phenelzine and pargyline inhibit adipogenesis in murine pre-adipocytes. In this study, however, we found that selective MAO-A inhibitors, moclobemide and Ro41-1049, and a selective MAO-B inhibitor, selegiline, promoted adiponectin production during adipocyte differentiation in hBM-MSCs, which suggested the anti-diabetic potential of these drugs. In contrast, non-selective MAO inhibitors, phenelzine and tranylcypromine, inhibited adipocyte differentiation of hBM-MSCs. Concomitant treatments of MAO-A and MAO-B selective inhibitors did not change the stimulatory effect on adiponectin production in hBM-MSCs. Taken together, the opposite effects of isotype-selective MAO inhibitors on adiponectin production during adipogenesis in hBM-MSCs may not be directly associated with the inhibitory effects of MAO, suggested that the structure of MAO inhibitors may contain a novel anti-diabetic pharmacophore. Copyright © 2013 Elsevier Ltd. All rights reserved.

Atherosclerotic Cardiovascular Disease and Heart Failure in Type 2 Diabetes – Mechanisms, Management, and Clinical Considerations

PubMed Central

Low Wang, Cecilia C.; Hess, Connie N.; Hiatt, William R.; Goldfine, Allison B.

2016-01-01

Cardiovascular disease remains the principal cause of death and disability among patients with diabetes mellitus. Diabetes exacerbates mechanisms underlying atherosclerosis and heart failure. Unfortunately, these mechanisms are not adequately modulated by therapeutic strategies focusing solely on optimal glycemic control with currently available drugs or approaches. In the setting of multi-factorial risk reduction with statins and other lipid lowering agents, anti-hypertensive therapies, and anti-hyperglycemic treatment strategies, cardiovascular complication rates are falling, yet remain higher for patients with diabetes than for those without. This review considers the mechanisms, history, controversies, new pharmacologic agents, and recent evidence for current guidelines for cardiovascular management in the patient with diabetes mellitus to support evidence-based care in the patient with diabetes and heart disease outside of the acute care setting. PMID:27297342

Will novel oral formulations change the management of inflammatory bowel disease?

PubMed

Nielsen, Ole Haagen; Seidelin, Jakob Benedict; Ainsworth, Mark; Coskun, Mehmet

2016-06-01

The traditional management of inflammatory bowel disease (IBD) with sulphasalazine/5-aminosalicylic acid, glucocorticoids and immunomodulators (i.e., thiopurines and methotrexate) was nearly two decades ago extended with intravenously or subcutaneously administered biologics (i.e., tumor necrosis factor inhibitors and later gut-selective integrin antagonists). However, recently, orally administered treatments with simple, well-characterized, and stable structures consisting of either small molecules or anti-sense therapy have been devised. This review discusses the current approaches with promising new oral drugs with distinct modes of action, including: the Janus kinase inhibitors (i.e., tofacitinib, filgotinib and peficitinib); the immunomodulatory drug (laquinimod); a small α4 antagonist (AJM300); agonists for sphingosine-phosphate receptors (i.e., ozanimod, APD334, and amiselimod), as well as anti-sense therapy (mongersen) targeting SMAD7, drugs which directly target intracellular pathways of relevance for intestinal inflammation. A new avenue using easily administered oral therapies for the management of IBD is being introduced. While their place in the clinical armamentarium remains to be proven, it is likely that many of these drugs will find their place in the treatment algorithm of IBD in the next few years. Thus, we will face times in which IBD therapy will be based on significantly more tablets than prescribed today.

Curcumin attenuates oxidative stress induced NFκB mediated inflammation and endoplasmic reticulum dependent apoptosis of splenocytes in diabetes.

PubMed

Rashid, Kahkashan; Chowdhury, Sayantani; Ghosh, Sumit; Sil, Parames C

2017-11-01

The present study was aimed to determine the curative role of curcumin against diabetes induced oxidative stress and its associated splenic complications. Diabetes was induced in the experimental rats via the intraperitoneal administration of a single dose of STZ (65mgkg -1 body weight). Increased blood glucose and intracellular ROS levels along with decreased body weight, the activity of cellular antioxidant enzymes and GSH/GSSG ratio were observed in the diabetic animals. Histological assessment showed white pulp depletion and damaged spleen anatomy in these animals. Oral administration of curcumin at a dose of 100mgkg -1 body weight daily for 8weeks, however, restored these alterations. Investigation of the mechanism of hyperglycemia induced oxidative stress mediated inflammation showed upregulation of inflammatory cytokines, chemokines, adhesion molecules and increased translocation of NFκB into the nucleus. Moreover, ER stress dependent cell death showed induction of eIF2α and CHOP mediated signalling pathways as well as increment in the expression of GRP78, Caspase-12, Calpain-1, phospho JNK, phospho p38 and phospho p53 in the diabetic group. Alteration of Bax/Bcl-2 ratio; disruption of mitochondrial membrane potential, release of cytochrome-C from mitochondria and upregulation of caspase 3 along with the formation of characteristic DNA ladder in the diabetic animals suggest the involvement of mitochondria dependent apoptotic pathway in the splenic cells. Treatment with curcumin could, however, protect cells from inflammatory damage and ER as well as mitochondrial apoptotic death by restoring the alterations of these parameters. Our results suggest that curcumin has the potential to act as an anti-diabetic, anti-oxidant, anti-inflammatory and anti-apoptotic therapeutic against diabetes mediated splenic damage. Copyright © 2017 Elsevier Inc. All rights reserved.

Nephroprotection with saxagliptin.

PubMed

Iazzetta, Nicolangelo; Garofalo, Carlo; Savino, Manuela; Sagliocca, Adelia; Santangelo, Sara; Pacilio, Mario; Liberti, Maria Elena; Camocardi, Andrea; Ambrosca, Camilla; Minutolo, Roberto; De Nicola, Luca; Conte, Giuseppe

2015-01-01

The nephroprotective effect of the new anti-diabetic drugs acting on incretin system is suggested by preclinical studies. However, no study evaluating kidney effects of these drugs as primary outcome on the long term has been conducted in patients followed in diabetes centers. We designed a pilot observational study involving two diabetes clinics to evaluate the effect of prolonged treatment with saxagliptin on renal function in type 2 diabetics. Patients were enrolled if treated for at least 12 months with saxagliptin without concurrent changes to anti-hypertensive and lipid-lowering therapy. Primary outcome was to evaluate the effect of saxagliptin on albuminuria and estimated glomerular filtration rate (eGFR). Secondary outcomes were the effects of treatment on common clinical and laboratory parameters. Sixty-three patients were enrolled. After 12 months of treatment with saxagliptin, albuminuria declined from a mean (95%CI) of 39 (25-52) to 22 (14-30) mg/l (P<0.001), and the prevalence of increased albuminuria (>20 mg/L) diminished by 27% versus baseline. The anti-albuminuric effect was independent of glycemic and blood pressure control. The eGFR remained unchanged after treatment in the presence of decreased glycated hemoglobin (from 7.1 to 6.7%). Therefore, this pilot study suggests that saxagliptin treatment in diabetic patients at high renal risk is associated with a reduction in albuminuria and GFR stability. Prospective trials are required to confirm the potential nephroprotective effects of saxagliptin.

Effectiveness and tolerability of second-line therapy with vildagliptin versus other oral agents in type 2 diabetes (EDGE): post-hoc subanalysis of the Belgian data.

PubMed

Hoste, J; Daci, E; Mathieu, C

2014-06-01

To assess the efficacy and safety of vildagliptin versus other oral glucose-lowering drugs added to antidiabetic monotherapy in Belgian patients with type 2 diabetes mellitus, in comparison to the global EDGE study results. This is a pre-specified post-hoc subanalysis of the Belgian patient cohort from a worldwide 1-year observational study that compared the effectiveness and tolerability of vildagliptin to other oral antidiabetic agents in type 2 diabetes patients failing monotherapy with oral glucose-lowering agents (EDGE). A total of 1793 Belgian patients were enrolled. Physicians could add any oral antidiabetic drug and patients entered either into the vildagliptin or the comparator cohort. The primary effectiveness and tolerability endpoint was defined as the proportion of patients having a treatment response (HbA1c reduction from baseline to month 12 endpoint >0·3%) without hypoglycemia, weight gain, peripheral oedema, or gastrointestinal side-effects. In the Belgian population, 37·8% of patients in the vildagliptin group and 32·8% in the comparator group had a decrease in HbA1c of >0·3% without the predefined tolerability issues of hypoglycemia, weight gain, oedema or, gastrointestinal complaints (primary endpoint), resulting in an unadjusted odds ratio of 1·24 (95% CI: 0·96-1·61). Mean HbA1c change from baseline was -0·81% in the vildagliptin cohort and -0·75% in the comparator cohort. Overall, vildagliptin was well tolerated with similarly low incidences of total adverse events (14·9% versus 14·5% in the compactor group) and serious adverse events (2·7% versus 2·5% in the comparator group). In this EDGE subgroup of Belgian patients with type 2 diabetes who do not achieve the glycemic targets with monotherapy, a similar trend as in the global EDGE study was observed. Adding vildagliptin as a second oral glucose-lowering agent resulted in lowering HbA1c to <7% without weight gain, hypoglycemia or peripheral oedema in a higher proportion of patients than comparator oral antidiabetic drugs, with no differences in the reported number of adverse events.

[Type 2 diabetes mellitus: new treatments].

PubMed

Ascaso, Juan F

2014-08-04

The benefits and problems associated with traditional hypoglycemic drugs, such as failure of beta cells, hypoglycemia and weight gain, that lead to a worsening of diabetes, are reviewed. New hypoglycemic drugs with incretin effect (glucagon-like peptide-1 agonists and dipeptidyl peptidase 4 inhibitors), achieve, in a glucose dependent manner, an glycosylated hemoglobin reduction without hypoglycemia or increase in body weight. Recently, another group of oral hypoglycemic drugs, sodium-glucose cotransporter type 2 inhibitors, have demonstrated efficacy in diabetes control by inhibiting renal glucose reabsorption. However, long-term effects and cardiovascular prevention remain to be demonstrated. We have more and better drugs nowadays. Hypoglycemic treatment should be customized (glycosylated hemoglobin levels, risk-benefit, risk of hypoglycemia, weight changes, cardiovascular risk), with a combination of drugs being necessary in most cases. However, we do not have yet an ideal hypoglycemic drug. Moreover we must remember that an early and intensive treatment of dyslipidemia and hypertension is essential for the prevention of cardiovascular disease in patients with type 2 diabetes. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Diabetes mellitus: An overview on its pharmacological aspects and reported medicinal plants having antidiabetic activity

PubMed Central

Patel, DK; Kumar, R; Laloo, D; Hemalatha, S

2012-01-01

Diabetes mellitus is not a single disease but is a group of metabolic disorders affecting a huge number of population in the world. It is mainly characterized by chronic hyperglycemia, resulting from defects in insulin secretion or insulin action. It is predicated that the number of diabetes person in the world could reach upto 366 million by the year 2030. Even though the cases of diabetes are increasing day by day, except insulin and oral hypoglycemic drugs no other way of treatment has been successfully developed so far. Thus, the objective of the present review is to provide an insight over the pathophysiological and etiological aspects of diabetes mellitus along with the remedies available for this metabolic disorder. The review also contains brief idea about diabetes mellitus and the experimental screening model with their relevant mechanism and significance mainly used nowadays. Alloxan and streptozotocin are mainly used for evaluating the antidiabetic activity of a particular drug. This review contain list of medicinal plants which have been tested for their antidiabetic activity in the alloxan induced diabetic rat model. From the available data in the literature, it was found that plant having antidiabetic activity is mainly due to the presence of the secondary metabolite. Thus, the information provided in this review will help the researchers for the development of an alternative methods rather than insulin and oral hypoglycemic agents for the treatment of diabetes mellitus, which will minimize the complication associated with the diabetes and related disorder. PMID:23569941

Prevalence of thyroid dysfunction and autoimmunity in pregnant women with gestational diabetes and diabetes type 1.

PubMed

Velkoska Nakova, V; Krstevska, B; Dimitrovski, Ch; Simeonova, S; Hadzi-Lega, M; Serafimoski, V

2010-01-01

The aim of the present study was to determine the prevalence of abnormal thyroid function and antithyroid antibodies during pregnancy in women with diabetes type 1 and gestational diabetes mellitus (GDM). The study group included 83 pregnant women who attended the Outpatient Department of the Endocrinology, Diabetes and Metabolic Disorders Clinic in the period from 05.2009 to 11.2009. The one hundred-g. oral glucose tolerance test (OGTT) was conducted on the pregnant women except for women with diabetes type 1. Thyroid functions were evaluated in all the pregnant women. After routine screening for GDM, thirty of the pregnant women were healthy and GDM was diagnosed in forty of them. The rest, thirteen women, had diabetes type 1. The women who developed GDM showed a mean free thyroxin concentration (fT4) significantly lower than that observed in the healthy pregnant women and women with diabetes type 1. Among the pregnant women with GDM, 10 women or 25% had fT4 concentrations below the lower cut-off with normal thyroid-stimulating hormone concentrations (TSH). A statistically significant difference was found in the prevalence of antithyroid antibodies (anti-TPO) between the (30%) women with diabetes type 1 and (10%) healthy pregnant women (p<0.05). In the women positive for anti-TPO, TSH was significantly higher (p<0.05). The significantly higher prevalence of hypothyroxinemia in GDM pregnancies and anti-TPO titres in pregnancies with diabetes type 1, than in healthy pregnant women warrants routine screening for thyroid abnormalities in these groups of pregnant women.

Ameliorating effect of anti-Alzheimer's drugs on the bidirectional association between type 2 diabetes mellitus and Alzheimer's disease.

PubMed

Ahmed, Amira S; Elgharabawy, Rehab M; Al-Najjar, Amal H

2017-07-01

Mild to severe forms of nervous system damage were exhibited by approximately 60-70% of diabetics. It is important to understand the association between type 2 diabetes mellitus and Alzheimer's disease. The aim of the present work is to understand the bidirectional association between type 2 diabetes and Alzheimer's disease pathogenesis, that was monitored by glycaemic status, lipid profile, amyloid beta 40 and 42 (Aβ40 and Aβ42), C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer and magnesium measurements, to assess the association between theses biochemical markers and each other, to estimate the possibility of utilizing the amyloid beta as biochemical marker of T2D in Alzheimer's patients, and to evaluate the effect of piracetam and memantine drugs on diabetes mellitus. This study involved 120 subjects divided into 20 healthy control (group I), 20 diabetic patients (group II), 20 Alzheimer's patients (group III), 20 diabetic Alzheimer's patients with symptomatic treatment (group IV), 20 diabetic Alzheimer's patients treated with memantine (group V), and 20 diabetic Alzheimer's patients treated with piracetam (group VI). The demographic characteristics, diabetic index, and lipid profile were monitored. Plasma amyloid beta 40 and amyloid beta 42, C-reactive protein, total creatine kinase, total lactate dehydrogenase, D-dimer, and magnesium were assayed. The levels of amyloid beta 40 and amyloid beta 42 were significantly elevated in diabetic Alzheimer's patients with symptomatic treatment (group IV) compared to group II (by 50.5 and 7.5 fold, respectively) and group III (by 25.4 and 2.8 fold, respectively). In groups II, III, IV, V and VI, significant and positive associations were monitored between insulin and amyloid beta 40, amyloid beta 42, C-reactive protein, total creatine kinase, and D-dimer. Diabetic markers were significantly decreased in diabetic Alzheimer's patients treated with anti-Alzheimer's drugs (especially piracetam) compared to group IV. This study reveals the role of amyloid beta 40, amyloid beta 42, insulin, HbA1c, lipid profile disturbance, C-reactive protein, D-dimer, and magnesium in the bidirectional correlation between T2D and pathogenesis of Alzheimer's disease, that is powered by their correlations, and therefore the possibility of utilizing Aβ as a biochemical marker of T2D in Alzheimer's patients is recommended. Impact statement Several aspects associated with T2D that contribute to AD and vice versa were investigated in this study. Additionally, this work reveals the role of Aβ40, Aβ42, insulin, HbA1c, lipid profile disturbance, CRP, D-dimer, and magnesium in the bidirectional association between T2D and the pathogenesis of AD, that is powered by their correlations, and therefore the possibility of utilizing Aβ as a biochemical marker of T2D in Alzheimer's patients is recommended. Furthermore, the ameloriating effect of anti-Alzheimer's drugs on diabetes mellitus confirms this association. Hereafter, a new approach for treating insulin resistance and diabetes may be developed by new therapeutic potentials such as neutralization of Aβ by anti-Aβ antibodies.

Erythritol reduces small intestinal glucose absorption, increases muscle glucose uptake, improves glucose metabolic enzymes activities and increases expression of Glut-4 and IRS-1 in type 2 diabetic rats.

PubMed

Chukwuma, Chika Ifeanyi; Mopuri, Ramgopal; Nagiah, Savania; Chuturgoon, Anil Amichund; Islam, Md Shahidul

2017-08-02

Studies have reported that erythritol, a low or non-glycemic sugar alcohol possesses anti-hyperglycemic and anti-diabetic potentials but the underlying mode of actions is not clear. This study investigated the underlying mode of actions behind the anti-hyperglycemic and anti-diabetic potentials of erythritol using different experimental models (experiment 1, 2 and 3). Experiment 1 examined the effects of increasing concentrations (2.5-20%) of erythritol on glucose absorption and uptake in isolated rat jejunum and psoas muscle, respectively. Experiments 2 and 3 examined the effects of a single oral dose of erythritol (1 g/kg bw) on intestinal glucose absorption, gastric emptying and postprandial blood glucose increase, glucose tolerance, serum insulin level, muscle/liver hexokinase and liver glucose-6 phosphatase activities, liver and muscle glycogen contents and mRNA and protein expression of muscle Glut-4 and IRS-1 in normal and type 2 diabetic animals. Experiment 1 revealed that erythritol dose dependently enhanced muscle glucose ex vivo. Experiment 2 demonstrated that erythritol feeding delayed gastric emptying and reduced small intestinal glucose absorption as well as postprandial blood glucose rise, especially in diabetic animals. Experiment 3 showed that erythritol feeding improved glucose tolerance, muscle/liver hexokinase and liver glucose-6 phosphatase activities, glycogen storage and also modulated expression of muscle Glut-4 and IRS-1 in diabetic animals. Data suggest that erythritol may exert anti-hyperglycemic effects not only via reducing small intestinal glucose absorption, but also by increasing muscle glucose uptake, improving glucose metabolic enzymes activity and modulating muscle Glut-4 and IRS-1 mRNA and protein expression. Hence, erythritol may be a useful dietary supplement for managing hyperglycemia, particularly for T2D.

Magnolia officinalis Extract Contains Potent Inhibitors against PTP1B and Attenuates Hyperglycemia in db/db Mice

PubMed Central

Sun, Jing; Wang, Yongsen; Fu, Xueqi; Chen, Yingli; Wang, Deli; Li, Wannan; Xing, Shu; Li, Guodong

2015-01-01

Protein tyrosine phosphatase 1B (PTP1B) is an established therapeutic target for type 2 diabetes mellitus (T2DM) and obesity. The aim of this study was to investigate the inhibitory activity of Magnolia officinalis extract (ME) on PTP1B and its anti-T2DM effects. Inhibition assays and inhibition kinetics of ME were performed in vitro. 3T3-L1 adipocytes and C2C12 myotubes were stimulated with ME to explore its bioavailability in cell level. The in vivo studies were performed on db/db mice to probe its anti-T2DM effects. In the present study, ME inhibited PTP1B in a reversible competitive manner and displayed good selectivity against PTPs in vitro. Furthermore, ME enhanced tyrosine phosphorylation levels of cellular proteins, especially the insulin-induced tyrosine phosphorylations of insulin receptor β-subunit (IRβ) and ERK1/2 in a dose-dependent manner in stimulated 3T3-L1 adipocytes and C2C12 myotubes. Meanwhile, ME enhanced insulin-stimulated GLUT4 translocation. More importantly, there was a significant decrease in fasting plasma glucose level of db/db diabetic mice treated orally with 0.5 g/kg ME for 4 weeks. These findings indicated that improvement of insulin sensitivity and hypoglycemic effects of ME may be attributed to the inhibition of PTP1B. Thereby, we pioneered the inhibitory potential of ME targeted on PTP1B as anti-T2DM drug discovery. PMID:26064877

Lecithin-gold hybrid nanocarriers as efficient and pH selective vehicles for oral delivery of diacerein-In-vitro and in-vivo study.

PubMed

Javed, Ibrahim; Hussain, Syed Zajif; Shahzad, Atif; Khan, Jahanzeb Muhammad; Ur-Rehman, Habib; Rehman, Mubashar; Usman, Faisal; Razi, Muhammad Tahir; Shah, Muhammad Raza; Hussain, Irshad

2016-05-01

We report the synthesis and evaluation of lecithin-gold hybrid nanocarriers for the oral delivery of drugs with improved pharmacokinetics, Au-drug interactive bioactivity and controlled drug releasing behavior at physiological pH inside human body. For this purpose, diacerein, a hydrophobic anti-arthritic drug, was loaded in lecithin NPs (LD NPs), which were further coated by Au NPs either by in-situ production of Au NPs on LD NPs or by employing pre-synthesized Au NPs. All LDAu NPs were found to release drug selectively at the physiological pH of 7.4 and showed 2.5 times increase in the oral bioavailability of diacerein. Pharmacological efficacy was significantly improved i.e., greater than the additive effect of diacerein and Au NPs alone. LDAu NPs started suppressing inflammation at first phase, whereas LD NPs showed activity in the second phase of inflammation. These results indicate the interaction of Au NPs with prostaglandins and histaminic mediators of first phase of carrageenan induced inflammation. Acute toxicity study showed no hepatic damage but the renal toxicity parameters were close to the upper safety limits. Toxicity parameters were dependent on surface engineering of LDAu NPs. Apart from enhancing the oral bioavailability of hydrophobic drugs and improving their anti-inflammatory activity, these hybrid nanocarriers may have potential applications in gold-based photothermal therapy and the tracing of inflammation at atherosclerotic and arthritic site. Copyright © 2016 Elsevier B.V. All rights reserved.

Updated Review: Improved Glycemic Control with Repaglinide-Metformin in Fixed Combination for Patients with Type 2 Diabetes

PubMed Central

Richard, John W.; Raskin, Philip

2011-01-01

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy. PMID:22879792

Updated review: improved glycemic control with repaglinide-metformin in fixed combination for patients with type 2 diabetes.

PubMed

Richard, John W; Raskin, Philip

2011-01-01

As the prevalence of type 2 diabetes continues to rise, new drug therapies will need to be explored to prevent morbidity and mortality associated with diabetes as well as growing health care costs. Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. Numerous oral medications are currently approved for the treatment of type 2 diabetes. A treat-to-failure approach has traditionally been adopted with step-wise additions of oral medications; however, a growing frequency of treatment failures with monotherapy has led to the use of combination therapies earlier in the treatment of type 2 diabetes. One such combination regimen is repaglinide (a prandial glucose optimizer that increases insulin release) plus metformin (an insulin sensitizer that inhibits hepatic glucose output and increases peripheral glucose uptake while minimizing weight gain). Findings from several clinical trials have shown repaglinide plus metformin combination therapy to be superior to either monotherapy with significant reductions in hemoglobin A1C and fasting glucose values. Repaglinide used in combination also has shown less incidence of hypoglycemia compared with other combination therapies such as sulphonylureas plus metformin. Repaglinide plus metformin combination therapy appears to be a valuable therapeutic option for type 2 diabetic patients seeking a less complex drug regimen while potentially achieving better glucose control if currently inadequately controlled on monotherapy.

Hypertensive Crisis and Left Ventricular Thrombi after an Upper Respiratory Infection during the Long-term Use of Oral Contraceptives.

PubMed

Suzuki, Natsuko; Suzuki, Keisuke; Mizuno, Tomofumi; Kato, Yukari; Suga, Norihiro; Yoshino, Masabumi; Miura, Naoto; Banno, Shogo; Imai, Hirokazu

2016-01-01

A 34-year-old woman who had been using oral contraceptives for 10 years developed hypertensive crisis with papilloedema after an upper respiratory infection. Laboratory data showed hyperreninemic hyperaldosteronism and elevated levels of fibrinogen, fibrin, and fibrinogen degradation products. Echocardiography demonstrated two masses (18 mm) in the left ventricle. On the fourth hospital day, cerebral infarction, renal infarction, and upper mesenteric artery occlusion suddenly occurred despite the blood pressure being well-controlled using anti-hypertensive drugs. Echocardiography revealed the disappearance of the left ventricular masses, which suggested left ventricular thrombi. Cessation of the contraceptives and administration of heparin, warfarin, and anti-platelets drugs improved her general condition.

Nanodrug formulations to enhance HIV drug exposure in lymphoid tissues and cells: clinical significance and potential impact on treatment and eradication of HIV/AIDS

PubMed Central

Shao, Jingwei; Kraft, John C; Li, Bowen; Yu, Jesse; Freeling, Jennifer; Koehn, Josefin; Ho, Rodney JY

2016-01-01

Although oral combination antiretroviral therapy effectively clears plasma HIV, patients on oral drugs exhibit much lower drug concentrations in lymph nodes than blood. This drug insufficiency is linked to residual HIV in cells of lymph nodes. While nanoformulations improve drug solubility, safety and delivery, most HIV nanoformulations are intended to extend plasma levels. A stable nanodrug combination that transports, delivers and accumulates in lymph nodes is needed to clear HIV in lymphoid tissues. This review discusses limitations of current oral combination antiretroviral therapy and advances in anti-HIV nanoformulations. A ‘systems approach’ has been proposed to overcome these limitations. This concept has been used to develop nanoformulations for overcoming drug insufficiency, extending cell and tissue exposure and clearing virus for treating HIV/AIDS. PMID:26892323

In vitro antifungal susceptibility to six antifungal agents of 229 Candida isolates from patients with diabetes mellitus.

PubMed

Manfredi, M; McCullough, M J; Polonelli, L; Conti, S; Al-Karaawi, Z M; Vescovi, P; Porter, S R

2006-06-01

The most common antifungal drugs in current clinical use for the treatment of oral candidosis are polyenes and azoles, mainly used topically. Poor glycaemic control in association with other local factors, such as the presence of oral dental prostheses, salivary pH, salivary flow rate and tobacco habits, may lead to the development of oral candidosis. Topical antifungal agents are frequently used to prevent the development of candidal infections in patients with poor metabolic control, particularly in the elderly wearing dentures. The aim of this study was to assess the antifungal susceptibility of Candida isolates to six antifungal agents using a commercially available kit, Fungitest. The isolated were collected from patients affected by diabetes mellitus from two different geographic localities (London, UK, and Parma, Italy) and from a group of healthy non-diabetic subjects. No differences in antifungal susceptibility to the six agents tested were observed between Candida isolates from diabetic and non-diabetic subjects. However, differences were observed between the two geographically different diabetes mellitus populations. Oral yeast isolates from diabetes mellitus patients in the UK more often displayed resistance or intermediate resistance to fluconazole (P=0.02), miconazole (P<0.0001), and ketoconazole (P=0.01) than did isolates from diabetes mellitus patients in Italy. In addition, more C. albicans isolates were found in diabetic and non-diabetic subjects that were susceptible to fluconazole (P=0.0008 and P=0.01, respectively) than non-albicans isolates. The difference in the antifungal resistance of isolates from the two populations of diabetes mellitus patients may be related to differences in the therapeutic management of candidal infections between the two centres.

Remission of Grave's disease after oral anti-thyroid drug treatment.

PubMed

Ishtiaq, Osama; Waseem, Sabiha; Haque, M Naeemul; Islam, Najmul; Jabbar, Abdul

2009-11-01

To evaluate remission rate of anti-thyroid drug treatment in patients with Grave's disease, and to study the factors associated with remission. A cross sectional study. The Endocrine Department of the Aga Khan University Hospital, Karachi from 1999 to 2000. Seventy four patients of Grave's disease were recruited who were prescribed medical treatment. Grave's disease was diagnosed in the presence of clinical and biochemical hyperthyroidism along with anti-microsomal (AMA) and anti-thyroglobulin antibodies (ATA) and thyroid scan. These patients were prescribed oral anti-thyroid drugs using titration regime and followed at 3, 6, 12 and 18 months. Patients were categorized into two groups: "remission group" and "treatment failure group" and results were compared using a chi-square test, t-test and logistic regression model with significance at p < 0.05. A majority of the patients were females (62.6%, n=46). During the follow-up period of 18 months, 41.9% patients went into remission. Univariate analysis showed that the initial free T4 level was significantly different (p < 0.05) in patients in remission and treatment failure groups. Multivariate analysis showed only initial free T4 level was a significant predictor of outcome. Positive AMA patients (n=27) had higher treatment failure (odds ratio: 2.55: 95%, CI 0.69 - 9:31), although the difference was not statistically significant (p = 0.13). Remission rates with oral anti-thyroid agents is markedly high. Patients should be offered alternate treatment options to those who do not enter remission during a period of 12-18 months of treatment, those who develop relapse, and those who have aggressive disease on initial presentation.

Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist

PubMed Central

Li, Ying; Zheng, Xuemin; Yi, Xiulin; Liu, Changxiao; Kong, Dexin; Zhang, Jianning; Gong, Min

2017-01-01

The physiologic properties of glucagon-like peptide 1 (GLP-1) make it a potent candidate drug target in the treatment of type 2 diabetes mellitus (T2DM). GLP-1 is capable of regulating the blood glucose level by insulin secretion after administration of oral glucose. The advantages of GLP-1 for the avoidance of hypoglycemia and the control of body weight are attractive despite its poor stability. The clinical efficacies of long-acting GLP-1 derivatives strongly support discovery pursuits aimed at identifying and developing orally active, small-molecule GLP-1 receptor (GLP-1R) agonists. The purpose of this study was to identify and characterize a novel oral agonist of GLP-1R (i.e., myricetin). The insulinotropic characterization of myricetin was performed in isolated islets and in Wistar rats. Long-term oral administration of myricetin demonstrated glucoregulatory activity. The data in this study suggest that myricetin might be a potential drug candidate for the treatment of T2DM as a GLP-1R agonist. Further structural modifications on myricetin might improve its pharmacology and pharmacokinetics.—Li, Y., Zheng, X., Yi, X., Liu, C., Kong, D., Zhang, J., Gong, M. Myricetin: a potent approach for the treatment of type 2 diabetes as a natural class B GPCR agonist. PMID:28270518

Utilisation of antihyperglycaemic drugs in ten European countries: different developments and different levels.

PubMed

Melander, A; Folino-Gallo, P; Walley, T; Schwabe, U; Groop, P-H; Klaukka, T; Vallano, A; Laporte, J-R; Gallego, M R; Schiappa, M; Røder, M; Kampmann, J P; de Swaef, A; Aberg, M; Månsson, N-O; Lindblad, U

2006-09-01

The aim of this study was to compare developments in the utilisation of antihyperglycaemic drugs (AHGDs) in ten European countries. Data on the yearly utilisation of insulin and oral AHGDs were collected from public registers in Denmark, Finland, Norway, Sweden, Belgium, England, Germany, Italy, Portugal and Spain, and were expressed as defined daily doses per 1,000 inhabitants per day. Total AGHD utilisation increased everywhere, but at different rates and levels. Insulin utilisation doubled in England and Germany, but hardly changed in Belgium, Portugal or Italy. Sulfonylurea utilisation doubled in Spain, England and Denmark but was reduced in Germany and Sweden. Metformin utilisation increased greatly everywhere. There were two- to three-fold differences in AHGD utilisation even between neighbouring countries. In Finland, there were more users of both insulin (+120%) and oral AHGDs (+80%) than in Denmark, and the daily oral AHGD doses were higher. In Denmark and Sweden, AHGD utilisation was equal in subjects aged <45 years, but in those >or=45 years of age, both insulin and oral AHGD utilisation were twice as high in Sweden. The ubiquitous increase in AHGD utilisation, particularly metformin, seems logical, considering the increasing prevalence of type 2 diabetes and the results of the UK Prospective Diabetes Study. However, the large differences even between neighbouring countries are more difficult to explain, and suggest different habits and attitudes in terms of screening and management of type 2 diabetes.

Protective effect of aqueous seed extract of Vitis Vinifera against oxidative stress, inflammation and apoptosis in the pancreas of adult male rats with diabetes mellitus.

PubMed

Adam, Siti Hajar; Giribabu, Nelli; Kassim, Normadiah; Kumar, Kilari Eswar; Brahmayya, Manuri; Arya, Aditya; Salleh, Naguib

2016-07-01

Protective effects of Vitis Vinifera seed aqueous extract (VVSAE) against pancreatic dysfunctions and elevation of oxidative stress, inflammation and apoptosis in the pancreas in diabetes were investigated. Histopathological changes in the pancreas were examined under light microscope. Blood and pancreas were collected from adult male diabetic rats receiving 28days treatment with VVSAE orally. Fasting blood glucose (FBG), glycated hemoglobin (HbA1c), insulin and lipid profile levels and activity levels of anti-oxidative enzymes (superoxide dismutase-SOD, catalase-CAT and glutathione peroxidase-GPx) in the pancreas were determined by biochemical assays. Histopathological changes in the pancreas were examined under light microscopy and levels of insulin, glucose transporter (GLUT)-2, tumor necrosis factor (TNF)-α, Ikkβ and caspase-3 mRNA and protein were analyzed by real-time PCR (qPCR) and immunohistochemistry respectively. Radical scavenging activity of VVSAE was evaluated by in-vitro anti-oxidant assay while gas chromatography-mass spectrometry (GC-MS) was used to identify the major compounds in the extract. GC-MS analyses indicated the presence of compounds that might exert anti-oxidative, anti-inflammatory and anti-apoptosis effects. Near normal FBG, HbAIc, lipid profile and serum insulin levels with lesser signs of pancreatic destruction were observed following administration of VVSAE to diabetic rats. Higher insulin, GLUT-2, SOD, CAT and GPx levels but lower TNF-α, Ikkβ and caspase-3 levels were also observed in the pancreas of VVSAE-treated diabetic rats (p<0.05 compared to non-treated diabetic rats). The extract possesses high in-vitro radical scavenging activities. In conclusions, administration of VVSAE to diabetic rats could help to protect the pancreas against oxidative stress, inflammation and apoptosis-induced damage while preserving pancreatic function near normal in diabetes. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Efficacy of combination herbal product (Curcuma longa and Eugenia jambolana) used for diabetes mellitus.

PubMed

Rao, Sadia Saleem; Najam, Rahila

2016-01-01

The purpose of this research was to evaluate the efficacy of a combination herbal product that is traditionally used for managing diabetes mellitus. Herbal drug contains Curcuma longa and Eugenia jambolanain the ratio of 1:1. It was orally administered at the dose of 1082 mg/70 kg twice a day for a period of 6 weeks to alloxan induced diabetic rats and compared with glibenclamide (standard). The effects of drug were observed at intervals, with respect to random and fasting glucose levels. HbA1C was also monitored after the drug treatment to monitor the overall diabetic effect. Results revealed that the combination of two herbs significantly reduced fasting and random glucose levels with HbA1C of less than 6% (p<0.001) in comparison to diabetic control. The control of fasting blood glucose levels by herbal combination is similar to the standard drug, glibenclamide (p<0.05). Random glucose levels by herbal combination is better than standard drug after one week and six weeks of treatment (p<0.01 and p<0.001 respectively) and similar after third week of treatment (p<0.05). Also, herbal drug combination showed HbA1C closer to the standard drug. It shows that this herbal combination can be of potential benefit in managing diabetes mellitus in future.

Gemigliptin, a novel dipeptidyl peptidase 4 inhibitor: first new anti-diabetic drug in the history of Korean pharmaceutical industry.

PubMed

Kim, Sung-Ho; Lee, Sung-Hack; Yim, Hyeon-Joo

2013-10-01

Gemigliptin, a potent, selective and long-acting DPP 4 inhibitor was developed by LG Life Sciences and approved for use in patients with type 2 diabetes mellitus by the Korean Food and Drug Administration in June 2012 under the trade name Zemiglo(®). Clinical pharmacokinetic and pharmacodynamic data suggest the efficacy and once daily dosing of gemigliptin. In clinical phase III studies, gemigliptin was efficacious as either monotherapy or combination therapy (add-on to metformin) and well tolerated in patients with type 2 diabetes. Further development of combination therapy is on-going.

[The vanadium compounds: chemistry, synthesis, insulinomimetic properties].

PubMed

Fedorova, E V; Buriakina, A V; Vorob'eva, N M; Baranova, N I

2014-01-01

The review considers the biological role of vanadium, its participation in various processes in humans and other mammals, and the anti-diabetic effect of its compounds. Vanadium salts have persistent hypoglycemic and antihyperlipidemic effects and reduce the probability of secondary complications in animals with experimental diabetes. The review contains a detailed description of all major synthesized vanadium complexes having antidiabetic activity. Currently, vanadium complexes with organic ligands are more effective and safer than the inorganic salts. Despite the proven efficacy of these compounds as the anti-diabetic agents in animal models, only one organic complex of vanadium is currently under the second phase of clinical trials. All of the considered data suggest that vanadium compound are a new promising class of drugs in modern pharmacotherapy of diabetes.

[Perception of insulin therapy in uncontrolled patients with type 2 diabetes mellitus].

PubMed

Leyva Jiménez, Rafael; Hernández Zambrano, Gustavo; Ibarra Maldonado, Silvia; Ibarra Ramírez, Carlos Tomás

2016-10-01

To determine the perception of insulin therapy by patients with uncontrolled type2 diabetes mellitus, who have been treated with oral hypoglycaemic agents or insulin. Prospective comparative cross-sectional study. Family Medicine Unit No. 53 León, Guanajuato of Mexican Institute of Social Security. Patients between 40 and 80years old with uncontrolled type2 mellitus diabetes, treated with insulin or oral hypoglycaemic agents. Perception was assessed using the insulin treatment appraisal scale (ITAS). The rating of the survey is from 20 to 100 points, as such that when score increases the greater is the negative opinion. A sample of 459 diabetes patients were interviewed and split into 2 groups of patients according to their treatment. The OH group were patients treated with oral hypoglycaemic drugs only (56.9%), and the IN group were patients treated with insulin alone or combined with an oral hypoglycaemic (43.1%). Perception score was significantly higher in OH group (56.95±7.78 versus 49.55±8.89 points) than in the IN group (P<.001). The perception of insulin therapy was worse in patients treated with only oral hypoglycaemic agents than in patients using insulin. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.

Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells.

PubMed

Sbaraglini, María Laura; Molinuevo, María Silvina; Sedlinsky, Claudia; Schurman, León; McCarthy, Antonio Desmond

2014-03-15

Diabetes mellitus is associated with a decrease in bone quality and an increase in fracture incidence. Additionally, treatment with anti-diabetic drugs can either adversely or positively affect bone metabolism. In this study we evaluated: the effect of a 3-week oral treatment with saxagliptin on femoral microarchitecture in young male non-type-2-diabetic Sprague Dawley rats; and the in vitro effect of saxagliptin and/or fetal bovine serum (FBS), insulin or insulin-like growth factor-1 (IGF1), on the proliferation, differentiation (Runx2 and PPAR-gamma expression, type-1 collagen production, osteocalcin expression, mineralization) and extracellular-regulated kinase (ERK) activation, in bone marrow stromal cells (MSC) obtained from control (untreated) rats and in MC3T3E1 osteoblast-like cells. In vivo, oral saxagliptin treatment induced a significant decrease in the femoral osteocytic and osteoblastic density of metaphyseal trabecular bone and in the average height of the proximal cartilage growth plate; and an increase in osteoclastic tartrate-resistant acid phosphatase (TRAP) activity of the primary spongiosa. In vitro, saxagliptin inhibited FBS-, insulin- and IGF1-induced ERK phosphorylation and cell proliferation, in both MSC and MC3T3E1 preosteoblasts. In the absence of growth factors, saxagliptin had no effect on ERK activation or cell proliferation. In both MSC and MC3T3E1 cells, saxagliptin in the presence of FBS inhibited Runx2 and osteocalcin expression, type-1 collagen production and mineralization, while increasing PPAR-gamma expression. In conclusion, orally administered saxagliptin induced alterations in long-bone microarchitecture that could be related to its in vitro down-regulation of the ERK signaling pathway for insulin and IGF1 in MSC, thus decreasing the osteogenic potential of these cells. Copyright © 2014 Elsevier B.V. All rights reserved.

Potent effects of the total saponins from Dioscorea nipponica Makino against streptozotocin-induced type 2 diabetes mellitus in rats.

PubMed

Yu, Hao; Zheng, Lingli; Xu, Lina; Yin, Lianhong; Lin, Yuan; Li, Hua; Liu, Kexin; Peng, Jinyong

2015-02-01

The aim of the present paper was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against type 2 diabetes mellitus. Streptozotocin (STZ) with high-fat diet induced type 2 diabetes mellitus (T2DM) rats were treated with TSDN. Some biochemical parameters, target proteins and genes were investigated. The results showed that TSDN decreased the levels of food/water intake, fasting blood glucose and serum lipid parameters, ameliorated oral glucose and insulin tolerance test levels, markedly increased body weight and serum insulin, reduced excess free radicals and affected ossification and renal protection. Histopathological examination indicated that TSDN increased liver glycogen, decreased the production of lipid vacuoles and lightened liver damage. Further investigation showed that TSDN down-regulated the protein expressions of NF-κB, GRP78, ATF6, eIF2 and the levels of MAPK phosphorylation and up-regulated the protein expressions of IRS-1, GLUT-4, p-Akt and p-AMPK. In addition, TSDN obviously decreased the gene expressions of TNF-a, IL-6, PEPCK, G6Pase, GSK-3β and GSK-3β activity, and increased the gene expressions of PFK, PK and GK activity. These findings show the anti-diabetic activity of total saponins from D. nipponica Makino, which should be developed as a new potent drug for treatment of diabetes mellitus in future. Copyright © 2014 John Wiley & Sons, Ltd.

Medicare coverage for patients with diabetes. A national plan with individual consequences.

PubMed

Ashkenazy, R; Abrahamson, M J

2006-04-01

The prevalence of diabetes in the U.S. Medicare population is growing at an alarming rate. From 1980 to 2004, the number of people aged 65 or older with diagnosed diabetes increased from 2.3 million to 5.8 million. According to the Centers for Medicare and Medicaid (CMS), 32% of Medicare spending is attributed to the diabetes population. Since its inception, Medicare has expanded medical coverage of monitoring devices, screening tests and visits, educational efforts, and preventive medical services for its diabetic enrollees. However, oral antidiabetic agents and insulin were excluded from reimbursement. In 2003, Congress passed the Medicare Modernization Act that includes a drug benefit to be administered either through Medicare Advantage drug plans or privately sponsored prescription drug plans for implementation in January 2006. In this article we highlight key patient and drug plan characteristics and resources that providers may focus upon to assist their patients choose a coverage plan. Using a case example, we illustrate the variable financial impact the adoption of Medicare part D may have on beneficiaries with diabetes due to their economic status. We further discuss the potential consequences the legislation will have on diabetic patients enrolled in Medicare, their providers, prescribing strategies, and the diabetes market.

Oral Administration of Apple Procyanidins Ameliorates Insulin Resistance via Suppression of Pro-Inflammatory Cytokine Expression in Liver of Diabetic ob/ob Mice.

PubMed

Ogura, Kasane; Ogura, Masahito; Shoji, Toshihiko; Sato, Yuichi; Tahara, Yumiko; Yamano, Gen; Sato, Hiroki; Sugizaki, Kazu; Fujita, Naotaka; Tatsuoka, Hisato; Usui, Ryota; Mukai, Eri; Fujimoto, Shimpei; Inagaki, Nobuya; Nagashima, Kazuaki

2016-11-23

Procyanidins, the main ingredient of apple polyphenols, are known to possess antioxidative and anti-inflammatory effects associated closely with the pathophysiology of insulin resistance and type 2 diabetes. We investigated the effects of orally administered apple procyanidins (APCs) on glucose metabolism using diabetic ob/ob mice. We found no difference in body weight or body composition between mice treated with APCs and untreated mice. A 4 week oral administration of APCs containing water [0.5% (w/v)] ameliorated glucose tolerance, insulin resistance, and hepatic gluconeogenesis in ob/ob mice. APCs also suppressed the increase in the level of the pancreatic β-cell. Insulin-stimulated Akt phosphorylation was significantly enhanced; pro-inflammatory cytokine expression levels were significantly decreased, and c-Jun N-terminal kinase phosphorylation was downregulated in the liver of those mice treated with APCs. In conclusion, APCs ameliorate insulin resistance by improving hepatic insulin signaling through suppression of hepatic inflammation in ob/ob mice, which may be a mechanism with possible beneficial health effects of APCs in disturbed glucose metabolism.

Comparison of the anti-diabetic effects of resveratrol, gliclazide and losartan in streptozotocin-induced experimental diabetes.

PubMed

Yazgan, Ümit Can; Taşdemir, Ezel; Bilgin, Hakkı Murat; Deniz Obay, Basra; Şermet, Abdurrahman; Elbey, Bilal

2015-01-01

The aim of this study was to compare the effect of the resveratrol with gliclazide and losartan in streptozotocin induced diabetic rats. Adult male Wistar albino rats were divided into five groups of seven rats each. Diabetes was induced with a single intraperitoneal (i.p.) injection of streptozotocin (55 mg/kg). Rats with blood glucose levels above 250 mg/dl after 48 h of streptozotocin injection were included in the diabetic group. Gliclazide and resveratrol were administered for 3 weeks at 5 mg/kg per day and losartan was administered for 3 weeks at 30 mg/kg per day in an oral aqueous suspension. At the end of the third week all rats were euthanized and fasting blood glucose, HbA1c and the metabolic activity of the hepatic enzymes hexokinase and glucose-6 phosphate dehydrogenase were measured in tail blood and liver specimens. All parameters were quantified using an ELISA plate reader. Resveratrol and gliclazide significantly reduced both blood glucose levels and HbA1c levels in diabetic rats (p < 0.001). However, losartan did not exhibit the same effects (p < 0.05). The enzymatic activity of the liver enzymes hexokinase, glucose-6 phosphate dehydrogenase, fructose 1,6-biphosphatase, pyruvate kinase and glucose-6 phosphatase were enhanced by resveratrol and gliclazide, while losartan treatment was not associated with significant changes in liver carbohydrate metabolism. Resveratrol was not effective in improving liver carbohydrate metabolism relative to gliclazide, a drug widely used to treat diabetes. Dose-response profile of resveratrol remains indeterminate and additional studies may be necessary to determine effective dosing in diabetes.

Evaluation of the anti-diabetic properties of Mucuna pruriens seed extract.

PubMed

Majekodunmi, Stephen O; Oyagbemi, Ademola A; Umukoro, Solomon; Odeku, Oluwatoyin A

2011-08-01

To explore the antidiabetic properties of Mucuna pruriens(M. pruriens). Diabetes was induced in Wistar rats by single intravenous injection of 120 mg/kg of alloxan monohydrate and different doses of the extract were administered to diabetic rats. The blood glucose level was determined using a glucometer and results were compared with normal and untreated diabetic rats. The acute toxicity was also determined in albino mice. Results showed that the administration of 5, 10, 20, 30, 40, 50, and 100 mg/kg of the crude ethanolic extract of M. pruriens seeds to alloxan-induced diabetic rats (plasma glucose > 450 mg/dL) resulted in 18.6%, 24.9%, 30.8%, 41.4%, 49.7%, 53.1% and 55.4% reduction, respectively in blood glucose level of the diabetic rats after 8h of treatment while the administration of glibenclamide (5 mg/kg/day) resulted in 59.7% reduction. Chronic administration of the extract resulted in a significant dose dependent reduction in the blood glucose level (P<0.001). It also showed that the antidiabetic activity of M. pruriens seeds resides in the methanolic and ethanolic fractions of the extract. Acute toxicity studies indicated that the extract was relatively safe at low doses, although some adverse reactions were observed at higher doses (8-32 mg/kg body weight), no death was recorded. Furthermore, oral administration of M. pruriens seed extract also significantly reduced the weight loss associated with diabetes. The study clearly supports the traditional use of M. pruriens for the treatment of diabetes and indicates that the plant could be a good source of potent antidiabetic drug. Copyright © 2011 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Brazilian guidelines on prevention of cardiovascular disease in patients with diabetes: a position statement from the Brazilian Diabetes Society (SBD), the Brazilian Cardiology Society (SBC) and the Brazilian Endocrinology and Metabolism Society (SBEM).

PubMed

Bertoluci, Marcello Casaccia; Moreira, Rodrigo Oliveira; Faludi, André; Izar, Maria Cristina; Schaan, Beatriz D; Valerio, Cynthia Melissa; Bertolami, Marcelo Chiara; Chacra, Ana Paula; Malachias, Marcus Vinicius Bolivar; Vencio, Sérgio; Saraiva, José Francisco Kerr; Betti, Roberto; Turatti, Luiz; Fonseca, Francisco Antonio Helfenstein; Bianco, Henrique Tria; Sulzbach, Marta; Bertolami, Adriana; Salles, João Eduardo Nunes; Hohl, Alexandre; Trujilho, Fábio; Lima, Eduardo Gomes; Miname, Marcio Hiroshi; Zanella, Maria Teresa; Lamounier, Rodrigo; Sá, João Roberto; Amodeo, Celso; Pires, Antonio Carlos; Santos, Raul D

2017-01-01

Since the first position statement on diabetes and cardiovascular prevention published in 2014 by the Brazilian Diabetes Society, the current view on primary and secondary prevention in diabetes has evolved as a result of new approaches on cardiovascular risk stratification, new cholesterol lowering drugs, and new anti-hyperglycemic drugs. Importantly, a pattern of risk heterogeneity has emerged, showing that not all diabetic patients are at high or very high risk. In fact, most younger patients who have no overt cardiovascular risk factors may be more adequately classified as being at intermediate or even low cardiovascular risk. Thus, there is a need for cardiovascular risk stratification in patients with diabetes. The present panel reviews the best current evidence and proposes a practical risk-based approach on treatment for patients with diabetes. The Brazilian Diabetes Society, the Brazilian Society of Cardiology, and the Brazilian Endocrinology and Metabolism Society gathered to form an expert panel including 28 cardiologists and endocrinologists to review the best available evidence and to draft up-to-date an evidence-based guideline with practical recommendations for risk stratification and prevention of cardiovascular disease in diabetes. The guideline includes 59 recommendations covering: (1) the impact of new anti-hyperglycemic drugs and new lipid lowering drugs on cardiovascular risk; (2) a guide to statin use, including new definitions of LDL-cholesterol and in non-HDL-cholesterol targets; (3) evaluation of silent myocardial ischemia and subclinical atherosclerosis in patients with diabetes; (4) hypertension treatment; and (5) the use of antiplatelet therapy. Diabetes is a heterogeneous disease. Although cardiovascular risk is increased in most patients, those without risk factors or evidence of sub-clinical atherosclerosis are at a lower risk. Optimal management must rely on an approach that will cover both cardiovascular disease prevention in individuals in the highest risk as well as protection from overtreatment in those at lower risk. Thus, cardiovascular prevention strategies should be individualized according to cardiovascular risk while intensification of treatment should focus on those at higher risk.

