Comparison of electrophysiological data from human-induced pluripotent stem cell-derived cardiomyocytes to functional preclinical safety assays.

PubMed

Harris, Kate; Aylott, Mike; Cui, Yi; Louttit, James B; McMahon, Nicholas C; Sridhar, Arun

2013-08-01

Human-induced pluripotent stem cell cardiomyocytes (hiPSC-CMs) are a potential source to develop assays for predictive electrophysiological safety screening. Published studies show that the relevant physiology and pharmacology exist but does not show the translation between stem cell cardiomyocyte assays and other preclinical safety screening assays, which is crucial for drug discovery and safety scientists and the regulators. Our studies are the first to show the pharmacology of ion channel blockade and compare them with existing functional cardiac electrophysiology studies. Ten compounds (a mixture of pure hERG [E-4031 and Cisapride], hERG and sodium [Flecainide, Mexiletine, Quinidine, and Terfenadine], calcium channel blockers [Nifedipine and Verapamil], and two proprietary compounds [GSK A and B]) were tested, and results from hiPSC-CMs studied on multielectrode arrays (MEA) were compared with other preclincial models and clinical drug concentrations and effects using integrated risk assessment plots. All ion channel blockers produced (1) functional effects on repolarization and depolarization around the IC25 and IC50 values and (2) excessive blockade of hERG and/or blockade of sodium current precipitated arrhythmias. Our MEA data show that hiPSC-CMs demonstrate relevant pharmacology and show excellent correlations to current functional cardiac electrophysiological studies. Based on these results, MEA assays using iPSC-CMs offer a reliable, cost effective, and surrogate to preclinical in vitro testing, in addition to the 3Rs (refine, reduce, and replace animals in research) benefit.

A multi-site comparison of in vivo safety pharmacology studies conducted to support ICH S7A & B regulatory submissions.

PubMed

Ewart, Lorna; Milne, Aileen; Adkins, Debbie; Benjamin, Amanda; Bialecki, Russell; Chen, Yafei; Ericsson, Ann-Christin; Gardner, Stacey; Grant, Claire; Lengel, David; Lindgren, Silvana; Lowing, Sarah; Marks, Louise; Moors, Jackie; Oldman, Karen; Pietras, Mark; Prior, Helen; Punton, James; Redfern, Will S; Salmond, Ross; Skinner, Matt; Some, Margareta; Stanton, Andrea; Swedberg, Michael; Finch, John; Valentin, Jean-Pierre

2013-01-01

Parts A and B of the ICH S7 guidelines on safety pharmacology describe the in vivo studies that must be conducted prior to first time in man administration of any new pharmaceutical. ICH S7A requires a consideration of the sensitivity and reproducibility of the test systems used. This could encompass maintaining a dataset of historical pre-dose values, power analyses, as well as a demonstration of acceptable model sensitivity and robust pharmacological validation. During the process of outsourcing safety pharmacology studies to Charles River Laboratories, AstraZeneca set out to ensure that models were performed identically in each facility and saw this as an opportunity to review the inter-laboratory variability of these essential models. The five in vivo studies outsourced were the conscious dog telemetry model for cardiovascular assessment, the rat whole body plethysmography model for respiratory assessment, the rat modified Irwin screen for central nervous system assessment, the rat charcoal meal study for gastrointestinal assessment and the rat metabolic cage study for assessment of renal function. Each study was validated with known reference compounds and data were compared across facilities. Statistical power was also calculated for each model. The results obtained indicated that each of the studies could be performed with comparable statistical power and could achieve a similar outcome, independent of facility. The consistency of results obtained from these models across multiple facilities was high thus providing confidence that the models can be run in different facilities and maintain compliance with ICH S7A and B. Copyright © 2013 Elsevier Inc. All rights reserved.

Transdermal fentanyl: pharmacology and toxicology.

PubMed

Nelson, Lewis; Schwaner, Robert

2009-12-01

To evaluate the underlying pharmacology, safety, and misuse/abuse of transdermal fentanyl, one of the cornerstone pharmacotherapies for patients with chronic pain. Literature was identified through searches of Medline (PubMed) and several textbooks in the areas of pharmacology, toxicology, and pain management. A bibliographical review of articles identified by these searches was also performed. Search terms included combinations of the following: fentanyl, transdermal, patch, pharmacology, kinetics, toxicity, and poisoning. All pertinent clinical trials, retrospective studies, and case reports relevant to fentanyl pharmacology and transdermal fentanyl administered by any route and published in English were identified. Each was reviewed for data regarding the clinical pharmacology, abuse, misuse, and safety of transdermal fentanyl. Data from these studies and information from review articles and pharmaceutical prescribing information were included in this review. Fentanyl is a high-potency opioid that has many uses in the treatment of both acute and chronic pain. Intentional or unintentional misuse, as well as abuse, may lead to significant clinical consequences, including death. Both the US Food and Drug Administration (FDA) and Health Canada have warned of potential pitfalls associated with transdermal fentanyl, although these have not been completely effective in preventing life-threatening adverse events and fatalities related to its inappropriate use. Clinically consequential adverse effects may occur unexpectedly with normal use of transdermal fentanyl, or if misused or abused. Misuse and therapeutic error may be largely preventable through better education at all levels for both the prescriber and patient. The prevention of intentional misuse or abuse may require regulatory intervention.

21 CFR 320.28 - Correlation of bioavailability with an acute pharmacological effect or clinical evidence.

Code of Federal Regulations, 2010 CFR

2010-04-01

... pharmacological effect or clinical evidence. 320.28 Section 320.28 Food and Drugs FOOD AND DRUG ADMINISTRATION... Correlation of bioavailability with an acute pharmacological effect or clinical evidence. Correlation of in vivo bioavailability data with an acute pharmacological effect or clinical evidence of safety and...

Natural Product-Derived Treatments for Attention-Deficit/Hyperactivity Disorder: Safety, Efficacy, and Therapeutic Potential of Combination Therapy

PubMed Central

Ahn, James; Ahn, Hyung Seok; Cheong, Jae Hoon; dela Peña, Ike

2016-01-01

Typical treatment plans for attention-deficit/hyperactivity disorder (ADHD) utilize nonpharmacological (behavioral/psychosocial) and/or pharmacological interventions. Limited accessibility to behavioral therapies and concerns over adverse effects of pharmacological treatments prompted research for alternative ADHD therapies such as natural product-derived treatments and nutritional supplements. In this study, we reviewed the herbal preparations and nutritional supplements evaluated in clinical studies as potential ADHD treatments and discussed their performance with regard to safety and efficacy in clinical trials. We also discussed some evidence suggesting that adjunct treatment of these agents (with another botanical agent or pharmacological ADHD treatments) may be a promising approach to treat ADHD. The analysis indicated mixed findings with regard to efficacy of natural product-derived ADHD interventions. Nevertheless, these treatments were considered as a “safer” approach than conventional ADHD medications. More comprehensive and appropriately controlled clinical studies are required to fully ascertain efficacy and safety of natural product-derived ADHD treatments. Studies that replicate encouraging findings on the efficacy of combining botanical agents and nutritional supplements with other natural product-derived therapies and widely used ADHD medications are also warranted. In conclusion, the risk-benefit balance of natural product-derived ADHD treatments should be carefully monitored when used as standalone treatment or when combined with other conventional ADHD treatments. PMID:26966583

Ventilatory function assessment in safety pharmacology: Optimization of rodent studies using normocapnic or hypercapnic conditions

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

Goineau, Sonia; Rompion, Sonia; Guillaume, Philippe

2010-09-15

Although the whole body plethysmography for unrestrained animals is the most widely used method to assess the respiratory risk of new drugs in safety pharmacology, non-appropriate experimental conditions may mask deleterious side effects of some substances. If stimulant or bronchodilatory effects can be easily evidenced in rodents under standard experimental conditions, i.e. normal air breathing and diurnal phase, drug-induced respiratory depression remains more difficult to detect. This study was aimed at comparing the responsiveness of Wistar rats, Duncan Hartley guinea-pigs or BALB/c mice to the respiratory properties of theophylline (50 or 100 mg/kg p.o.) or morphine (30 mg/kg i.p.) undermore » varying conditions (100% air versus 5% CO{sub 2}-enriched air, light versus dark day phase), in order to select the most appropriate experimental conditions to each species for safety airway investigations. Our results showed that under normocapnia the ventilatory depressant effects of morphine can be easily evidenced in mice, slightly observed in guinea-pigs and not detected in rats in any day phase. Slight hypercapnic conditions enhanced the responsiveness of rats to morphine but not that of guinea-pigs and importantly they did not blunt the airway responsiveness of rats to the stimulation and bronchodilation evoked by theophylline, the most widely used reference agent in safety pharmacology studies. In conclusion, hypercapnic conditions associated with the non-invasive whole body plethysmography should be considered for optimizing the assessment of both the ventilatory depressant potential of morphine-like substances or the respiratory stimulant effects of new drugs in the rat, the most extensively used species in rodent safety and toxicological investigations.« less

A review on indole alkaloids isolated from Uncaria rhynchophylla and their pharmacological studies.

PubMed

Ndagijimana, Andre; Wang, Xiaoming; Pan, Guixiang; Zhang, Fan; Feng, Hong; Olaleye, Olajide

2013-04-01

Uncaria rhynchophylla (Miq.) Jacks, Rubiaceae, is one of the original plants of the important Chinese crude drug, Gou-teng, mainly used for the treatment of convulsion, hypertension, epilepsy, eclampsia, and cerebral diseases. The pharmacological activities of this plant are related to the presence of active compounds predominantly indole alkaloids. In this article, we have reviewed some reports about the pharmacological activities of the main indole alkaloids isolated from U. rhynchophylla. This review paper will contribute to the studies on the chemistry, safety and quality control of medicinal preparations containing Uncaria species. Copyright © 2013 Elsevier B.V. All rights reserved.

Pharmacological mechanism-based drug safety assessment and prediction.

PubMed

Abernethy, D R; Woodcock, J; Lesko, L J

2011-06-01

Advances in cheminformatics, bioinformatics, and pharmacology in the context of biological systems are now at a point that these tools can be applied to mechanism-based drug safety assessment and prediction. The development of such predictive tools at the US Food and Drug Administration (FDA) will complement ongoing efforts in drug safety that are focused on spontaneous adverse event reporting and active surveillance to monitor drug safety. This effort will require the active collaboration of scientists in the pharmaceutical industry, academe, and the National Institutes of Health, as well as those at the FDA, to reach its full potential. Here, we describe the approaches and goals for the mechanism-based drug safety assessment and prediction program.

A predictive index of biomarkers for ictogenesis from tier I safety pharmacology testing that may warrant tier II EEG studies.

PubMed

Gauvin, David V; Zimmermann, Zachary J; Yoder, Joshua; Harter, Marci; Holdsworth, David; Kilgus, Quinn; May, Jonelle; Dalton, Jill; Baird, Theodore J

2018-05-08

Three significant contributions to the field of safety pharmacology were recently published detailing the use of electroencephalography (EEG) by telemetry in a critical role in the successful evaluation of a compound during drug development (1] Authier, Delatte, Kallman, Stevens & Markgraf; JPTM 2016; 81:274-285; 2] Accardi, Pugsley, Forster, Troncy, Huang & Authier; JPTM; 81: 47-59; 3] Bassett, Troncy, Pouliot, Paquette, Ascaha, & Authier; JPTM 2016; 70: 230-240). These authors present a convincing case for monitoring neocortical biopotential waveforms (EEG, ECoG, etc) during preclinical toxicology studies as an opportunity for early identification of a central nervous system (CNS) risk during Investigational New Drug (IND) Enabling Studies. This review is about "ictogenesis" not "epileptogenesis". It is intended to characterize overt behavioral and physiological changes suggestive of drug-induced neurotoxicity/ictogenesis in experimental animals during Tier 1 safety pharmacology testing, prior to first dose administration in man. It is the presence of these predictive or comorbid biomarkers expressed during the requisite conduct of daily clinical or cage side observations, and in early ICH S7A Tier I CNS, pulmonary and cardiovascular safety study designs that should initiate an early conversation regarding Tier II inclusion of EEG monitoring. We conclude that there is no single definitive clinical marker for seizure liability but plasma exposures might add to set proper safety margins when clinical convulsions are observed. Even the observation of a study-related full tonic-clonic convulsion does not establish solid ground to require the financial and temporal investment of a full EEG study under the current regulatory standards. For purposes of this review, we have adopted the FDA term "sponsor" as it refers to any person who takes the responsibility for and initiates a nonclinical investigations of new molecular entities; FDA uses the term "sponsor" primarily in relation to investigational new drug application submissions. Copyright © 2018. Published by Elsevier Inc.

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses

PubMed Central

2017-01-01

Introduction Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. Aim The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. Methods A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. Results The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Conclusion Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors. PMID:29077727

Biological substantiation of antipsychotic-associated pneumonia: Systematic literature review and computational analyses.

PubMed

Sultana, Janet; Calabró, Marco; Garcia-Serna, Ricard; Ferrajolo, Carmen; Crisafulli, Concetta; Mestres, Jordi; Trifirò', Gianluca

2017-01-01

Antipsychotic (AP) safety has been widely investigated. However, mechanisms underlying AP-associated pneumonia are not well-defined. The aim of this study was to investigate the known mechanisms of AP-associated pneumonia through a systematic literature review, confirm these mechanisms using an independent data source on drug targets and attempt to identify novel AP drug targets potentially linked to pneumonia. A search was conducted in Medline and Web of Science to identify studies exploring the association between pneumonia and antipsychotic use, from which information on hypothesized mechanism of action was extracted. All studies had to be in English and had to concern AP use as an intervention in persons of any age and for any indication, provided that the outcome was pneumonia. Information on the study design, population, exposure, outcome, risk estimate and mechanism of action was tabulated. Public repositories of pharmacology and drug safety data were used to identify the receptor binding profile and AP safety events. Cytoscape was then used to map biological pathways that could link AP targets and off-targets to pneumonia. The literature search yielded 200 articles; 41 were included in the review. Thirty studies reported a hypothesized mechanism of action, most commonly activation/inhibition of cholinergic, histaminergic and dopaminergic receptors. In vitro pharmacology data confirmed receptor affinities identified in the literature review. Two targets, thromboxane A2 receptor (TBXA2R) and platelet activating factor receptor (PTAFR) were found to be novel AP target receptors potentially associated with pneumonia. Biological pathways constructed using Cytoscape identified plausible biological links potentially leading to pneumonia downstream of TBXA2R and PTAFR. Innovative approaches for biological substantiation of drug-adverse event associations may strengthen evidence on drug safety profiles and help to tailor pharmacological therapies to patient risk factors.

Ambroxol chaperone therapy for neuronopathic Gaucher disease: A pilot study.

PubMed

Narita, Aya; Shirai, Kentarou; Itamura, Shinji; Matsuda, Atsue; Ishihara, Akiko; Matsushita, Kumi; Fukuda, Chisako; Kubota, Norika; Takayama, Rumiko; Shigematsu, Hideo; Hayashi, Anri; Kumada, Tomohiro; Yuge, Kotaro; Watanabe, Yoriko; Kosugi, Saori; Nishida, Hiroshi; Kimura, Yukiko; Endo, Yusuke; Higaki, Katsumi; Nanba, Eiji; Nishimura, Yoko; Tamasaki, Akiko; Togawa, Masami; Saito, Yoshiaki; Maegaki, Yoshihiro; Ohno, Kousaku; Suzuki, Yoshiyuki

2016-03-01

Gaucher disease (GD) is a lysosomal storage disease characterized by a deficiency of glucocerebrosidase. Although enzyme-replacement and substrate-reduction therapies are available, their efficacies in treating the neurological manifestations of GD are negligible. Pharmacological chaperone therapy is hypothesized to offer a new strategy for treating the neurological manifestations of this disease. Specifically, ambroxol, a commonly used expectorant, has been proposed as a candidate pharmacological chaperone. The purpose of this study was to evaluate the safety, tolerability, and neurological efficacy of ambroxol in patients with neuronopathic GD. This open-label pilot study included five patients who received high-dose oral ambroxol in combination with enzyme replacement therapy. Safety was assessed by adverse event query, physical examination, electrocardiography, laboratory studies, and drug concentration. Biochemical efficacy was assessed through evidence of glucocerebrosidase activity in the lymphocytes and glucosylsphingosine levels in the cerebrospinal fluid. Neurological efficacy was evaluated using the Unified Myoclonus Rating Scale, Gross Motor Function Measure, Functional Independence Measure, seizure frequency, pupillary light reflex, horizontal saccadic latency, and electrophysiologic studies. High-dose oral ambroxol had good safety and tolerability, significantly increased lymphocyte glucocerebrosidase activity, permeated the blood-brain barrier, and decreased glucosylsphingosine levels in the cerebrospinal fluid. Myoclonus, seizures, and pupillary light reflex dysfunction markedly improved in all patients. Relief from myoclonus led to impressive recovery of gross motor function in two patients, allowing them to walk again. Pharmacological chaperone therapy with high-dose oral ambroxol shows promise in treating neuronopathic GD, necessitating further clinical trials.

New treatment options for chronic constipation: Mechanisms, efficacy and safety

PubMed Central

Camilleri, Michael

2011-01-01

The present review has several objectives, the first of which is to review the pharmacology and selectivity of serotonergic agents to contrast the older serotonergic agents (which were withdrawn because of cardiac or vascular adverse effects) with the newer generation serotonin receptor subtype 4 agonists. Second, the chloride ion secretagogues that act through the guanylate cyclase C receptor are appraised and their pharmacology is compared with the approved medication, lubiprostone. Third, the efficacy and safety of the application of bile acid modulation to treat constipation are addressed. The long-term studies of surgically induced excess bile acid delivery to the colon are reviewed to ascertain the safety of this therapeutic approach. Finally, the new drugs for opiate-induced constipation are introduced. Assuming these drugs are approved, practitioners will have a choice; however, patient responsiveness will be based on trial and error. Nevertheless, the spectrum of mechanisms and demonstrated efficacy and safety augur well for satisfactory treatment outcomes. PMID:22114755

21 CFR 601.35 - Evaluation of safety.

Code of Federal Regulations, 2011 CFR

2011-04-01

... radiation dose; (2) The pharmacology and toxicology of the radiopharmaceutical, including any radionuclide... information, the following types of data: (A) Pharmacology data, (B) Toxicology data, (C) Clinical adverse...

Assessment of Safety, Tolerability, Pharmacokinetics, and Pharmacological Effect of Orally Administered CORT125134: An Adaptive, Double-Blind, Randomized, Placebo-Controlled Phase 1 Clinical Study.

PubMed

Hunt, Hazel; Donaldson, Kirsteen; Strem, Mark; Zann, Vanessa; Leung, Pui; Sweet, Suzanne; Connor, Alyson; Combs, Dan; Belanoff, Joseph

2018-05-01

CORT125134 is an orally active, high-affinity, selective antagonist of the glucocorticoid receptor that is being developed for indications that may benefit from the modulation of cortisol activity. This first-in-human study was conducted to evaluate the dose-related safety, tolerability, pharmacokinetics and pharmacological effects of CORT125134 and its active metabolite CORT125201. Eighty-one healthy male or female subjects received a single dose of 5 to 500 mg CORT125134 or matching placebo across 9 cohorts; 1 cohort received 150 mg CORT125134 after a high-fat breakfast; and 46 subjects received 50 to 500 mg CORT125134 or matching placebo once daily for up to 14 days across 4 cohorts. CORT125134 was well tolerated at doses up to 250 mg per day for 14 days. CORT125134 was absorbed rapidly and eliminated with a mean half-life ranging from 11 to 19 hours. Steady state was achieved by day 7. Exposure increased in a greater than proportional manner, particularly at lower doses. Exposure to CORT125201 at steady state was less than 5% that of parent CORT125134. Evidence for the desired pharmacological effect (glucocorticoid receptor antagonism) was demonstrated by the ability of CORT125134 to prevent several effects of the glucocorticoid receptor agonist prednisone. © 2018 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Safety pharmacology--current and emerging concepts.

PubMed

Hamdam, Junnat; Sethu, Swaminathan; Smith, Trevor; Alfirevic, Ana; Alhaidari, Mohammad; Atkinson, Jeffrey; Ayala, Mimieveshiofuo; Box, Helen; Cross, Michael; Delaunois, Annie; Dermody, Ailsa; Govindappa, Karthik; Guillon, Jean-Michel; Jenkins, Rosalind; Kenna, Gerry; Lemmer, Björn; Meecham, Ken; Olayanju, Adedamola; Pestel, Sabine; Rothfuss, Andreas; Sidaway, James; Sison-Young, Rowena; Smith, Emma; Stebbings, Richard; Tingle, Yulia; Valentin, Jean-Pierre; Williams, Awel; Williams, Dominic; Park, Kevin; Goldring, Christopher

2013-12-01

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combining toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. Copyright © 2013 Elsevier Inc. All rights reserved.

Clinical pharmacology review of escitalopram for the treatment of depression.

PubMed

Pastoor, Devin; Gobburu, Joga

2014-01-01

Depression is a serious and debilitating psychiatric condition with serious societal health and economic implications. Escitalopram , the S-enantiomer of racemic citalopram, is an effective treatment for major depressive disorder. This review covers the clinical pharmacology of escitalopram, with emphasis on regulatory approval. Its pharmacokinetics, pharmacodynamics and clinical efficacy for major depressive disorder are evaluated, along with data regarding safety and tolerability. Drug development of escitalopram was heavily guided by prior approval of citalopram. Select safety and efficacy studies for escitalopram in combination with supportive evidence from the results of prior citalopram studies allowed for regulatory approval for acute and maintenance claims in both adults and adolescents, while minimizing burden on the sponsor. Escitalopram has been shown to have better efficacy and safety profile than other selective serotonin reuptake inhibitor and serotonin norepinephrine reuptake inhibitor drugs, including racemic citalopram. The first generic escitalopram was approved in 2012, along with Abbreviated New Drug Applications. The associated cost savings have helped reduce the burden of weighing the benefits of escitalopram over less-expensive alternatives.

Efficacy and safety of pharmacological agents in the treatment of erythema migrans in early Lyme borreliosis-systematic review protocol.

PubMed

Torbahn, Gabriel; Hofmann, Heidelore; Allert, Roman; Freitag, Michael H; Dersch, Rick; Fingerle, Volker; Sommer, Harriet; Motschall, Edith; Meerpohl, Jörg J; Schmucker, Christine

2016-05-03

Erythema migrans represents an early cutaneous and most common manifestation of Lyme borreliosis. Recommendations regarding pharmacological agents, dose and duration of treatment are subject of intense debate. This review aims to explore differences in efficacy and safety between pharmacological treatments and control treatment. To identify relevant studies, we will conduct a systematic literature search. We will include randomised controlled trials (RCTs) and non-RCTs. Eligible comparative studies need to (1) consider patients with a diagnosis of erythema migrans resulting from Lyme borreliosis and (2) compare different pharmacological agents against each other, against any other non-pharmacological treatment, placebo or no treatment. Two review authors will independently assess included studies for risk of bias according to the methods of the Cochrane Handbook for Systematic Reviews of Interventions and related to specific study designs. We will address patient-relevant outcomes including clinical remission of cutaneous symptoms, any treatment-related adverse events, quality of life and progressive symptoms such as neuroborreliosis or Lyme carditis and flu-like symptoms. Provided that the identified trials are comparable in terms of clinical issues, combined estimates will be provided. Estimations of treatment effects will be calculated based on a random effects model. Heterogeneity will be evaluated based on I (2) and chi-square test. In case of significant heterogeneity, a pooled estimate will not be provided, but heterogeneity will be investigated on the basis of methodological and clinical study aspects. We plan subgroup analysis to reveal potential differences in the effect estimates between patient populations and treatment specifications. We will consider risk of bias using sensitivity analyses to decide whether to rely on the pooled estimates. The quality of a body of evidence for individual outcomes will be assessed using the GRADE approach. Benefits and harms of pharmacological treatment in erythema migrans have not yet been adequately assessed. This systematic review will evaluate and summarise available evidence addressing benefits and harms of different pharmacological treatments. In addition, this summary of clinical evidence will inform decision-making between clinicians and patients and will play an important part in patient care. CRD42016037932.

Treatment of Pancreatic Cancer with Pharmacological Ascorbate

PubMed Central

Cieslak, John A.; Cullen, Joseph J.

2016-01-01

The prognosis for patients diagnosed with pancreatic cancer remains dismal, with less than 3% survival at 5 years. Recent studies have demonstrated that high-dose, intravenous pharmacological ascorbate (ascorbic acid, vitamin C) induces cytotoxicity and oxidative stress selectively in pancreatic cancer cells vs. normal cells, suggesting a promising new role of ascorbate as a therapeutic agent. At physiologic concentrations, ascorbate functions as a reducing agent and antioxidant. However, when pharmacological ascorbate is given intravenously, it is possible to achieve millimolar plasma concentration. At these pharmacological levels, and in the presence of catalytic metal ions, ascorbate can induce oxidative stress through the generation of hydrogen peroxide (H2O2). Recent in vitro and in vivo studies have demonstrated ascorbate oxidation occurs extracellularly, generating H2O2 flux into cells resulting in oxidative stress. Pharmacologic ascorbate also inhibits the growth of pancreatic tumor xenografts and displays synergistic cytotoxic effects when combined with gemcitabine in pancreatic cancer. Phase I trials of pharmacological ascorbate in pancreatic cancer patients have demonstrated safety and potential efficacy. In this chapter, we will review the mechanism of ascorbate-induced cytotoxicity, examine the use of pharmacological ascorbate in treatment and assess the current data supporting its potential as an adjuvant in pancreatic cancer. PMID:26201606

Safety and efficacy of pharmacologic thromboprophylaxis following blunt head injury: a systematic review.

PubMed

Reeves, Fairleigh; Batty, Lachlan; Pitt, Veronica; Chau, Marisa; Pattuwage, Loyal; Gruen, Russell L

2013-10-01

Patients with blunt head injury are at high risk of venous thromboembolism. However, pharmacologic thromboprophylaxis (PTP) may cause progression of intracranial hemorrhage, and clinicians must often weigh up the risks and benefits. This review aimed to determine whether adding PTP to mechanical prophylaxis confers net benefit or harm and the optimal timing, dose, and agent for PTP in patients with blunt head injury. We searched MEDLINE, EMBASE, The Cochrane Library Central Register of Controlled Trials (CENTRAL), and www.clinicaltrials.gov on April 24, 2013, to identify controlled studies and ongoing trials that assessed the efficacy or safety of thromboprophylaxis interventions in the early management of head-injured patients. Studies were classified based on types of interventions and comparisons, and the quality of included studies was assessed using Cochrane risk-of-bias tool and the Newcastle-Ottawa Quality Assessment Scale. We intended to undertake a meta-analysis if studies were sufficiently similar. Sixteen studies met the inclusion criteria, including four randomized controlled trials. At least two randomized controlled trials were at high risk of bias owing to inadequate randomization and concealment of allocation, and observational studies were potentially confounded by substantial differences between comparison groups. Heterogeneity of included studies precluded meta-analysis. Results were mixed, with some studies supporting and others refuting addition of PTP to mechanical interventions. Little evidence was available about dose or choice of agent. The safety and efficacy of early PTP in patients without early progression of hemorrhage is unclear. There is currently insufficient evidence to guide thromboprophylaxis in patients with blunt head injury. Standardized definitions and outcome measurements would facilitate comparison of outcomes across future studies. Studies in mixed populations should report head-injured specific subgroup data. Future randomized controlled trials should investigate the efficacy and safety of early pharmacologic prophylaxis in addition to mechanical intervention. Systematic review, level IV.

The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease.

PubMed

Malerba, Mario; Radaeli, Alessandro; Santini, Giuseppe; Morjaria, Jaymin; Mores, Nadia; Mondino, Chiara; Macis, Giuseppe; Montuschi, Paolo

2018-06-01

Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M 3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre-clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined.

[Safety profile of zolpidem: two studies of 3805 patients by Swiss practitioners].

PubMed

Ganzoni, E; Gugger, M

1999-06-24

Evaluation and treatment of insomnia are frequent procedures in the physician's everyday practice, since many patients seek medical treatment for this condition. Knowledge of pharmacological therapeutical alternatives is therefore decisive, in order to identify the most efficaceous and safe therapy for the patient among the available hypnotics. The short-acting hypnotic zolpidem has been investigated in Switzerland in two multicenter safety studies in ambulatory practice. In the first study 8.9% (n = 125 of 1,972 treated patients), and in the second 7.2% of the patients (n = 175 of 1,833 treated patients) reported an adverse event. The most frequent events were related to the central nervous system (CNS) (somnolence, headache, confusion, vertigo); gastrointestinal and cutaneous symptoms were the most frequent non CNS-dependent effects. New, unknown or serious adverse events were not found and no specific risk factor or population at risk was identified. The safety profile of zolpidem is consistent with its known pharmacological properties, the results of previous clinical trials and the international experience obtained in large patients groups.

Breastfeeding information in pharmacology textbooks: a content analysis.

PubMed

Amir, Lisa H; Raval, Manjri; Hussainy, Safeera Y

2013-07-01

Women often need to take medicines while breastfeeding and pharmacists need to provide accurate information in order to avoid undue caution about the compatibility of medicines and breastfeeding. The objective of this study was to review information provided about breastfeeding in commonly used pharmacology textbooks. We asked 15 Australian universities teaching pharmacy courses to provide a list of recommended pharmacology textbooks in 2011. Ten universities responded, generating a list of 11 textbooks that we analysed for content relating to breastfeeding. Pharmacology textbooks outline the mechanisms of actions of medicines and their use: however, only a small emphasis is placed on the safety/compatibility of medicines for women during breastfeeding. Current pharmacology textbooks recommended by Australian universities have significant gaps in their coverage of medicine use in breastfeeding. Authors of textbooks should address this gap, so academic staff can recommend texts with the best lactation content.

Non-clinical studies in the process of new drug development - Part II: Good laboratory practice, metabolism, pharmacokinetics, safety and dose translation to clinical studies.

PubMed

Andrade, E L; Bento, A F; Cavalli, J; Oliveira, S K; Schwanke, R C; Siqueira, J M; Freitas, C S; Marcon, R; Calixto, J B

2016-12-12

The process of drug development involves non-clinical and clinical studies. Non-clinical studies are conducted using different protocols including animal studies, which mostly follow the Good Laboratory Practice (GLP) regulations. During the early pre-clinical development process, also known as Go/No-Go decision, a drug candidate needs to pass through several steps, such as determination of drug availability (studies on pharmacokinetics), absorption, distribution, metabolism and elimination (ADME) and preliminary studies that aim to investigate the candidate safety including genotoxicity, mutagenicity, safety pharmacology and general toxicology. These preliminary studies generally do not need to comply with GLP regulations. These studies aim at investigating the drug safety to obtain the first information about its tolerability in different systems that are relevant for further decisions. There are, however, other studies that should be performed according to GLP standards and are mandatory for the safe exposure to humans, such as repeated dose toxicity, genotoxicity and safety pharmacology. These studies must be conducted before the Investigational New Drug (IND) application. The package of non-clinical studies should cover all information needed for the safe transposition of drugs from animals to humans, generally based on the non-observed adverse effect level (NOAEL) obtained from general toxicity studies. After IND approval, other GLP experiments for the evaluation of chronic toxicity, reproductive and developmental toxicity, carcinogenicity and genotoxicity, are carried out during the clinical phase of development. However, the necessity of performing such studies depends on the new drug clinical application purpose.

Safety pharmacology — Current and emerging concepts

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

Hamdam, Junnat; Sethu, Swaminathan; Smith, Trevor

2013-12-01

Safety pharmacology (SP) is an essential part of the drug development process that aims to identify and predict adverse effects prior to clinical trials. SP studies are described in the International Conference on Harmonisation (ICH) S7A and S7B guidelines. The core battery and supplemental SP studies evaluate effects of a new chemical entity (NCE) at both anticipated therapeutic and supra-therapeutic exposures on major organ systems, including cardiovascular, central nervous, respiratory, renal and gastrointestinal. This review outlines the current practices and emerging concepts in SP studies including frontloading, parallel assessment of core battery studies, use of non-standard species, biomarkers, and combiningmore » toxicology and SP assessments. Integration of the newer approaches to routine SP studies may significantly enhance the scope of SP by refining and providing mechanistic insight to potential adverse effects associated with test compounds. - Highlights: • SP — mandatory non-clinical risk assessments performed during drug development. • SP organ system studies ensure the safety of clinical participants in FiH trials. • Frontloading in SP facilitates lead candidate drug selection. • Emerging trends: integrating SP-Toxicological endpoints; combined core battery tests.« less

Amitriptyline for the treatment of fibromyalgia: a comprehensive review.

PubMed

Rico-Villademoros, Fernando; Slim, Mahmoud; Calandre, Elena P

2015-10-01

Fibromyalgia is characterized by chronic generalized pain accompanied by a wide range of clinical manifestations. Most clinical practice guidelines recommend multidisciplinary treatment using a combination of pharmacological and non-pharmacological therapies. The tricyclic antidepressant amitriptyline has been most thoroughly studied in fibromyalgia. Amitriptyline has been evaluated in placebo-controlled studies, and it has served as an active comparator to other therapeutic interventions in the treatment of fibromyalgia. In addition, several systematic reviews and meta-analyses have evaluated its efficacy and safety for the treatment of fibromyalgia. Data from individual studies as well as from systematic reviews indicate that low doses (10-75 mg/day) of amitriptyline are effective for the treatment of fibromyalgia and, despite the limited quality of the data, they do not seem to be associated with relevant tolerability or safety issues. Consistent with some clinical guidelines, we believe amitriptyline in low doses should be considered a first-line drug for the treatment of fibromyalgia.

Cardiovascular Safety Pharmacology of Sibutramine.

PubMed

Yun, Jaesuk; Chung, Eunyong; Choi, Ki Hwan; Cho, Dae Hyun; Song, Yun Jeong; Han, Kyoung Moon; Cha, Hey Jin; Shin, Ji Soon; Seong, Won-Keun; Kim, Young-Hoon; Kim, Hyung Soo

2015-07-01

Sibutramine is an anorectic that has been banned since 2010 due to cardiovascular safety issues. However, counterfeit drugs or slimming products that include sibutramine are still available in the market. It has been reported that illegal sibutramine-contained pharmaceutical products induce cardiovascular crisis. However, the mechanism underlying sibutramine-induced cardiovascular adverse effect has not been fully evaluated yet. In this study, we performed cardiovascular safety pharmacology studies of sibutramine systemically using by hERG channel inhibition, action potential duration, and telemetry assays. Sibutramine inhibited hERG channel current of HEK293 cells with an IC50 of 3.92 μM in patch clamp assay and increased the heart rate and blood pressure (76 Δbpm in heart rate and 51 ΔmmHg in blood pressure) in beagle dogs at a dose of 30 mg/kg (per oral), while it shortened action potential duration (at 10 μM and 30 μM, resulted in 15% and 29% decreases in APD50, and 9% and 17% decreases in APD90, respectively) in the Purkinje fibers of rabbits and had no effects on the QTc interval in beagle dogs. These results suggest that sibutramine has a considerable adverse effect on the cardiovascular system and may contribute to accurate drug safety regulation.

Prediction of Safety Margin and Optimization of Dosing Protocol for a Novel Antibiotic using Quantitative Systems Pharmacology Modeling.

PubMed

Woodhead, Jeffrey L; Paech, Franziska; Maurer, Martina; Engelhardt, Marc; Schmitt-Hoffmann, Anne H; Spickermann, Jochen; Messner, Simon; Wind, Mathias; Witschi, Anne-Therese; Krähenbühl, Stephan; Siler, Scott Q; Watkins, Paul B; Howell, Brett A

2018-06-07

Elevations of liver enzymes have been observed in clinical trials with BAL30072, a novel antibiotic. In vitro assays have identified potential mechanisms for the observed hepatotoxicity, including electron transport chain (ETC) inhibition and reactive oxygen species (ROS) generation. DILIsym, a quantitative systems pharmacology (QSP) model of drug-induced liver injury, has been used to predict the likelihood that each mechanism explains the observed toxicity. DILIsym was also used to predict the safety margin for a novel BAL30072 dosing scheme; it was predicted to be low. DILIsym was then used to recommend potential modifications to this dosing scheme; weight-adjusted dosing and a requirement to assay plasma alanine aminotransferase (ALT) daily and stop dosing as soon as ALT increases were observed improved the predicted safety margin of BAL30072 and decreased the predicted likelihood of severe injury. This research demonstrates a potential application for QSP modeling in improving the safety profile of candidate drugs. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

THE ROLE OF MAMMALIAN DATA IN DETERMINING PHARMACEUTICAL RESPONSES IN AQUATIC SPECIES

EPA Science Inventory

Human pharmaceuticals are designed to be biologically active, and are extensively studies for physicalchemical, pharmacological, and toxicological properties. In those studies, efficacy and safety endpoints ED50s, LCSOs, NOAELs, LOAELs, etc.) are linked to plasma exposures (Cmax ...

Systems pharmacology augments drug safety surveillance

PubMed Central

Lorberbaum, Tal; Nasir, Mavra; Keiser, Michael J.; Vilar, Santiago; Hripcsak, George; Tatonetti, Nicholas P.

2014-01-01

Small molecule drugs are the foundation of modern medical practice yet their use is limited by the onset of unexpected and severe adverse events (AEs). Regulatory agencies rely on post-marketing surveillance to monitor safety once drugs are approved for clinical use. Despite advances in pharmacovigilance methods that address issues of confounding bias, clinical data of AEs are inherently noisy. Systems pharmacology– the integration of systems biology and chemical genomics – can illuminate drug mechanisms of action. We hypothesize that these data can improve drug safety surveillance by highlighting drugs with a mechanistic connection to the target phenotype (enriching true positives) and filtering those that do not (depleting false positives). We present an algorithm, the modular assembly of drug safety subnetworks (MADSS), to combine systems pharmacology and pharmacovigilance data and significantly improve drug safety monitoring for four clinically relevant adverse drug reactions. PMID:25670520

Emerging Drugs for the Treatment of Symptoms Associated with Autism Spectrum Disorders

PubMed Central

Wink, Logan K.; Plawecki, Martin H.; Erickson, Craig A.; Stigler, Kimberly A.; McDougle, Christopher J.

2010-01-01

Importance of the Field Autism spectrum disorders, or pervasive developmental disorders (PDDs), are neurodevelopmental disorders defined by qualitative impairment in social interaction, impaired communication, and stereotyped patterns of behavior. The most common forms of PDD are autstic disorder (autism), Asperger's disorder, and pervasive developmental disorder not otherwise specified (PDD NOS). Recent surveillance studies reveal an increase in the prevalence of autism and related PDDs. The use of pharmacologic agents in the treatment of these disorders can reduce the impact of interfering symptoms, providing relief for affected individuals and their families. Areas Covered in this Review This review examines results from neurobiologic research in an attempt to both elucidate the pathophysiology of autism and guide the development of pharmacologic agents for the treatment of associated symptoms. The safety and efficacy data of drugs currently in clinical use for the treatment of these symptoms, as well as pharmaceuticals currently under development, are discussed. What the Reader will Gain This comprehensive review will deepen the reader's current understanding of the research guiding the pharmacologic treatment of symptoms associated with autism and related PDDs. Areas of focus for future research are also discussed. The need for large-scale investigation of some commonly used pharmacologic agents, in addition to the development of drugs with improved efficacy and safety profiles, is made evident. Take Home Message Despite progress in the development of pharmacologic treatments for a number of interfering symptom domains associated with autism and other PDDs, a great deal of work remains. PMID:20470188

21 CFR 601.35 - Evaluation of safety.

Code of Federal Regulations, 2013 CFR

2013-04-01

... information, the following types of data: (A) Pharmacology data, (B) Toxicology data, (C) Clinical adverse event data, and (D) Radiation safety assessment. (2) The amount of new safety data required will depend... relevant to risk and will specify the amount and type of safety data that are appropriate for each category...

21 CFR 315.6 - Evaluation of safety.

Code of Federal Regulations, 2011 CFR

2011-04-01

... information, the following types of data: (i) Pharmacology data, (ii) Toxicology data, (iii) Clinical adverse... 21 Food and Drugs 5 2011-04-01 2011-04-01 false Evaluation of safety. 315.6 Section 315.6 Food and... USE DIAGNOSTIC RADIOPHARMACEUTICALS § 315.6 Evaluation of safety. (a) Factors considered in the safety...

Use of bipolar radiofrequency catheter ablation in treatment of cardiac arrhythmias.

PubMed

Soucek, Filip; Starek, Zdenek

2018-05-23

Background Arrhythmia management is a complex process involving both pharmacological and non-pharmacological approaches. Radiofrequency ablation is the pillar of non-pharmacological arrhythmia treatment. Unipolar ablation is considered to be the gold standard in the treatment of the majority of arrhythmias; however, its efficacy is limited to specific cases. In particular, the creation of deep or transmural lesions to eliminate intramurally originating arrhythmias remains inadequate. Bipolar ablation is proposed as an alternative to overcome unipolar ablation boundaries. Results Despite promising results gained from in vitro and animal studies showing that bipolar ablation is superior in creating transmural lesions, the use of bipolar ablation in daily clinical practice is limited. Several studies have been published showing that bipolar ablation is effective in the treatment of clinical arrhythmias after failed unipolar ablation, however there is inconsistency regarding safety of bipolar ablation within the available research papers. According to research evidence the most common indications for bipolar ablation use are ventricular originating rhythmic disorders in patients with structural heart disease resistant to standard radiofrequency ablation. Conclusions To allow wider clinical application the efficiency and safety of bipolar ablation need to be verified in future studies. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The new generation of intravenous iron: chemistry, pharmacology, and toxicology of ferric carboxymaltose.

PubMed

Funk, Felix; Ryle, Peter; Canclini, Camillo; Neiser, Susann; Geisser, Peter

2010-01-01

An ideal preparation for intravenous iron replacement therapy should balance effectiveness and safety. Compounds that release iron rapidly tend to cause toxicity, while large molecules can induce antibody formation and cause anaphylactic reactions. There is therefore a need for an intravenous iron preparation that delivers appropriate amounts of iron in a readily available form but with minimal side effects and thus with an excellent safety profile. In this paper, a review is given on the chemistry, pharmacology, and toxicology of ferric carboxymaltose (FCM, Ferinject), a stable and robust complex formulated as a colloidal solution with a physiological pH. The complex is gradually taken up mainly from the hepatic reticulo-endothelial system (RES), followed by effective delivery of iron to the endogeneous transport system for the haem synthesis in new erythrocytes, as shown in studies on the pharmacodynamics and pharmacokinetics with radio-labelled FCM. Studies with radio-labelled FCM also demonstrated a barrier function of the placenta and a low transfer of iron into the milk of lactating rats. Safety pharmacology studies indicated a favourable profile with regard to cardiovascular, central nervous, respiratory, and renal toxicity. A high maximum non-lethal dose was demonstrated in the single-dose toxicity studies. Furthermore, based on the No-Observed-Adverse-Effect-Levels (NOAELs) found in repeated-dose toxicity studies and on the cumulative doses administered, FCM has good safety margins. Reproductive and developmental toxicity studies did not reveal any direct or indirect harmful effects. No genotoxic potential was found in in vitro or in vivo studies. Moreover, antigenicity studies showed no cross-reactivity of FMC with anti-dextran antibodies and also suggested that FCM does not possess sensitizing potential. Lastly, no evidence of irritation was found in local tolerance studies with FCM. This excellent toxicity profile and the high effectiveness of FCM allow the administration of high doses as a single infusion or bolus injection, which will enhance the cost-effectiveness and convenience of iron replacement therapy. In conclusion, FCM has many of the characteristics of an ideal intravenous iron preparation.

Buprenorphine – an attractive opioid with underutilized potential in treatment of chronic pain

PubMed Central

Khanna, Ish K; Pillarisetti, Sivaram

2015-01-01

Despite proven clinical utility, buprenorphine has not been used widely for the treatment of chronic pain. Questions about “ceiling effect” or bell-shaped curve observed for analgesia in preclinical studies and potential withdrawal issues on combining with marketed μ-agonists continue to hinder progress in expanding full potential of buprenorphine in the treatment of cancer and noncancer pain. Mounting evidence from clinical studies and conclusions drawn by a panel of experts strongly support superior safety and efficacy profile of buprenorphine vs marketed opioids. No ceiling on analgesic effect has been reported in clinical studies. The receptor pharmacology and pharmacokinetics profile of buprenorphine is complex but unique and contributes to its distinct safety and efficacy. The buprenorphine pharmacology also allows it to be combined with other μ-receptor opioids for additivity in efficacy. Transdermal delivery products of buprenorphine have been preferred choices for the management of pain but new delivery options are under investigation for the treatment of both opioid dependence and chronic pain. PMID:26672499

Statistical reporting of clinical pharmacology research.

PubMed

Ring, Arne; Schall, Robert; Loke, Yoon K; Day, Simon

2017-06-01

Research in clinical pharmacology covers a wide range of experiments, trials and investigations: clinical trials, systematic reviews and meta-analyses of drug usage after market approval, the investigation of pharmacokinetic-pharmacodynamic relationships, the search for mechanisms of action or for potential signals for efficacy and safety using biomarkers. Often these investigations are exploratory in nature, which has implications for the way the data should be analysed and presented. Here we summarize some of the statistical issues that are of particular importance in clinical pharmacology research. © 2017 The British Pharmacological Society.

A multi-disciplinary approach to medication safety and the implication for nursing education and practice.

PubMed

Adhikari, Radha; Tocher, Jennifer; Smith, Pam; Corcoran, Janet; MacArthur, Juliet

2014-02-01

Medication management is a complex multi-stage and multi-disciplinary process, involving doctors, pharmacists, nurses and patients. Errors can occur at any stage from prescribing, dispensing and administering, to recording and reporting. There are a number of safety mechanisms built into the medication management system and it is recognised that nurses are the final stage of defence. However, medication error still remains a major challenge to patient safety globally. This paper aims to illustrate two main aspects of medication safety practices that have been elicited from an action research study in a Scottish Health Board and three local Higher Education Institutions: firstly current medication safety practices in two clinical settings; and secondly pre and post-registration nursing education and teaching on medication safety. This paper is based on Phase One and Two of an Action Research project. An ethnography-style observational method, influenced by an Appreciative Inquiry (AI) approach was adapted to study the everyday medication management systems and practices of two hospital wards. This was supplemented by seven in-depth interviews with nursing staff, numerous informal discussions with healthcare professionals, two focus-groups, one peer-interview and two in-depth individual interviews with final year nursing students from three Higher Education Institutions in Scotland. This paper highlights the current positive practical efforts in medication safety practices in the chosen clinical areas. Nursing staff do employ the traditional 'five right' principles - right patient, right medication, right dose, right route and right time - for safe administration. Nursing students are taught these principles in their pre-registration nursing education. However, there are some other challenges remaining: these include the establishment of a complete medication history (reconciliation) when patients come to hospital, the provision of an in-depth training in pharmacological knowledge to junior nursing staff and pre-registration nursing students. This paper argues that the 'five rights' principle during medication administration is not enough for holistic medication safety and explains two reasons why there is a need for strengthened multi-disciplinary team-work to achieve greater patient safety. To accomplish this, nurses need to have sufficient knowledge of pharmacology and medication safety issues. These findings have important educational implications and point to the requirement for the incorporation of medication management and pharmacology in to the teaching curriculum for nursing students. There is also a call for continuing professional development opportunities for nurses working in clinical settings. © 2014.

Pharmacologic Conversion during Dofetilide Treatment for Persistent Atrial Fibrillation.

PubMed

Steinberg, Jonathan S; Shah, Yash; Szepietowska, Barbara

2017-06-01

Dofetilide is a pure I Kr blocker and is one of the few drugs specifically studied and approved in the United States for the management of persistent atrial fibrillation (AF). Dofetilide has been noted to have a high rate of pharmacologic conversion during initial dosing in prior smaller studies. The intent of the study was to examine the safety of an inpatient loading strategy, and the incidence and patterns of pharmacologic conversion by dofetilide during the treatment of persistent AF in a large consecutive cohort. This is a retrospective analysis of 308 consecutive patients with persistent AF electively admitted for inpatient dofetilide loading. The initiation dose of dofetilide was determined by the creatinine clearance. Overall, 88% (n = 271) successfully completed initiation of dofetilide and were discharged in sinus rhythm. The most common reason for failure to complete initiation of dofetilide loading was QTc prolongation in 24 patients (7.8%), and torsade de pointes occurred in three patients (1%). Pharmacologic conversion was observed in 56% (n = 151) after a median of two doses. The rate of pharmacologic conversion based on the final dose was 75%, 9%, and 0% for 500 mcg, 250 mcg, and 125 mcg, respectively (P < 0.05). Dofetilide is a well-tolerated antiarrhythmic drug with a low incidence of proarrhythmia and an especially high rate of pharmacologic conversion in patients with persistent AF. © 2017 Wiley Periodicals, Inc.

Pharmacogenomics, pharmacokinetics and pharmacodynamics: interaction with biological differences between men and women

PubMed Central

Franconi, Flavia; Campesi, Ilaria

2014-01-01

Pharmacological response depends on multiple factors and one of them is sex–gender. Data on the specific effects of sex–gender on pharmacokinetics, as well as the safety and efficacy of numerous medications, are beginning to emerge. Nevertheless, the recruitment of women for clinical research is inadequate, especially during the first phases. In general, pharmacokinetic differences between males and females are more numerous and consistent than disparities in pharmacodynamics. However, sex–gender pharmacodynamic differences are now increasingly being identified at the molecular level. It is now even becoming apparent that sex–gender influences pharmacogenomics and pharmacogenetics. Sex-related differences have been reported for several parameters, and it is consistently shown that women have a worse safety profile, with drug adverse reactions being more frequent and severe in women than in men. Overall, the pharmacological status of women is less well studied than that of men and deserves much more attention. The design of clinical and preclinical studies should have a sex–gender-based approach with the aim of tailoring therapies to an individual's needs and concerns. Linked Articles This article is part of a themed section on Biological Sex and Cardiovascular Pharmacology. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2014.171.issue-3 PMID:23981051

Targeting the UPR to Circumvent Endocrine Resistance in Breast Cancer

DTIC Science & Technology

2014-10-01

activity relationship analyses ( QSAR ) to develop rationally designed NPPTA analogs with increased potency and optimized pharmacologic properties...vitro, with the strongest candidates being studied in vivo to provide preclinical safety, efficacy, and toxicology data to support later first-in-human

Pharmacokinetic and Pharmacodynamic Drug Interaction Study of Piragliatin, a Glucokinase Activator, and Glyburide, a Sulfonylurea, in Type 2 Diabetic Patients.

PubMed

Zhai, S; Georgy, A; Liang, Z; Zhi, J

2016-11-01

A glucokinase activator and a sulfonylurea might be coprescribed to synergize treatment success for type 2 diabetes (T2D). This clinical pharmacology study was designed to investigate the potential glucose-lowering effect or pharmacodynamic (PD), pharmacokinetic (PK), and safety/tolerability interactions between piragliatin and glyburide in T2D patients already taking glyburide but not adequately controlled. This was an open-label, multiple-dose, 3-period, single-sequence crossover design: on days -1, 6, and 12, PD and PK samples were drawn with glyburide alone (period 0), piragliatin + glyburide (period 1), and piragliatin alone (period 2) treatments. The glucose-lowering effect, including fasting plasma glucose (FPG), of piragliatin was more pronounced when it was administered concomitantly with glyburide as compared to piragliatin or glyburide administered alone. However, this enhancement cannot be explained by a potential PK interaction between piragliatin and glyburide. Other than hypoglycemia, there were no clinically relevant safety findings. Thus, the enhanced PD effect warrants further investigation to define the optimal dose combination between glucokinase activators and sulfonylureas with regard to efficacy, safety, and tolerability. © 2016, The American College of Clinical Pharmacology.

Use of a collaborative tool to simplify the outsourcing of preclinical safety studies: an insight into the AstraZeneca-Charles River Laboratories strategic relationship.

PubMed

Martin, Frederic D C; Benjamin, Amanda; MacLean, Ruth; Hollinshead, David M; Landqvist, Claire

2017-12-01

In 2012, AstraZeneca entered into a strategic relationship with Charles River Laboratories whereby preclinical safety packages comprising safety pharmacology, toxicology, formulation analysis, in vivo ADME, bioanalysis and pharmacokinetics studies are outsourced. New processes were put in place to ensure seamless workflows with the aim of accelerating the delivery of new medicines to patients. Here, we describe in more detail the AstraZeneca preclinical safety outsourcing model and the way in which a collaborative tool has helped to translate the processes in AstraZeneca and Charles River Laboratories into simpler integrated workflows that are efficient and visible across the two companies. Copyright © 2017 Elsevier Ltd. All rights reserved.

Nonclinical and clinical pharmacology evidence for cardiovascular safety of saxagliptin.

PubMed

Pollack, Pia S; Chadwick, Kristina D; Smith, David M; Billger, Martin; Hirshberg, Boaz; Iqbal, Nayyar; Boulton, David W

2017-09-13

In the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR) trial in patients with type 2 diabetes mellitus (T2D) at high risk of cardiovascular (CV) disease, saxagliptin did not increase the risk for major CV adverse events. However, there was an unexpected imbalance in events of hospitalization for heart failure (hHF), one of six components of the secondary CV composite endpoint, with a greater number of events observed with saxagliptin. Here, we examined findings from nonclinical safety and clinical pharmacology studies of saxagliptin with the aim of identifying any potential signals of myocardial injury. In vitro and in vivo (rat, dog, monkey) safety pharmacology and toxicology studies evaluating the potential effects of saxagliptin and its major active metabolite, 5-hydroxy saxagliptin, on the CV system are reviewed. In addition, results from saxagliptin clinical studies are discussed: one randomized, 2-period, double-blind, placebo-controlled single-ascending-dose study (up to 100 mg); one randomized, double-blind, placebo-controlled, sequential, multiple-ascending-high-dose study (up to 400 mg/day for 14 days); and one randomized, double-blind, 4-period, 4-treatment, cross-over thorough QTc study (up to 40 mg/day for 4 days) in healthy volunteers; as well as one randomized, placebo-controlled, sequential multiple-ascending-dose study in patients with T2D (up to 50 mg/day for 14 days). Neither saxagliptin nor 5-hydroxy saxagliptin affected ligand binding to receptors and ion channels (e.g. potassium channels) or action potential duration in in vitro studies. In animal toxicology studies, no changes in the cardiac conduction system, blood pressure, heart rate, contractility, heart weight, or heart histopathology were observed. In healthy participants and patients with T2D, there were no findings suggestive of myocyte injury or fluid overload. Serum chemistry abnormalities indicative of cardiac injury, nonspecific muscle damage, or fluid homeostasis changes were infrequent and balanced across treatment groups. There were no QTc changes associated with saxagliptin. No treatment-emergent adverse events suggestive of heart failure or myocardial damage were reported. The saxagliptin nonclinical and clinical pharmacology programs did not identify evidence of myocardial injury and/or CV harm that may have predicted or may explain the unexpected imbalance in the rate of hHF observed in SAVOR.

Trends in safety pharmacology: posters presented at the annual meetings of the Safety Pharmacology Society 2001-2010.

PubMed

Redfern, William S; Valentin, Jean-Pierre

2011-01-01

The inaugural meeting of the Safety Pharmacology Society (SPS) was in 2001, soon after ICH S7A had been adopted. The 10th anniversary is an appropriate milestone at which to analyse trends in the science and themes of safety pharmacology, as reflected in posters presented at the annual meetings. The source information was the poster abstract booklets from each of the first ten annual meetings. The number of posters rose steadily from 34 in 2001 to 201 in 2010. The proportion of posters containing in vitro data has remained constant throughout the decade at ~30%. In terms of organ functions, themes relating to the cardiovascular system (CVS) have always generated the majority of posters, remaining above 60% of the total for the last 9years. The dominant theme has been around 'QT liability'. This peaked in 2003 at 68% of all posters presented, around the time of the ICHS7B discussions, and has remained above 30% thereafter. Apart from 2003 (dipping to 4%), CNS-related posters have remained steady at 11-17% throughout the decade. Respiratory-related posters have remained at 5-8% over the last 5years. Gastrointestinal (GI)-related posters have contributed 2-6% throughout the decade, and renal-related posters 1-3%. Posters on combined organ assessments have appeared in recent years. The relative emphasis on the different organ functions is broadly proportional to the causes of candidate drug attrition preclinically, whereas both CNS and GI are under-represented when considering their contribution to significant adverse effects during clinical development. Trends are either regulatory-driven (e.g. increase in posters on abuse-dependence liability since EMEA/CHMP/SWP/94227/2004), technology-driven (e.g. automated hERG assay; left ventricular function; non-invasive CVS measurements; stem cells, etc.), or relate to the predictive ability of safety pharmacology data (e.g. clinical translation initiatives; concordance between in vitro and in vivo preclinical data; integrated risk assessment; PK-PD relationships, etc.). Copyright © 2011 Elsevier Inc. All rights reserved.

Nonclinical safety of the sodium-glucose cotransporter 2 inhibitor empagliflozin.

PubMed

Bogdanffy, Matthew S; Stachlewitz, Robert F; van Tongeren, Susan; Knight, Brian; Sharp, Dale E; Ku, Warren; Hart, Susan Emeigh; Blanchard, Kerry

2014-01-01

Empagliflozin, a selective inhibitor of the renal tubular sodium-glucose cotransporter 2, was developed for treatment of type 2 diabetes mellitus. Nonclinical safety of empagliflozin was studied in a battery of tests to support global market authorization. Safety pharmacology studies indicated no effect of empagliflozin on measures of respiratory or central nervous system function in rats or cardiovascular safety in telemeterized dogs. In CD-1 mouse, Wistar Han rat, or beagle dogs up to 13, 26, or 52 weeks of treatment, respectively, empagliflozin exhibited a toxicity profile consistent with secondary supratherapeutic pharmacology related to glucose loss and included decreased body weight and body fat, increased food consumption, diarrhea, dehydration, decreased serum glucose and increases in other serum parameters reflective of increased protein catabolism, gluconeogenesis, and electrolyte imbalances, and urinary changes such as polyuria and glucosuria. Microscopic changes were consistently observed in kidney and included tubular nephropathy and interstitial nephritis (dog), renal mineralization (rat) and tubular epithelial cell karyomegaly, single cell necrosis, cystic hyperplasia, and hypertrophy (mouse). Empagliflozin was not genotoxic. Empagliflozin was not carcinogenic in female mice or female rats. Renal adenoma and carcinoma were induced in male mice only at exposures 45 times the maximum clinical dose. These tumors were associated with a spectrum of nonneoplastic changes suggestive of a nongenotoxic, cytotoxic, and cellular proliferation-driven mechanism. In male rats, testicular interstitial cell tumors and hemangiomas of the mesenteric lymph node were observed; both tumors are common in rats and are unlikely to be relevant to humans. These studies demonstrate the nonclinical safety of empagliflozin. © The Author(s) 2014.

Mouse Models Applied to the Research of Pharmacological Treatments in Asthma.

PubMed

Marqués-García, Fernando; Marcos-Vadillo, Elena

2016-01-01

Models developed for the study of asthma mechanisms can be used to investigate new compounds with pharmacological activity against this disease. The increasing number of compounds requires a preclinical evaluation before starting the application in humans. Preclinical evaluation in animal models reduces the number of clinical trials positively impacting in the cost and in safety. In this chapter, three protocols for the study of drugs are shown: a model to investigate corticoids as a classical treatment of asthma; a protocol to test the effects of retinoic acid (RA) on asthma; and a mouse model to test new therapies in asthma as monoclonal antibodies.

Comprehensive in vitro Proarrhythmia Assay (CiPA): Pending issues for successful validation and implementation.

PubMed

Cavero, Icilio; Guillon, Jean-Michel; Ballet, Veronique; Clements, Mike; Gerbeau, Jean-Frédéric; Holzgrefe, Henry

2016-01-01

The Comprehensive in vitro Proarrhythmia Assay (CiPA) is a nonclinical Safety Pharmacology paradigm for discovering electrophysiological mechanisms that are likely to confer proarrhythmic liability to drug candidates intended for human use. Key talks delivered at the 'CiPA on my mind' session, held during the 2015 Annual Meeting of the Safety Pharmacology Society (SPS), are summarized. Issues and potential solutions relating to crucial constituents [e.g., biological materials (ion channels and pluripotent stem cell-derived cardiomyocytes), study platforms, drug solutions, and data analysis] of CiPA core assays are critically examined. In order to advance the CiPA paradigm from the current testing and validation stages to a research and regulatory drug development strategy, systematic guidance by CiPA stakeholders is necessary to expedite solutions to pending and newly arising issues. Once a study protocol is proved to yield robust and reproducible results within and across laboratories, it can be implemented as qualified regulatory procedure. Copyright © 2016 Elsevier Inc. All rights reserved.

New drugs and patient-centred end-points in old age: setting the wheels in motion.

PubMed

Mangoni, Arduino A; Pilotto, Alberto

2016-01-01

Older patients with various degrees of frailty and disability, a key population target of pharmacological interventions in acute and chronic disease states, are virtually neglected in pre-marketing studies assessing the efficacy and safety of investigational drugs. Moreover, aggressively pursuing established therapeutic targets in old age, e.g. blood pressure, serum glucose or cholesterol concentrations, is not necessarily associated with the beneficial effects, and the acceptable safety, reported in younger patient cohorts. Measures of self-reported health and functional status might represent additional, more meaningful, therapeutic end-points in the older population, particularly in patients with significant frailty and relatively short life expectancy, e.g. in the presence of cancer and/or neurodegenerative disease conditions. Strategies enhancing early knowledge about key pharmacological characteristics of investigational drugs targeting older adults are discussed, together with the rationale for incorporating non-traditional, patient-centred, end-points in this ever-increasing group.

Safety in Acute Pain Medicine-Pharmacologic Considerations and the Impact of Systems-Based Gaps.

PubMed

Weingarten, Toby N; Taenzer, Andreas H; Elkassabany, Nabil M; Le Wendling, Linda; Nin, Olga; Kent, Michael L

2018-05-02

In the setting of an expanding prevalence of acute pain medicine services and the aggressive use of multimodal analgesia, an overview of systems-based safety gaps and safety concerns in the setting of aggressive multimodal analgesia is provided below. Expert commentary. Recent evidence focused on systems-based gaps in acute pain medicine is discussed. A focused literature review was conducted to assess safety concerns related to commonly used multimodal pharmacologic agents (opioids, nonsteroidal anti-inflammatory drugs, gabapentanoids, ketamine, acetaminophen) in the setting of inpatient acute pain management. Optimization of systems-based gaps will increase the probability of accurate pain assessment, improve the application of uniform evidence-based multimodal analgesia, and ensure a continuum of pain care. While acute pain medicine strategies should be aggressively applied, multimodal regimens must be strategically utilized to minimize risk to patients and in a comorbidity-specific fashion.

Ethnobotany, phytochemistry and pharmacology of Arctotis arctotoides (L.f.) O. Hoffm.: A review.

PubMed

Saleh-E-In, Md Moshfekus; Van Staden, Johannes

2018-06-28

Arctotis arctotoides (Asteraceae) is part of the genus Arctotis. Arctotis is an African genus of approximately 70 species that occur widely in the African continent with diverse medicinal values. This plant is used for the treatment of indigestion and catarrh of the stomach, epilepsy, topical wounds and skin disorders among the ethnic groups in South Africa and reported to have a wide spectrum of pharmacological properties. The aim of the present review is to appraise the botany, traditional uses, phytochemistry, pharmacological potential, analytical methods and safety issues of A. arctotoides. Additionally, this review will help to fill the existing gaps in knowledge and highlight further research prospects in the field of phytochemistry and pharmacology. Information on A. arctotoides was collected from various resources, including books on African medicinal herbs and Zulu medicinal plants, theses, reports and the internet databases such as SciFinder, Google Scholar, Pubmed, Scopus, Web of Science, and Mendeley by using a combination of various meaningful keywords. This review surveys the available literature of the species from 1962 to April 2017. In vitro and in vivo studies of the medicinal properties of A. arctotoides were reviewed. The main isolated and identified compounds were reported as sesquiterpenes, farnesol derivatives, germacranolide, guaianolides and some steroids, of which, nine were reported as antimicrobial. Monoterpenoids and sesquiterpenoids were the predominant essential oil compound classes of the leaves, flowers, stems and roots. The present review revealed potential pharmacological properties such as anti-oxidant, antibacterial, antifungal and anticancer activities of plant extracts as well as isolated compounds. Moreover, the review reports the safety profile (toxicity) of the crude extracts that had been screened on brine shrimps, rats and human cell lines. The present review has focused on the phytochemistry, botany, ethnopharmacology, biological activities and toxicological information of A. arctotoides. On the basis of reported data, A. arctotoides has emerged as a good source of natural medicine for the treatment of microbial infections, skin diseases, anti-inflammatory and anticancer agents and also provides new insights for further isolation of new bioactive compounds, especially the discovery of antimicrobial, anti-inflammatory and anticancer novel therapeutic lead drug molecules. Additionally, intensive investigations regarding pharmacological properties, safety assessment and efficacy with their mechanism of action could be future research interests before starting clinical trials for medicinal practices. Copyright © 2018 Elsevier B.V. All rights reserved.

Pharmacology-based toxicity assessment: towards quantitative risk prediction in humans.

PubMed

Sahota, Tarjinder; Danhof, Meindert; Della Pasqua, Oscar

2016-05-01

Despite ongoing efforts to better understand the mechanisms underlying safety and toxicity, ~30% of the attrition in drug discovery and development is still due to safety concerns. Changes in current practice regarding the assessment of safety and toxicity are required to reduce late stage attrition and enable effective development of novel medicines. This review focuses on the implications of empirical evidence generation for the evaluation of safety and toxicity during drug development. A shift in paradigm is needed to (i) ensure that pharmacological concepts are incorporated into the evaluation of safety and toxicity; (ii) facilitate the integration of historical evidence and thereby the translation of findings across species as well as between in vitro and in vivo experiments and (iii) promote the use of experimental protocols tailored to address specific safety and toxicity questions. Based on historical examples, we highlight the challenges for the early characterisation of the safety profile of a new molecule and discuss how model-based methodologies can be applied for the design and analysis of experimental protocols. Issues relative to the scientific rationale are categorised and presented as a hierarchical tree describing the decision-making process. Focus is given to four different areas, namely, optimisation, translation, analytical construct and decision criteria. From a methodological perspective, the relevance of quantitative methods for estimation and extrapolation of risk from toxicology and safety pharmacology experimental protocols, such as points of departure and potency, is discussed in light of advancements in population and Bayesian modelling techniques (e.g. non-linear mixed effects modelling). Their use in the evaluation of pharmacokinetics (PK) and pharmacokinetic-pharmacodynamic relationships (PKPD) has enabled great insight into the dose rationale for medicines in humans, both in terms of efficacy and adverse events. Comparable benefits can be anticipated for the assessment of safety and toxicity profile of novel molecules. © The Author 2016. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Pharmacological and clinical dilemmas of prescribing in co-morbid adult attention-deficit/hyperactivity disorder and addiction

PubMed Central

Pérez de los Cobos, José; Siñol, Núria; Pérez, Víctor; Trujols, Joan

2014-01-01

The present article reviews whether available efficacy and safety data support the pharmacological treatment of adult attention-deficit/hyperactivity disorder (ADHD) in patients with concurrent substance use disorders (SUD). Arguments for and against treating adult ADHD with active SUD are discussed. Findings from 19 large open studies and controlled clinical trials show that the use of atomoxetine or extended-release methylphenidate formulations, together with psychological therapy, yield promising though inconclusive results about short term efficacy of these drugs in the treatment of adult ADHD in patients with SUD and no other severe mental disorders. However, the efficacy of these drugs is scant or lacking for treating concurrent SUD. No serious safety issues have been associated with these drugs in patients with co-morbid SUD-ADHD, given their low risk of abuse and favourable side effect and drug–drug interaction profile. The decision to treat adult ADHD in the context of active SUD depends on various factors, some directly related to SUD-ADHD co-morbidity (e.g. degree of diagnostic uncertainty for ADHD) and other factors related to the clinical expertise of the medical staff and availability of adequate resources (e.g. the means to monitor compliance with pharmacological treatment). Our recommendation is that clinical decisions be individualized and based on a careful analysis of the advantages and disadvantages of pharmacological treatment for ADHD on a case-by-case basis in the context of active SUD. PMID:23216449

Botany, traditional uses, phytochemistry and pharmacology of Apocynum venetum L. (Luobuma): A review.

PubMed

Xie, Wenyan; Zhang, Xiaoying; Wang, Tian; Hu, Jianjun

2012-05-07

Apocynum venetum L. (Apocynaceae, Luobuma ) has a long history as a Chinese traditional medicine with uses to calm the liver, soothe the nerves, dissipate heat, and promote diuresis. Recently, Luobuma tea has been commercialized as a sedative and anti-aging supplement that has become increasingly popular in North American and East Asian health food markets. The aim of this review is to provide an up-to-date and comprehensive overview of the botany, chemical constituents, traditional uses, pharmacological activities and safety aspects of Apocynum venetum in order to assess its ethnopharmacological use and to explore its therapeutic potentials and future opportunities for research. The accessible literature on Apocynum venetum written in English, Chinese and Japanese were collected and analyzed. The literatures included ancient Chinese herbal classics, pharmacopoeias and articles that included in Pubmed, Web of Science, Google Scholar and Wanfang. Modern pharmacological studies demonstrated that Apocynum venetum possess wide pharmacological activities that include antihypertensive, cardiotonic, hepatoprotective, antioxidant, lipid-lowering, antidepressant and anxiolytic effects, which can be explained by the presence of various flavonoid compounds in this plant. The traditional (Lop Nor region) use of Apocynum venetum with tobacco as an agent to detoxify nicotine may receive interest as a possible therapeutic option to detoxify the body from smoking. Based on animal studies and clinical trials, Apocynum venetum causes no severe side effects, even in a stable daily dosage (50mg/person/day) for more than three years. Apocynum venetum potentially has therapeutic potential in the prevention and treatment for the cardiovascular and neurological diseases, especially for high blood pressure, high cholesterol, neurasthenia, depression and anxiety. Further investigations are needed to explore individual bioactive compounds responsible for these in vitro and in vivo pharmacological effects and the mode of actions. Further safety assessments and clinical trials should be performed before it can be integrated into medicinal practices. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Building confidence in quantitative systems pharmacology models: An engineer's guide to exploring the rationale in model design and development.