Metabolic profiling of nuciferine in rat urine, plasma, bile and feces after oral administration using ultra-high performance liquid chromatography-diode array detection-quadrupole time-of-flight mass spectrometry.

PubMed

Wu, Xiao-Lei; Wu, Ming-Jiang; Chen, Xin-Ze; Ma, Hao-Ling; Ding, Li-Qin; Qiu, Feng; Pan, Qin; Zhang, De-Qin

2017-06-05

Nuciferine, a major alkaloid found in Nelumbinis Folium, exhibits a broad spectrum of bioactivities, such as antiobesity, anti-diabetes and anti-inflammatory. However, many research regarding nuciferine focused on the extraction, isolation and biological activity, the metabolism is not comprehensively explained in vivo. Thence, the present of this paper is to establish a simple method for speculating metabolites of nuciferine. A total of 15 metabolites were detected and tentatively identified through ultra high performance liquid chromatography-diode array detection-quadrupole time-of-flight mass spectrometry (UHPLC-DAD-QTOF-MS), including 7 new metabolites. Among them, we also discovered a previously unmentioned metabolically active site at the C 1 -OCH 3 position. These metabolites suggested that demethylation, oxidation, glucuronidation and sulfation were major metabolic pathways. This study provided significant experiment basis for its safety estimate and valuable information about the metabolism of nuciferine, which will be advantageous for new drug development. Copyright © 2017 Elsevier B.V. All rights reserved.

Traditional Uses, Pharmacological Efficacy, and Phytochemistry of Moringa peregrina (Forssk.) Fiori. —A Review

PubMed Central

Senthilkumar, Annadurai; Karuvantevida, Noushad; Rastrelli, Luca; Kurup, Shyam S.; Cheruth, Abdul J.

2018-01-01

Moringa is a sole genus of Moringaceae family with 13 species distributed in the tropical and sub-tropical regions. Among them, Moringa peregrina is one of the species which has wide range of traditional, nutritional, industrial, and medicinal values. The plant parts are used in folk medicine for many human health care purposes including diabetes, wound healing, disinfectant, fever, constipation, muscle pains, slimness, burns, labor pain, hypertension, malaria, stomach disorder, asthma, skin problems, and to expel a retained placenta. In addition to medicinal value, M. peregrina has cultural, spiritual, and religious connections with the native people of Arabian Peninsula. M. peregrina plant parts were tested for many pharmacological activities viz, antioxidant, anti-microbial, anti-diabetic, anti-spasmodic, hypertension, hepatotoxicity, lipid lowering activity, anti-inflammatory, anti-cancer, and memory disorders. Few active molecules belong to the class isothiocyanate, flavonoid, triterpenoid, phytosterol, polyphenol, and glycoside were also isolated, identified and reported for anti-microbial, anti-oxidant, anthelmintic, anti-mutagenic, neuroprotective, anti-cancer, anti-hypertensive, anti-diabetic, anti-infective, anti-allergic, anti-inflammatory, herbicidal, lipid lowering potential, anti-trypanosomal, and cytotoxic activities. So, the aim of the present review is to provide comprehensive information from recognized sources on the traditional uses, pharmacological efficacy and phytochemistry of the desert medicinal plant, M. peregrina. The information provided in this review will be very useful for further studies to develop novel therapeutic drugs. PMID:29867473

Traditional Uses, Pharmacological Efficacy, and Phytochemistry of Moringa peregrina (Forssk.) Fiori. -A Review.

PubMed

Senthilkumar, Annadurai; Karuvantevida, Noushad; Rastrelli, Luca; Kurup, Shyam S; Cheruth, Abdul J

2018-01-01

Moringa is a sole genus of Moringaceae family with 13 species distributed in the tropical and sub-tropical regions. Among them, Moringa peregrina is one of the species which has wide range of traditional, nutritional, industrial, and medicinal values. The plant parts are used in folk medicine for many human health care purposes including diabetes, wound healing, disinfectant, fever, constipation, muscle pains, slimness, burns, labor pain, hypertension, malaria, stomach disorder, asthma, skin problems, and to expel a retained placenta. In addition to medicinal value, M. peregrina has cultural, spiritual, and religious connections with the native people of Arabian Peninsula. M. peregrina plant parts were tested for many pharmacological activities viz , antioxidant, anti-microbial, anti-diabetic, anti-spasmodic, hypertension, hepatotoxicity, lipid lowering activity, anti-inflammatory, anti-cancer, and memory disorders. Few active molecules belong to the class isothiocyanate, flavonoid, triterpenoid, phytosterol, polyphenol, and glycoside were also isolated, identified and reported for anti-microbial, anti-oxidant, anthelmintic, anti-mutagenic, neuroprotective, anti-cancer, anti-hypertensive, anti-diabetic, anti-infective, anti-allergic, anti-inflammatory, herbicidal, lipid lowering potential, anti-trypanosomal, and cytotoxic activities. So, the aim of the present review is to provide comprehensive information from recognized sources on the traditional uses, pharmacological efficacy and phytochemistry of the desert medicinal plant, M. peregrina . The information provided in this review will be very useful for further studies to develop novel therapeutic drugs.

Comparison quality of life patients treated with insulin and oral hypoglycemic drugs

NASA Astrophysics Data System (ADS)

Harahap, A. W.; Nasution, M. S.

2018-03-01

Diabetes mellitus (DM) is a group of chronic metabolic diseases with characteristic hyperglycemia that occurs due to abnormalities in insulin secretion, insulin action or both. Improved quality of life is one of the goals of DM management. This study aims to compare thequality of life in40 patients with type 2 diabetes using insulin therapy and 40 patients using oral hypoglycemic drugs in H. Adam Malik Hospital year 2015. This study is an observational study with cross-sectionalstudy designand consecutive sampling method. Evaluation of the patient’s quality of life taken through interviews and questionnaires using the Short Form-36 questionnaire consistingof8 domains of quality of life. Statistical analysis using unpaired t-test and Mann-Whitney test. Results of the quality of life-based on patient characteristics showed significant differences in education factor (p=0.005) and employment factor (p=0.001). Quality of life-based on therapy showed significant differences in domain role of physical (p=0.005) and domain role of emotional (p=0.038).The quality of life of patients with type 2 diabetes using insulin better than using hypoglycemic drug significantly in domain role of physical and domain role of emotions.

ENOblock, a unique small molecule inhibitor of the non-glycolytic functions of enolase, alleviates the symptoms of type 2 diabetes

PubMed Central

Cho, Haaglim; Um, JungIn; Lee, Ji-Hyung; Kim, Woong-Hee; Kang, Wan Seok; Kim, So Hun; Ha, Hyung-Ho; Kim, Yong-Chul; Ahn, Young-Keun; Jung, Da-Woon; Williams, Darren R.

2017-01-01

Type 2 diabetes mellitus (T2DM) significantly impacts on human health and patient numbers are predicted to rise. Discovering novel drugs and targets for treating T2DM is a research priority. In this study, we investigated targeting of the glycolysis enzyme, enolase, using the small molecule ENOblock, which binds enolase and modulates its non-glycolytic ‘moonlighting’ functions. In insulin-responsive cells ENOblock induced enolase nuclear translocation, where this enzyme acts as a transcriptional repressor. In a mammalian model of T2DM, ENOblock treatment reduced hyperglycemia and hyperlipidemia. Liver and kidney tissue of ENOblock-treated mice showed down-regulation of known enolase target genes and reduced enolase enzyme activity. Indicators of secondary diabetic complications, such as tissue apoptosis, inflammatory markers and fibrosis were inhibited by ENOblock treatment. Compared to the well-characterized anti-diabetes drug, rosiglitazone, ENOblock produced greater beneficial effects on lipid homeostasis, fibrosis, inflammatory markers, nephrotoxicity and cardiac hypertrophy. ENOblock treatment was associated with the down-regulation of phosphoenolpyruvate carboxykinase and sterol regulatory element-binding protein-1, which are known to produce anti-diabetic effects. In summary, these findings indicate that ENOblock has potential for therapeutic development to treat T2DM. Previously considered as a ‘boring’ housekeeping gene, these results also implicate enolase as a novel drug target for T2DM. PMID:28272459

Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331 288 participants

PubMed Central

2015-01-01

Summary Background Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. Methods We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA1c (HbA1c ≥6·5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG ≥7·0 mmol/L or 2hOGTT ≥11·1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Findings Population prevalence of diabetes based on FPG-or-2hOGTT was correlated with prevalence based on FPG alone (r=0·98), but was higher by 2–6 percentage points at different prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42·8% of age–sex–survey groups and higher in another 41·6%; in the other 15·6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA1c 6·5% or more had a pooled sensitivity of 52·8% (95% CI 51·3–54·3%) and a pooled specificity of 99·74% (99·71–99·78%) compared with FPG 7·0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30·5% (28·7–32·3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG. Interpretation Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA1c-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test. Funding Wellcome Trust, US National Institutes of Health. PMID:26109024

The potential of sanrego (Lunasia amara) in enhancing fertility and anti-hyperglycemic effect in diabetic induced male rats

NASA Astrophysics Data System (ADS)

Nor Raidah, R.; Mahanem M., N.; Mohd Shazrul Fazry, S.

2014-09-01

Study on the effects of Lunasia amara (LA) aqueous extract on male fertility and its anti-hyperglycemic activity was carried out. Twelve adult male Sprague-Dawley rats were divided into two groups for fertility test; control given orally distilled water (n=6) and treatment (n=6) given 60 mg/kg aqueous extract of LA for 42 days. On day 43, all rats were sacrificed and cauda epididymis was isolated for sperm quality analysis that includes parameter of sperm count, motility and viability. Anti-hyperglycemic study was done on five groups of male rats; I-normal control, II-Diabetic control and three other groups induced diabetic given 500 mg/kg metformin, 60 mg/kg LA and 120 mg/kg LA respectively. Diabetes was induced in the male rats by intravenous injection of 55 mg/kg streptozotocin. On day 7, the fasting blood glucose level was measured from blood drawn by tail snip. Results showed that aqueous extract of LA increased significantly (p < 0.05) sperm count (39.88 ± 2.33) × 106, viability 82.46 ± 1.91 % and progressive motility 76.00 ± 1.51and of sperm data in treated group compared to control group. LA aqueous extract at dose 120 mg/kg was significantly reduced the fasting blood glucose in the diabetic rats by 49.53 %. In conclusion, the aqueous extract of LA effective in increasing sperm quality of male rats and suggest that LA may possess anti-hyperglycemic property.

Anti-inflammatory activity of D-002: an active product isolated from beeswax.

PubMed

Carbajal, D; Molina, V; Valdés, S; Arruzazabala, M L; Más, R; Magraner, J

1998-10-01

D-002 is a natural mixture of high molecular weight alcohols isolated and purified from beeswax, which contains triacontanol among its main components. This study was undertaken to investigate the anti-inflammatory effects of D-002 administered by the oral route in two animal models commonly used in the pharmacological screening of anti-inflammatory drugs. D-002 administered orally to rats (100 and 200 mg/kg) produced a mild but significant reduction of exudate volume in carrageenan-induced pleuritic inflammation that was accompanied by a marked and significant decrease of leukotriene B4 (LTB4) levels in the exudate. D-002 (25, 50 and 200 mg/kg) also significantly diminished the granuloma weight in the cotton pellet granuloma in rats. In both cases, D-002 was less effective than indomethacin, which was used as an established anti-inflammatory reference drug. On the other hand, D-002 administered from 25-1000 mg/kg did not induce erosions or gastromucosal lesions in rats, which differs from results usually obtained with non steroidal anti-inflammatory drugs. These results indicate that D-002 is a mild anti-inflammatory agent without any ulcerogenic effect associated. The results suggest that these effects are probably not mediated through an inhibition of cyclooxygenase, but a reduction in LTB4 levels induced by D-002 could explain these results.

Minocycline-Induced Drug Hypersensitivity Syndrome Followed by Multiple Autoimmune Sequelae

PubMed Central

Brown, Rebecca J.; Rother, Kristina I.; Artman, Henry; Mercurio, Mary Gail; Wang, Roger; Looney, R. John; Cowen, Edward W.

2010-01-01

Background Drug hypersensitivity syndrome (DHS) is a severe, multisystem adverse drug reaction that may occur following the use of numerous medications, including anticonvulsants, sulfonamides, and minocycline hydrochloride. Long-term autoimmune sequelae of DHS have been reported, including hypothyroidism. Observations A 15-year-old female adolescent developed DHS 4 weeks after starting minocycline therapy for acne vulgaris. Seven weeks later she developed autoimmune hyperthyroidism (Graves disease), and 7 months after discontinuing minocycline therapy she developed autoimmune type 1 diabetes mellitus. In addition, she developed elevated titers of several markers of systemic autoimmune disease, including antinuclear, anti-Sjögren syndrome A, and anti-Smith antibodies. Conclusions Minocycline-associated DHS may be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and elevated markers of systemic autoimmunity. Long-term follow-up is needed in patients with DHS to determine the natural history of DHS-associated sequelae. PMID:19153345

Antidiabetic Effects of Aqueous and Dichloromethane/Methanol Stem Bark Extracts of Pterocarpus soyauxii Taub (Papilionaceae) on Streptozotocin-induced Diabetic Rats

PubMed Central

Tchamadeu, Marie Claire; Dzeufiet, Paul Désiré Djomeni; Blaes, Nelly; Girolami, Jean-Pierre; Kamtchouing, Pierre; Dimo, Théophile

2017-01-01

Aim of the Study: The aim is to evaluate the hypoglycemic and antidiabetic effects of aqueous and CH2Cl2/CH3OH stem bark extracts of Pterocarpus soyauxii Taub in normal and diabetic rats. Materials and Methods: Streptozotocin (STZ)-induced diabetic and normal adult Wistar rats were orally administered with aqueous and CH2Cl2/CH3OH plant extracts of P. soyauxii at various doses (38–300 mg/kg) in a single administration. In addition, STZ-induced diabetic rats received prolonged daily administration for 14 days. Glibenclamide (GB) (10 mg/kg) was used as reference treatment. In acute test, fasting blood glucose was followed for 5 h. In subacute test, body weight, food and water intakes, and blood glucose were followed weekly and serum biochemical parameters evaluated after 14 days treatment. Results: Acute administration of aqueous and CH2Cl2/CH3OH stem bark extracts moderately decreased fasting blood glucose compared to GB, significantly in normal rats (P < 0.05 to P < 0.01) but, as GB, not significantly in diabetic rats. Prolonged treatments in diabetic rats with aqueous and CH2Cl2/CH3OH extracts reduced blood glucose to an extent, respectively, superior or similar to GB. Moreover, P. soyauxii also significantly (P < 0.01) reduced weight loss, and diabetes increased serum triglycerides, total cholesterol, and transaminases (alanine aminotransferase/aspartate aminotransferase) elevations. Conclusion: P. soyauxii Taub stem bark extracts have possible value for antidiabetic oral medication. SUMMARY Aqueous and Dichloromethane/Methanol stem bark extracts of Pterocarpus soyauxii Taub have potent (compared to Glibenclamide) antidiabetic effects in STZ-diabetic rats, with specific kinetics and dose-responses.Moderate hypoglycemia effects upon acute P. soyauxii administration.Potent anti-hyperglycemic effects of sub-acute P. soyauxii administration in STZ-diabetic rats.Potent anti-hyperlipidemic effects of sub-acute P. soyauxii administration in STZ-diabetic rats.Improved hepatic and renal serum parameters after sub-acute P. soyauxii administration in STZ-diabetic rats.P. soyauxii extracts may be useful for oral treatment of diabetes and related metabolic disorders. Abbreviations Used: CH2Cl2/CH3OH: Dichloromethane/Methanol; STZ: Streptozotocin; GB: Glibenclamide; AE: Aqueous extract; OE: Organic extract; FeCl3: Iron (III) chloride; NaCl: Sodium chloride; K3Fe(CN)6: Potassium ferricyanide; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; H: Hour; BW: Body weight, W1 and W2: Weeks 1 and 2; CHOD: Cholesterol oxidase; GPO: Glycerol-3 Phosphate oxidase; PAP: Phenol + Aminophenazone PMID:28250659

Evidence-based guidelines for anti-allergic drug withdrawal times before allergen-specific intradermal and IgE serological tests in dogs.

PubMed

Olivry, Thierry; Saridomichelakis, Manolis

2013-04-01

Anti-allergic drugs (e.g. antihistamines, glucocorticoids and ciclosporin) are often administered to dogs with atopic dermatitis to relieve pruritus and skin lesions. Allergen-specific intradermal tests (IDT) and allergen-specific IgE serological (ASIS) tests are used to characterize the allergens to which dogs are hypersensitive. Anti-allergic drugs have the potential to influence the results or interpretation of these tests. To provide evidence-based recommendations for anti-allergic drug withdrawal times before IDT and ASIS tests. Three citation databases and abstracts from international meetings were searched for relevant studies. Studies were grouped based on similar interventions and types of tests. Withdrawal times for each type of drug and test were then extrapolated from the study results. Before the assessment of immediate reactions to IDT, proposed optimal withdrawal times for antihistamines, oral glucocorticoids, topical/otic glucocorticoids and ciclosporin are 7, 14, 14 and 0 days, respectively. Studies have provided no evidence for drug withdrawal prior to ASIS tests for oral ciclosporin or prednisone/prednisolone. Owing to a lack of studies, recommendations for withdrawal times before ASIS tests cannot be made for topical glucocorticoids and antihistamines. These proposed withdrawal times are based on the existing evidence at the end of 2011. Care must be taken before extrapolating the suggested withdrawal times to other species, higher dosages, different formulations and/or durations of administration of tested drugs, as well as to other medications from the same category. © 2013 The Authors. Veterinary Dermatology © 2013 ESVD and ACVD.

Naringenin interferes with the anti-diabetic actions of pioglitazone via pharmacodynamic interactions.

PubMed

Yoshida, Hiroki; Tsuhako, Rika; Atsumi, Toshiyuki; Narumi, Keiko; Watanabe, Wataru; Sugita, Chihiro; Kurokawa, Masahiko

2017-04-01

Pioglitazone is a peroxisome proliferator-activated receptor gamma (PPARγ) full agonist and useful for the treatment of type 2 diabetes mellitus. Naringenin is a citrus flavonoid with anti-inflammatory actions, which has been shown to prevent obesity-related diseases and to activate PPARγ. The aim of this study was to investigate whether dietary naringenin affects the actions of pioglitazone. We administered naringenin (100 mg/kg) and pioglitazone (10 mg/kg) to Tsumura Suzuki Obese Diabetes (TSOD) mice for 4 weeks and then conducted an oral glucose tolerance test. We found that oral administration of naringenin attenuated the hypoglycemic action of pioglitazone in TSOD mice. However, pioglitazone and naringenin did not affect fasting blood glucose levels, epididymal fat pad weight and body weight changes in this administration period. Pioglitazone suppressed expression of obesity-related adipokines such as tissue inhibitor of metalloproteinases-1 in adipose tissue of TSOD mice, but this effect was attenuated by naringenin. However, naringenin did not affect the pharmacokinetics of pioglitazone after single or repeated administration. Naringenin exhibited weak partial agonist activity in time-resolved fluorescence resonance energy transfer assay, but naringenin interfered with pioglitazone agonism, consistent with partial agonism. Our results suggest that it is advisable to avoid administering a combination of naringenin and pioglitazone.

Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol

PubMed Central

Balata, Gehan F; Essa, Ebtessam A; Shamardl, Hanan A; Zaidan, Samira H; Abourehab, Mohammed AS

2016-01-01

Resveratrol is a nonflavonoid polyphenolic compound which has a broad range of desirable biological actions which include antioxidant, anti-inflammatory, antidiabetic, cardioprotective, and antitumor activities. However, there is concern that the bioavailability of resveratrol may limit some of its clinical utility. So, the aim of this study was to enhance the dissolution rate and oral hypoglycemic and hypolipidemic effect of resveratrol. This was achieved using self-emulsifying drug delivery system. The solubility of resveratrol was determined in various oils, surfactants, and cosurfactants. Phase diagram was plotted to identify the efficient self-emulsification regions using olive oil, Tween 80, and propylene glycol. The prepared self-emulsifying drug delivery system formulations were tested for thermodynamic stability, emulsification efficiency, droplet size, zeta potential, and in vitro drug release. Self-emulsification time averaged 17–99 seconds without precipitation and the mean droplet sizes ranged from 285 to 823 nm with overall zeta potential of −2.24 to −15.4 mv. All formulations improved drug dissolution in relation to unprocessed drug with a trend of decreased dissolution parameters with increasing oil content. The optimized formula, F19, with dissolution efficiency of 94% compared to only 42% of pure drug was used to study the in vivo hypoglycemic and hypolipidemic effects of resveratrol in diabetic-induced albino rats and comparing these effects with that of pure resveratrol in different doses. Treatment with the optimized formula, F19, at 10 mg/kg had significant hypoglycemic and hypolipidemic effects in diabetic-induced albino rats which were nearly similar to the high dose (20 mg/kg) of unprocessed resveratrol. From the study, it was concluded that formulation F19 has good emulsification property with uniform globule size, satisfactory in vitro drug release profile, and significant in vivo hypoglycemic effects which identify future opportunities for resveratrol delivery. PMID:26792979

Self-emulsifying drug delivery systems as a tool to improve solubility and bioavailability of resveratrol.

PubMed

Balata, Gehan F; Essa, Ebtessam A; Shamardl, Hanan A; Zaidan, Samira H; Abourehab, Mohammed As

2016-01-01

Resveratrol is a nonflavonoid polyphenolic compound which has a broad range of desirable biological actions which include antioxidant, anti-inflammatory, antidiabetic, cardioprotective, and antitumor activities. However, there is concern that the bioavailability of resveratrol may limit some of its clinical utility. So, the aim of this study was to enhance the dissolution rate and oral hypoglycemic and hypolipidemic effect of resveratrol. This was achieved using self-emulsifying drug delivery system. The solubility of resveratrol was determined in various oils, surfactants, and cosurfactants. Phase diagram was plotted to identify the efficient self-emulsification regions using olive oil, Tween 80, and propylene glycol. The prepared self-emulsifying drug delivery system formulations were tested for thermodynamic stability, emulsification efficiency, droplet size, zeta potential, and in vitro drug release. Self-emulsification time averaged 17-99 seconds without precipitation and the mean droplet sizes ranged from 285 to 823 nm with overall zeta potential of -2.24 to -15.4 mv. All formulations improved drug dissolution in relation to unprocessed drug with a trend of decreased dissolution parameters with increasing oil content. The optimized formula, F19, with dissolution efficiency of 94% compared to only 42% of pure drug was used to study the in vivo hypoglycemic and hypolipidemic effects of resveratrol in diabetic-induced albino rats and comparing these effects with that of pure resveratrol in different doses. Treatment with the optimized formula, F19, at 10 mg/kg had significant hypoglycemic and hypolipidemic effects in diabetic-induced albino rats which were nearly similar to the high dose (20 mg/kg) of unprocessed resveratrol. From the study, it was concluded that formulation F19 has good emulsification property with uniform globule size, satisfactory in vitro drug release profile, and significant in vivo hypoglycemic effects which identify future opportunities for resveratrol delivery.

Thiomers for oral delivery of hydrophilic macromolecular drugs.

PubMed

Bernkop-Schnürch, Andreas; Hoffer, Martin H; Kafedjiiski, Krum

2004-11-01

In recent years thiolated polymers (thiomers) have appeared as a promising new tool in oral drug delivery. Thiomers are obtained by the immobilisation of thio-bearing ligands to mucoadhesive polymeric excipients. By the formation of disulfide bonds with mucus glycoproteins, the mucoadhesive properties of thiomers are up to 130-fold improved compared with the corresponding unmodified polymers. Owing to the formation of inter- and intramolecular disulfide bonds within the thiomer itself, matrix tablets and particulate delivery systems show strong cohesive properties, resulting in comparatively higher stability, prolonged disintegration times and a more controlled drug release. The permeation of hydrophilic macromolecular drugs through the gastrointestinal (GI) mucosa can be improved by the use of thiomers. Furthermore, some thiomers exhibit improved inhibitory properties towards GI peptidases. The efficacy of thiomers in oral drug delivery has been demonstrated by various in vivo studies. A pharmacological efficacy of 1%, for example, was achieved in rats by oral administration of calcitonin tablets comprising a thiomer. Furthermore, tablets comprising a thiomer and pegylated insulin resulted in a pharmacological efficacy of 7% after oral application to diabetic mice. Low-molecular-weight heparin embedded in thiolated polycarbophil led to an absolute bioavailability of > or = 20% after oral administration to rats. In these studies, formulations comprising the corresponding unmodified polymer had only a marginal or no effect. These results indicate drug carrier systems based on thiomers appear to be a promising tool for oral delivery of hydrophilic macromolecular drugs.

Modulation of the lipid profile and insulin levels of streptozotocin induced diabetic rats by ethanol extract of Cnidoscolus aconitifolius leaves and some fractions: Effect on the oral glucose tolerance of normoglycemic rats.

PubMed

Achi, N K; Ohaeri, O C; Ijeh, I I; Eleazu, C

2017-02-01

No study to date has investigated the effect of different polar solvent extracts from Cnidoscolus aconitifolius leaves on glycemic control as used in folk medicine. Hence this study which investigated the effect of ethanol extract and fractions of C. aconitifolius leaves on body weights, relative organ weights, serum levels of glucose, lipid profiles and insulin in streptozotocin induced diabetic rats and on oral glucose tolerance of normoglycemic rats. The ethanol extract was partitioned using methanol, hexane and chloroform to obtain different fractions. The ethanol extract, fractions or glibenclamide demonstrated hypoglycemic/therapeutic actions as seen from the reduction of serum glucose but increase in serum insulin and body weights of the diabetic rats at the end of experimentation following their administration, unlike the diabetic control that had significant alteration of these parameters with respect to the normal control. Whereas the diabetic control had significant increase in pancreatic weights with no alteration in the heart weights, the ethanol extract, fractions or glibenclamide had no effect on these organs. The ethanol extract, methanol fractions or glibenclamide showed better hypoglycemic actions than the n-hexane or chloroform fractions at the doses used and results obtained were corroborated by histology. Furthermore, the ethanol extract, n-hexane (at 250mg/kg) and methanol fractions or glibenclamide improved glucose tolerance in glucose loaded normal rats. The methanol fraction (500mg/kg) demonstrated anti-hypercholesterolemic, anti-hypertriglyceridemic and insulin modulatory properties in a manner akin to glibenclamide. Acute toxicity study revealed the non toxicity of the plant CONCLUSION: The study justifies the use of polar solvent extracts of this plant in the management of diabetes mellitus. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

The plant extracts of Momordica charantia and Trigonella foenum graecum have antioxidant and anti-hyperglycemic properties for cardiac tissue during diabetes mellitus

PubMed Central

Tripathi, Uma Nath

2009-01-01

Oxidative stress is currently suggested to play a major role in the development of diabetes mellitus. There is an increasing demand of natural anti-diabetic agents, as continuous administration of existing drugs and insulin are associated with many side effects and toxicity. The present study was aimed to investigate the effect of Momordica charantia (MC) and Trigonella foenum graecum (TFG) extracts (aqueous) on antioxidant status and lipid peroxidation in heart tissue of normal and alloxan induced diabetic rats. In a 30 days treatment, rats were divided into six groups (I-VI) of five animals in each, experiments were repeated thrice. Administration of MC (13.33 g pulp/kg body weight/day) and TFG (9 g seeds powder/kg body weight/day) extracts in diabetic rats has remarkably improved the elevated levels of fasting blood glucose. A significant decrease in lipid peroxidation (p<0.001) and significant increase in the activities of key antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT), glutathione-s-transferase (GST) and reduced glutathione (GSH ) contents in heart tissue of diabetic rats were observed (group V and VI) upon MC and TFG treatment. Our studies demonstrate the anti-hyperglycemic and anti-oxidative potential of Momordica charantia and Trigonella foenum graecum, which could exert beneficial effects against the diabetes and associated free radicals complications in heart tissue. PMID:20716916

Insulin 70/30 mix plus metformin versus triple oral therapy in the treatment of type 2 diabetes after failure of two oral drugs: efficacy, safety, and cost analysis.

PubMed

Schwartz, Sherwyn; Sievers, Richard; Strange, Poul; Lyness, William H; Hollander, Priscilla

2003-08-01

Subjects (n = 188) with type 2 diabetes and inadequate response to two oral medications (A1C >8.0%) were randomly assigned to treatment with either a third oral medication or an insulin 70/30 mix b.i.d. plus metformin for a comparison of efficacy, safety, and cost. The protocol called for aggressive dose titration to achieve target values of fasting blood glucose (80-120 mg/dl), postprandial glucose (<160 mg/dl), and A1C (<7%). These efficacy parameters were evaluated at weeks 2, 6, 12, and 24 of therapy. If dose adjustments failed to achieve targeted glycemic control, subjects were switched to an alternate therapy. At the end of study (week 24 of therapy), A1C and fasting plasma glucose (FPG) values showed comparable decreases in the two treatment groups. Only 31% (oral therapy) and 32% (insulin plus metformin) of subjects achieved target values of A1C (<7%). A total of 10 of the 98 subjects randomized to triple oral therapy (10.2%) who failed to improve sufficiently were switched to insulin therapy. An additional four subjects dropped out of the oral treatment group due to adverse events felt to be potentially drug related. Only two of the subjects randomized to insulin plus metformin had to be switched to basal-bolus regimens (regular insulin and NPH insulin). Cost analysis determined that insulin plus metformin (mean cost 3.20 dollars/day) provided efficacy equal to that of a triple oral drug regimen (10.40 dollars/day). Insulin 70/30 mix plus metformin was as effective as triple oral therapy in lowering A1C and FPG values. The triple oral regimen was not as cost effective, and a high percentage of subjects (total of 16.3%) did not complete this regimen due to lack of efficacy or side effects.

Development of a pharmaceutical cocrystal with solution crystallization technology: Preparation, characterization, and evaluation of myricetin-proline cocrystals.

PubMed

Liu, Mingyu; Hong, Chao; Yao, Yashu; Shen, Hongyi; Ji, Guang; Li, Guowen; Xie, Yan

2016-10-01

Myricetin shows low oral bioavailability (<10%) in rats due to poor aqueous solubility, although it has demonstrated various pharmacological activities such as those related to anticancer, anti-diabetes, and hepatic protection. To overcome this issue, in this study, pharmaceutical cocrystals were designed to efficiently deliver myricetin by oral administration. A 1:2 stoichiometric cocrystal of myricetin with proline was prepared successfully by solution crystallization based on the ternary phase diagram (TPD) principle, and it is presented as a new sphericity-like crystalline phase characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM). The formation of myricetin-proline cocrystals was a spontaneous and exothermic process, probably due to the supramolecular interactions between themselves, which were determined by Fourier transform-infrared spectroscopy (FT-IR). Consequently, the dissolution efficiency of myricetin from cocrystals was increased 7.69-fold compared with that of coarse myricetin, and the oral bioavailability of myricetin cocrystals in rats was enhanced by approximately 3.03 times compared with that of pure myricetin. The present study provides useful information for the potential application of cocrystal technology for water-insoluble drugs, especially flavonoid compounds. Copyright © 2016 Elsevier B.V. All rights reserved.

Chrysin Induces Antidiabetic, Antidyslipidemic and Anti-Inflammatory Effects in Athymic Nude Diabetic Mice.

PubMed

Ramírez-Espinosa, Juan José; Saldaña-Ríos, Johann; García-Jiménez, Sara; Villalobos-Molina, Rafael; Ávila-Villarreal, Gabriela; Rodríguez-Ocampo, Angélica Nallelhy; Bernal-Fernández, Germán; Estrada-Soto, Samuel

2017-12-28

Extensive knowledge of diabetes and its complications is helpful to find new drugs for proper treatment to stop degenerative changes derived from this disease. In this context, chrysin (5,7-dihydroxyflavone) is a natural product that occurs in a variety of flowers and fruits with anti-inflammatory and antidiabetic effects, among others. Thus, a diabetic model in athymic nude mice was developed and used to establish the ability of chrysin to decrease the secretion of pro-inflammatory cytokines. Also, it was determined the acute (50 mg/kg) and sub-acute (50 mg/kg/day/10 days) antidiabetic and antihyperlipidemic activities after the period of time treatment. Results indicate that chrysin has significant acute antihyperglycemic and antidiabetic effects in nude diabetic mice ( p < 0.05). Moreover, triglyceride blood levels were reduced and IL-1β and TNF-α were diminished after 10 days' treatment compared with control group ( p < 0.05). In conclusion, it was found that chrysin could produce similar effects as metformin, a drug used for the treatment of diabetes, since both test samples decreased glucose and triglycerides levels, they impaired the generation of pro-inflammatory cytokines involved in the development of diabetes and its consequences, such as atherosclerosis and other cardiovascular diseases.

Drug Discovery and Development of Type 2 Diabetes Mellitus: Modern-Integrative Medicinal Approach.

PubMed

Ghosh, Debosree; Parida, Pratap

2016-01-01

Type 2 diabetes is a disorder of ages, which has become deadlier because of life style modification and adaptation in the modern world. Extensive sudy of the pathophysiology of diabetes has opened up various mysteries about the disease and has helped us to know and understand diabetes in a better manner. Presently, we know many minute details about the pathophysiology of diabetes mellitus and are thus well weaponed to fight against it. Treatment regime has been evolving daily. Besides the conventional anti-diabetic drugs, integrated medicinal approach for treating diabetes type 2 with a compact therapeutic approach consisting of various targeted treatments for individual symptoms associated with the disease are being tried currently. Diabetes associated complications like high blood pressure, hyperglycemia, microalbumuria, dyslipidemia, pro -coagulation, etc. are being targeted and dealt with individually in the integrative medicinal approach. The results are promising and thus ignite hope for a better and more successful handling of diabetes and diabetes related pathophysiological complications in near future.

Prevalence and prescription patterns of oral glucocorticoids in adults: a retrospective cross-sectional and cohort analysis in France

PubMed Central

Bénard-Laribière, Anne; Pariente, Antoine; Pambrun, Elodie; Bégaud, Bernard; Fardet, Laurence; Noize, Pernelle

2017-01-01

Objectives To study trends in use of oral glucocorticoids (GCs) among adults, characteristics of oral GC initiators and prescriptions for the prevention of potential adverse effects associated with GC therapy. Design First, a cross-sectional study repeated yearly was performed from 2007 to 2014 in a nationwide representative sample. Second, characteristics of initiators and patterns of GC therapy during the year following treatment initiation were described in a cohort of patients who began GC between 2007 and 2013. Setting Population-based study using data from the French reimbursement healthcare system (covering approximately 90% of the population) in patients aged ≥18 years. Results Over the study period, the prevalence of oral GC use ranged from 14.7% to 17.1% (95% CI 17.0%–17.2%) with a significant increase of 14.1% (95% CI +13.5% to +14.8%). The 2007–2013 cohort of oral GC initiators comprised 206 759 individuals. Oral GC use was mostly short-term (68% of unique reimbursement) and more than half of short-term users took concurrent antibiotics or respiratory/otological drugs. Chronic users (≥6 reimbursements/year) represented 1.8% (n=3789) of the cohort. The proportion of chronic users with comorbidities likely to be worsened by GC use (diabetes, psychotic disorders, osteoporosis) was 25%. Among patients at increased risk of osteoporosis, 62% received specific prevention/monitoring measures and only 27% had a bisphosphonate. Half of chronic oral GC users had a concurrent reimbursement of a proton pump inhibitor in the absence of non-steroidal anti-inflammatory drug use. Conclusions Oral GC use was highly widespread and increased among adults from 2007 to 2014. The overwhelming short-term use could mainly concern a growing use of unjustified prescriptions rather than situations with a favourable benefit/risk ratio. For chronic users, our findings plead for the development of interventions designed to improve monitoring with regard to the frequent comorbidities at risk and inappropriate prescribing of preventive therapeutic measures. PMID:28760791

Drug evaluation: tagatose in the treatment of type 2 diabetes and obesity.

PubMed

Moore, Mary Courtney

2006-10-01

Spherix Inc (formerly Biospherics) is developing tagatose, an orally active lactose derivative for the potential treatment of obesity and type 2 diabetes. The compound is also under investigation for the potential treatment of anemia, hemophilia and medical problems related to infertility, birth weight and excessive maternal food intake. Phase I and II clinical trials have been completed.

Evaluation of the anti-hyperglycemic effect and safety of microorganism 1-deoxynojirimycin.

PubMed

Takasu, Soo; Parida, Isabella Supardi; Onose, Shinji; Ito, Junya; Ikeda, Ryoichi; Yamagishi, Kenji; Higuchi, Oki; Tanaka, Fukuyo; Kimura, Toshiyuki; Miyazawa, Teruo; Nakagawa, Kiyotaka

2018-01-01

1-Deoxynojirimycin (DNJ) is a potent α-glucosidase inhibitor and thus beneficial for prevention of diabetes. While we have succeeded in obtaining the culture supernatant extract (CSE) rich in DNJ from microorganism source, information regarding its anti-hyperglycemic effect and safety were still limited. Therefore, this study was aimed to evaluate the anti-hyperglycemic effect and safety of microorganism DNJ. Oral sucrose tolerance test was performed, and the result showed that CSE was able to significantly suppress the blood glucose elevation and suggested DNJ as the main active compound. To determine its safety, the absorption and excretion of microorganism DNJ were evaluated using 15N labeling method. Our findings investigated the recovery rate of 15N from DNJ reached 80% up to 48 hours after oral administration, suggesting its rapid excretion, suggesting the safety of DNJ. This study verified the functional properties and safety of DNJ from microorganisms, suggesting its potential use for functional purpose.

Candida spp. and gingivitis in children with nephrotic syndrome or type 1 diabetes.

PubMed

Olczak-Kowalczyk, Dorota; Pyrżak, Beata; Dąbkowska, Maria; Pańczyk-Tomaszewska, Małgorzata; Miszkurka, Grażyna; Rogozińska, Izabela; Swoboda-Kopeć, Ewa; Gozdowski, Dariusz; Kalińska, Angelika; Piróg, Anna; Mizerska-Wasiak, Małgorzata; Roszkowska-Blaim, Maria

2015-05-08

Diabetes and Nephrotic syndrome (NS) promote plaque-related gingivitis and yeast-like fungal infections. The study assesses the impact of Candida spp. and general disease- or treatment-related factors on plaque-related gingivitis severity in children and adolescents with Nephrotic syndrome /diabetes. Body mass index (BMI), BMI standard deviation score, and oral cavity (Plaque Index--PLI, Gingival Index--GI, mucosa status, presence and Candida enzymatic activity) were assessed in 96 patients (32 with NS: 30- immunosuppressive treatment, 35--type 1 diabetes, and 29 generally healthy), aged; 3-18 years. Laboratory included cholesterol and triglyceride measurements; in diabetic subjects- glycated haemoglobin, in NS: total protein, albumin, creatinine, haemoglobin, haematocrit, white cell count, urinary protein excretion. Medical records supplied information on disease duration and treatment. A statistical analysis was performed; Kendall Tau coefficient, chi-square test, t-test, and multiple regression analysis ( P < 0.05). Candida spp. often occurred in healthy patients, but oral candidiasis was found only in the NS and diabetes groups (9.37% and 11.43%). Gingivitis occurred more frequently in patients with NS/diabetes. Gingivitis severity was correlated with PLI, age, and yeast enzyme activity in NS--to with immunosuppressive treatment with >1 drug, drug doses, treatment duration, lipid disorders, and BMI; in diabetes, with blood glucose and glycated haemoglobin >8%. Poor hygiene control is the main cause of gingivitis. Gingivitis severity is most likely related to age, lipid disorders and increase in body mass. Candida spp., in uncompensated diabetes and in those using immunosuppressive treatment, might intensify plaque-related gingivitis.

Piracetam Facilitates the Anti-Amnesic but not Anti-Diabetic Activity of Metformin in Experimentally Induced Type-2 Diabetic Encephalopathic Rats.

PubMed

Pandey, Shruti; Garabadu, Debapriya

2017-07-01

Piracetam exhibits anti-amnesic activity in several animal models of dementia. However, its anti-amnesic potential has yet to be evaluated in type-2 diabetes mellitus (T2DM)-induced encephalopathy. Therefore, in the present study, piracetam (25, 50 and 100 mg/kg) was screened for anti-amnesic and anti-diabetic activity in T2DM-induced encephalopathic male rats. Subsequently, anti-amnesic and anti-diabetic activities were evaluated for piracetam, metformin and their combination in T2DM-induced encephalopathic animals. Rats received streptozotocin (45 mg/kg) and nicotinamide (110 mg/kg) injections on day-1 (D-1) of the experimental schedule and were kept undisturbed for 35 days to exhibit T2DM-induced encephalopathy. All drug treatments were continued from D-7 to D-35 in both experiments. Piracetam (100 mg/kg) attenuated loss in learning and memory in terms of increase in escape latency on D-4 (D-34) and decrease in time spent in the target quadrant on D-5 (D-35) of Morris water maze test protocol, and spatial memory in terms of reduced spontaneous alternation behavior in Y-maze test of encephalopathic rats. Additionally, piracetam attenuated altered levels of fasting plasma glucose and insulin, HOMA-IR and HOMA-B in encephalopathic animals, comparatively lesser than metformin. In the next experiment, combination of piracetam and metformin exhibited better anti-amnesic but not anti-diabetic activity than respective monotherapies in encephalopathic rats. Further, the combination attenuated reduced acetylcholine level and increased acetylcholinesterase activity, increased glycogen synthase kinase-3β level and decreased brain-derived neurotropic factor level in hippocampus and pre-frontal cortex of encephalopathic animals. Thus, piracetam could be used as an adjuvant to metformin in the management of dementia in T2DM-induced encephalopathy.

Metabolomics Study of Type 2 Diabetes Mellitus and the AntiDiabetic Effect of Berberine in Zucker Diabetic Fatty Rats Using Uplc-ESI-Hdms.

PubMed

Dong, Yu; Chen, Yi-Tao; Yang, Yuan-Xiao; Zhou, Xiao-Jie; Dai, Shi-Jie; Tong, Jun-Feng; Shou, Dan; Li, Changyu

2016-05-01

The present study aimed to evaluate the pathogenesis of type 2 diabetes mellitus (T2DM) and the anti-diabetic effect of berberine in Zucker diabetic fatty (ZDF) rats. A urinary metabolomics analysis was performed with ultra-performance liquid chromatography/electrospray ionization synapt high-definition mass spectrometry. Pattern recognition approaches were integrated to discover differentiating metabolites. We identified 29 ions (13 in negative mode and 16 in positive mode) as 'differentiating metabolites' with this metabolomic approach. A functional pathway analysis revealed that the alterations were mainly associated with glyoxylate and dicarboxylate metabolism, pentose and glucuronate interconversions and sphingolipid metabolism. These results indicated that the dysfunctions of glycometabolism and lipometabolism are involved in the pathological process of T2DM. Berberine could decrease the serum levels of glycosylated hemoglobin, total cholesterol and triglyceride and increase the secretion of insulin. The urinary metabolomics analysis showed that berberine could reduce the concentrations of citric acid, tetrahydrocortisol, ribothymidine and sphinganine to a near-normal state. These results suggested that the anti-diabetic effect of berberine occurred mainly via its regulation of glycometabolism and lipometabolism and activation of adenosine 5'-monophosphate-activated protein kinase. Our work not only provides a better understanding of the anti-diabetic effect of berberine in ZDF rats but also supplies a useful database for further study in humans and for investigating the pharmacological actions of drugs. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Bacillus spore-based oral carriers loading curcumin for the therapy of colon cancer.

PubMed

Yin, Liang; Meng, Zhan; Zhang, Yuxiao; Hu, Kaikai; Chen, Wuya; Han, Kaibin; Wu, Bao-Yan; You, Rong; Li, Chu-Hua; Jin, Ying; Guan, Yan-Qing

2018-02-10

Oral drug delivery has attracted substantial attention due to its advantages over other administration routes. Bacillus spores, as oral probiotic agents, are applied widely. In this paper, a novel Bacillus spore-based oral colon targeted carrier loading curcumin was developed for colon cancer treatment. Curcumin was linked covalently with the outer coat of Bacillus spore and folate, respectively (SPORE-CUR-FA). Bacillus spores are capable of delivering drugs to the colon area through gastric barrier, taking the advantage of its tolerance to the harsh conditions and disintegration of the outer coat of spores after germination in the colon. The drug release in vitro and in vivo of SPORE-CUR-FA was investigated. Results showed that SPORE-CUR-FA had the characteristics of colon-targeted drug release. Pharmacokinetic studies confirmed that Bacillus spore-based carriers could efficiently improve the oral bioavailability of curcumin. In vitro and in vivo anti-tumor studies showed that SPORE-CUR-FA had substantial ability for inhibiting colon cancer cells. These findings suggest that this Bacillus spore-based oral drug delivery system has a great potential for the treatment of colon cancer. Copyright © 2017 Elsevier B.V. All rights reserved.

Brand-name prescription drug use among Veterans Affairs and Medicare Part D patients with diabetes: a national cohort comparison.

PubMed

Gellad, Walid F; Donohue, Julie M; Zhao, Xinhua; Mor, Maria K; Thorpe, Carolyn T; Smith, Jeremy; Good, Chester B; Fine, Michael J; Morden, Nancy E

2013-07-16

Medicare Part D and the U.S. Department of Veterans Affairs (VA) use different approaches to manage prescription drug benefits, with implications for spending. Medicare relies on private plans with distinct formularies, whereas the VA administers its own benefit using a national formulary. To compare overall and regional rates of brand-name drug use among older adults with diabetes in Medicare and the VA. Retrospective cohort. Medicare and the VA, 2008. 1,061,095 Medicare Part D beneficiaries and 510,485 veterans aged 65 years or older with diabetes. Percentage of patients taking oral hypoglycemics, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) who filled brand-name drug prescriptions and percentage of patients taking long-acting insulins who filled analogue prescriptions. Sociodemographic- and health status-adjusted hospital referral region (HRR) brand-name drug use was compared, and changes in spending were calculated if use of brand-name drugs in 1 system mirrored the other. Brand-name drug use in Medicare was 2 to 3 times that in the VA: 35.3% versus 12.7% for oral hypoglycemics, 50.7% versus 18.2% for statins, 42.5% versus 20.8% for ACE inhibitors or ARBs, and 75.1% versus 27.0% for insulin analogues. Adjusted HRR-level brand-name statin use ranged (from the 5th to 95th percentiles) from 41.0% to 58.3% in Medicare and 6.2% to 38.2% in the VA. For each drug group, the 95th-percentile HRR in the VA had lower brand-name drug use than the 5th-percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name drug use matched that of the VA. This analysis cannot fully describe the factors underlying differences in brand-name drug use. Medicare beneficiaries with diabetes use 2 to 3 times more brand-name drugs than a comparable group within the VA, at substantial excess cost.

Brand-Name Prescription Drug Use Among Veterans Affairs and Medicare Part D Patients With Diabetes

PubMed Central

Gellad, Walid F.; Donohue, Julie M.; Zhao, Xinhua; Mor, Maria K.; Thorpe, Carolyn T.; Smith, Jeremy; Good, Chester B.; Fine, Michael J.; Morden, Nancy E.

2013-01-01

Background: Medicare Part D and the U.S. Department of Veterans Affairs (VA) use different approaches to manage prescription drug benefits, with implications for spending. Medicare relies on private plans with distinct formularies, whereas the VA administers its own benefit using a national formulary. Objective: To compare overall and regional rates of brand-name drug use among older adults with diabetes in Medicare and the VA. Design: Retrospective cohort. Setting: Medicare and the VA, 2008. Patients: 1 061 095 Medicare Part D beneficiaries and 510 485 veterans aged 65 years or older with diabetes. Measurements: Percentage of patients taking oral hypoglycemics, statins, and angiotensin-converting enzyme (ACE) inhibitors or angiotensin-receptor blockers (ARBs) who filled brand-name drug prescriptions and percentage of patients taking long-acting insulins who filled analogue prescriptions. Sociodemographic- and health status–adjusted hospital referral region (HRR) brand-name drug use was compared, and changes in spending were calculated if use of brand-name drugs in 1 system mirrored the other. Results: Brand-name drug use in Medicare was 2 to 3 times that in the VA: 35.3% versus 12.7% for oral hypoglycemics, 50.7% versus 18.2% for statins, 42.5% versus 20.8% for ACE inhibitors or ARBs, and 75.1% versus 27.0% for insulin analogues. Adjusted HRR-level brand-name statin use ranged (from the 5th to 95th percentiles) from 41.0% to 58.3% in Medicare and 6.2% to 38.2% in the VA. For each drug group, the 95th-percentile HRR in the VA had lower brand-name drug use than the 5th-percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name drug use matched that of the VA. Limitation: This analysis cannot fully describe the factors underlying differences in brand-name drug use. Conclusion: Medicare beneficiaries with diabetes use 2 to 3 times more brand-name drugs than a comparable group within the VA, at substantial excess cost. Primary Funding Source: U.S. Department of Veterans Affairs, National Institutes of Health, and Robert Wood Johnson Foundation. PMID:19264942

Meal-induced platelet activation in Type 2 diabetes mellitus: effects of treatment with repaglinide and glibenclamide.

PubMed

Yngen, M; Ostenson, C-G; Hjemdahl, P; Wallén, N H

2006-02-01

To compare the effects of treatment with repaglinide and glibenclamide on platelet function and endothelial markers in patients with Type 2 diabetes mellitus, before and after a standardized meal. Fifteen patients with Type 2 diabetes were investigated on three occasions: at baseline without oral hypoglycaemic drug treatment, and after 6 weeks' treatment with repaglinide or glibenclamide, respectively, in an open randomized cross-over study. Agonist-induced platelet P-selectin expression and platelet aggregation, urinary thromboxane, soluble P-selectin, von Willebrand factor (VWF), soluble E-selectin, intercellular adhesion molecule (ICAM-1) and C-reactive protein (CRP) were measured. In addition, pre-meal data were compared with non-diabetic control subjects (n = 15), matched for sex, age and BMI. Adenosine diphosphate (ADP)-induced platelet P-selectin expression increased post-meal in Type 2 diabetic patients both at baseline and after treatment with repaglinide and glibenclamide (P < 0.01 for all; repeated measures anova). Repaglinide treatment reduced fasting ADP-induced P-selectin expression compared with baseline (P = 0.01), but did not influence meal-induced platelet hyper-reactivity (P = 0.32). No significant anti-platelet effects of glibenclamide treatment were found. Plasma concentrations of VWF and ICAM-1 were elevated in patients with Type 2 diabetes compared with control subjects (P < 0.05 for both) and were reduced during treatment with repaglinide (P < 0.01 for both) but did not change during glibenclamide treatment. The post-meal state is associated with enhanced platelet reactivity in patients with Type 2 diabetes mellitus. Pre-meal treatment with repaglinide or glibenclamide does not inhibit postprandial platelet activation, but repaglinide treatment is associated with attenuated platelet and endothelial activity in the fasting state.

Steroid acne vs. Pityrosporum folliculitis: the incidence of Pityrosporum ovale and the effect of antifungal drugs in steroid acne.

PubMed

Yu, H J; Lee, S K; Son, S J; Kim, Y S; Yang, H Y; Kim, J H

1998-10-01

Steroid acne is a folliculitis that can result from systemic or topical administration of steroid, and has been described as showing a similar clinical picture to Pityrosporum folliculitis, but there have been few reports about the incidence of Pityrosporum ovale and the effect of antimycotic drugs in steroid acne and other acneiform eruptions. Our purpose was to describe the association between steroid acne and P. ovale, and to confirm the superior efficacy of oral antifungal drugs over anti-acne drugs in the treatment of steroid acne. The history, clinical features direct microscopy, histopathologic analysis, and therapeutic results of 125 cases with steroid acne or other acneiform eruptions were described and compared. Over 80% of patients with acneiform eruption receiving systemic steroid revealed significant numbers of P. ovale in the lesional follicle. Furthermore, oral antifungal drug (itraconazole) showed significantly better clinical and mycologic effects than any other group of medications used in this study. Steroid acne and other acneiform eruptions showing discrete follicular papules and/or pustules localized to the upper trunk and acneiform facial skin lesions associated with multiple acneiform lesions on the body in the summer period should be suspected as Pityrosporum folliculitis. In addition, oral antifungal drugs recommended for Pityrosporum folliculitis; however, it will require a larger case-control study to confirm the superiority of antifungal therapy over anti-acne treatment.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hsu, Wei-Hsuan; Lee, Bao-Hong; Chang, Yu-Ying

Methylglyoxal (MG) is a toxic-glucose metabolite and a major precursor of advanced glycation endproducts (AGEs). MG has been reported to result in inflammation by activating receptor for AGEs (RAGE). We recently found that Monascus-fermented metabolite monascin acts as a novel natural peroxisome proliferator-activated receptor-γ (PPARγ) agonist that improves insulin sensitivity. We investigated the metabolic, biochemical, and molecular abnormalities characteristic of type 2 diabetes in MG-treated Wistar rats treated with oral administration of monascin or rosiglitazone. Monascin (a novel PPARγ agonist) activated nuclear factor-erythroid 2-related factor 2 (Nrf2) and down-regulated hyperinsulinmia in oral glucose tolerance test (OGTT). Monascin was able tomore » elevate glyoxalase-1 expression via activation of hepatic Nrf2, hence, resulting in MG metabolism to D-lactic acid and protected from AGEs production in MG-treated rats. Rosiglitazone did not activate Nrf2 nor glyoxalase expression to lower serum and hepatic AGEs levels. Monascin acts as a novel natural Nrf2 activator with PPARγ-agonist activity were confirmed by Nrf2 and PPARγ reporter assays in Hep G2 cells. These findings suggest that monascin acts as an anti-diabetic and anti-oxidative stress agent to a greater degree than rosiglitazone and thus may have therapeutic potential for the prevention of diabetes. - Highlights: • Monascin acts as a PPARgamma agonist. • Monascin activates Nrf2 and AMPK. • Monascin promotes MG metabolism into D-lactic acid. • Monascin attenuates inflammation and diabetes in vivo.« less

Leflunomide biodegradable microspheres intended for intra-articular administration: Development, anti-inflammatory activity and histopathological studies.

PubMed

El-Setouhy, Doaa Ahmed; Abdelmalak, Nevine Shawky; Anis, Shady E; Louis, Dina

2015-11-30

Leflunomide, the disease-modifying anti-rheumatic drug was formulated as microspheres for prolonged drug release in the form of intraarticular injection. Eight formulations were developed using three biodegradable PDLG polymers (lactide/glycolide copolymer) and polycaprolactone (PLC) at two drug:polymer ratios (1:2 and 1:4). Solvent evaporation method was employed using polyvinyl alcohol or hydropxypropyl methylcellulose as stabilizers. Formulations were assessed for encapsulation efficiency, yield, particle size, release pattern and SEM. F6 (PDLG 5010), with appropriate particle size and prolonged drug release, was chosen for in-vivo studies using arthritis induced rats, which were intrarticularly injected with F6 or took oral Avara(®). Nuclear factor-kappa B measurements and histopathologic studies were conducted. There was significant reduction of inflammation caused by both F6 and oral Avara(®). Histopathologic studies showed minimal infiltration by chronic inflammatory cells and no angiogenesis in F6 compared to Avara(®). Results also revealed biocompatibility of the polymer used. Copyright © 2015 Elsevier B.V. All rights reserved.

Evolving guidelines in the use of topical nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis.

PubMed

Balmaceda, Casilda M

2014-01-21

Nonsteroidal anti-inflammatory drugs (NSAIDs) are a standard treatment for osteoarthritis (OA), but the use of oral NSAIDs has been linked to an elevated risk for cardiovascular and gastrointestinal adverse events and renal toxicity. Topical NSAIDs are thought to afford efficacy that is comparable to oral formulations while reducing widespread systemic drug exposure, which may provide a benefit in terms of safety and tolerability. As a result, European treatment guidelines have, for many years, recommended the use of topical NSAIDs as a safe and effective treatment option for OA. Following the recent approval of several topical NSAID formulations by the US Food and Drug Administration, US treatment guidelines are increasingly recommending the use of topical NSAIDs as an alternative therapy and, in some cases, as a first-line option for OA. This commentary summarizes OA treatment guidelines that are currently available and discusses their potential evolution with regard to the increased inclusion of topical NSAIDs.

Evolving guidelines in the use of topical nonsteroidal anti-inflammatory drugs in the treatment of osteoarthritis

PubMed Central

2014-01-01

Background Nonsteroidal anti-inflammatory drugs (NSAIDs) are a standard treatment for osteoarthritis (OA), but the use of oral NSAIDs has been linked to an elevated risk for cardiovascular and gastrointestinal adverse events and renal toxicity. Topical NSAIDs are thought to afford efficacy that is comparable to oral formulations while reducing widespread systemic drug exposure, which may provide a benefit in terms of safety and tolerability. As a result, European treatment guidelines have, for many years, recommended the use of topical NSAIDs as a safe and effective treatment option for OA. Following the recent approval of several topical NSAID formulations by the US Food and Drug Administration, US treatment guidelines are increasingly recommending the use of topical NSAIDs as an alternative therapy and, in some cases, as a first-line option for OA. This commentary summarizes OA treatment guidelines that are currently available and discusses their potential evolution with regard to the increased inclusion of topical NSAIDs. PMID:24444047

Comparison of treatment costs in inadequately controlled type 2 diabetes in Germany based on the APOLLO trial with insulin glargine.

PubMed

Bretzel, Reinhard G; Dippel, Franz-Werner; Linn, Thomas; Neilson, Aileen Rae

2009-06-01

A cost analysis of once-daily insulin glargine versus three-times daily insulin lispro in combination with oral antidiabetic drugs (OADs) for insulin-naive type 2 diabetes patients in Germany based on the APOLLO trial (A Parallel design comparing an Oral antidiabetic drug combination therapy with either Lantus once daily or Lispro at mealtime in type 2 diabetes patients failing Oral treatment). Annual direct treatment costs were estimated from the perspective of the German statutory health insurance (SHI). Costs accounted for included insulin medication, disposable pens and consumable items (needles, blood glucose test strips and lancets). Sensitivity analyses (on resource use and unit costs) were performed to reflect current German practice. Average treatment costs per patient per year in the base case were 1,073 euro for glargine and 1,794 euro for lispro. Insulin costs represented 65% vs. 37% of total costs respectively. Acquisition costs of glargine were offset by the lower costs of consumable items (380 euro vs. 1,139 euro). Sensitivity analyses confirmed the robustness of the results in favour of glargine. All scenarios yielded cost savings in total treatment costs ranging from 84 euro to 727 euro. Combination therapy of once-daily insulin glargine versus three-times daily insulin lispro both with OADs, in the management of insulin-dependent type 2 diabetes offers the potential for substantial cost savings from the German SHI perspective.

Anti-hyperglycemic and anti-hypercholesterolemic effects of Aloe vera leaf gel in hyperlipidemic type 2 diabetic patients: a randomized double-blind placebo-controlled clinical trial.

PubMed

Huseini, Hasan Fallah; Kianbakht, Saeed; Hajiaghaee, Reza; Dabaghian, Fataneh Hashem

2012-03-01

Diabetes mellitus type 2 with dyslipidemia is a common disease. Previous studies suggest that aloe (Aloe vera L.) leaf gel may positively affect the blood glucose and lipid levels in dyslipidemic type 2 diabetic patients. Thus, in this randomized double-blind placebo-controlled clinical trial with hyperlipidemic (hypercholesterolemic and/or hypertriglyceridemic) type 2 diabetic patients aged 40 to 60 years not using other anti-hyperlipidemic agents and resistant to daily intake of two 5 mg glyburide tablets and two 500 mg metformin tablets, the efficacy and safety of taking aloe gel (one 300 mg capsule every 12 hours for 2 months) combined with the aforementioned drugs in treatment of 30 patients were evaluated and compared with the placebo group (n = 30). The aloe gel lowered the fasting blood glucose, HbA1c, total cholesterol, and LDL levels significantly (p = 0.036, p = 0.036, p = 0.006, and p = 0.004, respectively) without any significant effects on the other blood lipid levels and liver/kidney function tests (p > 0.05) compared with the placebo at the endpoint. No adverse effects were reported. The results suggest that aloe gel may be a safe anti-hyperglycemic and anti-hypercholesterolemic agent for hyperlipidemic type 2 diabetic patients. © Georg Thieme Verlag KG Stuttgart · New York.

The role of primary health care in patient education for diabetes control.

PubMed

Koura, M R; Khairy, A E; Abdel-Aal, N M; Mohamed, H F; Amin, G A; Sabra, A Y

2001-01-01

The major components of diabetes management are dietary therapy, exercise and drug treatment. Therefore, education of people with diabetes is the cornerstone of management. The aim of the present work was to study the role of primary health care (PHC) in patient education for diabetes control in Alexandria. Accordingly, the knowledge and perception concerning diabetes and its management of all 88 PHC physicians and 104 nurses working in the two rural health centers and two randomly chosen urban health centers of Alexandria governorate were assessed by pre-designed self-administered questionnaire. All diabetic patients over 20 years of age attending the study health facilities over a period of two months were assessed for their knowledge and attitude concerning diabetes and self-management and asked about their degree of satisfaction with the provided PHC services by a pre-designed interview questionnaire. They amounted to 560 diabetic patients. The results revealed that the PHC physicians had sufficient knowledge about causes and complications of the disease, but insufficient knowledge about diagnosis and management, as only 10.2% & 4.5% of the physicians recognized the importance of regular exercise and patient education for diabetes management. Some misconceptions and false beliefs were observed among PHC nurses, as many of them considered diabetes a contagious disease or primarily caused by stress; that liver failure, hearing impairment and splenomegaly are among the complications of diabetes and that young age and immunodeficiency disorders are among the risk factors for developing diabetes. Moreover, most of them believed that the amount of carbohydrates given to diabetic patients should be reduced or even completely restricted; that vitamins are essential for all diabetic patients and that hot-water bottles are good for providing warmth to the diabetic feet. They also disagreed on the use of artificial sweeteners as sugar substitutes. Most of the diabetic patients had poor knowledge about diabetes and its management (85.7%) and a negative attitude towards self-management (61.6%) and only 23.6% of them were satisfied with the services provided by the PHC facilities for diabetes control. They were mainly dissatisfied with the role of PHC physicians in patient education. Some misconceptions and false beliefs were also recognized among diabetic patients. Many of them considered diabetes a contagious disease or primarily caused by stress. They didn't know the importance of regular exercise in diabetes control. They also believed in the efficacy of herbal therapy in diabetes control; that vitamins are essential for all people with diabetes; that water intake should be decreased when passing large amounts of urine, that anti-diabetic drugs should be stopped during associated illnesses and that patients on insulin treatment can't be shifted to oral drugs. Moreover, they believed that the amount of carbohydrates in diet should be reduced or even restricted and that the amount of proteins should not be reduced. They also refused the use of artificial sweeteners as sugar substitutes. Thus, it may be concluded that there is a serious gap in the provision of basic educational services to the majority of diabetic patients attending PHC facilities in Alexandria.

Safety and efficacy of tinea pedis and onychomycosis treatment in people with diabetes: a systematic review

PubMed Central

2011-01-01

Background Effective treatment of tinea pedis and onychomycosis is crucial for patients with diabetes as these infections may lead to foot ulcers and secondary bacterial infections resulting in eventual lower limb amputation. Although numerous studies have assessed the effectiveness of antifungal drug and treatment regimens, most exclude patients with diabetes and examine otherwise healthy individuals. While these studies are useful, results cannot necessarily be extrapolated to patients with diabetes. The purpose of this study was to therefore identify the best evidence-based treatment interventions for tinea pedis or onychomycosis in people with diabetes. Methods The question for this systemic review was: 'what evidence is there for the safety and/or efficacy of all treatment interventions for adults with tinea pedis and/or onychomycosis in people with diabetes'? A systematic literature search of four electronic databases (Scopus, EbscoHost, Ovid, Web of Science) was undertaken (6/1/11). The primary outcome measure for safety was self-reported adverse events likely to be drug-related, while the primary outcome measures assessed for 'efficacy' were mycological, clinical and complete cure. Results The systematic review identified six studies that examined the safety and/or efficacy of treatment interventions for onychomycosis in people with diabetes. No studies were identified that examined treatment for tinea pedis. Of the studies identified, two were randomised controlled trials (RCTs) and four were case series. Based on the best available evidence identified, it can be suggested that oral terbinafine is as safe and effective as oral itraconazole therapy for the treatment of onychomycosis in people with diabetes. However, efficacy results were found to be poor. Conclusions This review indicates that there is good evidence (Level II) to suggest oral terbinafine is as safe and effective as itraconazole therapy for the treatment of onychomycosis in people with diabetes. Further research is needed to establish the evidence for other treatment modalities and treatment for tinea pedis for people with diabetes. Future efforts are needed to improve the efficacy of treatment intervention. PMID:22136082

Anti-diabetic effect of Xylopia aethiopica (Dunal) A. Rich. (Annonaceae) fruit acetone fraction in a type 2 diabetes model of rats.

PubMed

Mohammed, Aminu; Koorbanally, Neil Anthony; Islam, Md Shahidul

2016-03-02

In traditional medicine from West Africa, the fruit decoction of Xylopia aethiopica (Dunal) A. Rich. is widely used for the treatment of diabetes mellitus (DM) either alone or in combination with other plants. The present study is designed to investigate the anti-diabetic effects of X. aethiopica acetone fraction (XAAF) from fruit ethanolic extract in a type 2 diabetes (T2D) model of rats. T2D was induced in rats by feeding a 10% fructose solution ad libitum for 2 weeks followed by a single intraperitoneal injection of streptozotocin (40 mg/kg body weight) and the animals were orally treated with 150 or 300 mg/kg body weight (bw) of the XAAF once daily for four weeks. After 4 weeks study period, diabetic untreated animals (DBC) exhibited significantly higher serum glucose, serum fructosamine, LDH, CK-MB, serum lipids, liver glycogen, insulin resistance (HOMA-IR), AI, CRI and lower serum insulin, β-cell function (HOMA-β) and glucose tolerance ability compared to the normal animals. Histopathological examination of their pancreas revealed corresponding pathological changes in the islets and β-cells. These alterations were reverted to near-normal after the treatment of XAAF at 150 (DXAL) and 300 (DXAH) mg/kg bw with the effects being more pronounced in the DXAH group compared to the DXAL group. Moreover, the effects in the animals of DXAH group were comparable to the diabetic metformin (DMF) treated animals. In addition, no significant alterations were observed in non-diabetic animals treated with 300 mg/kg bw of XAAF (NXAH). The results of our study suggest that XAAF treatment showed excellent anti-diabetic effects in a T2D model of rats. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Up-regulation of glyoxalase 1 by mangiferin prevents diabetic nephropathy progression in streptozotocin-induced diabetic rats.

PubMed

Liu, Yao-Wu; Zhu, Xia; Zhang, Liang; Lu, Qian; Wang, Jian-Yun; Zhang, Fan; Guo, Hao; Yin, Jia-Le; Yin, Xiao-Xing

2013-12-05

Advanced glycation endproducts (AGEs) and its precursor methylglyoxal are associated with diabetic nephropathy (DN). Mangiferin has many beneficial biological activities, including anti-inflammatory, anti-oxidative and anti-diabetic effects. We investigated the effect of mangiferin on DN and its potential mechanism associated with glyoxalase 1 (Glo-1), a detoxifying enzyme of methylglyoxal, in streptozotocin-induced rat model of DN. Diabetic rats were treated orally with mangiferin (15, 30, and 60 mg/kg) or distilled water for 9 weeks. Kidney tissues were collected for morphologic observation and the determination of associated biochemical parameters. The cultured mesangial cells were used to measure the activity of Glo-1 in vitro. Chronic treatment with mangiferin significantly ameliorated renal dysfunction in diabetic rats, as evidenced by decreases in albuminuria, blood urea nitrogen, kidney weight index, periodic acid-schiff stain positive mesangial matrix area, glomerular extracellular matrix expansion and accumulation, and glomerular basement membrane thickness. Meanwhile, mangiferin treatment caused substantial increases in the enzymatic activity of Glo-1 in vivo and in vitro, and protein and mRNA expression of Glo-1, reduced levels of AGEs and the protein and mRNA expression of their receptor (RAGE) in the renal cortex of diabetic rats. Moreover, mangiferin significantly attenuated oxidative stress damage as reflected by the lowered malondialdehyde and the increased glutathione levels in the kidney of diabetic rats. However, mangiferin did not affect the blood glucose and body weight of diabetic rats. Therefore, mangiferin can remarkably ameliorate DN in rats through inhibiting the AGEs/RAGE aix and oxidative stress damage, and Glo-1 may be a target for mangiferin action. Copyright © 2013 Elsevier B.V. All rights reserved.

Meaningful use stage 2 e-prescribing threshold and adverse drug events in the Medicare Part D population with diabetes

PubMed Central

Gabriel, Meghan Hufstader; Encinosa, William; Mostashari, Farzad; Bynum, Julie

2015-01-01

Evidence supports the potential for e-prescribing to reduce the incidence of adverse drug events (ADEs) in hospital-based studies, but studies in the ambulatory setting have not used occurrence of ADE as their outcome. Using the “prescription origin code” in 2011 Medicare Part D prescription drug events files, the authors investigate whether physicians who meet the meaningful use stage 2 threshold for e-prescribing (≥50% of prescriptions e-prescribed) have lower rates of ADEs among their diabetic patients. Risk of any patient with diabetes in the provider’s panel having an ADE from anti-diabetic medications was modeled adjusted for prescriber and patient panel characteristics. Physician e-prescribing to Medicare beneficiaries was associated with reduced risk of ADEs among their diabetes patients (Odds Ratio: 0.95; 95% CI, 0.94-0.96), as were several prescriber and panel characteristics. However, these physicians treated fewer patients from disadvantaged populations. PMID:25948698

[Treatment with inhibitors of new oral direct anticoagulants in patients with severe bleedings or urgent surgical procedures. The new dabigatran antidote: the place of idarucizumab in clinical practice].

PubMed

Boda, Zoltán

2016-03-20

Only vitamin K antagonists could be applied as oral anticoagulants over the past six decades. Coumarols have narrow therapeutic range, and unpredictable anticoagulant effects are resulted by multiple drug interactions. Therefore, regular routine monitoring of the international normalized ratio is necessary. There are two groups of factor-specific anticoagulants: molecules with anti-FIIa (dabigatran) and anti-FXa (rivaroxaban, apixaban and edoxaban) effect. Author summarizes the most important clinical features of the new oral anticoagulants, their indications and the possibilities of laboratory controls. Bleedings are the most important side effects of anticoagulants. This review summarizes the current published evidences for new oral anticoagulants reversal (non-specific and specific) agents, especially in cases with severe acute bleedings or urgent surgery procedures. It reports on how to use inhibitors, the recommended doses and the most important clinical results. The review focuses on idarucizumab - already approved by the U.S. Food and Drug Administration and the European Medicines Agency - which has a key role as the first specific inhibitor of dabigatran.

Horizon 2020 in Diabetic Kidney Disease: The Clinical Trial Pipeline for Add-On Therapies on Top of Renin Angiotensin System Blockade

PubMed Central

Perez-Gomez, Maria Vanessa; Sanchez-Niño, Maria Dolores; Sanz, Ana Belen; Martín-Cleary, Catalina; Ruiz-Ortega, Marta; Egido, Jesus; Navarro-González, Juan F.; Ortiz, Alberto; Fernandez-Fernandez, Beatriz

2015-01-01

Diabetic kidney disease is the most frequent cause of end-stage renal disease. This implies failure of current therapeutic approaches based on renin-angiotensin system (RAS) blockade. Recent phase 3 clinical trials of paricalcitol in early diabetic kidney disease and bardoxolone methyl in advanced diabetic kidney disease failed to meet the primary endpoint or terminated on safety concerns, respectively. However, various novel strategies are undergoing phase 2 and 3 randomized controlled trials targeting inflammation, fibrosis and signaling pathways. Among agents currently undergoing trials that may modify the clinical practice on top of RAS blockade in a 5-year horizon, anti-inflammatory agents currently hold the most promise while anti-fibrotic agents have so far disappointed. Pentoxifylline, an anti-inflammatory agent already in clinical use, was recently reported to delay estimated glomerular filtration rate (eGFR) loss in chronic kidney disease (CKD) stage 3–4 diabetic kidney disease when associated with RAS blockade and promising phase 2 data are available for the pentoxifylline derivative CTP-499. Among agents targeting chemokines or chemokine receptors, the oral small molecule C-C chemokine receptor type 2 (CCR2) inhibitor CCX140 decreased albuminuria and eGFR loss in phase 2 trials. A dose-finding trial of the anti-IL-1β antibody gevokizumab in diabetic kidney disease will start in 2015. However, clinical development is most advanced for the endothelin receptor A blocker atrasentan, which is undergoing a phase 3 trial with a primary outcome of preserving eGFR. The potential for success of these approaches and other pipeline agents is discussed in detail. PMID:26239562

Prescribing Pattern of Oral Antihyperglycaemic Drugs, Rationality and Adherence to American Diabetes Association (ADA) Treatment Guidelines among Type 2 Diabetes Mellitus (T2DM) Postmenopausal Women.

PubMed

Sharma, Sudhaa; Tandon, Vishal R; Roshi; Mahajan, Annil

2016-01-01

Oral antihyperglycaemic prescription trends keep on changing and thus the drug prescription trend study may prove to be powerful exploratory tool for health care providers. To investigate trends in prescriptions of oral antihyperglycaemic drugs (OHDs) among postmenopausal women suffering from T2DM in India and evaluate the rationality and adherence to ADA treatment guidelines. An observational, cross-sectional descriptive prescription audit (n=500) was carried. Postmenopausal women were interviewed in their local language using pre-tested pre validated questionnaire after verbal informed consent at a teaching tertiary care hospital of north India. Oral antihyperglycaemic drugs (OHDs) drugs were categorized as per the pharmacological classification. Adherence to available clinical practice guidelines/recommendations issued under American Diabetes Association (ADA) 2015 Guidelines as well as rationality of these prescriptions were assessed using WHO Guide to Good Prescribing. Mean age of the study population was 58.14±12.86. Mean duration since menopause was 5.3 years and of T2DM was 9.5 years. A 93.4% of the prescriptions had only OHDs whereas 6.6% of the prescriptions had various insulin preprations + OHDs (p<0.0001). Biguanides followed by sulfonylureas, thiazolidinediones, DPP-inhibitors and alpha-glucosidases inhibitor were prescribed in 85.6%, 59.8%, 26.6%, 26% and 12.2% respectively as monotherapy or in combination. Among biguanides, metformin was the most frequently prescribed OHDs. In spite of black box warning on pioglitazone, it was prescribed in 26.6% as FDC. However, clear increase use of vidagliptine was noticed upto 26%. Among combinations most frequent was metformin plus glimipride followed by voglibose plus metformin, whereas, among FDC, metformin plus glimipride followed by metformin plus vidagliptine were most frequently prescribed. Metformin was the most common OHDs to be prescribed followed by glimepiride. Although pioglitazone still continues to be prescribed after safety alert but apparently it appears that the share of pioglitazone has been shifted to vidagliptin or combinations like metformin plus glimipride. Polypharmacy, high use of FDC, & prescription by brand names were some of the irrationalities. Relatively low adherence to ADA treatment guidelines was observed.

Drug use evaluation of diabetes mellitus in hospitalized patients of a tertiary care referral hospital.

PubMed

Khalam, Ameera; Dilip, Chandrasekhar; Shinu, Cholamugath

2012-01-01

Many drugs are available for the treatment of diabetes mellitus and are sometimes prescribed in combination. Irrational use of drugs is increasing expenditure and strain on health budgets. The aim of this study was to determine patient demographic characteristics, analyze prescription patterns of antidiabetic drugs, distribution of complications of diabetes, distribution of co-existing illnesses, distribution of common symptoms of diabetes and distribution of adverse drug reactions. A study was carried out for 11 months in diabetic inpatients in the General Medicine Department. Data of 200 patients were collected and evaluated. The pattern of drug prescription in diabetes shows that insulin (80.5%) was most frequently prescribed followed by biguanides (23%), sulfonylureas (22.5%), thiazolidinediones (11%), dipeptidyl peptidase-IV (DPP-4) inhibitors (9.5%) and meglitinides (5.5%). The percentage of patients on diet control therapy was found to be 3%. Combination therapy was prescribed to 26.5% and monotherapy to 65% of patients; 47.5% of these patients were male and 52.5% were female. The most common co-existing illness was found to be hypertension (53.5%). In addition, 67% of patients had irregular blood sugar monitoring and the remaining 33% had regular (either 4 or 6 hourly) monitoring. It is concluded that the prescribing trend is moving away from monotherapy with insulin and sulfonylureas and towards combination therapies. There is also a significant increase in prescriptions of newer oral antidiabetic drugs, such as DPP-4 inhibitors and insulin analogs. Most inpatients had their blood glucose checked irregularly and haphazardly by ward staff. This study strongly highlights the need for patient education or counseling on use of antidiabetic and concomitant drugs, monitoring of blood glucose and glycosylated hemoglobin (HbA1c) levels, diet control and correction of diabetic complications.

Antidiabetic activity of Pongamia pinnata leaf extracts in alloxan-induced diabetic rats

PubMed Central

Sikarwar, Mukesh S.; Patil, M.B.

2010-01-01

The antidiabetic activity of Pongamia pinnata ( Family: Leguminosae) leaf extracts was investigated in alloxan-induced diabetic albino rats. A comparison was made between the action of different extracts of P. pinnata and a known antidiabetic drug glibenclamide (600 μg/kg b. wt.). An oral glucose tolerance test (OGTT) was also performed in experimental diabetic rats. The petroleum ether, chloroform, alcohol and aqueous extracts of P. pinnata were obtained by simple maceration method and were subjected to standardization using pharmacognostical and phytochemical screening methods. Dose selection was made on the basis of acute oral toxicity study (50-5000 mg/kg b. w.) as per OECD guidelines. P. pinnata ethanolic extract (PPEE) and aqueous extract (PPAE) showed significant (P < 0.001) antidiabetic activity. In alloxan-induced model, blood glucose levels of these extracts on 7th day of the study were 155.83 ± 11.211mg/dl (PPEE) and 132.00 ± 4.955mg/dl (PPAE) in comparison of diabetic control (413.50 ± 4.752mg/dl) and chloroform extract (210.83 ± 14.912mg/dl). In glucose loaded rats, PPEE exhibited glucose level of 164.50 ± 6.350mg/dl after 30 min and 156.50 ± 4.089mg/dl after 90 min, whereas the levels in PPAE treated animals were 176 ± 3.724mg/dl after 30 min and 110.33 ± 6.687mg/dl after 90 min. These extracts also prevented body weight loss in diabetic rats. The drug has the potential to act as an antidiabetic drug. PMID:21455444

Reversible adrenal insufficiency and heterophile antibodies in a case of autoimmune polyendocrinopathy syndrome

PubMed Central

Kharb, Sandeep; Gundgurthi, Abhay; Dutta, Manoj K.; Garg, M. K.

2013-01-01

A 27-year-old male was admitted with diabetic ketoacidosis and altered sensorium with slurring of speech and ataxia. He was managed with intravenous insulin and fluids and later shifted to basal bolus insulin regimen and during further evaluation was diagnosed to be suffering from primary hypothyroidism and adrenal insufficiency. He was started on thyroxin replacement and steroids only during stress. After three months of follow up he was clinically euthyroid. His glycemic control was adequate on oral anti-hyperglycemic drugs and adrenal insufficiency recovered. However, his thyrotropin levels were persistently elevated on adequate replacement doses of thyroxin. His repeat TSH was estimated after precipitating serum with polyethylene glycol which revealed normal TSH. Here we report reversible adrenal insufficiency with hypothyroidism with falsely raised TSH because of presence of heterophile antibodies in a case of poly glandular endocrinopathy syndrome. PMID:24910843

Reversible adrenal insufficiency and heterophile antibodies in a case of autoimmune polyendocrinopathy syndrome.

PubMed

Kharb, Sandeep; Gundgurthi, Abhay; Dutta, Manoj K; Garg, M K

2013-12-01

A 27-year-old male was admitted with diabetic ketoacidosis and altered sensorium with slurring of speech and ataxia. He was managed with intravenous insulin and fluids and later shifted to basal bolus insulin regimen and during further evaluation was diagnosed to be suffering from primary hypothyroidism and adrenal insufficiency. He was started on thyroxin replacement and steroids only during stress. After three months of follow up he was clinically euthyroid. His glycemic control was adequate on oral anti-hyperglycemic drugs and adrenal insufficiency recovered. However, his thyrotropin levels were persistently elevated on adequate replacement doses of thyroxin. His repeat TSH was estimated after precipitating serum with polyethylene glycol which revealed normal TSH. Here we report reversible adrenal insufficiency with hypothyroidism with falsely raised TSH because of presence of heterophile antibodies in a case of poly glandular endocrinopathy syndrome.

A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents.

PubMed

Nørregaard, Pia K; Deryabina, Maria A; Tofteng Shelton, Pernille; Fog, Jacob U; Daugaard, Jens R; Eriksson, Per-Olof; Larsen, Lone F; Jessen, Lene

2018-01-01

To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity. © 2017 John Wiley & Sons Ltd.

Analysis of access to hypertensive and diabetic drugs in the Family Health Strategy, State of Pernambuco, Brazil.

PubMed

Barreto, Maria Nelly Sobreira de Carvalho; Cesse, Eduarda Ângela Pessoa; Lima, Rodrigo Fonseca; Marinho, Michelly Geórgia da Silva; Specht, Yuri da Silva; de Carvalho, Eduardo Maia Freese; Fontbonne, Annick

2015-01-01

To evaluate the access to drugs for hypertension and diabetes and the direct cost of buying them among users of the Family Health Strategy (FHS) in the state of Pernambuco, Brazil. Population-based, cross-sectional study of a systematic random sample of 785 patients with hypertension and 823 patients with diabetes mellitus who were registered in 208 randomly selected FHS teams in 35 municipalities of the state of Pernambuco. The selected municipalities were classified into three levels with probability proportional to municipality size (LS, large-sized; MS, medium-sized; SS, small-sized). To verify differences between the cities, we used the χ2 test. Pharmacological treatment was used by 91.2% patients with hypertension whereas 85.6% patients with diabetes mellitus used oral antidiabetic drugs (OADs), and 15.4% used insulin. The FHS team itself provided antihypertensive medications to 69.0% patients with hypertension, OADs to 75.0% patients with diabetes mellitus, and insulin treatment to 65.4%. The 36.9% patients with hypertension and 29.8% with diabetes mellitus that had to buy all or part of their medications reported median monthly cost of R$ 18.30, R$ 14.00, and R$ 27.61 for antihypertensive drugs, OADs, and insulin, respectively. It is necessary to increase efforts to ensure access to these drugs in the primary health care network.

Diabetes area participation analysis: a review of companies and targets described in the 2008 - 2010 patent literature.

PubMed

Carpino, Philip A; Goodwin, Bryan

2010-12-01

Type 2 diabetes is a chronic disease characterized by the development of insulin resistance, impaired pancreatic β-cell function and, ultimately, hyperglycemia. The disease is highly associated with obesity and it is thought that the inappropriate deposition of lipid in tissues such as liver and muscle contributes to a reduction in insulin sensitivity which, in turn, places a burden on the β-cell to secrete more insulin to achieve normoglycemia. Over an extended period of time, this can result in β-cell failure and diminished glycemic control. When poorly managed, type 2 diabetes increases the risk of developing both microvascular and macrovascular complications, including retinopathy, nephropathy and coronary artery disease. The number of Americans with diabetes has approached 24 million in 2007 and the prevalence of the disease is projected to increase with the sedentary lifestyles and high caloric diets that are common today. First-line treatment for the disease involves lifestyle modifications and, if unsuccessful, pharmacotherapy to control symptoms. Anti-diabetic drugs belonging to several mechanistic classes are available (e.g., insulin secretagogues, insulin sensitizers, insulin mimetics and DPP IV inhibitors); however, many of these drugs lose their effectiveness over time, are not well-tolerated in some patients or may have suboptimal risk:benefit ratios. The search for new anti-diabetic drugs has continued to attract considerable interest from both academia and the pharmaceutical industry. An analysis of 2008 - 2010 patent applications claiming diabetes as an indication has been undertaken. An understanding of: i) the pharmaceutical companies that have filed patent applications in the anti-diabetes area during 2008 - 2010; ii) the different pharmacological targets under investigation and the patent activity around such targets; iii) some of the targets in the research portfolios of selected companies; iv) chemical structures of compounds that modulate emerging targets and v) the pharmacological rationale underlying several targets with the largest patent counts. Type 2 diabetes is a complex disease with many potential points of intervention for pharmacotherapy. A majority of anti-diabetic patent applications claim chemical matter for just eight targets which include five enzymes, a GPCR, a family of nuclear hormone receptors and a class of sodium-dependent glucose co-transporters (11β-HSD1, DGAT1, DPP IV, glucokinase, GPR119, PPAR-α, -δ, -γ, SGLT1 and SGLT2, and stearoyl-CoA desaturase 1 (SCD1)). The major pharmaceutical companies are all pursuing some combination of these top eight targets. Several companies stand out for the breadth of new targets under investigation (e.g., F. Hoffmann-La Roche, Merck & Co., Pfizer, Takeda Pharmaceuticals, Sanofi-Aventis).

Repositioning drugs for inflammatory disease – fishing for new anti-inflammatory agents

PubMed Central

Hall, Christopher J.; Wicker, Sophie M.; Chien, An-Tzu; Tromp, Alisha; Lawrence, Lisa M.; Sun, Xueying; Krissansen, Geoffrey W.; Crosier, Kathryn E.; Crosier, Philip S.

2014-01-01

Inflammation is an important and appropriate host response to infection or injury. However, dysregulation of this response, with resulting persistent or inappropriate inflammation, underlies a broad range of pathological processes, from inflammatory dermatoses to type 2 diabetes and cancer. As such, identifying new drugs to suppress inflammation is an area of intense interest. Despite notable successes, there still exists an unmet need for new effective therapeutic approaches to treat inflammation. Traditional drug discovery, including structure-based drug design, have largely fallen short of satisfying this unmet need. With faster development times and reduced safety and pharmacokinetic uncertainty, drug repositioning – the process of finding new uses for existing drugs – is emerging as an alternative strategy to traditional drug design that promises an improved risk-reward trade-off. Using a zebrafish in vivo neutrophil migration assay, we undertook a drug repositioning screen to identify unknown anti-inflammatory activities for known drugs. By interrogating a library of 1280 approved drugs for their ability to suppress the recruitment of neutrophils to tail fin injury, we identified a number of drugs with significant anti-inflammatory activity that have not previously been characterized as general anti-inflammatories. Importantly, we reveal that the ten most potent repositioned drugs from our zebrafish screen displayed conserved anti-inflammatory activity in a mouse model of skin inflammation (atopic dermatitis). This study provides compelling evidence that exploiting the zebrafish as an in vivo drug repositioning platform holds promise as a strategy to reveal new anti-inflammatory activities for existing drugs. PMID:25038060

Differential anti-diabetic effects and mechanism of action of charantin-rich extract of Taiwanese Momordica charantia between type 1 and type 2 diabetic mice.

PubMed

Wang, Hsien-Yi; Kan, Wei-Chih; Cheng, Tain-Junn; Yu, Sung-Hsun; Chang, Liang-Hao; Chuu, Jiunn-Jye

2014-07-01

Momordica charantia Linn. (Cucurbitaceae), also called bitter melon, has traditionally been used as a natural anti-diabetic agent for anti-hyperglycemic activity in several animal models and clinical trials. We investigated the differences in the anti-diabetic properties and mechanism of action of Taiwanese M. charantia (MC) between type 1 diabetic (T1D) and type 2 diabetic (T2D) mice. To clarify the beneficial effects of MC, we measured non-fasting glucose, oral glucose tolerance, and plasma insulin levels in KK/HIJ mice with high-fat diet-induced diabetes (200 mg/kg/day of charantin-rich extract of MC [CEMC]) and in ICR mice with STZ-induced diabetes. After 8 weeks, all the mice were exsanguinated, and the expression of the insulin-signaling-associated proteins in their tissue was evaluated, in coordination with the protective effects of CEMC against pancreatic β-cell toxicity (in vitro). Eight weeks of data indicated that CEMC caused a significant decline in non-fasting blood glucose, plasma glucose intolerance, and insulin resistance in the KK/HIJ mice, but not in the ICR mice. Furthermore, CEMC decreased plasma insulin and promoted the sensitivity of insulin by increasing the expression of GLUT4 in the skeletal muscle and of IRS-1 in the liver of KK/HIJ mice; however, CEMC extract had no effect on the insulin sensitivity of ICR mice. In vitro study showed that CEMC prevented pancreatic β cells from high-glucose-induced cytotoxicity after 24 h of incubation, but the protective effect was not detectable after 72 h. Collectively, the hypoglycemic effects of CEMC suggest that it has potential for increasing insulin sensitivity in patients with T2D rather than for protecting patients with T1D against β-cell dysfunction. Copyright © 2014 Elsevier Ltd. All rights reserved.

Biospectroscopy for studying the influences of anti-diabetic metals (V, Cr, Mo, and W) to the insulin signaling pathway

NASA Astrophysics Data System (ADS)

Safitri, Anna; Levina, Aviva; Lee, Joonsup; Carter, Elizabeth A.; Lay, Peter A.

2017-03-01

The prevalence of diabetes, particularly with respect to type 2 diabetes, has reached epidemic proportions and continues to grow worldwide. One of the potential therapeutic targets in the treatment of type 2 diabetes involves the role of protein tyrosine phosphatases in the negative regulation of insulin signaling. The complexes of V(V/IV), Cr(III), W(VI), and Mo(VI), have all been proposed as possible drugs in the treatment of diabetes mellitus. Anti-diabetic activities of V(V/IV), Cr(III), Mo(VI), and W(VI) compounds are likely to be based on similar mechanisms, which involve phosphorylation/dephosphorylation reactions in the glucose uptake and metabolism. In order to clearly understand biological activities and phosphorylation/dephosphorylation reactions involved in anti-diabetic actions of Cr(III), V(V/IV), Mo(VI), and W(VI) complexes, the current research involves the use of cultured insulin-sensitive cells treated with these compounds. These reactions were investigated through vibrational spectroscopy. Protein phosphorylation/dephosphorylation induced conformational changes in secondary protein structure from α-helix to β-sheet, and these changes were detected by the IR spectra, which showed changes in the wavenumber and intensities of signals within the composite protein amide I band.

A review of the use of Piper betel in oxidative stress disorders.

PubMed

Lee, C Y; Nurul Zaidah, A S; Nur Amalina, G; Muhammad Azree, Ema; Das, S; Zar, C T

2014-01-01

Increase in prevalence of disease related oxidative stress disorders have been on the rise in the entire world since the past decades. Significant positive effects with few antioxidant properties in the modern drugs pave for the alternative medicines in managing the disease. Piper betel (P. betel), a herb, is known to possess high anti-oxidant, anti-diabetic, anti-atherosclerosis, anti-hyperlipidemic, anti-cancer and neuroprotective property. This review focused on the effect of P. betel on diabetes mellitus, atherosclerosis and chronic kidney disease, Alzheimer's disease and breast cancer. P. betel proved to show positive effects with specific outcomes towards these diseases. Moreover, the promising effect of P. betel in vitro studies was also highlighted in the present review. It is believed that the findings obtained in this review will draw the attention of the medical professionals and general public towards P. betel and it will open the door for further detailed research.

Boswellia carterii liquisolid systems with promoted anti-inflammatory activity.

PubMed

Mostafa, Dina Mahmoud; Ammar, Nagwa Mohammed; Abd El-Alim, Sameh Hosam; Kassem, Ahmed Alaa; Hussein, Rehab Ali; Awad, Gamal; El-Awdan, Sally Abdul-Wanees

2015-01-01

Boswellia carterii (BC) Birdwood oleogum resin is an ancient remedy of inflammation processes known since Ancient Egyptian time. Of boswellic acids, 3-acetyl-11-keto-β-boswellic acid (AKBA) is the most potent anti-inflammatory active principle. Liquisolid systems of the biologically active fraction of BC oleogum resin were prepared for improving dissolution properties using low dose oral delivery to achieve enhanced anti-inflammatory activity, in comparison with the standard oral anti-inflammatory; Indomethacin. AKBA was assayed, employing an accurate and sensitive HPLC method. Detection was carried out at 210 nm using UV/Vis detector. A solubility study for the bioactive fraction was conducted. Microcrystalline cellulose and Aeroperl®300 Pharma were used as carrier and coating materials. Angle of slide, liquid load factor and Carr's flow index were estimated. Six systems were prepared using polyethylene glycol 400, solvent and two drug loading concentrations; 20 and 40 %. For each concentration, three carrier: coat ratios were dispensed; 20:1, 10:1, and 5:1. Dissolution study was performed and two systems were selected for characterization and in vivo evaluation by investigating upper GIT ulcerogenic effect and anti-inflammatory efficacy in rats. Results indicate absence of ulcers and significantly higher and prolonged anti-inflammatory efficacy for formulations F1 and F2, with carrier: coat ratio, 5:1 and drug loads of 20 and 40 %, respectively, compared with standard oral indomethacin. We conclude higher efficacy of BC bioactive fraction liquisolids compared with Indomethacin with greater safety on GIT, longer duration of action and hence better patient compliance.

Protective effect of crude Curcuma longa and its methanolic extract in alloxanized rabbits.

PubMed

Ahmad, Mobasher; Kamran, Sairah Hafeez; Mobasher, Afroze

2014-01-01

Curcuma longa (C. longa) is commonly found in different areas of Pakistan. It has been locally utilized as a traditional medicine. The aim of this study was to evaluate the antidiabetic, hepatoprotective and total antioxidant effect of the crude drug and its methanolic extract in rabbits. Diabetes was induced with alloxan (180mg/kg). Two major groups were designed, curative and protective groups. In curative group the crude drug and its methanolic extract was orally administered to the diabetic animals and acute study was performed. On the other hand in protective group the crude drug and its methanolic extract were administered for eight days prior to the diabetes induction. Results indicated that in Curative group the crude and methanolic extract of C. longa significantly improved the levels of serum glucose, serum transaminases and antioxidant activity (AOA). In protective group, serum glucose, serum transaminases were not significantly increased by alloxan, in both crude as well as methanolic extract group. This study shows that C. longa acts as antidiabetic, hepatoprotective and antioxidant in diabetes especially type 1 diabetes.

Herb-drug interaction of Andrographis paniculata (Nees) extract and andrographolide on pharmacokinetic and pharmacodynamic of naproxen in rats.

PubMed

Balap, Aishwarya; Lohidasan, Sathiyanarayanan; Sinnathambi, Arulmozhi; Mahadik, Kakasaheb

2017-01-04

Andrographis paniculata Nees (Acanthacae) have broad range of pharmacological effects such as hepatoprotective, antifertility, antimalarial, antidiabetic, suppression of various cancer cells and anti-inflammatory properties and is widely used medicinal plant in the traditional Unani and Ayurvedic medicinal systems. Andrographolide (AN) is one of the active constituent of the A. paniculata Nees extract (APE). They have been found in many traditional herbal formulations in India and proven to be effective as anti-inflammatory drug. To evaluate the pharmacokinetic and pharmacodynamic (anti arthritic) herb-drug interactions of A. paniculata Nees extract (APE) and pure andrographolide (AN) with naproxen (NP) after oral co-administration in wistar rats. After oral co-administration of APE (200mg/Kg) and AN (60mg/kg) with NP (7.5mg/kg) in rats, drug concentrations in plasma were determined using HPLC method. The main pharmacokinetic parameters of C max , t max , t 1/2 , MRT, Vd, CL, and AUC were calculated by non-compartment model. Change in paw volume, mechanical nociceptive threshold, mechanical hyperalgesia, histopathology and hematological parameters were evaluated to study antiarthritic activity. Co-administration of NP with APE and pure AN decreased systemic exposure level of NP in vivo. The C max , t max, AUC 0-t of NP was decreased. In pharmacodynamic study, NP (10mg/kg) alone and NP+AN (10+60mg/kg) groups exhibited significant synergistic anti-arthritic activity as compared to groups NP+APE, APE and AN alone. The results obtained from this study suggested that NP, APE and pure AN existed pharmacokinetic herb-drug interactions in rat which is correlated with anti-arthritic study. The knowledge regarding possible herb-drug interaction of NP might be helpful for physicians as well as patients using AP. So further studies should be done to understand the effect of other herbal ingredients of APE on NP as well as to predict the herb-drug interaction in humans. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Postoperative effects of laparoscopic sleeve gastrectomy in morbid obese patients with type 2 diabetes.

PubMed

Mihmanli, Mehmet; Isil, Riza Gurhan; Bozkurt, Emre; Demir, Uygar; Kaya, Cemal; Bostanci, Ozgur; Isil, Canan Tulay; Sayin, Pinar; Oba, Sibel; Ozturk, Feyza Yener; Altuntas, Yuksel

2016-01-01

Laparoscopic Sleeve Gastrectomy has become one of the most popular bariatric surgery types and helps treating not only obesity but also endocrinological diseases related to obesity. Therefore we aimed to evaluate the effects of laparoscopic sleeve gastrectomy on the treatment of type 2 diabetes. All patients, who underwent morbid obesity surgery during 2013-2014 and had a HbA1c >6 % were included in this prospective study. Demographical data, usage of oral antidiabetic drugs or insulin were recorded, and laboratory findings as HbA1c and fasting plasma glucose were evaluated preoperatively and postoperatively at the 6th and 12th months. Diabetes remission criteria were used to assess success of the surgical treatment. Totally 88 patients were included in this study. 55 patients were using oral antidiabetic drugs and 33 patients were using insulin. At the 6th month complete remission was observed in 80 (90.9 %), partial remission in 3 (3.4 %) and persistent diabetes in 5 (5.6 %) patients. At the 12th month complete remission was observed in 84 (95.4 %), partial remission in 1 (1.1 %) and persistent diabetes in 3 (3.4 %) patients. This study indicated that laparoscopic sleeve gastrectomy surgery achieved a complete remission of diabetes in 95.4 % patients having type 2 diabetes during a 1 year fallow up period. However, complete remission of type 2 diabetes has been reported as 80 % during long term fallow up in the literature. In our opinion this rate may change with longer follow up periods and studies involving more patients suffering type 2 diabetes.

Diabetes care and outcomes for American Indians and Alaska natives in commercial integrated delivery systems: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) Study.

PubMed

Schmittdiel, Julie A; Steiner, John F; Adams, Alyce S; Dyer, Wendy; Beals, Janette; Henderson, William G; Desai, Jay; Morales, Leo S; Nichols, Gregory A; Lawrence, Jean M; Waitzfelder, Beth; Butler, Melissa G; Pathak, Ram D; Hamman, Richard F; Manson, Spero M

2014-01-01

To compare cardiovascular disease risk factor testing rates and intermediate outcomes of care between American Indian/Alaska Native (AI/AN) patients with diabetes and non-Hispanic Caucasians enrolled in nine commercial integrated delivery systems in the USA. We used modified Poisson regression models to compare the annual testing rates and risk factor control levels for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and systolic blood pressure (SBP); number of unique diabetes drug classes; insulin use; and oral diabetes drug medication adherence between insured AI/AN and non-Hispanic white adults with diabetes aged ≥18 in 2011. 5831 AI/AN patients (1.8% of the cohort) met inclusion criteria. After adjusting for age, gender, comorbidities, insulin use, and geocoded socioeconomic status, AI/AN patients had similar rates of annual HbA1c, LDL-C, and SBP testing, and LDL-C and SBP control, compared with non-Hispanic Caucasians. However, AI/AN patients were significantly more likely to have HbA1c >9% (>74.9 mmol/mol; RR=1.47, 95% CI 1.38 to 1.58), and significantly less likely to adhere to their oral diabetes medications (RR=0.90, 95% CI 0.88 to 0.93) compared with non-Hispanic Caucasians. AI/AN patients in commercial integrated delivery systems have similar blood pressure and cholesterol testing and control, but significantly lower rates of HbA1c control and diabetes medication adherence, compared with non-Hispanic Caucasians. As more AI/ANs move to urban and suburban settings, clinicians and health plans should focus on addressing disparities in diabetes care and outcomes in this population.

Diabetes care and outcomes for American Indians and Alaska natives in commercial integrated delivery systems: a SUrveillance, PREvention, and ManagEment of Diabetes Mellitus (SUPREME-DM) Study

PubMed Central

Schmittdiel, Julie A; Steiner, John F; Adams, Alyce S; Dyer, Wendy; Beals, Janette; Henderson, William G; Desai, Jay; Morales, Leo S; Nichols, Gregory A; Lawrence, Jean M; Waitzfelder, Beth; Butler, Melissa G; Pathak, Ram D; Hamman, Richard F; Manson, Spero M

2014-01-01

Objective To compare cardiovascular disease risk factor testing rates and intermediate outcomes of care between American Indian/Alaska Native (AI/AN) patients with diabetes and non-Hispanic Caucasians enrolled in nine commercial integrated delivery systems in the USA. Research design and methods We used modified Poisson regression models to compare the annual testing rates and risk factor control levels for glycated haemoglobin (HbA1c), low-density lipoprotein cholesterol (LDL-C), and systolic blood pressure (SBP); number of unique diabetes drug classes; insulin use; and oral diabetes drug medication adherence between insured AI/AN and non-Hispanic white adults with diabetes aged ≥18 in 2011. Results 5831 AI/AN patients (1.8% of the cohort) met inclusion criteria. After adjusting for age, gender, comorbidities, insulin use, and geocoded socioeconomic status, AI/AN patients had similar rates of annual HbA1c, LDL-C, and SBP testing, and LDL-C and SBP control, compared with non-Hispanic Caucasians. However, AI/AN patients were significantly more likely to have HbA1c >9% (>74.9 mmol/mol; RR=1.47, 95% CI 1.38 to 1.58), and significantly less likely to adhere to their oral diabetes medications (RR=0.90, 95% CI 0.88 to 0.93) compared with non-Hispanic Caucasians. Conclusions AI/AN patients in commercial integrated delivery systems have similar blood pressure and cholesterol testing and control, but significantly lower rates of HbA1c control and diabetes medication adherence, compared with non-Hispanic Caucasians. As more AI/ANs move to urban and suburban settings, clinicians and health plans should focus on addressing disparities in diabetes care and outcomes in this population. PMID:25452877

Enteric-coated capsules filled with mono-disperse micro-particles containing PLGA-lipid-PEG nanoparticles for oral delivery of insulin.