PubMed

Timmis, J; Alden, K; Andrews, P; Clark, E; Nellis, A; Naylor, B; Coles, M; Kaye, P

2017-03-01

This tutorial promotes good practice for exploring the rationale of systems pharmacology models. A safety systems engineering inspired notation approach provides much needed rigor and transparency in development and application of models for therapeutic discovery and design of intervention strategies. Structured arguments over a model's development, underpinning biological knowledge, and analyses of model behaviors are constructed to determine the confidence that a model is fit for the purpose for which it will be applied. © 2016 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Management of Fatigue in Persons with Multiple Sclerosis

PubMed Central

Khan, Fary; Amatya, Bhasker; Galea, Mary

2014-01-01

Fatigue is one of the most common symptoms of multiple sclerosis. Despite advances in pharmacological and non-pharmacological treatment, fatigue continues to be the disabling symptom in persons with MS (pwMS), affecting almost 80% of pwMS. In current practice, both pharmacological and non-pharmacological interventions are used in combination, encompassing a multi-disciplinary approach. The body of research investigating the effect of these interventions is growing. This review systematically evaluated the existing evidence on the effectiveness and safety of different interventions currently applied for the management of fatigue in person with multiple sclerosis in improving patient outcomes, to guide treating clinicians. PMID:25309504

Pharmacology education for nurse prescribing students – a lesson in reusable learning objects

PubMed Central

Lymn, Joanne S; Bath-Hextall, Fiona; Wharrad, Heather J

2008-01-01

Background The shift away from a biological science to a social science model of nursing care has resulted in a reduction in pharmacology knowledge and understanding in pre-registration nursing students. This has a significant impact on nurse prescribing training where pharmacology is a critical component of the course from a patient safety perspective. Methods Reusable learning objects (RLOs) are electronic resources based on a single learning objective which use high quality graphics and audio to help engagement with the material and to facilitate learning. This study used questionnaire data from three successive cohorts of nurse prescribing students (n = 84) to evaluate the use of RLOs focussed around pharmacology concepts to promote the understanding of these concepts in students. A small number of students (n = 10) were followed up by telephone interview one year after qualification to gain further insight into students' perceptions of the value of RLOs as an educational tool. Results Students' perceptions of their own understanding of pharmacology concepts increased substantially following the introduction of RLOs to supplement the pharmacology component of the course. Student evaluation of the RLOs themselves was extremely positive with a number of students continuing to access these tools post-qualification. Conclusion The use of RLOs to support the pharmacology component of nurse prescribing courses successfully resulted in a perceived increase in pharmacology understanding, with some students directly implicating these educational tools in developing confidence in their own prescribing abilities. PMID:18215261

Current Status and Prospects for Cannabidiol Preparations as New Therapeutic Agents.

PubMed

Fasinu, Pius S; Phillips, Sarah; ElSohly, Mahmoud A; Walker, Larry A

2016-07-01

States and the federal government are under growing pressure to legalize the use of cannabis products for medical purposes in the United States. Sixteen states have legalized (or decriminalized possession of) products high in cannabidiol (CBD) and with restricted ∆(9) -tetrahydrocannabinol (∆(9) -THC) content. In most of these states, the intent is for use in refractory epileptic seizures in children, but in a few states, the indications are broader. This review provides an overview of the pharmacology and toxicology of CBD; summarizes some of the regulatory, safety, and cultural issues relevant to the further exploitation of its antiepileptic or other pharmacologic activities; and assesses the current status and prospects for clinical development of CBD and CBD-rich preparations for medical use in the United States. Unlike Δ(9) -THC, CBD elicits its pharmacologic effects without exerting any significant intrinsic activity on the cannabinoid receptors, whose activation results in the psychotropic effects characteristic of Δ(9) -THC, and CBD possesses several pharmacologic activities that give it a high potential for therapeutic use. CBD exhibits neuroprotective, antiepileptic, anxiolytic, antipsychotic, and antiinflammatory properties. In combination with Δ(9) -THC, CBD has received regulatory approvals in several European countries and is currently under study in trials registered by the U.S. Food and Drug Administration in the United States. A number of states have passed legislation to allow for the use of CBD-rich, limited Δ(9) -THC-content preparations of cannabis for certain pathologic conditions. CBD is currently being studied in several clinical trials and is at different stages of clinical development for various medical indications. Judging from clinical findings reported so far, CBD and CBD-enriched preparations have great potential utility, but uncertainties regarding sourcing, long-term safety, abuse potential, and regulatory dilemmas remain. © 2016 Pharmacotherapy Publications, Inc.

Obesity and Pediatric Drug Development.

PubMed

Vaughns, Janelle D; Conklin, Laurie S; Long, Ying; Zheng, Panli; Faruque, Fahim; Green, Dionna J; van den Anker, John N; Burckart, Gilbert J

2018-05-01

There is a lack of dosing guidelines for use in obese children. Moreover, the impact of obesity on drug safety and clinical outcomes is poorly defined. The paucity of information needed for the safe and effective use of drugs in obese patients remains a problem, even after drug approval. To assess the current incorporation of obesity as a covariate in pediatric drug development, the pediatric medical and clinical pharmacology reviews under the Food and Drug Administration (FDA) Amendments Act of 2007 and the FDA Safety and Innovation Act (FDASIA) of 2012 were reviewed for obesity studies. FDA labels were also reviewed for statements addressing obesity in pediatric patients. Forty-five drugs studied in pediatric patients under the FDA Amendments Act were found to have statements and key words in the medical and clinical pharmacology reviews and labels related to obesity. Forty-four products were identified similarly with pediatric studies under FDASIA. Of the 89 product labels identified, none provided dosing information related to obesity. The effect of body mass index on drug pharmacokinetics was mentioned in only 4 labels. We conclude that there is little information presently available to provide guidance related to dosing in obese pediatric patients. Moving forward, regulators, clinicians, and the pharmaceutical industry should consider situations in drug development in which the inclusion of obese patients in pediatric trials is necessary to facilitate the safe and effective use of new drug products in the obese pediatric population. © 2018, The American College of Clinical Pharmacology.

Renal Safety Pharmacology in Drug Discovery and Development.

PubMed

Benjamin, Amanda; Nogueira da Costa, Andre; Delaunois, Annie; Rosseels, Marie-Luce; Valentin, Jean-Pierre

2015-01-01

The kidney is a complex excretory organ playing a crucial role in various physiological processes such as fluid and electrolyte balance, control of blood pressure, removal of waste products, and drug disposition. Drug-induced kidney injury (DIKI) remains a significant cause of candidate drug attrition during drug development. However, the incidence of renal toxicities in preclinical studies is low, and the mechanisms by which drugs induce kidney injury are still poorly understood. Although some in vitro investigational tools have been developed, the in vivo assessment of renal function remains the most widely used methodology to identify DIKI. Stand-alone safety pharmacology studies usually include assessment of glomerular and hemodynamic function, coupled with urine and plasma analyses. However, as renal function is not part of the ICH S7A core battery, such studies are not routinely conducted by pharmaceutical companies. The most common approach consists in integrating renal/urinary measurements in repeat-dose toxicity studies. In addition to the standard analyses and histopathological examination of kidneys, novel promising urinary biomarkers have emerged over the last decade, offering greater sensitivity and specificity than traditional renal parameters. Seven of these biomarkers have been qualified by regulatory agencies for use in rat toxicity studies.

Interventions to reduce weight gain in schizophrenia.

PubMed

Faulkner, G; Cohn, T; Remington, G

2007-01-24

Weight gain is common for people with schizophrenia and this has serious implications for health and well being. To determine the effects of both pharmacological (excluding medication switching) and non pharmacological strategies for reducing or preventing weight gain in people with schizophrenia. We searched key databases and the Cochrane Schizophrenia Group's trials register (April 2006), reference sections within relevant papers, hand searched key journals, and contacted the first author of each relevant study and other experts to collect further information. We included all clinical randomised controlled trials comparing any pharmacological or non pharmacological intervention for weight gain (diet and exercise counselling) with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. We reliably selected, quality assessed and extracted data from studies. As weight is a continuous outcome measurement, weighted mean differences (WMD) of the change from baseline were calculated. The primary outcome measure was weight loss. Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD -3.38 kg CI -4.2 to -2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD - 1.16 kg CI -1.9 to -0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD -1.69 kg CI -2.8 to -0.6) compared with standard care. Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia.

Bringing ayahuasca to the clinical research laboratory.

PubMed

Riba, Jordi; Barbanoj, Manel J

2005-06-01

Since the winter of 1999, the authors and their research team have been conducting clinical studies involving the administration of ayahuasca to healthy volunteers. The rationale for conducting this kind of research is twofold. First, the growing interest of many individuals for traditional indigenous practices involving the ingestion of natural psychotropic drugs such as ayahuasca demands the systematic study of their pharmacological profiles in the target species, i.e., human beings. The complex nature of ayahuasca brews combining a large number of pharmacologically active compounds requires that research be carried out to establish the safety and overall pharmacological profile of these products. Second, the authors believe that the study of psychedelics in general calls for renewed attention. Although the molecular and electrophysiological level effects of these drugs are relatively well characterized, current knowledge of the mechanisms by which these compounds modify the higher order cognitive processes in the way they do is still incomplete, to say the least. The present article describes the development of the research effort carried out at the Autonomous University of Barcelona, commenting on several methodological aspects and reviewing the basic clinical findings. It also describes the research currently underway in our laboratory, and briefly comments on two new studies we plan to undertake in order to further our knowledge of the pharmacology of ayahuasca.

Nonclinical Profile of BLZ-100, a Tumor-Targeting Fluorescent Imaging Agent.

PubMed

Parrish-Novak, Julia; Byrnes-Blake, Kelly; Lalayeva, Narine; Burleson, Stefanie; Fidel, Janean; Gilmore, Rhonda; Gayheart-Walsten, Pamela; Bricker, Gregory A; Crumb, William J; Tarlo, K S; Hansen, Stacey; Wiss, Valorie; Malta, Errol; Dernell, William S; Olson, James M; Miller, Dennis M

BLZ-100 is a single intravenous use, fluorescent imaging agent that labels tumor tissue to enable more complete and precise surgical resection. It is composed of a chlorotoxin peptide covalently bound to the near-infrared fluorophore indocyanine green. BLZ-100 is in clinical development for intraoperative visualization of human tumors. The nonclinical safety and pharmacokinetic (PK) profile of BLZ-100 was evaluated in mice, rats, canines, and nonhuman primates (NHP). Single bolus intravenous administration of BLZ-100 was well tolerated, and no adverse changes were observed in cardiovascular safety pharmacology, PK, and toxicology studies in rats and NHP. The single-dose no-observed-adverse-effect-levels (NOAELs) were 7 mg (28 mg/kg) in rats and 60 mg (20 mg/kg) in NHP, corresponding to peak concentration values of 89 400 and 436 000 ng/mL and area-under-the-curve exposure values of 130 000 and 1 240 000 h·ng/mL, respectively. Based on a human imaging dose of 3 mg, dose safety margins are >100 for rat and monkey. BLZ-100 produced hypersensitivity reactions in canine imaging studies (lethargy, pruritus, swollen muzzle, etc). The severity of the reactions was not dose related. In a follow-up study in dogs, plasma histamine concentrations were increased 5 to 60 minutes after BLZ-100 injection; this coincided with signs of hypersensitivity, supporting the conclusion that the reactions were histamine based. Hypersensitivity reactions were not observed in other species or in BLZ-100 human clinical studies conducted to date. The combined imaging, safety pharmacology, PK, and toxicology studies contributed to an extensive initial nonclinical profile for BLZ-100, supporting first-in-human clinical trials.

Recent Updates on the Phytochemistry, Pharmacological, and Toxicological Activities of Zingiber zerumbet (L.) Roscoe ex Sm.

PubMed

Haque, Md Areeful; Jantan, Ibrahim

2017-01-01

Zingiber zerumbet (L.) Roscoe ex Sm. (family, Zingiberaceae) is a potent medicinal herb widely known as shampoo ginger and its rhizome is used in numerous ethnomedicinal applications including antipyretic, anti-inflammatory, antibacterial, anti-diarrheal, antidiabetics, carminative, and diuretic. The aim of this review was to bring together all the scientific updates on the phytochemistry and pharmacological activities of this herb, including their toxicological studies, and critically analyzed the outcomes to provide directions for future research on the herb as potential source of bioactive metabolites for pharmaceutical and nutraceutical applications. A structured electronic search on worldwide accepted scientific databases (Web of Science, PubMed, Google Scholar, Science Direct, SciFinder, Wiley Online Library) was carried out to compile the relevant information. Some information was obtained from books and database on medicinal plants used in various countries. About 60 metabolites, mainly polyphenols, and terpenoids have been isolated and identified. However, most of the reported pharmacological studies were based on crude extracts, and only a few of those isolated metabolites, particularly zerumbone have been investigated for biological and pharmacological activities. Many of the mechanistic studies to understand the pharmacological effects of the plant are limited by many considerations with regard to design, experimentation and interpretation. The bioactive metabolites should be further investigated on their safety and more elaborate preclinical studies before clinical trials can be undertaken. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Improving Interpretation of New and Old Serum Biomarkers of Drug-Induced Liver Injury Through Mechanistic Modeling.

PubMed

Watkins, Paul B

2018-04-26

The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Role of mixed ion channel effects in the cardiovascular safety assessment of the novel anti-MRSA fluoroquinolone JNJ-Q2.

PubMed

Eichenbaum, G; Pugsley, M K; Gallacher, D J; Towart, R; McIntyre, G; Shukla, U; Davenport, J M; Lu, H R; Rohrbacher, J; Hillsamer, V

2012-07-01

JNJ-Q2, a novel broad-spectrum fluoroquinolone with anti-methicillin-resistant Staphylococcus aureus activity, was evaluated in a comprehensive set of non-clinical and clinical cardiovascular safety studies. The effect of JNJ-Q2 on different cardiovascular parameters was compared with that of moxifloxacin, sparfloxacin and ofloxacin. Through comparisons with these well-known fluoroquinolones, the importance of effects on compensatory ion channels to the cardiovascular safety of JNJ-Q2 was investigated. JNJ-Q2 and comparator fluoroquinolones were evaluated in the following models/test systems: hERG-transfected HEK293 cells sodium channel-transfected CHO cells, guinea pig right atria, arterially perfused rabbit left ventricular wedge preparations and in vivo studies in anaesthetized guinea pigs, anaesthetized and conscious telemetered dogs, and a thorough QT study in humans. The trend for effects of JNJ-Q2 on Tp-Te, QT, QRS and PR intervals in the non-clinical models and the plateau in QTc with increasing plasma concentration in humans are consistent with offsetting sodium and calcium channel activities that were observed in the non-clinical studies. These mixed ion channel activities result in the less pronounced or comparable increase in QTc interval for JNJ-Q2 compared with moxifloxacin and sparfloxacin despite its greater in vitro inhibition of I(Kr). Based on the non-clinical and clinical cardiovascular safety assessment, JNJ-Q2 has a safe cardiovascular profile for administration in humans with comparable or reduced potential to prolong QT intervals, compared with moxifloxacin. The results demonstrate the importance of compensatory sodium and calcium channel activity in offsetting potassium channel activity for compounds with a fluoroquinolone core. © 2012 Janssen Pharmaceutical Companies of Johnson & Johnson. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Lonicerae Japonicae Flos and Lonicerae Flos: A Systematic Pharmacology Review

PubMed Central

Li, Yujie; Cai, Weiyan; Weng, Xiaogang; Li, Qi; Wang, Yajie; Chen, Ying; Zhang, Wei; Yang, Qing; Guo, Yan; Zhu, Xiaoxin; Wang, Hainan

2015-01-01

Lonicerae japonicae flos, a widely used traditional Chinese medicine (TCM), has been used for several thousand years in China. Chinese Pharmacopeia once included Lonicerae japonicae flos of Caprifoliaceae family and plants of the same species named Lonicerae flos in general in the same group. Chinese Pharmacopeia (2005 Edition) lists Lonicerae japonicae flos and Lonicerae flos under different categories, although they have the similar history of efficacy. In this study, we research ancient books of TCM, 4 main databases of Chinese academic journals, and MEDLINE/PubMed to verify the origins and effects of Lonicerae japonicae flos and Lonicerae flos in traditional medicine and systematically summarized the research data in light of modern pharmacology and toxicology. Our results show that Lonicerae japonicae flos and Lonicerae flos are similar pharmacologically, but they also differ significantly in certain aspects. A comprehensive systematic review and a standard comparative pharmacological study of Lonicerae japonicae flos and Lonicerae flos as well as other species of Lonicerae flos support their clinical safety and application. Our study provides evidence supporting separate listing of Lonicerae japonicae flos and Lonicerae flos in Chinese Pharmacopeia as well as references for revision of relevant pharmacopeial records dealing with traditional efficacy of Lonicerae japonicae flos and Lonicerae flos. PMID:26257818

Traditional uses, phytochemistry, and pharmacology of the genus Acer (maple): A review.

PubMed

Bi, Wu; Gao, Ying; Shen, Jie; He, Chunnian; Liu, Haibo; Peng, Yong; Zhang, Chunhong; Xiao, Peigen

2016-08-02

The genus Acer (Aceraceae), commonly known as maple, comprises approximately 129 species that primarily grow in the northern hemisphere, especially in the temperate regions of East Asia, eastern North America, and Europe. These plants have been traditionally used to treat a wide range of diseases in East Asia and North America. Moreover, clinical studies have shown that medicinal plants belonging to Acer are highly effective in the treatment of rheumatism, bruises, hepatic disorders, eye disease, and pain, and in detoxification. This review provides a systematic and constructive overview of the traditional uses, chemical constituents, and pharmacological activities of plants of the genus Acer. This review is based on a literature study of scientific journals and books from libraries and electronic sources such as SciFinder, ScienceDirect, Springer, PubMed, CNKI, Google Scholar, Baidu Scholar, and Web of Science. The literature in this review related to chemical constituents and pharmacological activities dates from 1922 to the end of October 2015. Furthermore, ethnopharmacological information on this genus was obtained from libraries and herbaria in China and USA. In traditional medicine, 40 species, 11 subspecies, and one varieta of the genus Acer are known to exhibit a broad spectrum of biological activities. To date, 331 compounds have been identified from 34 species of the genus Acer, including flavonoids, tannins, phenylpropanoids, diarylheptanoids, terpenoids, benzoic acid derivatives, and several other types of compounds, such as phenylethanoid glycosides and alkaloids. Preliminary pharmacological studies have shown that the extracts and compounds isolated from this genus exhibit a broad spectrum of biological activities such as antioxidant, antitumor, anti-inflammatory, antidiabetic, hepatoprotective, and antiobesity activities, as well as promoting osteoblast differentiation. To date, reports on the toxicity of Acer species to humans are very limited, and the major safety concern of these plants is in the veterinary field. Based on our systematic review, Acer species can be used to treat rheumatism, hepatic disorders, eye disease, pain, etc. effectively. Some indications from ethnomedicine have been validated by pharmacological activities, such as the anti-inflammatory and hepatoprotective activities of the species. The available literature showed that most of the activities of these species can be attributed to flavonoids and tannins. To ensure the safety and efficacy in clinical practice in the future, studies identifying active molecules and clarifying their pharmacological mechanisms as well as toxicity are needed. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Influence of pharmacological education on perceptions, attitudes and use of dietary supplements by medical students.

PubMed

Stanojević-Ristić, Z; Stević, S; Rašić, J; Valjarević, D; Dejanović, M; Valjarević, A

2017-12-11

The ready availability and use of dietary supplements (DS) by the public means that healthcare professionals require education in this area. In the Republic of Serbia, education related to use of DS is included in undergraduate medical training and it is therefore important to assess the effectiveness of this education. The aim of our survey was to investigate the influence of pharmacological education on the use, attitudes and perceptions of risks associated with DS among medical students. Medical students at the University of Kosovska Mitrovica participated in the survey. Three hundred eighty questionnaires were distributed, yielding a response rate of 89% (n = 334). Data were categorized by year of study, completion of a one-year course in pharmacology and having passed the final exam. The results were compared between 192 (58%) medical students educated in pharmacology (MSEP) and 142 (42%) medical students not educated in pharmacology (MSNEP). The questionnaire was divided into 4 parts: socio-demographic and lifestyle/behavioral characteristics, use of DS, attitudes about efficacy, safety and perception of risk due to DS use. Chi-square test, Student's t-test, and Mann-Whitney U test were used for statistical analysis. About 53% of respondents used some form of DS. Attitudes regarding the safety of DS consumption showed a difference between the groups. MSEP were more likely to agree that DS have the potential to cause adverse reactions (Likert scale mean 4.1 vs. 3.5, p < 0.001) as well as interactions with conventional drugs (Likert scale mean 4.2 vs. 3.2, p < 0.001) than MSNEP. Finally, MSEP ranked St. John's wort and ginkgo as the most dangerous DS, but creatine and vitamin C were both ranked as relatively safe. Conversely, MSNEP considered ginkgo and vitamin C the most harmful DS, claiming that omega-3 fatty acids and vitamin D had the least hazardous side effects. Our results showed that pharmacological education gives young medical students a better understanding of the risks of DS-drug interactions and potential adverse effects. However, their overall attitudes and perception of risk indicate the need for further education.

The Safety Pharmacology Society salary survey.

PubMed

Pugsley, Michael K; Authier, Simon; Brabham, Tiffini; Soloviev, Maxim; Markgraf, Carrie G; Correll, Krystle; Traebert, Martin; Greiter-Wilke, Andrea; Valentin, Jean-Pierre; Vargas, Hugo; Botchway, Alfred; Leishman, Derek J; Curtis, Michael J

2017-11-01

Safety pharmacology is a growing discipline with scientists broadly distributed across international geographical regions. This electronic salary survey is the first to be distributed amongst the entire Safety Pharmacology Society (SPS) membership. An electronic survey was sent to all members of the Society. Categorical survey questions assessed membership employment types, annual incomes, and professional certifications, along with other associated career attributes. This survey was distributed to the SPS membership that is comprised of safety pharmacologists, toxicologists and pharmacologists working globally in the pharmaceutical industry, at contract research organizations (CRO), regulatory agencies, and academia or within the technology provider industry. The survey was open for responses from December 2015 to March 2016. The survey response rate was 28% (129/453). North America (68%) was the region with the largest number of respondents followed by Europe (28%). A preponderance of respondents (77%) had 12years of industry experience or more. 52% of responders earned annually between $40,000 and $120,000. As expected, salary was generally positively correlated with the number of years of experience in the industry or the educational background but there was no correlation between salary and the number of employee's directly supervised. The median salary was higher for male vs female respondents, but so was median age, indicative of no gender 'salary gap'. Our 2016 SPS salary survey results showcased significant diversity regarding factors that can influence salary compensation within this discipline. These data provided insights into the complex global job market trends. They also revealed the level of scientific specialization embedded within the organization, presently uniquely positioned to support the dynamic career paths of current and future safety pharmacologists. Copyright © 2017 Elsevier Inc. All rights reserved.

Safety pharmacology investigations on the nervous system: An industry survey.

PubMed

Authier, Simon; Arezzo, Joseph; Delatte, Marcus S; Kallman, Mary-Jeanne; Markgraf, Carrie; Paquette, Dominique; Pugsley, Michael K; Ratcliffe, Sian; Redfern, William S; Stevens, Joanne; Valentin, Jean-Pierre; Vargas, Hugo M; Curtis, Michael J

2016-01-01

The Safety Pharmacology Society (SPS) conducted an industry survey in 2015 to identify industry practices as they relate to central, peripheral and autonomic nervous system ('CNS') drug safety testing. One hundred fifty-eight (158) participants from Asia (16%), Europe (20%) and North America (56%) responded to the survey. 52% of participants were from pharmaceutical companies (>1000 employees). Oncology (67%) and neurology/psychiatry (66%) were the most frequent target indications pursued by companies followed by inflammation (48%), cardiovascular (43%), metabolic (39%), infectious (37%), orphan (32%) and respiratory (29%) diseases. Seizures (67% of participants), gait abnormalities (67%), tremors (65%), emesis (56%), sedation (52%) and salivation (47%) were the most commonly encountered CNS issues in pre-clinical drug development while headache (65%), emesis/nausea (60%), fatigue (51%) and dizziness (49%) were the most frequent issues encountered in Phase I clinical trials. 54% of respondents reported that a standard battery of tests applied to screen drug candidates was the approach most commonly used to address non-clinical CNS safety testing. A minority (14% of all participants) reported using electroencephalography (EEG) screening prior to animal inclusion on toxicology studies. The most frequent group size was n=8 for functional observation battery (FOB), polysomnography and seizure liability studies. FOB evaluations were conducted in a dedicated room (78%) by blinded personnel (66%) with control for circadian cycle (55%) effects (e.g., dosing at a standardized time; balancing time of day across treatment groups). The rat was reported as the most common species used for seizure liability, nerve conduction and drug-abuse liability testing. Copyright © 2016 Elsevier Inc. All rights reserved.

The pharmacologic and clinical effects of medical cannabis.

PubMed

Borgelt, Laura M; Franson, Kari L; Nussbaum, Abraham M; Wang, George S

2013-02-01

Cannabis, or marijuana, has been used for medicinal purposes for many years. Several types of cannabinoid medicines are available in the United States and Canada. Dronabinol (schedule III), nabilone (schedule II), and nabiximols (not U.S. Food and Drug Administration approved) are cannabis-derived pharmaceuticals. Medical cannabis or medical marijuana, a leafy plant cultivated for the production of its leaves and flowering tops, is a schedule I drug, but patients obtain it through cannabis dispensaries and statewide programs. The effect that cannabinoid compounds have on the cannabinoid receptors (CB(1) and CB(2) ) found in the brain can create varying pharmacologic responses based on formulation and patient characteristics. The cannabinoid Δ(9) -tetrahydrocannabinol has been determined to have the primary psychoactive effects; the effects of several other key cannabinoid compounds have yet to be fully elucidated. Dronabinol and nabilone are indicated for the treatment of nausea and vomiting associated with cancer chemotherapy and of anorexia associated with weight loss in patients with acquired immune deficiency syndrome. However, pain and muscle spasms are the most common reasons that medical cannabis is being recommended. Studies of medical cannabis show significant improvement in various types of pain and muscle spasticity. Reported adverse effects are typically not serious, with the most common being dizziness. Safety concerns regarding cannabis include the increased risk of developing schizophrenia with adolescent use, impairments in memory and cognition, accidental pediatric ingestions, and lack of safety packaging for medical cannabis formulations. This article will describe the pharmacology of cannabis, effects of various dosage formulations, therapeutics benefits and risks of cannabis for pain and muscle spasm, and safety concerns of medical cannabis use. © 2013 Pharmacotherapy Publications, Inc.

Pharmacokinetics and Safety Assessment of l-Tetrahydropalmatine in Cocaine Users: A Randomized, Double-Blind, Placebo-Controlled Study.

PubMed

Hassan, Hazem E; Kelly, Deanna; Honick, Moshe; Shukla, Sagar; Ibrahim, Ahmed; Gorelick, David A; Glassman, Matthew; McMahon, Robert P; Wehring, Heidi J; Kearns, Ann Marie; Feldman, Stephanie; Yu, Mingming; Bauer, Ken; Wang, Jia Bei

2017-02-01

Cocaine use disorder (CUD) remains a significant public health challenge. l-Tetrahydropalmatine (l-THP), a well-tolerated and nonaddictive compound, shows promise for the management of CUD. Its pharmacologic profile includes blockade at dopamine and other monoamine receptors and attenuation of cocaine self-administration, reinstatement, and rewarding properties in rats. This study evaluated the safety of l-THP in human cocaine users and its influence on the safety and pharmacokinetics (PK) of cocaine. Twenty-four cocaine-using adult men were randomized to receive l-THP (30 mg twice a day orally) or placebo double-blind for 4 days, with an intranasal cocaine (40 mg) challenge on the fourth day. Safety and tolerability were evaluated using vital signs, ECG, clinical laboratory tests, and standardized self-report instruments. Peripheral venous blood was collected periodically and later assayed for l-THP and cocaine using highly sensitive and specific ultraperformance liquid chromatography-fluorescence detection (UPLC-FLD) methods. Twenty subjects completed the study, of whom 19 provided complete PK data. The short 3.5-day course of l-THP was safe and well tolerated and did not affect cocaine's PK or its acute cardiovascular effects. The cocaine AUC 0→∞ was 211.5 and 261.4 h·ng/mL, and the C max was 83.3 and 104.5 ng/mL for the l-THP and placebo groups, respectively. In addition there were no significant differences in the number of side effects reported in each group (l-THP group 22 [48%], placebo group 24 [52%]) or vital signs including, heart rate, blood pressure, complete blood count, or ECG. These findings suggest that oral THP has promise for further development as a treatment for CUD. © 2016, The American College of Clinical Pharmacology.

Interventions to reduce weight gain in schizophrenia

PubMed Central

Faulkner, Guy; Cohn, Tony; Remington, Gary

2014-01-01

Background Weight gain is common for people with schizophrenia and this has serious implications for health and well being. Objectives To determine the effects of both pharmacological (excluding medication switching) and non pharmacological strategies for reducing or preventing weight gain in people with schizophrenia. Search methods We searched key databases and the Cochrane Schizophrenia Group’s trials register (April 2006), reference sections within relevant papers, hand searched key journals, and contacted the first author of each relevant study and other experts to collect further information. Selection criteria We included all clinical randomised controlled trials comparing any pharmacological or non pharmacological intervention for weight gain (diet and exercise counselling) with standard care or other treatments for people with schizophrenia or schizophrenia-like illnesses. Data collection and analysis We reliably selected, quality assessed and extracted data from studies. As weight is a continuous outcome measurement, weighted mean differences (WMD) of the change from baseline were calculated. The primary outcome measure was weight loss. Main results Twenty-three randomised controlled trials met the inclusion criteria for this review. Five trials assessed a cognitive/behavioural intervention and eighteen assessed a pharmacological adjunct. In terms of prevention, two cognitive/behavioural trials showed significant treatment effect (mean weight change) at end of treatment (n=104, 2 RCTs, WMD −3.38 kg CI −4.2 to −2.0). Pharmacological adjunct treatments were significant with a modest prevention of weight gain (n=274, 6 RCTs, WMD − 1.16 kg CI −1.9 to −0.4). In terms of treatments for weight loss, we found significantly greater weight reduction in the cognitive behavioural intervention group (n=129, 3 RCTs, WMD −1.69 kg CI −2.8 to −0.6) compared with standard care. Authors’ conclusions Modest weight loss can be achieved with selective pharmacological and non pharmacological interventions. However, interpretation is limited by the small number of studies, small sample size, short study duration and by variability of the interventions themselves, their intensity and duration. Future studies adequately powered, with longer treatment duration and rigorous methodology will be needed in further evaluating the efficacy and safety of weight loss interventions for moderating weight gain. At this stage, there is insufficient evidence to support the general use of pharmacological interventions for weight management in people with schizophrenia. PMID:17253540

Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects.

PubMed

Smeriglio, Antonella; Barreca, Davide; Bellocco, Ersilia; Trombetta, Domenico

2017-06-01

Tannins are a heterogeneous group of high MW, water-soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti-cancer, anti-nutritional and cardio-protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress-related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease-prevention properties, as well as their bioavailability, safety and toxicology. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

Local Anesthetics: Review of Pharmacological Considerations

PubMed Central

Becker, Daniel E; Reed, Kenneth L

2012-01-01

Local anesthetics have an impressive history of efficacy and safety in medical and dental practice. Their use is so routine, and adverse effects are so infrequent, that providers may understandably overlook many of their pharmacotherapeutic principles. The purpose of this continuing education article is to provide a review and update of essential pharmacology for the various local anesthetic formulations in current use. Technical considerations will be addressed in a subsequent article. PMID:22822998

A Review of Botanical Characteristics, Traditional Usage, Chemical Components, Pharmacological Activities, and Safety of Pereskia bleo (Kunth) DC

PubMed Central

Tan, Chay-Hoon

2014-01-01

Pereskia bleo, a leafy cactus, is a medicinal plant native to West and South America and distributed in tropical and subtropical areas. It is traditionally used as a dietary vegetable, barrier hedge, water purifier, and insect repellant and for maintaining health, detoxification, prevention of cancer, and/or treatment of cancer, hypertension, diabetes, stomach ache, muscle pain, and inflammatory diseases such as dermatitis and rheumatism. The aim of this paper was to provide an up-to-date and comprehensive review of the botanical characteristics, traditional usage, phytochemistry, pharmacological activities, and safety of P. bleo. A literature search using MEDLINE (via PubMed), Science direct, Scopus and Google scholar and China Academic Journals Full-Text Database (CNKI) and available eBooks and books in the National University of Singapore libraries in English and Chinese was conducted. The following keywords were used: Pereskia bleo, Pereskia panamensis, Pereskia corrugata, Rhodocacus corrugatus, Rhodocacus bleo, Cactus panamensis, Cactus bleo, Spinach cactus, wax rose, Perescia, and Chinese rose. This review revealed the association between the traditional usage of P. bleo and reported pharmacological properties in the literature. Further investigation on the pharmacological properties and phytoconstituents of P. bleo is warranted to further exploit its potentials as a source of novel therapeutic agents or lead compounds. PMID:24987426

A Review of Botanical Characteristics, Traditional Usage, Chemical Components, Pharmacological Activities, and Safety of Pereskia bleo (Kunth) DC.

PubMed

Zareisedehizadeh, Sogand; Tan, Chay-Hoon; Koh, Hwee-Ling

2014-01-01

Pereskia bleo, a leafy cactus, is a medicinal plant native to West and South America and distributed in tropical and subtropical areas. It is traditionally used as a dietary vegetable, barrier hedge, water purifier, and insect repellant and for maintaining health, detoxification, prevention of cancer, and/or treatment of cancer, hypertension, diabetes, stomach ache, muscle pain, and inflammatory diseases such as dermatitis and rheumatism. The aim of this paper was to provide an up-to-date and comprehensive review of the botanical characteristics, traditional usage, phytochemistry, pharmacological activities, and safety of P. bleo. A literature search using MEDLINE (via PubMed), Science direct, Scopus and Google scholar and China Academic Journals Full-Text Database (CNKI) and available eBooks and books in the National University of Singapore libraries in English and Chinese was conducted. The following keywords were used: Pereskia bleo, Pereskia panamensis, Pereskia corrugata, Rhodocacus corrugatus, Rhodocacus bleo, Cactus panamensis, Cactus bleo, Spinach cactus, wax rose, Perescia, and Chinese rose. This review revealed the association between the traditional usage of P. bleo and reported pharmacological properties in the literature. Further investigation on the pharmacological properties and phytoconstituents of P. bleo is warranted to further exploit its potentials as a source of novel therapeutic agents or lead compounds.

Pharmacological interventions for challenging behaviour in children with intellectual disabilities: a systematic review and meta-analysis.

PubMed

McQuire, Cheryl; Hassiotis, Angela; Harrison, Bronwyn; Pilling, Stephen

2015-11-26

Psychotropic medications are frequently used to treat challenging behaviour in children with intellectual disabilities, despite a lack of evidence for their efficacy. This systematic review and meta-analysis aimed to determine the safety and efficacy of pharmacological interventions for challenging behaviour among children with intellectual disabilities. Electronic databases were searched and supplemented with a hand search of reference lists and trial registries. Randomised controlled trials of pharmacological interventions for challenging behaviour among children with intellectual disabilities were included. Data were analysed using meta-analysis or described narratively if meta-analysis was not possible. For quality assessment, the Cochrane Risk of Bias tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach were used. Fourteen studies including 912 participants met inclusion criteria. Antipsychotic medication reduced challenging behaviour among children with intellectual disabilities in the short-term (SMD = -1.09, p < 0.001 for risperidone; SMD = -0.64, p <0.001 for aripiprazole). However, there were significant side-effects including elevated prolactin levels (SMD = 3.22, p < 0.001) and weight gain (SMD = 0.82, p < 0.001). Evidence was inconclusive regarding the effectiveness of anticonvulsants and antioxidants for reducing challenging behaviour. The quality of all evidence was low and there were no long term follow up studies. Antipsychotic medications appear to be effective for reducing challenging behaviour in the short-term among children with intellectual disabilities, but they carry a risk of significant side effects. Findings from this review must be interpreted with caution as studies were typically of low quality and most outcomes were based on a small number of studies. Further long-term, high-quality research is needed to determine the effectiveness and safety of psychotropic medication for reducing challenging behaviour.

Renal studies in safety pharmacology and toxicology: A survey conducted in the top 15 pharmaceutical companies.