PubMed

Yu, Fei; Li, Yang; Liu, Chang Sheng; Chen, Qin; Wang, Gui Huan; Guo, Wei; Wu, Xue E; Li, Dong Hui; Wu, Winston Duo; Chen, Xiao Dong

2015-04-30

The success of the oral delivery of insulin (INS) as a therapeutic protein drug would significantly improve the quality of life of diabetic patients who would otherwise receive multiple daily INS injections. The oral delivery of INS, however, is still limited in its delivery efficiency, which could be due to the chemical, enzymatic, and adsorption barriers. In this work, in an attempt to improve the delivery efficiency, the INS-loaded polymer-lipid hybrid nanoparticles (INS-PLGA-lipid-PEG NPs) were designed and constructed through a double-emulsion solvent evaporation technique, followed by formulation of the spherical micro-particles using a spray freeze dryer (SFD). This kind of dryers has a uniquely designed microfluidic aerosol nozzle (MFAN), ensuring the formation of uniform particles. The resulted particles of ∼212 μm could easily be reverted to discrete INS-PLGA-lipid-PEG NPs in an aqueous solution. The INS-PLGA-lipid-PEG NPs created in this work showed a highly negative surface charge, excellent entrapment efficiency (92.3%) and a sustained drug release (∼24 h). Confocal laser scanning microscopy and flow cytometer were used to show that the cellular uptake efficiency for the INS-PLGA-lipid-PEG NPs was more effective than the INS in Caco-2 cells. More importantly, the in vivo pharmacodynamics demonstrated that the orally delivered system induced a prolonged decrease in blood glucose levels among diabetic rats. The relative bioavailability of INS compared with subcutaneous injection in diabetic rats was found to be approximately 12%. These results suggested that the encapsulated INS-PLGA-lipid-PEG NPs are promising and should be investigated further in the near future as an effective INS oral delivery system. Copyright © 2015. Published by Elsevier B.V.

Thalidomide attenuates multiple low-dose streptozotocin-induced diabetes in mice by inhibition of proinflammatory cytokines.

PubMed

Amirshahrokhi, K; Ghazi-Khansari, M

2012-11-01

Thalidomide is an immunomodulatory and anti-inflammatory agent and is used in autoimmune disorders. It has been shown that thalidomide inhibits proinflammatory cytokines production. The purpose of this study was to investigate the effect of thalidomide on the prevention of autoimmune diabetes in mice. Diabetes was induced by multiple low-dose of streptozotocin (MLDS) injection. Mice were treated with thalidomide (300 mg/kg/day orally) for 21 days. Plasma levels of glucose, insulin and nitrate/nitrite as well as pancreatic cytokine levels were measured. Pathological examinations of the pancreas revealed that thalidomide reduced the islet inflammation (insulitis) and destruction of beta cells. Thalidomide treatment prevented hyperglycemia and preserved pancreatic insulin secretion in the diabetic mice. Thalidomide treatment also significantly decreased plasma levels of nitric oxide and pancreatic proinflammatory cytokines [tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-12, IL-17 and interferon (IFN)-γ)] while increased anti-inflammatory cytokine IL-10. In conclusion, these findings indicate that thalidomide may have a protective effect against the autoimmune destruction of the pancreatic beta-cells during the development of MLDS-induced type 1 diabetes in mice. Copyright © 2012 Elsevier Ltd. All rights reserved.

Chromium picolinate and biotin combination improves glucose metabolism in treated, uncontrolled overweight to obese patients with type 2 diabetes.

PubMed

Albarracin, Cesar A; Fuqua, Burcham C; Evans, Joseph L; Goldfine, Ira D

2008-01-01

Chromium and biotin play essential roles in regulating carbohydrate metabolism. This randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of the combination of chromium picolinate and biotin on glycaemic control. Four hundred and forty-seven subjects with poorly controlled type 2 diabetes (HbA(1c) > or = 7.0%) were enrolled and received either chromium picolinate (600 microg Cr(+3)) with biotin (2 mg), or matching placebo, for 90 days in combination with stable oral anti-diabetic agents (OADs). Major endpoints were reductions in HbA(1c), fasting glucose, and lipids. Safety and tolerability were assessed. Change in HbA(1c) was significantly different between treatment groups (p = 0.03). HbA(1c) in the chromium picolinate/biotin group decreased 0.54%. The decrease in HbA(1c) was most pronounced in chromium picolinate/biotin subjects whose baseline HbA(1c) > or = 10%, and highly significant when compared with placebo (-1.76% vs - 0.68%; p = 0.005). Fasting glucose levels were reduced in the entire chromium picolinate/biotin group versus placebo (-9.8 mg/dL vs 0.7 mg/dL; p = 0.02). Reductions in fasting glucose were also most marked in those subjects whose baseline HbA(1c) > or = 10.0%, and significant when compared to placebo (-35.8 mg/dL vs. 16.2 mg/dL; p = 0.01). Treatment was well tolerated with no adverse effects dissimilar from placebo. These results suggest that the chromium picolinate/biotin combination, administered as an adjuvant to current prescription anti-diabetic medication, can improve glycaemic control in overweight to obese individuals with type 2 diabetes; especially those patients with poor glycaemic control on oral therapy. 2007 John Wiley & Sons, Ltd

The anti-tubercular drug delamanid as a potential oral treatment for visceral leishmaniasis

PubMed Central

Patterson, Stephen; Wyllie, Susan; Norval, Suzanne; Stojanovski, Laste; Simeons, Frederick RC; Auer, Jennifer L; Osuna-Cabello, Maria; Read, Kevin D; Fairlamb, Alan H

2016-01-01

There is an urgent requirement for safe, oral and cost-effective drugs for the treatment of visceral leishmaniasis (VL). We report that delamanid (OPC-67683), an approved drug for multi-drug resistant tuberculosis, is a potent inhibitor of Leishmania donovani both in vitro and in vivo. Twice-daily oral dosing of delamanid at 30 mg kg-1 for 5 days resulted in sterile cures in a mouse model of VL. Treatment with lower doses revealed a U-shaped (hormetic) dose-response curve with greater parasite suppression at 1 mg kg-1 than at 3 mg kg-1 (5 or 10 day dosing). Dosing delamanid for 10 days confirmed the hormetic dose-response and improved the efficacy at all doses investigated. Mechanistic studies reveal that delamanid is rapidly metabolised by parasites via an enzyme, distinct from the nitroreductase that activates fexinidazole. Delamanid has the potential to be repurposed as a much-needed oral therapy for VL. DOI: http://dx.doi.org/10.7554/eLife.09744.001 PMID:27215734

Simvastatin may induce insulin resistance through a novel fatty acid mediated cholesterol independent mechanism

PubMed Central

Kain, Vasundhara; Kapadia, Bandish; Misra, Parimal; Saxena, Uday

2015-01-01

Statins are a class of oral drugs that are widely used for treatment of hypercholesterolemia. Recent clinical data suggest that chronic use of these drugs increases the frequency of new onset diabetes. Studies to define the risks of statin-induced diabetes and its underlying mechanisms are clearly necessary. We explored the possible mechanism of statin induced insulin resistance using a well-established cell based model and simvastatin as a prototype statin. Our data show that simvastatin induces insulin resistance in a cholesterol biosynthesis inhibition independent fashion but does so by a fatty acid mediated effect on insulin signaling pathway. These data may help design strategies for prevention of statin induced insulin resistance and diabetes in patients with hypercholesterolemia. PMID:26345110

Anti-oxidative and reno-restorative effects of physalis angulata (whole plant extract) in alloxan-induced diabetic male Wistar rats.

PubMed

Adewoye, E O; Oguntola, M A; Ige, A O

2016-05-01

Backgroiound: Hyperglycemia has been reported to increase protein glycation and generation of free radicals which predispose to diabetic renal dysfunction. Physalis ahgulata has been shown to have hypoglycacmic and anti-lipidemic properties but there is dearth of information regarding its effect on kidney functions in diabetes. This study investigated the anti-oxidative and reno-restorative effects of methanol extract of whole plant of Physalis angulata (MEPA) in alloxan-induced diabetic rats. Twenty male Wistar rats (150-180g) were randomly divided into four groups: Group 1 (control) received 0.2 ml distilled water, groups 2-4 were made diabetic by single intra-peritoneal dose of alloxan monohydrate (100mg/kg) and treated with 0.2 ml distilled water, 500 mg/kg MEPA and 150 mg/kg metformin respectively. All treatments were given orally for 14 days. Blood samples were collected from each animal through retro-orbital puncture. The serum obtained were analysed for fructosamine, glycated hemoglobin (HbAlc), creatinine and blood urea nitrogen (BUN). Kidney samples were harvested into cold phosphate buffer, homogenized and centrifuged at- 7500rpm for 15 minutes. The supernatant obtained was analyzed for malondialdehyde and superoxide dismutase (SOD) activities. Values were compared using ANOVA at P<0.05. The MEPA-treated groups showed significant decrease (P<0.05) in blood glucose, kidney weights, fructosamine,. HbAlc, malondialdehyde, creatinine and BUN, while the body weights and SOD significantly increased (P<0.05) compared to diabetic untreated group. Treatment with methanol extract of Physalis angulata (whole plant) reduced hyperglycemia, malondialdehyde and glycation end- products, which could have contributed to the development of diabetic nephropathy if diabetes is left untreated.

Anti-diabetic effects of Sargassum oligocystum on Streptozotocin-induced diabetic rat.

PubMed

Akbarzadeh, Samad; Gholampour, Hossein; Farzadinia, Parviz; Daneshi, Adel; Ramavandi, Bahman; Moazzeni, Ali; Keshavarz, Mojtaba; Bargahi, Afshar

2018-03-01

Diabetes is a metabolic syndrome which is associated with the worldwide major public health problems. There are many natural compounds from the sea-market, as a valuable aquatic source, along with the variety of health and therapeutic benefits. In the present research, with respect to the traditional and ethnic uses of Sargassum oligocystum algae for healing of some diseases which have similar metabolic mechanism to the diabetes, its anti-diabetic effects in animal model was proposed. The animals (rat) were divided into the normal control, diabetic control, positive control and, the test groups. The test groups were gavaged with oral doses of 150 and 300 mg/kg of algae hydroalcoholic extracts. After 30 days of intervention the serum glucose, cholesterol, triglyceride, HDL C , LDL C , insulin, insulin resistance, β-cells function and, the histopathology of pancreatic tissue were evaluated. In animals that were fed with algae extracts a significant decrease in the fasting blood glucose, triglyceride and HOMA-IR and an increase in the HOMA-B with no significant impacts on the insulin, cholesterol and HDL were observed. Also, the histopathology evaluations in the groups which were treated with algae extract revealed the regeneration and reconstitution of damaged pancreatic β-cells. The results give evidence that, the S. oligocystum algae extract has a healing effect on diabetes which can be considered as a new research prospect for the natural therapy of diabetes.

A nurse-delivered advice intervention can reduce chronic non-steroidal anti-inflammatory drug use in general practice: a randomized controlled trial.

PubMed

Jones, A C; Coulson, L; Muir, K; Tolley, K; Lophatananon, A; Everitt, L; Pringle, M; Doherty, M

2002-01-01

To find out whether a nurse-delivered educational package can reduce chronic oral non-steroidal anti-inflammatory drug (NSAID) usage in general practice. A prospective randomized controlled trial with assessment of economic cost/benefits was carried out in five general practices in Nottinghamshire with computerized prescribing systems, representing a mix of rural/urban and fundholding/non-fundholding practices. Patients suffering from non-malignant, non-inflammatory musculoskeletal pain received repeat prescriptions for oral NSAIDs. Two hundred and twenty-two patients were randomized to a control group (simple advice regarding NSAID use) or an intervention group (asked to withdraw their NSAIDs and employ appropriate alternative drug and non-drug therapies). All advice was supported by patient literature and delivered by a nurse practitioner trained in musculoskeletal assessment. The primary outcome measure was change in NSAID use 6 months after the intervention. Secondary outcome measures were changes in health and quality of life (SF-36 and EQ-5D questionnaires) and drug, health service and patient costs. An extra 28% of patients in the intervention group either stopped taking oral NSAIDs or reduced dosage by > or =50% at 6 months compared with controls. There was no detrimental effect on health and well-being. Oral NSAID prescription costs were significantly lowered in the intervention group but not in the control group. A non-significant increase in total drug prescription costs occurred in both groups. Nurse-based intervention can reduce chronic NSAID usage and costs in primary care and would be cost-effective if maintained in the long term. This intervention package would be readily applicable in primary care.

Cardiovascular benefits and safety of non-insulin medications used in the treatment of type 2 diabetes mellitus.

PubMed

Yandrapalli, Srikanth; Jolly, George; Horblitt, Adam; Sanaani, Abdallah; Aronow, Wilbert S

2017-11-01

Diabetes mellitus is a growing in exponential proportions. If the current growth trend continues, it may result in every third adult in the United States having diabetes mellitus by 2050, and every 10 th adult worldwide. Type 2 diabetes mellitus (T2DM) confers a 2- to 3-fold increased risk of cardiovascular (CV) events compared with non-diabetic patients, and CV mortality is responsible for around 80% mortality in this population. Patients with T2DM can have other features of insulin resistance-metabolic syndrome like hypertension, lipid abnormalities, and obesity which are all associated with increased CV disease and stroke risk even in the absence of T2DM. The management of a T2DM calls for employing a holistic risk factor control approach. Metformin is the first line therapy for T2DM and has been shown to have cardiovascular beneficial effects. Intense debate regarding the risk of myocardial infarction with rosiglitazone led to regulatory agencies necessitating cardiovascular outcome trials with upcoming anti-diabetic medications. Glucagon like peptide-1 agonists and sodium glucose co-transporter-2 inhibitors have shown promising CV safety and additional CV benefit in recent clinical trials. These drugs have favorable effects on traditional CV risk factors. The findings from these studies further support that fact that CV risk factor control plays an important role in reducing morbidity and mortality in T2DM patients. This review article will discuss briefly the cardiovascular safety and benefits of the oral medications which are currently being used for T2DM and will then discuss in detail about the newer medications being investigated for the treatment of T2DM.

21 CFR 310.517 - Labeling for oral hypoglycemic drugs of the sulfonylurea class.

Code of Federal Regulations, 2012 CFR

2012-04-01

... cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on... vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who...

21 CFR 310.517 - Labeling for oral hypoglycemic drugs of the sulfonylurea class.

Code of Federal Regulations, 2013 CFR

2013-04-01

... cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on... vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who...

21 CFR 310.517 - Labeling for oral hypoglycemic drugs of the sulfonylurea class.

Code of Federal Regulations, 2014 CFR

2014-04-01

... cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on... vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who...

21 CFR 310.517 - Labeling for oral hypoglycemic drugs of the sulfonylurea class.

Code of Federal Regulations, 2011 CFR

2011-04-01

... cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on... vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who...

21 CFR 310.517 - Labeling for oral hypoglycemic drugs of the sulfonylurea class.

Code of Federal Regulations, 2010 CFR

2010-04-01

... cardiovascular mortality as compared to treatment with diet alone or diet plus insulin. This warning is based on... vascular complications in patients with non-insulin-dependent diabetes. The study involved 823 patients who...

Development and in-vivo assessment of the bioavailability of oridonin solid dispersions by the gas anti-solvent technique.

PubMed

Li, Songming; Liu, Ying; Liu, Tao; Zhao, Ling; Zhao, Jihui; Feng, Nianping

2011-06-15

We developed solid dispersions, using the gas anti-solvent technique (GAS), to improve the oral bioavailability of the poorly water-soluble active component oridonin. The solubility of oridonin in supercritical carbon dioxide was measured under various pressures and temperatures. To prepare oridonin solid dispersions using the GAS technique, ethanol was used as the solvent, CO(2) was used as the anti-solvent and the hydrophilic polymer polyvinylpyrrolidone K17 (PVP K17) was used as the drug carrier matrix. Characterization of the obtained preparations was undertaken using scanning electron microscopy (SEM), X-ray diffraction (XRD) analyses and a drug release study. Oridonin solid dispersions were formed and oridonin was present in an amorphous form in these dispersions. Oridonin solid dispersions significantly increased the drug dissolution rate compared with that of oridonin powder, primarily through drug amorphization. Compared with the physical mixture of oridonin and PVP K17, oridonin solid dispersions gave higher values of AUC and C(max), and the absorption of oridonin from solid dispersions resulted in 26.4-fold improvement in bioavailability. The present study illustrated the feasibility of applying the GAS technique to prepare oridonin solid dispersions, and of using them for the delivery of oridonin via the oral route. Copyright © 2011 Elsevier B.V. All rights reserved.

Development and characterization of a novel drug nanocarrier for oral delivery, based on self-assembled β-casein micelles.

PubMed

Bachar, Michal; Mandelbaum, Amitai; Portnaya, Irina; Perlstein, Hadas; Even-Chen, Simcha; Barenholz, Yechezkel; Danino, Dganit

2012-06-10

β-casein is an amphiphilic protein that self-organizes into well-defined core-shell micelles. We developed these micelles as efficient nanocarriers for oral drug delivery. Our model drug is celecoxib, an anti-inflammatory hydrophobic drug utilized for treatment of rheumatoid arthritis and osteoarthritis, now also evaluated as a potent anticancer drug. This system is unique as it enables encapsulation loads >100-fold higher than other β-casein/drug formulations, and does not require additives as do other formulations that have high loadings. This is combined with the ability to lyophilize the formulation without a cryoprotectant, long-term physical and chemical stability of the resulting powder, and fully reversible reconstitution of the structures by rehydration. The dry dosage form, in which >95% of the drug is encapsulated, meets the daily dose. Cryo-TEM and DLS prove that drug encapsulation results in micelle swelling, and X-ray diffraction shows that the encapsulated drug is amorphous. Altogether, our novel dosage form is highly advantageous for oral administration. Copyright © 2012 Elsevier B.V. All rights reserved.

Anti-obesity drugs: past, present and future

PubMed Central

Rodgers, R. John; Tschöp, Matthias H.; Wilding, John P. H.

2012-01-01

The ideal anti-obesity drug would produce sustained weight loss with minimal side effects. The mechanisms that regulate energy balance have substantial built-in redundancy, overlap considerably with other physiological functions, and are influenced by social, hedonic and psychological factors that limit the effectiveness of pharmacological interventions. It is therefore unsurprising that anti-obesity drug discovery programmes have been littered with false starts, failures in clinical development, and withdrawals due to adverse effects that were not fully appreciated at the time of launch. Drugs that target pathways in metabolic tissues, such as adipocytes, liver and skeletal muscle, have shown potential in preclinical studies but none has yet reached clinical development. Recent improvements in the understanding of peptidergic signalling of hunger and satiety from the gastrointestinal tract mediated by ghrelin, cholecystokinin (CCK), peptide YY (PYY) and glucagon-like peptide-1 (GLP-1), and of homeostatic mechanisms related to leptin and its upstream pathways in the hypothalamus, have opened up new possibilities. Although some have now reached clinical development, it is uncertain whether they will meet the strict regulatory hurdles required for licensing of an anti-obesity drug. However, GLP-1 receptor agonists have already succeeded in diabetes treatment and, owing to their attractive body-weight-lowering effects in humans, will perhaps also pave the way for other anti-obesity agents. To succeed in developing drugs that control body weight to the extent seen following surgical intervention, it seems obvious that a new paradigm is needed. In other therapeutic arenas, such as diabetes and hypertension, lower doses of multiple agents targeting different pathways often yield better results than strategies that modify one pathway alone. Some combination approaches using peptides and small molecules have now reached clinical trials, although recent regulatory experience suggests that large challenges lie ahead. In future, this polytherapeutic strategy could possibly rival surgery in terms of efficacy, safety and sustainability of weight loss. PMID:22915024

Antidiabetic activity of aqueous root extract of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats

PubMed Central

Barik, Rakesh; Jain, Sanjay; Qwatra, Deep; Joshi, Amit; Tripathi, Girraj Sharan; Goyal, Ravi

2008-01-01

Objective: To evaluate the antidiabetic activity of aqueous extract of roots of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats. Materials and Methods: Streptozotocin-nicotinamide induced type-II diabetic rats (n = 6) were administered aqueous root extract (250 and 500 mg/kg, p.o.) of Ichnocarpus frutescens or vehicle (gum acacia solution) or standard drug glibenclamide (0.25 mg/kg) for 15 days. Blood samples were collected by retro-orbital puncture and were analyzed for serum glucose on days 0, 5, 10, and 15 by using glucose oxidase-peroxidase reactive strips and a glucometer. For oral glucose tolerance test, glucose (2 g/kg, p.o.) was administered to nondiabetic control rats and the rats treated with glibenclamide (10 mg/kg, p.o.) and aqueous root extract of Ichnocarpus frutescens. The serum glucose levels were analyzed at 0, 30, 60, and 120 min after drug administration. The effect of the extract on the body weight of the diabetic rats was also observed. Results: The aqueous root extract of Ichnocarpus frutescens (250 and 500 mg/kg, p.o.) induced significant reduction (P < 0.05) of fasting blood glucose levels in streptozotocin-nicotinamide induced type-II diabetic rats on the 10th and 15th days. In the oral glucose tolerance test, the extract increased the glucose tolerance. It also brought about an increase in the body weight of diabetic rats. Conclusion: It is concluded that Ichnocarpus frutescens has significant antidiabetic activity as it lowers the fasting blood sugar level in diabetic rats and increases the glucose tolerance. PMID:21264156

Antidiabetic activity of aqueous root extract of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats.

PubMed

Barik, Rakesh; Jain, Sanjay; Qwatra, Deep; Joshi, Amit; Tripathi, Girraj Sharan; Goyal, Ravi

2008-01-01

To evaluate the antidiabetic activity of aqueous extract of roots of Ichnocarpus frutescens in streptozotocin-nicotinamide induced type-II diabetes in rats. Streptozotocin-nicotinamide induced type-II diabetic rats (n = 6) were administered aqueous root extract (250 and 500 mg/kg, p.o.) of Ichnocarpus frutescens or vehicle (gum acacia solution) or standard drug glibenclamide (0.25 mg/kg) for 15 days. Blood samples were collected by retro-orbital puncture and were analyzed for serum glucose on days 0, 5, 10, and 15 by using glucose oxidase-peroxidase reactive strips and a glucometer. For oral glucose tolerance test, glucose (2 g/kg, p.o.) was administered to nondiabetic control rats and the rats treated with glibenclamide (10 mg/kg, p.o.) and aqueous root extract of Ichnocarpus frutescens. The serum glucose levels were analyzed at 0, 30, 60, and 120 min after drug administration. The effect of the extract on the body weight of the diabetic rats was also observed. The aqueous root extract of Ichnocarpus frutescens (250 and 500 mg/kg, p.o.) induced significant reduction (P < 0.05) of fasting blood glucose levels in streptozotocin-nicotinamide induced type-II diabetic rats on the 10(th) and 15(th) days. In the oral glucose tolerance test, the extract increased the glucose tolerance. It also brought about an increase in the body weight of diabetic rats. It is concluded that Ichnocarpus frutescens has significant antidiabetic activity as it lowers the fasting blood sugar level in diabetic rats and increases the glucose tolerance.

[Polyneuropathy in diabetes type 1].

PubMed

Wilczyńska, Małgorzata

2002-01-01

Diabetic neuropathy is a clinical state of nerve damage caused by hyperglicaemia, raised activation of polyol pathway, oxydative stress, changes in endoneurial arteries and myelinated fibres. Patient complains of pain and paresthesiae in hands and limbs. The feelings of pain, temperature, touch, vibration are significantly reduced. The changes may also concern cranial nerves (IIII, IV, VI, VII), intracostal nerves, hands and limbs (Garland and Tavemer syndrome). Autonomic neuropathy concerns the impairment of autonomic functions of cardio-vascular, gastro-intestinal, uro-genital and other systems. The treatment concerns the improvement of diabetes metabolic control. Antiinflammatory antisteroid drugs are widely used but their usefulness is limited. Antidepressive drugs are the most often used group. The improvement is observed after 6 months of treatment. The side effects - orthostatic hypotension, heart rhythm disturbation and obstipation are harmful for the patients with coronary heart disease. In the cases of persistent pain the oral antiepileptic drugs may be used or cream with capsaicin for skin surface.

A Review of Ranibizumab for the Treatment of Diabetic Retinopathy.

PubMed

Stewart, Michael W

2017-06-01

Laser photocoagulation has been the standard treatment for diabetic macular edema (DME) and proliferative diabetic retinopathy (PDR) for several decades. The discovery of vascular endothelial growth factor (VEGF) and the subsequent determination of its critical role in the development DME and PDR has led to the development of VEGF inhibitory drugs. Ranibizumab was the first anti-VEGF drug approved for the treatment of both DME and diabetic retinopathy in eyes with DME. Medline searches with the keywords "ranibizumab," "diabetic macular edema," and "proliferative diabetic retinopathy" were performed to identify pertinent pre-clinical studies and clinical trials. Top-line data, with emphasis on pivotal trials, was identified and incorporated into this manuscript. Findings from small uncontrolled trials were generally not used unless they filled important gaps in our understanding of anti-VEGF therapy. Ranibizumab is a recombinant humanized antibody fragment that binds all isoforms of VEGF-A with high affinity. Three parallel lines of clinical research have produced level I evidence supporting the superiority of ranibizumab over laser photocoagulation for the treatment of DME. Regular injections also lead to improvement in diabetic retinopathy severity scores in a large minority of eyes. Ranibizumab is effective for PDR and produces less visual field loss than laser photocoagulation. It has an excellent safety profile, with low incidence of ocular and systemic adverse events. Ranibizumab has become a frequently used first-line therapy for the treatment of DME. Emerging data suggest that it may become an important treatment for DR and PDR.

Drug delivery strategies for Alzheimer's disease treatment.

PubMed

Di Stefano, Antonio; Iannitelli, Antonio; Laserra, Sara; Sozio, Piera

2011-05-01

Current Alzheimer's disease (AD) therapy is based on the administration of the drugs donepezil, galantamine, rivastigmine and memantine. Until disease-modifying therapies become available, further research is needed to develop new drug delivery strategies to ensure ease of administration and treatment persistence. In addition to the conventional oral formulations, a variety of drug delivery strategies applied to the treatment of AD are reviewed in this paper, with a focus on strategies leading to simplified dosage regimens and to providing new pharmacological tools. Alternatives include extended release, orally disintegrating or sublingual formulations, intranasal or short- and long-acting intramuscular or transdermal forms, and nanotechnology-based delivery systems. The advent of new research on molecular mechanisms of AD pathogenesis has outlined new strategies for therapeutic intervention; these include the stimulation of α-secretase cleavage, the inhibition of γ-secretase activity, the use of non-steroidal anti-inflammatory drugs, neuroprotection based on antioxidant therapy, the use of estrogens, NO synthetase inhibitors, and natural agents such as polyphenols. Unfortunately, these compounds might not help patients with end stage AD, but might hopefully slow or stop the disease process in its early stage. Nanotechnologies may prove to be a promising contribution in future AD drug delivery strategies, in particular drug carrier nano- or microsystems, which can limit the side effects of anti-Alzheimer drugs.

Type 2 diabetes in youth from the Western Pacific region: glycaemic control, diabetes care and complications.

PubMed

Eppens, Maike C; Craig, Maria E; Jones, Timothy W; Silink, Martin; Ong, Stephanie; Ping, Yeo Jing

2006-05-01

To describe the glycaemic control, diabetes care and prevalence of complications in youth with type 2 diabetes from the Western Pacific Region. Cross-sectional, clinic-based audit of 331 patients aged < 18 years from 56 centres in Australia, China-Beijing, China-Shanghai, China-Hong Kong, Indonesia, Japan, South Korea, Malaysia, Philippines, Singapore, Taiwan and Thailand. Clinical and management data were recorded along with glycated haemoglobin (HbA(1c)), lipids and complication rates. Glycaemic control, complications, diabetes management. Median age was 14.9 years (interquartile range 13.2-16.4 years) and median diabetes duration 2.3 years (1.4-3.6 years). Median HbA(1c) was 7% (5.9-9.9%) and HbA(1c) was > 7.5% in 40% of patients. In multiple regression analysis, glycaemic control varied significantly between countries (p = 0.02); higher HbA(1c) was associated with fewer home blood glucose measurements (p = 0.005) and higher insulin dose/kg (p < 0.0001). Blood glucose monitoring was performed by 65% of patients (range 33-96% by country). In 25% of patients, management consisted of diet alone or no treatment (range 0-53% by country); oral anti-diabetic drugs alone were used in 49%, insulin alone in 11% and both in 15%. Microalbuminuria was found in 8% and hypertension in 24%. The risk of hypertension increased with higher BMI (OR 1.16, 95% CI 1.09-1.24, p < 0.0001); antihypertensive agents were used in 4% of patients. The management of type 2 diabetes in youth from the Western Pacific Region varies widely. Hypertension and microalbuminuria were frequent, but not commonly treated. Further investigation into the natural history and risk factors for complications in youth with type 2 diabetes is required to assist in developing evidence based management guidelines.

Evaluation of antidiabetic effect of total calystegines extracted from Hyoscyamus albus.

PubMed

Bourebaba, Lynda; Saci, Souaad; Touguit, Damia; Gali, Lynda; Terkmane, Schahinez; Oukil, Naima; Bedjou, Fatiha

2016-08-01

Hyoscyamus albus L. (Solanaceae) an old medicinal plant is a rich source of tropane and nortropane alkaloids which confers to this plant a number of very interesting and beneficial therapeutic effects. Calystegines that are polyhydroxylated alkaloids and imino-sugars poccess significant glycosidases inhibitory activities and are therefore good candidats for the treatment of diabetes mellitus. Calystegines extracted from Hyoscyamys albus seeds were tested for teir acute oral toxicity and investigated for their in-vivo antidiabetic effect on Streptozotocine induced diabetes in mice. Calystegines were extracted from the seeds plant using an Ion exchange column; the remaining extract was then administrated orally to mice at several single doses for acute toxicity assay. A dose of 130mg/kg streptozotocine was injected to mice to induce diabetes mellitus, and diabetic mice were treated orally during 20days with 10mg/kg and 20mg/kg calystegines and 20mg/kg glibenclamide as the reference drug. Acute oral toxicity showed that calystegines are not toxic up to a dose of 2000mg/kg with absence of any signs of intoxication and damages in Liver and kidney tissues. The nortropane alkaloids markedly reduced blood glucose levels and lipid parameters of diabetic mice to normal concentrations after 20days of treatment at 10mg/kg and 20mg/kg (p<0.05). Histopathological study of diabetic mice pancreas indicated that calystegines of Hyoscyamus albus have minimized streptozotocine damages on β-cells of islets of langerhans, stimulated β-cells regeneration and improved with this insulin secretion. The findings of this study suggest that calystegines are potent antidiabetic agents with antihyperglicemic and hypolipidemic effects, and a protective fonction on pancreas in streptozotocin induced diabetes in mice. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Development and Phytochemical Characterization of High Polyphenol Red Lettuce with Anti-Diabetic Properties

PubMed Central

Cheng, Diana M.; Pogrebnyak, Natalia; Kuhn, Peter; Krueger, Christian G.; Johnson, William D.; Raskin, Ilya

2014-01-01

Polyphenol-rich Rutgers Scarlet Lettuce (RSL) (Lactuca sativa L.) was developed through somaclonal variation and selection in tissue culture. RSL may contain among the highest reported contents of polyphenols and antioxidants in the category of common fruits and vegetables (95.6 mg/g dry weight and 8.7 mg/g fresh weight gallic acid equivalents and 2721 µmol/g dry weight and 223 µmol/g fresh weight Trolox equivalents). Three main compounds accumulate at particularly high levels in RSL: chlorogenic acid, up to 27.6 mg/g dry weight, cyanidin malonyl-glucoside, up to 20.5 mg/g dry weight, and quercetin malonyl-glucoside, up to 35.7 mg/g dry weight. Major polyphenolic constituents of RSL have been associated with health promotion as well as anti-diabetic and/or anti-inflammatory activities. Daily oral administration of RSL (100 or 300 mg/kg) for up to eight days acutely reduced hyperglycemia and improved insulin sensitivity in high fat diet-induced obese hyperglycemic mice compared to vehicle (water) control. Data presented here support possible use of RSL as a functional food for the dietary management of diabetes. PMID:24637790

Lenalidomide, an anti-tumor drug, regulates retinal endothelial cell function: Implication for treating ocular neovascular disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dong, Ling-Feng; Yao, Jin; Wang, Xiao-Qun

Ocular angiogenesis is an important pathologic character of several ocular diseases, such as retinopathy of prematurity, diabetic retinopathy and age-related macular degeneration (AMD). Inhibition of ocular angiogenesis has great therapeutic value for treating these dieses. Here we show that lenalidomide, an anti-tumor drug, has great anti-angiogenic potential in ocular diseases. Lenalidomide inhibits retinal endothelial cell viability in normal and pathological condition, and inhibits VEGF-induced endothelial cell migration and tube formation in vitro. Moreover, lenalidomide inhibits ocular angiogenesis in vivo through the reduction of angiogenesis- and inflammation-related protein expression. Collectively, lenalidomide is a promising drug for treating ocular angiogenesis through its anti-proliferative andmore » anti-inflammatory property. - Highlights: • Lenalidomide inhibits retinal endothelial cell viability in vitro. • Lenalidomide inhibits retinal endothelial cell migration and tube formation. • Lenalidomide inhibits pathological ocular angiogenesis in vivo. • Lenalidomide inhibits angiogenesis- and inflammation-related protein expression.« less

An Intestinal "Transformers"-like Nanocarrier System for Enhancing the Oral Bioavailability of Poorly Water-Soluble Drugs.

PubMed

Chuang, Er-Yuan; Lin, Kun-Ju; Huang, Tring-Yo; Chen, Hsin-Lung; Miao, Yang-Bao; Lin, Po-Yen; Chen, Chiung-Tong; Juang, Jyuhn-Huarng; Sung, Hsing-Wen

2018-06-06

Increasing the intestinal dissolution of orally administered poorly water-soluble drugs that have poor oral bioavailability to a therapeutically effective level has long been an elusive goal. In this work, an approach that can greatly enhance the oral bioavailability of a poorly water-soluble drug such as curcumin (CUR) is developed, using a "Transformers"-like nanocarrier system (TLNS) that can self-emulsify the drug molecules in the intestinal lumen to form nanoemulsions. Owing to its known anti-inflammation activity, the use of CUR in treating pancreatitis is evaluated herein. Structural changes of the TLNS in the intestinal environment to form the CUR-laden nanoemulsions are confirmed in vitro. The therapeutic efficacy of this TLNS is evaluated in rats with experimentally induced acute pancreatitis (AP). Notably, the CUR-laden nanoemulsions that are obtained using the proposed TLNS can passively target intestinal M cells, in which they are transcytosed and then transported into the pancreatic tissues via the intestinal lymphatic system. The pancreases in rats that are treated with the TLNS yield approximately 12 times stronger CUR signals than their counterparts receiving free CUR, potentially improving the recovery of AP. These findings demonstrate that the proposed TLNS can markedly increase the intestinal drug dissolution, making oral delivery a favorable noninvasive means of administering poorly water-soluble drugs.

A mathematical approach for the simultaneous in vitro spectrophotometric analysis of rifampicin and isoniazid from modified-release anti-TB drug delivery systems.

PubMed

du Toit, Lisa; Pillay, Viness; Choonara, Yahya

2010-01-01

Dissolution testing with subsequent analysis is considered as an imperative tool for quality evaluation of the combination rifampicin-isoniazid (RIF-INH) combination. Partial least squares (PLS) regression has been successfully undertaken to select suitable predictor variables and to identify outliers for the generation of equations for RIF and INH determination in fixed-dose combinations (FDCs). The aim of this investigation was to ascertain the applicability of the described technique in testing a novel oral FDC anti-TB drug delivery system and currently available two-drug FDCs, in comparison to the United States Pharmacopeial method for analysis of RIF and INH Capsules with chromatographic determination of INH and colorimetric RIF determination. Regression equations generated employing the statistical coefficients satisfactorily predicted RIF release at each sampling point (R(2)>or=0.9350). There was an acceptable degree of correlation between the drug release data, as predicted by regressional analysis of UV spectrophotometric data, and chromatographic and colorimetric determination of INH (R(2)=0.9793 and R(2)=0.9739) and RIF (R(2)= 0.9976 and R(2)=0.9996) for the two-drug FDC and the novel oral anti-TB drug delivery system, respectively. Regressional analysis of UV spectrophotometric data for simultaneous RIF and INH prediction thus provides a simplified methodology for use in diverse research settings for the assurance of RIF bioavailability from FDC formulations, specifically modified-release forms.

Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs

PubMed Central

Boukhatem, Mohamed Nadjib; Ferhat, Mohamed Amine; Kameli, Abdelkrim; Saidi, Fairouz; Kebir, Hadjer Tchoketch

2014-01-01

Background Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. Aims In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. Methods The chemical profile of LGEO as determined by gas chromatography–mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. Results LGEO exhibited promising antifungal effect against Candida albicans, C. tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35–90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. Conclusion Results of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of fungal infections and skin inflammation that should be explored in future studies. PMID:25242268

Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs.

PubMed

Boukhatem, Mohamed Nadjib; Ferhat, Mohamed Amine; Kameli, Abdelkrim; Saidi, Fairouz; Kebir, Hadjer Tchoketch

2014-01-01

Background Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. Aims In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. Methods The chemical profile of LGEO as determined by gas chromatography-mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. Results LGEO exhibited promising antifungal effect against Candida albicans, C.tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35-90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. Conclusion Results of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of fungal infections and skin inflammation that should be explored in future studies.

Lemon grass (Cymbopogon citratus) essential oil as a potent anti-inflammatory and antifungal drugs.

PubMed

Boukhatem, Mohamed Nadjib; Ferhat, Mohamed Amine; Kameli, Abdelkrim; Saidi, Fairouz; Kebir, Hadjer Tchoketch

2014-01-01

Volatile oils obtained from lemon grass [Cymbopogon citratus (DC.) Stapf, Poaceae family] are used in traditional medicine as remedies for the treatment of various diseases. In the present study, lemon grass essential oil (LGEO) was evaluated for its in vivo topical and oral anti-inflammatory effects, and for its in vitro antifungal activity using both liquid and vapor phases. The chemical profile of LGEO as determined by gas chromatography-mass spectrometry analysis revealed two major components: geranial (42.2%), and neral (31.5%). The antifungal activity of LGEO was evaluated against several pathogenic yeasts and filamentous fungi using disc diffusion and vapor diffusion methods. LGEO exhibited promising antifungal effect against Candida albicans, C. tropicalis, and Aspergillus niger, with different inhibition zone diameters (IZDs) (35-90 mm). IZD increased with increasing oil volume. Significantly, higher anti-Candida activity was observed in the vapor phase. For the evaluation of the anti-inflammatory effect, LGEO (10 mg/kg, administered orally) significantly reduced carrageenan-induced paw edema with a similar effect to that observed for oral diclofenac (50 mg/kg), which was used as the positive control. Oral administration of LGEO showed dose-dependent anti-inflammatory activity. In addition, topical application of LGEO in vivo resulted in a potent anti-inflammatory effect, as demonstrated by using the mouse model of croton oil-induced ear edema. To our knowledge, this is the first such report to be published. The topical application of LGEO at doses of 5 and 10 µL/ear significantly reduced acute ear edema induced by croton oil in 62.5 and 75% of the mice, respectively. In addition, histological analysis clearly confirmed that LGEO inhibits the skin inflammatory response in animal models. RESULTS of the present study indicate that LGEO has a noteworthy potential for the development of drugs for the treatment of fungal infections and skin inflammation that should be explored in future studies.

Development of a pharmacokinetic/pharmacodynamic/disease progression model in NC/Nga mice for development of novel anti-atopic dermatitis drugs.

PubMed

Baek, In-Hwan; Lee, Byung-Yo; Chae, Jung-Woo; Song, Gyu Yong; Kang, Wonku; Kwon, Kwang-Il

2014-11-01

1. JHL45, a novel immune modulator against atopic dermatitis (AD), was synthesized from decursin isolated from Angelica gigas. The goal is to evaluate the lead compound using quantitative modeling approaches to novel anti-AD drug development. 2. We tested the anti-inflammatory effect of JHL45 by in vitro screening, characterized its in vitro pharmacokinetic (PK) properties. The dose-dependent efficacy of JHL45 was developed using a pharmacokinetics/pharmacodynamics/disease progression (PK/PD/DIS) model in NC/Nga mice. 3. JHL45 has drug-like properties and pharmacological effects when administered orally to treat atopic dermatitis. The developed PK/PD/DIS model described well the rapid metabolism of JHL45, double-peak phenomenon in the PK of decursinol and inhibition of IgE generation by compounds in NC/Nga mice. Also, a quantitative model was developed and used to elucidate the complex interactions between serum IgE concentration and atopic dermatitis symptoms. 4. Our findings indicate that JHL45 has good physicochemical properties and powerful pharmacological effects when administered orally for treatment of AD in rodents.

Review of patient-reported outcome instruments measuring health-related quality of life and satisfaction in patients with type 2 diabetes treated with oral therapy.

PubMed

Roborel de Climens, Aude; Tunceli, Kaan; Arnould, Benoit; Germain, Nicola; Iglay, Kristy; Norquist, Josephine; Brodovicz, Kimberly G

2015-04-01

Treatments and their mode of administration may represent a burden for patients and can therefore impact their health-related quality of life (HRQL) or treatment/health satisfaction. Patients with type 2 diabetes mellitus (T2DM) can be treated with oral hypoglycemic agents (OHAs), injectable medications (such as insulin), or a combination of agents. This review aimed to identify patient-reported outcome (PRO) instruments measuring HRQL and/or satisfaction that could differentiate between oral medications based on medication related attributes such as efficacy, tolerability, weight loss, dosing frequency and pill burden. Medline, Embase, PsycINFO, Cochrane Library and the Patient-Reported Outcome and Quality of Life Questionnaires (PROQOLID) biomedical databases were searched to identify instruments and document their development methodology, content and psychometric properties (i.e. validity, reliability), responsiveness and ability to detect changes between treatments. Nineteen instruments were retained based on their potential to differentiate between OHAs. Ten instruments assessed HRQL, amongst which the Audit of Diabetes Dependent Quality of Life, Diabetes 39, Diabetes Health Profile and Impact of Weight on Quality of Life displayed good psychometric properties in T2DM populations and comprehensive HRQL content. Nine instruments assessed satisfaction. Both the Oral Hypoglycemic Agent Questionnaire (OHAQ) and Diabetes Medication Satisfaction (DiabMedSat) Questionnaire have highly relevant content regarding drug attributes. The OHAQ is specific to oral treatment and the DiabMedSat includes HRQL items. The Diabetes Treatment Satisfaction Questionnaire is a standard instrument that is extensively used and provides conclusive results in studies of patients with T2DM. Very few of the existing PRO instruments are specific to OHAs. Despite satisfaction instruments being recommended to differentiate between OHAs in studies of T2DM based on medication attributes, we find that none of the existing instruments appear to be useful in detecting differences between treatments, therefore limiting their use in clinical and observational research.

Rates and reasons for lack of persistence with anti-osteoporotic drugs: analysis of the Campania region database.

PubMed

Iolascon, Giovanni; Gimigliano, Francesca; Moretti, Antimo; Riccio, Ilaria; Di Gennaro, Massimo; Illario, Maddalena; Monetti, Valeria Marina; Orlando, Valentina; Menditto, Enrica

2016-01-01

Subjects with chronic diseases are more likely to be nonpersistent to pharmacological treatment. Lack of persistence is common among subjects using oral anti-osteoporotic drugs, and leads to increased risk of fragility fracture. The aim of our retrospective study is to analyze the rates and reasons for discontinuation of anti-osteoporotic drugs in the Campania Region. Subjects aged over 40 years were included if they had received at least one prescription for any anti-osteoporotic drugs. Data were obtained from an administrative database of regional data on outpatient drug prescriptions reimbursed by the National Health Service. Patients were followed until the discontinuation of anti-osteoporotic therapy or until the end of the observation period. A total of 30,048 were incident users of anti-osteoporotic drugs: 28,317 (94.2%) females. The mean age of the cohort was 69.0±10.0 years. Weekly bis-phosphonates (51.1%) were the most commonly prescribed drugs. In the overall population, persistence rates were 34.8% after 6 months and 13.4% at one year. A multivariate Cox proportional hazard analysis showed that daily regimen (HR 1.9) treatments remained at higher risk of early discontinuation compared to weekly regimen therapies. Our data showed that the persistence to osteoporosis therapy is significantly worse than reported in literature.

Curcumin-mediated regulation of intestinal barrier function: The mechanism underlying its beneficial effects.

PubMed

Ghosh, Siddhartha S; He, Hongliang; Wang, Jing; Gehr, Todd W; Ghosh, Shobha

2018-01-02

Curcumin has anti-inflammatory, anti-oxidant and anti-proliferative properties established largely by in vitro studies. Accordingly, oral administration of curcumin beneficially modulates many diseases including diabetes, fatty-liver disease, atherosclerosis, arthritis, cancer and neurological disorders such as depression, Alzheimer's or Parkinson's disease. However, limited bioavailability and inability to detect curcumin in circulation or target tissues has hindered the validation of a causal role. We established curcumin-mediated decrease in the release of gut bacteria-derived lipopolysaccharide (LPS) into circulation by maintaining the integrity of the intestinal barrier function as the mechanism underlying the attenuation of metabolic diseases (diabetes, atherosclerosis, kidney disease) by curcumin supplementation precluding the need for curcumin absorption. In view of the causative role of circulating LPS and resulting chronic inflammation in the development of diseases listed above, this review summarizes the mechanism by which curcumin affects the several layers of the intestinal barrier and, despite negligible absorption, can beneficially modulate these diseases.

Effects of diabetes definition on global surveillance of diabetes prevalence and diagnosis: a pooled analysis of 96 population-based studies with 331,288 participants.

PubMed

2015-08-01

Diabetes has been defined on the basis of different biomarkers, including fasting plasma glucose (FPG), 2-h plasma glucose in an oral glucose tolerance test (2hOGTT), and HbA1c. We assessed the effect of different diagnostic definitions on both the population prevalence of diabetes and the classification of previously undiagnosed individuals as having diabetes versus not having diabetes in a pooled analysis of data from population-based health examination surveys in different regions. We used data from 96 population-based health examination surveys that had measured at least two of the biomarkers used for defining diabetes. Diabetes was defined using HbA1c (HbA1c ≥6·5% or history of diabetes diagnosis or using insulin or oral hypoglycaemic drugs) compared with either FPG only or FPG-or-2hOGTT definitions (FPG ≥7·0 mmol/L or 2hOGTT ≥11·1 mmol/L or history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated diabetes prevalence, taking into account complex survey design and survey sample weights. We compared the prevalences of diabetes using different definitions graphically and by regression analyses. We calculated sensitivity and specificity of diabetes diagnosis based on HbA1c compared with diagnosis based on glucose among previously undiagnosed individuals (ie, excluding those with history of diabetes or using insulin or oral hypoglycaemic drugs). We calculated sensitivity and specificity in each survey, and then pooled results using a random-effects model. We assessed the sources of heterogeneity of sensitivity by meta-regressions for study characteristics selected a priori. Population prevalence of diabetes based on FPG-or-2hOGTT was correlated with prevalence based on FPG alone (r=0·98), but was higher by 2-6 percentage points at different prevalence levels. Prevalence based on HbA1c was lower than prevalence based on FPG in 42·8% of age-sex-survey groups and higher in another 41·6%; in the other 15·6%, the two definitions provided similar prevalence estimates. The variation across studies in the relation between glucose-based and HbA1c-based prevalences was partly related to participants' age, followed by natural logarithm of per person gross domestic product, the year of survey, mean BMI, and whether the survey population was national, subnational, or from specific communities. Diabetes defined as HbA1c 6·5% or more had a pooled sensitivity of 52·8% (95% CI 51·3-54·3%) and a pooled specificity of 99·74% (99·71-99·78%) compared with FPG 7·0 mmol/L or more for diagnosing previously undiagnosed participants; sensitivity compared with diabetes defined based on FPG-or-2hOGTT was 30·5% (28·7-32·3%). None of the preselected study-level characteristics explained the heterogeneity in the sensitivity of HbA1c versus FPG. Different biomarkers and definitions for diabetes can provide different estimates of population prevalence of diabetes, and differentially identify people without previous diagnosis as having diabetes. Using an HbA1c-based definition alone in health surveys will not identify a substantial proportion of previously undiagnosed people who would be considered as having diabetes using a glucose-based test. Wellcome Trust, US National Institutes of Health. Copyright © 2015 NCD Risk Factor Collaboration. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.

TRX-4 (TolerRx Inc).

PubMed

Brown, William M

2006-04-01

TolerRx Inc, under license from BTG plc, is developing TRX-4, an anti-CD3 humanized monoclonal antibody for the potential treatment of type 1 diabetes and psoriasis. Phase II trials of the therapeutic antibody in type 1 diabetes have been completed and the company is planning a pivotal phase III trial for this indication. TolerRx is also enrolling psoriasis patients in a phase Ib clinical study of TRX-4. TRX-4 has been awarded Orphan Drug status for recent-onset type 1 diabetes.

Effect of tangeretin, a polymethoxylated flavone on glucose metabolism in streptozotocin-induced diabetic rats.

PubMed

Sundaram, Ramalingam; Shanthi, Palanivelu; Sachdanandam, Panchanatham

2014-05-15

The present study was designed to evaluate the antihyperglycemic potential of tangeretin on the activities of key enzymes of carbohydrate and glycogen metabolism in control and streptozotocin induced diabetic rats. The daily oral administration of tangeretin (100mg/kg body weight) to diabetic rats for 30 days resulted in a significant reduction in the levels of plasma glucose, glycosylated hemoglobin (HbA1c) and increase in the levels of insulin and hemoglobin. The altered activities of the key enzymes of carbohydrate metabolism such as hexokinase, pyruvate kinase, lactate dehydrogenase, glucose-6-phosphatase, fructose-1,6-bisphosphatase, glucose-6-phosphate dehydrogenase, glycogen synthase and glycogen phosphorylase in liver of diabetic rats were significantly reverted to near normal levels by the administration of tangeretin. Further, tangeretin administration to diabetic rats improved hepatic glycogen content suggesting the antihyperglycemic potential of tangeretin in diabetic rats. The effect produced by tangeretin on various parameters was comparable to that of glibenclamide - a standard oral hypoglycemic drug. Thus, these results show that tangeretin modulates the activities of hepatic enzymes via enhanced secretion of insulin and decreases the blood glucose in streptozotocin induced diabetic rats by its antioxidant potential. Copyright © 2014 Elsevier GmbH. All rights reserved.