PubMed

Benjamin, Amanda; Gallacher, David J; Greiter-Wilke, Andrea; Guillon, Jean-Michel; Kasai, Cheiko; Ledieu, David; Levesque, Paul; Prelle, Katja; Ratcliffe, Sian; Sannajust, Frederick; Valentin, Jean-Pierre

2015-01-01

With the recent development of more sensitive biomarkers to assess kidney injury preclinically, a survey was designed i) to investigate what strategies are used to investigate renal toxicity in both ICH S7A compliant Safety Pharmacology (SP) studies after a single dose of a compound and within repeat-dose toxicity studies by large pharmaceutical companies today; ii) to understand whether renal SP studies have impact or utility in drug development and/or if it may be more appropriate to assess renal effects after multiple doses of compounds; iii) to ascertain how much mechanistic work is performed by the top 15 largest pharmaceutical companies (as determined by R&D revenue size); iv) to gain an insight into the impact of the validation of DIKI biomarkers and their introduction in the safety evaluation paradigm; and v) to understand the impact of renal/urinary safety study data on progression of projects. Two short anonymous surveys were submitted to SP leaders of the top 15 pharmaceutical companies, as defined by 2012 R&D portfolio size. Fourteen multiple choice questions were designed to explore the strategies used to investigate renal effects in both ICH S7A compliant SP studies and within toxicology studies. A 67% and 60% response rate was obtained in the first and second surveys, respectively. Nine out of ten respondent companies conduct renal excretory measurements (eg. urine analysis) in toxicology studies whereas only five out of ten conduct specific renal SP studies; and all of those 5 also conduct the renal excretory measurements in toxicology studies. These companies measure and/or calculate a variety of parameters as part of these studies, and also on a case by case basis include regulatory qualified and non-qualified DIKI biomarkers. Finally, only one company has used renal/urinary functional data alone to stop a project, whereas the majority of respondents combine renal data with other target organ assessments to form an integrated decision-making set. These short surveys highlighted areas of similarity: a) urinary measurements are most commonly taken on repeat-dose toxicity studies, and b) renal SP studies are less often utilised. The two major differences are a) lack of consistent use of DIKI biomarkers in urinary safety studies and b) the way large pharmaceutical companies assess renal function. Finally, suggestions were made to improve the safety assessment methods for determining the safety of compounds with potential renal liability. Copyright © 2015 Elsevier Inc. All rights reserved.

The use of monoamine pharmacological agents in the treatment of sexual dysfunction: evidence in the literature.

PubMed

Moll, Jennifer L; Brown, Candace S

2011-04-01

The monoamine neurotransmitters serotonin, dopamine, and norepinephrine play an important role in many medical and psychological conditions, including sexual responsiveness and behavior. Pharmacological agents that modulate monoamines may help alleviate sexual dysfunction. To provide an overview of pharmacological agents that modulate monoamines and their use in the treatment of sexual dysfunction. EMBASE and PubMed search for articles published between 1950 and 2010 using key words "sexual dysfunction,"monoamines,"monoaminergic receptors," and "generic names for pharmacological agents." To assess the literature evaluating the efficacy of monoamine pharmacologic agents used in the treatment of sexual dysfunction. The literature primarily cites the use of monoaminergic agents to treat sexual side effects from serotonergic reuptake inhibitors (SSRIs), with bupropion, buspirone and ropinirole providing the most convincing evidence. Controlled trials have shown that bupropion improves overall sexual dysfunction, but not frequency of sexual activity in depressed and nondepressed patients. Nefazodone and apomorphine have been used to treat sexual dysfunction, but their use is limited by significant side effect and safety profiles. New research on pharmacologic agents with subtype selectivity at dopaminergic and serotonergic receptors and those that possess dual mechanisms of action are being investigated. There has been tremendous progress over the past 50 years in understanding the role of monoamines in sexual function and the effect of pharmacologic agents which stimulate or antagonize monoaminergic receptors on sexual dysfunction. Nevertheless, large, double-blind, placebo-controlled studies evaluating the efficacy of currently available agents in populations without comorbid disorders are limited, preventing adequate interpretation of data. Continued research on sexual function and specific receptor subtypes will result in the development of more selective pharmacologic agents with the goal of increasing efficacy without the dose-limiting side effects of nonselective agents. © 2011 International Society for Sexual Medicine.

The Pharmacology of Actoprotectors: Practical Application for Improvement of Mental and Physical Performance

PubMed Central

Oliynyk, Sergiy; Oh, Seikwan

2012-01-01

Actoprotectors are preparations that enhance body stability against physical loads without increasing oxygen consumption or heat production. Or, in short, actoprotectors are synthetic adaptogens with a significant capacity to improve physical performance. This paper explores the history of actoprotectors’development, their pharmacological properties, mechanism of action, and practical application to the improvement of mental and physical performance. A brief summary of the clinico-pharmacological characteristics of the main representatives of this class (bemitil and bromantane) is provided. Some other synthesized compounds, and even natural ones such as ginseng, also are regarded as potential actoprotectors, and these are treated herein as well. Actoprotectors, owing to their wide-ranging pharmacological activities, high efficiency and safety, can be applied under either normal or extreme conditions. PMID:24009833

Rosuvastatin: A Review of the Pharmacology and Clinical Effectiveness in Cardiovascular Disease

PubMed Central

Luvai, Ahai; Mbagaya, Wycliffe; Hall, Alistair S.; Barth, Julian H.

2012-01-01

Rosuvastatin is a new generation HMG-CoA reductase inhibitor which exhibits some unique pharmacologic and pharmacokinetic properties. It has low extrahepatic tissue penetration, low potential for CYP3A4 interactions and substantial LDL-C lowering capacity and therefore has distinct advantages. We conducted a Medline literature search to identify rosuvastatin papers published in English. In this review, we outline the pharmacology of rosuvastatin, highlighting its efficacy and safety. We also review the major clinical trials with reference to primary and secondary prevention, familial hypercholesterolaemia and comparison with other statins. Finally we address its place in clinical practice. PMID:22442638

PHARMACOLOGIC INTERVENTIONS FOR THE PREVENTION AND TREATMENT OF RETINOPATHY OF PREMATURITY

PubMed Central

Beharry, Kay D.; Valencia, G.B.; Lazzaro, D.R.; Aranda, J.V.

2016-01-01

Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are key in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, anti-oxidants, and others have decreased ROP occurrence. The timing of pharmacologic intervention remains unsettled, but early prevention rather than controlling disease progression may be preferred. These drugs act through different mechanisms and synergistic approaches should be considered to maximize efficacy and safety. PMID:26831641

The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

PubMed

Heal, D J; Cheetham, S C; Smith, S L

2009-12-01

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

Ethnomedical research and review of Q'eqchi Maya women's reproductive health in the Lake Izabal region of Guatemala: Past, present and future prospects.

PubMed

Michel, Joanna L; Caceres, Armando; Mahady, Gail B

2016-02-03

In Central America, most Maya women use ethnomedicines for all aspects of their reproductive cycle including menstruation, pregnancy and menopause. However, very few of these plants have been documented, collected and tested in appropriate pharmacological assays to determine possible safety and efficacy. The aim of this work was to provide an overview of information on the ethnomedical uses, ethnopharmacology, chemistry and pharmacological research for medicinal plants used for women's reproductive health in Guatemala, with a special emphasis on the Q'eqchi Maya of the Lake Izabal region, to demonstrate therapeutic potential and support future research in the field. Reviews of the ethnobotanical, ethnomedical and ethnopharmacological literature were performed for 30 plants collected in the Lake Izabal region of Guatemala and used by the Q'eqchi Maya for treatment of reproductive health issues were performed up to and including July 2015 using multiple databases, library searches for abstracts, books, dissertations, and websites. Review of the published research confirms that many of the plants used by Q'eqchi Maya women for the management of reproductive health issues have pharmacological activities, including analgesic, anti-inflammatory, estrogenic, progestagenic and/or serotonergic effects, that support the use of these plants and provide plausible mechanisms of action for their traditional uses. Furthermore, a new serotonin agonist, 9, 10-methylenedioxy-5, 6-Z-fadyenolide was isolated, thereby demonstrating an untapped potential for drug discovery. However, to date much of the pharmacological assays have been in vitro only, and few in vivo studies have been performed. Considering the large percentage of the Maya population in Guatemala that use traditional medicines, there remains a significant lack of pharmacological and toxicological data for these plants. Future research should focus on the safety and efficacy of medicinal plants using in vivo preclinical studies and clinical trials, as well as chemical analysis. Since medicinal plants from the Piperaceae are most commonly used as traditional medicines by the Q'eqchi Maya women, and new bioactive compounds have been identified from Piper species, investigations of commonly used plants from this family would be an appropriate place to start. Data generated from such studies would contribute to Guatemala's national effort to promote a complementary relationship between traditional Maya medicine and public health services. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Bachelors of Science in Nursing Students and a Qualitative Analysis of Their Medication Administration Experiences

ERIC Educational Resources Information Center

Betts, Kelly J.

2016-01-01

Lack of medication knowledge and skills is detrimental to the safety and welfare of patients. Lack of pharmacology knowledge and skills is detrimental to the safety and welfare of patients. In a southern baccalaureate nursing program, students demonstrated deficiencies in their medication knowledge and skill proficiency. This qualitative study…

Postmarket Safety Outcomes for New Molecular Entity (NME) Drugs Approved by the Food and Drug Administration Between 2002 and 2014.

PubMed

Pinnow, Ellen; Amr, Sania; Bentzen, Søren M; Brajovic, Sonja; Hungerford, Laura; St George, Diane Marie; Dal Pan, Gerald

2017-12-20

We ascertained a comprehensive list of postmarket safety outcomes, defined as a safety-related market withdrawal or an update to a safety-related section of product label for 278 new molecular entity drugs (NMEs) with a follow-up period of up to 13 years. At least one safety-related update was added to 195 (70.1%) labels of the drugs studied. Updates occurred as early as 160 days after approval and throughout the follow-up period. The period between the second and eighth postapproval year was the most active, with a slight attenuation thereafter. The times to the first safety outcome were significantly shorter for NMEs approved with a fast-track designation (P = 0.02) or under an accelerated approval using a surrogate endpoint (P = 0.03). Our findings underscore the importance of a robust safety surveillance system throughout a drug's lifecycle and for practitioners and patients to remain updated on drug safety profiles. © 2017, The American Society for Clinical Pharmacology and Therapeutics.

Safety and pharmacodynamic effects of a pharmacological chaperone on α-galactosidase A activity and globotriaosylceramide clearance in Fabry disease: report from two phase 2 clinical studies

PubMed Central

2012-01-01

Background Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A), which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally at 150 mg every-other-day. Methods Two open-label uncontrolled phase 2 studies of 12 and 24 weeks (NCT00283959 and NCT00283933) in 9 males with FD were combined. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Results Compared to baseline, increased α-Gal A activity of at least 50% was demonstrated in blood, skin and kidney in 6 of 9 patients. Patients’ increased α-Gal A activities paralleled the α-Gal A increases observed in vitro in HEK-293 cells transfected with the corresponding mutant form of the enzyme. The same 6 patients who demonstrated increases of α-Gal A activity also had GL-3 reduction in skin, urine and/or kidney, and had α-Gal A mutations that responded in transfected cells incubated with the drug. The 3 patients who did not show a consistent response in vivo had α-Gal A mutations that did not respond to migalastat HCl in transfected cells. Migalastat HCl was well tolerated. Conclusions Migalastat HCl is a candidate pharmacological chaperone that provides a novel genotype-specific treatment for FD. It enhanced α-Gal A activity and resulted in GL-3 substrate decrease in patients with responsive GLA mutations. Phase 3 studies are ongoing. Trial registration Clinicaltrial.gov: NCT00283959 and NCT00283933 PMID:23176611

Bidirectional interactions between dietary curcumin and gut microbiota.

PubMed

Shen, Liang; Ji, Hong-Fang

2018-05-21

Curcumin is a polyphenolic compound with a long history of use as an herbal remedy, dietary spice and food-coloring agent. Despite curcumin possesses a wide range of biological and pharmacological activities, it exhibits extremely poor bioavailability, which makes its pharmacology intriguing and also hinders its clinical application. In recent years, there is ample evidence supporting the associations between the alteration of gut microbiota and many diseases. Interestingly, after oral administration, curcumin shows its preferential distribution and accumulation in the intestine. In view of the above aspects, we reviewed the updated knowledge regarding the bidirectional interactions between curcumin and gut microbiota from two perspectives: i) gut microbiota regulation by curcumin and ii) curcumin biotransformation by digestive microbiota. Besides the study deals with 3 potential pharmacological implications: i) identification of metabolites being more active and bioavaliable than parent curcumin; ii) assessment of contribution of gut microbiota regulation of curcumin to its pharmacological effects and iii) development of gut microbiota regulation-based disease prevention/treatment strategy for curcumin in view of its clinical safety. This review is important to deepen our understanding of the mechanisms of action of curcumin and to provide future directions about how to use this natural compound to combat human diseases.

Effect of Wearing a Telemetry Jacket on Behavioral and Physiologic Parameters of Dogs in the Open‑Field Test

PubMed Central

Fish, Richard E; Foster, Melanie L; Gruen, Margaret E; Sherman, Barbara L; Dorman, David C

2017-01-01

Safety pharmacology studies in dogs often integrate behavioral assessments made using video recording with physiologic measurements collected by telemetry. However, whether merely wearing the telemetry vest affects canine behavior and other parameters has not been evaluated. This pilot study assessed the effect of a telemetry vest on behavioral and physiologic responses to an environmental stressor, the sounds of a thunderstorm, in Labrador retrievers. Dogs were assigned to one of 2 experimental groups (Vest and No-Vest, n = 8 dogs per group) by using a matched pairs design, with a previously determined, sound-associated anxiety score as the blocking variable. Dogs were individually retested with the same standardized sound stimulus (thunderstorm) in an open-field arena, and their behavioral responses were video recorded. Video analysis of locomotor activity and anxiety-related behavior and manual determination of heart rate and body temperature were performed; results were compared between groups. Vest wearing did not affect total locomotor activity or rectal body temperature but significantly decreased heart rate by 8% and overall mean anxiety score by 34% during open-field test sessions. Our results suggest that the use of telemetry vests in dogs influences the measurement of physiologic parameters and behaviors that are assessed in safety pharmacology studies. PMID:28724487

Attitudes toward pharmacological cognitive enhancement—a review

PubMed Central

Schelle, Kimberly J.; Faulmüller, Nadira; Caviola, Lucius; Hewstone, Miles

2014-01-01

A primary means for the augmentation of cognitive brain functions is “pharmacological cognitive enhancement” (PCE). The term usually refers to the off-label use of medical substances to improve mental performance in healthy individuals. With the final aim to advance the normative debate taking place on that topic, several empirical studies have been conducted to assess the attitudes toward PCE in the public, i.e., in groups outside of the academic debate. In this review, we provide an overview of the 40 empirical studies published so far, reporting both their methodology and results. Overall, we find that several concerns about the use of PCE are prevalent in the public. These concerns largely match those discussed in the normative academic debate. We present our findings structured around the three most common concerns: medical safety, coercion, and fairness. Fairness is divided into three subthemes: equality of opportunity, honesty, and authenticity. Attitudes regarding some concerns are coherent across studies (e.g., coercion), whereas for others we find mixed results (e.g., authenticity). Moreover, we find differences in how specific groups—such as users, nonusers, students, parents, and health care providers—perceive PCE: a coherent finding is that nonusers display more concerns regarding medical safety and fairness than users. We discuss potential psychological explanations for these differences. PMID:24860438

Effect of Wearing a Telemetry Jacket on Behavioral and Physiologic Parameters of Dogs in the Open-Field Test.

PubMed

Fish, Richard E; Foster, Melanie L; Gruen, Margaret E; Sherman, Barbara L; Dorman, Davidc C

2017-07-01

Safety pharmacology studies in dogs often integrate behavioral assessments made using video recording with physiologic measurements collected by telemetry. However, whether merely wearing the telemetry vest affects canine behavior and other parameters has not been evaluated. This pilot study assessed the effect of a telemetry vest on behavioral and physiologic responses to an environmental stressor, the sounds of a thunderstorm, in Labrador retrievers. Dogs were assigned to one of 2 experimental groups (Vest and No-Vest, n = 8 dogs per group) by using a matched pairs design, with a previously determined, sound-associated anxiety score as the blocking variable. Dogs were individually retested with the same standardized sound stimulus (thunderstorm) in an open-field arena, and their behavioral responses were video recorded. Video analysis of locomotor activity and anxiety-related behavior and manual determination of heart rate and body temperature were performed; results were compared between groups. Vest wearing did not affect total locomotor activity or rectal body temperature but significantly decreased heart rate by 8% and overall mean anxiety score by 34% during open-field test sessions. Our results suggest that the use of telemetry vests in dogs influences the measurement of physiologic parameters and behaviors that are assessed in safety pharmacology studies.

Translation and Clinical Development of Bispecific T‐cell Engaging Antibodies for Cancer Treatment

PubMed Central

Yuraszeck, T; Kasichayanula, S

2017-01-01

Bispecific T‐cell Engagers (BiTE®) antibody constructs enable a polyclonal T‐cell response to cell‐surface tumor‐associated antigens, bypassing the narrow specificities of T‐cell receptors and the need for antigen presentation through the major histocompatibility complex pathways. Blinatumomab, a CD19xCD3 BiTE® antibody construct, received accelerated approval for the treatment of relapsed/refractory Philadelphia chromosome negative acute lymphoblastic leukemia. Herein we review the pharmacology, safety, and efficacy observed in studies of blinatumomab and other BiTE® antibody constructs. Quantitative systems pharmacology is envisioned as a means to optimize dosing decisions for trials in which BiTE® antibody constructs are administered as monotherapy or in combination with other immunotherapies. PMID:28182247

Ultrasound-guided stellate ganglion blocks combined with pharmacological and occupational therapy in Complex Regional Pain Syndrome (CRPS): a pilot case series ad interim.

PubMed

Wei, Karin; Feldmann, Robert E; Brascher, Anne-Kathrin; Benrath, Justus

2014-12-01

This preliminary and retrospective pilot case series examines a treatment concept consisting of ultrasound-guided stellate ganglion blocks (SGBs) combined with pharmacological and occupational therapy in patients with complex regional pain syndrome (CRPS) of the hand. Efficacy of combined treatment concepts and safety of ultrasound-guided SGB have not been sufficiently investigated yet. A total number of 156 blocks were evaluated in 16 patients with CRPS in a retrospective analysis. All patients received pharmacotherapy and a standard regimen of occupational therapy offered simultaneously to the SGBs. Changes in both spontaneous and evoked pain levels were assessed by numerical pain rating score before and after the last blockade of a series. Side effects were documented. The overall mean pain reduction was 63.2% regarding spontaneous and 45.3% regarding evoked pain. Mild complications, such as hoarseness or dysphagia, occurred in 13.5% of the blocks (21 SGBs). Serious complications, such as plexus paresis or accidental puncture of vessels or other structures, did not occur. Time between symptom onset and start of treatment did not affect the extent of pain reduction. The combination of ultrasound-guided SGB and simultaneous pharmacological and occupational therapy showed encouraging treatment results under conditions of this pilot case series. Assessment of efficacy of this combined treatment concept and safety of ultrasound-guided SGB require further prospective clinical studies with larger number of participants. Wiley Periodicals, Inc.

New developments in pediatric venous thromboembolism and anticoagulation, including the target-specific oral anticoagulants.

PubMed

Lyle, Courtney A; Sidonio, Robert F; Goldenberg, Neil A

2015-02-01

Pediatric venous thromboembolism (VTE) can affect children of all ages, requiring considerable pharmacologic intervention and is often associated with significant morbidity. Current research efforts are directed toward the development of risk-stratified VTE prevention strategies employing pharmacologic thromboprophylaxis, the optimization of conventional anticoagulation, and the investigation of the safety and efficacy of target-specific oral anticoagulants (TSOACs) in children. Recent research has considerably improved the understanding of risk factors of hospital-acquired VTE and how these factors may be employed in risk-stratified paradigms for VTE prevention in children. Additional insight has been gained in the optimization of conventional anticoagulants in special populations such as neonates and children with inflammatory conditions, and in improving the overall safety and compliance with periprocedural anticoagulation and the use of home International Normalized Ratio monitoring. Furthermore, the use of TSOACs has been described in children and is the focus of numerous ongoing clinical trials that are evaluating the safety and efficacy of these agents in children with VTE. Identification of hospital-acquired VTE risk factors may inform pediatric VTE prevention strategies. Although initial use of TSOACs may be promising, investigation of safety and efficacy in children is still underway.

Optimizing oncology therapeutics through quantitative translational and clinical pharmacology: challenges and opportunities.

PubMed

Venkatakrishnan, K; Friberg, L E; Ouellet, D; Mettetal, J T; Stein, A; Trocóniz, I F; Bruno, R; Mehrotra, N; Gobburu, J; Mould, D R

2015-01-01

Despite advances in biomedical research that have deepened our understanding of cancer hallmarks, resulting in the discovery and development of targeted therapies, the success rates of oncology drug development remain low. Opportunities remain for objective dose selection informed by exposure-response understanding to optimize the benefit-risk balance of novel therapies for cancer patients. This review article discusses the principles and applications of modeling and simulation approaches across the lifecycle of development of oncology therapeutics. Illustrative examples are used to convey the value gained from integration of quantitative clinical pharmacology strategies from the preclinical-translational phase through confirmatory clinical evaluation of efficacy and safety. © 2014 American Society for Clinical Pharmacology and Therapeutics.

Pharmacologic interventions for the prevention and treatment of retinopathy of prematurity.

PubMed

Beharry, Kay D; Valencia, Gloria B; Lazzaro, Douglas R; Aranda, Jacob V

2016-04-01

Retinopathy of prematurity (ROP), a significant morbidity in prematurely born infants, is the most common cause of visual impairment and blindness in children and persists till adulthood. Strict control of oxygen therapy and prevention of intermittent hypoxia are the keys in the prevention of ROP, but pharmacologic interventions have decreased risk of ROP. Various drug classes such as methylxanthines (caffeine), VEGF inhibitors, antioxidants, and others have decreased ROP occurrence. The timing of pharmacologic intervention remains unsettled, but early prevention rather than controlling disease progression may be preferred. These drugs act through different mechanisms, and synergistic approaches should be considered to maximize efficacy and safety. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Comparison of Pharmacological Potency and Safety of Glutamate Blocker IEM-1913 and Memantine.

PubMed

Gmiro, V E; Serdyuk, S E; Veselkina, O S

2015-11-01

Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.

Safety and efficacy of extracorporeal shock wave myocardial revascularization therapy for refractory angina pectoris.

PubMed

Cassar, Andrew; Prasad, Megha; Rodriguez-Porcel, Martin; Reeder, Guy S; Karia, Darshak; DeMaria, Anthony N; Lerman, Amir

2014-03-01

To assess the safety and efficacy of extracorporeal shockwave myocardial revascularization (ESMR) therapy in treating patients with refractory angina pectoris. A single-arm multicenter prospective trial to assess safety and efficacy of the ESMR therapy in patients with refractory angina (class III/IV angina) was performed. Screening exercise treadmill tests and pharmacological single-photon emission computed tomography (SPECT) were performed for all patients to assess exercise capacity and ischemic burden. Patients were treated with 9 sessions of ESMR to ischemic areas over 9 weeks. Efficacy end points were exercise capacity by using treadmill test as well as ischemic burden on pharmacological SPECT at 4 months after the last ESMR treatment. Safety measures included electrocardiography, echocardiography, troponin, creatine kinase, and brain natriuretic peptide testing, and pain questionnaires. Fifteen patients with medically refractory angina and no revascularization options were enrolled. There was a statistically significant mean increase of 122.3±156.9 seconds (38% increase compared with baseline; P=.01) in exercise treadmill time from baseline (319.8±157.2 seconds) to last follow-up after the ESMR treatment (422.1±183.3 seconds). There was no improvement in the summed stress perfusion scores after pharmacologically induced stress SPECT at 4 months after the last ESMR treatment in comparison to that at screening; however, SPECT summed stress score revealed that untreated areas had greater progression in ischemic burden vs treated areas (3.69±6.2 vs 0.31±4.5; P=.03). There was no significant change in the mean summed echo score from baseline to posttreatment (0.4±5.1; P=.70). The ESMR therapy was performed safely without any adverse events in electrocardiography, echocardiography, troponins, creatine kinase, or brain natriuretic peptide. Pain during the ESMR treatment was minimal (a score of 0.5±1.2 to 1.1±1.2 out of 10). In this multicenter feasibility study, ESMR seems to be a safe and efficacious treatment for patients with refractory angina pectoris. However, larger sham-controlled trials will be required to confirm these findings. Copyright © 2014 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.

Traditional uses, phytochemistry and pharmacological properties of the genus Peucedanum: a review.

PubMed

Sarkhail, Parisa

2014-10-28

The genus Peucedanum (Apiaceae) comprising more than 120 species is widely distributed in Europe, Asia and Africa. The ethnopharmacologial history of this genus indicated that some extracts of aerial and underground parts of several Peucedanum species have been used in folk medicine for treatment of various conditions, such as cough, cramps, pain, rheumatism, asthma and angina. This review focuses on ethnopharmacological uses of Peucedanum species, as well as the phytochemical, pharmacological and toxicological studies on this genus. Through this review, I intend to highlight the known and potential effects of the Peucedanum species or their isolated compounds and show which traditional medicine uses have been supported by pharmacological investigations. Information on the Peucedanum species was collected from scientific journals, books, thesis and reports via a library and electronic search (using Google Scholar, Pubmed, Scopus, Web of Science and ScienceDirect). This review covers the available literature from 1970 to the end of September 2013. Although, there are about 120 species in this genus, so far many species have received no or little attention and most of pharmacological studies were performed on just about 20 species. Many phytochemical investigations on this genus confirmed that Peucedanum species are rich in essential oils and coumarins. The present review article shows that Peucedanum species have a wide spectrum of pharmacological activities and the most reported activities of Peucedanum plants come back to the presence of coumarins, flavonoids, phenolics and essential oils. The present review confirms that some Peucedanum species have emerged as a good source of the traditional medicine for treatment of inflammation, microbial infections, cardiopulmonary diseases and provides new insights for further investigations on isolated compounds, especially on praeruptorins, to find novel therapeutics and aid drug discovery. However, for using Peucedanum species to prevent and treat various diseases, additional pharmacological studies to find the mechanism of action, safety and efficacy of them before starting clinical trials are required. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

The genus Pterocaulon (Asteraceae) - A review on traditional medicinal uses, chemical constituents and biological properties.

PubMed

Medeiros-Neves, Bruna; Teixeira, Helder Ferreira; von Poser, Gilsane Lino

2018-06-15

Species of the genus Pterocaulon (Asteraceae) are used in different parts of the world for mainly to treat skin and liver diseases, as well as disorders of the respiratory system, among others. This review aims to discuss the present state of the art concerning the ethnobotanical uses, secondary metabolites and biological effects of Pterocaulon species and their chemical components. The available information on the genus Pterocaulon was gathered from scientific databases (Web of Science, Pubmed, ScienceDirect, Scopus, ChemSpider, SciFinder ACS Publications, Wiley Online Library). Information was also obtained from local publications, M.Sc. and Ph.D. dissertations. All studies on the ethnobotany, phytochemistry, pharmacology and toxicology of the plants until December 2017 were included in this review. Approximately 40 coumarins and 30 flavonoids have been isolated from Pterocaulon species. Coumarins have been considered the chemotaxonomic markers in the genus and the most active components. Pharmacological studies carried out with extracts and isolated compounds revealed in vitro bioactivities that include antifungal, antiviral, and cytotoxicity. Most of the pharmacological investigations were not correlated with traditional uses of the plants. Pterocaulon species, a rich source of coumarins, have great ethnomedical potential. Nevertheless, further studies into the pharmacological activities are necessary since none of the purported effects of these plants was fully assessed. In-depth research regarding the toxicity are also required to ensure the safety of these medicinal plants. Copyright © 2018 Elsevier Ireland Ltd. All rights reserved.

Aloysia citrodora Paláu (Lemon verbena): A review of phytochemistry and pharmacology.

PubMed

Bahramsoltani, Roodabeh; Rostamiasrabadi, Pourouchista; Shahpiri, Zahra; Marques, André M; Rahimi, Roja; Farzaei, Mohammad Hosein

2018-08-10

Aloysia citrodora Paláu (Lippia citriodora Kunth), commonly known as "lemon verbena" is a medicinal plant native to South America, North Africa, and South of Europe which is used by native people for several indications such as diarrhea, flatulence, insomnia, and rheumatism. Despite the wide biological activities of lemon verbena, there is no current review summarizing medicinal properties of the plant; thus, this paper aims to discuss current state of the art regarding the phytochemistry, pharmacology, and therapeutic applications of A. citrodora considering in vitro, in vivo, and clinical studies. Electronic databases including PubMed, Scifinder, Cochrane library, Scopus, and Science direct were searched with the scientific name of the plant and its synonyms, as well as the common name. All studies on the ethnobotany, phytochemistry, pharmacology, and clinical application of the plant until October 2017 were included in this review. Despite the few number of studies on the ethnopharmacology of the plant, A. citrodora is widely assessed regarding its phytochemistry and biological activities. Neral and geranial are the main ingredients of the essential oil; whereas verbascoside is the most significant component of the extract. Biological activities such as antioxidant, anxiolytic, neuroprotective, anticancer, anesthetic, antimicrobial, and sedative effects are proved in cell cultures, as well as animal studies. Several pharmacological activities have been reported for A. citrodora; however, the plant is not fully assessed regarding its safety and efficacy in human. Future well-designed human studies are essential to confirm the therapeutic benefits of this plant in clinical settings. Copyright © 2018 Elsevier B.V. All rights reserved.

An Overview of the Evidence and Mechanisms of Herb–Drug Interactions

PubMed Central

Fasinu, Pius S.; Bouic, Patrick J.; Rosenkranz, Bernd

2012-01-01

Despite the lack of sufficient information on the safety of herbal products, their use as alternative and/or complementary medicine is globally popular. There is also an increasing interest in medicinal herbs as precursor for pharmacological actives. Of serious concern is the concurrent consumption of herbal products and conventional drugs. Herb–drug interaction (HDI) is the single most important clinical consequence of this practice. Using a structured assessment procedure, the evidence of HDI presents with varying degree of clinical significance. While the potential for HDI for a number of herbal products is inferred from non-human studies, certain HDIs are well established through human studies and documented case reports. Various mechanisms of pharmacokinetic HDI have been identified and include the alteration in the gastrointestinal functions with consequent effects on drug absorption; induction and inhibition of metabolic enzymes and transport proteins; and alteration of renal excretion of drugs and their metabolites. Due to the intrinsic pharmacologic properties of phytochemicals, pharmacodynamic HDIs are also known to occur. The effects could be synergistic, additive, and/or antagonistic. Poor reporting on the part of patients and the inability to promptly identify HDI by health providers are identified as major factors limiting the extensive compilation of clinically relevant HDIs. A general overview and the significance of pharmacokinetic and pharmacodynamic HDI are provided, detailing basic mechanism, and nature of evidence available. An increased level of awareness of HDI is necessary among health professionals and drug discovery scientists. With the increasing number of plant-sourced pharmacological actives, the potential for HDI should always be assessed in the non-clinical safety assessment phase of drug development process. More clinically relevant research is also required in this area as current information on HDI is insufficient for clinical applications. PMID:22557968

Avelumab for the treatment of urothelial cancer.

PubMed

Rodriguez-Vida, Alejo; Bellmunt, Joaquim

2018-05-01

Metastatic urothelial carcinoma (UC) remains an aggressive disease associated with limited treatment options and a reduced survival. In spite of this, the first-line treatment based on platinum-based combinations has remained virtually unchanged for the last 20-30 years. Similarly, before the advent of the immune checkpoint inhibitors, there were no FDA-approved drugs for second-line therapy. In the last few years, impressive signs of anti-tumor activity have been reported with several immunotherapy agents targeting the programmed cell death-1 (PD-1) pathway. Avelumab, a PD-1 ligand (PD-L1) inhibitor, is currently being investigated for the treatment of UC. Areas covered: This article will review the pharmacological characteristics of avelumab, the efficacy studies which led to its approval, its safety profile, as well as its place within the management of urothelial carcinoma with immunotherapy. For that matter, we undertook a literature review of all the studies assessing the pharmacology of avelumab and its efficacy within clinical trials. Expert commentary: Avelumab has shown promising antitumor activity and a manageable safety profile in patients with UC. Its dual mechanism of action, blocking the interaction between PD-L1 and PD-1 and promoting antibody-dependent cell-mediated cytotoxicity could potentially be of great interest since it could produce synergistic clinical efficacy.

Psychopharmacology of aggression in children and adolescents with primary neuropsychiatric disorders: a review of current and potentially promising treatment options.

PubMed

Nevels, Robert M; Dehon, Erin E; Alexander, Katrina; Gontkovsky, Samuel T

2010-04-01

Research examining the role of pharmacological therapy in the treatment of children and adolescents with clinical disorders is growing. Clinical disorders that present with comorbid aggression can add a challenge to treatment. Child and adolescent neuropsychiatric disorders associated with aggression include attention-deficit hyperactivity disorder, various mood disorders and in particular bipolar disorders/pediatric mania, schizophrenia, mental retardation, oppositional defiant disorder, conduct disorder, and autism spectrum disorders. This review describes the psychopharmacy to treat these disorders and the aggression that often appears comorbidly. Existing literature regarding the efficacy and safety of psychotropics for youth with neuropsychiatric disorders also is discussed. In addition, general guidelines for psychopharmacy of aggression in children and adolescents are presented. Studies reviewed in this article provide evidence for the use of psychostimulants, alpha-2 agonists, beta blockers, lithium, anticonvulsant mood-stabilizers, atypical antipsychotics, traditional antipsychotics, and selective serotonin reuptake inhibitors in treating pediatric aggression with the choice of medication dependent on symptomology. Despite increased support for pediatric psychotropic use, there is a need for more long-term safety and efficacy studies of existing medications and newer, safer, and more effective agents with fewer side effects for the pharmacological treatment of all childhood disorders in which aggression is prominent. 2010 APA, all rights reserved

Statistical power analysis of cardiovascular safety pharmacology studies in conscious rats.

PubMed

Bhatt, Siddhartha; Li, Dingzhou; Flynn, Declan; Wisialowski, Todd; Hemkens, Michelle; Steidl-Nichols, Jill

2016-01-01

Cardiovascular (CV) toxicity and related attrition are a major challenge for novel therapeutic entities and identifying CV liability early is critical for effective derisking. CV safety pharmacology studies in rats are a valuable tool for early investigation of CV risk. Thorough understanding of data analysis techniques and statistical power of these studies is currently lacking and is imperative for enabling sound decision-making. Data from 24 crossover and 12 parallel design CV telemetry rat studies were used for statistical power calculations. Average values of telemetry parameters (heart rate, blood pressure, body temperature, and activity) were logged every 60s (from 1h predose to 24h post-dose) and reduced to 15min mean values. These data were subsequently binned into super intervals for statistical analysis. A repeated measure analysis of variance was used for statistical analysis of crossover studies and a repeated measure analysis of covariance was used for parallel studies. Statistical power analysis was performed to generate power curves and establish relationships between detectable CV (blood pressure and heart rate) changes and statistical power. Additionally, data from a crossover CV study with phentolamine at 4, 20 and 100mg/kg are reported as a representative example of data analysis methods. Phentolamine produced a CV profile characteristic of alpha adrenergic receptor antagonism, evidenced by a dose-dependent decrease in blood pressure and reflex tachycardia. Detectable blood pressure changes at 80% statistical power for crossover studies (n=8) were 4-5mmHg. For parallel studies (n=8), detectable changes at 80% power were 6-7mmHg. Detectable heart rate changes for both study designs were 20-22bpm. Based on our results, the conscious rat CV model is a sensitive tool to detect and mitigate CV risk in early safety studies. Furthermore, these results will enable informed selection of appropriate models and study design for early stage CV studies. Copyright © 2016 Elsevier Inc. All rights reserved.

Pharmacological Review on Centella asiatica: A Potential Herbal Cure-all

PubMed Central

Gohil, Kashmira J.; Patel, Jagruti A.; Gajjar, Anuradha K.