Computational and Pharmacological Evaluation of Ferrocene-Based Acyl Ureas and Homoleptic Cadmium Carboxylate Derivatives for Anti-diabetic Potential.

PubMed

Bano, Shahar; Khan, Arif-Ullah; Asghar, Faiza; Usman, Muhammad; Badshah, Amin; Ali, Saqib

2017-01-01

We investigated possible anti-diabetic effect of ferrocene-based acyl ureas: 4-ferrocenyl aniline (PFA), 1-(4-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DPC1), 1-(3-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DMC1), 1-(2-chlorobenzoyl)-3-(4-ferrocenylphenyl) urea (DOC1) and homoleptic cadmium carboxylates: bis (diphenylacetato) cadmium (II) (DPAA), bis (4-chlorophenylacetato) cadmium (II) (CPAA), using in silico and in vivo techniques. PFA, DPC1, DMC1, DOC1, DPAA and CPAA exhibited high binding affinities (ACE ≥ -350 Kcal/mol) against targets: aldose reductase, peroxisome proliferator-activated receptor γ, 11β-hydroxysteroid dehydrogenase-1, C-alpha glucosidase and glucokinase, while showed moderate affinities (ACE ≥ -250 Kcal/mol) against N-alpha glucosidase, dipeptidyl peptidase-IV, phosphorylated-Akt, glycogen synthase kinase-3β, fructose-1,6-bisphosphatase and phosphoenolpyruvate carboxykinase, whereas revealed lower affinities (ACE < -250 Kcal/mol) vs. alpha amylase, protein tyrosine phosphatases 1B, glycogen phosphorylase and phosphatidylinositol 3 kinase. In alloxan (300 mg/Kg)-induced diabetic mice, DPAA and DPC1 (1-10 mg/Kg) at day 1, 5, 10, 15, and 20th decreased blood glucose levels, compared to diabetic control group and improved the treated animals body weight. DPAA (10 mg/Kg) and DPC1 (5 mg/Kg) in time-dependent manner (30-120 min.) enhanced tolerance of oral glucose overload in mice. DPAA and DPCI dose-dependently at 1, 5, and 10 mg/Kg decreased glycosylated hemoglobin levels in diabetic animals, as caused by metformin. These results indicate that aforementioned derivatives of ferrocene and cadmium possess anti-diabetic potential.

Efficacy and safety of once-weekly oral trelagliptin switched from once-daily dipeptidyl peptidase-4 inhibitor in patients with type 2 diabetes mellitus: An open-label, phase 3 exploratory study.

PubMed

Inagaki, Nobuya; Sano, Hiroki; Seki, Yoshifumi; Kuroda, Shingo; Kaku, Kohei

2018-03-01

Trelagliptin, a novel once-weekly oral dipeptidyl peptidase-4 (DPP-4) inhibitor, has shown favorable efficacy and safety in type 2 diabetes mellitus patients. Trelagliptin was launched in Japan, and is expected to be initially used for switchover from a daily DPP-4 inhibitor in the clinical setting. Thus, the present study was carried out to explore the efficacy and safety of trelagliptin after a daily DPP-4 inhibitor was switched to it. This was an open-label, phase 3 exploratory study to evaluate the efficacy and safety of trelagliptin in Japanese type 2 diabetes mellitus patients who had stable glycemic control on once-daily sitagliptin therapy. Eligible patients received trelagliptin 100 mg orally before breakfast once a week for 12 weeks. The primary end-point was blood glucose by the meal tolerance test, and additional end-points were glycemic control (efficacy) and safety. Altogether, 14 patients received the study drug. The blood glucose did not markedly change from baseline at major assessment points in the meal tolerance test, and a decrease in blood glucose was observed at several other assessment points. Adverse events were reported in 42.9% (6/14) of patients, but all adverse events were mild or moderate in severity, and most were not related to the study drug. No cases of death, serious adverse events or hypoglycemia were reported. It is considered possible to switch a once-daily DPP-4 inhibitor to trelagliptin in type 2 diabetes mellitus patients with stable glycemic control in combination with diet and exercise therapy without any major influences on glycemic control or safety. © 2017 The Authors. Journal of Diabetes Investigation published by Asian Association for the Study of Diabetes (AASD) and John Wiley & Sons Australia, Ltd.

Neglected disease - african sleeping sickness: recent synthetic and modeling advances.

PubMed

Paliwal, Sarvesh K; Verma, Ankita Narayan; Paliwal, Shailendra

2011-01-01

Human African Trypanosomiasis (HAT) also called sleeping sickness is caused by subspecies of the parasitic hemoflagellate Trypanosoma brucei that mostly occurs in sub-Saharan Africa. The current chemotherapy of the human trypanosomiases relies on only six drugs, five of which have been developed more than 30 years ago, have undesirable toxic side effects and most of them show drug-resistance. Though development of new anti-trypanosomal drugs seems to be a priority area research in this area has lagged far behind. The given review mainly focus upon the recent synthetic and computer based approaches made by various research groups for the development of newer anti-trypanosomal analogues which may have improved efficacy and oral bioavailability than the present ones. The given paper also attempts to investigate the relationship between the various physiochemical parameters and anti-trypanosomal activity that may be helpful in development of potent anti-trypanosomal agents against sleeping sickness.

Gallic acid and p-coumaric acid attenuate type 2 diabetes-induced neurodegeneration in rats.

PubMed

Abdel-Moneim, Adel; Yousef, Ahmed I; Abd El-Twab, Sanaa M; Abdel Reheim, Eman S; Ashour, Mohamed B

2017-08-01

The brain of diabetics revealed deterioration in many regions, especially the hippocampus. Hence, the present study aimed to evaluate the effects of gallic acid and p-coumaric acid against the hippocampal neurodegeneration in type 2 diabetic rats. Adult male albino rats were randomly allocated into four groups: Group 1 served as control ones and others were induced with diabetes. Group 2 considered as diabetic, and groups 3 and 4 were further orally treated with gallic acid (20 mg/kg b.wt./day) and p-coumaric acid (40 mg/kg b.wt./day) for six weeks. Diabetic rats revealed significant elevation in the levels of serum glucose, blood glycosylated hemoglobin and serum tumor necrosis factor-α, while the level of serum insulin was significantly declined. Furthermore, the brain of diabetic rats showed a marked increase in oxidative stress and a decrease of antioxidant parameters as well as upregulation the protein expression of Bax and downregulation the protein expression of Bcl-2 in the hippocampus. Treatment of diabetic rats with gallic acid and p-coumaric acid significantly ameliorated glucose tolerance, diminished the brain oxidative stress and improved antioxidant status, declined inflammation and inhibited apoptosis in the hippocampus. The overall results suggested that gallic acid and p-coumaric acid may inhibit hippocampal neurodegeneration via their potent antioxidant, anti-inflammatory and anti-apoptotic properties. Therefore, both compounds can be recommended as hopeful adjuvant agents against brain neurodegeneration in diabetics.

Momordica charantia polysaccharides mitigate the progression of STZ induced diabetic nephropathy in rats.

PubMed

Raish, Mohammad; Ahmad, Ajaz; Jan, Basit L; Alkharfy, Khalid M; Ansari, Mushtaq Ahmad; Mohsin, Kazi; Jenoobi, Fahad Al; Al-Mohizea, Abdullah

2016-10-01

Diabetic nephropathy (DN) has become a primary cause of end-stage kidney disease. Several complex dynamics converge together to accelerate the advancement of DN. The present investigation was postulated to explore the mechanism of reno-protective nature of Momordica Charantia polysaccharides (MCP) by evaluating the anti-hyperglycemic, anti-lipidemic as well as markers for oxidative stress and antioxidant proficiency in streptozotocin (STZ)-induced diabetic rats. The oral administration of MCP showed a significant normalization in the levels of kidney function test in the STZ-induced diabetic rats. The levels of blood urea nitrogen (BUN), urea protein and creatinine increased by 316.58%, 195.14% and 800.97% respectively, in STZ-induced diabetic rats when compared with normal rats. MCP treatment also illustrated a significant improvement in glutathione peroxidase, superoxide dismutase and catalase levels, with a significant decline in MDA in diabetic kidneys. Immunoblots of heme-oxygenase 1 (HO-1) and Nrf2 of MCP treated diabetic rats showed a significant up-regulation of HO-1 and Nrf2 protein. Histological and ultra-structural observations also reveal that MCP efficiently protects the kidneys from hyperglycemia-mediated oxidative damage. These findings illustrate that the reno-protective nature of MCP mitigates the progression of STZ induced DN in rats by suppression of oxidative stress and amelioration of the HO-1/Nrf2 pathway. Copyright © 2016 Elsevier B.V. All rights reserved.

Physicochemical properties and oral bioavailability of ursolic acid nanoparticles using supercritical anti-solvent (SAS) process.

PubMed

Yang, Lei; Sun, Zhen; Zu, Yuangang; Zhao, Chunjian; Sun, Xiaowei; Zhang, Zhonghua; Zhang, Lin

2012-05-01

The objective of the study was to prepare ursolic acid (UA) nanoparticles using the supercritical anti-solvent (SAS) process and evaluate its physicochemical properties and oral bioavailability. The effects of four process variables, pressure, temperature, drug concentration and drug solution flow rate, on drug particle formation during SAS process, were investigated. Particles with mean particle size ranging from 139.2±19.7 to 1039.8±65.2nm were obtained by varying the process parameters. The UA was characterised by scanning electron microscopy, X-ray diffraction, Fourier-transform infrared spectroscopy, thermal gravimetric analysis, specific surface area, dissolution test and bioavailability test. It was concluded that physicochemical properties and bioavailability of crystalline UA could be improved by physical modification, such as particle size reduction and generation of amorphous state using SAS process. Further, SAS process was a powerful methodology for improving the physicochemical properties and bioavailability of UA. Copyright © 2011 Elsevier Ltd. All rights reserved.

Broad bean (Vicia faba L.) pods: a rich source of bioactive ingredients with antimicrobial, antioxidant, enzyme inhibitory, anti-diabetic and health-promoting properties.

PubMed

Mejri, Faiza; Selmi, Slimen; Martins, Alice; Benkhoud, Haifa; Baati, Tarek; Chaabane, Hedia; Njim, Leila; Serralheiro, Maria L M; Rauter, Amélia P; Hosni, Karim

2018-04-25

This study was aimed at investigating the chemical composition (proximate, minerals, fatty acids and phenolic compounds) and the in vitro (antimicrobial, radical scavenging, anti-acetylcholinesterase and protein denaturing activities) and in vivo (anti-diabetic and histo-protective effects in alloxan-induced diabetic mice) biological activities of broad bean pods (BBPs), a food waste by-product material. The results showed that BBPs have high dietary fiber (57.46%), carbohydrate (18.93%) and protein (13.81%) content versus low fat content (<1%) contributing to a low energy value of 139.24 kcal per 100 g. Profiling of fatty acids showed an abundance of the essential polyunsaturated α-linolenic and linoleic acids, exhibiting an excellent nutritional quality as revealed by their low atherogenic and thrombogenic indices and their hypocholesterolemic properties. The methanol extract which exhibited the highest total phenolic, flavonoid and tannin contents was found to be the most active extract in terms of antimicrobial and anti-radical activities. In alloxan-induced diabetic mice, the oral administration of a methanol extract (500 mg per kg bw) attenuated the elevated levels of serum alanine aminotransferase (ALA), aspartate aminotransferase (AST), and alkaline phosphatase activities, and urea, uric acid, and creatinine. It effectively normalized the status of lipid profiles, mitigated oxidative stress through the activation of antioxidant enzymes (CAT, GPx and SOD), and alleviated oxidative stress-mediated histopathological changes in the pancreas, liver, kidney and testis. Compositional analysis by HPLC-PDA-ESI-MS/MS revealed the presence of flavan-3-ols (catechin, epicatechin and their derivatives), flavones (apigenin derivatives) and flavonols (glycosides of quercetin and kaempferol), among others. These findings suggest that BBPs may be an effective functional food for the management of diabetes and its complications.

Combined effects of fangchinoline from Stephania tetrandra Radix and formononetin and calycosin from Astragalus membranaceus Radix on hyperglycemia and hypoinsulinemia in streptozotocin-diabetic mice.

PubMed

Ma, Wenjie; Nomura, Masaaki; Takahashi-Nishioka, Tatsuo; Kobayashi, Shinjiro

2007-11-01

The anti-hyperglycemic action of Stephania tetrandra Radix (Stephania) is potentiated by Astragalus membranaceus BUNGE Radix (Astragali) in streptozotocin (STZ)-diabetic ddY mice (Tsutsumi et al., Biol. Pharm. Bull., 26, 313 (2003)). Fangchinoline (0.3-3 mg/kg), a main constituent of Stephania, decreased the high level of blood glucose and increased the low level of blood insulin in STZ-diabetic mice. Here, we investigated the combined effects of fangchinoline with isoflavone or isoflavonoid components (formononetin, calycosin and ononin) of Astragali on the hyperglycemia and hypoinsulinemia of STZ-diabetic mice. Formononetin, calycosin and ononin (0.03-0.1 mg/kg) alone did not affect the blood glucose or blood insulin level of the diabetic mice. Formononetin and calycosin (0.03-0.1 mg/kg) potentiated the anti-hyperglycemic action of fangchinoline (0.3 mg/kg), but ononin did not. Formononetin (0.1 mg/kg) facilitated the fangchinoline-induced insulin release, and calycosin (0.1 mg/kg) also facilitated it, though without statistical significance. In conclusion, the combined effect of fangchinoline with formononetin and calycosin on hyperglycemia in the diabetic mice accounted well for the therapeutic effect of the combination of Stephania with Astragali in Boi-ogi-to. The anti-hyperglycemic action of formononetin appeared to be due to its potentiating action on insulin release. Our strategy for studying combinations of crude drugs and their components in Kampo medicine has uncovered new potentiating effects of formononetin and calycosin on the anti-hyperglycemic action of fangchinoline in STZ-diabetic mice.

Spirulina platensis prevents hyperglycemia in rats by modulating gluconeogenesis and apoptosis via modification of oxidative stress and MAPK-pathways.

PubMed

Sadek, Kadry M; Lebda, Mohamed A; Nasr, Sherif M; Shoukry, Moustafa

2017-08-01

Spirulina platensis (SP) is a microalga with antioxidant, antidiabetic and anti-inflammatory properties. The present study explored the ability and potential mechanism(s) by which SP induced glucose lowering impact in diabetic rat model. Forty rats were allocated into four groups: control; streptozotocin (STZ)-induced diabetes (STZ, 45mg/kg b.w., intraperitoneally); SP (500mg/kg b.w., orally twice weekly for 2 months) and STZ-induced diabetes+SP group. In the STZ-induced diabetic rats, SP significantly decreased (P>0.05) serum glucose, glycated hemoglobin (HbA1c), malondialdehyde (MDA) levels and significantly increased (P>0.05) serum insulin, the activity of antioxidant enzymes and normalized their mRNA gene expression. Furthermore, SP attenuates STZ-induced upregulation of the gluconeogenic enzyme pyruvate carboxylase (PC), the pro-apoptotic Bax and caspase-3 (CASP-3), tumor necrosis factor alpha (TNF-α) gene expression. The Western blot results revealed that, SP induced downregulation of mitogen activated protein kinase pathway (MAPK) protein expression in hepatic tissues of diabetic rats. Additionally, SP reestablished the typical histological structure of the liver and pancreas of diabetic rats. Acute toxicity study further shows that SP is relatively safe. This study demonstrates that SP is rich in antioxidant compounds and has powerful glucose lowering effect through the normalization of increased hepatic PC gene expression. Interestingly, SP induced recovery of damaged hepatocytes and pancreatic β-cells via its anti-inflammatory, antioxidant and anti-apoptotic properties. The MAPK signaling cascade is a pivotal component of the proapoptotic signaling pathway induced by diabetes mellitus. MAPK activation may be dependent from ROS production, since SP which exhibited antioxidant activities did have a significant impact on MAPK activity. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

The impact of new insights and revised practice guidelines on prescribing drugs in the treatment of Type 2 diabetes mellitus

PubMed Central

Lub, René; Denig, Petra; van den Berg, Paul B; Hoogenberg, Klaas; de Jong-van den Berg, Lolkje T W

2006-01-01

Aims The aim of this study was to investigate the impact of new insights and revised guidelines on initial and follow-up treatment with antihyperglycaemic drugs over the period 1998–2003. Methods The InterAction Database (IADB), which contains pharmacy dispensing data from 53 community pharmacies in the Northern and Eastern part of the Netherlands, was used in this study. Prevalence and incidence rates of oral antihyperglycaemic drug use were calculated for each year. Follow-up treatment was compared for two cohorts of initial users of oral antihyperglycaemic drugs, starting treatment either 1 year before or 1 year after guideline revision. Results The prevalence and incidence rate of oral antihyperglycaemic drug use increased over the study period from 1.8% to 2.4% (P < 0.001) and 0.3% to 0.4% (P= 0.04). The proportion of metformin as initial treatment increased rapidly in the observation period from 14% to 50% (P < 0.001). Initial users of metformin in 2000 received additional treatment with a sulphonylurea in the follow-up period less often compared with those who started metformin in 1998 (46%vs. 60%, P < 0.004). In contrast, initial users of sulphonylurea in 2000 received additional treatment with metformin more often compared with those who started a sulphonylurea in 1998 (42%vs. 36%, P < 0.008). The new drugs, thiazolidinediones and meglitinides, were seldom used as initial treatment Conclusions New insights and the revision of the practice guideline were followed by a significant increase in both initial and follow-up treatment with metformin among patients with Type 2 diabetes mellitus. PMID:16796700

Risk of new acute myocardial infarction hospitalization associated with use of oral and parenteral non-steroidal anti-inflammation drugs (NSAIDs): a case-crossover study of Taiwan's National Health Insurance claims database and review of current evidence.

PubMed

Shau, Wen-Yi; Chen, Hsi-Chieh; Chen, Shu-Ting; Chou, Hsu-Wen; Chang, Chia-Hsuin; Kuo, Chuei-Wen; Lai, Mei-Shu

2012-02-02

Previous studies have documented the increased cardiovascular risk associated with the use of some nonsteroidal anti-inflammatory drugs (NSAIDs). Despite this, many old NSAIDs are still prescribed worldwide. Most of the studies to date have been focused on specific oral drugs or limited by the number of cases examined. We studied the risk of new acute myocardial infarction (AMI) hospitalization with current use of a variety of oral and parenteral NSAIDs in a nationwide population, and compared our results with existing evidence. We conducted a case-crossover study using the Taiwan's National Health Insurance claim database, identifying patients with new AMI hospitalized in 2006. The 1-30 days and 91-120 days prior to the admission were defined as case and matched control period for each patient, respectively. Uses of NSAIDs during the respective periods were compared using conditional logistic regression and adjusted for use of co-medications. 8354 new AMI hospitalization patients fulfilled the study criteria. 14 oral and 3 parenteral NSAIDs were selected based on drug utilization profile among 13.7 million NSAID users. The adjusted odds ratio, aOR (95% confidence interval), for risk of AMI and use of oral and parenteral non-selective NSAIDs were 1.42 (1.29, 1.56) and 3.35 (2.50, 4.47), respectively, and significantly greater for parenteral than oral drugs (p for interaction<0.01). Ketorolac was associated with the highest AMI risk among both of oral and parenteral NSAIDs studied, the aORs were 2.02 (1.00, 4.09) and 4.27 (2.90, 6.29) respectively. Use of oral flurbiprofen, ibuprofen, sulindac, diclofenac, and parenteral ketoprofen were also significantly associated with increased AMI risk. The results of the present study were consistent with the majority of evidence from previous studies. The collective evidence revealed the tendency of increased AMI risk with current use of some NSAIDs. A higher AMI risk associated with use of parenteral NSAIDs was observed in the present study. Ketorolac had the highest associated risk in both oral and parenteral NSAIDs studied. Though further investigation to confirm the association is warranted, prescribing physicians and the general public should be cautious about the potential risk of AMI when using NSAIDs.

Pancreatic regulation of glucose homeostasis

PubMed Central

Röder, Pia V; Wu, Bingbing; Liu, Yixian; Han, Weiping

2016-01-01

In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed. PMID:26964835

Dangerous triplet: Polycystic ovary syndrome, oral contraceptives and Kounis syndrome.

PubMed

Erol, Nurdan; Karaagac, Aysu Turkmen; Kounis, Nicholas G

2014-12-26

Polycystic ovary syndrome is characterized by ovulatory dysfunction, androgen excess and polycystic ovaries and is associated with hypertension, diabetes, metabolic syndrome and cardiovascular events. Oral contraceptives constitute first-line treatment, particularly when symptomatic hyperandrogenism is present. However, these drugs are associated with cardiovascular events and hypersensitivity reactions that pose problem in differential diagnosis and therapy. We present a 14 year-old female with polycystic ovary syndrome taking oral contraceptive and suffering from recurrent coronary ischemic attacks with increased eosinophils, and troponin levels suggesting Kounis syndrome.

Effect of race and ethnicity on vildagliptin efficacy: A pooled analysis of phase II and III studies.

PubMed

Kozlovski, Plamen; Fonseca, Marilia; Mohan, Viswanathan; Lukashevich, Valentina; Odawara, Masato; Paldánius, Päivi M; Kothny, Wolfgang

2017-03-01

To determine the impact of race and ethnicity on the efficacy, body weight and hypoglycaemia incidence with vildagliptin treatment in patients with type 2 diabetes mellitus using patient-level data from the vildagliptin clinical trial programme. Data from 22 randomized, placebo-controlled global and local (Japan, China) registration studies of vildagliptin (50 mg once-daily or twice-daily) of ≥12-week duration were analysed by race (Caucasian [n = 2764] and Asian [n = 2232]) and by ethnicity (Japanese, Chinese, and Indian). The placebo-subtracted differences in the change in glycated haemoglobin (HbA1c) and body weight from baseline to week 12 or week 24 were evaluated by race or ethnicity using repeated measure analysis of unstructured covariance. Hypoglycaemia incidences were summarized using descriptive statistics. The HbA1c reduction from baseline with vildagliptin was similar across the racial/ethnic subgroups (-0.83% ± 0.02% to -1.01% ± 0.05%). Placebo-corrected HbA1c reduction was similar between Caucasian (-0.68% ± 0.03%) and Asian (-0.80% ± 0.03%) patients ( P value for interaction = .56); analysis by race and ethnicity showed better efficacy ( P < .02) in Japanese patients. Japanese patients were drug-naïve and treated with a single oral anti-diabetes drug only; they showed no response to placebo. Weight neutrality of vildagliptin was demonstrated in all groups (0.47 ± 0.11 kg to -0.29 ± 0.08 kg). Hypoglycaemic events (≥1) were infrequent in all ethnic subgroups. The glycaemic efficacy of vildagliptin was similar in Caucasian and Asian patients. The slightly better efficacy observed in Japanese patients was driven by the absence of placebo effect and might be explained by their earlier stage of diabetes compared to other subgroups. © 2016 Novartis Pharma AG. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.

The socio-political roots of pharmaceutical uncertainty in the evaluation of 'innovative' diabetes drugs in the European Union and the US.

PubMed

Davis, Courtney; Abraham, John

2011-05-01

The prevalence of diabetes is growing in many countries. Prescription oral medications have been developed to treat the disease since the 1950s. More recently, a group of diabetes drugs, known as the glitazones, have been developed and introduced on to North American and European markets since the late 1990s. When first introduced, the glitazones were widely regarded as 'innovative' pharmaceuticals and have remained on the American and EU markets, among others, throughout the 2000s. Yet, enormous uncertainties about their therapeutic value have remained since they came on the market a decade ago. This paper investigates how socio-political systems of drug development and regulation generate such pharmaceutical uncertainty consequent upon the limited informational value that diabetes drug trials provide about the health risks and benefits of such medications when used in clinical practice. Drawing on documentary research and fieldwork interviews, the first in-depth analysis of regulation of 'innovative' pharmaceuticals in both the US and supranational EU is presented. It is argued that these pharmaceutical uncertainties can be explained by reference to four key factors: regulatory paradigms using surrogate markers for drug efficacy; drug approval standards in policy and legislation; ideological expectations of innovation within regulatory agencies; and pharmaceutical industry shaping of drug evaluation. Copyright © 2011 Elsevier Ltd. All rights reserved.

[Impact of anti-diabetic therapy based on glucagon-like peptide-1 receptor agonists on the cardiovascular risk of patients with type 2 diabetes mellitus].

PubMed

Camafort-Babkowski, Miguel

2013-08-17

Anti-diabetic drugs have, in addition to their well-known glucose lowering-effect, different effects in the rest of cardiovascular factors that are associated with diabetes mellitus. Glucagon-like peptide-1 (GLP-1) receptor agonists have recently been incorporated to the therapeutic arsenal of type 2 diabetes mellitus. The objective of this review is to summarize the available evidence on the effect of the GLP-1 receptor agonists on different cardiovascular risk factors, mediated by the effect of GLP-1 receptor agonists on the control of hyperglycaemia and the GLP-1 receptor agonists effect on other cardiovascular risk factors (weight control, blood pressure control, lipid profile and all other cardiovascular risk biomarkers). In addition, we present the emerging evidence with regards to the impact that GLP-1 receptor agonists therapy could have in the reduction of cardiovascular events and the currently ongoing studies addressing this issue. Copyright © 2012 Elsevier España, S.L. All rights reserved.

In vitro callus and in vivo leaf extract of Gymnema sylvestre stimulate β-cells regeneration and anti-diabetic activity in Wistar rats.

PubMed

Ahmed, A Bakrudeen Ali; Rao, A S; Rao, M V

2010-11-01

A methanol extract of Gymnema sylvestre leaf and callus showed anti-diabetic activities through regenerating β-cells. Optimum callus was developed under stress conditions of blue light with 2,4-D (1.5 mg/l) and KN (0.5 mg/l), which induced maximum biomass of green compact callus at 45 days, as determined by growth curve analysis. Leaf and optimum callus extracts contains gymnemic acid, which was analyzed using TLC, HPTLC and HPLC methods. The research reported here deals with leaf and callus extracts of G. sylvestre, which significantly increase the weight of the whole body, liver, pancreas and liver glycogen content in alloxan-induced diabetic rats (Wistar rats). The gymnemic acid of leaf and callus extracts significantly increases the regeneration of β-cells in treated rats, when compared with the standard diabetic rats. It could have potential as a pharmaceutical drug for insulin-dependent diabetes mellitus (IDDM). Copyright © 2010 Elsevier GmbH. All rights reserved.

Utility of genetic and non-genetic risk factors in prediction of type 2 diabetes: Whitehall II prospective cohort study.

PubMed

Talmud, Philippa J; Hingorani, Aroon D; Cooper, Jackie A; Marmot, Michael G; Brunner, Eric J; Kumari, Meena; Kivimäki, Mika; Humphries, Steve E

2010-01-14

To assess the performance of a panel of common single nucleotide polymorphisms (genotypes) associated with type 2 diabetes in distinguishing incident cases of future type 2 diabetes (discrimination), and to examine the effect of adding genetic information to previously validated non-genetic (phenotype based) models developed to estimate the absolute risk of type 2 diabetes. Workplace based prospective cohort study with three 5 yearly medical screenings. 5535 initially healthy people (mean age 49 years; 33% women), of whom 302 developed new onset type 2 diabetes over 10 years. Non-genetic variables included in two established risk models-the Cambridge type 2 diabetes risk score (age, sex, drug treatment, family history of type 2 diabetes, body mass index, smoking status) and the Framingham offspring study type 2 diabetes risk score (age, sex, parental history of type 2 diabetes, body mass index, high density lipoprotein cholesterol, triglycerides, fasting glucose)-and 20 single nucleotide polymorphisms associated with susceptibility to type 2 diabetes. Cases of incident type 2 diabetes were defined on the basis of a standard oral glucose tolerance test, self report of a doctor's diagnosis, or the use of anti-diabetic drugs. A genetic score based on the number of risk alleles carried (range 0-40; area under receiver operating characteristics curve 0.54, 95% confidence interval 0.50 to 0.58) and a genetic risk function in which carriage of risk alleles was weighted according to the summary odds ratios of their effect from meta-analyses of genetic studies (area under receiver operating characteristics curve 0.55, 0.51 to 0.59) did not effectively discriminate cases of diabetes. The Cambridge risk score (area under curve 0.72, 0.69 to 0.76) and the Framingham offspring risk score (area under curve 0.78, 0.75 to 0.82) led to better discrimination of cases than did genotype based tests. Adding genetic information to phenotype based risk models did not improve discrimination and provided only a small improvement in model calibration and a modest net reclassification improvement of about 5% when added to the Cambridge risk score but not when added to the Framingham offspring risk score. The phenotype based risk models provided greater discrimination for type 2 diabetes than did models based on 20 common independently inherited diabetes risk alleles. The addition of genotypes to phenotype based risk models produced only minimal improvement in accuracy of risk estimation assessed by recalibration and, at best, a minor net reclassification improvement. The major translational application of the currently known common, small effect genetic variants influencing susceptibility to type 2 diabetes is likely to come from the insight they provide on causes of disease and potential therapeutic targets.

Circulating growth factors data associated with insulin secretagogue use in women with incident breast cancer.

PubMed

Wintrob, Zachary A P; Hammel, Jeffrey P; Nimako, George K; Gaile, Dan P; Forrest, Alan; Ceacareanu, Alice C

2017-04-01

Oral drugs stimulating insulin production may impact growth factor levels. The data presented shows the relationship between pre-existing insulin secretagogues use, growth factor profiles at the time of breast cancer diagnosis and subsequent cancer outcomes in women diagnosed with breast cancer and type 2 diabetes mellitus. A Pearson correlation analysis evaluating the relationship between growth factors stratified by diabetes pharmacotherapy and controls is also provided.

Evaluation and management of abnormal uterine bleeding in premenopausal women.

PubMed

Sweet, Mary Gayle; Schmidt-Dalton, Tarin A; Weiss, Patrice M; Madsen, Keith P

2012-01-01

Up to 14 percent of women experience irregular or excessively heavy menstrual bleeding. This abnormal uterine bleeding generally can be divided into anovulatory and ovulatory patterns. Chronic anovulation can lead to irregular bleeding, prolonged unopposed estrogen stimulation of the endometrium, and increased risk of endometrial cancer. Causes include polycystic ovary syndrome, uncontrolled diabetes mellitus, thyroid dysfunction, hyperprolactinemia, and use of antipsychotics or antiepileptics. Women 35 years or older with recurrent anovulation, women younger than 35 years with risk factors for endometrial cancer, and women with excessive bleeding unresponsive to medical therapy should undergo endometrial biopsy. Treatment with combination oral contraceptives or progestins may regulate menstrual cycles. Histologic findings of hyperplasia without atypia may be treated with cyclic or continuous progestin. Women who have hyperplasia with atypia or adenocarcinoma should be referred to a gynecologist or gynecologic oncologist, respectively. Ovulatory abnormal uterine bleeding, or menorrhagia, may be caused by thyroid dysfunction, coagulation defects (most commonly von Willebrand disease), endometrial polyps, and submucosal fibroids. Transvaginal ultrasonography or saline infusion sonohysterography may be used to evaluate menorrhagia. The levonorgestrel-releasing intrauterine system is an effective treatment for menorrhagia. Oral progesterone for 21 days per month and nonsteroidal anti-inflammatory drugs are also effective. Tranexamic acid is approved by the U.S. Food and Drug Administration for the treatment of ovulatory bleeding, but is expensive. When clear structural causes are identified or medical management is ineffective, polypectomy, fibroidectomy, uterine artery embolization, and endometrial ablation may be considered. Hysterectomy is the most definitive treatment.

Effect of plantain banana on gastric ulceration in NIDDM rats: role of gastric mucosal glycoproteins, cell proliferation, antioxidants and free radicals.

PubMed

Mohan Kumar, M; Joshi, M C; Prabha, T; Dorababu, M; Goel, R K

2006-04-01

Methanolic extract of Musa sapientum var. Paradisiaca (MSE, 100 mg/kg) was studied for its antiulcer and mucosal defensive factors in normal and non-insulin dependent diabetes mellitus (NIDDM) rats. NIDDM was induced by administering streptozotocin (STZ, 70 mg/kg, ip) to 5 days old rat pups. The animals showing blood glucose level >140mg/dL after 12 weeks of STZ administration were considered as NIDDM positive. Effects of MSE were compared with known ulcer protective drug, sucralfate (SFT, 500 mg/kg) and anti-diabetic drug glibenclamide (GLC, 0.6 mg/kg) when administered orally, once daily for 6 days against gastric ulcers (GU) induced by cold-restraint stress (CRS) and ethanol and subsequent changes in gastric mucosal glycoproteins, cell proliferation, free radicals (lipid peroxidation and nitric oxide) and anti-oxidants enzymes (super oxide dismutase and catalase) and glutathione (GSH) levels. MSE showed better ulcer protective effect in NIDDM rats compared with SFT and GLC in CRS-induced GU. NIDDM caused a significant decrease in gastric mucosal glycoprotein level without having any effect on cell proliferation. However, all the test drugs reversed the decrease in glycoprotein level in NIDDM rats, but cell proliferation was enhanced in case of MSE alone. Both CRS or NIDDM as such enhanced gastric mucosal LPO, NO and SOD, but decreased CAT levels while CRS plus NIDDM rats caused further increase in LPO and NO level without causing any further changes in SOD and CAT level. MSE pretreatment showed reversal in the levels of all the above parameters better than GLC. Ethanol caused a decrease in glutathione level which was further reduced in NIDDM-ethanol rats. MSE reversed the above changes significantly in both normal as well as in NIDDM rats, while GLC reversed it only in NIDDM rats. However, SFT was ineffective in reversing the changes induced by CRS or ethanol or when given in NIDDM-CRS or NIDDM-ethanol rats. The results indicated that the ulcer protective effect of MSE could be due to its predominant effect on mucosal glycoprotein, cell proliferation, free radicals and antioxidant systems.

Insulin-like plant proteins as potential innovative drugs to treat diabetes-The Moringa oleifera case study.

PubMed

Paula, P C; Oliveira, J T A; Sousa, D O B; Alves, B G T; Carvalho, A F U; Franco, O L; Vasconcelos, I M

2017-10-25

Various plant species have long been used in traditional medicine worldwide to treat diabetes. Among the plant-based compounds with hypoglycemic properties, studies on insulin-like proteins isolated from leaves, fruits and seeds are rarely reported in the relevant literature. Our research group has been investigating the presence of insulin-like proteins in Moringa oleifera, a plant species native to India, and we have obtained a leaf protein isolate and semi-purified derived fractions, as well as a seed coat protein fraction (Mo-SC), with hypoglycemic activity in chemically induced diabetic mice that have increased tolerance to orally administered glucose. Equally importantly, Mo-SC possesses insulin-like antigenic epitopes. In this context, the present review aims to highlight that prospection of insulin-like proteins in plants is of the utmost importance both for finding new drugs for the treatment of diabetes and for shedding light on the mechanisms involved in diabetes. Copyright © 2016 Elsevier B.V. All rights reserved.

The anti-ALS drug riluzole attenuates pericyte loss in the diabetic retinopathy of streptozotocin-treated mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Jeong A.

Loss of pericytes, considered an early hallmark of diabetic retinopathy, is thought to involve abnormal activation of protein kinase C (PKC). We previously showed that the anti-amyotrophic lateral sclerosis (ALS) drug riluzole functions as a PKC inhibitor. Here, we examined the effects of riluzole on pathological changes in diabetic retinopathy. Pathological endpoints examined in vivo included the number of pericytes and integrity of retinal vessels in streptozotocin (STZ)-induced diabetic mice. In addition, PKC activation and the induction of monocyte chemotactic protein (MCP1) were assessed in diabetic mice and in human retinal pericytes exposed to advanced glycation end product (AGE) ormore » modified low-density lipoprotein (mLDL). The diameter of retinal vessels and the number of pericytes were severely reduced, and the levels of MCP1 and PKC were increased in STZ-induced diabetic mice. Administration of riluzole reversed all of these changes. Furthermore, the increased expression of MCP1 in AGE- or mLDL-treated cultured retinal pericytes was inhibited by treatment with riluzole or the PKC inhibitor GF109203X. In silico modeling showed that riluzole fits well within the catalytic pocket of PKC. Taken together, our results demonstrate that riluzole attenuates both MCP1 induction and pericyte loss in diabetic retinopathy, likely through its direct inhibitory effect on PKC. - Highlights: • The effects of riluzole were examined in streptozotocin-induced diabetic mice. • The diameter of retinal vessels and the number of pericytes were severely reduced. • The levels of MCP1 and PKC were increased, while riluzole reversed all changes. • Riluzole attenuated the level of MCP1 in AGE- or mLDL-treated retinal pericytes. • Riluzole attenuated both MCP1 induction and pericyte loss in diabetic retinopathy.« less

Antidiabetic activity of medium-polar extract from the leaves of Stevia rebaudiana Bert. (Bertoni) on alloxan-induced diabetic rats

PubMed Central

Misra, Himanshu; Soni, Manish; Silawat, Narendra; Mehta, Darshana; Mehta, B. K.; Jain, D. C.

2011-01-01

Objective: To investigate the medicative effects of medium-polar (benzene:acetone, 1:1, v/v) extract of leaves from Stevia rebaudiana (family Asteraceae) on alloxan-induced diabetic rats. Materials and Methods: Diabetes was induced in adult albino Wistar rats by intraperitoneal (i.p.) injection of alloxan (180 mg/kg). Medium-polar extract was administered orally at daily dose of 200 and 400 mg/kg body wt. basis for 10 days. The control group received normal saline (0.9%) for the same duration. Glibenclamide was used as positive control reference drug against Stevia extract. Results: Medium-polar leaf extract of S. rebaudiana (200 and 400 mg/kg) produced a delayed but significant (P < 0.01) decrease in the blood glucose level, without producing condition of hypoglycemia after treatment, together with lesser loss in the body weight as compared with standard positive control drug glibenclamide. Conclusions: Treatment of diabetes with sulfonylurea drugs (glibenclamide) causes hypoglycemia followed by greater reduction in body weight, which are the most worrisome effects of these drugs. Stevia extract was found to antagonize the necrotic action of alloxan and thus had a re-vitalizing effect on β-cells of pancreas. PMID:21687353

Diabetes insipidus as a rare cause of acute cognitive impairment in multiple sclerosis.

PubMed

Tiedje, V; Schlamann, M; Führer, D; Moeller, L C

2013-10-01

Multiple sclerosis (MS) is a complex neurodegenerative disease presenting with a diversity of clinical symptoms including palsy and cognitive impairment. We present a 59-year-old woman with a history of secondary progressive MS since 1987, who was referred to our department because of recent onset of confusion and polydipsia. Initial lab tests showed mildly elevated serum sodium levels and low urine osmolality. Under water deprivation, diuresis and low urine osmolality persisted and serum sodium levels rose above 150 mmol/l. Oral desmopressin resulted in normalisation of serum sodium as well as urine osmolarity, confirming a diagnosis of central diabetes insipidus. As drug-induced diabetes could be excluded, pituitary magnetic resonance imaging (MRI) was performed. A demyelinating lesion was detected in the hypothalamus. The patient was started on oral desmopressin treatment (0.2 mg/day). Fluid intake and serum sodium levels have since remained normal. In summary, we report the rare case of a patient presenting with diabetes insipidus due to progressive MS. Diabetes insipidus should be considered in MS patients who develop new onset of polydipsia.

Inhibition of pancreatic lipase and amylase by extracts of different spices and plants.

PubMed

Sellami, Mohamed; Louati, Hanen; Kamoun, Jannet; Kchaou, Ali; Damak, Mohamed; Gargouri, Youssef

2017-05-01

The aim of this study is to search new anti-obesity and anti-diabetic agents from plant and spices crude extracts as alternative to synthetic drugs. The inhibitory effect of 72 extracts was evaluated, in vitro, on lipase and amylase activities. Aqueous extracts of cinnamon and black tea exhibited an appreciable inhibitory effect on pancreatic amylase with IC 50 values of 18 and 87 μg, respectively. Aqueous extracts of cinnamon and mint showed strong inhibitory effects against pancreatic lipase with IC 50 of 45 and 62 μg, respectively. The presence of bile salts and colipase or an excess of interface failed to restore the lipase activity. Therefore, the inhibition of pancreatic lipase, by extracts of spices and plants, belongs to an irreversible inhibition. Crude extract of cinnamon showed the strongest anti-lipase and anti-amylase activities which offer a prospective therapeutic approach for the management of diabetes and obesity.

Vibrational frequencies of anti-diabetic drug studied by terahertz time-domain spectroscopy

NASA Astrophysics Data System (ADS)

Du, S. Q.; Li, H.; Xie, L.; Chen, L.; Peng, Y.; Zhu, Y. M.; Li, H.; Dong, P.; Wang, J. T.

2012-04-01

By using terahertz time-domain spectroscopy, the absorption spectra of seven anti-diabetic pills have been investigated. For gliquidone, glipizide, gliclazide, and glimepiride, an obvious resonance peak is found at 1.37 THz. Furthermore, to overcome the limit of density functional theory that can analyze the normal mode frequencies of the ground state of organic material, we also present a method that relies on pharmacophore recognition, from which we can obtain the resonance peak at 1.37 THz can be attributed to the vibration of sulfonylurea group. The results indicate that the veracity of density functional theory can be increased by combining pharmacophore recognition.

New horizons in anticoagulation: Direct oral anticoagulants and their implications in oral surgery

PubMed Central

Ripollés-de Ramón, Jorge; Collado-Yurrita, Luis; Vaello-Checa, Iris; Colmenero-Ruiz, Constantino; Helm, Alexandra; Ciudad-Cabañas, Maria-José; Serrano-Cuenca, Victoriano

2017-01-01

Background Thrombotic disorders remain a leading cause of death in the Western World. For decades, vitamin K antagonists used in the prevention of this pathology, such as warfarin or sintrom, were the only oral agents available for long-term anticoagulation, in spite of their disadvantages. Material and Methods An electronic database search was carried out on MedLine and The Cochrane Library Plus, without restrictions on the type of study nor dates, in English and Spanish. Abstracts were reviewed, and complete articles if necessary, considering all articles that included recommendations on DOACs and oral surgery. Results In recent years, the so-called “new oral anticoagulants” have been introduced in clinical practice to treat those patients whose medical conditions require long-term anticoagulant treatment, replacing traditional oral anticoagulants. Conclusions The new oral anticoagulants represent new therapeutic options, with a number of advantages such as poor interaction with food, minor drug interactions, and do not require periodic dose adjustments or routine controls. The purpose of this review is to establish an update on the new oral anticoagulants: Dabigatran, Rivarozaban, Apixaban and Edoxaban. Key words:Novel oral anticoagulants, Dabigatran, Rivaroxaban, Apixaban, Edoxaban, bleeding management, oral surgery, Anti-IIa, Anti Xa. PMID:28809374

Potential Compounds for Oral Cancer Treatment: Resveratrol, Nimbolide, Lovastatin, Bortezomib, Vorinostat, Berberine, Pterostilbene, Deguelin, Andrographolide, and Colchicine

PubMed Central

Bundela, Saurabh; Sharma, Anjana; Bisen, Prakash S.

2015-01-01

Oral cancer is one of the main causes of cancer-related deaths in South-Asian countries. There are very limited treatment options available for oral cancer. Research endeavors focused on discovery and development of novel therapies for oral cancer, is necessary to control the ever rising oral cancer related mortalities. We mined the large pool of compounds from the publicly available compound databases, to identify potential therapeutic compounds for oral cancer. Over 84 million compounds were screened for the possible anti-cancer activity by custom build SVM classifier. The molecular targets of the predicted anti-cancer compounds were mined from reliable sources like experimental bioassays studies associated with the compound, and from protein-compound interaction databases. Therapeutic compounds from DrugBank, and a list of natural anti-cancer compounds derived from literature mining of published studies, were used for building partial least squares regression model. The regression model thus built, was used for the estimation of oral cancer specific weights based on the molecular targets. These weights were used to compute scores for screening the predicted anti-cancer compounds for their potential to treat oral cancer. The list of potential compounds was annotated with corresponding physicochemical properties, cancer specific bioactivity evidences, and literature evidences. In all, 288 compounds with the potential to treat oral cancer were identified in the current study. The majority of the compounds in this list are natural products, which are well-tolerated and have minimal side-effects compared to the synthetic counterparts. Some of the potential therapeutic compounds identified in the current study are resveratrol, nimbolide, lovastatin, bortezomib, vorinostat, berberine, pterostilbene, deguelin, andrographolide, and colchicine. PMID:26536350

Effect of acarbose to delay progression of carotid intima-media thickness in early diabetes.

PubMed

Patel, Y R; Kirkman, M S; Considine, R V; Hannon, T S; Mather, K J

2013-10-01

The anti-diabetic agent acarbose reduces postprandial glucose excursions. We have evaluated the effect of randomized treatment with acarbose on the progression of carotid intima-media thickness (IMT) in early diabetes. The Early Diabetes Intervention Program was a randomized trial of acarbose versus placebo in 219 participants with early diabetes characterized by glucose values over 11.1 mmol/L 2 h after a 75 g oral glucose load and a mean HbA1c of 6.3%. IMT was measured at baseline and yearly. Follow-up was discontinued if participants progressed to the study glucose endpoints; IMT readings were available for a median of 2 years, with 72 subjects followed for 5 years. Progressive increases in IMT were seen in both treatment groups, but progression was reduced in participants randomized to acarbose (p = 0.047). In age, sex and smoking-adjusted analyses, IMT progression was associated with greater fasting and oral glucose tolerance test-excursion glucose, fasting insulin, cholesterol and glycated low-density lipoprotein concentrations. IMT progression was reduced with study-related changes in weight, insulin and non-esterified fatty acids; these features were more strongly associated with reduced IMT progression than acarbose treatment. Despite strong associations of baseline glycemia with IMT progression, study-related changes in glucose were not important determinants of IMT progression. Acarbose can delay progression of carotid intima-media thickness in early diabetes defined by an oral glucose tolerance test. Glucose, weight, insulin and lipids contributed to risk of progression but reductions in glycemia were not major determinants of reduced rate of IMT progression. Vascular benefits of acarbose may be independent of its glycemic effects. Copyright © 2013 John Wiley & Sons, Ltd.

Anti-Diabetic Potential of Ocimum gratissimum Leaf Fractions in Fortified Diet-Fed Streptozotocin Treated Rat Model of Type-2 Diabetes

PubMed Central

Umar, Isamila A.; James, Dorcas B.; Inuwa, Hajiya M.

2017-01-01

Background: Ocimum gratissimum (OG) is used in the traditional management of diabetes in Nigeria. This study investigated the anti-diabetic potential of OG leaf fractions (OGLF) in a rat model of Type-2 diabetes (T2D). Methods: Methanol crude extract of OG leaf was fractionated with solvents of increasing order of polarity (n-hexane, chloroform, ethyl-acetate, n-butanol and water). The anti-diabetic potential of the fractions was evaluated in vivo. T2D was induced in Albino Wistar rats and treated with OGLF. Results: The T2D rats showed significant elevation in serum levels of fasting blood glucose (FBG), liver and kidney function biomarkers. At 4-week of intervention with OGLF, the untreated diabetic control group maintained severe hyperglycaemia in the presence of 61.7% serum insulin, 17.3% pancreatic β-cell function (HOMA-β) and 51.5% Insulin sensitivity. The glucose tolerance ability was enhanced in the n-butanol-fraction (OGb) treated group. With 74.8% available serum insulin and 38.6% improvement in insulin sensitivity, the OGb treated group had a 63.5% reduction in FBG and it was found to be most effective as it ameliorates a majority of the changes caused in the studied parameters in diabetic rats. Conclusions: The data from this study suggest that OGb fraction is a potential candidate for the development of an effective drug for the management of T2D. PMID:29019956

Anti-Diabetic Potential of Ocimum gratissimum Leaf Fractions in Fortified Diet-Fed Streptozotocin Treated Rat Model of Type-2 Diabetes.

PubMed

Okoduwa, Stanley I R; Umar, Isamila A; James, Dorcas B; Inuwa, Hajiya M

2017-10-11

Background : Ocimum gratissimum (OG) is used in the traditional management of diabetes in Nigeria. This study investigated the anti-diabetic potential of OG leaf fractions (OGLF) in a rat model of Type-2 diabetes (T2D). Method : Methanol crude extract of OG leaf was fractionated with solvents of increasing order of polarity ( n -hexane, chloroform, ethyl-acetate, n -butanol and water). The anti-diabetic potential of the fractions was evaluated in vivo. T2D was induced in Albino Wistar rats and treated with OGLF. Result : The T2D rats showed significant elevation in serum levels of fasting blood glucose (FBG), liver and kidney function biomarkers. At 4-weeks of intervention with OGLF, the untreated diabetic control group maintained severe hyperglycaemia in the presence of 61.7% serum insulin, 17.3% pancreatic β-cell function (HOMA-β) and 51.5% Insulin sensitivity. The glucose tolerance ability was enhanced in the n -butanol-fraction (OGb) treated group. With 74.8% available serum insulin and 38.6% improvement in insulin sensitivity, the OGb treated group had a 63.5% reduction in FBG and it was found to be most effective as it ameliorates a majority of the changes caused in the studied parameters in diabetic rats. Conclusions : The data from this study suggest that OGb fraction is a potential candidate for the development of an effective drug for the management of T2D.

Canagliflozin-current status in the treatment of type 2 diabetes mellitus with focus on clinical trial data

PubMed Central

Bhatia, Jagriti; Gamad, Nanda; Bharti, Saurabh; Arya, Dharamvir Singh

2014-01-01

Canagliflozin (CFZ) is a member of new class of glucose lowering agents, sodium-glucose co-transporter (SGLT) inhibitors, which got approval by food and drug administration. It has insulin independent action by blocking the transporter protein SGLT2 in the kidneys, resulting in urinary glucose excretion and reduction in blood glucose levels. In clinical trials, CFZ significantly decreased HbA1c level when administered either as monotherapy or as combined therapy with other anti-diabetic drugs. Intriguingly, it showed additional benefits like weight reduction and lowering of blood pressure. The commonly observed side effects were urinary and genital infections. It has exhibited favorable pharmacokinetic and pharmacodynamic profiles even in patients with renal and hepatic damage. Hence, this review purports to outline CFZ as a newer beneficial drug for type 2 diabetes mellitus. PMID:24936262

Anti-diabetic effects of Sargassum oligocystum on Streptozotocin-induced diabetic rat

PubMed Central

Akbarzadeh, Samad; Gholampour, Hossein; Farzadinia, Parviz; Daneshi, Adel; Ramavandi, Bahman; Moazzeni, Ali; Keshavarz, Mojtaba; Bargahi, Afshar

2018-01-01

Objective(s): Diabetes is a metabolic syndrome which is associated with the worldwide major public health problems. There are many natural compounds from the sea-market, as a valuable aquatic source, along with the variety of health and therapeutic benefits. In the present research, with respect to the traditional and ethnic uses of Sargassum oligocystum algae for healing of some diseases which have similar metabolic mechanism to the diabetes, its anti-diabetic effects in animal model was proposed. Materials and Methods: The animals (rat) were divided into the normal control, diabetic control, positive control and, the test groups. The test groups were gavaged with oral doses of 150 and 300 mg/kg of algae hydroalcoholic extracts. After 30 days of intervention the serum glucose, cholesterol, triglyceride, HDLC, LDLC, insulin, insulin resistance, β-cells function and, the histopathology of pancreatic tissue were evaluated. Results: In animals that were fed with algae extracts a significant decrease in the fasting blood glucose, triglyceride and HOMA-IR and an increase in the HOMA-B with no significant impacts on the insulin, cholesterol and HDL were observed. Also, the histopathology evaluations in the groups which were treated with algae extract revealed the regeneration and reconstitution of damaged pancreatic β-cells. Conclusion: The results give evidence that, the S. oligocystum algae extract has a healing effect on diabetes which can be considered as a new research prospect for the natural therapy of diabetes. PMID:29511502

Anti-diabetic effects of shubat in type 2 diabetic rats induced by combination of high-glucose-fat diet and low-dose streptozotocin.