2010-01-01

In recent times, focus on plant research has increased all over the world. Centella asiatica is an important medicinal herb that is widely used in the orient and is becoming popular in the West. Triterpenoid, saponins, the primary constituents of Centella asiatica are manly believed to be responsible for its wide therapeutic actions. Apart from wound healing, the herb is recommended for the treatment of various skin conditions such as leprosy, lupus, varicose ulcers, eczema, psoriasis, diarrhoea, fever, amenorrhea, diseases of the female genitourinary tract and also for relieving anxiety and improving cognition. The present review attempts to provide comprehensive information on pharmacology, mechanisms of action, various preclinical and clinical studies, safety precautions and current research prospects of the herb. At the same time, studies to evaluate the likelihood of interactions with drugs and herbs on simultaneous use, which is imperative for optimal and safe utilization of the herb, are discussed. PMID:21694984

Safety of Reiki Therapy for Newborns at Risk for Neonatal Abstinence Syndrome

PubMed Central

Wright-Esber, Sandra; Zupancic, Julie; Gargiulo, Deb; Woodall, Patricia

2018-01-01

The incidence of opioid abuse and subsequent drug withdrawal is exponentially on the rise in the United States for many populations including newborns who are born to drug-addicted mothers. These newborns often exhibit symptoms of neonatal abstinence syndrome (NAS) within 24 to 72 hours of birth. Treatment of NAS includes monitoring of withdrawal symptoms, managing physiological parameters, and the use of supportive and pharmacologic treatments. Although a few randomized controlled trials exist, studies on supportive intervention are generally limited by small sample sizes, case study reports, expert opinions, and descriptive design. Few studies address the safety of Reiki for newborns at risk for NAS using neonatal parameters. This pilot study addresses feasibility and demonstrates that Reiki is safe when administered to this high-risk population. Considerations for future studies are discussed. PMID:29315084

A Comprehensive Review on Chemical Profiling of Nelumbo Nucifera: Potential for Drug Development.

PubMed

Sharma, Bhesh Raj; Gautam, Lekh Nath S; Adhikari, Deepak; Karki, Rajendra

2017-01-01

Nelumbo nucifera, also known as sacred lotus, has primarily been used as food throughout the Asian continent, and its medicinal values have been described in Ayurvedic and Traditional Chinese Medicine. The purpose of this study is to systematically characterize the chemical profiling and pharmacological activities of N. nucifera. Herein, we critically reviewed and analysed the phytochemical and pharmacological reports of N. nucifera. Our search for the keyword 'Nelumbo nucifera pharmacology' in all databases reported in Web of Science yielded 373 results excluding reviews and abstracts in document types. Two hundred and forty-three spectrum natural compounds from different parts of N. nucifera belonging to diverse chemical groups, including alkaloids, flavonoids, glycosides, terpenoids, steroids, fatty acids, proteins, minerals, and vitamins have been reported. In addition, distinct pharmacological activities, mainly against cancer, microbial infection, diabetes, inflammation, atherosclerosis, and obesity, have been associated with crude extracts, fractions, and isolated compounds. This review highlights potential use of neferine, liensinine, isoliensinine, and nuciferine in clinical trials. In depth, mechanism of the potential chemical entities from N. nucifera via structure activity relationship needs to be explored to guarantee the stability and safety for the clinical use. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Proanthocyanidins and hydrolysable tannins: occurrence, dietary intake and pharmacological effects

PubMed Central

Smeriglio, Antonella; Bellocco, Ersilia; Trombetta, Domenico

2016-01-01

Tannins are a heterogeneous group of high MW, water‐soluble, polyphenolic compounds, naturally present in cereals, leguminous seeds and, predominantly, in many fruits and vegetables, where they provide protection against a wide range of biotic and abiotic stressors. Tannins exert several pharmacological effects, including antioxidant and free radical scavenging activity as well as antimicrobial, anti‐cancer, anti‐nutritional and cardio‐protective properties. They also seem to exert beneficial effects on metabolic disorders and prevent the onset of several oxidative stress‐related diseases. Although the bioavailability and pharmacokinetic data for these phytochemicals are still sparse, gut absorption of these compounds seems to be inversely correlated with the degree of polymerization. Further studies are mandatory to better clarify how these molecules and their metabolites are able to cross the intestinal barrier in order to exert their biological properties. This review summarizes the current literature on tannins, focusing on the main, recently proposed mechanisms of action that underlie their pharmacological and disease‐prevention properties, as well as their bioavailability, safety and toxicology. Linked Articles This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc PMID:27646690

The pharmacologic management of nausea and vomiting of pregnancy.

PubMed

Niebyl, Jennifer R; Briggs, Gerald G

2014-02-01

Nausea and vomiting are common in early pregnancy. Forty percent or more of pregnant women may continue to suffer beyond the first trimester and 10% beyond the second trimester. A focus of the assessment is to confirm that the nausea and vomiting is due to the pregnancy and not some other cause. Nonpharmacologic options, particularly dietary modification, are a mainstay of treatment. For those who continue to experience symptoms, pharmacologic management can be employed. The combination of doxylamine succinate/pyridoxine hydrochloride was reintroduced in the United States following FDA approval in early 2013. The product was given a pregnancy safety rating of A and is recommended as first-line pharmacologic treatment for NVP. Other options include antihistamines, metoclopramide, ondansetron, phenothiazines, and after the first trimester, corticosteroids.

The potential effects of Ocimum basilicum on health: a review of pharmacological and toxicological studies.

PubMed

Sestili, Piero; Ismail, Tariq; Calcabrini, Cinzia; Guescini, Michele; Catanzaro, Elena; Turrini, Eleonora; Layla, Anam; Akhtar, Saeed; Fimognari, Carmela

2018-07-01

Basil (Ocimum basilicum L., OB) is a plant world widely used as a spice and a typical ingredient of the healthy Mediterranean diet. In traditional medicine, OB is indicated for many maladies and conditions; OB-containing nutritional supplements are increasingly sold. Conversely, safety concerns have been raised about the promutagens and procarcinogens alkenylbenzenes contained in OB. Areas covered: A critical review of the current status of OB as a nutraceutical, the pharmacology of its bioactive components, the rationale for its indications, and its safety. Expert opinion: Due to the polyphenolic and flavonoidic content, OB can be considered as an important ingredient in healthy diets; OB preparations may be effective as chemopreventive agents or adjunctive therapy in the treatment of different clinical conditions. From a toxicological perspective, since the tumorigenic potential of alkenylbenzenes is counteracted by other OB constituents such as nevadensin, it can be concluded that OB consumption in food and preparations is safe. The only concern relates to OB essential oils: in this case, a concentration limit for alkenylbenzenes should be precautionary defined, and the use of plant chemotypes with no or low levels of these alkylbenzenes for the preparation of essential oils should be made compulsory.

Trends in qualifying biomarkers in drug safety. Consensus of the 2011 meeting of the spanish society of clinical pharmacology.

PubMed

Agúndez, José A G; Del Barrio, Jaime; Padró, Teresa; Stephens, Camilla; Farré, Magí; Andrade, Raúl J; Badimon, Lina; García-Martín, Elena; Vilahur, Gemma; Lucena, M Isabel

2012-01-01

In this paper we discuss the consensus view on the use of qualifying biomarkers in drug safety, raised within the frame of the XXIV meeting of the Spanish Society of Clinical Pharmacology held in Málaga (Spain) in October, 2011. The widespread use of biomarkers as surrogate endpoints is a goal that scientists have long been pursuing. Thirty years ago, when molecular pharmacogenomics evolved, we anticipated that these genetic biomarkers would soon obviate the routine use of drug therapies in a way that patients should adapt to the therapy rather than the opposite. This expected revolution in routine clinical practice never took place as quickly nor with the intensity as initially expected. The concerted action of operating multicenter networks holds great promise for future studies to identify biomarkers related to drug toxicity and to provide better insight into the underlying pathogenesis. Today some pharmacogenomic advances are already widely accepted, but pharmacogenomics still needs further development to elaborate more precise algorithms and many barriers to implementing individualized medicine exist. We briefly discuss our view about these barriers and we provide suggestions and areas of focus to advance in the field.

Feasibility and safety of exercise stress testing using an anti-gravity treadmill with Tc-99m tetrofosmin single-photon emission computed tomography (SPECT) myocardial perfusion imaging: A pilot non-randomized controlled study.

PubMed

Daly, Patrick; Kayse, Regina; Rudick, Steven; Robbins, Nathan; Scheler, Jennifer; Harris, David; O'Donnell, Robert; Dwivedi, Alok K; Gerson, Myron C

2017-08-31

Exercise is the AHA/ACC guideline-recommended stress modality for myocardial perfusion imaging, but many patients are unable to exercise to target heart rate on a conventional treadmill. We examined the feasibility and safety of stress imaging using an anti-gravity treadmill in patients with perceived poor exercise capacity. 49 patients were recruited for stress testing by anti-gravity treadmill (n = 29) or to a regadenoson control group (n = 20). Seventeen anti-gravity test patients (59%) reached target heart rate obviating the need for a pharmacologic stress agent. Adverse effects of the anti-gravity treadmill were limited to minor muscle aches in 5 subjects. Stress myocardial perfusion image quality judged by 3 blinded readers on a 5-point scale was comparable for the anti-gravity treadmill (4.30 ± SD 0.87) vs pharmacologic stress (4.28 ± SD 0.66). Stress testing using an anti-gravity treadmill is feasible and may help some patients safely achieve target heart rate.

Recanalization Therapies in Acute Ischemic Stroke: Pharmacological Agents, Devices, and Combinations

PubMed Central

Sharma, Vijay K.; Teoh, Hock Luen; Wong, Lily Y. H.; Su, Jie; Ong, Benjamin K. C.; Chan, Bernard P. L.

2010-01-01

The primary aim of thrombolysis in acute ischemic stroke is recanalization of an occluded intracranial artery. Recanalization is an important predictor of stroke outcome as timely restoration of regional cerebral perfusion helps salvage threatened ischemic tissue. At present, intravenously administered tissue plasminogen activator (IV-TPA) remains the only FDA-approved therapeutic agent for the treatment of ischemic stroke within 3 hours of symptom onset. Recent studies have demonstrated safety as well as efficacy of IV-TPA even in an extended therapeutic window. However, the short therapeutic window, low rates of recanalization, and only modest benefits with IV-TPA have prompted a quest for alternative approaches to restore blood flow in an occluded artery in acute ischemic stroke. Although intra-arterial delivery of the thrombolytic agent seems effective, various logistic constraints limit its routine use and as yet no lytic agent have not received full regulatory approval for intra-arterial therapy. Mechanical devices and approaches can achieve higher rates of recanalization but their safety and efficacy still need to be established in larger clinical trials. The field of acute revascularization is rapidly evolving, and various combinations of pharmacologic agents, mechanical devices, and novel microbubble/ultrasound technologies are being tested in multiple clinical trials. PMID:20798838

Emtricitabine: a once-daily nucleoside reverse transcriptase inhibitor.

PubMed

Modrzejewski, Krysten A; Herman, Ronald A

2004-06-01

To review the pharmacology, virology, pharmacokinetics, safety, and efficacy of the nucleoside reverse transcriptase inhibitor (NRTI) emtricitabine. English-language reports were accessed using MEDLINE (1966-June 2003) and the Iowa Drug Information Service database (1966-June 2003) using emtricitabine and Coviracil as key words. (Coviracil was the proposed trade name for the product prior to approval.) The Internet was also searched using the terms HIV/AIDS conferences, then emtricitabine within the conference proceedings. Abstracts, posters, and oral presentations from scientific conferences, both published and unpublished, were included. Preference was given to published controlled trials. Studies providing a description of the pharmacology, virology, effectiveness, safety, or pharmacokinetics of emtricitabine were used in this review. Emtricitabine is an NRTI used to treat HIV-1 infection. Once-daily administration can decrease pill burden and potentially increase adherence to multidrug HIV therapy. Further, emtricitabine has shown equivalent or improved outcomes compared with lamivudine and stavudine. Emtricitabine is a safe and effective option for HIV-1 infection in adults as part of a multidrug regimen. It may be a better alternative than lamivudine for once-daily therapy because of its extended intracellular half-life and better than lamivudine and stavudine because of a possibly decreased potential for drug resistance.

Misoprostol for tinnitus.

PubMed

Crinnion, C L; McCart, G M

1995-01-01

Practitioners should realize that further study of misoprostol in larger patient populations must be undertaken to determine its efficacy and safety in the treatment of tinnitus. Previous approaches to treating tinnitus have included carbamazepine, phenytoin, lidocaine, tocainide, flecainide acetate, alprazolam, and nortriptyline. Studies using lidocaine, nortriptyline, or alprazolam have shown encouraging results. The relative contribution of misoprostol remains to be seen; however, it may offer a new treatment option to patients who have experienced adverse effects or have contraindications to the pharmacologic agents currently available.

Single dose pharmacokinetics, pharmacodynamics, tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein.

PubMed

Boettcher, Michael-Friedrich; Heinig, Roland; Schmeck, Carsten; Kohlsdorfer, Christian; Ludwig, Matthias; Schaefer, Anja; Gelfert-Peukert, Sabine; Wensing, Georg; Weber, Olaf

2012-02-01

To determine pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of BAY 60-5521, a potent inhibitor of cholesteryl ester transfer protein (CETP). The first in man (FIM) study investigated the safety, tolerability, pharmacodynamics and pharmacokinetics in healthy male subjects following administration of single oral doses. The study was performed using a randomized, single-blind, placebo-controlled, single dose-escalation design. Thirty-eight young healthy male subjects (aged 20-45 years) received an oral dose of 5, 12.5, 25 or 50 mg BAY 60-5521 (n= 28) or were treated with a placebo (n= 10). In all four dose steps, only one adverse event (25 mg; mild skin rash) was considered drug related. Clinical laboratory parameters showed no clinically relevant changes. A clear dose-dependent CETP inhibition could be demonstrated starting at a dose of 5 mg. At a dose of 25 mg, a CETP inhibition >50% over 18 h was observed. After 50 mg, CETP inhibition >50% lasted more than 50 h. Twenty-four h after administration mean HDL-C-values showed a nearly dose-proportional increase. Following administration of 50 mg, a significant HDL-C increase of about 30% relative to baseline values was found. BAY 60-5521 was slowly absorbed reaching maximum concentrations in plasma after 4 to 6 h. The disposition in plasma was multi-exponential with an estimated mean terminal half-life of 76 to 144 h. BAY 60-5521 was clinically safe and well tolerated. No effects on heart rate, blood pressure and ECG recordings were observed during the study. A clear pharmacodynamic effect on CETP inhibition and HDL could be demonstrated. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Systematic review for geo-authentic Lonicerae Japonicae Flos.

PubMed

Yang, Xingyue; Liu, Yali; Hou, Aijuan; Yang, Yang; Tian, Xin; He, Liyun

2017-06-01

In traditional Chinese medicine, Lonicerae Japonicae Flos is commonly used as anti-inflammatory, antiviral, and antipyretic herbal medicine, and geo-authentic herbs are believed to present the highest quality among all samples from different regions. To discuss the current situation and trend of geo-authentic Lonicerae Japonicae Flos, we searched Chinese Biomedicine Literature Database, Chinese Journal Full-text Database, Chinese Scientific Journal Full-text Database, Cochrane Central Register of Controlled Trials, Wanfang, and PubMed. We investigated all studies up to November 2015 pertaining to quality assessment, discrimination, pharmacological effects, planting or processing, or ecological system of geo-authentic Lonicerae Japonicae Flos. Sixty-five studies mainly discussing about chemical fingerprint, component analysis, planting and processing, discrimination between varieties, ecological system, pharmacological effects, and safety were systematically reviewed. By analyzing these studies, we found that the key points of geo-authentic Lonicerae Japonicae Flos research were quality and application. Further studies should focus on improving the quality by selecting the more superior of all varieties and evaluating clinical effectiveness.

Pharmacological and clinical profile of bivalirudin in the treatment of patients with acute coronary syndrome.

PubMed

White, Harvey D

2009-05-01

Bivalirudin is a direct thrombin inhibitor with several pharmacological advantages over heparin. It has been studied extensively in non-ST elevation acute 60 coronary syndromes (NSTE-ACS) and in percutaneous coronary intervention. Bivalirudin has also recently been investigated in patients with ST-elevation myocardial infarction (STEMI) treated with primary angioplasty and stenting. More than 27,000 patients were randomized in these trials. To provide an overview of the pharmacological properties of bivalirudin and its efficacy and safety profile in patients across the spectrum of acute coronary syndromes (ACS). All published, peer-reviewed clinical trials were reviewed and as relevant were included. Bivalirudin with provisional IIb/IIIa antagonists provides consistent results across the full spectrum of ACS, with similar or non-inferior protection from ischemic events and significantly reduces bleeding complications compared with heparin and IIb/IIIa antagonists. In STEMI, mortality at 30 days and 1 year is significantly reduced. The unique pharmacokinetic profile of bivalirudin allows for simultaneous reductions in both ischemic and hemorrhagic events and makes it an appropriate alternative to heparin.

New developments in diagnosis and treatment update: Schizophrenia/first episode psychosis in children and adolescents.

PubMed

Lachman, Anusha

2014-01-01

Childhood onset schizophrenia (COS) is diagnosed before the age of 13 years, and early onset schizophrenia (EOS) is diagnosed before the age of 18 years. EOS is considered extremely rare and its prevalence in comparison to the worldwide prevalence of schizophrenia (1%) has not adequately been studied. Patients who experience the first episode of psychosis need to be treated early and optimally to lessen the morbidity and improve the outcome of the illness. Treatment needs to be a combination of both pharmacological and non-pharmacological modalities. Pharmacological intervention is necessary for remission, improvement of positive symptoms and to aid with the efficacy of psychosocial interventions. There is a lack of efficacy and safety data of the use of antipsychotic medication in children, with most of the information available being extrapolations of adult data. An increased use of atypical antipsychotic drugs in the treatment of EOS has been accompanied by growing concern about the appropriate use and associated side effects in children and adolescents. This update highlights new developments, concepts and treatment trends in EOS.

Drugs for the treatment of pediatric type 2 diabetes mellitus and related co-morbidities.

PubMed

Tabatabaei-Malazy, Ozra; Nikfar, Shekoufeh; Larijani, Bagher; Abdollahi, Mohammad

2016-12-01

The continuing global epidemic of obesity in adolescents has raised the prevalence of type 2 diabetes mellitus (T2DM). Despite the wealth of information concerning T2DM in adults, rare data are available targeting treatment of T2DM in pediatric. Areas covered: This article has reviewed clinical practice guidelines, particularly the American Diabetes Association and the Pediatric Endocrine Society consensus, jointly with clinical trial data available in databases with respect to the use of available pharmacological options to treat T2DM and its complications in youth. Expert opinion: The use of other pharmacological treatments of T2DM in addition to metformin and insulin entails several problems. Since rare studies have been conducted on the medications available to manage T2DM in children, treating them may be more difficult than that of adults. It needs longer and larger size clinical trials along with better pharmacological agents to affect various pathophysiological mechanisms of diabetes. Meanwhile, the efficacy and safety of combinations therapies should be completed in preclinical and clinical phases.

Novel, broad-spectrum anticonvulsants containing a sulfamide group: pharmacological properties of (S)-N-[(6-chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112).

PubMed

McComsey, David F; Smith-Swintosky, Virginia L; Parker, Michael H; Brenneman, Douglas E; Malatynska, Ewa; White, H Steve; Klein, Brian D; Wilcox, Karen S; Milewski, Michael E; Herb, Mark; Finley, Michael F A; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B; Maryanoff, Bruce E

2013-11-27

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such "neurostabilizers" have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4-9, 10a-i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically induced, and chemically induced seizures. Mechanistically, 4 inhibited voltage-gated Na(+) channels and N-type Ca(2+) channels and was effective as a K(+) channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies.

Novel, Broad-Spectrum Anticonvulsants Containing a Sulfamide Group: Pharmacological Properties of (S)-N-[(6-Chloro-2,3-dihydrobenzo[1,4]dioxin-2-yl)methyl]sulfamide (JNJ-26489112)

PubMed Central

McComsey, David F.; Smith-Swintosky, Virginia L.; Parker, Michael H.; Brenneman, Douglas E.; Malatynska, Ewa; White, H. Steve; Klein, Brian D.; Wilcox, Karen S.; Milewski, Michael E.; Herb, Mark; Finley, Michael F. A.; Liu, Yi; Lubin, Mary Lou; Qin, Ning; Reitz, Allen B.; Maryanoff, Bruce E.

2014-01-01

Broad-spectrum anticonvulsants are of considerable interest as antiepileptic drugs, especially because of their potential for treating refractory patients. Such “neurostabilizers” have also been used to treat other neurological disorders, including migraine, bipolar disorder, and neuropathic pain. We synthesized a series of sulfamide derivatives (4–9, 10a–i, 11a, 11b, 12) and evaluated their anticonvulsant activity. Thus, we identified promising sulfamide 4 (JNJ-26489112) and explored its pharmacological properties. Compound 4 exhibited excellent anticonvulsant activity in rodents against audiogenic, electrically-induced, and chemically-induced seizures. Mechanistically, 4 inhibited voltage-gated Na+ channels and N-type Ca2+ channels, and was effective as a K+ channel opener. The anticonvulsant profile of 4 suggests that it may be useful for treating multiple forms of epilepsy (generalized tonic-clonic, complex partial, absence seizures), including refractory (or pharmacoresistant) epilepsy, at dose levels that confer a good safety margin. On the basis of its pharmacology and other favorable characteristics, 4 was advanced into human clinical studies. PMID:24205976

[Pharmacokinetic alterations in pregnancy and use of therapeutic drug monitoring].

PubMed

Panchaud, Alice; Weisskopf, Etienne; Winterfeld, Ursula; Baud, David; Guidi, Monia; Eap, Chin B; Csajka, Chantal; Widmer, Nicolas

2014-01-01

Following the thalidomide tragedy, pharmacological research in pregnant women focused primarily on drug safety for the unborn child and remains only limited regarding the efficacy and safety of treatment for the mother. Significant physiological changes during pregnancy may yet affect the pharmacokinetics of drugs and thus compromise its efficacy and/or safety. Therapeutic drug monitoring (TDM) would maximize the potential effectiveness of treatments, while minimizing the potential risk of toxicity for the mother and the fetus. At present, because of the lack of concentration-response relationship studies in pregnant women, TDM can rely only on individual assessment (based on an effective concentration before pregnancy) and remains reserved only to unexpected situations such as signs of toxicity or unexplained inefficiency. © 2014 Société Française de Pharmacologie et de Thérapeutique.

Pharmacological management of obesity in pediatric patients.

PubMed

Boland, Cassie L; Harris, John Brock; Harris, Kira B

2015-02-01

To review current evidence of pharmacological options for managing pediatric obesity and provide potential areas for future research. A MEDLINE search (1966 to October 2014) was conducted using the following keywords: exenatide, liraglutide, lorcaserin, metformin, obesity, orlistat, pediatric, phentermine, pramlintide, topiramate, weight loss, and zonisamide. Identified articles were evaluated for inclusion, with priority given to randomized controlled trials with orlistat, metformin, glucagon-like peptide-1 agonists, topiramate, and zonisamide in human subjects and articles written in English. References were also reviewed for additional trials. Whereas lifestyle modification is considered first-line therapy for obese pediatric patients, severe obesity may benefit from pharmacotherapy. Orlistat is the only Food and Drug Administration (FDA)-approved medication for pediatric obesity and reduced body mass index (BMI) by 0.5 to 4 kg/m(2), but gastrointestinal (GI) adverse effects may limit use. Metformin has demonstrated BMI reductions of 0.17 to 1.8 kg/m(2), with mild GI adverse effects usually managed with dose titration. Exenatide reduced BMI by 1.1 to 1.7 kg/m(2) and was well-tolerated with mostly transient or mild GI adverse effects. Topiramate and zonisamide reduced weight when used in the treatment of epilepsy. Future studies should examine efficacy and safety of pharmacological agents in addition to lifestyle modifications for pediatric obesity. Lifestyle interventions remain the treatment of choice in pediatric obesity, but concomitant pharmacotherapy may be beneficial in some patients. Orlistat should be considered as second-line therapy for pediatric obesity. Evidence suggests that other diabetes and antiepileptic medications may also provide weight-loss benefits, but safety should be further evaluated. © The Author(s) 2014.

Clinical efficacy and safety of imepitoin in comparison with phenobarbital for the control of idiopathic epilepsy in dogs.

PubMed

Tipold, A; Keefe, T J; Löscher, W; Rundfeldt, C; de Vries, F

2015-04-01

The anticonvulsant activity and safety of imepitoin, a novel antiepileptic drug licensed in the European Union, were evaluated in a multicentre field efficacy study as well as in a safety study under laboratory conditions. Efficacy of imepitoin was compared with phenobarbital in 226 client-owned dogs in a blinded parallel group design. The administration of imepitoin twice daily in incremental doses of 10, 20 or 30 mg/kg demonstrated comparable efficacy to phenobarbital in controlling seizures in dogs. The frequency of adverse events including somnolence/sedation, polydipsia and increased appetite was significantly higher in the phenobarbital group. In phenobarbital-treated dogs, significantly increased levels of alkaline phosphatase, gamma-glutamyl-transferase and other liver enzymes occurred, while no such effect was observed in the imepitoin group. In a safety study under laboratory conditions, healthy beagle dogs were administered 0, 30, 90 or 150 mg/kg imepitoin twice daily for 26 weeks. A complete safety evaluation including histopathology was included in the study. A no-observed-adverse-event level of 90 mg/kg twice daily was determined. These results indicate that imepitoin is a potent and safe antiepileptic drug for dogs. © 2014 The Authors. Journal of Veterinary Pharmacology and Therapeutics Published by John Wiley & Sons Ltd.

Lippia javanica (Burm.f.) Spreng.: Traditional and Commercial Uses and Phytochemical and Pharmacological Significance in the African and Indian Subcontinent

PubMed Central

2017-01-01

Lippia javanica occurs naturally in central, eastern, and southern Africa and has also been recorded in the tropical Indian subcontinent. The potential of L. javanica as herbal or recreational tea and herbal medicine and its associated phytochemistry and biological properties are reviewed. The extensive literature survey revealed that L. javanica is used as herbal tea and has ethnomedicinal applications such as in colds, cough, fever, malaria, wounds, diarrhoea, chest pains, bronchitis, and asthma. Multiple classes of phytochemicals including volatile and nonvolatile secondary metabolites such as alkaloids, amino acids, flavonoids, iridoids, and triterpenes as well as several minerals have been identified from L. javanica. Scientific studies on L. javanica indicate that it has a wide range of pharmacological activities which include anticancer, antiamoebic, antidiabetic, antimalarial, antimicrobial, antioxidant, antiplasmodial, and pesticidal effects. Although many of the traditional uses of L. javanica have been validated by phytochemical and pharmacological studies, there are still some gaps where current knowledge could be improved. Lippia javanica is popular as both herbal and recreational tea, but there is need for more precise studies to evaluate the safety and clinical value of its main active crude and pure compounds and to clarify their mechanisms of action. PMID:28115974

21 CFR 5.1100 - Headquarters.

Code of Federal Regulations, 2011 CFR

2011-04-01

... Laboratories Complex Staff. Division of Engineering Services. Environment, Safety And Strategic Initiatives.... Office of Cellular, Tissue, and Gene Therapies. Regulatory Management Staff. Division of Cellular and Gene Therapies. Division of Clinical Evaluation and Pharmacology/Toxicology. Division of Human Tissues...

Pharmacological and toxicological assessment of innovative self-assembled polymeric micelles as powders for insulin pulmonary delivery.

PubMed

Andrade, Fernanda; Fonte, Pedro; Costa, Ana; Reis, Cassilda Cunha; Nunes, Rute; Almeida, Andreia; Ferreira, Domingos; Oliva, Mireia; Sarmento, Bruno

2016-09-01

Explore the use of polymeric micelles in the development of powders intended for pulmonary delivery of biopharmaceuticals, using insulin as a model protein. Formulations were assessed in vitro for aerosolization properties and in vivo for efficacy and safety using a streptozotocin-induced diabetic rat model. Powders presented good aerosolization properties like fine particle fraction superior to 40% and a mass median aerodynamic diameter inferior of 6 μm. Endotracheally instilled powders have shown a faster onset of action than subcutaneous administration of insulin at a dose of 10 IU/kg, with pharmacological availabilities up to 32.5% of those achieved by subcutaneous route. Additionally, micelles improved the hypoglycemic effect of insulin. Bronchoalveolar lavage screening for toxicity markers (e.g., lactate dehydrogenase, cytokines) revealed no signs of lung inflammation and cytotoxicity 14 days postadministration. Developed powders showed promising safety and efficacy characteristics for the systemic delivery of insulin by pulmonary administration.

Randomized comparison of renal denervation versus intensified pharmacotherapy including spironolactone in true-resistant hypertension: six-month results from the Prague-15 study.

PubMed

Rosa, Ján; Widimský, Petr; Toušek, Petr; Petrák, Ondřej; Čurila, Karol; Waldauf, Petr; Bednář, František; Zelinka, Tomáš; Holaj, Robert; Štrauch, Branislav; Šomlóová, Zuzana; Táborský, Miloš; Václavík, Jan; Kociánová, Eva; Branny, Marian; Nykl, Igor; Jiravský, Otakar; Widimský, Jiří

2015-02-01

This prospective, randomized, open-label multicenter trial evaluated the efficacy of catheter-based renal denervation (Symplicity, Medtronic) versus intensified pharmacological treatment including spironolactone (if tolerated) in patients with true-resistant hypertension. This was confirmed by 24-hour ambulatory blood pressure monitoring after excluding secondary hypertension and confirmation of adherence to therapy by measurement of plasma antihypertensive drug levels before enrollment. One-hundred six patients were randomized to renal denervation (n=52), or intensified pharmacological treatment (n=54) with baseline systolic blood pressure of 159±17 and 155±17 mm Hg and average number of drugs 5.1 and 5.4, respectively. A significant reduction in 24-hour average systolic blood pressure after 6 months (-8.6 [95% cofidence interval: -11.8, -5.3] mm Hg; P<0.001 in renal denervation versus -8.1 [95% cofidence interval: -12.7, -3.4] mm Hg; P=0.001 in pharmacological group) was observed, which was comparable in both groups. Similarly, a significant reduction in systolic office blood pressure (-12.4 [95% cofidence interval: -17.0, -7.8] mm Hg; P<0.001 in renal denervation versus -14.3 [95% cofidence interval: -19.7, -8.9] mm Hg; P<0.001 in pharmacological group) was present. Between-group differences in change were not significant. The average number of antihypertensive drugs used after 6 months was significantly higher in the pharmacological group (+0.3 drugs; P<0.001). A significant increase in serum creatinine and a parallel decrease of creatinine clearance were observed in the pharmacological group; between-group difference were borderline significant. The 6-month results of this study confirmed the safety of renal denervation. In conclusion, renal denervation achieved reduction of blood pressure comparable with intensified pharmacotherapy. © 2014 American Heart Association, Inc.

Leveraging Big Data in Pediatric Development Programs: Proceedings From the 2016 American College of Clinical Pharmacology Annual Meeting Symposium.

PubMed

Mulugeta, Lily Yeruk; Yao, Lynne; Mould, Diane; Jacobs, Brian; Florian, Jeffrey; Smith, Brian; Sinha, Vikram; Barrett, Jeffrey S

2018-01-10

This article discusses the use of big data in pediatric drug development. The article covers key topics discussed at the ACCP annual meeting symposium in 2016 including the extent to which big data or real-world data can inform clinical trial design and substitute for efficacy and safety data typically obtained in clinical trials. The current states of use, opportunities, and challenges with the use of big data in future pediatric drug development are discussed. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Medicinal Uses, Phytochemistry, and Pharmacology of Origanum onites (L.): A Review.

PubMed

Tepe, Bektas; Cakir, Ahmet; Sihoglu Tepe, Arzuhan

2016-05-01

Origanum onites L., known as Turkish oregano, has great traditional, medicinal, preservative, and commercial importance. It is used for the treatment of several kinds of ailments, such as gastrointestinal disorders, diabetes, high cholesterol, leukemia, bronchitis, etc. In this review, traditional use, phytochemistry, and pharmacology of O. onites reported between 1988 and 2014 were discussed. This review was prepared based on literature survey on scientific journals and books from libraries and electronic sources, such as Web of Science, PubMed, Scopus, Google Scholar, etc. All databases were searched up to June 2014. Several different classes of terpenoids, triterpene acids, phenolic acids, hydroquinones, flavonoids, hydrocarbons, sterols, pigments, fatty acids, tocopherols, and inorganic compounds were detected mainly in the aerial parts of this plant. Pharmacological studies revealed that extracts obtained from several solvents and individual compounds exhibited antimicrobial, antiviral, antioxidant, insecticidal, anticancer, hepatoprotective, genotoxic, antidiabetic, cholinesterase inhibitory, anti-inflammatory, analgesic activities, etc. O. onites, in general, exhibited remarkable activity potential in almost all test systems. The results of toxicity studies indicated that O. onites did not show any significant toxicity and mutagenicity on Drosophila and Salmonella. Toxicity of the extracts/essential oils and also individual compounds should be evaluated on mammalian cells to ensure their safety. The bioactivity of individual compounds aside from terpenoids should also be assessed in detail. Additionally, mode of action for the bioactive compounds should be evaluated to understand the complex pharmacological effects of these phytochemicals. © 2016 Verlag Helvetica Chimica Acta AG, Zürich.

Improving the Pharmacologic Management of Pain in Older Adults: Identifying the Research Gaps and Methods to Address Them

PubMed Central

Reid, M. C.; Bennett, David A.; Chen, Wen G.; Eldadah, Basil A.; Farrar, John T.; Ferrell, Bruce; Gallagher, Rollin M.; Hanlon, Joseph T.; Herr, Keela; Horn, Susan D.; Inturrisi, Charles E.; Lemtouni, Salma; Lin, Yu Woody; Michaud, Kaleb; Morrison, R. Sean; Neogi, Tuhina; Porter, Linda L.; Solomon, Daniel H.; Von Korff, Michael; Weiss, Karen; Witter, James; Zacharoff, Kevin L.

2011-01-01

Objective There has been a growing recognition of the need for better pharmacologic management of chronic pain among older adults. To address this need, the National Institutes of Health Pain Consortium sponsored an “Expert Panel Discussion on the Pharmacological Management of Chronic Pain in Older Adults” conference in September, 2010, to identify research gaps and strategies to address them. Specific emphasis was placed on ascertaining gaps regarding use of opioid and non-steroidal anti-inflammatory medications because of continued uncertainties regarding their risks and benefits. Design Eighteen panel members provided oral presentations; each was followed by a multidisciplinary panel discussion. Meeting transcripts and panelists’ slide presentations were reviewed to identify the gaps, and the types of studies and research methods panelists suggested could best address them. Results Fifteen gaps were identified in the areas of treatment(e.g., uncertainty regarding the long-term safety and efficacy of commonly prescribed analgesics), epidemiology (e.g., lack of knowledge regarding the course of common pain syndromes), and implementation(e.g., limited understanding of optimal strategies to translate evidence-based pain treatments into practice). Analyses of data from electronic health care databases, observational cohort studies, and ongoing cohort studies (augmented with pain and other relevant outcomes measures) were felt to be practical methods for building an age-appropriate evidence base to improve the pharmacologic management of pain in later life. Conclusions Addressing the gaps presented in the current report was judged by the panel to have substantial potential to improve the health and well being of older adults with chronic pain. PMID:21834914

The Neuropsychopharmacology of Pathological Gambling.

PubMed

Zakeri, Kourosh; Potenza, Marc N

2012-02-01

Pathological gambling (PG) is an impulse control disorder with prevalence estimates in the range of 0.2-2% in the general population. PG can significantly impact one's ability to function as it may negatively influence social, financial, and occupational aspects of life. Historically, PG has received relatively little attention from researchers and clinicians, and few treatments, particularly pharmacological, have been both validated and widely employed. Given the clinical relevance of PG, it is important that researchers examine pharmacological and behavioral treatments for their safety and efficacy and that clinicians use empirically validated therapies. Multiple neurochemicals, including serotonin, dopamine, norepinephrine, and opioids, and related neurocircuitry, particularly ventral cortico-striatal pathways, have been implicated in PG. The neurobiological rationale for therapies, particularly pharmacological ones, is reviewed with a perspective on the generation of improved prevention and treatment strategies for PG.

Aerospace Medicine and Biology: A continuing bibliography, supplement 216

NASA Technical Reports Server (NTRS)

1981-01-01

One hundred twenty reports, articles, and other documents introduced into the NASA scientific and technical information system in January 1981 are listed. Topics include: sanitary problems; pharmacology; toxicology; safety and survival; life support systems; exobiology; and personnel factors.

The Challenges of Treating Sciatica Pain in Older Adults.

PubMed

Ferreira, Manuela L; McLachlan, Andrew

2016-11-01

Sciatica is a debilitating condition affecting approximately 25 % of the population. Typically, the patient will complain of lower limb pain that is more severe than pain in the lower back, usually accompanied by numbness and motor weakness. Most international guidelines recommend pharmacological management for the pain relief of sciatica, including paracetamol, non-steroidal anti-inflammatory drugs, opioid analgesics, anticonvulsants, and corticosteroids, among others. However, the evidence for most of these pharmacological options is scarce, and the majority of clinical trials exclude older patients. There is overall very limited information on the efficacy, safety, and tolerability of these medicines in older patients with sciatica. This review presents a critical appraisal of the existing evidence for the pharmacological treatment of sciatica, with a special focus on the older adult. The age-related changes in the health of older patients, as well as their impact on the response to pharmacological treatment, including polypharmacy, drug interactions, and drug-disease interactions, is also discussed.

Defining Desirable Central Nervous System Drug Space through the Alignment of Molecular Properties, in Vitro ADME, and Safety Attributes

PubMed Central

2010-01-01

As part of our effort to increase survival of drug candidates and to move our medicinal chemistry design to higher probability space for success in the Neuroscience therapeutic area, we embarked on a detailed study of the property space for a collection of central nervous system (CNS) molecules. We carried out a thorough analysis of properties for 119 marketed CNS drugs and a set of 108 Pfizer CNS candidates. In particular, we focused on understanding the relationships between physicochemical properties, in vitro ADME (absorption, distribution, metabolism, and elimination) attributes, primary pharmacology binding efficiencies, and in vitro safety data for these two sets of compounds. This scholarship provides guidance for the design of CNS molecules in a property space with increased probability of success and may lead to the identification of druglike candidates with favorable safety profiles that can successfully test hypotheses in the clinic. PMID:22778836

Fesoterodine: Pharmacological properties and clinical implications.

PubMed

Gamé, Xavier; Peyronnet, Benoit; Cornu, Jean-Nicolas

2018-05-24

Fesoterodine (as one of three drugs: dutasteride, finasteride and fesoterodine) was classified B (beneficial) by LUTS-FORTA 2014, indicating that it is a medicinal product with proven or obvious efficacy in the elderly, with limited side effects and/or safety concerns. A systematic literature review was undertaken in January 2018 using the PubMed and Google Scholar databases with the following individual and combined keywords: "fesoterodine", "pharmacology", "overactive bladder" and "antimuscarinics". The aim of the review was to determine which of fesoterodine's pharmacological properties explains its clinical benefits in general patient populations with OAB and the elderly in particular. The articles in the results were then selected by publication language (English and French only), methodology (off-topic studies, reported cases and literature reviews were excluded), relevance to the subject matter and publication date prior to 31 January 2018. A total of 205 articles was initially obtained, with 115 read and 45 selected. It appears that the association of four pharmacological properties specific to fesoterodine can explain that this drug has a good balance between efficacy and tolerability. These properties are namely the drug's high and nearly equal affinity for both the M2 and M3 muscarinic receptors, poor penetration of the blood-brain barrier, lack of hepatic first-pass activation -fesoterodine being rapidly and extensively converted to its active metabolite, 5-hydroxymethyl tolterodine, by ubiquitous esterases-, and its extended-release formulation. Fesoterodine's pharmacological profile is optimal for the treatment of overactive bladder. It is now recognized as one of the leading first-line treatment for this indication. Copyright © 2018 Elsevier B.V. All rights reserved.

Generalizability of Clinical Trial Results for Adolescent Major Depressive Disorder.

PubMed

Blanco, Carlos; Hoertel, Nicolas; Franco, Silvia; Olfson, Mark; He, Jian-Ping; López, Saioa; González-Pinto, Ana; Limosin, Frédéric; Merikangas, Kathleen R

2017-12-01

Although there have been a number of clinical trials evaluating treatments for adolescents with major depressive disorder (MDD), the generalizability of those trials to samples of depressed adolescents who present for routine clinical care is unknown. Examining the generalizability of clinical trials of pharmacological and psychotherapy interventions for adolescent depression can help administrators and frontline practitioners determine the relevance of these studies for their patients and may also guide eligibility criteria for future clinical trials in this clinical population. Data on nationally representative adolescents were derived from the National Comorbidity Survey: Adolescent Supplement. To assess the generalizability of adolescent clinical trials for MDD, we applied a standard set of eligibility criteria representative of clinical trials to all adolescents in the National Comorbidity Survey: Adolescent Supplement with a Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD ( N = 592). From the overall MDD sample, 61.9% would have been excluded from a typical pharmacological trial, whereas 42.2% would have been excluded from a psychotherapy trial. Among those who sought treatment ( n = 412), the corresponding exclusion rates were 72.7% for a pharmacological trial and 52.2% for a psychotherapy trial. The criterion leading to the largest number of exclusions was "significant risk of suicide" in both pharmacological and psychotherapy trials. Pharmacological and, to a lesser extent, psychotherapy clinical trials likely exclude most adolescents with MDD. Careful consideration should be given to balancing eligibility criteria and internal validity with applicability in routine clinical care while ensuring patient safety. Copyright © 2017 by the American Academy of Pediatrics.

Novel pharmacological targets for the rhythm control management of atrial fibrillation.

PubMed

Burashnikov, Alexander; Antzelevitch, Charles

2011-12-01

Atrial fibrillation (AF) is a growing clinical problem associated with increased morbidity and mortality. Development of safe and effective pharmacological treatments for AF is one of the greatest unmet medical needs facing our society. In spite of significant progress in non-pharmacological AF treatments (largely due to the use of catheter ablation techniques), anti-arrhythmic agents (AADs) remain first line therapy for rhythm control management of AF for most AF patients. When considering efficacy, safety and tolerability, currently available AADs for rhythm control of AF are less than optimal. Ion channel inhibition remains the principal strategy for termination of AF and prevention of its recurrence. Practical clinical experience indicates that multi-ion channel blockers are generally more optimal for rhythm control of AF compared to ion channel-selective blockers. Recent studies suggest that atrial-selective sodium channel block can lead to safe and effective suppression of AF and that concurrent inhibition of potassium ion channels may potentiate this effect. An important limitation of the ion channel block approach for AF treatment is that non-electrical factors (largely structural remodeling) may importantly determine the generation of AF, so that "upstream therapy", aimed at preventing or reversing structural remodeling, may be required for effective rhythm control management. This review focuses on novel pharmacological targets for the rhythm control management of AF. Copyright © 2011 Elsevier Inc. All rights reserved.

Pharmacology and safety of glycerol phenylbutyrate in healthy adults and adults with cirrhosis.

PubMed

McGuire, Brendan M; Zupanets, Igor A; Lowe, Mark E; Xiao, Xunjun; Syplyviy, Vasyliy A; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F

2010-06-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted.

Pharmacology and Safety of Glycerol Phenylbutyrate in Healthy Adults and Adults with Cirrhosis

PubMed Central

MCGuire, Brendan M.; Zupanets, Igor A.; Lowe, Mark E.; Xiao, Xunjun; Syplyviy, Vasyliy A.; Monteleone, Jon; Gargosky, Sharron; Dickinson, Klara; Martinez, Antonia; Mokhtarani, Masoud; Scharschmidt, Bruce F.

2013-01-01

Phenylbutyric acid (PBA), which is approved for treatment of urea cycle disorders (UCDs) as sodium phenylbutyrate (NaPBA), mediates waste nitrogen excretion via combination of PBA-derived phenylacetic acid with glutamine to form phenylactylglutamine (PAGN) that is excreted in urine. Glycerol phenylbutyrate (GPB), a liquid triglyceride pro-drug of PBA, containing no sodium and having favorable palatability, is being studied for treatment of hepatic encephalopathy (HE). In vitro and clinical studies have been performed to assess GPB digestion, safety, and pharmacology in healthy adults and individuals with cirrhosis. GPB hydrolysis was measured in vitro by way of pH titration. Twenty-four healthy adults underwent single-dose administration of GPB and NaPBA and eight healthy adults and 24 cirrhotic subjects underwent single-day and multiple-day dosing of GPB, with metabolites measured in blood and urine. Simulations were performed to assess GPB dosing at higher levels. GPB was hydrolyzed by human pancreatic triglyceride lipase, pancreatic lipase-related protein 2, and carboxyl-ester lipase. Clinical safety was satisfactory. Compared with NaPBA, peak metabolite blood levels with GPB occurred later and were lower; urinary PAGN excretion was similar but took longer. Steady state was achieved within 4 days for both NaPBA and GPB; intact GPB was not detected in blood or urine. Cirrhotic subjects converted GPB to PAGN similarly to healthy adults. Simulations suggest that GPB can be administered safely to cirrhotic subjects at levels equivalent to the highest approved NaPBA dose for UCDs. Conclusion GPB exhibits delayed release characteristics, presumably reflecting gradual PBA release by pancreatic lipases, and is well tolerated in adults with cirrhosis, suggesting that further clinical testing for HE is warranted. PMID:20512995

Functional Observational Battery Testing for Nervous System Effects of Drugs and Other Chemicals

EPA Science Inventory

Screening for behavioral toxicity, or neurotoxicity, has become standard practice in preclinical safety pharmacology and toxicology. Behavior represents the integrated sum of activities mediated by the nervous system. Current screening batteries, such as the functional observat...

[Non-Pharmacological Interventions for Pregnancy-Related Sleep Disturbances].

PubMed

Hung, Hsuan-Man; Chiang, Hsiao-Ching

2017-02-01

Most women experience the worse sleep quality of their life during pregnancy and the early postpartum period. Although pregnancy typically accounts for a relatively short part of a woman's life, the related sleep disturbances may have a significant and negative impact on her long-term health. Approximately 78-80% of pregnant women experience sleep disturbances, including interruptions in deep sleep, decreased total sleep time, poor subjective sleep quality, frequent night waking, and reduced sleep efficacy. Sleep disturbances during pregnancy start during the first trimester and become prevalent during the third trimester. Related factors include physiological and psychosocial changes and an unhealthy lifestyle. As non-pharmacological interventions have the potential to improve sleep quality in 70% to 80% of patients with insomnia, this is the main approached that is currently used to treat pregnancy-related sleep disturbances. Examples of these non-pharmacological interventions include music therapy, aerobic exercise, massage, progressive muscle relaxation, multi-modal interventions, and the use of a maternity support belt. The efficacy and safety of other related non-pharmacological interventions such as auricular acupressure, cognitive therapy, tai chi, and aromatherapy remain uncertain, with more empirical research required. Additionally, non-pharmacological interventions do not effectively treat sleep disturbances in all pregnant women.

A comprehensive review of plants and their active constituents with wound healing activity in traditional Iranian medicine.

PubMed

Hosein Farzaei, Mohammad; Abbasabadi, Zahra; Reza Shams-Ardekani, Mohammad; Abdollahi, Mohammad; Rahimi, Roja

2014-07-01

Wound healing is a complex cascade of events with various cellular and biochemical processes that result in reconstruction and regeneration of damaged tissue. The objective of the current study was to scientifically evaluate the medicinal plants said to produce wound healing activity in traditional Iranian medicine (TIM). Electronic databases were searched for the names of medicinal plants claimed in TIM literature for having wound healing activity. Articles were evaluated to obtain any in vitro, animal, or clinical evidence of their efficacy and possible mechanisms involved in would healing. Mechanisms of action for some of these plants, including Tamarix spp., Rosa spp., Piper betle, Plantago major, Oxalis spp., Olea europaea, Malva spp., Linum usitatissimum, and Tamarindus indica, have not been yet clarified. In contrast, some herbs such as Vitis vinifera, Quercus spp., Punica granatum, Pinus spp., Polygonum spp., Lilium spp., Gentiana lutea, Arnebia euchroma, Aloe spp., and Caesalpinia spp. have various biological and pharmacological mechanisms that have been verified for wound healing activity. Overall, TIM resources have introduced various medicinal plants for wounds with confirmed effectiveness according to current pharmacological studies. These herbal remedies could be considered as future drugs for healing of wounds. Further pharmacological and clinical investigations are recommended for exploring safety, exact mechanisms, and efficacy of these herbal remedies. .

An update on the safety of nutraceuticals and effects on lipid parameters.

PubMed

Cicero, Arrigo F G; Colletti, Alessandro

2018-03-01

Cardiovascular diseases (CVDs) are the leading cause of mortality and disability in developed countries, whereas a large portion of patients in primary prevention have uncontrolled level of CVD risk factors. Dietary supplementation with bioactive natural compounds with demonstrated lipid-lowering effects is currently supported by the international guidelines for CVD prevention and some international expert panels. Areas covered: This review provides insights on issues concerning the tolerability and safety of the most commonly used nutraceuticals with demonstrated lipid-lowering effect in humans. They will be then divided into three main categories according to their mechanism of action (cholesterol synthesis inhibitors, intestinal cholesterol absorption inhibitors, and LDL-C excretion stimulants) and their pharmacological profile will be discussed. Expert opinion: A growing body of preclinical, epidemiological and clinical evidence has defined the tolerability and safety profile of the most commonly used lipid-lowering nutraceuticals. In the most part of cases, the side effects are mild and reversible. However, detailed knowledge of specific health risks and pharmacological interactions for each individual compound is needed for the management of frail patients, such as children, elderly, patients with liver or renal failure, and patients consuming numerous drugs.

Interventions for treating constipation in pregnancy.

PubMed

Rungsiprakarn, Phassawan; Laopaiboon, Malinee; Sangkomkamhang, Ussanee S; Lumbiganon, Pisake; Pratt, Jeremy J

2015-09-04

Constipation is a common symptom experienced during pregnancy. It has a range of consequences from reduced quality of life and perception of physical health to haemorrhoids. An understanding of the effectiveness and safety of treatments for constipation in pregnancy is important for the clinician managing pregnant women. To assess the effectiveness and safety of interventions (pharmacological and non-pharmacological) for treating constipation in pregnancy. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (30 April 2015), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (30 April 2015) and reference lists of retrieved studies. We considered all published, unpublished and ongoing randomised controlled trials (RCTs), cluster-RCTs and quasi-RCTs, evaluating interventions (pharmacological and non-pharmacological) for constipation in pregnancy. Cross-over studies were not eligible for inclusion in this review. Trials published in abstract form only (without full text publication) were not eligible for inclusion.We compared one intervention (pharmacological or non-pharmacological) against another intervention, placebo or no treatment. Two review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. Four studies were included, but only two studies with a total of 180 women contributed data to this review. It was not clear whether they were RCTs or quasi-RCTs because the sequence generation was unclear. We classified the overall risk of bias of three studies as moderate and one study as high risk of bias. No meta-analyses were carried out due to insufficient data.There were no cluster-RCTs identified for inclusion. Comparisons were available for stimulant laxatives versus bulk-forming laxatives, and fibre supplementation versus no intervention. There were no data available for any other comparisons.During the review process we found that studies reported changes in symptoms in different ways. To capture all data available, we added a new primary outcome (improvement in constipation) - this new outcome was not prespecified in our published protocol. Stimulant laxatives versus bulk-forming laxativesNo data were identified for any of this review's prespecified primary outcomes: pain on defecation, frequency of stools and consistency of stools.Compared to bulk-forming laxatives, pregnant women who received stimulant laxatives had significantly more improvement in constipation (risk ratio (RR) 1.59, 95% confidence interval (CI) 1.21 to 2.09; 140 women, one study, moderate quality of evidence), but also significantly more abdominal discomfort (RR 2.33, 95% CI 1.15 to 4.73; 140 women, one study, low quality of evidence), and borderline difference in diarrhoea (RR 4.50, 95% CI 1.01 to 20.09; 140 women, one study, moderate quality of evidence). In addition, there was no significant difference in women's satisfaction (RR 1.06, 95% CI 0.77 to 1.46; 140 women, one study, moderate quality of evidence).No usable data were identified for any of this review's secondary outcomes: quality of life; dehydration; electrolyte imbalance; acute allergic reaction; or asthma. Fibre supplementation versus no interventionPregnant women who received fibre supplementation had significantly higher frequency of stools compared to no intervention (mean difference (MD) 2.24 times per week, 95% CI 0.96 to 3.52; 40 women, one study, moderate quality of evidence). Fibre supplementation was associated with improved stool consistency as defined by trialists (hard stool decreased by 11% to 14%, normal stool increased by 5% to 10%, and loose stool increased by 0% to 6%).No usable data were reported for either the primary outcomes of pain on defecation and improvement in constipation or any of this review's secondary outcomes as listed above. Quality Five outcomes were assessed with the GRADE software: improvement in constipation, frequency of stools, abdominal discomfort, diarrhoea and women's satisfaction. These were assessed to be of moderate quality except for abdominal discomfort which was assessed to be of low quality. The results should therefore be interpreted with caution. There were no data available for evaluation of pain on defecation or consistency of stools. There is insufficient evidence to comprehensively assess the effectiveness and safety of interventions (pharmacological and non-pharmacological) for treating constipation in pregnancy, due to limited data (few studies with small sample size and no meta-analyses). Compared with bulk-forming laxatives, stimulant laxatives appear to be more effective in improvement of constipation (moderate quality evidence), but are accompanied by an increase in diarrhoea (moderate quality evidence) and abdominal discomfort (low quality evidence) and no difference in women's satisfaction (moderate quality evidence). Additionally, fibre supplementation may increase frequency of stools compared with no intervention (moderate quality evidence), although these results were of moderate risk of bias.There were no data for a comparison of other types of interventions, such as osmotic laxatives, stool softeners, lubricant laxatives and enemas and suppositories.More RCTs evaluating interventions for treating constipation in pregnancy are needed. These should cover different settings and evaluate the effectiveness of various interventions (including fibre, osmotic, and stimulant laxatives) on improvement in constipation, pain on defecation, frequency of stools and consistency of stools.

Experimental human influenza: observations from studies of influenza antivirals.

PubMed

Hayden, Frederick G

2012-01-01

Randomized, placebo-controlled trials have been conducted for nearly five decades in experimentally induced human influenza infections to assess the effectiveness, tolerability and pharmacological properties of influenza antivirals. The results of such studies have not only provided key proof-of-concept data to facilitate drug development but also contributed to our understanding of influenza pathogenesis and transmission. The lack of availability of contemporary, safety-tested virus inoculation pools in recent years needs to be resolved in order to avoid hindering the development of new drugs and vaccines.

Systematic review of clinical trials assessing pharmacological properties of Salvia species on memory, cognitive impairment and Alzheimer's disease.

PubMed

Miroddi, Marco; Navarra, Michele; Quattropani, Maria C; Calapai, Fabrizio; Gangemi, Sebastiano; Calapai, Gioacchino

2014-06-01

Salvia officinalis L. and Salvia lavandulaefolia L. have a longstanding use as traditional herbal remedies that can enhance memory and improve cognitive functions. Pharmacological actions of S. officinalis and S. lavandulaefolia on healthy subjects and on patients suffering of cognitive decline have been investigated. Aim of this review was to summarize published clinical trials assessing effectiveness and safety of S. officinalis and S. lavandulaefolia in the enhancement of cognitive performance in healthy subjects and neurodegenerative illnesses. Furthermore, to purchase a more complete view on safety of S. officinalis and S. lavandulaefolia, we collected and discussed articles regarding toxicity and adverse reactions. Eight clinical studies investigating on acute effects of S. officinalis on healthy subjects were included in the review. Six studies investigated on the effects of S. officinalis and S. lavandaeluaefolia on cognitive performance in healthy subjects. The two remaining were carried out to study the effects of sage on Azheimer's disease. Our review shows that S. officinalis and S. lavandulaefolia exert beneficial effects by enhancing cognitive performance both in healthy subjects and patients with dementia or cognitive impairment and is safe for this indication. Unfortunately, promising beneficial effects are debased by methodological issues, use of different herbal preparations (extracts, essential oil, use of raw material), lack of details on herbal products used. We believe that sage promising effects need further higher methodological standard clinical trials. © 2014 John Wiley & Sons Ltd.

An overview of fotemustine in high-grade gliomas: from single agent to association with bevacizumab.

PubMed

Lombardi, Giuseppe; Farina, Patrizia; Della Puppa, Alessandro; Cecchin, Diego; Pambuku, Ardi; Bellu, Luisa; Zagonel, Vittorina

2014-01-01

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas.

An Overview of Fotemustine in High-Grade Gliomas: From Single Agent to Association with Bevacizumab

PubMed Central

Lombardi, Giuseppe; Farina, Patrizia; Della Puppa, Alessandro; Cecchin, Diego; Pambuku, Ardi; Bellu, Luisa; Zagonel, Vittorina

2014-01-01

Fotemustine is a third-generation nitrosourea showing efficacy in various types of tumors such as melanoma and glioma. We reviewed the most important studies on fotemustine treatment in glioma patients analyzing its pharmacological profile and its activity and safety. Fotemustine was used as single agent or in association with new targeted drugs such as bevacizumab; fotemustine was used both as first-line chemotherapy before temozolomide era and in refractory-temozolomide patients during temozolomide era. Finally, analyzing and comparing the activity and safety of fotemustine alone or in combination with bevacizumab versus other nitrosoureas such as lomustine, we may suggest that the combination treatment with bevacizumab and fotemustine may be active and tolerable in patients with high grade gliomas. PMID:24800248

Medication safety and knowledge-based functions: a stepwise approach against information overload.

PubMed

Patapovas, Andrius; Dormann, Harald; Sedlmayr, Brita; Kirchner, Melanie; Sonst, Anja; Müller, Fabian; Pfistermeister, Barbara; Plank-Kiegele, Bettina; Vogler, Renate; Maas, Renke; Criegee-Rieck, Manfred; Prokosch, Hans-Ulrich; Bürkle, Thomas

2013-09-01

The aim was to improve medication safety in an emergency department (ED) by enhancing the integration and presentation of safety information for drug therapy. Based on an evaluation of safety of drug therapy issues in the ED and a review of computer-assisted intervention technologies we redesigned an electronic case sheet and implemented computer-assisted interventions into the routine work flow. We devised a four step system of alerts, and facilitated access to different levels of drug information. System use was analyzed over a period of 6 months. In addition, physicians answered a survey based on the technology acceptance model TAM2. The new application was implemented in an informal manner to avoid work flow disruption. Log files demonstrated that step I, 'valid indication' was utilized for 3% of the recorded drugs and step II 'tooltip for well-known drug risks' for 48% of the drugs. In the questionnaire, the computer-assisted interventions were rated better than previous paper based measures (checklists, posters) with regard to usefulness, support of work and information quality. A stepwise assisting intervention received positive user acceptance. Some intervention steps have been seldom used, others quite often. We think that we were able to avoid over-alerting and work flow intrusion in a critical ED environment. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Present state and future perspectives of using pluripotent stem cells in toxicology research

PubMed Central

Löser, Peter

2011-01-01

The use of novel drugs and chemicals requires reliable data on their potential toxic effects on humans. Current test systems are mainly based on animals or in vitro–cultured animal-derived cells and do not or not sufficiently mirror the situation in humans. Therefore, in vitro models based on human pluripotent stem cells (hPSCs) have become an attractive alternative. The article summarizes the characteristics of pluripotent stem cells, including embryonic carcinoma and embryonic germ cells, and discusses the potential of pluripotent stem cells for safety pharmacology and toxicology. Special attention is directed to the potential application of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) for the assessment of developmental toxicology as well as cardio- and hepatotoxicology. With respect to embryotoxicology, recent achievements of the embryonic stem cell test (EST) are described and current limitations as well as prospects of embryotoxicity studies using pluripotent stem cells are discussed. Furthermore, recent efforts to establish hPSC-based cell models for testing cardio- and hepatotoxicity are presented. In this context, methods for differentiation and selection of cardiac and hepatic cells from hPSCs are summarized, requirements and implications with respect to the use of these cells in safety pharmacology and toxicology are presented, and future challenges and perspectives of using hPSCs are discussed. PMID:21225242

Recommended treatment strategies for patients with excessive daytime sleepiness.

PubMed

Rosenberg, Russell P

2015-10-01

Excessive daytime sleepiness (EDS) is a common and bothersome phenomenon. It can be associated with insufficient sleep syndrome, narcolepsy, idiopathic hypersomnia, obstructive sleep apnea, shift work disorder, Kleine-Levin syndrome, or Parkinson's disease. Once the underlying cause of the excessive sleepiness is determined, clinicians must select the most appropriate behavioral and pharmacologic interventions to reduce daytime sleepiness, alleviate other symptoms, improve functioning, and ensure the safety of patients and those around them. Patient history, adverse effects, and efficacy in specific conditions should be considered in pharmacologic treatment options for patients with EDS. © Copyright 2015 Physicians Postgraduate Press, Inc.

[Lack of bioavailability of generic lopinavir/ritonavir not prequalified by WHO marketed in Africa (Congo Brazzaville)].

PubMed

Camara, S; Zucman, D; Vasse, M; Goudjo, A; Guillard, E; Peytavin, G

2015-02-01

Although second-line generic antiretroviral drugs are of great value in developing countries there are concerns regarding their quality and safety. This study is a case report and pharmacological study in healthy volunteers. A French subject of sub-saharan origin who visited Republic of Congo received a post-exposure treatment with AZT+3TC and LPV/r (200/50 mg, Arga-L®, India) following unprotected sexual intercourse. Two days later, in France, tests showed that plasma concentrations of lopinavir and ritonavir were undetectable. The WHO prequalification list showed Arga-L® was not prequalified. A pharmacological study in healthy volunteers evaluated oral bioavailability: plasma concentrations of generic LPV/r Arga-L® and LPV/r Kaletra® (400/100 mg) were measured after one single dose at 7 days apart in four healthy volunteers. Concentrations of Arga-L® at 12 h after intake were considerably lower than those of Kaletra®, revealing very low oral bioavailability of generic lopinavir and ritonavir (<10%) compared to the brand-name drug. We found that Arga-L®, despite having adequate qualitative and quantitative drug contents, had very poor bio availability compared to Kaletra®. In order to avoid the selection and the spread of drug-resistant HIV strains, rigorous pharmacological monitoring of generic antiretroviral drugs that are not pre-qualified by WHO, but are marketed in Africa, must be a priority for health authorities.

Phytosomal curcumin: A review of pharmacokinetic, experimental and clinical studies.

PubMed

Mirzaei, Hamed; Shakeri, Abolfazl; Rashidi, Bahman; Jalili, Amin; Banikazemi, Zarrin; Sahebkar, Amirhossein

2017-01-01

Curcumin, a hydrophobic polyphenol, is the principal constituent extracted from dried rhizomes of Curcuma longa L. (turmeric). Curcumin is known as a strong anti-oxidant and anti-inflammatory agent that has different pharmacological effects. In addition, several studies have demonstrated that curcumin is safe even at dosages as high as 8g per day; however, instability at physiological pH, low solubility in water and rapid metabolism results in a low oral bioavailability of curcumin. The phytosomal formulation of curcumin (a complex of curcumin with phosphatidylcholine) has been shown to improve curcumin bioavailability. Existence of phospholipids in phytosomes leads to specific physicochemical properties such as amphiphilic nature that allows dispersion in both hydrophilic and lipophilic media. The efficacy and safety of curcumin phytosomes have been shown against several human diseases including cancer, osteoarthritis, diabetic microangiopathy and retinopathy, and inflammatory diseases. This review focuses on the pharmacokinetics as well as pharmacological and clinical effects of phytosomal curcumin. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Pharmacologic studies in vulnerable populations: Using the pediatric experience.

PubMed

Zimmerman, Kanecia; Gonzalez, Daniel; Swamy, Geeta K; Cohen-Wolkowiez, Michael

2015-11-01

Historically, few data exist to guide dosing in children and pregnant women. Multiple barriers to inclusion of these vulnerable populations in clinical trials have led to this paucity of data. However, federal legislation targeted at pediatric therapeutics, innovative clinical trial design, use of quantitative clinical pharmacology methods, pediatric thought leadership, and collaboration have successfully overcome many existing barriers. This success has resulted in improved knowledge on pharmacokinetics, safety, and efficacy of therapeutics in children. To date, research in pregnant women has not been characterized by similar success. Wide gaps in knowledge remain despite the common use of therapeutics in pregnancy. Given the similar barriers to drug research and development in pediatric and pregnant populations, the route toward success in children may serve as a model for the advancement of drug development and appropriate drug administration in pregnant women. Copyright © 2015 Elsevier Inc. All rights reserved.

Biological properties of 6-gingerol: a brief review.

PubMed

Wang, Shaopeng; Zhang, Caihua; Yang, Guang; Yang, Yanzong

2014-07-01

Numerous studies have revealed that regular consumption of certain fruits and vegetables can reduce the risk of many diseases. The rhizome of Zingiber officinale (ginger) is consumed worldwide as a spice and herbal medicine. It contains pungent phenolic substances collectively known as gingerols. 6-Gingerol is the major pharmacologically-active component of ginger. It is known to exhibit a variety of biological activities including anticancer, anti-inflammation, and anti-oxidation. 6-Gingerol has been found to possess anticancer activities via its effect on a variety of biological pathways involved in apoptosis, cell cycle regulation, cytotoxic activity, and inhibition of angiogenesis. Thus, due to its efficacy and regulation of multiple targets, as well as its safety for human use, 6-gingerol has received considerable interest as a potential therapeutic agent for the prevention and/or treatment of various diseases. Taken together, this review summarizes the various in vitro and in vivo pharmacological aspects of 6-gingerol and the underlying mechanisms.

Digitalis metabolism and human liver alcohol dehydrogenase.

PubMed Central

Frey, W A; Vallee, B L

1980-01-01

Human liver alcohol dehydrogenase (alcohol: NAD" oxidoreductase, EC 1.1.1.1) catalyzes the oxidation of the 3 beta-OH group of digitoxigenin, digoxigenin, and gitoxigenin to their 3-keto derivatives, which have been characterized by high performance liquid chromatography and mass spectrometry. These studies have identified human liver alcohol dehydrogenase as the unknown NAD(H)-dependent liver enzyme specific for the free hydroxyl group at C3 of the cardiac genins; this hydroxyl is the critical site of the genins' enzymatic oxidation and concomitant pharmacological inactivation in humans. Several kinetic approaches have demonstrated that ethanol and the pharmacologically active components of the digitalis glycosides are oxidized with closely similar kcat/Km values at the same site on human liver alcohol dehydrogenase, for which they compete. Human liver alcohol dehydrogenase thereby becomes an important biochemical link in the metabolism, pharmacology, and toxicology of ethanol and these glycosides, structurally unrelated agents that are both used widely. Both the competition of ethanol with these cardiac sterols and the narrow margin of safety in the therapeutic use of digitalis derivatives would seem to place at increased risk those individuals who receive digitalis and simultaneously consume large amounts of ethanol or whose alcohol dehydrogenase function is impaired. PMID:6987673

Coptidis rhizoma and its main bioactive components: recent advances in chemical investigation, quality evaluation and pharmacological activity.

PubMed

Meng, Fan-Cheng; Wu, Zheng-Feng; Yin, Zhi-Qi; Lin, Li-Gen; Wang, Ruibing; Zhang, Qing-Wen

2018-01-01

Coptidis rhizoma (CR) is the dried rhizome of Coptis chinensis Franch., C. deltoidea C. Y. Cheng et Hsiao or C. teeta Wall. (Ranunculaceae) and is commonly used in Traditional Chinese Medicine for the treatment of various diseases including bacillary dysentery, typhoid, tuberculosis, epidemic cerebrospinal meningitis, empyrosis, pertussis, and other illnesses. A literature survey was conducted via SciFinder, ScieneDirect, PubMed, Springer, and Wiley databases. A total of 139 selected references were classified on the basis of their research scopes, including chemical investigation, quality evaluation and pharmacological studies. Many types of secondary metabolites including alkaloids, lignans, phenylpropanoids, flavonoids, phenolic compounds, saccharides, and steroids have been isolated from CR. Among them, protoberberine-type alkaloids, such as berberine, palmatine, coptisine, epiberberine, jatrorrhizine, columamine, are the main components of CR. Quantitative determination of these alkaloids is a very important aspect in the quality evaluation of CR. In recent years, with the advances in isolation and detection technologies, many new instruments and methods have been developed for the quantitative and qualitative analysis of the main alkaloids from CR. The quality control of CR has provided safety for pharmacological applications. These quality evaluation methods are also frequently employed to screen the active components from CR. Various investigations have shown that CR and its main alkaloids exhibited many powerful pharmacological effects including anti-inflammatory, anti-cancer, anti-diabetic, neuroprotective, cardioprotective, hypoglycemic, anti-Alzheimer and hepatoprotective activities. This review summarizes the recent phytochemical investigations, quality evaluation methods, the biological studies focusing on CR as well as its main alkaloids.

Cuscuta chinensis Lam.: A systematic review on ethnopharmacology, phytochemistry and pharmacology of an important traditional herbal medicine.

PubMed

Donnapee, Sineeporn; Li, Jin; Yang, Xi; Ge, Ai-hua; Donkor, Paul Owusu; Gao, Xiu-mei; Chang, Yan-xu

2014-11-18

Cuscuta chinensis Lam. has found its use as a traditional medicine in China, Korea, Pakistan, Vietnam, India and Thailand. It is commonly used as an anti-aging agent, anti-inflammatory agent, pain reliever and aphrodisiac. To provide an overview of the ethnopharmacology, phytochemistry, pharmacokinetics, pharmacology and clinical applications of Cuscuta chinensis, as well as being an evidence base for further research works of the plant. The present review covers the literature available from 1985 to 2014. The information was collected from journals, books, theses and electronic search (Google Scholar, PubMed, ScienceDirect, ESBCO, Springerlink and CNKI). Literature abstracts and full-text articles were analyzed and included in the review. Many phytochemicals have been isolated, identified and published to date, including: at least 18 flavonoids; 13 phenolic acids; 2 steroids; 1 hydroquinone; 10 volatile oils; 22 lignans; 9 polysaccharides; 2 resin glycosides; 16 fatty acids. These phytochemicals and plant extracts exhibit a range of pharmacological activities that include hepatoprotective, renoprotective, antiosteoporotic, antioxidant, anti-aging, antimutagenic, antidepressant, improve sexual function, abortifacient effects, etc. This present review offers primary information for further studies of Cuscuta chinensis. The in vitro studies and in vivo models have provided a bioscientific explanation for its various ethnopharmacological uses and pharmacological activities (most notably antioxidant effects) especially in the prevention of hepatic disease and renal failure. It is necessary and important to do more pharmacokinetic and toxicological research works on human subjects in order to inform the possible active compounds in the body and validate its safety in clinical uses. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Dexamethasone facilitates fear extinction and safety discrimination in PTSD: A placebo-controlled, double-blind study.