PubMed

Manaer, Tabusi; Yu, Lan; Zhang, Yi; Xiao, Xue-Jun; Nabi, Xin-Hua

2015-07-01

Shubat, probiotic fermented camel milk, has been used both as a drink with ethnic flavor and a medicine among Kazakh population for diabetic patients. Kazakh people have lower diabetic prevalence and impaired fasting glucose (IFG) than do other ethnic groups living in Xinjiang China, which might be related to the beneficial properties of shubat. We therefore prepared shubat in laboratory and tested anti-diabetic activity and evaluated its possible hypolipidemic and renoprotective effects in type 2 diabetic rats. Type 2 diabetic rats were induced by an administration of high-glucose-fat diet for 6 weeks and an intraperitoneal injection of streptozotocin (STZ, 30mg/kg). Diabetic rats were divided randomly into four groups and treated for 28 days with sitagliptin (30mg/kg) or shubat (6.97×10(6) lactic acid bacteria+2.20×10(4) yeasts) CFU/mL, (6.97×10(7) lactic acid bacteria+2.20×10(5) yeasts) CFU/mL and (6.97×10(8) lactic acid bacteria+2.20×10(6) yeasts) CFU/mL. In addition, a normal control group and a diabetic control group were used for comparison. All drugs were given orally once daily 10mL/kg for 4 weeks. Fasting blood glucose (FBG) and body weight (BW) were measured before treatment and every week thereafter. Total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), serum creatinine (SCr), blood urea nitrogen (BUN), C-peptide, glycated hemoglobin (HbAlc), glucagon-like peptide-1 (GLP-1) levels and pancreas tissue sections were tested after 4 weeks. Shubat demonstrated positive hypoglycemic activity on FBG, HbAlc, C-peptide and GLP-1 levels, high dose shubat decreased FBG (P<0.01) and HbAlc (P<0.05), increased C-peptide (P<0.05) and GLP-1 (P<0.01), decreased serum TC, TG, LDL-c (P<0.05), increased HDL-c (P<0.01), and improved the reduction of body weight as well as decreased SCr and BUN levels (P<0.01) compared to diabetic controls. Histological analysis showed shubat protected the function of islets of type 2 diabetic rats. The results of this study indicate that shubat has significant hypoglycemic potential in T2D rats and may modulate lipid metabolism and protect renal function in the type 2 diabetic condition, which might be related to various probiotics acting through promoting the release of GLP-1 and improving the function of β-cells. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Reduction of gastrointestinal symptoms in Parkinson's disease after a switch from oral therapy to rotigotine transdermal patch: a non-interventional prospective multicenter trial.

PubMed

Woitalla, Dirk; Kassubek, Jan; Timmermann, Lars; Lauterbach, Thomas; Berkels, Reinhard; Grieger, Frank; Müller, Thomas

2015-03-01

Gastrointestinal (GI) symptoms are common among patients with Parkinson's disease (PD), due to both the disease itself and anti-PD drugs. We hypothesized that transdermal drug administration may result in fewer GI problems. This prospective observational study (ClinicalTrials.gov: NCT01159691) investigated effect of switching to rotigotine transdermal patch from oral anti-PD medications in patients with PD and existing GI symptoms. Patients were enrolled if their physician was planning to switch them to rotigotine because of GI symptoms experienced while receiving oral anti-PD medications. Effectiveness assessments included a visual analog scale (VAS) measuring intensity of GI symptoms from 0 (no disorder) to 100 mm (extremely severe disorder), a questionnaire on the frequency and intensity of six individual GI complaints (heartburn, bloating, nausea, vomiting, abdominal pain, diarrhea), each rated 0-12 for a sum score of 0-72, and patient satisfaction regarding GI symptoms over approximately 6 weeks after switching. Of 75 patients who received rotigotine, 58 had follow-up data available for final analysis. Intensity of GI complaints improved numerically on both the VAS (47.5 ± 24.4 mm [n = 65] at baseline, 19.7 ± 23.3 mm [n = 58] after around 6 weeks) and the sum score of GI complaints (11.2 ± 9.0 at baseline, 2.1 ± 4.4 [n = 58] after around 6 weeks). Fifty of 58 patients were "satisfied" or "very satisfied" regarding GI symptoms over around 6 weeks following switch to the patch. This study suggests that a switch from oral anti-PD medications to rotigotine transdermal patch may improve existing GI symptoms among patients with PD. Additional controlled studies are needed to confirm this finding. Copyright © 2014 Elsevier Ltd. All rights reserved.

Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats.

PubMed

Chai, Hann-Juang; Kiew, Lik-Voon; Chin, Yunni; Norazit, Anwar; Mohd Noor, Suzita; Lo, Yoke-Lin; Looi, Chung-Yeng; Lau, Yeh-Siang; Lim, Tuck-Meng; Wong, Won-Fen; Abdullah, Nor Azizan; Abdul Sattar, Munavvar Zubaid; Johns, Edward J; Chik, Zamri; Chung, Lip-Yong

2017-01-01

Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. 3 H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3 H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier.

Renal targeting potential of a polymeric drug carrier, poly-l-glutamic acid, in normal and diabetic rats

PubMed Central

Chai, Hann-Juang; Kiew, Lik-Voon; Chin, Yunni; Norazit, Anwar; Mohd Noor, Suzita; Lo, Yoke-Lin; Looi, Chung-Yeng; Lau, Yeh-Siang; Lim, Tuck-Meng; Wong, Won-Fen; Abdullah, Nor Azizan; Abdul Sattar, Munavvar Zubaid; Johns, Edward J; Chik, Zamri; Chung, Lip-Yong

2017-01-01

Background and purpose Poly-l-glutamic acid (PG) has been used widely as a carrier to deliver anticancer chemotherapeutics. This study evaluates PG as a selective renal drug carrier. Experimental approach 3H-deoxycytidine-labeled PGs (17 or 41 kDa) and 3H-deoxycytidine were administered intravenously to normal rats and streptozotocin-induced diabetic rats. The biodistribution of these compounds was determined over 24 h. Accumulation of PG in normal kidneys was also tracked using 5-(aminoacetamido) fluorescein (fluoresceinyl glycine amide)-labeled PG (PG-AF). To evaluate the potential of PGs in ferrying renal protective anti-oxidative stress compounds, the model drug 4-(2-aminoethyl)benzenesulfonyl fluoride hydrochloride (AEBSF) was conjugated to 41 kDa PG to form PG-AEBSF. PG-AEBSF was then characterized and evaluated for intracellular anti-oxidative stress efficacy (relative to free AEBSF). Results In the normal rat kidneys, 17 kDa radiolabeled PG (PG-Tr) presents a 7-fold higher, while 41 kDa PG-Tr shows a 15-fold higher renal accumulation than the free radiolabel after 24 h post injection. The accumulation of PG-AF was primarily found in the renal tubular tissues at 2 and 6 h after an intravenous administration. In the diabetic (oxidative stress-induced) kidneys, 41 kDa PG-Tr showed the greatest renal accumulation of 8-fold higher than the free compound 24 h post dose. Meanwhile, the synthesized PG-AEBSF was found to inhibit intracellular nicotinamide adenine dinucleotide phosphate oxidase (a reactive oxygen species generator) at an efficiency that is comparable to that of free AEBSF. This indicates the preservation of the anti-oxidative stress properties of AEBSF in the conjugated state. Conclusion/Implications The favorable accumulation property of 41 kDa PG in normal and oxidative stress-induced kidneys, along with its capabilities in conserving the pharmacological properties of the conjugated renal protective drugs, supports its role as a potential renal targeting drug carrier. PMID:28144140

Valproic acid reduces insulin-resistance, fat deposition and FOXO1-mediated gluconeogenesis in type-2 diabetic rat.

PubMed

Khan, Sabbir; Kumar, Sandeep; Jena, Gopabandhu

2016-06-01

Recent evidences highlighted the role of histone deacetylases (HDACs) in insulin-resistance, gluconeogenesis and islet function. HDACs can modulate the expression of various genes, which directly or indirectly affect glucose metabolism. This study was aimed to evaluate the role of valproic acid (VPA) on fat deposition, insulin-resistance and gluconeogenesis in type-2 diabetic rat. Diabetes was developed in Sprague-Dawley rats by the combination of high-fat diet and low dose streptozotocin. VPA at the doses of 150 and 300 mg/kg/day and metformin (positive control) 150 mg/kg twice daily for 10 weeks were administered by oral gavage. Insulin-resistance, dyslipidemia and glycemia were evaluated by biochemical estimations, while fat accumulation and structural alteration were assessed by histopathology. Protein expression and insulin signaling were evaluated by western blot and immunohistochemistry. VPA treatment significantly reduced the plasma glucose, HbA1c, insulin-resistance, fat deposition in brown adipose tissue, white adipose tissue and liver, which are comparable to metformin treatment. Further, VPA inhibited the gluconeogenesis and glucagon expression as well as restored the histopathological alterations in pancreas and liver. Our findings provide new insights on the anti-diabetic role of VPA in type-2 diabetes mellitus by the modulation of insulin signaling and forkhead box protein O1 (FOXO1)-mediated gluconeogenesis. Since VPA is a well established clinical drug, the detailed molecular mechanisms of the present findings can be further investigated for possible clinical use. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Anti-diabetic properties and phytochemistry of Momordica charantia L. (Cucurbitaceae).

PubMed

Raman, A; Lau, C

1996-03-01

Unripe fruit, seeds and aerial parts of Momordica charantia Linn. (Cucurbitaceae) have been used in various parts of the world to treat diabetes. Oral administration of the fruit juice or seed powder causes a reduction in fasting blood glucose and improves glucose tolerance in normal and diabetic animals and in humans. Animal and in vitro data support both insulin secretagogue and insulinomimetic activity of the fruit. However, enhanced insulin levels in vivo in response to its administration have not been observed. Although a wide range of compounds have been isolated from Momordica charantia, notably steroidal compounds and proteins, the orally active antidiabetic principle has not been adequately identified. A polypeptide, p-insulin, produces hypoglycaemic effects in humans and animals on subcutaneous injection, but oral activity is questionable. Other reported hypoglycaemic principles from Momordica charantia include the sterol glucoside mixture charantin (fruit) and the pyrimidine nucleoside vicine (seeds). However these are only effective at doses too high to account for all the activity of the plant extract. Principal toxicity of Momordica charantia in animals is to the liver and reproductive system. These effects have not been reported in humans despite widespread use of the fruit medicinally and as a vegetable. Copyright © 1996 Gustav Fischer Verlag · Struttgart · Jena · New York. Published by Elsevier GmbH.. All rights reserved.

Protective potential of Averrhoa bilimbi fruits in ameliorating the hepatic key enzymes in streptozotocin-induced diabetic rats.

PubMed

Kurup, Surya B; S, Mini

2017-01-01

Diabetes is a mutifactorial disease which leads to several complications. Currently available drug regimens for management of diabetes have certain drawbacks. Need for safer and effective medicines from natural sources having potent antidiabetic activity. Averrhoa bilimbi Linn. (Oxalidaceae) is a medicinal plant and is reported to possess hypoglycemic activity. To investigate the antidiabetic potential of Averrhoa bilimbi fruit extract in streptozotocin-induced diabetic rats. Diabetes was induced in male Sprague Dawley rats by single intraperitoneal injection of streptozotocin (STZ) (40mg/kg body weight). The diabetic rats were treated orally with ethyl acetate fraction of A. bilimbi fruits (ABE) (25mg/kg body weight) and metformin (100mg/kg body weight) by intragastric intubation for 60days. After 60days, the rats were sacrificed; blood, liver and pancreas were collected. Several indices such as blood glucose, plasma insulin, toxicity markers and the activities of carbohydrate-metabolizing enzymes were assayed. The phytochemicals present in the ABE was identified by gas chromatography-mass spectrometry analysis. ABE significantly (p<0.05) reduced the level of blood glucose and hepatic toxicity markers and increased plasma insulin in diabetic rats. ABE modulated the activities of carbohydrate-metabolizing enzymes, significantly increased the activities of hexokinase (59%) and pyruvate kinase (68%) and reduced the activities of glucose-6-phosphatase (32%) and fructose-1, 6-bisphosphatase (20%). The histological studies of the pancreas also supported our findings. The results were compared with metformin, a standard oral hypoglycemic drug. GC-MS analysis of ABE revealed the presence of 11 chemical constituents in the extract. ABE exerts its antidiabetic effect by promoting glucose metabolism via glycolysis and inhibiting hepatic endogenous glucose production via gluconeogenesis. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Role of chrysin on expression of insulin signaling molecules

PubMed Central

Satyanarayana, Kottireddy; Sravanthi, Koora; Shaker, Ivvala Anand; Ponnulakshmi, Rajagopal; Selvaraj, Jayaraman

2015-01-01

Background: Currently available drugs are unsuccessful for the treatment of tye-2 diabetes due to their adverseside-effects. Hence, a search for novel drugs, especially ofplant origin, continues. Chrysin (5,7-dihydroxyflavone) is a flavonoid, natural component of traditional medicinal herbs, present in honey, propolis and many plant extracts that hasbeen used in traditional medicine around the world to treat numerous ailments. Objective: The present study was aimed to identify the protective role of chrysin on the expression of insulin-signaling molecules in the skeletal muscle of high fat and sucrose-induced type-2 diabetic adult male rats. Materials and Methods: The oral effective dose of chrysin (100 mg/kg body weight) was given once a day until the end of the study (30 days post-induction of diabetes) to high fat diet-induced diabetic rats. At the end of the experimental period, fasting blood glucose, oral glucose tolerance, serum lipid profile, lipid peroxidation (LPO) and free radical generation, as well as the levels of insulin signaling molecules and tissue glycogen in the gastrocnemius muscle were assessed. Results: Diabetic rats showed impaired glucose tolerance and impairment in insulin signaling molecules (IR, IRS-1, p-IRS-1Tyr632, p- AktThr308), glucose transporter subtype 4 [GLUT4] proteins and glycogen concentration. Serum insulin, lipid profile, LPO and free radical generation were found to be increased in diabetic control rats. The treatment with chrysin normalized the altered levels of blood glucose, serum insulin, lipid profile, LPO and insulin signaling molecules as well as GLUT4 proteins. Conclusion: Our present findings indicate that chrysin improves glycemic control through activation of insulin signal transduction in the gastrocnemius muscle of high fat and sucrose-induced type-2 diabetic male rats. PMID:26834424

Insulin sensitizing and alpha-glucoamylase inhibitory action of sennosides, rheins and rhaponticin in Rhei Rhizoma.

PubMed

Choi, Soo Bong; Ko, Byoung Seob; Park, Seong Kyu; Jang, Jin Sun; Park, Sunmin

2006-01-25

Extracts from Rhei Rhizoma extracts (RR) have been reported to attenuate metabolic disorders such as diabetic nephropathy, hypercholesterolemia and platelet aggregation. With this study we investigated the anti-diabetic action of 70% ethanol RR extract in streptozotocin-induced diabetic mice, and determined the action mechanism of active compounds of RR in vitro. In the diabetic mice, serum glucose levels at fasting and post-prandial states and glucose area under the curve at modified oral glucose tolerance tests were lowered without altering serum insulin levels, indicating that RR contained potential anti-diabetic agents. The fractions fractionated from RR extracts by XAD-4 column revealed that 60%, 80% and 100% methanol fractions enhanced insulin sensitivity and inhibited alpha-glucoamylase activity. The major compounds of these fractions were sennosides, rhein and rhaponticin. Rhaponticin and rhein enhanced insulin-stimulated glucose uptake in 3T3-L1 adipocytes. Rhaponticin increased adipocytes with a differentiating effect similar to pioglitazone, but rhein and sennoside B decreased triglyceride accumulation. Sennoside A and B inhibited alpha-glucoamylase activity as much as acarbose. In conclusion, a crude extract of RR improves glucose intolerance by enhancing insulin-stimulated glucose uptake and decreasing carbohydrate digestion via inhibiting alpha-glucoamylase activity. Rhein and rhaponticin are potential candidates for hypoglycemic agents.

Spirulina Extract Enhanced a Protective Effect in Type 1 Diabetes by Anti-Apoptosis and Anti-ROS Production

PubMed Central

Lee, Jiyeong; Park, Arum; Kim, Mi Jeong; Lim, Hee-Joung; Rha, Young-Ah

2017-01-01

Interest in the nutritional value and pharmacological activities of blue-green algae has gradually increased. Spirulina extracts show protective effects against apoptosis and inflammatory damage in various cell types. Here, we investigated the protective effects of extracts from Spirulina maxima in a cytokine-mediated type 1 diabetes model in vitro and in streptozotocin-induced diabetic Wistar rats in vivo. Interleukin-1β and interferon-gamma induced substantial cytotoxicity to RINm5F rat insulinoma cells, increasing nitric oxide (NO) production, nuclear factor-kappa B (NF-κB) activity, the expression of endoplasmic reticulum (ER) stress genes, and activation of mitogen-activated protein kinases and key genes related apoptosis. However, the cytotoxicity of cytokines was significantly attenuated by Spirulina extract, which effectively prevented NO production by inhibiting the synthesis of cytokine-activated NO synthase (iNOS), and apoptosis was suppressed. These results suggest that Spirulina extract might be effective to preserve the viability and function of pancreatic β-cells against cytotoxic conditions. Moreover, diabetic mice orally administered Spirulina extract showed decreased glucose levels, increased insulin, and improvement in liver enzyme markers. The antioxidant effect of Spirulina extract may be helpful in treating type 1 diabetes by enhancing the survival, and reducing or delaying cytokine-mediated β-cells destruction. PMID:29244751

Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats

PubMed Central

Attanayake, Anoja P.; Jayatilaka, Kamani A. P. W.; Pathirana, Chitra; Mudduwa, Lakmini K. B.

2013-01-01

Background: Diabetes mellitus, for a long time, has been treated with plant derived medicines in Sri Lanka. Aim: The aim of this study is to determine the efficacy and dose response of oral antihyperglycaemic activity of eight Sri Lankan medicinal plant extracts, which are used to treat diabetes in traditional medicine in diabetic rats. Materials and Methods: Medicinal plants selected for the study on the basis of documented effectiveness and wide use among traditional Ayurveda physicians in the Southern region of Sri Lanka for the treatment of diabetes mellitus. The effect of different doses of aqueous stem bark extracts of Spondias pinnata (Anacardiaceae), Kokoona zeylanica (Celastraceae), Syzygium caryophyllatum (Myrtaceae), Gmelina arborea (Verbenaceae), aerial part extracts of Scoparia dulcis (Scrophulariaceae), Sida alnifolia (Malvaceae), leaf extract of Coccinia grandis (Cucurbitaceae) and root extract of Languas galanga (Zingiberaceae) on oral glucose tolerance test was evaluated. A single dose of 0.25, 0.50, 0.75, 1.00, 1.25, 2.00 g/kg of plant extract was administered orally to alloxan induced (150 mg/kg, ip) diabetic Wistar rats (n = 6). Glibenclamide (0.50 mg/kg) was used as the standard drug. The acute effect was evaluated over a 4 h period using area under the oral glucose tolerance curve. Statistical Analysis: The results were evaluated by analysis of variance followed by Dunnett's test. Results: The eight plant extracts showed statistically significant dose dependent improvement on glucose tolerance (P < 0.05). The optimum effective dose on glucose tolerance for six extracts was found to be 1.00 g/kg in diabetic rats with the exception of C. grandis: 0.75 g/kg and L. galanga: 1.25 g/kg. Conclusion: The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats. PMID:24991066

Study of antihyperglycaemic activity of medicinal plant extracts in alloxan induced diabetic rats.

PubMed

Attanayake, Anoja P; Jayatilaka, Kamani A P W; Pathirana, Chitra; Mudduwa, Lakmini K B

2013-04-01

Diabetes mellitus, for a long time, has been treated with plant derived medicines in Sri Lanka. The aim of this study is to determine the efficacy and dose response of oral antihyperglycaemic activity of eight Sri Lankan medicinal plant extracts, which are used to treat diabetes in traditional medicine in diabetic rats. Medicinal plants selected for the study on the basis of documented effectiveness and wide use among traditional Ayurveda physicians in the Southern region of Sri Lanka for the treatment of diabetes mellitus. The effect of different doses of aqueous stem bark extracts of Spondias pinnata (Anacardiaceae), Kokoona zeylanica (Celastraceae), Syzygium caryophyllatum (Myrtaceae), Gmelina arborea (Verbenaceae), aerial part extracts of Scoparia dulcis (Scrophulariaceae), Sida alnifolia (Malvaceae), leaf extract of Coccinia grandis (Cucurbitaceae) and root extract of Languas galanga (Zingiberaceae) on oral glucose tolerance test was evaluated. A single dose of 0.25, 0.50, 0.75, 1.00, 1.25, 2.00 g/kg of plant extract was administered orally to alloxan induced (150 mg/kg, ip) diabetic Wistar rats (n = 6). Glibenclamide (0.50 mg/kg) was used as the standard drug. The acute effect was evaluated over a 4 h period using area under the oral glucose tolerance curve. The results were evaluated by analysis of variance followed by Dunnett's test. The eight plant extracts showed statistically significant dose dependent improvement on glucose tolerance (P < 0.05). The optimum effective dose on glucose tolerance for six extracts was found to be 1.00 g/kg in diabetic rats with the exception of C. grandis: 0.75 g/kg and L. galanga: 1.25 g/kg. The aqueous extract of G. arborea, S. pinnata, K. zeylanica, S. caryophyllatum, S. dulcis, S. alnifolia, L. galanga and C. grandis possess potent acute antihyperglycaemic activity in alloxan induced diabetic rats.

Fatal hypersensitivity reaction to an oral spray of flurbiprofen: a case report.

PubMed

Calapai, G; Imbesi, S; Cafeo, V; Ventura Spagnolo, E; Minciullo, P L; Caputi, A P; Gangemi, S; Milone, L

2013-08-01

Safety of the anti-inflammatory drug flurbiprofen is comparable with that of other non-steroidal anti-inflammatory drugs of the propionic acid class, which are commonly associated with gastrointestinal and renal side effects. Here we report a case of a fatal hypersensitivity reaction to an oral spray of flurbiprofen taken for sore throat. A 29-year-old man came to the emergency care unit reporting sore throat with an intense burning sensation associated with fever. Pharyngotonsillitis was diagnosed, and local treatment with oral flurbiprofen spray was prescribed. Immediately after using the spray, the patient experienced a severe reaction characterized by serious dyspnoea, followed by death. The cause of death was heart failure with acute asphyxia from oedema of the glottis. The cause of death was concluded to be hypersensitivity to flurbiprofen spray. Oral propionic acid derivatives have been associated with a relatively high frequency of allergic reactions. However, allergy to flurbiprofen has rarely been documented. Scientific literature reports two relevant cases of hypersensitivity reaction to flurbiprofen: in one case, a patient presented with a maculopapular rash 48 h after having taken oral flurbiprofen followed by angio-oedema and hypotension. In another case, a single oral dose of flurbiprofen caused itching and swelling around the eyes, redness and increased lacrimation. We describe, for the first time, a fatal case of hypersensitivity reaction to flurbiprofen oral spray. Hypersensitivity reactions to flurbiprofen are infrequent; however, health professionals should be aware of potential adverse reactions, even during topical administration as oral spray. © 2013 John Wiley & Sons Ltd.

Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval

PubMed Central

Zimmerman, Kanecia; Putera, Martin; Hornik, Christoph P.; Smith, P. Brian; Benjamin, Daniel K.; Mulugeta, Yeruk; Burckart, Gilbert J.; Cohen-Wolkowiez, Michael; Gonzalez, Daniel

2016-01-01

Purpose Over the last decade, few novel antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. Methods We reviewed anti-infective submissions to the FDA (2002–2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. Findings We identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. Implications Future research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults. PMID:27364807

Exposure Matching of Pediatric Anti-infective Drugs: Review of Drugs Submitted to the Food and Drug Administration for Pediatric Approval.

PubMed

Zimmerman, Kanecia; Putera, Martin; Hornik, Christoph P; Brian Smith, P; Benjamin, Daniel K; Mulugeta, Yeruk; Burckart, Gilbert J; Cohen-Wolkowiez, Michael; Gonzalez, Daniel

2016-09-01

Over the last decade, few new antibiotics have been approved by the Food and Drug Administration (FDA) for pediatric use. For most anti-infective agents, including antibiotics, extrapolation of efficacy from adults to children is possible if the disease and therapeutic exposures are similar between the 2 populations. This approach reduces the number of studies required in children, but relies heavily on exposure matching between children and adults. Failures in exposure matching can lead to delays in pediatric approvals of new anti-infective agents. We sought to determine the extent of exposure matching, defined by a comparison of area under the concentration-time curve, between children and adults, for anti-infective drug products submitted to the FDA for approval. We reviewed anti-infective submissions to the FDA (2002-2014) for pediatric indication. We included drug products administered via oral, intravenous, or intramuscular administration routes, and those with AUC estimates for children in available FDA reports. Our main outcome of interest was the proportion of drugs with median (or mean) pediatric AUC within 20% of the median (or mean) reported adult value. We identified 29 drug products that met inclusion criteria, 14 (48%) of which had mean (or median) AUCs of all submitted age groups within 20% of that in adults. Only route of administration and drug class were associated with pediatric AUC within 20% of adult AUC. Future research is needed to define criteria for and predictors of successful exposure matching of anti-infectives between children and adults. Published by Elsevier Inc.

Effect of two hydrophobic polymers on the release of gliclazide from their matrix tablets.

PubMed

Hussain, Talib; Saeed, Tariq; Mumtaz, Ahmad M; Javaid, Zeeshan; Abbas, Khizar; Awais, Azeema; Idrees, Hafiz Arfat

2013-01-01

Gliclazide is an oral hypoglycemic agent, indicated in non insulin dependent diabetes mellitus and in patients with diabetic retinopathy. It has good tolerability and is a short acting sulfonyl urea that requires large dose to maintain the blood glucose level. So development of a sustained release formulation of gliclazide (GLZ) is required for better patient compliance. This study was conducted to assess the effects of different drug polymer ratios on the release profile of gliclazide from the matrix. Oral matrix tablets of gliclazide were prepared by hot melt method, using pure and blended mixture of glyceryl monostearate (GMS) and stearic acid (SA) in different ratios. In vitro release pattern was studied for 8 h in phosphate buffer media (pH 7.4). Different kinetic models including zero order, first order, Higuchi and Peppas were applied to evaluate drug release behavior. Drug excipient compatibility was evaluated by scanning with DSC and FTIR. Higuchi model was found the most appropriate model for describing the release profile of GLZ and non-Fickian release was found predominant mechanism of drug release. The release of drug from the matrix was greatly controlled by GMS while SA appeared to facilitate the release of drug from matrix tablets. FTIR results showed no chemical interaction between drug and the polymers, and DSC results indicated amorphous state of GLZ and polymers without significant complex formation. The results indicate that matrix tablets of gliclazide using glyceryl monostearate and stearic acid showed marked sustained release properties.

Fear of hypoglycaemia: defining a minimum clinically important difference in patients with type 2 diabetes

PubMed Central

Stargardt, Tom; Gonder-Frederick, Linda; Krobot, Karl J; Alexander, Charles M

2009-01-01

Background To explore the concept of the Minimum Clinically Important Difference (MID) of the Worry Scale of the Hypoglycaemia Fear Survey (HFS-II) and to quantify the clinical importance of different types of patient-reported hypoglycaemia. Methods An observational study was conducted in Germany with 392 patients with type 2 diabetes mellitus treated with combinations of oral anti-hyperglycaemic agents. Patients completed the HFS-II, the Treatment Satisfaction Questionnaire for Medication (TSQM), and reported on severity of hypoglycaemia. Distribution- and anchor-based methods were used to determine MID. In turn, MID was used to determine if hypoglycaemia with or without need for assistance was clinically meaningful compared to having had no hypoglycaemia. Results 112 patients (28.6%) reported hypoglycaemic episodes, with 15 patients (3.8%) reporting episodes that required assistance from others. Distribution- and anchor-based methods resulted in MID between 2.0 and 5.8 and 3.6 and 3.9 for the HFS-II, respectively. Patients who reported hypoglycaemia with (21.6) and without (12.1) need for assistance scored higher on the HFS-II (range 0 to 72) than patients who did not report hypoglycaemia (6.0). Conclusion We provide MID for HFS-II. Our findings indicate that the differences between having reported no hypoglycaemia, hypoglycaemia without need for assistance, and hypoglycaemia with need for assistance appear to be clinically important in patients with type 2 diabetes mellitus treated with oral anti-hyperglycaemic agents. PMID:19849828

Predictors for the initiation of a basal supported oral therapy (BOT) in type 2 diabetic patients under real-life conditions in Germany.

PubMed

Kostev, Karel; Dippel, Franz-Werner

2012-12-01

To assess the predictors for the initiation of a basal supported oral therapy (BOT) in type 2 diabetic patients under real-life conditions in Germany. A historical cohort study based on representative German real life data (IMS(®) Disease Analyzer) was performed. The study included patients with type 2 diabetes who started an oral antidiabetic drug (OAD) treatment between 01/1995 and 12/2011. Patients with consecutive treatment data for at least 12 months before the initiation of an OAD treatment were eligible for the analysis. The time-dependent rate of patients starting an insulin therapy with a long-acting insulin was calculated by use of the Kaplan-Meier method. Multivariate Cox regression analyses were applied to identify associated factors. The study included 194,967 patients with type 2 diabetes mellitus being on OAD therapy. 24,964 patients were switched to BOT during the observational period. The probability of switching to insulin therapy was associated with three main predictors such as (1) poor metabolic control, (2) midlife age and (3) number and type of the OAD before insulinization. The variation of the HbA1c threshold to HbA1c≥7.5 leads to comparable outcomes with significant HR. The highest probability of initiating a basal supported oral therapy (BOT) under real life conditions was found for patients with poor metabolic control, midlife age and pre-treatment with specific OADs such as SU, GLI or AGI before initiation of insulin therapy. Copyright © 2012 Primary Care Diabetes Europe. Published by Elsevier Ltd. All rights reserved.

Microemulsion-Based Topical Hydrogels of Tenoxicam for Treatment of Arthritis.

PubMed

Goindi, Shishu; Narula, Manleen; Kalra, Atin

2016-06-01

Tenoxicam (TNX) is a non-steroidal anti-inflammatory drug (NSAID) used for the treatment of rheumatoid arthritis, osteoarthritis, ankylosing spondylitis, backache and pain. However, prolonged oral use of this drug is associated with gastrointestinal adverse events like peptic ulceration, thus necessitating its development as topical formulation that could obviate the adverse effects and improve patient compliance. The present study was aimed at development of microemulsion-based formulations of TNX for topical delivery at the affected site. The pseudoternary phase diagrams were developed and microemulsion formulations were prepared using Captex 300/oleic acid as oil, Tween 80 as surfactant and n-butanol/ethanol as co-surfactant. Optimized microemulsions were characterized for drug content, droplet size, viscosity, pH and zeta potential. The ex vivo permeation studies through Laca mice skin were performed using Franz diffusion cell assembly, and the permeation profile of the microemulsion formulation was compared with aqueous suspension of drug and drug incorporated in conventional cream. Microemulsion formulations of TNX showed significantly higher (p < 0.001) mean cumulative percent permeation values in comparison to conventional cream and suspension of drug. In vivo anti-arthritic and anti-inflammatory activity of the developed TNX formulations was evaluated using various inflammatory models such as air pouch model, xylene-induced ear edema, cotton pellet granuloma and carrageenan-induced inflammation. Microemulsion formulations were found to be superior in controlling inflammation as compared to conventional topical dosage forms and showed efficacy equivalent to oral formulation. Results suggest that the developed microemulsion formulations may be used for effective topical delivery of TNX to treat various inflammatory conditions.

77 FR 13612 - Anti-Infective Drugs Advisory Committee; Notice of Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-03-07

.../phone line to learn about possible modifications before coming to the meeting. Agenda: On April 3, 2012... supplements for LEVAQUIN (levofloxacin) tablets, injection, and oral solution (NDA 20-634, NDA 20-635, and NDA...

Glyburide Is Anti-inflammatory and Associated with Reduced Mortality in Melioidosis

PubMed Central

Maude, Rapeephan R.; Schreiber, M. Fernanda; Limmathurotsakul, Direk; Wiersinga, W. Joost; Wuthiekanun, Vanaporn; Lee, Sue J.; Mahavanakul, Weera; Chaowagul, Wipada; Chierakul, Wirongrong; White, Nicholas J.; van der Poll, Tom; Day, Nicholas P. J.; Dougan, Gordon; Peacock, Sharon J.

2011-01-01

Background. Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This KATP-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection. Methods. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea. Results. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28–.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group. Conclusions. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system. PMID:21293047

Glyburide is anti-inflammatory and associated with reduced mortality in melioidosis.

PubMed

Koh, Gavin C K W; Maude, Rapeephan R; Schreiber, M Fernanda; Limmathurotsakul, Direk; Wiersinga, W Joost; Wuthiekanun, Vanaporn; Lee, Sue J; Mahavanakul, Weera; Chaowagul, Wipada; Chierakul, Wirongrong; White, Nicholas J; van der Poll, Tom; Day, Nicholas P J; Dougan, Gordon; Peacock, Sharon J

2011-03-15

Patients with diabetes mellitus are more prone to bacterial sepsis, but there are conflicting data on whether outcomes are worse in diabetics after presentation with sepsis. Glyburide is an oral hypoglycemic agent used to treat diabetes mellitus. This K(ATP)-channel blocker and broad-spectrum ATP-binding cassette (ABC) transporter inhibitor has broad-ranging effects on the immune system, including inhibition of inflammasome assembly and would be predicted to influence the host response to infection. We studied a cohort of 1160 patients with gram-negative sepsis caused by a single pathogen (Burkholderia pseudomallei), 410 (35%) of whom were known to have diabetes. We subsequently studied prospectively diabetics with B. pseudomallei infection (n = 20) to compare the gene expression profile of peripheral whole blood leukocytes in patients who were taking glyburide against those not taking any sulfonylurea. Survival was greater in diabetics than in nondiabetics (38% vs 45%, respectively, P = .04), but the survival benefit was confined to the patient group taking glyburide (adjusted odds ratio .47, 95% confidence interval .28-.74, P = .005). We identified differential expression of 63 immune-related genes (P = .001) in patients taking glyburide, the sum effect of which we predict to be antiinflammatory in the glyburide group. We present observational evidence for a glyburide-associated benefit during human melioidosis and correlate this with an anti-inflammatory effect of glyburide on the immune system.

Analgesic and anti-inflammatory activities of 80% methanol root extract of Jasminum abyssinicum Hochst. ex. Dc. (Oleaceae) in mice.

PubMed

Tadiwos, Yohannes; Nedi, Teshome; Engidawork, Ephrem

2017-04-18

Pain and inflammation are associated with the pathophysiology of various clinical conditions. Most analgesic and anti-inflammatory drugs available in the market present a wide range of problems. The current study was aimed at investigating the analgesic and anti-inflammatory activity of 80% methanol extract of J. abyssinicum root. The analgesic activity was determined using tail-flick test and acetic acid induced writhing, whereas anti-inflammatory activity was determined by carrageenan induced paw edema and formalin induced pedal edema, carried out in vivo. The test group received three different doses of the extract (50mg/kg, 100mg/kg and 200mg/kg) orally. The positive control group received diclofenac (10mg/kg), aspirin (100mg/kg or 150mg/kg) or morphine (20mg/kg) orally. The negative control group received vehicle (2% Tween 80, 10ml/kg) orally. Furthermore, preliminary phytochemical screening was carried out. Oral administration of J. abbysinicum 80% methanol extract (at all doses) significantly (p<0.001) inhibit pain sensation in the pain models. Similarly, the extract demonstrated anti-inflammatory effect in the inflammation models in mice. Preliminary phytochemical screening showed the presence of saponins, flavonoids, terpenoids, triterpenens and glycosides. The data obtained from the present study indicates that the extract possessed a significant analgesic and anti-inflammatory activity, upholding the folkloric use of the plant. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Antidiabetic, antioxidant and anti inflammatory properties of water and n-butanol soluble extracts from Saharian Anvillea radiata in high-fat-diet fed mice.

PubMed

Kandouli, Chouaib; Cassien, Mathieu; Mercier, Anne; Delehedde, Caroline; Ricquebourg, Emilie; Stocker, Pierre; Mekaouche, Mourad; Leulmi, Zineb; Mechakra, Aicha; Thétiot-Laurent, Sophie; Culcasi, Marcel; Pietri, Sylvia

2017-07-31

According to Saharian traditional medicine, Anvillea radiata Coss. & Dur. (Asteraceae) has been valued for treating a variety of ailments such as gastro-intestinal, liver and pulmonary diseases, and has gained awareness for its beneficial effect on postprandial hyperglycemia. However, to best of our knowledge, no detailed study of the antidiabetic curative effects of this plant has been conducted yet. To determine the hypoglycemic and antidiabetic effect of dietary supplementation with Anvillea radiata extracts on high-fat-diet (HFD)-induced obesity and insulin resistance in C57BL/6J mice in relation with antioxidant, anti-inflammatory, pancreatic beta-cells and skeletal muscle protection, and digestive enzyme inhibiting properties. Six extracts (water soluble and organic) from aerial parts of the plant were analyzed phytochemically (total phenolic and flavonoid content) and screened for in vitro superoxide (by chemiluminescence) and hydroxyl radical (by electron paramagnetic resonance spin-trapping) scavenging, antioxidant (DPPH, TRAP and ORAC assays), xanthine oxidase, metal chelating, α-amylase and α-glucosidase inhibitory property, and protective effects on copper-induced lipoprotein oxidation. Then selected hydroalcoholic and aqueous extracts were assessed for toxicity in normal human lung fibroblasts and A549 cancer cells using FMCA and MTT assays. Two water-soluble extracts having the best overall properties were assessed for their (i) protective effect at 1-15µg/mL on metabolic activity of rat insulinoma-derived INS-1 cells exposed to hyperglycemic medium, and (ii) acute hypoglycemic effect on 16-weeks HFD-induced diabetic mice. Then diabetic mice were administered HFD supplemented by extracts (up to 150mg/kg/day) for 12 additional weeks using standard diet as control and the antidiabetic drug, metformin (150mg/kg), as positive control. Then the antidiabetic, anti-inflammatory and antioxidant activity of extracts were determined. Of the highly efficient polyphenolics-enriched hydroalcoholic and ethyl acetate extracts, the lyophilized aqueous (AQL) and butanol extracts were not toxic in cells (≤ 400µg/mL) or when given orally in normal mice (≤ 2000mg/kg), exerted a dose-dependent hypoglycemic action in diabetic mice, which was maximal at the dose of 150mg/kg. Upon administering this dose for 12 weeks, both extracts significantly ameliorated body weight control capacity, recovery of plasma glucose and insulin level, reduced oxidative stress in blood, myocardial and skeletal muscles, and improved hyperlipidemic and inflammatory status. Moreover, diabetes-related complications were optimally ameliorated by oral therapy based on halved doses (75mg/kg) of a mixture of AQL and metformin. Current investigation supports the traditional medicinal usage of Anvillea radiata and suggests that both readily accessible and low-cost bio-extracts have the potency to develop an antihyperglycemic, antihyperlipidemic and protective agent against beta-cells and muscle dysfunction at doses compatible with the common practices of indigenous people for the management of metabolic disorders. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

Spectrophotometric and HPLC determinations of anti-diabetic drugs, rosiglitazone maleate and metformin hydrochloride, in pure form and in pharmaceutical preparations.

PubMed

Onal, Armağan

2009-12-01

In this study, three spectrophotometric methods and one HPLC method were developed for analysis of anti-diabetic drugs in tablets. The two spectrophotometric methods were based on the reaction of rosiglitazone (RSG) with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and bromocresol green (BCG). Linear relationship between the absorbance at lambda(max) and the drug concentration was found to be in the ranges 6.0-50.0 and 1.5-12 microg ml(-1) for DDQ and BCG methods, respectively. The third spectrophotometric method consists of a zero-crossing first-derivative spectrophotometric method for simultaneous analysis of RSG and metformin (MTF) in tablets. The calibration curves were linear within the concentration ranges of 5.0-50 microg ml(-1) for RSG and 1.0-10.0 microg ml(-1) for MTF. The fourth method is a rapid stability-indicating HPLC method developed for the determination of RSG. A linear response was observed within the concentration range of 0.25-2.5 microg ml(-1). The proposed methods have been successfully applied to the tablet analysis.

PIXE analysis of some Nigerian anti-diabetic medicinal plants (II)

NASA Astrophysics Data System (ADS)

Olabanji, S. O.; Adebajo, A. C.; Omobuwajo, O. R.; Ceccato, D.; Buoso, M. C.; Moschini, G.

2014-01-01

Diabetes mellitus, a metabolic disease characterized by high blood glucose levels (hyperglycemia) due to defects in insulin secretion, or action, or both, is a debilitating disease leading to other complications and death of many people in the world. Some of the medicinal plants implicated in the herbal recipes for the treatment of diabetes in Nigeria have been reported. Additional medicinal plants used for the treatment of diabetes in Nigeria are presented in this work. These medicinal plants are becoming increasingly important and relevant as herbal drugs due to their use as antioxidants, nutraceuticals, food additives and supplements in combating diabetes. Elemental compositions of these anti-diabetic medicinal plants were determined using PIXE technique. The 1.8 MV collimated proton beam from the 2.5 MV AN 2000 Van de Graaff accelerator at Istituto Nazionale di Fisica Nucleare (INFN), Laboratori Nazionali di Legnaro (LNL) Legnaro (Padova) Italy was employed for the work. The results show the detection of twenty-one elements which include Mg, P, Ca, K, Mn, Cu, Zn, S, Cr, Co, Ni and V that are implicated in the regulation of insulin and the control of the blood-sugar levels in the human body. The entire plant of Boerhavia diffusa, Securidaca longipedunculata stem, leaves of Peperomia pellucida, Macrosphyra longistyla, Olax subscorpioidea, Phyllanthus muerillanus, Jatropha gossypifolia, Cassia occidentalis, Phyllanthus amarus, and leaf and stem of Murraya koenigii, which have high concentrations of these elements could be recommended as vegetables, nutraceuticals, food additives, supplements and drugs in the control and management of diabetes, if toxicity profiles indicate that they are safe. However, significantly high contents of Al and Si in the entire plant of Bryophyllum pinnatum, and As, Cr, and Cu in Ocimum gratissimum leaf suggest that these plants should be avoided by diabetic patients to prevent complications.

Interaction of insulin with prokinetic drugs in STZ-induced diabetic mice

PubMed Central

Shalaby, Mohamed A Fouad; Latif, Hekma A Abd El; Sayed, Mostafa E El

2013-01-01

AIM: To study the possible interactions of metoclopramide, domperidone and erythromycin in streptozotocin-induced diabetic mice treated with insulin by various parameters. METHODS: Effects of the individual as well as combined drugs were studied in diabetic mice via estimation of the blood glucose and serum insulin levels, small intestinal transit (SIT), gastric emptying (GE), xylose absorption and glucose tolerance tests. Groups were given insulin 2 IU/kg s.c., metoclopramide 20 mg/kg p.o., domperidone 20 mg/kg p.o. and erythromycin 6 mg/kg p.o. individually and in combination. There were also normal and diabetic control groups. The first set of experiments was carried out to investigate the subchronic effect on blood glucose and serum insulin levels in diabetic mice of one week of daily dose administration of the tested drugs individually as well as the combination of insulin with each prokinetic drug. The other five sets of experiments were carried out to investigate the acute effect of a single dose of each drug individually and in combination on blood glucose and serum insulin levels, SIT, GE, oral xylose absorption and glucose tolerance tests. RESULTS: The study included the prokinetic drugs metoclopramide (20 mg/kg), domperidone (20 mg/kg) and erythromycin (6 mg/kg), as well as insulin (2 IU/kg), which was individually effective in decreasing SIT, enhancing GE and increasing xylose absorption significantly in diabetic mice. Erythromycin tended to decrease blood glucose level and increase serum insulin level after 1 wk of daily administration in diabetic mice. Erythromycin potentiated the effect of insulin on blood glucose level and serum insulin level whereas other prokinetic agents failed to do so after repeated dose administration in diabetic mice. Metoclopramide or erythromycin in combination with insulin significantly decreased SIT, in diabetic mice, to lower levels than with insulin alone. Administration of prokinetic drugs along with insulin antagonized the action of insulin on xylose absorption. These combinations also increased the rate of glucose absorption from the gut. CONCLUSION: The present study suggests that prokinetic drugs could potentially improve glycemic control in diabetic gastroparesis by allowing a more predictable absorption of nutrients, matched to the action of exogenous insulin. The use of prokinetics, such as erythromycin, may be interesting in the clinic in decreasing the need for insulin in diabetic patients. The dose of insulin may be safely decreased with erythromycin in chronic treatments. PMID:23667771

High performance thin layer chromatography fingerprinting, phytochemical and physico-chemical studies of anti-diabetic herbal extracts

PubMed Central

Itankar, Prakash R.; Sawant, Dattatray B.; Tauqeer, Mohd.; Charde, Sonal S.

2015-01-01

Introduction: Herbal medicines have gained increasing popularity in the last few decades, and this global resurgence of herbal medicines increases their commercial value. However, this increasing demand has resulted in a decline in their quality, primarily due to a lack of adequate regulations pertaining to herbal medicines. Aim: To develop an optimized methodology for the standardization of herbal raw materials. Materials and Methods: The present study has been designed to examine each of the five herbal anti-diabetic drugs, Gymnema sylvester R. Br., Pterocarpus marsupium Roxburgh., Enicostema littorale Blume., Syzygium cumini (L.) Skeels. and Emblica officinalis Gaertn. The in-house extracts and marketed extracts were evaluated using physicochemical parameters, preliminary phytochemical screening, quantification of polyphenols (Folin–Ciocalteu colorimetric method) and high performance thin layer chromatography (HPTLC) fingerprint profiling with reference to marker compounds in plant extracts. Results: All the plants mainly contain polyphenolic compounds and are quantified in the range of 3.6–21.72% w/w. E. officinalis contain the highest and E. littorale contain the lowest content of polyphenol among plant extracts analyzed. HPTLC fingerprinting showed that the in-house extracts were of better quality than marketed extracts. Conclusion: The results obtained from the study could be utilized for setting limits for the reference phytoconstituents (biomarker) for the quality control and quality assurance of these anti-diabetic drugs. PMID:27011722

The effects of anti-hypertensives and type 2 diabetes on salivary flow and total antioxidant capacity.

PubMed

Djukić, L J; Roganović, J; Brajović, M D; Bokonjić, D; Stojić, D

2015-07-01

The present cross-sectional study aimed to determine the effect of first-line anti-hypertensive drugs (enalapril, metoprolol, and combinations of enalapril with metoprolol and/or hydrochlorothiazide) on salivary gland function and salivary total antioxidant capacity (TAC) in hypertensive patients with/without diabetes mellitus (DM) type 2. Salivary gland function was measured as xerostomia (interview) and unstimulated whole saliva flow rate (UWSFR) in 447 subjects (387 hypertensive and 60 healthy). Salivary TAC was evaluated by spectrophotometric assay. Enalapril is not xerogenic, while metoprolol and drug combinations are. In the presence of DM type 2, all drugs, except metoprolol, had pronounced xerogenic effect. Binary logistic regression analysis found enalapril to be significantly associated with decreased risk of xerogenic effect development, while DM type 2 with increased risk. In the presence of enalapril in hypertensive patients with/without DM type 2 salivary TAC was similar to that in healthy subjects, while for metoprolol was reduced. Enalapril is not xerogenic but is antioxidant, which moderately reduces the risk of xerogenic effect development even in the presence of DM type 2. However, metoprolol and drug combinations exhibit xerogenic effect. In DM type 2, xerogenic effect of all drugs was pronounced except of metoprolol. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Obesity pharmacotherapy: What is next?

PubMed Central

Colon-Gonzalez, Francheska; Kim, Gilbert W.; Lin, Jieru E.; Valentino, Michael A.; Waldman, Scott A.

2014-01-01

The increase in obesity in the Unites States and around the world in the last decade is overwhelming. The number of overweight adults in the world surpassed 1 billion in 2008. Health hazards associated with obesity are serious and include heart disease, sleep apnea, diabetes, and cancer. Although lifestyle modifications are the most straightforward way to control weight, a large portion of the population may not be able to rely on this modality alone. Thus, the development of anti-obesity therapeutics represents a major unmet medical need. Historically, anti-obesity pharmacotherapies have been unsafe and minimally efficacious. A better understanding of the biology of appetite and metabolism provides an opportunity to develop drugs that may offer safer and more effective alternatives for weight management. This review discusses drugs that are currently on the market and in development as anti-obesity therapeutics based on their target and mechanism of action. It should serve as a roadmap to establish expectations for the near future for anti-obesity drug development. PMID:23103610

A site-specific PEGylated analog of exendin-4 with improved pharmacokinetics and pharmacodynamics in vivo.

PubMed

Gao, Mingming; Jin, Yuhao; Tong, Yue; Tian, Hong; Gao, Xiangdong; Yao, Wenbing

2012-11-01

Our aim was to improve the in vivo pharmacokinetics and pharmacodynamics of exendin-4 by using site-specific PEGylation. We designed the PEGylated peptide based on its structure and activity relationship and prepared the conjugate by two steps of chromatographic purification. After obtained the conjugate we confirmed its glucose-lowering activity in normal mice and determined its half-life in SD rats. Then we evaluated its anti-diabetic activity in a multiple low-dose Streptozocin (STZ)-induced diabetic mice model. With the process established in this study the product conjugate was obtained with a yield of over 60% and purity of above 99%. The conjugate maintained its original conformation after modification. In SD rats its half-life was prolonged to 27.12 ± 5.75 h which was 17.61-fold longer than that of the natural exendin-4 for which the half-life was only 1.54 ± 0.47 h. Its anti-diabetic activity was significantly improved in the diabetic mice. Compare with native exendin-4, the C-terminal site-specific PEGylated analog of exendin-4 obtained in this study has an improved pharmacokinetics and pharmacodynamics in vivo and could be regarded as a potential candidate for the future development of anti-diabetic drugs. © 2012 The Authors. JPP © 2012 Royal Pharmaceutical Society.