PubMed

Michopoulos, Vasiliki; Norrholm, Seth D; Stevens, Jennifer S; Glover, Ebony M; Rothbaum, Barbara O; Gillespie, Charles F; Schwartz, Ann C; Ressler, Kerry J; Jovanovic, Tanja

2017-09-01

Psychophysiological hallmarks of posttraumatic stress disorder (PTSD) include exaggerated fear responses, impaired inhibition and extinction of conditioned fear, and decreased discrimination between safety and fear cues. This increased fear load associated with PTSD can be a barrier to effective therapy thus indicating the need for new treatments to reduce fear expression in people with PTSD. One potential biological target for reducing fear expression in PTSD is the hypothalamic-pituitary-adrenal (HPA) axis, which is dysregulated in PTSD. Recent translational rodent studies and cross-sectional clinical studies have shown that dexamethasone administration and the resulting suppression of cortisol in individuals with PTSD leads to a decrease in the fear responses characteristic of PTSD. These data, taken together, suggest that dexamethasone may serve as a novel pharmacologic intervention for heightened fear responses in PTSD. We conducted a double-blind, placebo-controlled trial to test our hypothesis that dexamethasone administration and the concomitant suppression of HPA axis hyperactivity would attenuate fear expression and enhance fear extinction in individuals with PTSD. Study participants (n=62) were recruited from Grady Memorial Hospital in Atlanta, GA. Participants were randomized to receive dexamethasone or placebo prior to fear conditioning and extinction, in a counterbalanced design (treatments separated by a week). Both PTSD- (n=37) and PTSD+ (n=25) participants showed significant startle increases in the presence of the danger signal during placebo and dexamethasone treatments (all p<0.05). However, only PTSD- control participants showed decreases in fear-potentiated startle across extinction blocks during both conditions (p's≤0.001), with PTSD+ participants showing deficits in fear extinction and safety discrimination in the placebo condition. Notably, extinction and discrimination deficits in PTSD+ subjects were markedly reversed with dexamethasone (p<0.001). These data suggest that dexamethasone may serve as a pharmacological agent with which to facilitate fear extinction and discrimination in individuals with PTSD. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cardiac safety strategies. 25-26 October 2005, the Radisson SAS Hotel, Nice, France.

PubMed

Hanton, Gilles; Tilbury, Lorraine

2006-03-01

This meeting was organised by IIR Life Sciences. It was chaired by Brian Guth, (head of General Pharmacology at Boehringer Ingelheim Pharma) and brought together scientists and clinicians from the pharmaceutical industry, university and regulatory agencies. The meeting presented emerging trends in cardiac safety, including its regulatory context pertaining to ICH S7A, S7B and E14. ICH S7A and S7B highlight the importance of the hERG test and telemetric studies in non-rodents. ICH E14 describes the clinical 'thorough QT study' that is required by the FDA for any new drug. Marked physiological variability in QT interval over time can be observed, partly as a result of fluctuation in autonomic tone. Beat-to-beat QT variability and T-wave morphology should be considered as a part of an integrated estimate of proarrhythmic risk. A case study illustrated the predictivity of preclinical data for proarrhythmic risk in humans, showing the importance of evaluating QT effects in patients to establish a safety margin.

Improvements in safety and recovery following cystectomy: reassessing the role of pre-operative bowel preparation and interventions to speed return of post-operative bowel function.

PubMed

Zaid, Harras B; Kaffenberger, Samuel D; Chang, Sam S

2013-04-01

For radical cystectomy, historical practice trends have favored the use of preoperative bowel preparations to reduce complications, including surgical site infections, ileus, and anastomotic leaks. However, emerging data has questioned this practice. Postoperative cystectomy care also remains in flux, as new pharmacologic agents that may potentiate earlier return of bowel function are studied. We review the current literature with regards to preoperative and postoperative cystectomy bowel management.

Safety of ephedra: lessons learned.

PubMed

Soni, Madhusudan G; Carabin, Ioana G; Griffiths, James C; Burdock, George A

2004-04-15

The safe use of ephedra represents the best possible outcome of a convergence of variables, some with troubling potential outcomes. Commercially used ephedra and its products is prepared from Ephedra spp. and as such is subject to a variety of influences (including differences in species and strain; growth, harvest and storage conditions) all of which may influence the content of constituents (which may, in turn, affect the absorption, distribution, and metabolism of active constituents) and taken together, influences the net pharmacological effect. Further, as a natural substance with an easily perceived and desirable (i.e. weight-loss) pharmacological effect, ephedra is also susceptible to a variety of adulterants, both economic and efficacious. All of the foregoing represent potential for misadventure before ephedra even reaches the consumer. The consumer introduces a constellation of variables as well, including, but not limited to, acute and chronic diseases, inborn errors in metabolism, simultaneous use of prescription and over-the-counter drugs, dietary supplements, alcohol, illicit substances and certain foods (e.g. chocolate, caffeinated drinks), all or some of which may exert synergistic, additive or even antagonistic influences on the desired physiologic outcome. The foregoing not withstanding, the majority of the published nonclinical and clinical studies, and history of use, support the safety of ephedra at the proposed use levels. However, the reports of adverse events submitted to FDA raise concern about the risk associated with ephedra without establishing a direct causal relationship. Given the foregoing, how best can a decision on safety be made? Should the question actually be "can ephedra be as toxic as reported?"

Nutraceuticals: opening the debate for a regulatory framework.

PubMed

Santini, Antonello; Cammarata, Silvia Miriam; Capone, Giacomo; Ianaro, Angela; Tenore, Gian Carlo; Pani, Luca; Novellino, Ettore

2018-04-01

Currently, nutraceuticals do not have a specific definition distinct from those of other food-derived categories, such as food supplements, herbal products, pre- and probiotics, functional foods, and fortified foods. Many studies have led to an understanding of the potential mechanisms of action of pharmaceutically active components contained in food that may improve health and reduce the risk of pathological conditions while enhancing overall well-being. Nevertheless, there is a lack of clear information and, often, the claimed health benefits may not be properly substantiated by safety and efficacy information or in vitro and in vivo data, which can induce false expectations and miss the target for a product to be effective, as claimed. An officially shared and accepted definition of nutraceuticals is still missing, as nutraceuticals are mostly referred to as pharma-foods, a powerful toolbox to be used beyond the diet but before the drugs to prevent and treat pathological conditions, such as in subjects who may not yet be eligible for conventional pharmaceutical therapy. Hence, it is of utmost importance to have a proper and unequivocal definition of nutraceuticals and shared regulations. It also seems wise to assess the safety, mechanism of action and efficacy of nutraceuticals with clinical data. A growing demand exists for nutraceuticals, which seem to reside in the grey area between pharmaceuticals and food. Nonetheless, given specific legislation from different countries, nutraceuticals are experiencing challenges with safety and health claim substantiation. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Management strategies for premenstrual syndrome/premenstrual dysphoric disorder.

PubMed

Jarvis, Courtney I; Lynch, Ann M; Morin, Anna K

2008-07-01

To evaluate the current nonpharmacologic and pharmacologic treatment options for symptoms of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD). Literature was obtained through searches of MEDLINE Ovid (1950-March week 3, 2008) and EMBASE Drugs and Pharmacology (all years), as well as a bibliographic review of articles identified by the searches. Key terms included premenstrual syndrome, premenstrual dysphoric disorder, PMS, PMDD, and treatment. All pertinent clinical trials, retrospective studies, and case reports in human subjects published in the English language were identified and evaluated for the safety and efficacy of pharmacologic and nonpharmacologic treatments of PMS/PMDD. Data from these studies and information from review articles were included in this review. Selective serotonin-reuptake inhibitors (SSRIs) have been proven safe and effective for the treatment of PMDD and are recommended as first-line agents when pharmacotherapy is warranted. Currently fluoxetine, controlled-release paroxetine, and sertraline are the only Food and Drug Administration-approved agents for this indication. Suppression of ovulation using hormonal therapies is an alternative approach to treating PMDD when SSRIs or second-line psychotropic agents are ineffective; however, adverse effects limit their use. Anxiolytics, spironolactone, and nonsteroidal antiinflammatory drugs can be used as supportive care to relieve symptoms. Despite lack of specific evidence, lifestyle modifications and exercise are first-line recommendations for all women with PMS/PMDD and may be all that is needed to treat mild-to-moderate symptoms. Herbal and vitamin supplementation and complementary and alternative medicine have been evaluated for use in PMS/PMDD and have produced unclear or conflicting results. More controlled clinical trials are needed to determine their safety and efficacy and potential for drug interactions. Healthcare providers need to be aware of the symptoms of PMS and PMDD and the treatment options available. Treatment selection should be based on individual patient symptoms, concomitant medical history, and need for contraception.

Computational modeling for cardiac safety pharmacology analysis: Contribution of fibroblasts.

PubMed

Gao, Xin; Engel, Tyler; Carlson, Brian E; Wakatsuki, Tetsuro

2017-09-01

Drug-induced proarrhythmic potential is an important regulatory criterion in safety pharmacology. The application of in silico approaches to predict proarrhythmic potential of new compounds is under consideration as part of future guidelines. Current approaches simulate the electrophysiology of a single human adult ventricular cardiomyocyte. However, drug-induced proarrhythmic potential can be different when cardiomyocytes are surrounded by non-muscle cells. Incorporating fibroblasts in models of myocardium is important particularly for predicting a drugs cardiac liability in the aging population - a growing population who take more medications and exhibit increased cardiac fibrosis. In this study, we used computational models to investigate the effects of fibroblast coupling on the electrophysiology and response to drugs of cardiomyocytes. A computational model of cardiomyocyte electrophysiology and ion handling (O'Hara, Virag, Varro, & Rudy, 2011) is coupled to a passive model of fibroblast electrophysiology to test the effects of three compounds that block cardiomyocyte ion channels. Results are compared to model results without fibroblast coupling to see how fibroblasts affect cardiomyocyte action potential duration at 90% repolarization (APD 90 ) and propensity for early after depolarization (EAD). Simulation results show changes in cardiomyocyte APD 90 with increasing concentration of three drugs that affect cardiac function (dofetilide, vardenafil and nebivolol) when no fibroblasts are coupled to the cardiomyocyte. Coupling fibroblasts to cardiomyocytes markedly shortens APD 90 . Moreover, increasing the number of fibroblasts can augment the shortening effect. Coupling cardiomyocytes and fibroblasts are predicted to decrease proarrhythmic susceptibility under dofetilide, vardenafil and nebivolol block. However, this result is sensitive to parameters which define the electrophysiological function of the fibroblast. Fibroblast membrane capacitance and conductance (C FB and G FB ) have less of an effect on APD 90 than the fibroblast resting membrane potential (E FB ). This study suggests that in both theoretical models and experimental tissue constructs that represent cardiac tissue, both cardiomyocytes and non-muscle cells should be considered when testing cardiac pharmacological agents. Copyright © 2017 Elsevier Inc. All rights reserved.

Evaluation and Synthesis of Polar Aryl- and Heteroaryl Spiroazetidine-Piperidine Acetamides as Ghrelin Inverse Agonists

PubMed Central

2014-01-01

Several polar heteroaromatic acetic acids and their piperidine amides were synthesized and evaluated as ghrelin or type 1a growth hormone secretagogue receptor (GHS-R1a) inverse agonists. Efforts to improve pharmacokinetic and safety profile was achieved by modulating physicochemical properties and, more specifically, emphasizing increased polarity of our chemical series. ortho-Carboxamide containing compounds provided optimal physicochemical, pharmacologic, and safety profile. pH-dependent chemical stability was also assessed with our series. PMID:25699143

Russian guidelines for the management of COPD: algorithm of pharmacologic treatment

PubMed Central

Aisanov, Zaurbek; Avdeev, Sergey; Arkhipov, Vladimir; Belevskiy, Andrey; Chuchalin, Alexander; Leshchenko, Igor; Ovcharenko, Svetlana; Shmelev, Evgeny; Miravitlles, Marc

2018-01-01

The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A–D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation. PMID:29386887

Russian guidelines for the management of COPD: algorithm of pharmacologic treatment.

PubMed

Aisanov, Zaurbek; Avdeev, Sergey; Arkhipov, Vladimir; Belevskiy, Andrey; Chuchalin, Alexander; Leshchenko, Igor; Ovcharenko, Svetlana; Shmelev, Evgeny; Miravitlles, Marc

2018-01-01

The high prevalence of COPD together with its high level of misdiagnosis and late diagnosis dictate the necessity for the development and implementation of clinical practice guidelines (CPGs) in order to improve the management of this disease. High-quality, evidence-based international CPGs need to be adapted to the particular situation of each country or region. A new version of the Russian Respiratory Society guidelines released at the end of 2016 was based on the proposal by Global Initiative for Obstructive Lung Disease but adapted to the characteristics of the Russian health system and included an algorithm of pharmacologic treatment of COPD. The proposed algorithm had to comply with the requirements of the Russian Ministry of Health to be included into the unified electronic rubricator, which required a balance between the level of information and the simplicity of the graphic design. This was achieved by: exclusion of the initial diagnostic process, grouping together the common pharmacologic and nonpharmacologic measures for all patients, and the decision not to use the letters A-D for simplicity and clarity. At all stages of the treatment algorithm, efficacy and safety have to be carefully assessed. Escalation and de-escalation is possible in the case of lack of or insufficient efficacy or safety issues. Bronchodilators should not be discontinued except in the case of significant side effects. At the same time, inhaled corticosteroid (ICS) withdrawal is not represented in the algorithm, because it was agreed that there is insufficient evidence to establish clear criteria for ICSs discontinuation. Finally, based on the Global Initiative for Obstructive Lung Disease statement, the proposed algorithm reflects and summarizes different approaches to the pharmacological treatment of COPD taking into account the reality of health care in the Russian Federation.

The pharmacology of palmitoylethanolamide and first data on the therapeutic efficacy of some of its new formulations.

PubMed

Petrosino, Stefania; Di Marzo, Vincenzo

2017-06-01

Palmitoylethanolamide (PEA) has emerged as a potential nutraceutical, because this compound is naturally produced in many plant and animal food sources, as well as in cells and tissues of mammals, and endowed with important neuroprotective, anti-inflammatory and analgesic actions. Several efforts have been made to identify the molecular mechanism of action of PEA and explain its multiple effects both in the central and the peripheral nervous system. Here, we provide an overview of the pharmacology, efficacy and safety of PEA in neurodegenerative disorders, pain perception and inflammatory diseases. The current knowledge of new formulations of PEA with smaller particle size (i.e. micronized and ultra-micronized) when given alone or in combination with antioxidant flavonoids (i.e. luteolin) and stilbenes (i.e. polydatin) is also reviewed. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2016 The British Pharmacological Society.

Safety Surveillance of Traditional Chinese Medicine: Current and Future

PubMed Central

Liu, Shwu-Huey; Chuang, Wu-Chang; Lam, Wing; Jiang, Zaoli

2015-01-01

Herbal medicine, including traditional Chinese medicine, has been used for the prevention, treatment, and cure of disorders or diseases for centuries. In addition to being used directly as therapeutic agents, medicinal plants are also important sources for pharmacological drug research and development. With the increasing consumption of herbal products intended to promote better health, it is extremely important to assure the safety and quality of herbal preparations. However, under current regulation surveillance, herbal preparations may not meet expectations in safety, quality, and efficacy. The challenge is how to assure the safety and quality of herbal products for consumers. It is the responsibility of producers to minimize hazardous contamination and additives during cultivation, harvesting, handling, processing, storage, and distribution. This article reviews the current safety obstacles that have been involved in traditional Chinese herbal medicine preparations with examples of popular herbs. Approaches to improve the safety of traditional Chinese medicine are proposed. PMID:25647717

Pharmacological targeting of exercise adaptations in skeletal muscle: Benefits and pitfalls.

PubMed

Weihrauch, Martin; Handschin, Christoph

2018-01-01

Exercise exerts significant effects on the prevention and treatment of many diseases. However, even though some of the key regulators of training adaptation in skeletal muscle have been identified, this biological program is still poorly understood. Accordingly, exercise-based pharmacological interventions for many muscle wasting diseases and also for pathologies that are triggered by a sedentary lifestyle remain scarce. The most efficacious compounds that induce muscle hypertrophy or endurance are hampered by severe side effects and are classified as doping. In contrast, dietary supplements with a higher safety margin exert milder outcomes. In recent years, the design of pharmacological agents that activate the training program, so-called "exercise mimetics", has been proposed, although the feasibility of such an approach is highly debated. In this review, the most recent insights into key regulatory factors and therapeutic approaches aimed at leveraging exercise adaptations are discussed. Copyright © 2017 Elsevier Inc. All rights reserved.

Comparing the novel method of assessing PrEP adherence/exposure using hair samples to other pharmacologic and traditional measures.

PubMed

Baxi, Sanjiv M; Liu, Albert; Bacchetti, Peter; Mutua, Gaudensia; Sanders, Eduard J; Kibengo, Freddie M; Haberer, Jessica E; Rooney, James; Hendrix, Craig W; Anderson, Peter L; Huang, Yong; Priddy, Frances; Gandhi, Monica

2015-01-01

The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41-0.86, all P < 0.001). Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted.

Comparing the Novel Method of Assessing PrEP Adherence/Exposure Using Hair Samples to Other Pharmacologic and Traditional Measures

PubMed Central

Baxi, Sanjiv M.; Liu, Albert; Bacchetti, Peter; Mutua, Gaudensia; Sanders, Eduard J.; Kibengo, Freddie M.; Haberer, Jessica E.; Rooney, James; Hendrix, Craig W.; Anderson, Peter L.; Huang, Yong; Priddy, Frances

2015-01-01

Objective: The efficacy of pre-exposure prophylaxis (PrEP) in HIV will diminish with poor adherence; pharmacologic measures of drug exposure have proven critical to PrEP trial interpretation. We assessed drug exposure in hair against other pharmacologic and more routinely used measures to assess pill-taking. Design: Participants were randomized to placebo, daily PrEP, or intermittent PrEP to evaluate safety and tolerability of daily versus intermittent tenofovir/emtricitabine (TFV/FTC) in 2 phase II PrEP clinical trials conducted in Africa. Different measures of drug exposure, including self-report, medication event monitoring system (MEMS)-caps openings, and TFV/FTC levels in hair and other biomatrices were compared. Methods: At weeks 8 and 16, self-reported pill-taking, MEMS-caps openings, and TFV/FTC levels in hair, plasma, and peripheral blood mononuclear cells (PBMCs) were measured. Regression models evaluated predictors of TFV/FTC concentrations in the 3 biomatrices; correlation coefficients between pharmacologic and nonpharmacologic measures were calculated. Both trials were registered on ClinicalTrials.gov (NCT00931346/NCT00971230). Results: Hair collection was highly feasible and acceptable (100% in week 8; 96% in week 16). In multivariate analysis, strong associations were seen between pharmacologic measures and MEMS-caps openings (all P < 0.001); self-report was only weakly associated with pharmacologic measures. TFV/FTC hair concentrations were significantly correlated with levels in plasma and PBMCs (correlation coefficients, 0.41–0.86, all P < 0.001). Conclusions: Measuring TFV/FTC exposure in small hair samples in African PrEP trials was feasible and acceptable. Hair levels correlated strongly with PBMC, plasma concentrations, and MEMS-caps openings. As in other PrEP trials, self-report was the weakest measure of exposure. Further study of hair TFV/FTC levels in PrEP trials and demonstration projects to assess adherence/exposure is warranted. PMID:25296098

Recent Advances in Tourette Syndrome

PubMed Central

Bloch, Michael; State, Matthew; Pittenger, Christopher

2014-01-01

Purpose of review The purpose of this review is to consider the recent literature pertaining to the neurobiology, genetics and treatment of Tourette syndrome (TS). Recent findings Over the last several years, both neuropathological and genetic findings have further focused attention on long-standing hypotheses regarding the role of the basal ganglia in the etiology of tics and TS. Moreover, while the field awaits the results the first large-scale genetic studies, recent findings have already mirrored developments in the neuropsychiatric genetics literature more broadly, highlighting the value of the study of rare variation and the overlap of risks among seemingly disparate diagnostic categories. Finally, treatment studies have underscored the importance of cognitive-behavioral as well as pharmacological interventions for the treatment of tic disorders. Summary Recent findings have led to novel, testable hypotheses regarding the molecular and cellular mechanisms underlying TS. These, in turn, have begun to provide new avenues to conceptualizing treatment strategies. While the development of additional medication options is a pressing need, recent data has demonstrated both the safety and efficacy of non-pharmacological approaches. PMID:21386676

Efficacy and safety of a herbo-mineral ayurvedic formulation ‘Afrodet Plus®’ in male rats

PubMed Central

Dhumal, Rohit; Vijaykumar, Tushara; Dighe, Vikas; Selkar, Nilakash; Chawda, Mukesh; Vahlia, Mahesh; Vanage, Geeta

2013-01-01

Background: Reverse pharmacology for drug development has been highly productive and cost-effective in recent past as it is based on the documented therapeutic effects of plants in ancient texts. Afrodet Plus® is formulated for the treatment of male infertility, which contains ancient herbo-minerals. Its efficacy and safety are validated through this animal study in reverse pharmacology mode. Objectives: This study was undertaken to evaluate efficacy and safety of an Ayurvedic formulation Afrodet Plus® in adult male rats. Materials and Methods: Twelve male rats (Holtzman) between 8 and 10 weeks of age were randomly selected and animals were assigned to a control and two treatment groups. Dosing was performed daily. Various parameters such as weekly body weight, hematology, serum testosterone levels, epididymal sperm count, and efficiency of Daily Sperm Production (DSP) were evaluated. Results: It was found that epididymal sperm count had significantly increased in both low-dose (+27.39%) and high-dose (+40.5%) groups as compared to control group. The DSP also showed an increase of 43.7% at high dose of 180 mg/kg body weight as compared to the control group. An increase in sperm motility and especially progressive motility was observed when evaluated by Computer Assisted Semen Analyzer. Histological evaluation of testicular tissue for spermatogenic index revealed that the index had increased in treatment group as compared to control group. Conclusion: This study revealed that oral administration of Afrodet Plus® resulted in significant increase in DSP in the testis along with increase in epididymal sperm count and progressive motility as compared to control group without producing any treatment-related adverse effects. These findings provide the documentary evidence that the use of Afrodet Plus® at 90 and 180 mg/kg body weight is effective and safe for the treatment of male infertility especially to improve sperm count and progressive motility. PMID:24250145

Improving the safety of vaccine delivery.

PubMed

Evans, Huw P; Cooper, Alison; Williams, Huw; Carson-Stevens, Andrew

2016-05-03

Vaccines save millions of lives per annum as an integral part of community primary care provision worldwide. Adverse events due to the vaccine delivery process outnumber those arising from the pharmacological properties of the vaccines themselves. Whilst one in three patients receiving a vaccine will encounter some form of error, little is known about their underlying causes and how to mitigate them in practice. Patient safety incident reporting systems and adverse drug event surveillance offer a rich opportunity for understanding the underlying causes of those errors. Reducing harm relies on the identification and implementation of changes to improve vaccine safety at multiple levels: from patient interventions through to organizational actions at local, national and international levels. Here we highlight the potential for maximizing learning from patient safety incident reports to improve the quality and safety of vaccine delivery.

Ketamine for Treatment-Resistant Unipolar Depression

PubMed Central

Mathew, Sanjay J.; Shah, Asim; Lapidus, Kyle; Clark, Crystal; Jarun, Noor; Ostermeyer, Britta; Murrough, James W.

2013-01-01

Currently available drugs for unipolar major depressive disorder (MDD), which target monoaminergic systems, have a delayed onset of action and significant limitations in efficacy. Antidepressants with primary pharmacological targets outside the monoamine system may offer the potential for more rapid activity with improved therapeutic benefit. The glutamate system has been scrutinized as a target for antidepressant drug discovery. The purpose of this article is to review emerging literature on the potential rapid-onset antidepressant properties of the glutamate NMDA receptor antagonist ketamine, an established anaesthetic agent. The pharmacology of ketamine and its enantiomer S-ketamine is reviewed, followed by examples of its clinical application in chronic, refractory pain conditions, which are commonly co-morbid with depression. The first generation of studies in patients with treatment-resistant depression (TRD) reported the safety and acute efficacy of a single subanaesthetic dose (0.5 mg/kg) of intravenous ketamine. A second generation of ketamine studies is focused on testing alternate routes of drug delivery, identifying methods to prevent relapse following resolution of depressive symptoms and understanding the neural basis for the putative antidepressant actions of ketamine. In addition to traditional depression rating endpoints, ongoing research is examining the impact of ketamine on neurocognition. Although the first clinical report in MDD was published in 2000, there is a paucity of adequately controlled double-blind trials, and limited clinical experience outside of research settings. Given the potential risks of ketamine, safety considerations will ultimately determine whether this old drug is successfully repositioned as a new therapy for TRD. PMID:22303887

Vorapaxar in atherosclerotic disease management.

PubMed

Cheng, Judy W M; Colucci, Vincent; Howard, Patricia A; Nappi, Jean M; Spinler, Sarah A

2015-05-01

To review the pharmacology, efficacy, and safety of vorapaxar, a protease activator receptor-1 (PAR-1) antagonist, in the management of atherosclerotic diseases. Peer-reviewed clinical trials and review articles were identified from MEDLINE and Current Content database (both 1966 to December 31, 2014) using the search terms vorapaxar and protease activator receptor antagonist. A total of 30 clinical studies were identified (16 clinical trials, including subanalyses, 14 related to pharmacology, pharmacokinetics, and pharmacodynamics and drug interactions). Two phase III clinical trials with vorapaxar have been published. In patients with non-ST segment elevation myocardial infarction (MI), vorapaxar failed to significantly reduce the primary efficacy end point (composite of cardiovascular death, MI, stroke, recurrent ischemia with hospitalization, and urgent coronary revascularization). Conversely, in a study of secondary prevention for patients with cardiovascular disease, the composite end point of cardiovascular death, MI, or stroke was significantly reduced. In both trials, the safety end points of major/minor bleeding were increased compared with placebo. In the secondary prevention trial, an increased incidence of intracranial hemorrhage led to the exclusion of patients with a prior history of stroke. Vorapaxar is approved for use with aspirin and/or clopidogrel in the secondary prevention of cardiovascular events in stable patients with peripheral arterial disease or a history of MI. However, the addition of vorapaxar to other antiplatelets can significantly increase the risk of bleeding. It is, therefore, essential to balance the need for further reduction of risk of thrombotic event with patient's individual bleeding risk. © The Author(s) 2015.

Potential Psychiatric Uses for MDMA.

PubMed

Yazar-Klosinski, B B; Mithoefer, M C

2017-02-01

Phase II trials of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy have demonstrated initial safety and efficacy for treatment of posttraumatic stress disorder (PTSD), with potential for expansion to depression and anxiety disorders. In these trials, single doses of MDMA are administered in a model of medication-assisted psychotherapy, differing from trials involving daily drug administration without psychotherapy. This model presents an opportunity to utilize accelerated regulatory pathways, such as the US Food and Drug Administration (FDA) Breakthrough Therapy Designation, to most effectively and expeditiously test such novel approaches. © 2016, The Authors. Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Safety considerations in the pharmacological management of atrial fibrillation.

PubMed

Camm, A John

2008-07-21

The pharmacological management of atrial fibrillation (AF) requires careful consideration from a safety perspective. This article focuses primarily on maintenance therapy using antiarrhythmic drugs (AADs). The foremost safety issue for AADs is the propensity of class IA and III agents to cause torsade de pointes arrhythmias. Class IA drugs, particularly quinidine, can induce torsade de pointes at low or subtherapeutic doses, but higher doses are not necessarily associated with an increased incidence. 'Pure' class III drugs such as dofetilide induce torsade de pointes in a dose-related manner, but some class III agents with more complex actions such as amiodarone have a markedly lower potential to cause this arrhythmia. The risk of torsade de pointes precludes the use of class IA and 'pure' class III agents in patients with left ventricular hypertrophy and bradycardia. Class IC agents may cause sustained monomorphic ventricular tachycardias and are generally precluded in ischaemic and structural heart disease. Advanced heart failure patients may be treated with amiodarone or dofetilide, but most other AADs are unsuitable. The most important extracardiac toxicities occurring with AADs are those of amiodarone. Drug interactions are a significant safety issue in the management of AF, including pharmacokinetic interactions in which plasma levels of the AAD are raised - increasing the risk of proarrhythmia - and concomitant use of drugs that prolong the QT interval. Notwithstanding these considerations, most patients with AF can be considered for rhythm control, provided there is adequate pre-treatment assessment and protocols for initiation, dosing and monitoring are followed with care.

Anti-inflammatory drugs and analgesics for managing symptoms in people with cystic fibrosis-related arthritis.

PubMed

Thornton, Judith; Rangaraj, Satyapal

2016-01-21

Arthritis remains a relatively infrequent complication of cystic fibrosis, but is a cause of significant morbidity when it does occur. Two distinct types of arthritis are described in cystic fibrosis: cystic fibrosis-related arthropathy (CFA) and hypertrophic pulmonary osteoarthropathy (HPO). Management of arthritis in people with cystic fibrosis is uncertain and complex because of the underlying disease and its intense treatment. This is an update of a previously published review. To review the effectiveness and safety of pharmacological agents for the symptomatic management of cystic fibrosis-related arthritis in adults and children with cystic fibrosis. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of relevant journals and abstract books of conference proceedings.Date of most recent search: 19 January 2016. Randomised controlled studies which compared the efficacy and safety of anti-inflammatory and analgesic agents (e.g. non-steroidal anti-inflammatory agents, systemic corticosteroids, intra-articular corticosteroids) with each other, with no treatment or with placebo for CFA and HPO. No relevant studies were identified. No studies were included in this review. Although it is generally recognised that CFA may be episodic and resolve spontaneously, treatment with analgesics and anti-inflammatory agents may be needed. While this approach may be sufficient to manage symptoms, it is disappointing that no randomised controlled trials to rigorously evaluate these agents were found, nor could the authors identify any quasi-randomised. This systematic review has identified the need for a well-designed adequately-powered randomised controlled trial to assess the efficacy and safety of pharmacological agents for the symptomatic management of cystic fibrosis-related arthritis (CFA and HPO) in adults and children with cystic fibrosis. Studies should also better define the two conditions. A study has recently been conducted in CFA and may help fill this gap when analysed and published.There are no trials included in the review up to January 2016. We will continue to run searches to identify any potentially relevant studies; however, we do not plan to update other sections of the review until new studies are published.

Turning mirror-image oligonucleotides into drugs: the evolution of Spiegelmer(®) therapeutics.

PubMed

Vater, Axel; Klussmann, Sven

2015-01-01

Spiegelmers are synthetic target-binding oligonucleotides built from non-natural l-nucleotides. Like aptamers, Spiegelmers fold into distinct shapes that bind the targets with high affinity and selectivity. Furthermore, the mirror-image configuration confers plasma stability and immunological passivity. Various Spiegelmers against pharmacologically attractive targets were shown to be efficacious in animal models. Three Spiegelmer candidates: emapticap pegol (NOX-E36; anti-CCL2), olaptesed pegol (NOX-A12; anti-CXCL12) and lexaptepid pegol (NOX-H94; anti-hepcidin), underwent regulatory safety studies, demonstrated good safety profiles in healthy volunteers and were taken into Phase IIa studies in patients. Proof-of-concept for emapticap pegol has recently been demonstrated in diabetic nephropathy patients. Furthermore, promising interim Phase IIa data of olaptesed pegol and lexapteptid pegol also suggest efficacy in the respective patient populations. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

Safety Evaluation of Crocin (a constituent of saffron) Tablets in Healthy Volunteers

PubMed Central

Mohamadpour, Amir Houshang; Ayati, Zahara; Parizadeh, Mohammad–Reza; Rajbai, Omid; Hosseinzadeh, Hossein

2013-01-01

Objective(s): Crocin is the chemical ingredient primarily responsible for the color of saffron. It has different pharmacological effects such as antioxidant, anticancer and memory improving activities. Crocin tablets were evaluated for short-term safety and tolerability in healthy adult volunteers. Materials and Methods: The study was a randomized, double-blind, placebo-controlled design consisting of one month treatment of crocin tablets. Volunteers who fulfilled inclusion and exclusion criteria were randomized into 2 groups of 22 each (males and females) and received 20 mg crocin tablets or placebo. General measures of health were recorded during the study such as hematological, biochemical, hormonal and urinary parameters in pre and post-treatment periods. Results: No major adverse events were reported during the trial. Crocin tablets did not change the above parameters except that it decreased amylase, mixed white blood cells and PTT in healthy volunteers after one month. Conclusion: This clinical safety evaluation showed a relatively safe and normal profile for crocin in healthy volunteers at the given doses within the trial period. PMID:23638291

The safety of pharmacologic treatment for pediatric obesity.

PubMed

Chao, Ariana M; Wadden, Thomas A; Berkowitz, Robert I

2018-04-01

Pediatric obesity is a serious public health concern. Five medications have been approved by the Food and Drug Administration (FDA) for chronic weight management in adults with obesity, when used as an adjunct to lifestyle modification. Orlistat is the only FDA-approved medication for pediatric patients aged 12 years and above. Areas covered: This paper summarizes safety and efficacy data from clinical trials of weight loss medications conducted among pediatric samples. Relevant studies were identified through searches in PubMed. Expert opinion: Orlistat, as an adjunct to lifestyle modification, results in modest weight losses and may be beneficial for some pediatric patients with obesity. However, gastrointestinal side effects are common and may limit use. In adults taking orlistat, rare but severe adverse events, including liver and renal events, have been reported. Recent pediatric pharmacokinetic studies of liraglutide have demonstrated similar safety and tolerability profiles as found in adults, with gastrointestinal disorders being the most common adverse events. Clinical trials are needed of liraglutide, as well as other medications for obesity, that systematically evaluate their risks and benefits in pediatric patients.

Pericardium-6 Acupressure for the Prevention of Postoperative Nausea and Vomiting

DTIC Science & Technology

1999-10-01

designed not only to inform anesthesia providers on the use of an alternative treatment method but also to aid in patient care and safety during...14 x Current Pharmacological Treatment for PONV............................................. 16 Proposed Mechanisms of Action...of Acupressure .......................................... 20 Acupressure for Treatment of PONV

Cardiac Safety of Ozanimod, a Novel Sphingosine-1-Phosphate Receptor Modulator: Results of a Thorough QT/QTc Study.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Olson, Allan D; Mendzelevski, Boaz; Timony, Gregg A; Boehm, Marcus F; Peach, Robert J; Gujrathi, Sheila; Frohna, Paul A

2018-03-01

Ozanimod is a novel, selective, oral sphingosine-1-phosphate (1 and 5) receptor modulator in development for multiple sclerosis and inflammatory bowel disease. This randomized, double-blind, placebo-controlled, positive-controlled, parallel-group thorough QT study characterized the effects of ozanimod on cardiac repolarization in healthy subjects. Eligible subjects were randomized to 1 of 2 groups: ozanimod (escalated from 0.25 to 2 mg over 14 days) or placebo (for 14 days). A single dose of moxifloxacin 400 mg or placebo was administered on days 2 and 17. The primary end point was the time-matched, placebo-corrected, baseline-adjusted mean QTcF (ΔΔQTcF). A total of 113/124 (91.1%) subjects completed the study. The upper limits of the 2-sided 90% confidence intervals for ΔΔQTcF for both ozanimod 1 and 2 mg were below the 10-millisecond regulatory threshold. No QTcF >480 milliseconds or postdose change in QTcF of >60 milliseconds was observed. There was no evidence of a positive relationship between concentrations of ozanimod and its active metabolites and ΔΔQTcF. Although ozanimod blunted the observed diurnal increase in heart rate, excursions below predose heart rates were no greater than with placebo. Results demonstrate that ozanimod does not prolong the QTc interval or cause clinically significant bradycardia, supporting ozanimod's evolving favorable cardiac safety profile. © 2017 The Authors. Clinical Pharmacology in Drug Development Published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

A review of the pharmacology and clinical efficacy of brivaracetam

PubMed Central

Klein, Pavel; Diaz, Anyzeila; Gasalla, Teresa; Whitesides, John

2018-01-01

Brivaracetam (BRV; Briviact) is a new antiepileptic drug (AED) approved for adjunctive treatment of focal (partial-onset) seizures in adults. BRV is a selective, high-affinity ligand for synaptic vesicle 2A (SV2A) with 15- to 30-fold higher affinity than levetiracetam, the first AED acting on SV2A. It has high lipid solubility and rapid brain penetration, with engagement of the target molecule, SV2A, within minutes of administration. BRV has potent broad-spectrum antiepileptic activity in animal models. Phase I studies indicated BRV was well tolerated and showed a favorable pharmacokinetic profile over a wide dose range following single (10–1,000 mg) and multiple (200–800 mg/day) oral dosing. Three pivotal Phase III studies have demonstrated promising efficacy and a good safety and tolerability profile across doses of 50–200 mg/day in the adjunctive treatment of refractory focal seizures. Long-term data indicate that the response to BRV is sustained, with good tolerability and retention rate. BRV is highly effective in patients experiencing secondarily generalized tonic–clonic seizures. Safety data to date suggest a favorable psychiatric adverse effect profile in controlled studies, although limited postmarketing data are available. BRV is easy to use, with no titration and little drug–drug interaction. It can be initiated at target dose with no titration. Efficacy is seen on day 1 of oral use in a significant percentage of patients. Intravenous administration in a 2-minute bolus and 15-minute infusion is well tolerated. Here, we review the pharmacology, pharmacokinetics, and clinical data of BRV. PMID:29403319

Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia's survey.