Cost-effectiveness analysis of exenatide twice daily (BID) vs insulin glargine once daily (QD) as add-on therapy in Chinese patients with Type 2 diabetes mellitus inadequately controlled by oral therapies.

PubMed

Deng, Jing; Gu, Shuyan; Shao, Hui; Dong, Hengjin; Zou, Dajin; Shi, Lizheng

2015-01-01

To estimate cost-effectiveness of exenatide twice daily (BID) vs insulin glargine once daily (QD) as add-on therapy in Chinese type 2 diabetes patients not well controlled by oral anti-diabetic (OAD) agents. The Cardiff model was populated with data synthesized from three head-to-head randomized clinical trials of up to 30 weeks in China comparing exenatide BID vs insulin glargine as add-on therapies to oral therapies in the Chinese population. The Cardiff model generated outputs including macrovascular and microvascular complications, diabetes-specific mortality, costs, and quality-adjusted life years (QALYs). Cost and QALYs were estimated with a time horizon of 40 years at a discount rate of 3% from a societal perspective. Compared with insulin glargine plus OAD treatments, patients on exenatide BID plus OAD gained 1.88 QALYs, at an incremental cost saving of Chinese Renminbi (RMB) 114,593 (i.e., cost saving of RMB 61078/QALY). The cost-effectiveness results were robust to various sensitivity analyses including probabilistic sensitivity analysis. The variables with the most impact on incremental cost-effectiveness ratio included HbA1c level at baseline, health utilities decrement, and BMI at baseline. Compared with insulin glargine QD, exenatide BID as add-on therapy to OAD is a cost-effective treatment in Chinese patients inadequately controlled by OAD treatments.

Levetiracetam synergises with common analgesics in producing antinociception in a mouse model of painful diabetic neuropathy.

PubMed

Micov, Ana; Tomić, Maja; Pecikoza, Uroš; Ugrešić, Nenad; Stepanović-Petrović, Radica

2015-07-01

Painful diabetic neuropathy is difficult to treat. Single analgesics often have insufficient efficacy and poor tolerability. Combination therapy may therefore be of particular benefit, because it might provide optimal analgesia with fewer adverse effects. This study aimed to examine the type of interaction between levetiracetam, a novel anticonvulsant with analgesic properties, and commonly used analgesics (ibuprofen, aspirin and paracetamol) in a mouse model of painful diabetic neuropathy. Diabetes was induced in C57BL/6 mice with a single high dose of streptozotocin, applied intraperitoneally (150 mg/kg). Thermal (tail-flick test) and mechanical (electronic von Frey test) nociceptive thresholds were measured before and three weeks after diabetes induction. The antinociceptive effects of orally administered levetiracetam, analgesics, and their combinations were examined in diabetic mice that developed thermal/mechanical hypersensitivity. In combination experiments, the drugs were co-administered in fixed-dose fractions of single drug ED50 and the type of interaction was determined by isobolographic analysis. Levetiracetam (10-100 mg/kg), ibuprofen (2-50 mg/kg), aspirin (5-75 mg/kg), paracetamol (5-100 mg/kg), and levetiracetam-analgesic combinations produced significant, dose-dependent antinociceptive effects in diabetic mice in both tests. In the tail-flick test, isobolographic analysis revealed 15-, and 19-fold reduction of doses of both drugs in the combination of levetiracetam with aspirin/ibuprofen, and paracetamol, respectively. In the von Frey test, approximately 7- and 9-fold reduction of doses of both drugs was detected in levetiracetam-ibuprofen and levetiracetam-aspirin/levetiracetam-paracetamol combinations, respectively. These results show synergism between levetiracetam and ibuprofen/aspirin/paracetamol in a model of painful diabetic neuropathy and might provide a useful approach to the treatment of patients suffering from painful diabetic neuropathy. Copyright © 2015 Elsevier Ltd. All rights reserved.

Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs.

PubMed

Agrawal, Mukta; Saraf, Swarnlata; Saraf, Shailendra; Antimisiaris, Sophia G; Chougule, Mahavir Bhupal; Shoyele, Sunday A; Alexander, Amit

2018-07-10

According to the Alzheimer Association Report (2017), Alzheimer's disease (AD) is the 6th primary cause of death in the USA, which affects nearly 5.5 million people. In the year 2017 itself, the cost of AD treatment in the USA has been reported to rise to $259 billion. This statistic shows the severity of the disease in the USA which is very much similar across the globe. On the other hand, the treatment remains limited to a few conventional oral medications (approved by FDA). These are mainly acting superficially from mild to the moderate AD. The therapeutic efficacy of the drug is not only affected by its reduced concentration in the brain owing to the existence of blood-brain-barrier (BBB) but also due to its low brain permeability. In this context, the intranasal (IN) route of drug administration has emerged as an alternative route over the systemic (oral and parenteral) drug delivery to the brain. The delivery of the drug via an IN route offers various advantages over systemic drug delivery system, as it directly delivers the drug into the brain via olfactory route. Presence of drug in the olfactory bulb, in turn, increases the drug bioavailability in the brain and reduces the drug degradation as well as wastage of the drug through` systemic clearance. However, there is also some limitation associated with IN like poor drug permeation through the nasal mucosa and mucociliary clearance. The delivery system various through novel strategies (nano drug carrier system, colloidal carriers, mucoadhesive devices, controlled delivery system, pro-drug, etc.) are adapted to overcome the above-stated limitations. Although, after all, such successful research claims, very few of the nose-to-brain drug delivery of anti-AD drugs have gained market approval due to lack of sufficient clinical evidence. Onzetra Xsail® is one such marketed preparations approved for IN delivery used for the treatment of a brain disorder; migraine. In the field of patents also, no work is found which could present sufficient experimental findings to support its clinical safety profile. It also underlines the fact that majority of work related to the nose-to-brain delivery of anti-AD drugs is limited only up to preclinical studies. In this review article, we have discussed the latest works on various novel formulations loaded with various anti-Alzheimer agents. These agents include galantamine, deferoxamine, tacrine, tarenflurbil, rivastigmine, risperidone, curcumin, quercetin, piperine, insulin, etc. and various peptides towards the development of a promising IN drug delivery system for the treatment of AD. Through this review article, we want to drag the attention of the researchers working in this field towards the challenges and hurdles of practical applicability IN delivery of anti-AD drugs. Moreover, the attention towards the clinical studies will ease the approval process for the administration of anti-Alzheimer drugs via IN route. Copyright © 2018 Elsevier B.V. All rights reserved.

PPARγ and its ligands: therapeutic implications in cardiovascular disease

PubMed Central

Villacorta, Luis; Schopfer, Francisco J.; Zhang, Jifeng; Freeman, Bruce A.; Chen, Y. Eugene

2009-01-01

The relevance of peroxisome proliferator-activated receptor-γ (PPARγ) as an important therapeutic target for the treatment of diabetes arises from its hypoglycemic effects in diabetic patients and also from the critical role in the regulation of cardiovascular functions. From a clinical perspective, differences between currently FDA-approved PPARγ drugs have been observed in terms of atherosclerosis, cardiac and stroke events. The adverse effects of PPARγ-specific treatments that hamper their cardiovascular protective roles, affirm the strong need to evaluate the efficacy of the current drugs. Therefore, active research is directed towards high-throughput screening and pharmacologic testing of a plethora of newly identified natural or synthetic compounds. Here we describe the rationale behind drug design strategies targeting PPARγ, based on current knowledge regarding the effects of such drugs in experimental animal models as well as in the clinical practice. Regarding endogenous PPARγ ligands, several fatty acid derivatives bind PPARγ with different affinity, though the physiological relevance of these interactions is not always evident. Recently, nitric oxide-derived unsaturated fatty acids were found to be potent agonists of PPARs, with preferential affinity for PPARγ, compared to oxidized fatty acid derivatives. Nitroalkenes exert important bioactivities of relevance for the cardiovascular system including anti-inflammatory and anti-platelet actions and are important mediators of vascular tone. A new generation of insulin sensitizers with PPARγ function for the treatment of diabetes, may serve to limit patients from the increased cardiovascular burden of this disease. PMID:19118492

Oral administration of Nitraria retusa ethanolic extract enhances hepatic lipid metabolism in db/db mice model 'BKS.Cg-Dock7(m)+/+ Lepr(db/)J' through the modulation of lipogenesis-lipolysis balance.

PubMed

Zar Kalai, Feten; Han, Junkyu; Ksouri, Riadh; Abdelly, Chedly; Isoda, Hiroko

2014-10-01

The medicinal plants can be used in the prevention or treatment of many diseases. Several studies concerning the potential of bioactive components in plants and food products and their link to obesity and related metabolic disorders, have been gaining big interest. Diabetes is a serious metabolic syndrome. Searching for alternative natural bioactive molecules is considered main strategy to manage diabetes through weight management. In the present study, an edible halophyte Nitraria retusa was selected and in vivo experiment was conducted using db/db model mice. We orally administrated its ethanol extract (NRE) to BKS.Cg-Dock7(m)+/+ Lepr(db/)J mice model for a period of 4 weeks. The effect was evaluated on the body weight and adiposity changes and on the biochemical parameters of db/db NRE-treated mice. The molecular mechanism underlying the anti-obesity effect was investigated by testing the gene expression related to hepatic lipid metabolism. NRE was found to significantly supress increases in body and fat mass weight, decreases triglycerides and LDL-cholesterol levels and enhances gene expression related to lipid homeostasis in liver showing anti-obesity actions. Our findings, indicate that NRE possesses potential anti-obesity effects in BKS.Cg-Dock7(m)+/+ Lepr(db/)J model mice and may relieve obesity-related symptoms including hyperlipidemia through modulating the lipolysis-lipogenesis balance. Copyright © 2014 Elsevier Ltd. All rights reserved.

Diabetic foot infections: microbiological aspects, current and future antibiotic therapy focusing on methicillin-resistant Staphylococcus aureus.

PubMed

Ambrosch, Andreas; Haefner, Simone; Jude, Edward; Lobmann, Ralf

2011-12-01

Diabetic patients are at increased risk of complicated skin, skin structure and bone infections including infections of diabetic foot ulcerations (DFU). Analyses of epidemiology and microbial pathogenicity show that staphylococci seem to be predestined to induce such infections. In addition, multidrug resistance particularly due to an increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) seems to be the challenge for effective antibiotic therapy. With regard to infections with MRSA, classical agents like vancomycin, linezolid, fosfomycin or trimethroprim-sulphametoxazol might be agents of choice in DFU. New-generation drugs including broad-spectrum tetracyclines like tigecycline, first and second generation of cyclic lipopeptides, anti-MRSA β-lactams including ceftobiprole and anti-MRSA antibodies are developed or in progress and the hope for the future. © 2011 The Authors. © 2011 Blackwell Publishing Ltd and Medicalhelplines.com Inc.

In Vivo Hypoglycemic Effect of Kigelia africana (Lam): Studies With Alloxan-Induced Diabetic Mice.

PubMed

Njogu, Stephen M; Arika, Wycliffe M; Machocho, Alex K; Ngeranwa, Joseph J N; Njagi, Eliud N M

2018-01-01

The claims by the traditional herbal medicine practitioners that Kigelia africana has bioactivity against several diseases, including diabetes mellitus, were investigated in this study. Type I diabetes mellitus was induced in mice by intraperitoneal administration of alloxan monohydrate followed by treatment with the therapeutic doses of the aqueous and ethyl acetate leaf extract of K africana to the experimentally diabetic mice. The treatment effects were compared with the normal control, diabetic control, and diabetic control rats treated with a standard antidiabetic drugs (insulin administered intraperitoneally at 1 IU/kg body weight in 0.1 mL physiological saline or glibenclamide administered orally at 3 mg/kg body weight in 0.1 mL physiological saline). Phytochemical composition of the leaf extract was assessed using standard procedures and mineral elements assessed using atomic absorption spectrophotometry and total reflection X-ray fluorescence system. Oral and intraperitoneal administration of the aqueous and ethyl acetate leaf extract caused a statistically significant dose-independent reduction in plasma glucose level in alloxan-induced diabetic mice. The observed hypoglycemic activity of this plant extract could be attributed to the observed phytochemicals and trace elements, which have been associated with exhibiting antidiabetic properties. Therefore, the data appear to support the hypoglycemic effects of K africana validating its folkloric usage.

Hydroethanolic extract of the inner stem bark of Cedrela odorata has low toxicity and reduces hyperglycemia induced by an overload of sucrose and glucose.

PubMed

Giordani, Morenna Alana; Collicchio, Thiago Carvalho Mamede; Ascêncio, Sergio Donizeti; Martins, Domingos Tabajara de Oliveira; Balogun, Sikiru Olaitan; Bieski, Isanete Geraldini Costa; da Silva, Leilane Aparecida; Colodel, Edson Moleta; de Souza, Roberto Lopes; de Souza, Damiana Luiza Pereira; de França, Suélem Aparecida; Andrade, Claudia Marlise Balbinotti; Kawashita, Nair Honda

2015-03-13

Cedrela odorata L. (Meliaceae) is a native plant of the Amazon region and its inner stem bark is used in the treatment of diabetes in the form of maceration in Brazilian popular medicine. Until now, there is no scientific study on this activity. The present study was aimed at evaluating the anti-hyperglycemic activity, anti-diabetic, toxicity, antioxidant and potential mechanism of action of hydroethanolic extract of the inner stem bark of Cedrela odorata. The inner stem bark extract of Cedrela odorata was prepared by maceration in 70% ethanol for 7 days to obtain hydroethanolic extract of Cedrela odorata (HeECo). The preliminary phytochemical analysis was performed according to procedures described in the literature. Selected secondary metabolites detected were quantified by high performance liquid chromatography (HPLC). Acute toxicity of HeECo was investigated in male and female mice with oral administration of graded doses of HeECo from 10 to 5000 mg/kg. Subchronic oral toxicity study was done by oral administration of HeECo (500 mg/kg) and vehicle for 30 days to both sexes of Wistar rats. Clinical observations and toxicological related parameters were determined. Blood was collected for biochemical and hematological analyses, while histological examinations were performed on selected organs. Anti-hiperglycemic and antidiabetic effects were evaluated in streptozotocin-induced diabetic rats. In acute evaluation, the animals received pretreatment with 250 and 500 mg/kg of HeECo, before carbohydrate overload. For subchronic effect, the antidiabetic activity of HeECo was evaluated using the same doses for 21 days. At the end of the treatments, the levels of triacylglycerols, malondialdehyde, total antioxidant status, superoxide dismutase and glutathione peroxidase activities were evaluated in the plasma. The extract showed low acute toxicity. HeECo exhibited inhibitory activity against α-glucosidase and caused a lowering in the peak levels of blood glucose in animals that received glucose overload by 36.7% and 24.1% in the area under the glucose curve (AUC). When the overload was sucrose, HeECo reduced the blood glucose level by 44.4% without affecting AUC. Treatment with HeECo of the blood glucose of the diabetic animals for 21 days did not lead to improvement in weight gain and regularization of the blood glucose level, but reduced the triacylglycerol and malondialdehyde levels by 36.6% and 48.1%, respectively. The activity of the antioxidant enzymes, superoxide dismutase and glutathione peroxidase were significantly increased when compared to diabetic control rats. HPLC analysis showed the presence of polyphenols, such as gallic acid, (-)- gallocatechin and (+)- catechin, the latter is present in higher quantity. Collectively, these data showed that HeECo could blunt the postprandial glycemic surge in rats; possibly through inhibition of alpha-glucosidase and positive modulation of antioxidant enzymes. Our findings confirmed the anti-hiperglycemic activity of HeECo in STZ- diabetic rats. Cedrela odorata is effective in diminishing glucose levels in vitro and in vivo and in ameliorating oxidative damage that occurs in diabetes and/or due to hyperglycemia in rats. According to our results, the efficacy of Cedrela odorata preparation could be due to the presence of active principles with different mode of actions at the molecular level, including α-glycosidases and glucose transporter inhibitors and antioxidant property. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Research: Treatment Study to determine the durability of glycaemic control with early treatment with a vildagliptin–metformin combination regimen vs. standard-of-care metformin monotherapy—the VERIFY trial: a randomized double-blind trial

PubMed Central

Del Prato, S; Foley, J E; Kothny, W; Kozlovski, P; Stumvoll, M; Paldánius, P M; Matthews, D R

2014-01-01

Aims Durability of good glycaemic control (HbA1c) is of importance as it can be the foundation for delaying diabetic complications. It has been hypothesized that early initiation of treatment with the combination of oral anti-diabetes agents with complementary mechanisms of action can increase the durability of glycaemic control compared with metformin monotherapy followed by a stepwise addition of oral agents. Dipeptidyl peptidase-4 inhibitors are good candidates for early use as they are efficacious in combination with metformin, show weight neutrality and a low risk of hypoglycaemia. We aimed to test the hypothesis that early combined treatment of metformin and vildagliptin slows β-cell deterioration as measured by HbA1c. Methods Approximately 2000 people with Type 2 diabetes mellitus who were drug-naive or who were treated with metformin for less than 1 month, and who have HbA1c of 48–58 mmol/mol (6.5–7.5%), will be randomized in a 1:1 ratio in VERIFY, a 5-year multinational, double-blind, parallel-group study designed to compare early initiation of a vildagliptin–metformin combination with standard-of-care initiation of metformin monotherapy, followed by the stepwise addition of vildagliptin when glycaemia deteriorates. Further deterioration will be treated with insulin. The primary analysis for treatment failure will be from a Cox proportional hazard regression model and the durability of glycaemic control will be evaluated by assessing treatment failure rate and the rate of loss in glycaemic control over time as co-primary endpoints. Summary VERIFY is the first study to investigate the long-term clinical benefits of early combination treatment vs. the standard-of-care metformin monotherapy with a second agent added by threshold criteria. PMID:24863949

Interaction of Herbs and Glibenclamide: A Review

PubMed Central

Rai, Amita; Eapen, Cicy; Prasanth, V. G.

2012-01-01

Herbs and herbal products are considered to be safer and people mix it often with the oral hypoglycemic agent in diabetes therapy. But numerous reports say that every combination of herbs and drugs is not safe. Some combinations may be beneficial and some may be harmful also. So before taking any herbal remedies with oral hypoglycemic agent, patient should consult physician. In this paper we are summarizing the reports available on the interaction of herbal remedies to one of the oral hypoglycemic agents (glibenclamide) and categorizing the effect of the combination is beneficial and harmful. PMID:22844612

Hypoglycemic and hypolipidemic effects of triterpenoid-enriched Jamun (Eugenia jambolana Lam.) fruit extract in streptozotocin-induced type 1 diabetic mice.

PubMed

Xu, Jialin; Liu, Tingting; Li, Yuanyuan; Yuan, Chunhui; Ma, Hang; Seeram, Navindra P; Liu, Feifei; Mu, Yu; Huang, Xueshi; Li, Liya

2018-06-20

The edible berries of Eugenia jambolana Lam. (known as Jamun) are consumed in various parts of the world. Our previous studies revealed that a triterpenoid-enriched Jamun fruit extract (TJFE) showed beneficial effects on glucose homeostasis in non-diabetic mice. Herein, the anti-diabetic effects of TJFE (100 mg kg-1 by oral gavage for ten days) were evaluated in streptozotocin (STZ)-induced type 1 diabetic mice. TJFE significantly attenuated STZ-induced hyperglycemia and glucose intolerance, suppressed the abnormal elevation of hepatic gluconeogenesis, and improved dyslipidemia in the mice. Histopathology and mechanism-based studies revealed that TJFE preserved the architecture and function of pancreatic islets, attenuated insulin secretion deficiency, enhanced insulin/Akt signaling transduction, reduced lipogenic gene expression, and prevented the abnormal activation of Erk MAPK in the liver tissues of the STZ-induced diabetic mice. The current study adds to previously published data supporting the potential beneficial effects of this edible fruit on diabetes management.

Further Studies on Antioxidant Potential and Protection of Pancreatic β-Cells by Embelia ribes in Experimental Diabetes

PubMed Central

Bhandari, Uma; Jain, Neeti; Pillai, K. K.

2007-01-01

This study was designed to examine the antioxidant defense by ethanolic extract of Embelia ribes on streptozotocin-(40 mg/kg, intravenously, single-injection) induced diabetes in Wistar rats. Forty days of oral feeding the extract (100 mg/kg and 200 mg/kg) to diabetic rats resulted in significant (P < .01) decrease in blood glucose, blood glycosylated haemoglobin, serum lactate dehydrogenase, creatine kinase, and increase in blood glutathione levels as compared to pathogenic diabetic rats. Further, the extract also significantly (P < .01) decreased the pancreatic thiobarbituric acid-reactive substances (TBARS) levels and significantly (P < .01) increased the superoxide dismutase, catalase, and glutathione levels as compared to above levels in pancreatic tissue of pathogenic diabetic rats. The islets were shrunken in diabetic rats in comparison to normal rats. In the drug-treated diabetic rats, there was expansion of islets. The results of test drug were comparable to gliclazide (25 mg/kg, daily), a standard antihyperglycemic agent. The study concludes that Embelia ribes enhances the antioxidant defense against reactive oxygen species produced under hyperglycemic condition and this protects β-cells against loss, and exhibit antidiabetic property. PMID:17641739

Drug-induced bullous pemphigoid in diabetes mellitus patients receiving dipeptidyl peptidase-IV inhibitors plus metformin.

PubMed

Skandalis, K; Spirova, M; Gaitanis, G; Tsartsarakis, A; Bassukas, I D

2012-02-01

Preclinical data and reports of adverse skin reactions in patients treated with dipeptidyl peptidase-IV inhibitors (gliptins) have increased awareness towards skin-targeting side-effects of these anti-hyperglycaemic drugs. Bullous pemphigoid (BP), sometimes drug-induced, is the most commonly acquired autoimmune blistering dermatosis in western countries, typically a disease of the elderly people with significant morbidity and excess mortality. To report the development of BP in five diabetics under gliptin (4 vildagliptin, 1 sitagliptin) plus metformin in fixed-dose drug combinations. From March to August 2010 six out of nine newly diagnosed BP patients in our Department were type 2 diabetics. Five of them were on gliptin plus metformin (three different trade preparations) for 2-13 months prior to BP onset. In all cases BP was controlled after withdrawal of the suspected medication and relatively mild therapeutic interventions. In two cases the eliciting role of the preceding treatment is supported by evidence at the level 'probable/likely' according to the WHO-UMC algorithm. This is the first report of drug-induced BP as a group adverse event of the gliptins plus metformin combination therapy for glycaemia control in type 2 diabetes mellitus patients. © 2011 The Authors. Journal of the European Academy of Dermatology and Venereology © 2011 European Academy of Dermatology and Venereology.

Butanol fraction of Parkia biglobosa (Jacq.) G. Don leaves enhance pancreatic β-cell functions, stimulates insulin secretion and ameliorates other type 2 diabetes-associated complications in rats.

PubMed

Ibrahim, Mohammed Auwal; Habila, James Dama; Koorbanally, Neil Anthony; Islam, Md Shahidul

2016-05-13

Ethnopharmacological surveys have reported that Parkia biglobosa (Jacq.) G. Don (Leguminosae) is among the plants commonly used in the traditional management of diabetes mellitus in Nigeria and Togo. This study investigated the anti-diabetic activity of the butanol fraction of P. biglobosa leaves (PBBF) in a type 2 diabetes (T2D) model of rats and a possible bioactive compound in the fraction. T2D was induced by feeding rats with a 10% fructose solution ad libitum for two weeks followed by an intraperitoneal injection of 40mg/kg body weight streptozotocin and the animals were orally treated with 150 and 300mg/kg BW of the PBBF for five days in a week. Another group of rats was non-diabetic but similarly administered with 300mg/kg BW of the PBBF. Food and fluid intakes, body weight changes and blood glucose levels were monitored during the experiment while other relevant diabetes-associated parameters were measured at the end of the experiment. The PBBF treatments significantly (P<0.05) decreased the blood glucose levels and improved the glucose tolerance ability compared to untreated diabetic rats. Furthermore, the treatments were found to improve pancreatic β cell function (HOMA-β), stimulate insulin secretions, decrease insulin resistance (HOMA-IR), restore liver glycogen, ameliorate serum dyslipidaemia and prevent hepatic and renal damages compared to untreated diabetic rats. Phytochemical analysis of the fraction led to the isolation of lupeol which inhibited α-glucosidase and α-amylase in non-competitive and uncompetitive inhibition patterns respectively. It was concluded that PBBF possessed remarkable anti-T2D activity which is mediated through modulation of β-cell function and stimulation of insulin secretion and the lower dose (150mg/kg BW) was found optimum for anti-T2D activity compared to the high dose (300mg/kg BW) in this study. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Attenuation of inflammatory response by a novel chalcone protects kidney and heart from hyperglycemia-induced injuries in type 1 diabetic mice

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fang, Qilu; Diabetes Center and Department of Endocrinology, the Second Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang; Wang, Jingying

High glucose-induced inflammatory response in diabetic complications plays an important role in disease occurrence and development. With inflammatory cytokines and signaling pathways as important mediators, targeting inflammation may be a new avenue for treating diabetic complications. Chalcones are a class of natural products with various pharmacological activities. Previously, we identified L2H17 as a chalcone with good anti-inflammatory activity, inhibiting LPS-induced inflammatory response in macrophages. In this study, we examined L2H17's effect on hyperglycemia-induced inflammation both in mouse peritoneal macrophages and a streptozotocin-induced T1D mouse model. Our results indicate that L2H17 exhibits a strong inhibitory effect on the expression of pro-inflammatorymore » cytokines, cell adhesion molecules, chemokines and macrophage adhesion via modulation of the MAPK/NF-κB pathway. Furthermore, in vivo oral administration of L2H17 resulted in a significant decrease in the expression of pro-inflammatory cytokines and cell adhesion molecules, contributing to a reduction of key markers for renal and cardiac dysfunction and improvements in fibrosis and pathological changes in both renal and cardiac tissues of diabetic mice. These findings provide the evidence supporting targeting MAPK/NF-κB pathway may be effective therapeutic strategy for diabetic complications, and suggest that L2H17 may be a promising anti-inflammatory agent with potential as a therapeutic agent in the treatment of renal and cardiac diabetic complications. - Highlights: • Chalcones are a class of natural products with various pharmacological activities. • We identified L2H17 a chalcone with good anti-inflammatory activity. • L2H17 improved histological abnormalities both in diabetic heart and kidney. • L2H17 reduced inflammatory responses in HG-stimulated mouse peritoneal macrophages. • MAPKs/NF-κB pathway may be a promising therapeutic target for diabetic complications.« less

Changes in Adenosine Deaminase Activity in Patients with Type 2 Diabetes Mellitus and Effect of DPP-4 Inhibitor Treatment on ADA Activity.

PubMed

Lee, Jae-Geun; Kang, Dong Gu; Yu, Jung Re; Kim, Youngree; Kim, Jinsoek; Koh, Gwanpyo; Lee, Daeho

2011-04-01

Dipeptidyl peptidase 4 (DPP-4, also known as CD26) binds with adenosine deaminase (ADA) to activate T lymphocytes. Here, we investigated whether ADA activity is specifically affected by treatment with DPP-4 inhibitor (DPP4I) compared with other anti-diabetic agents. Fasting ADA activity, in addition to various metabolic and biochemical parameters, were measured in 262 type 2 diabetes mellitus (T2DM) patients taking various anti-diabetic agents and in 46 non-diabetic control subjects. ADA activity was increased in T2DM patients compared with that in non-diabetic control subjects (mean±standard error, 23.1±0.6 U/L vs. 18.6±0.8 U/L; P<0.05). ADA activity was correlated with fasting plasma glucose (r=0.258, P<0.05), HbA1c (r=0.208, P<0.05), aspartate aminotransferase (r=0.325, P<0.05), and alanine aminotransferase (r=0.248, P<0.05). Compared with the well-controlled T2DM patients (HbA1c<7%), the poorly controlled group (HbA1c>9%) showed significantly increased ADA activity (21.1±0.8 U/L vs. 25.4±1.6 U/L; P<0.05). The effect of DPP4I on ADA activity in T2DM patients did not differ from those of other oral anti-diabetic agents or insulin. T2DM patients on metformin monotherapy showed a lower ADA activity (20.9±1.0 U/L vs. 28.1±2.8 U/L; P<0.05) compared with that of those on sulfonylurea monotherapy. Our results show that ADA activity is increased in T2DM patients compared to that in non-diabetic patients, is positively correlated with blood glucose level, and that DPP4I has no additional specific effect on ADA activity, except for a glycemic control- or HbA1c-dependent effect.

Dietary carbohydrates and glucose metabolism in diabetic patients.

PubMed

Parillo, M; Riccardi, G

1995-12-01

Dietary carbohydrates represent one of the major sources of energy for the human body. However, the main (if not the only) therapy for diabetes since ancient times has been based on reducing dietary carbohydrates drastically because of their effects on blood glucose levels. The introduction of insulin in the 1920s and then of oral hypoglycaemic drugs led to various studies evaluating the biochemical characteristics of carbohydrates and their effects on glucose metabolism in diabetic patients. This review considers the role of dietary carbohydrates in the diet of diabetic patients in the light of the most recent studies and provides a short summary of the biochemistry of carbohydrates and the physiology of carbohydrate digestion.

[Sodium-glucose co-transporter-2 inhibitors: from the bark of apple trees and familial renal glycosuria to the treatment of type 2 diabetes mellitus].

PubMed

Mauricio, Dídac

2013-09-01

The therapeutic armamentarium for the treatment of hyperglycemia in type 2 diabetes mellitus is still inadequate. We are currently witnessing the introduction of a new mode of hypoglycemic treatment through induction of glycosuria to decrease the availability of the metabolic substrate, i.e. glucose. Clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors are as efficacious as other oral hypoglycemic drugs. This article discusses the basic features of this new treatment concept and the efficacy and safety of this new drug group. Copyright © 2013 Elsevier España, S.L. All rights reserved.

Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population.

PubMed

Wen, S W; Yang, T; Krewski, D; Yang, Q; Nimrod, C; Garner, P; Fraser, W; Olatunbosun, O; Walker, M C

2008-05-01

To examine prescription Food and Drug Administration (FDA) C, D and X drugs in general obstetric population. Historical cohort study. A total of 18 575 women who gave a birth in Saskatchewan between January 1997 and December 2000 were included. Among them, 3604 (19.4%) received FDA C, D or X drugs at least once during pregnancy. The pregnancy exposure rates were 15.8, 5.2 and 3.9%, respectively, for category C, D and X drugs, and were 11.2, 7.3 and 8.2%, respectively, in the first, second and third trimesters. Salbutamol (albuterol), trimethoprim/sulfamethoxazole (co-trimoxazole), ibuprofen, naproxen and oral contraceptives were the most common C, D, X drugs used during pregnancy. About one in every five women uses FDA C, D and X drugs at least once during pregnancy, and the most common prescription drugs in pregnancy are antiasthmatic, antibiotics, nonsteroid anti-inflammation drugs, antianxiety or antidepressants and oral contraceptives.

Brand-Name Prescription Drug Use Among Diabetes Patients in the VA and Medicare Part D: A National Comparison

PubMed Central

Gellad, Walid F.; Donohue, Julie M.; Zhao, Xinhua; Mor, Maria K.; Thorpe, Carolyn T.; Smith, Jeremy; Good, Chester B.; Fine, Michael J.; Morden, Nancy E.

2013-01-01

Background Medicare Part D and the Department of Veterans Affairs (VA) use different approaches to manage prescription drug benefits, with implications for spending. Medicare relies on private plans with distinct formularies, whereas VA administers its own benefit using a national formulary. Objective To compare overall and regional rates of brand-name drug use among older adults with diabetes in Medicare and VA. Design Retrospective cohort Setting Medicare and VA Patients National sample in 2008 of 1,061,095 Part D beneficiaries and 510,485 Veterans age 65+ with diabetes. Measurements Percent of patients on oral hypoglycemics, statins, and angiotensin-converting-enzyme inhibitors/angiotensin-receptor-blockers who filled brand-name drugs and percent of patients on long-acting insulin who filled analogues. We compared sociodemographic and health-status adjusted hospital referral region (HRR) brand-name use to examine local practice patterns, and calculated changes in spending if each system’s brand-name use mirrored the other. Results Brand-name use in Medicare was 2–3 times that of VA: 35.3% vs. 12.7% for oral hypoglycemics, 50.7% vs. 18.2% for statins, 42.5% vs. 20.8% for angiotensin-converting-enzyme inhibitors/angiotensin-receptor-blockers, and 75.1% vs. 27.0% for insulin analogues. Adjusted HRR brand-name statin use ranged (5th to 95th percentile) from 41.0%–58.3% in Medicare and 6.2%–38.2% in VA. For each drug group, the HRR at the 95th percentile in VA had lower brand-name use than the 5th percentile HRR in Medicare. Medicare spending in this population would have been $1.4 billion less if brand-name use matched the VA for these medications. Limitation This analysis cannot fully describe the factors underlying differences in brand-name use. Conclusions Medicare beneficiaries with diabetes use 2–3 times more brand-name drugs than a comparable group within VA, at substantial excess cost. Primary Funding Sources VA; NIH; RWJF PMID:23752663

Oral administration of acarbose ameliorates imiquimod-induced psoriasis-like dermatitis in a mouse model.

PubMed

Chen, Hsin-Hua; Chao, Ya-Hsuan; Chen, Der-Yuan; Yang, Deng-Ho; Chung, Ting-Wen; Li, Yi-Rong; Lin, Chi Chen

2016-04-01

Psoriasis is a chronic autoimmune disease of undefined etiology that involves dysregulated interplay between immune cells and keratinocytes. Acarbose was found to decrease inflammatory parameters in diabetic patients in addition to its anti-diabetic effects. Here, we report that imiquimod (IMQ)-induced epidermal hyperplasia and psoriasis like-inflammation were significantly inhibited by acarbose treatment. Real-time PCR showed that mRNA levels of the cytokines TNF-α, IL-6, IL-1β IL-17A, and IL-22 in skin were also decreased significantly by acarbose. In addition, we found that acarbose reduced infiltration of CD3(+) T cells and GR-1(+) neutrophils in lesional skin and also reduced the percentage of IL-17-producing CD4(+) T cells (Th17) and IL-17- and IL-22-producing γδ T cells in the spleen. In contrast, acarbose increased the frequency of IL-10-producing CD4(+) regulator Tr1 T cells in the spleen and small intestine. These results indicate that oral administration of acarbose can attenuate the severity of imiquimod-induced psoriasis with local and systemic anti-inflammatory and immune modulation effects, thus suggesting that acarbose is an effective therapeutic strategy for psoriasis regulation. Copyright © 2016 Elsevier B.V. All rights reserved.

Cardiac ion channel modulation by the hypoglycaemic agent rosiglitazone.

PubMed

Hancox, J C

2011-06-01

The hypoglycaemic thiazolidinedione rosiglitazone is used clinically in the treatment of type 2 diabetes. However, in 2010, information relating to rosiglitazone-associated increased cardiovascular risk led the European Medicines Agency to recommend suspension of marketing authorizations for rosiglitazone-containing anti-diabetes drugs, while the US Food and Drug Administration recommended significant restriction on the agent's use. Two timely studies in this issue of the British Journal of Phrarmacology provide new information regarding modification of cardiac cellular electrophysiology by rosiglitazone. Szentandrássy et al. demonstrate canine ventricular action potential modification and concentration-dependent suppression of L-type Ca current and of transient outward and rapid delayed rectifier K currents. Jeong et al. demonstrate concentration-dependent inhibition of recombinant K(v) 4.3 channels, providing mechanistic insight into the likely molecular basis of transient outward K current inhibition by the compound. Further studies using diabetic models would be of value to determine whether, in a diabetic setting, rosiglitazone modification of these channels could affect the risk of arrhythmia at clinically relevant drug concentrations. © 2011 The Author. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Guaifenesin enhances the analgesic potency of ibuprofen, nimesulide and celecoxib in mice.

PubMed

Sliva, Jiri; Dolezal, Tomas; Sykora, David; Vosmanska, Magda; Krsiak, Miloslav

2009-01-01

Previously, we found that guaifenesin enhances analgesia induced by paracetamol. The aim of the present study was to determine whether guaifenesin is able to also increase analgesic activity in the non-steroid anti-inflammatory drugs ibuprofen, nimesulide and celecoxib. In addition we investigated the influence of guaifenesin on plasma levels of nimesulide. A model of visceral pain consisting of intraperitoneal injection of acetic acid (writhing test) was used. Levels of nimesulide in plasma were measured by HPLC. All drugs were given orally and tested in mice. Guaifenesin alone did not produce any antinociceptive effect. Simultaneous administration of guaifenesin (200 mg/kg) and subanalgesic doses of ibuprofen (10 and 30 mg/kg), nimesulide (10 and 20 mg/kg) or celecoxib (1 and 5 mg/kg) resulted in a significant antinociceptive effects. The plasma levels of nimesulide were significantly higher in combination with guaifenesin at 30, 60 and 90 min after oral administration in comparison to nimesulide monotherapy. The present results suggest that guaifenesin might enhance the analgesic activity of various non-steroidal anti-inflammatory drugs.

Pharmacotherapy of Scleritis: Current Paradigms and Future Directions

PubMed Central

Beardsley, Robert M.; Suhler, Eric B.; Rosenbaum, James T.; Lin, Phoebe

2013-01-01

Introduction Scleritis is an inflammatory condition affecting the eye wall that may be associated with a number of systemic inflammatory diseases. Because scleritis can be refractory to standard treatment, knowledge of the body of available and emerging therapies is paramount and is reviewed here. Areas Covered This review focuses on both traditional and emerging therapies for non-infectious scleritis. We will cover the mechanisms of action and potential adverse effects of each of the treatment modalities. Additionally, a summary of the significant MEDLINE indexed literature under the subject heading “scleritis,” “treatment,” “immunomodulator” will be provided on each therapy, including commentary on appropriate use and relative contraindications. Lastly, novel treatments and potential drug candidates that are currently being evaluated in clinical trials with therapeutic potential will also be reviewed. Expert Opinion While oral non-steroidal anti-inflammatory drugs (NSAIDs) and oral corticosteroids are widely used, effective, first-line agents for inflammatory scleritis, refractory cases require anti-metabolites, T cell inhibitors, or biologic response modifiers. In particular, there is emerging evidence for the use of targeted biologic response modifiers, and potentially, for local drug delivery. PMID:23425055

Effects of Incretin-Based Therapies and SGLT2 Inhibitors on Skeletal Health.

PubMed

Egger, Andrea; Kraenzlin, Marius E; Meier, Christian

2016-12-01

Anti-diabetic drugs are widely used and are essential for adequate glycemic control in patients with type 2 diabetes. Recently, marketed anti-diabetic drugs include incretin-based therapies (GLP-1 receptor agonists and DPP-4 inhibitors) and sodium-glucose co-transporter 2 (SGLT2) inhibitors. In contrast to well-known detrimental effects of thiazolidinediones on bone metabolism and fracture risk, clinical data on the safety of incretin-based therapies is limited. Based on meta-analyses of trials investigating the glycemic-lowering effect of GLP-1 receptor agonists and DPP4 inhibitors, it seems that incretin-based therapies are not associated with an increase in fracture risk. Sodium-glucose co-transporter 2 inhibitors may alter calcium and phosphate homeostasis as a result of secondary hyperparathyroidism induced by increased phosphate reabsorption. Although these changes may suggest detrimental effects of SGLT-2 inhibitors on skeletal integrity, treatment-related direct effects on bone metabolism seem unlikely. Observed changes in BMD, however, seem to result from increased bone turnover in the early phase of drug-induced weight loss. Fracture risk, which is observed in older patients with impaired renal function and elevated cardiovascular disease risk treated with SGLT2 inhibitors, seems to be independent of direct effects on bone but more likely to be associated with falls and changes in hydration status secondary to osmotic diuresis.

Self-Nanoemulsifying Drug Delivery System for Resveratrol: Enhanced Oral Bioavailability and Reduced Physical Fatigue in Rats

PubMed Central

Yen, Ching-Chi; Hsu, Mei-Chich; Wu, Yu-Tse

2017-01-01

Resveratrol (RES), a natural polyphenolic compound, exerts anti-fatigue activity, but its administration is complicated by its low water solubility. To improve RES bioavailability, this study developed a self-nanoemulsifying drug delivery system (SNEDDS) for RES and evaluated its anti-fatigue activity and rat exercise performance by measuring fatigue-related parameters, namely lactate, ammonia, plasma creatinine phosphokinase, and glucose levels and the swimming time to exhaustion. Through solubility and emulsification testing, the optimized SNEDDS composed of Capryol 90, Cremophor EL, and Tween 20 was developed; the average particle size in this formulation, which had favorable self-emulsification ability, was approximately 41.3 ± 4.1 nm. Pharmacokinetic studies revealed that the oral bioavailability of the optimized RES-SNEDDS increased by 3.2-fold compared with that of the unformulated RES-solution. Pretreatment using the RES-SNEDDS before exercise accelerated the recovery of lactate after exercise; compared with the vehicle group, the plasma ammonia level in the RES-SNEDDS group significantly decreased by 65.4%, whereas the glucose level significantly increased by approximately 1.8-fold. Moreover, the swimming time to exhaustion increased by 2.1- and 1.8-fold, respectively, compared with the vehicle and RES-solution pretreatment groups. Therefore, the developed RES-SNEDDS not only enhances the oral bioavailability of RES but may also exert anti-fatigue pharmacological effect. PMID:28841149

Accelerator-based analytical technique in the study of some anti-diabetic medicinal plants of Nigeria

NASA Astrophysics Data System (ADS)

Olabanji, S. O.; Omobuwajo, O. R.; Ceccato, D.; Adebajo, A. C.; Buoso, M. C.; Moschini, G.

2008-05-01

Diabetes mellitus, a clinical syndrome characterized by hyperglycemia due to deficiency of insulin, is a disease involving the endocrine pancreas and causes considerable morbidity and mortality in the world. In Nigeria, many plants, especially those implicated in herbal recipes for the treatment of diabetes, have not been screened for their elemental constituents while information on phytochemistry of some of them is not available. There is therefore the need to document these constituents as some of these plants are becoming increasingly important as herbal drugs or food additives. The accelerator-based technique PIXE, using the 1.8 MeV collimated proton beam from the 2.5 MV AN 2000 Van de Graaff accelerator at INFN, LNL, Legnaro (Padova) Italy, was employed in the determination of the elemental constituents of these anti-diabetic medicinal plants. Leaves of Gardenia ternifolia, Caesalpina pulcherrima, Solemostenon monostachys, whole plant of Momordica charantia and leaf and stem bark of Hunteria umbellata could be taken as vegetables, neutraceuticals, food additives and supplements in the management of diabetes. However, Hexabolus monopetalus root should be used under prescription.

Approaches for the Development of Drugs for Treatment of Obesity and Metabolic Syndrome.

PubMed

Maksimov, Maksim L; Svistunov, Andrey A; Tarasov, Vadim V; Chubarev, Vladimir N; Ávila-Rodriguez, Marco; Barreto, George E; Dralova, Olga V; Aliev, Gjumrakch

2016-01-01

Obesity and metabolic syndrome (MS) are risk factors for diabetes, cancer, some cardiovascular and musculoskeletal diseases. Pharmacotherapy should be used when the body mass index (BMI) exceeds 30 kg/m² or 27 kg/m² with comorbidity. Efficacy and safety of pharmacotherapy depend on the mechanism of action of drugs. In this context, drugs affecting the central and peripheral mediator systems such as cannabinoid receptor antagonists (Rimonabant), neuronal reuptake inhibitor of NE and 5 HT (Sibutramine), neuronal reuptake inhibitor of NE 5-HT DA (Tesofensine), agonist of 5 HT 2C receptors (Lorcaserin) have a high risk of side effects on the central nervous and cardiovascular systems when used for a long period. Apparently, the drugs design targeting obesity should screen safer drugs that affect fat absorption (Orlistat), activate energy metabolism (Adipokines), inhibit MetAP2 (Beloranib) and other peripheral metabolic processes. The use of synergies of anti-obesity drugs with different mechanisms of action is an effective approach for developing new combined pharmaceutical compositions (Contrave®, EmpaticTM, Qsymia et al). The purpose of this article is to review the currently available anti-obesity drugs and some new promising trends in development of anti-obesity therapy.

Pharmacotherapy-Based Problems in the Management of Diabetes Mellitus: Needs Much More to be Done!

PubMed

Ali, N; Shah, Swa; Khan, J; Rehman, S; Imran, M; Hussian, I; Shehbaz, N; Jamshed, H; Khan, S

2010-07-01

A total of 856 diabetic patients were evaluated for pharmacotherapy-based problems like for possible drug interactions, adverse drug reactions, and other mismatches, if any. Poor correlation between the advised insulin therapy and patients' fasting blood glucose levels (12%, n=103) was observed. To most of the patients (41.66%, n= 357), insulin therapy was advised in combination with glucocorticoides, thiazides diuretics, and propranolol. Prescribing beta blocker (propranolol) with insulin is contraindicated. The higher incidence of diabetic foot patients was in the mean age of 57±3.4 years that was controlled with combination therapy of insulin and oral antidiabetics (63.0%, n=516). 11.1% of the treated patients could not take the prescribed therapy due to poor acceptance of insulin therapy due to its syringe needle prick. 41.66% risks of potential drug interactions, 7.93% adverse drug reactions, and 6.6% mismatches were recorded, as per the international approved algorithm, for managing a diabetes mellitus that reflects poor health care system. All these events necessitate for coordinating with other health professionals to make the therapy safer in the better interest of the patients. It is concluded that in practice prescribing pattern carries more risks for patients. It is imperative to improve the practice of pharmacotherapeutics rather than to practice in routine.

Treatment of diabetic retinopathy: Recent advances and unresolved challenges.

PubMed

Stewart, Michael W

2016-08-25

Diabetic retinopathy (DR) is the leading cause of blindness in industrialized countries. Remarkable advances in the diagnosis and treatment of DR have been made during the past 30 years, but several important management questions and treatment deficiencies remain unanswered. The global diabetes epidemic threatens to overwhelm resources and increase the incidence of blindness, necessitating the development of innovative programs to diagnose and treat patients. The introduction and rapid adoption of intravitreal pharmacologic agents, particularly drugs that block the actions of vascular endothelial growth factor (VEGF) and corticosteroids, have changed the goal of DR treatment from stabilization of vision to improvement. Anti-VEGF injections improve visual acuity in patients with diabetic macular edema (DME) from 8-12 letters and improvements with corticosteroids are only slightly less. Unfortunately, a third of patients have an incomplete response to anti-VEGF therapy, but the best second-line therapy remains unknown. Current first-line therapy requires monthly visits and injections; longer acting therapies are needed to free up healthcare resources and improve patient compliance. VEGF suppression may be as effective as panretinal photocoagulation (PRP) for proliferative diabetic retinopathy, but more studies are needed before PRP is abandoned. For over 30 years laser was the mainstay for the treatment of DME, but recent studies question its role in the pharmacologic era. Aggressive treatment improves vision in most patients, but many still do not achieve reading and driving vision. New drugs are needed to add to gains achieved with available therapies.

The incretin effect in healthy individuals and those with type 2 diabetes: physiology, pathophysiology, and response to therapeutic interventions.

PubMed

Nauck, Michael A; Meier, Juris J

2016-06-01

The incretin effect describes the phenomenon whereby oral glucose elicits higher insulin secretory responses than does intravenous glucose, despite inducing similar levels of glycaemia, in healthy individuals. This effect, which is uniformly defective in patients with type 2 diabetes, is mediated by the gut-derived incretin hormones glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1). The importance of the incretin effect for the maintenance of glucose homoeostasis is clearly established, and incretin-based therapies are among the most promising new therapies for type 2 diabetes. However, despite the effectiveness of these therapies in many patients, the idea that they restore the incretin effect is a common misconception. In type 2 diabetes, the endocrine pancreas remains responsive to GLP-1 but is no longer responsive to GIP, which is the most likely reason for a reduced or absent incretin effect. Incretin-based drugs, including GLP-1 receptor agonists and dipeptidyl peptidase 4 (DPP-4) inhibitors, stimulate GLP-1 receptors and thus augment insulin secretion in response to both oral and intravenous glucose stimulation, thereby abolishing any potential difference in the responses to these stimuli. These drugs therefore do not restore the defective incretin effect in patients. By contrast, some bariatric surgical procedures enhance GLP-1 responses and also restore the incretin effect in obese individuals with type 2 diabetes. Thus, not all biological actions elicited by the stimulation of GLP-1 receptors lead to quantitative changes to the incretin effect. Copyright © 2016 Elsevier Ltd. All rights reserved.

Renoprotective effect of aged garlic extract in streptozotocin-induced diabetic rats

PubMed Central

Shiju, T. M.; Rajesh, N. G.; Viswanathan, Pragasam

2013-01-01

Objective: Aged garlic extract (AGE) has been proven to exhibit antioxidant, hypolipidemic, hypoglycemic and antidiabetic properties. However, its effect on diabetic nephropathy was unexplored. Therefore, the present study was designed to investigate the renoprotective effect of AGE in streptozotocin-induced diabetic rats. Materials and Methods: Albino Wistar rats were induced with diabetes by a single intraperitoneal injection of 45 mg/kg b.w. of streptozotocin. Commercially available AGE was supplemented orally at a dose of 500 mg/kg body weight/day. Aminoguanidine, which has been proven to be an anti-glycation agent was used as positive control and was supplemented at a dose of 1 g/L in drinking water. The serum and urinary biochemical parameters were analyzed in all the groups and at the end of 12 weeks follow up, the renal histological examination were performed using H & E and PAS staining. Results: The diabetic rats showed a significant change in the urine (P < 0.001) and serum (P < 0.01) constituents such as albumin, creatinine, urea nitrogen and glycated hemoglobin. In addition, the serum lipid profile of the diabetic rats were altered significantly (P < 0.05) compared to that of the control rats. However, the diabetic rats supplemented with aged garlic extract restored all these biochemical changes. The efficacy of the extract was substantiated by the histopathological changes in the kidney. Conclusion: From our results, we conclude that aged garlic extract has the ability to ameliorate kidney damage in diabetic rats and the renoprotective effect of AGE may be attributed to its anti-glycation and hypolipidemic activities. PMID:23543654

Pancreatoprotective effects of Geniotrigona thoracica stingless bee honey in streptozotocin-nicotinamide-induced male diabetic rats.

PubMed

Aziz, Muhammad Shakir Abdul; Giribabu, Nelli; Rao, Pasupuleti Visweswara; Salleh, Naguib

2017-05-01

Stingless bee honey (SLBH) has been claimed to possess multiple health benefits. Its anti-diabetic properties are however unknown. In this study, ability of SLBH from Geniotrigona thoracica stingless bee species in ameliorating pancreatic damage and in maintaining metabolic profiles were investigated in diabetic condition. SLBH at 1 and 2g/kg/b.w. was given orally to streptozotocin (STZ)-nicotinamide-induced male diabetic rats for 28days. Metabolic parameters (fasting blood glucose-FBG and lipid profiles-LP and serum insulin) were measured by biochemical assays. Distribution and expression level of insulin, oxidative stress marker i.e. catalase, inflammatory markers i.e. IKK-β, TNF-α, IL-1β and apoptosis marker i.e. caspase-9 in the pancreatic islets were identified and quantified respectively by immunohistochemistry. Levels of NF-κβ in pancreas were determined by enzyme-linked immunoassay (ELISA). SLBH administration to diabetic male rats prevented increase in FBG, total cholesterols (TC), triglyceride (TG) and low density lipoprotein (LDL) levels. However, high density lipoprotein (HDL) and serum insulin levels in diabetic rats receiving SLBH increased. Additionally, histopathological changes and expression level of oxidative stress, inflammation and apoptosis markers in pancreatic islets of diabetic rats decreased with increased expression level of insulin in the islets. LC-MS analysis revealed the presence of several compounds in SLBH that might be responsible for these effects. SLBH has great potential to be used as agent to protect the pancreas against damage and dysfunction where these could account for its anti-diabetic properties. Copyright © 2017 Elsevier Masson SAS. All rights reserved.

Rare sugar D-allulose: Potential role and therapeutic monitoring in maintaining obesity and type 2 diabetes mellitus.

PubMed

Hossain, Akram; Yamaguchi, Fuminori; Matsuo, Tatsuhiro; Tsukamoto, Ikuko; Toyoda, Yukiyasu; Ogawa, Masahiro; Nagata, Yasuo; Tokuda, Masaaki

2015-11-01

Obesity and type 2 diabetes mellitus (T2DM) are the leading worldwide risk factors for mortality. The inextricably interlinked pathological progression from excessive weight gain, obesity, and hyperglycemia to T2DM, usually commencing from obesity, typically originates from overconsumption of sugar and high-fat diets. Although most patients require medications, T2DM is manageable or even preventable with consumption of low-calorie diet and maintaining body weight. Medicines like insulin, metformin, and thiazolidinediones that improve glycemic control; however, these are associated with weight gain, high blood pressure, and dyslipidemia. These situations warrant the attentive consideration of the role of balanced foods. Recently, we have discovered advantages of a rare sugar, D-allulose, a zero-calorie functional sweetener having strong anti-hyperlipidemic and anti-hyperglycemic effects. Study revealed that after oral administration in rats D-allulose readily entered the blood stream and was eliminated into urine within 24h. Cell culture study showed that D-allulose enters into and leaves the intestinal enterocytes via glucose transporters GLUT5 and GLUT2, respectively. In addition to D-allulose's short-term effects, the characterization of long-term effects has been focused on preventing commencement and progression of T2DM in diabetic rats. Human trials showed that D-allulose attenuates postprandial glucose levels in healthy subjects and in borderline diabetic subjects. The anti-hyperlipidemic effect of D-allulose, combined with its anti-inflammatory actions on adipocytes, is beneficial for the prevention of both obesity and atherosclerosis and is accompanied by improvements in insulin resistance and impaired glucose tolerance. Therefore, this review presents brief discussions focusing on physiological functions and potential benefits of D-allulose on obesity and T2DM. Copyright © 2015 Elsevier Inc. All rights reserved.

Effect of Vanadyl Rosiglitazone, a New Insulin-Mimetic Vanadium Complexes, on Glucose Homeostasis of Diabetic Mice.

PubMed

Jiang, Pingzhe; Dong, Zhen; Ma, Baicheng; Ni, Zaizhong; Duan, Huikun; Li, Xiaodan; Wang, Bin; Ma, Xiaofeng; Wei, Qian; Ji, Xiangzhen; Li, Minggang

2016-11-01

Diabetes has been cited as the most challenging health problem in the twenty-first century. Accordingly, it is urgent to develop a new type of efficient and low-toxic antidiabetic medication. Since vanadium compounds have insulin-mimetic and potential hypoglycemic activities for type 1 and type 2 diabetes, a new trend has been developed using vanadium and organic ligands to form a new compound in order to increase the intestinal absorption and reduce the toxicity of vanadium compound. In the current investigation, a new organic vanadium compounds, vanadyl rosiglitazone, was synthesized and determined by infrared spectra. Vanadyl rosiglitazone and three other organic vanadium compounds were administered to the diabetic mice through oral administration for 5 weeks. The results of mouse model test indicated that vanadyl rosiglitazone could regulate the blood glucose level and relieve the symptoms of polydipsia, polyphagia, polyuria, and weight loss without side effects and was more effective than the other three organic vanadium compounds including vanadyl trehalose, vanadyl metformin, and vanadyl quercetin. The study indicated that vanadyl rosiglitazone presents insulin-mimetic activities, and it will be a good potential candidate for the development of a new type of oral drug for type 2 diabetes.

Effects of commonly used antidiabetic drugs on antioxidant enzymes and liver function test markers in type 2 diabetes mellitus subjects - pilot study.

PubMed

Ghadge, A; Harke, S; Khadke, S; Diwan, A; Pankaj, M; Kulkarni, O; Ranjekar, P; Harsulkar, A; Kuvalekar, A A

2015-09-01

The present study analyzed the effects of antidiabetic drugs on antioxidant enzymes and liver function test (LFT) markers and their association with homeostatic model assessment of insulin resistance (HOMA-IR) in type 2 diabetic subjects. We assessed healthy and diabetic subjects (100 each). Diabetic subjects were divided based on treatment with only metformin, metformin in combination with other antidiabetic drugs and insulin in combination with other antidiabetic drugs. LFT markers, antioxidant status and HOMA-IR were assessed in the subjects. Superoxide dismutase activity was higher (p<0.01) while catalase activity was lower (p<0.01) in the diabetic subjects as compared to controls. Serum glutamate-pyruvate transaminase (SGPT) (p<0.01) and bilirubin (p<0.05) levels were higher in diabetic male subjects while urea (p<0.05) levels were lower and SGPT (p<0.01) levels were higher in diabetic female subjects. In male subjects consuming only metformin, a positive association between HOMA-IR and insulin (p<0.05) was seen. A positive association between HOMA-IR and glucose (p<0.01), insulin (p<0.01), SOD (p<0.01) and SGPT (p<0.05) was seen in males receiving metformin with other drugs. Interestingly, the female subjects on metformin displayed a positive association between HOMA-IR and insulin (p<0.05) only. A positive association of HOMA-IR with glucose (p<0.01) and insulin (p<0.05) was seen in females on metformin in combination with other anti-diabetic drugs. The alterations in the antioxidant enzyme activities and liver function tests are dependent upon the gender and glycemic status of subjects while the variations in correlations of HOMA-IR with antioxidant enzymes, liver function tests and inflammatory markers are dependent on type of treatments. © Georg Thieme Verlag KG Stuttgart · New York.

Antidiabetic effects of Cuscuta reflexa Roxb. in streptozotocin induced diabetic rats.

PubMed

Rath, Diptirani; Kar, Durga Madhab; Panigrahi, Sandeep Kumar; Maharana, Laxmidhar

2016-11-04

Cuscuta reflexa Roxb. (Convolvulaceae) is traditionally used to treat diabetes mellitus by tribal people of north-east India and Bangladesh. To evaluate the anti-diabetic effects of methanol and aqueous extracts of the aerial parts of Cuscuta reflexa Roxb. in normal, glucose loaded and Streptozotocin (STZ) induced diabetic rats. The methanol (MECR) and aqueous (AECR) extracts (200 and 400mg/kg body weight) were administered orally to normal and diabetic rats with Metformin and solvent control as comparison groups. Long term effects like FBG, OGTT, lipid profile, HbA1c, body weight, histopathology of major organs, etc. were investigated. MECR and AECR did not have hypoglycemic effects in normal rats. Both AECR and MECR (400mg/kg) treatments showed significant reduction in blood glucose during OGTT in diabetic rats at 3h. Single oral administration of methanol and aqueous extracts (400mg/kg) to diabetic rats significantly reduced (p<0.05) blood glucose level to 61.90% and 55.39% respectively as compared to the Metformin group i.e. 68.32% at the end of 8h. MECR (400mg/kg body weight for 30 days to diabetic rats) showed a significant decrease (p<0.01) of blood glucose level to 60.00% as compared to other groups. The treatment also resulted an improvement in body weights, decreased HbA1c and restored lipid profile. Histopathological injury was not observed, rather repair of beta cells was seen in extract treated diabetic rats. Methanolic extract of C. reflexa has significant antidiabetic effects and improves metabolic alterations thereby justifying its traditional folkloric claims. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Geraniol, a natural monoterpene, ameliorates hyperglycemia by attenuating the key enzymes of carbohydrate metabolism in streptozotocin-induced diabetic rats.

PubMed

Babukumar, Sukumar; Vinothkumar, Veerasamy; Sankaranarayanan, Chandrasekaran; Srinivasan, Subramani

2017-12-01

Geraniol, an acyclic monoterpene alcohol is found in medicinal plants, is used traditionally for several medical purposes including diabetes. The present study evaluates the antihyperglycemic potential of geraniol on key enzymes of carbohydrate metabolism in streptozotocin (STZ)-induced diabetic rats. Diabetes was induced in experimental rats, by a single intraperitoneal (i.p) injection of STZ [40 mg/kg body weight (b.w.)]. Different doses of geraniol (100, 200 and 400 mg/kg b.w.) and glyclazide (5 mg/kg b.w.) were administrated orally to diabetic rats for 45 days. Body weight, food intake, plasma glucose, insulin, blood haemoglobin (Hb), glycosylated haemoglobin (HbA 1c ), hepatic glucose metabolic enzymes and glycogen were examined. The LD 50 value of geraniol is 3600 mg/kg b.w. at oral administration in rats. Administration of geraniol in a dose-dependent manner (100, 200, 400 mg/kg b.w.) and glyclazide (5 mg/kg b.w.) for 45 days significantly improved the levels of insulin, Hb and decreased plasma glucose, HbA 1C in diabetic-treated rats. Geraniol at its effective dose (200 mg/kg b.w.) ameliorated the altered activities of carbohydrate metabolic enzymes near normal effects compared with two other doses (100 and 400 mg/kg b.w.). Geraniol treatment to diabetic rats improved hepatic glycogen content suggesting its anti-hyperglycemic potential. Geraniol supplement was found to preserve the normal histological appearance of hepatic cells and pancreatic β-cells in diabetic rats. The present findings suggest that geraniol can potentially ameliorate key enzymes of glucose metabolism in experimental diabetes even though clinical studies used to evaluate this possibility are warranted.

Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

PubMed Central

Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

2016-01-01

Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents. PMID:27094554

Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

NASA Astrophysics Data System (ADS)

Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

2016-04-01

Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1-3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

Investigation of the biotransformation of osthole by liquid chromatography/tandem mass spectrometry.

PubMed

Li, Jie; Chan, Wan

2013-02-23

Osthole is an active ingredient and one of the major coumarin compounds that were identified in the genus Cnidium moonnieri (L.) Cussion, the fruit of which was used as traditional Chinese medicine to treat male impotence, ringworm infection and blood stasis conventionally. Recent studies revealed that osthole has diverse pharmacological effects, such as improving male sexual dysfunction, anti-diabetes, and anti-hypertentions. The inhibition of thrombosis and platelet aggregation and protection of central nerve were also observed. On the other hand, the metabolism of osthole has not yet been investigated thoroughly. Herein the biotransformation of osthole in rat was investigated after oral administration of osthole by using efficient and sensitive ultra-performance liquid chromatography-tandem quadrupole-time of flight mass spectrometry (UPLC-QTOF/MS). Eighteen osthole metabolites and the parent drug were detected and identified in rat urine. Fourteen metabolites of osthole were identified and characterized for the first time. Structures of metabolites of osthole were elucidated by comparing fragment pattern under MS/MS scan and change of molecular weight with those of osthole. The main phase I metabolic pathways were summed as 7-demethylation, 8-dehydrogenation, hydroxylation on coumarin and 3,4-epoxide. Sulfate conjugates were detected as phase II metabolites of osthole. Copyright © 2012 Elsevier B.V. All rights reserved.

Fabrication and in vivo evaluation of Nelfinavir loaded PLGA nanoparticles for enhancing oral bioavailability and therapeutic effect

PubMed Central

Venkatesh, D. Nagasamy; Baskaran, Mahendran; Karri, Veera Venkata Satyanarayana Reddy; Mannemala, Sai Sandeep; Radhakrishna, Kollipara; Goti, Sandip

2015-01-01

Nelfinavir mesylate (NFV) is an anti-viral drug, used in the treatment of Acquired Immunodeficiency Syndrome (AIDS). Poor oral bioavailability and shorter half-life (3.5–5 h) remain a major clinical limitation of NFV leading to unpredictable drug bioavailability and frequent dosing. In this context, the objective of the present study was to formulate NFV loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticles (NPs), which can increase the solubility and oral bioavailability along with sustained release of the drug. NFV loaded PLGA-NPs were prepared by nanoprecipitation method using PLGA and Poloxomer 407. The prepared NPs were evaluated for particle size, zeta potential, morphology, drug content, entrapment efficiency (EE) and in vitro dissolution studies. Oral bioavailability studies were carried out in New Zealand rabbits by administering developed NFV PLGA-NPs and pure drug suspension. PLGA-NPs prepared by using 1:4 ratio of drug and PLGA, with a stirring rate of 1500 rpm for 4 h. The prepared NPs were in the size of 185 ± 0.83 nm with a zeta potential of 28.7 ± 0.09 mV. The developed NPs were found to be spherical with uniform size distribution. The drug content and EE of the optimized formulation were found to be 36 ± 0.19% and 72 ± 0.47% respectively. After oral administration of NFV PLGA-NPs, the relative bioavailability was enhanced about 4.94 fold compared to NFV suspension as a control. The results describe an effective strategy for oral delivery of NFV loaded PLGA NPs that helps in enhancing bioavailability and reduce the frequency of dosing. PMID:26702262

DRESS syndrome associated with type 2 diabetes in a child

PubMed Central

Erdem, Semiha Bahceci; Bag, Ozlem; Karkiner, Canan Sule Unsal; Korkmaz, Huseyin Anil; Can, Demet

2016-01-01

Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon, life-threatening drug reaction. The basic findings are skin rash, multiorgan involvement, and eosinophilia. Most of the aromatic anticonvulsants, such as phenytoin, phenobarbital and carbamazepine can induce DRESS. Herein we report a 14-year-old patient with DRESS syndrome related to carbamazepine use. The patient presented with signs of involvement of the skin, lungs, liver, and microscopic hematuria. Carbamazepine treatment was discontinued; antihistamines and steroids were started. Hyperglycemia, commencing on the first dose of the steroid given, persisted even after the discontinuation of steroids and improvement of other signs. There were no signs of pancreatitis or type 1 diabetes clinically in laboratory tests. Her blood glucose levels were regulated at first with insulin and later with metformin. Within 1 year of follow-up, still regulated with oral antidiabetics, she has been diagnosed with type 2 diabetes. Formerly, long-term sequelae related to “drug rash with eosinophilia and systemic symptoms syndrome” such as hepatic and renal failure, type 1 diabetes mellitus, Grave's disease, autoimmune hemolytic anemia, and lupus have also been reported. However, up to date, no cases with type 2 diabetes have been reported as long-term sequelae. To our knowledge, this is the first case in the literature presenting with type 2 diabetes as long-term sequelae. PMID:26862317

Ameliorating effect of Semecarpus anacardium Linn. nut milk extract on altered glucose metabolism in high fat diet STZ induced type 2 diabetic rats.

PubMed

Khan, Haseena Banu Hedayathullah; Vinayagam, Kaladevi Siddhi; Palanivelu, Shanthi; Panchanadham, Sachdanandam

2012-12-01

To explore the protective effect of the drug Semecarpus anacardium (S. anacardium)on altered glucose metabolism in diabetic rats. Type 2 diabetes mellitus was induced by feeding rats with high fat diet followed by single intraperitoneal injection of streptozotocin (STZ) (35 mg/kg b.w.). Seven days after STZ induction, diabetic rats received nut milk extract of S. anacardium Linn. nut milk extract orally at a dosage of 200 mg/kg daily for 4 weeks. The effect of nut milk extract of S. anacardium on blood glucose, plasma insulin, glucose metabolising enzymes and GSK were studied. Treatment with SA extract showed a significant reduction in blood glucose levels and increase in plasma insulin levels and also increase in HOMA - β and decrease in HOMA -IR. The drug significantly increased the activity of glycolytic enzymes and glucose-6-phosphate dehydrogenase activity and increased the glycogen content in liver of diabetic rats while reducing the activities of gluconeogenic enzymes. The drug also effectively ameliorated the alterations in GSK-3 mRNA expression. Overall, the present study demonstrates the possible mechanism of glucose regulation of S. anacardium suggestive of its therapeutic potential for the management of diabetes mellitus. Copyright © 2012 Hainan Medical College. Published by Elsevier B.V. All rights reserved.

Efficacy and safety of saxagliptin, a dipeptidyl peptidase-4 inhibitor, in hemodialysis patients with diabetic nephropathy: A randomized open-label prospective trial.

PubMed

Abe, Masanori; Higuchi, Terumi; Moriuchi, Masari; Okamura, Masahiro; Tei, Ritsukou; Nagura, Chinami; Takashima, Hiroyuki; Kikuchi, Fumito; Tomita, Hyoe; Okada, Kazuyoshi

2016-06-01

Saxagliptin is a dipeptidyl peptidase-4 inhibitor that was approved in Japan for the treatment of type 2 diabetes in 2013. We examined its efficacy and safety in Japanese hemodialysis patients with diabetic nephropathy. In this prospective, open-label, parallel-group study, Japanese hemodialysis patients were randomized to receive either oral saxagliptin (2.5mg/day) or usual care (control group) for 24weeks. Before randomization, patients received fixed doses of conventional antidiabetic drugs (oral drugs and/or insulin) for 8weeks; these drugs were continued during the study. Endpoints included changes in glycated albumin (GA), hemoglobin A1c (HbA1c), postprandial plasma glucose (PPG), and adverse events. Both groups included 41 patients. Mean GA, HbA1c, and PPG decreased significantly in the saxagliptin group (-3.4%, -0.6% [-7mmol/mol], and -38.3mg/dL, respectively; all P<0.0001) but not in the control group (0%, -0.1% [-1mmol/mol], and -3.7mg/dL, respectively) (P<0.0001, P<0.001, and P<0.0001, respectively). In saxagliptin-treated patients, the reduction in GA was significantly greater when saxagliptin was administered as monotherapy than in combination therapy (-4.2% vs. -3.0%, P=0.012) despite similar baseline values (24.5% vs. 23.3%). Reductions in GA, HbA1c, and PPG were greater in patients whose baseline values exceeded the median (23.8% for GA, 6.6% for HbA1c, and 180mg/dL for PPG). There were no adverse events associated with saxagliptin. Saxagliptin (2.5mg/day) was effective and well tolerated when used as monotherapy or combined with other antidiabetic drugs in Japanese hemodialysis patients with type 2 diabetes. UMIN000018445. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Diabetes and oral health: doctors' knowledge, perception and practices.

PubMed

Al-Habashneh, Rola; Barghout, Nicola; Humbert, Lewis; Khader, Yousef; Alwaeli, Hayder

2010-10-01

To assess Jordanian doctors' knowledge of the connection between diabetes and oral health and assess their willingness to advise their diabetic patients to seek dental treatment and determine the associated factors. Data were collected from 164 doctors practising in Jordan using a structured questionnaire. Chi-squared test and regression analyses were conducted to reveal factors influencing the awareness, perception and knowledge of health care professionals regarding diabetes and oral health. Of the respondents, 70% had heard of the link between diabetes and oral health. The majority agreed that diabetes increased the tendency to have periodontitis but only half advised their diabetic patients to consult a dentist concerning their oral health. Only a third of doctors agreed that oral health was an issue in controlling diabetes. Books, magazines and pamphlets were the main source of information with the rate of 58%, medical journals and medical curriculum were the second and third sources, respectively. General medical practitioners were less informed than specialized doctors about the relationship between oral health and diabetes. Factors that significantly predicted doctors would advise dental visits were: (1) being a specialist (P = 0.037); (2) having positive knowledge about the association between diabetes and oral health (P = 0.02, P = 0.007 and P = 0.004, respectively). There is limited knowledge of the relationships between oral health and diabetes. The more knowledgeable doctors are, the more likely they are to make dental referrals. Screening and referral by health professionals may benefit diabetic patients by improving access to dental care. Therefore, there is a need to educate doctors about oral health and diabetes. © 2010 Blackwell Publishing Ltd.

The diabetic patient in Ramadan.

PubMed

Chamsi-Pasha, Hassan; Aljabri, Khalid S

2014-04-01

During the month of Ramadan, all healthy, adult Muslims are required to fast from dawn to sunset. Fasting during Ramadan involves abstaining from food, water, beverages, smoking, oral drugs, and sexual intercourse. Although the Quran exempts chronically ill from fasting, many Muslims with diabetes still fast during Ramadan. Patients with diabetes who fast during the month of Ramadan can have acute complications. The risk of complications in fasting individuals with diabetes increases with longer periods of fasting. All patients with diabetes who wish to fast during Ramadan should be prepared by undergoing a medical assessment and engaging in a structured education program to undertake the fast as safely as possible. Although some guidelines do exist, there is an overwhelming need for better designed clinical trials which could provide us with evidence-based information and guidance in the management of patients with diabetes fasting Ramadan.

Drug reimbursement and GPs' prescribing decisions: a randomized case-vignette study about the pharmacotherapy of obesity associated with type 2 diabetes: how GPs react to drug reimbursement.

PubMed

Verger, Pierre; Rolland, Sophie; Paraponaris, Alain; Bouvenot, Julien; Ventelou, Bruno

2010-08-01

This study sought to identify the effect of drug reimbursability--a decision made in France by the National Authority for Health--on physicians' prescribing practices for a diet drug such as rimonabant, approved for obese or overweight patients with type-2 diabetes. A cross-sectional survey of French general practitioners (GPs) presented a case-vignette about a patient for whom this drug is indicated in two alternative versions, differing only in its reimbursability, to two separate randomized subsamples of GPs in early 2007, before any decision was made about reimbursement. The results indicate that (i) more than 20% of GPs in private practice would be willing to prescribe a non-reimbursed diet drug for patients with obesity complicated by type 2 diabetes; (ii) the number of GPs willing to prescribe it would increase by 47.6% if the drug were reimbursed, and (iii) such a drug would be adopted at a higher rate by GPs who have regular contacts with pharmaceutical sales representatives. In France, unlike most other countries, drug reimbursement status is a signal of quality. However, our results suggest that a significant proportion of GPs would spontaneously adopt anti-obesity drugs even if they were not reimbursed. Decisions about reimbursement of pharmaceutical products should be made taking into account that reimbursement is likely to intensify prescription.

FT011, a new anti-fibrotic drug, attenuates fibrosis and chronic heart failure in experimental diabetic cardiomyopathy.

PubMed

Zhang, Yuan; Edgley, Amanda J; Cox, Alison J; Powell, Andrew K; Wang, Bing; Kompa, Andrew R; Stapleton, David I; Zammit, Steven C; Williams, Spencer J; Krum, Henry; Gilbert, Richard E; Kelly, Darren J

2012-05-01

Cardiac remodelling in diabetes includes pathological accumulation of extracellular matrix and myocyte hypertrophy that contribute to heart dysfunction. Attenuation of remodelling represents a potential therapeutic target. We tested this hypothesis using a new anti-fibrotic drug, FT011 (Fibrotech Therapeutics Pty Ltd), on diabetic Ren-2 rats, a model which replicates many of the structural and functional manifestations of diabetic cardiomyopathy in humans. Homozygous Ren-2 rats were randomized to receive streptozotocin or vehicle then further randomized to FT011 (200 mg/kg/day) or vehicle treatment for 6 weeks. Prior to tissue collection, cardiac function was assessed via echocardiography and cardiac catheterization. Total collagen deposition and cardiomyocyte hypertrophy were assessed by picrosirius red and haematoxylin and eosin staining, respectively. Macrophage interstitial infiltration and type I and III collagen were quantitated by immunostaining. Without affecting blood pressure or hyperglycaemia, treatment of diabetic rats with FT011 significantly attenuated interstitial fibrosis (total collagen, 5.09 ±1.28 vs, 2.42 ±0.43%/area; type I collagen, 4.09 ±1.16 vs. 1.42 ±0.38%/area; type III collagen, 1.52 ±0.33 vs. 0.71 ±0.14 %/area; P < 0.05), cardiomyocyte hypertrophy (882 ±38 vs. 659 ±28 µm(2); P < 0.05), and interstitial macrophage influx (66 ±5.3 vs, 44 ±7.9 number/section; P < 0.05). Cardiac myopathic dilatation was normalized, as evidenced by reduced left ventricular inner diameter at diastole (0.642 ±0.016 vs. 0.577 ±0.024 cm), increased ejection fraction (75 ±1.1 vs. 83 ±1.2%) and preload recruitable stroke work relationship (44 ±6.7 vs. 77 ±6.3 slope-mmHg; P < 0.05), and reduced end-diastolic pressure-volume relationship (0.059 ±0.011 vs. 0.02 ±0.003 slope-mmHg/μL; P < 0.05). A direct anti-fibrotic agent, FT011, attenuates cardiac remodelling and dysfunction in experimental diabetic cardiomyopathy. This represents a novel therapy for the treatment of diabetic cardiomyopathy associated with cardiac fibrosis and hypertrophy.

Oral delivery of exenatide via microspheres prepared by cross-linking of alginate and hyaluronate.

PubMed

Zhang, Baojie; He, Dongyang; Fan, Yu; Liu, Nan; Chen, Yijun

2014-01-01

Exenatide is an FDA-approved glucose-lowering peptide drug for the treatment of type 2 diabetes by subcutaneous injection. To address the issues on the inconvenience for patient use and the difficulty of oral administration of peptide drugs, chemical cross-linking of two pH-responsive biomaterials, alginate and hyaluronate, was carried out to prepare a new material for the encapsulation of exenatide as a form of microspheres. The exenatide-loaded microspheres exhibited spherical structures with excellent loading and release behaviors in the simulated gastrointestinal tract environments. After oral administration of the microspheres in db/db mice, maximum plasma concentration of exenatide appeared at 4 hours, and blood glucose was effectively reduced to a normal level within 2 hours and maintained for another 4 hours. The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%. Collectively, the present study demonstrated the feasibility of orally delivering exenatide with the new cross-linked biomaterial and formulation, and showed therapeutic potential for clinical applications.

Oral Delivery of Exenatide via Microspheres Prepared by Cross-Linking of Alginate and Hyaluronate

PubMed Central

Zhang, Baojie; He, Dongyang; Fan, Yu; Liu, Nan; Chen, Yijun

2014-01-01

Exenatide is an FDA-approved glucose-lowering peptide drug for the treatment of type 2 diabetes by subcutaneous injection. To address the issues on the inconvenience for patient use and the difficulty of oral administration of peptide drugs, chemical cross-linking of two pH-responsive biomaterials, alginate and hyaluronate, was carried out to prepare a new material for the encapsulation of exenatide as a form of microspheres. The exenatide-loaded microspheres exhibited spherical structures with excellent loading and release behaviors in the simulated gastrointestinal tract environments. After oral administration of the microspheres in db/db mice, maximum plasma concentration of exenatide appeared at 4 hours, and blood glucose was effectively reduced to a normal level within 2 hours and maintained for another 4 hours. The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%. Collectively, the present study demonstrated the feasibility of orally delivering exenatide with the new cross-linked biomaterial and formulation, and showed therapeutic potential for clinical applications. PMID:24465870

[Constitutional syndrome associated to metformin induced hepatotoxicity].

PubMed

de la Poza Gómez, Gema; Rivero Fernández, Miguel; Vázquez Romero, Manuel; Angueira Lapeña, Teresa; Arranz de la Mata, Gemma; Boixeda de Miquel, Daniel

2008-12-01

Metformin is an oral antidiabetic agent frequently used to manage type II diabetes. This drug produces nonspecific gastrointestinal symptoms in 5-20% of patients and, more rarely, has also been associated with severe adverse effects such as lactic acidosis. Only a few isolated cases of hepatotoxicity due to this drug have been documented. We report the case of an 83-year-old man with constitutional syndrome and hepatic biochemical alterations, which were attributed to metformin after ruling out an oncologic etiology and observing complete clinical and biochemical resolution after withdrawal of the drug.

β-cell regenerative efficacy of a polysaccharide isolated from methanolic extract of Tinospora cordifolia stem on streptozotocin -induced diabetic Wistar rats.

PubMed

Rajalakshmi, Manikkam; Anita, Roy

2016-01-05

The use of herbal supplements either as extracts or plant-derived individual molecules has significantly increased in the process of drug discovery and development for their potential efficacy or reduced risk in treating human disorders. Tinospora cordifolia (T. cordifolia) is a widely used herbal source to treat various human ailments, including diabetes mellitus. The present study was aimed on evaluating the antidiabetic property of a novel polysaccharide isolated from the methanolic extract of T. cordifolia stem. Bioassay guided fractionation was followed to isolate a compound from the methanol extract. The compound was administered orally at a dose of 20 mg/kg.b.wt for 60 days to control and STZ-induced diabetic male Wistar rats. It was found that plasma glucose was significantly (p < 0.05) reduced compared to normal. Oral administration of the compound significantly decreased HBA1c, triglycerides and total cholesterol and at the same time markedly increased hemoglobin, tissue glycogen and HDL cholesterol. Also the compounds restored the altered carbohydrate metabolizing enzymes, insulin, C-peptide, (14)C-glucose oxidation levels to near normal. In addition, the histological studies revealed that there was regeneration of β-cells in the pancreatic sections. The expression of Glut-4 mRNA and protein in the gasrtocnemius muscle were significantly enhanced after the compound treatment. These results confirm that the novel polysaccharide possesses hypoglycemic, glucose oxidizing, hypolipidemic and β-cell regenerative properties and hence it could be developed into potential oral hypoglycemic drug with lesser side effects. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Glycaemic control and implementation of the ADA/EASD-2006 consensus algorithm in type 2 diabetes mellitus patients in primary care in Spain.

PubMed

Alvarez-Guisasola, F

2014-01-01

In 2006, the American Diabetes Association and the European Association for the Study of Diabetes established a consensus algorithm (ADA/EASD-2006) for the adjustment of drug therapy for type 2 diabetes mellitus (T2DM). To study glycaemic control in T2DM patients and the implementation of the ADA/EASD-2006 recommendations in primary care centres in Spain. Prospective observational study in 1194 patients with T2DM conducted in 250 primary care centres in Spain. Patients were assessed at study inclusion (V0) and at 3 (V1) and 6 months (V2) post baseline. Information was collected at the level of DM control, HbA(1c) < 7% (HbC) and implementation of the ADA/EASD-2006 guidelines. Type 2 diabetes mellitus patients (53% women; mean age 64.9 years) had a mean (SD) HbA(1c) 7.8 (1.4)% and HbC 25.2% at baseline, 95% of them were receiving oral antihyperglycaemic agents (AAs) only. At V1, HbA(1c) was 7.3 (1.1)% and HbC was 38.1%; 65.0% of patients were receiving oral AAs, 5.6% insulin and 27.9% oral AAs plus insulin. At V2, HbA(1c) was 7.1 (0.9)% and HbC was 48.0%; 57.1% of patients were receiving oral AAs, 5.0% insulin and 36.9% oral AAs plus insulin. The ADA/EASD-2006 algorithm was adhered to in 33% patients up to study month 3, vs. 17.2% throughout the entire 6-month period. In patients with T2DM seen in primary care, the HbA1c target was met in 48.0% after adjusting their AAs. However, this is not reflected in greater implementation of the ADA/EASD-2006 guidelines, which are adhered to in only 17%. © 2013 John Wiley & Sons Ltd.

A clinical perspective of obesity, metabolic syndrome and cardiovascular disease.

PubMed

Han, Thang S; Lean, Mike Ej

2016-01-01

The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30-40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5-10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35-40 kg/m(2) with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists.

A clinical perspective of obesity, metabolic syndrome and cardiovascular disease

PubMed Central

Lean, Mike EJ

2016-01-01

The metabolic syndrome is a condition characterized by a special constellation of reversible major risk factors for cardiovascular disease and type 2 diabetes. The main, diagnostic, components are reduced HDL-cholesterol, raised triglycerides, blood pressure and fasting plasma glucose, all of which are related to weight gain, specifically intra-abdominal/ectopic fat accumulation and a large waist circumference. Using internationally adopted arbitrary cut-off values for waist circumference, having metabolic syndrome doubles the risk of cardiovascular disease, but offers an effective treatment approach through weight management. Metabolic syndrome now affects 30–40% of people by age 65, driven mainly by adult weight gain, and by a genetic or epigenetic predisposition to intra-abdominal/ectopic fat accumulation related to poor intra-uterine growth. Metabolic syndrome is also promoted by a lack of subcutaneous adipose tissue, low skeletal muscle mass and anti-retroviral drugs. Reducing weight by 5–10%, by diet and exercise, with or without, anti-obesity drugs, substantially lowers all metabolic syndrome components, and risk of type 2 diabetes and cardiovascular disease. Other cardiovascular disease risk factors such as smoking should be corrected as a priority. Anti-diabetic agents which improve insulin resistance and reduce blood pressure, lipids and weight should be preferred for diabetic patients with metabolic syndrome. Bariatric surgery offers an alternative treatment for those with BMI ≥ 40 or 35–40 kg/m2 with other significant co-morbidity. The prevalence of the metabolic syndrome and cardiovascular disease is expected to rise along with the global obesity epidemic: greater emphasis should be given to effective early weight-management to reduce risk in pre-symptomatic individuals with large waists. PMID:26998259

Pemetrexed-Induced Nephrogenic Diabetes Insipidus

PubMed Central

Fung, Enrica; Anand, Shuchi; Bhalla, Vivek

2016-01-01

Pemetrexed is an approved anti-metabolite agent, now widely used for treating locally advanced or metastatic non-squamous, non–small cell lung cancer. Although no electrolyte abnormalities are described in the prescribing information for this drug, several case reports have noted nephrogenic diabetes insipidus with associated acute kidney injury. We present a case of nephrogenic diabetes insipidus without severely reduced kidney function and propose a mechanism for the isolated finding. Severe hypernatremia can lead to encephalopathy and osmotic demyelination, and our report highlights the importance of careful monitoring of electrolytes and kidney function in patients with lung cancer receiving pemetrexed. PMID:27241854

Antihyperglycemic effect of crude extracts of some Egyptian plants and algae.

PubMed

AbouZid, Sameh Fekry; Ahmed, Osama Mohamed; Ahmed, Rasha Rashad; Mahmoud, Ayman; Abdella, Ehab; Ashour, Mohamed Badr

2014-03-01

Diabetes mellitus is a major global health problem. Various plant extracts have proven antidiabetic activity and are considered as promising substitution for antidiabetic drugs. The antihyperglycemic effect of 16 plants and 4 algae, commonly used in Egypt for the treatment of diabetes mellitus, was investigated. A diabetes model was induced by intraperitoneal injection of nicotinamide (120 mg/kg body weight [b.wt.]), then streptozotocin (200 mg/kg b.wt.) after 15 min. Hydroethanolic extracts (80%) of the plants and algae under investigation were prepared. The extracts were orally administered to nicotinamide-streptozotocin-induced diabetic mice by a gastric tube at doses 10 or 50 mg/kg b.wt. for 1 week. The antidiabetic activity was assessed by detection of serum glucose concentrations at the fasting state and after 2 h of oral glucose loading (4.2 mg/kg b.wt.). Extracts prepared from Cassia acutifolia, Fraxinus ornus, Salix aegyptiaca, Cichorium intybus, and Eucalyptus globulus showed the highest antihyperglycemic activity among the tested plants. Extracts prepared from Sonchus oleraceus, Bougainvillea spectabilis (leaves), Plantago psyllium (seeds), Morus nigra (leaves), and Serena repens (fruits) were found to have antihyperglycemic potentials. Extracts prepared from Caulerpa lentillifera and Spirulina versicolor showed the most potent antihyperglycemic activity among the tested algae. However, some of the tested plants have insulinotropic effects, all assessed algae have not. Identification of lead compounds from these plants and algae for novel antidiabetic drug development is recommended.

Identification of a novel selective PPARγ ligand with a unique binding mode and improved therapeutic profile in vitro

PubMed Central

Yi, Wei; Shi, Jingjing; Zhao, Guanguan; Zhou, X. Edward; Suino-Powell, Kelly; Melcher, Karsten; Xu, H. Eric

2017-01-01

Thiazolidinediones (TZD) function as potent anti-diabetic drugs through their direct action on the nuclear receptor peroxisome proliferator-activated receptor γ (PPARγ), but their therapeutic benefits are compromised by severe side effects. To address this concern, here we developed a potent “hit” compound, VSP-51, which is a novel selective PPARγ-modulating ligand with improved therapeutic profiles in vitro compared to the multi-billion dollar TZD drug rosiglitazone (Rosi). Unlike Rosi, VSP-51 is a partial agonist of PPARγ with improved insulin sensitivity due to its ability to bind PPARγ with high affinity without stimulating adipocyte differentiation and the expression of adipogenesis-related genes. We have determined the crystal structure of the PPARγ ligand-binding domain (LBD) in complex with VSP-51, which revealed a unique mode of binding for VSP-51 and provides the molecular basis for the discrimination between VSP-51 from TZDs and other ligands such as telmisartan, SR1663 and SR1664. Taken together, our findings demonstrate that: a) VSP-51 can serve as a promising candidate for anti-diabetic drug discovery; and b) provide a rational basis for the development of future pharmacological agents targeting PPARγ with advantages over current TZD drugs. PMID:28128331

Effect of the Polyphenol Rich Ethyl Acetate Fraction from the Leaves of Lycium chinenseMill. on Oxidative Stress, Dyslipidemia, and Diabetes Mellitus in Streptozotocin-Nicotinamide Induced Diabetic Rats.

PubMed

Olatunji, Opeyemi J; Chen, Hongxia; Zhou, Yifeng

2017-10-01

Lycium chinenseMill., popularly known as boxthorn, is a plant that is traditionally used for treating night sweat, cough, inflammation and diabetes mellitus. However, the leaves have received little or no attention despite their potentials as a potent therapeutic agent. This study was aimed at investigating the hypoglycemic and hypolipidemic effects of the polyphenols-rich ethyl acetate fraction from the leaves of Lycium chinenseMill. on streptozotocin-nicotinamide induced diabetic rats. The ethyl acetate fraction (LFE) was selected and orally gavaged at 100, 200, and 400 mg/kg dose to streptozotocin (STZ)-nicotinamide induced diabetic rats. The rats' body weight, fasting blood glucose (FBG), lipid profile and oxidative stress markers were evaluated after the treatment period. Treatment with LFE resulted in a significant decrease in the FBG level, altered lipid profiles, and reduced the activities of the enzymes alkaline phosphatase (ALP), aspartate transaminase (AST), alanine transaminase (ALT) in the treated diabetic rats. Furthermore, LFE significantly elevated the antioxidant status (superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GSH-Px) activities) and reducing malondialdehyde (MDA) levels in the treated rats. The present study has revealed that L. chinenseMill. possess anti-hyperglycemic and anti-hyperlipidemic properties which is mediated through modulation of oxidative stress and polyphenolics might be responsible for the action. © 2017 Wiley-VHCA AG, Zurich, Switzerland.

The effect of xerostomia and hyposalivation on the quality of life of patients with type II diabetes mellitus

PubMed Central

Molania, Tahereh; Alimohammadi, Mona; Akha, Ozra; Mousavi, Jaber; Razvini, Ramin; Salehi, Maedeh

2017-01-01

Background Diabetes mellitus is a chronic metabolic disease which can have numerous physical effects for patient. Xerostomia is one of these complications. Compared to healthy people, patients with diabetes mellitus, have a worse quality of life, and complications of diabetes are the main determinants of quality of life in these patients. Objective The aim of this study was to determine the effects of xerostomia and hyposalivation on quality of life of patients with type 2 diabetes mellitus. Methods This descriptive-analytical epidemiological study was conducted on 200 patients with type 2 diabetes mellitus referred to the diabetes clinic of Shahid Mostafavi in Sari city from October 2015 to January in 2016. A questionnaire containing personal characteristics and medical situation was completed by each person. Then, the Persian Oral Health Impact Profile-14 (OHIP-14-PER) questionnaire was completed by the patients. Eventually, with the use of chewable paraffin for 1.5 min by the patient, stimulated salivary flow rate (SSFR) test was performed, and in order to determine hyposalivation, their saliva amount underwent a gravimetric test. Finally, using statistical software SPSS16, the information was statistically analyzed by independent-samples t-test, Mann-Whitney U, Chi-squared and fisher exact tests. Results The average age of patient was 56.41 years old (43% male and 57% female). Mean SSFR was 0.7 ml/min in patients and xerostomia were confirmed in 112 patients. Difference between age, gender, drug use, years affecting to diabetes and FBS amount in patient with hyposalivation were not statistically meaningful in proportion to patients without it. But difference between HbA1C and SSFR in patients with hyposalivation were statistically meaningful than to patients without it (p=0.03, p=0.001 respectively). The mean patient score to OHIP-14 were obtained as 38.17. The questionnaire score difference in patients with hyposalivation in proportion to patients without it were not statistically meaningful. Conclusion Hyposalivation possibility increases in diabetic patients with low metabolic control which can cause more severe side effects in relation to oral health. Xerostomia in diabetic patients has negative effects on oral health related quality of life. Diabetic control and patients’ oral problem improvement is effective in their quality of life promotion. PMID:29403624

The effect of xerostomia and hyposalivation on the quality of life of patients with type II diabetes mellitus.

PubMed

Molania, Tahereh; Alimohammadi, Mona; Akha, Ozra; Mousavi, Jaber; Razvini, Ramin; Salehi, Maedeh

2017-11-01

Diabetes mellitus is a chronic metabolic disease which can have numerous physical effects for patient. Xerostomia is one of these complications. Compared to healthy people, patients with diabetes mellitus, have a worse quality of life, and complications of diabetes are the main determinants of quality of life in these patients. The aim of this study was to determine the effects of xerostomia and hyposalivation on quality of life of patients with type 2 diabetes mellitus. This descriptive-analytical epidemiological study was conducted on 200 patients with type 2 diabetes mellitus referred to the diabetes clinic of Shahid Mostafavi in Sari city from October 2015 to January in 2016. A questionnaire containing personal characteristics and medical situation was completed by each person. Then, the Persian Oral Health Impact Profile-14 (OHIP-14-PER) questionnaire was completed by the patients. Eventually, with the use of chewable paraffin for 1.5 min by the patient, stimulated salivary flow rate (SSFR) test was performed, and in order to determine hyposalivation, their saliva amount underwent a gravimetric test. Finally, using statistical software SPSS16, the information was statistically analyzed by independent-samples t-test, Mann-Whitney U, Chi-squared and fisher exact tests. The average age of patient was 56.41 years old (43% male and 57% female). Mean SSFR was 0.7 ml/min in patients and xerostomia were confirmed in 112 patients. Difference between age, gender, drug use, years affecting to diabetes and FBS amount in patient with hyposalivation were not statistically meaningful in proportion to patients without it. But difference between HbA1C and SSFR in patients with hyposalivation were statistically meaningful than to patients without it (p=0.03, p=0.001 respectively). The mean patient score to OHIP-14 were obtained as 38.17. The questionnaire score difference in patients with hyposalivation in proportion to patients without it were not statistically meaningful. Hyposalivation possibility increases in diabetic patients with low metabolic control which can cause more severe side effects in relation to oral health. Xerostomia in diabetic patients has negative effects on oral health related quality of life. Diabetic control and patients' oral problem improvement is effective in their quality of life promotion.

Effects of crocin and voluntary exercise, alone or combined, on heart VEGF-A and HOMA-IR of HFD/STZ induced type 2 diabetic rats.

PubMed

Ghorbanzadeh, V; Mohammadi, M; Dariushnejad, H; Chodari, L; Mohaddes, G

2016-10-01

Hyperglycemia is the main risk factor for microvascular complications in type 2 diabetes. Crocin and voluntary exercise have anti-hyperglycemic effects in diabetes. In this research, we evaluated the effects of crocin and voluntary exercise alone or combined on glycemia control and heart level of VEGF-A. Animals were divided into eight groups as: control (con), diabetes (Dia), crocin (Cro), voluntary exercise (Exe), crocin and voluntary exercise (Cro-Exe), diabetic-crocin (Dia-Cro), diabetic-voluntary exercise (Dia-Exe), diabetic-crocin-voluntary exercise (Dia-Cro-Exe). Type 2 diabetes was induced by a high-fat diet (4 weeks) and injection of streptozotocin (STZ) (i.p, 35 mg/kg). Animals received oral administration of crocin (50 mg/kg) or performed voluntary exercise alone or together for 8 weeks. Oral glucose tolerance test (OGTT) was performed on overnight fasted control, diabetic and treated rats after 8 weeks of treatment. Then, serum insulin and heart VEGF-A protein levels were measured. Crocin combined with voluntary exercise significantly decreased blood glucose levels (p < 0.001) and insulin resistance (HOMA-IR) (p < 0.001) compared to diabetic group. VEGF-A level was significantly (p < 0.01) lower in Dia group compared to control group. The combination of crocin and voluntary exercise significantly enhanced VEGF-A protein levels in Dia-Cro-Exe and Cro-Exe group compared to diabetic and control groups, respectively; p < 0.001 and p < 0.05. Crocin combined with voluntary exercise improved insulin resistance (HOMA-IR) and reduced glucose levels in diabetic rats. Since both crocin and voluntary exercise can increase VEGF-A protein expression in heart tissue, they probably are able to increase angiogenesis in diabetic animals.

Field-based performance of three pre-market rapid hepatitis C virus antibody assays in STAHR (Study to Assess Hepatitis C Risk) among young adults who inject drugs in San Diego, CA.

PubMed

Jewett, A; Smith, B D; Garfein, R S; Cuevas-Mota, J; Teshale, E H; Weinbaum, C M

2012-07-01

Approximately 4.1 million Americans are estimated to have been infected with hepatitis C virus (HCV), 45-85% of whom are unaware of their infection. Persons who inject drugs (PWID) account for 55.8% of all persons with HCV antibody (anti-HCV) in the U.S. PWID have limited access to healthcare and are infrequently tested for anti-HCV using conventional laboratory assays. To evaluate performance characteristics (sensitivity and specificity) of three, pre-market rapid point-of-care tests (one oral fluid and two finger-stick assays) from two manufacturers (Chembio and MedMira) in settings providing services to young adult PWID in San Diego, CA. Behavioral risk assessment surveys and testing for HCV were conducted among persons who reported injection drug use (IDU) within the past 6 months as part of the Study to Assess Hepatitis C Risk (STAHR) among PWID aged 18-40 years in 2009-2010. Sensitivity and specificity of the rapid anti-HCV assays were evaluated among STAHR participants, using two commonly used testing algorithms. Variability in sensitivity (76.6-97.1%) and specificity (99.0-100.0%) was found across assays. The highest sensitivity achieved for the Chembio finger-stick blood, Chembio oral fluid and MedMira finger-stick blood tests was 97.1%, 85.4% and 80.0% respectively; the highest specificity was 99.0%, 100.0% and 100.0%, respectively. In multivariate analysis false negative anti-HCV results were associated with female sex for the MedMira blood assay. Sensitive anti-HCV rapid assays are appropriate and feasible for high-prevalence, high-risk populations such as young PWID. Copyright © 2012 Elsevier B.V. All rights reserved.

Anti-inflammatory Effect of Astaxanthin on the Sickness Behavior Induced by Diabetes Mellitus.

PubMed

Ying, Chang-jiang; Zhang, Fang; Zhou, Xiao-yan; Hu, Xiao-tong; Chen, Jing; Wen, Xiang-ru; Sun, Ying; Zheng, Kui-yang; Tang, Ren-xian; Song, Yuan-jian

2015-10-01

Chronic inflammation appears to play a critical role in sickness behavior caused by diabetes mellitus. Astaxanthin has been used in treating diabetes mellitus and diabetic complications because of its neuroprotective and anti-inflammatory actions. However, whether astaxanthin can improve sickness behavior induced by diabetes and its potential mechanisms are still unknown. The aim of this study was to investigate the effects of astaxanthin on diabetes-elicited abnormal behavior in mice and its corresponding mechanisms. An experimental diabetic model was induced by streptozotocin (150 mg/kg) and astaxanthin (25 mg/kg/day) was provided orally for 10 weeks. Body weight and water consumption were measured, and the sickness behavior was evaluated by the open field test (OFT) and closed field test (CFT). The expression of glial fibrillary acidic protein (GFAP) was measured, and the frontal cortical cleaved caspase-3 positive cells, interleukin-6 (IL-6), and interleukin-1β (IL-1β) expression levels were also investigated. Furthermore, cystathionine β-synthase (CBS) in the frontal cortex was detected to determine whether the protective effect of astaxanthin on sickness behavior in diabetic mice is closely related to CBS. As expected, we observed that astaxanthin improved general symptoms and significantly increase horizontal distance and the number of crossings in the OFT and CFT. Furthermore, data showed that astaxanthin could decrease GFAP-positive cells in the brain and down-regulate the cleaved caspase-3, IL-6, and IL-1β, and up-regulate CBS in the frontal cortex. These results suggest that astaxanthin provides neuroprotection against diabetes-induced sickness behavior through inhibiting inflammation, and the protective effects may involve CBS expression in the brain.

Concanavalin A conjugated biodegradable nanoparticles for oral insulin delivery

NASA Astrophysics Data System (ADS)

Hurkat, Pooja; Jain, Aviral; Jain, Ashish; Shilpi, Satish; Gulbake, Arvind; Jain, Sanjay K.

2012-11-01

Major research issues in oral protein delivery include the stabilization of protein in delivery devices which could increase its oral bioavailability. The study deals with development of oral insulin delivery system utilizing biodegradable poly(lactic-co-glycolic acid) (PLGA) nanoparticles and modifying its surface with Concanavalin A to increase lymphatic uptake. Surface-modified PLGA nanoparticles were characterized for conjugation efficiency of ligand, shape and surface morphology, particle size, zeta potential, polydispersity index, entrapment efficiency, and in vitro drug release. Stability of insulin in the developed formulation was confirmed by SDS-PAGE, and integrity of entrapped insulin was assessed using circular dichroism spectrum. Ex vivo study was performed on Wistar rats, which exhibited the higher intestinal uptake of Con A conjugated nanoparticles. In vivo study performed on streptozotocin-induced diabetic rats which indicate that a surface-modified nanoparticle reduces blood glucose level effectively within 4 h of its oral administration. In conclusion, the present work resulted in successful production of Con A NPs bearing insulin with sustained release profile, and better absorption and stability. The Con A NPs showed high insulin uptake, due to its relative high affinity for non-reducing carbohydrate residues i.e., fucose present on M cells and have the potential for oral insulin delivery in effective management of Type 1 diabetes condition.