PubMed

Mathern, Gary W; Beninsig, Laurie; Nehlig, Astrid

2015-01-01

From May 20 to September 1 2014, Epilepsia conducted an online survey seeking opinions about the use of medical marijuana and cannabidiol (CBD) for people with epilepsy. This study reports the findings of that poll. The survey consisted of eight questions. Four questions asked if there were sufficient safety and efficacy data, whether responders would advise trying medical marijuana in cases of severe refractory epilepsy, and if pharmacologic grade compounds containing CBD should be available. Four questions addressed occupation, geographic region of residence, if responders had read the paper, and if they were International League Against Epilepsy/International Bureau for Epilepsy (ILAE/IBE) members. Of 776 who started or completed the survey, 58% were patients from North America, and 22% were epileptologists and general neurologists from Europe and North America. A minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% would advise using medical marijuana in severe cases of epilepsy. By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, saying that there were sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public. This survey indicates that there is a wide disparity in opinion on the use of medical marijuana and CBD in the treatment of people with epilepsy, which varied substantially, with fewer medical specialists supporting its use compared with general medical personal, and patients and the public. Wiley Periodicals, Inc. © 2014 International League Against Epilepsy.

The Use of Medical Expulsive Therapy During Pregnancy: A Worldwide Perspective Among Experts.

PubMed

Lloyd, Granville L; Lim, Amy; Hamoui, Nabeel; Nakada, Stephen Y; Kielb, Stephanie J

2016-03-01

Medical expulsive therapy (MET) is a pharmacologic approach thought to augment the spontaneous passage of ureteral calculi. The usage of MET pharmacologics for presumed ureteral calculi during pregnancy has not been studied and their safety and utility are unknown. We sought to characterize the worldwide usage of MET in the setting of pregnancy with presumed ureteral calculus (P-MET), as well as factors associated with physician use. Experts in stone management were specifically sought. A nine-question survey was delivered through society-administered e-mail. Questions gathered physician's worldwide region, degree of specialization in stone disease, practice type, interval since training, and willingness to use both MET and P-MET. We assessed drugs of choice in those using P-MET and reasons for avoidance in non-P-MET users. Finally, we assessed the impact of physician-perceived medicolegal risk on usage of P-MET. Five hundred sixty-five responses were recorded. Sixty-three percent were US-based practitioners and the remaining represented a worldwide distribution. Worldwide usage of MET was 97.6%, and tamsulosin was globally preferred by over 90% of urologists. P-MET was endorsed by only 44.3%. 23.6% of European practitioners used this strategy compared with 51.1% of US physicians. Time from training and practice type did not significantly interact with adoption of P-MET; experts were less likely to use P-MET. Physician nonuse of MET during pregnancy was adverse outcome related: 76.7% reported either the fear of legal risk (52.8%) or concerns about safety (23.9%). Respondents report impressive worldwide adoption of MET. P-MET is less trusted, and fears of legal risk and safety far outweigh questions about effectiveness. The effectiveness of drugs during pregnancy-induced ureteral dilation is unknown. Still, 44% of global respondents embrace usage of this drug strategy despite a paucity of evidence supporting either safety or effectiveness during pregnancy.

Use of aripiprazole for delirium in the elderly: a short review.

PubMed

Kirino, Eiji

2015-03-01

The effects and tolerability of antipsychotics in delirium treatment remain controversial. Compared to other antipsychotics, aripiprazole differs in pharmacological activity because it exerts its effect as a dopamine D2 partial agonist. The guidelines of the American Psychiatric Association rank aripiprazole highly among antipsychotics with regard to safety, and this drug is likely to be useful for delirium treatment. Here, we reviewed the efficacy and safety of aripiprazole for delirium. The results of our literature review on the efficacy and safety of delirium treatments suggest that aripiprazole is an effective treatment option for delirium in the elderly. Aripiprazole is as effective as other antipsychotics in improving delirium symptoms, and it is safer because it is less likely to cause extrapyramidal symptoms, excessive sedation, and weight gain. However, these findings are based on only a few clinical studies of elderly patients with delirium. Therefore, further investigations are necessary. © 2014 The Author. Psychogeriatrics © 2014 Japanese Psychogeriatric Society.

Pharmacological interventions for unilateral spatial neglect after stroke.

PubMed

Luvizutto, Gustavo José; Bazan, Rodrigo; Braga, Gabriel Pereira; Resende, Luiz Antônio de Lima; Bazan, Silméia Garcia Z; El Dib, Regina

2015-11-06

Unilateral spatial neglect (USN) is characterized by the inability to report or respond to people or objects presented on the side contralateral to the lesioned side of the brain and has been associated with poor functional outcomes and long stays in hospitals and rehabilitation centers. Pharmacological interventions (medical interventions only, use of drugs to improve the health condition), such as dopamine and noradrenergic agonists or pro-cholinergic treatment, have been used in people affected by USN after stroke, and effects of these treatments could provide new insights for health professionals and policy makers. To evaluate the effectiveness and safety of pharmacological interventions for USN after stroke. We searched the Cochrane Stroke Group Trials Register (April 2015), the Cochrane Central Register of Controlled Trials (April 2015), MEDLINE (1946 to April 2015), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) (1982 to April 2015), EMBASE (1980 to April 2015), PsycINFO (1806 to April 2015) and Latin American Caribbean Health Sciences Literature (LILACS) (1982 to April 2015). We also searched trials and research registers, screened reference lists, and contacted study authors and pharmaceutical companies (April 2015). We included randomized controlled trials (RCTs) and quasi-randomized controlled trials (quasi-RCTs) of pharmacological interventions for USN after stroke. Two review authors independently assessed risk of bias in the included studies and extracted data. We included in the review two studies with a total of 30 randomly assigned participants. We rated the quality of the evidence as very low as the result of study limitations, small numbers of events, and small sample sizes, with imprecision in the confidence interval (CI). We were not able to perform meta-analysis because of heterogeneity related to the different interventions evaluated between included studies. Very low-quality evidence from one trial (20 participants) comparing effects of rivastigmine plus rehabilitation versus rehabilitation on overall USN at discharge showed the following: Barrage (mean difference (MD) 0.30, 95% confidence interval (CI) -0.18 to 0.78); Letter Cancellation (MD 10.60, 95% CI 2.07 to 19.13); Sentence Reading (MD 0.20, 95% CI -0.69 to 1.09), and the Wundt-Jastrow Area Illusion Test (MD -4.40, 95% CI -8.28 to -0.52); no statistical significance was observed for the same outcomes at 30 days' follow-up. In another trial (10 participants), study authors showed statistically significant reduction in omissions in the three cancellation tasks under transdermal nicotine treatment (mean number of omissions 2.93 ± 0.5) compared with both baseline (4.95 ± 0.8) and placebo (5.14 ± 0.9) (main effect of treatment condition: F (2.23) = 11.06; P value < 0.0001). One major adverse event occurred in the transdermal nicotine treatment group, and treatment was discontinued in the affected participant. None of the included trials reported data on several of the prespecified outcomes (falls, balance, depression or anxiety, poststroke fatigue, and quality of life). The quality of the evidence from available RCTs was very low. The effectiveness and safety of pharmacological interventions for USN after stroke are therefore uncertain. Additional large RCTs are needed to evaluate these treatments.

Therapeutic Uses and Pharmacological Properties of Garlic, Shallot, and Their Biologically Active Compounds

PubMed Central

Mikaili, Peyman; Maadirad, Surush; Moloudizargari, Milad; Aghajanshakeri, Shahin; Sarahroodi, Shadi

2013-01-01

Objective(s): Garlic (Allium sativum L. family Liliaceae) is well known in Iran and its leaves, flowers, and cloves have been used in traditional medicine for a long time. Research in recent decades has shown widespread pharmacological effects of A. sativum and its organosulfur compounds especially Allicin. Studies carried out on the chemical composition of the plant show that the most important constituents of this plant are organosulfur compounds such as allicin, diallyl disulphide, S-allylcysteine, and diallyl trisulfide. Allicin represents one of the most studied among these naturally occurring compounds. In addition to A. sativum, these compounds are also present in A. hirtifolium (shallot) and have been used to treat various diseases. This article reviews the pharmacological effects and traditional uses of A. sativum, A. hirtifolium, and their active constituents to show whether or not they can be further used as potential natural sources for the development of novel drugs. Materials and Methods: For this purpose, the authors went through a vast number of sources and articles and all needed data was gathered. The findings were reviewed and classified on the basis of relevance to the topic and a summary of all effects were reported as tables. Conclusion: Garlic and shallots are safe and rich sources of biologically active compounds with low toxicity. Further studies are needed to confirm the safety and quality of the plants to be used by clinicians as therapeutic agents. PMID:24379960

Research development of a new GnRH antagonist (Elagolix) for the treatment of endometriosis: a review of the literature.

PubMed

Alessandro, Pontis; Luigi, Nappi; Felice, Sorrentino; Maria, Paoletti Anna; Benedetto, Melis Gian; Stefano, Angioni

2017-04-01

Limitated studies have reported the efficacy of GnRH antagonist on endometriosis symptoms. The aim of our study was to review all available trials to investigate the medical treatment of endometriosis with only GnRH antagonists, with special attention to pharmacodynamic activity, safety, and efficacy. Pub Med and Sciencedirect database were searched using terms of "endometriosis treatment", "GnRH antagonist", and "Elagolix". The search was limited to clinical studies published in English. Title and abstract were screened to identify relevant articles. Five studies covering use of GnRH antagonist were found. A phase 1 study evaluated the safety, pharmacokinetics, and inhibitory effects on gonadotropins and estradiol of single dose and 7 day elagolix administration to healthy premenopausal women; two phase II studies evaluated efficacy in patient with endometriosis. Moreover, there are two Phase III clinical trials just completed. GnRH antagonists may have the advantage of oral administration and lower incidence of adverse events. Currently, only Phase II studies have been published demonstrating promising results in terms of efficacy, safety, and tolerability. From the results of the phase III studies, elagolix may become a valuable addition to the armamentarium of pharmacological agents to treat endometriosis-related pain.

Vedolizumab: an α4β7 integrin inhibitor for inflammatory bowel diseases.

PubMed

Smith, Michael A; Mohammad, Rima A

2014-12-01

To review the pharmacology, efficacy, and safety of vedolizumab in the treatment of patients with ulcerative colitis (UC) and Crohn's disease (CD). A literature search through clinicialtrials.gov, EMBASE and MEDLINE was conducted (January 1966-June 2014) using the terms vedolizumab and MLN0002. References from retrieved articles were reviewed for any additional material. Additionally, the prescribing information was retrieved. Phase 1, 2, and 3 human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of vedolizumab were identified. Vedolizumab, an α4β7 integrin inhibitor, was recently approved for adult patients with moderate to severe active UC or CD who are refractory or intolerant to standard therapies or who are dependent on corticosteroids. Trial data have demonstrated that vedolizumab 300 mg at weeks 0, 2, and 6 followed by every 8 weeks is effective at inducing and maintaining clinical response and remission, improving mucosal appearance, and achieving corticosteroid-free remission in patients with UC. This regimen is also effective at achieving clinical response, remission, and corticosteroid-free remission in patients with CD. Patients treated with vedolizumab, unadjusted for exposure, reported experiencing nasopharyngitis, headache, nausea, arthralgias, pyrexia, upper-respiratory-tract infections, fatigue, and cough. Vedolizumab is an effective agent at inducing and maintaining remission in patients with UC or CD. Vedolizumab is generally well tolerated and has not been associated with progressive multifocal leukoencephalopathy. © The Author(s) 2014.

Label-free pharmacological profiling based on dynamic mass redistribution for characterization and authentication of hazardous natural products.

PubMed

Song, Hui-Peng; Wang, Hong; Zhao, Xiaoai; He, Ling; Zhong, Huailing; Wu, Si-Qi; Li, Ping; Yang, Hua

2017-07-05

Natural products are becoming increasingly popular in multiple fields involving medicines, foods and beverages. However, due to the frequent occurrence of poisoning incidents, their toxicity and safety have caused a serious concern. Here we report a method of biosensor-based two-phase pharmacological profiling (BTPP) for discovery, monitor and control of receptor-targeted natural products. BTPP uses a resonant waveguide grating biosensor for label-free and non-invasive detection of intracellular dynamic mass redistribution (DMR), a phenomenon caused by protein relocalization after receptors receiving stimulation from toxicants. The method can not only facilitate the identification of hazardous materials but also quantify their bioactivity by EC 50 . As a proof of concept, the method was successfully applied to recognize Daturae Flos (DF), an herb that can antagonize muscarinic acetylcholine M 2 receptor and further cause poisoning, from other easily confused species. BTPP combined with high performance liquid chromatography revealed that scopolamine and hyoscyamine in DF were the key marker compounds. Moreover, the method accurately picked out 2 M 2 receptor antagonists from 25 natural compounds, displaying its potential in high-throughput screening. This study provides a systematic illustration about the establishment, applicability and advantages of BTPP, which contributes to the safety assessment of natural products in related fields. Copyright © 2017 Elsevier B.V. All rights reserved.

Does patient reporting lead to earlier detection of drug safety signals? A retrospective comparison of time to reporting between patients and healthcare professionals in a global database.

PubMed

Rolfes, Leàn; van Hunsel, Florence; Caster, Ola; Taavola, Henric; Taxis, Katja; van Puijenbroek, Eugène

2018-03-09

To explore if there is a difference between patients and healthcare professionals (HCPs) in time to reporting drug-adverse drug reaction (ADR) associations that led to drug safety signals. This was a retrospective comparison of time to reporting selected drug-ADR associations which led to drug safety signals between patients and HCPs. ADR reports were selected from the World Health Organization Global database of individual case safety reports, VigiBase. Reports were selected based on drug-ADR associations of actual drug safety signals. Primary outcome was the difference in time to reporting between patients and HCPs. The date of the first report for each individual signal was used as time zero. The difference in time between the date of the reports and time zero was calculated. Statistical differences in timing were analysed on the corresponding survival curves using a Mann-Whitney U test. In total, 2822 reports were included, of which 52.7% were patient reports, with a median of 25% for all included signals. For all signals, median time to signal detection was 10.4 years. Overall, HCPs reported earlier than patients: median 7.0 vs. 8.3 years (P < 0.001). Patients contributed a large proportion of reports on drug-ADR pairs that eventually became signals. HCPs reported 1.3 year earlier than patients. These findings strengthen the evidence on the value of patient reporting in signal detection and highlight an opportunity to encourage patients to report suspected ADRs even earlier in the future. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Safety, tolerability and pharmacokinetics of the histamine H3 receptor antagonist, ABT-288, in healthy young adults and elderly volunteers.

PubMed

Othman, Ahmed A; Haig, George; Florian, Hana; Locke, Charles; Zhang, Jun; Dutta, Sandeep

2013-05-01

The objective of this work was to characterize the safety, tolerability and pharmacokinetics of ABT-288, a highly selective histamine H3 receptor antagonist, in healthy young adults and elderly subjects following single and multiple dosing in a phase 1 setting. Single doses (0.1, 0.3, 1, 3, 10, 20 and 40 mg ABT-288) and multiple doses (0.5, 1.5, 3 and 6 mg ABT-288 once-daily for 14 days) were evaluated in young adults and multiple doses (0.5, 1.5, 3 and 5 mg ABT-288 once-daily for 12 days) were evaluated in elderly subjects using randomized, double-blind, placebo-controlled, dose-escalating study designs. The effect of food on ABT-288 pharmacokinetics (5 mg single dose) was evaluated using an open label, randomized, crossover design. ABT-288 safety, tolerability and pharmacokinetics were comparable in young and elderly subjects. Single doses up to 40 mg and multiple doses up to 3 mg once-daily were generally safe and well tolerated. The most frequently reported adverse events were hot flush, headache, abnormal dreams, insomnia, nausea and dizziness. ABT-288 exposure (AUC) was dose-proportional over the evaluated dose ranges. The mean elimination half-life ranged from 40 to 61 h across dose groups. Steady state was achieved by day 10 of once-daily dosing with 3.4- to 4.2-fold accumulation. Food did not have a clinically meaningful effect on ABT-288 exposure. Based on the above results, 1 and 3 mg once-daily doses of ABT-288 were advanced to phase 2 evaluation in Alzheimer's patients. © 2012 Abbott Laboratories. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 237

NASA Technical Reports Server (NTRS)

1982-01-01

A bibliography is given on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects of biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. In general, emphasis is placed on applied research, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 139

NASA Technical Reports Server (NTRS)

1975-01-01

The biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space are referenced. Similar effects on biological organisms of lower order are also included. Related topics such as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors are discussed. Applied research is emphasized, but references to fundamental studies and theoretical principles related to experimental development are also included. A total of 242 reports, articles, and other documents are listed.

Aerospace Medicine and Biology: A Continuing Bibliography. Supplement 483

NASA Technical Reports Server (NTRS)

1999-01-01

Aerospace Medicine and Biology concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Economic Evaluation of “Pulse Dose” Radiofrequency in the Treatment of Occipital Neuralgia Headache

PubMed Central

Giovannini, Vittoria; Pusateri, Rachele; Russo, Viera; Viscardi, Daniela; Palomba, Rosa

2012-01-01

Headache occipital neuralgia is an example of pain-disease for which treatment both pharmacological protocols and invasive methods are used. Among the latter, the RF (Radiofrequency) pulse-dose has been of interest for the prospects of analgesic efficacy, safety and patient compliance, although at the moment only data concerning the pulsed RF and not the RF pulse-dose, that represents its evolution, are discussed in scientific literature. The purpose of this study is a “simple” economic evaluation of this method in headache occipital neuralgia. PMID:23905049

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles.

PubMed

Jin, Yan; Smith, Claire; Hu, Leijun; Coutant, David E; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2018-01-01

Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator-blind, parallel-group, multiple-ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose-dependent blockade of the EP4 receptor. Compared with placebo, 24-h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. © 2017 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Carcinogenicity assessment of the Hedgehog pathway inhibitor, vismodegib in Tg.rasH2 mice and Sprague-Dawley rats.

PubMed

Li, Jinze; Morinello, Eric; Larsen, Thomas; Frost, Denzil; Caro, Ivor; Gould, Stephen; Wong, Lisa; Hendricks, Angela; Dybdal, Noel; Dambach, Donna; Schutten, Melissa

2018-02-01

Vismodegib (also known as GDC-0449) is a novel small molecule inhibitor of the Hedgehog (Hh) signaling pathway currently approved for the treatment of metastatic or locally advanced basal cell carcinoma (BCC) in humans. Its tumorigenic potential was assessed in dedicated carcinogenicity studies in rasH2 transgenic (Tg.rasH2) mice and Sprague Dawley (SD) rats. Tumorigenicity potential of vismodegib was identified in rats only and was limited to benign hair follicle tumors, including pilomatricomas and keratoacanthomas at exposures of ≥0.1-fold and ≥0.6-fold, respectively, of the steady-state exposure (AUC 0-24h ) of the recommended human dose. No malignant tumors were identified in either species. Overall, the totality of pharmacology and nonclinical safety data (lack of genotoxicity, in vitro secondary pharmacological binding, and immunoregulatory effects, and limited effects on the endocrine system) suggests that the development of the benign hair follicle tumors may be related to pharmacologically-mediated disruption of hair follicle morphogenesis, although the exact mechanism of tumorigenesis is unclear. Hair follicle tumors have not been reported in vismodegib-treated patients. The relevance of this finding in rats to patients is uncertain. Copyright © 2018 Elsevier Inc. All rights reserved.

The Pharmacological Basis of Cannabis Therapy for Epilepsy.

PubMed

Reddy, Doodipala Samba; Golub, Victoria M

2016-04-01

Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy, both adults and children, who do not respond to current medications. There is a large unmet medical need for new antiepileptics that would not interfere with normal function in patients with refractory epilepsy and conditions associated with refractory seizures. The two chief cannabinoids are Δ-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major nonpsychoactive component of marijuana. Claims of clinical efficacy in epilepsy of CBD-predominant cannabis or medical marijuana come mostly from limited studies, surveys, or case reports. However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy. CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood. A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy of their use in the treatment of epilepsy. Identification of mechanisms underlying the anticonvulsant efficacy of CBD is also critical for identifying other potential treatment options. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

Traditional uses, phytochemistry, pharmacology and toxicology of the genus Cimicifuga: A review.

PubMed

Guo, Yaqing; Yin, Tong; Wang, Xiaoming; Zhang, Fan; Pan, Guixiang; Lv, Hong; Wang, Xianrui; Owoicho Orgah, John; Zhu, Yan; Wu, Honghua

2017-09-14

Plants of the genus Cimicifuga have long been used as an ethnomedicine in China, Europe, and North America for its high medicinal value and health benefits. Their dried rhizomes are widely used for treating wind-heat headache, toothache, aphtha, sore throat, measles, spot poison, archoptosis, and uterine prolapse. In addition, it is used as a dietary supplement for preventing women menopausal symptoms and osteoporosis. This paper aims to provide up-to-date information on the genus Cimicifuga, including botanical characterization, medicinal resources, traditional medicinal uses, phytochemistry, quality control, pharmacological research as well as the toxicology. The possible structural-activity relationships and molecular mechanisms of the bioactive constituents are discussed in ways that contribute to the structural optimization and preclinical safety assessment for further drug design. The relevant information on Cimicifuga was collected from scientific databases (such as Google Scholar, PubMed, SciFinder Scholar, Science Direct, CNKI, Baidu Scholar, Web of Science, China Knowledge Resource Integrated Database), Chinese herbal classics, ethnobotanical books, PhD and MSc dissertations, Chinese Pharmacopoeia, published articles in peer-reviewed journals, local magazines, and unpublished materials. In addition, the Plant List (TPL, www.theplantlist.org) was also used to validate the scientific names and synonyms of this plant. The literature cited in this review dated from 1953 to 2017. The majority of chemical constituents of this plant include triterpenoid glycosides, phenylpropanoids, nitrogenous compounds, chromones, flavonoids and 4α-methyl steroid. Among them, the primary bioactive constituents are believed to be present in the triterpene glycoside fraction. To date, investigation of seven Cimicifuga spp. plants led to the identification of more than 457 compounds. Years of pharmacological research proved that the crude extracts and certain pure compounds obtained from Cimicifuga exhibited menopausal syndrome-treatment, anti-osteoporosis, antiviral, antitumor, antioxidant and antiangiogenic activities. On the other hand, Cimicifuga plant-induced toxicities of liver, cardiovascular, central and peripheral nervous systems have also been reported. Therefore, safety consideration should be placed into a high priority for herbal medicine Cimicifuga therapy in the early stages of development and clinical trials. This review presents information on botany, medicinal resources, and traditional medicinal history of some Cimicifuga plants. Modern pharmacology researchers have validated many traditional uses of Cimicifuga species. As the quality control and safety assessment of Cimicifuga plants is still incomplete, only a small part of the plant is permitted to be used as medicines. Expansion of medicinal resources in Cimicifuga is urgently needed to enable its full use. Currently research primarily focuses on the triterpenoid glycosides but there are many other types of compounds which may possess new biological activities however the systematic studies of these compounds are lacking. Extensive study is required on Cimicifuga plant before it can be fully used in clinics as a potent drug candidate. Copyright © 2017 Elsevier Ireland Ltd. All rights reserved.

National Partnership for Maternal Safety: Consensus Bundle on Venous Thromboembolism.

PubMed

D'Alton, Mary E; Friedman, Alexander M; Smiley, Richard M; Montgomery, Douglas M; Paidas, Michael J; D'Oria, Robyn; Frost, Jennifer L; Hameed, Afshan B; Karsnitz, Deborah; Levy, Barbara S; Clark, Steven L

2016-10-01

Obstetric venous thromboembolism is a leading cause of severe maternal morbidity and mortality. Maternal death from thromboembolism is amenable to prevention, and thromboprophylaxis is the most readily implementable means of systematically reducing the maternal death rate. Observational data support the benefit of risk-factor-based prophylaxis in reducing obstetric thromboembolism. This bundle, developed by a multidisciplinary working group and published by the National Partnership for Maternal Safety under the guidance of the Council on Patient Safety in Women's Health Care, supports routine thromboembolism risk assessment for obstetric patients, with appropriate use of pharmacologic and mechanical thromboprophylaxis. Safety bundles outline critical clinical practices that should be implemented in every maternity unit. The safety bundle is organized into four domains: Readiness, Recognition, Response, and Reporting and Systems Learning. Although the bundle components may be adapted to meet the resources available in individual facilities, standardization within an institution is strongly encouraged.

Biomarker-guided clinical development of the first-in-class anti-inflammatory FPR2/ALX agonist ACT-389949.

PubMed

Stalder, Anna K; Lott, Dominik; Strasser, Daniel S; Cruz, Hans G; Krause, Andreas; Groenen, Peter M A; Dingemanse, Jasper

2017-03-01

The main objectives of these two phase I studies were to investigate safety and tolerability as well as the pharmacokinetic/pharmacodynamic profile of the novel potent and selective formyl peptide receptor type 2 (FPR2)/Lipoxin A 4 receptor (ALX) agonist ACT-389949. A challenge model was used to assess the drug's anti-inflammatory potential, with the aim of selecting a dosing regimen for future patient studies. Two double-blind, randomized phase I studies investigated the safety, tolerability, pharmacokinetics and pharmacodynamics of ACT-389949 at different doses and dosing regimens. Drug exposure was correlated with target engagement markers such as receptor internalization and cytokine measurements. The effect of FPR2/ALX agonism on neutrophil migration was studied in a lipopolysaccharide (LPS) inhalation model. ACT-389949 was well tolerated. Maximum concentrations were reached around 2 h after dosing, with a mean terminal half-life of 29.3 h [95% confidence interval (CI) 25.5, 33.7]. After multiple-dose administration, exposure increased by 111% (95% CI 89, 136), indicating drug accumulation. Administration of ACT-389949 resulted in a dose-dependent, long-lasting internalization of FPR2/ALX into leukocytes. Pro- and anti-inflammatory cytokines were dose-dependently but transiently upregulated only after the first dose. No pharmacological effect on neutrophil count was observed in the LPS challenge test performed at steady state. FPR2/ALX agonism with ACT-389949 was shown to be safe and well tolerated in healthy subjects. Receptor internalization and downstream mediators pointed towards a desensitization of the system, which may explain the lack of effect on neutrophil recruitment in the LPS challenge model. © 2016 The British Pharmacological Society.

The "highs and lows" of the human brain on dopaminergics: Evidence from neuropharmacology.

PubMed

Martins, Daniel; Mehta, Mitul A; Prata, Diana

2017-09-01

Rewards are appetitive events that elicit approach. Ground-breaking findings from neurophysiological experiments in animals, alongside neuropharmacology and neuroimaging research in human samples have identified dopamine as the main neurochemical messenger of global reward processing in the brain. However, dopamine's contribution to the different components of reward processing remains to be precisely defined. To facilitate the informed design and interpretation of reward studies in humans, we have systematically reviewed all existing human pharmacological studies investigating how drug manipulation of the dopamine system affects reward-related behaviour and its neural correlates. Pharmacological experiments in humans face methodological challenges in terms of the: 1) specificity and safety of the available drugs for administration in humans, 2) uncertainties about pre- or post-synaptic modes of action, and 3) possible interactions with inter-individual neuropsychological or genotypic variables. In order to circumvent some of these limitations, future research should rely on the combination of different levels of observation, in integrative pharmaco-genetics-neurobehavioral approaches, to more completely characterize dopamine's role in both general and modality-specific processing of reward. Copyright © 2017 Elsevier Ltd. All rights reserved.

Multi-ingredient, caffeine-containing dietary supplements: history, safety, and efficacy.

PubMed

Gurley, Bill J; Steelman, Susan C; Thomas, Sheila L

2015-02-01

Our objective was to review the history, safety, and efficacy of caffeine-containing dietary supplements in the United States and Canada. PubMed and Web of Science databases (1980-2014) were searched for articles related to the pharmacology, toxicology, and efficacy of caffeine-containing dietary supplements with an emphasis on Ephedra-containing supplements, Ephedra-free supplements, and energy drinks or shots. Among the first and most successful dietary supplements to be marketed in the United States were those containing Ephedra—combinations of ephedrine alkaloids, caffeine, and other phytochemicals. A decade after their inception, serious tolerability concerns prompted removal of Ephedra supplements from the US and Canadian markets. Ephedra-free products, however, quickly filled this void. Ephedra-free supplements typically contain multiple caffeine sources in conjunction with other botanical extracts whose purposes can often be puzzling and their pharmacologic properties difficult to predict. Ingestion of these products in the form of tablets, capsules, or other solid dosage forms as weight loss aids, exercise performance enhancers, or energy boosters have once again brought their tolerability and efficacy into question. In addition to Ephedra-free solid dosage forms, caffeine-containing energy drinks have gained a foothold in the world market along with concerns about their tolerability. This review addresses some of the pharmacologic and pharmaceutical issues that distinguish caffeine-containing dietary supplement formulations from traditional caffeine-containing beverages. Such distinctions may account for the increasing tolerability concerns affiliated with these products. Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.

Considerations for the nonclinical safety evaluation of antibody drug conjugates for oncology.

PubMed

Roberts, Stanley A; Andrews, Paul A; Blanset, Diann; Flagella, Kelly M; Gorovits, Boris; Lynch, Carmel M; Martin, Pauline L; Kramer-Stickland, Kimberly; Thibault, Stephane; Warner, Garvin

2013-12-01

Antibody drug conjugates (ADCs) include monoclonal antibodies that are linked to cytotoxic small molecules. A number of these agents are currently being developed as anti-cancer agents designed to improve the therapeutic index of the cytotoxin (i.e., cytotoxic small molecule or cytotoxic agent) by specifically delivering it to tumor cells. This paper presents primary considerations for the nonclinical safety evaluation of ADCs and includes strategies for the evaluation of the entire ADC or the various individual components (i.e., antibody, linker or the cytotoxin). Considerations are presented on how to design a nonclinical safety assessment program to identify the on- and off-target toxicities to enable first-in-human (FIH) studies. Specific discussions are also included that provide details as to the need and how to conduct the studies for evaluating ADCs in genetic toxicology, tissue cross-reactivity, safety pharmacology, carcinogenicity, developmental and reproductive toxicology, biotransformation, toxicokinetic monitoring, bioanalytical assays, immunogenicity testing, test article stability and the selection of the FIH dose. Given the complexity of these molecules and our evolving understanding of their properties, there is no single all-encompassing nonclinical strategy. Instead, each ADC should be evaluated on a case-by-case scientifically-based approach that is consistent with ICH and animal research guidelines. Copyright © 2013 Elsevier Inc. All rights reserved.

Tenofovir alafenamide (TAF) treatment of HBV, what are the unanswered questions?

PubMed

Viganò, Mauro; Loglio, Alessandro; Grossi, Glenda; Lampertico, Pietro

2018-02-01

Tenofovir disoproxil fumarate (TDF), an ester prodrug of tenofovir (TFV), is one of the recommended drugs for chronic hepatitis B (CHB) patients. However, reduced kidney function and loss of bone mineral density have been reported in some CHB patients treated with TDF. Consequent to these safety issues, tenofovir alafenamide (TAF) [Vemlidy®], a phosphonate prodrug of TFV, was developed for the treatment of CHB patients. Areas covered: The favourable pharmacological profile of TAF allows a marked reduction in dosage (25 mg/day) thus reducing systemic exposure to tenofovir and improving the bone and renal safety, keeping however the same virological efficacy, compared to TDF 300 mg/day. In two ongoing 96-week phase III trials in mainly treatment-naive HBeAg-positive or -negative patients, TAF showed similar viral suppression but was associated with significantly higher alanine aminotransferase normalization rates and more favourable renal and bone safety compared to TDF. In a 48-week TAF switch study enrolling patients treated with TDF for 96 weeks, glomerular, tubular and bone safety parameters rapidly improved while virological suppression was maintained. Expert commentary: Waiting long-term large scale clinical practice studies aimed to confirm these advantages, TAF represents an helpful treatment option for both naïve and TDF-exposed CHB patients.

Regulatory Forum Opinion Piece*: Use and Utility of Animal Models of Disease for Nonclinical Safety Assessment: A Pharmaceutical Industry Survey.

PubMed

Morgan, Sherry J; Couch, Jessica; Guzzie-Peck, Peggy; Keller, Douglas A; Kemper, Ray; Otieno, Monicah A; Schulingkamp, Robert J; Jones, Thomas W

2017-04-01

An Innovation and Quality (IQ) Consortium focus group conducted a cross-company survey to evaluate current practices and perceptions around the use of animal models of disease (AMDs) in nonclinical safety assessment of molecules in clinical development. The IQ Consortium group is an organization of pharmaceutical and biotechnology companies with the mission of advancing science and technology. The survey queried the utilization of AMDs during drug discovery in which drug candidates are evaluated in efficacy models and limited short-duration non-Good Laboratory Practices (GLP) toxicology testing and during drug development in which drug candidates are evaluated in GLP toxicology studies. The survey determined that the majority of companies used AMDs during drug discovery primarily as a means for proactively assessing potential nonclinical safety issues prior to the conduct of toxicology studies, followed closely by the use of AMDs to better understand toxicities associated with exaggerated pharmacology in traditional toxicology models or to derisk issues when the target is only expressed in the disease state. In contrast, the survey results indicated that the use of AMDs in development is infrequent, being used primarily to investigate nonclinical safety issues associated with targets expressed only in disease states and/or in response to requests from global regulatory authorities.

Use of betahistine in the treatment of peripheral vertigo.

PubMed

Ramos Alcocer, Rubén; Ledezma Rodríguez, José Gregorio; Navas Romero, Antonio; Cardenas Nuñez, José Luis; Rodríguez Montoya, Vicente; Deschamps, Jose Junior; Liviac Ticse, Jorge Anibal

2015-01-01

Clinical studies and meta-analyses demonstrated that betahistine is effective and safe in the treatment of Ménière's disease, BPPV (benign paroxysmal positional vertigo), vestibular neuronitis, and other types of peripheral vertigo. The goal of this paper is to review the pharmacological profile of betahistine and the evidence for its effectiveness and safety in the treatment of peripheral vertigo. Selection criteria for the publications on betahistine included randomized clinical trials that evaluated the effectiveness and safety of betahistine vs placebo or active control in the treatment of peripheral vertigo. Recent meta-analyses were also included. Databases searched included PubMed, the Cochrane Ear, Nose and Throat Disorders Group Trials Register, and ICTRP. The review also presents an update on the mechanisms of action, pharmacodynamics, and pharmacokinetics of betahistine. Efficacy and safety of betahistine has been demonstrated in numerous clinical trials. The precise mechanism of action of betahistine is still not completely understood, but the clinical experience demonstrated the benefit of betahistine in different types of peripheral vertigo. In more than 40 years of clinical use, betahistine has shown an excellent safety profile with the usual dose range from 8-48 mg daily. According to clinical studies, betahistine 48 mg daily during 3 months is an effective and safe option for the treatment of peripheral vertigo.

Advancements in the treatment of agitation in Alzheimer's disease.

PubMed

Antonsdottir, Inga M; Smith, Jessica; Keltz, Melanie; Porsteinsson, Anton P

2015-01-01

Neuropsychiatric symptoms (NPS) in Alzheimer's disease (AD) are associated with significant negative outcomes for patients and their caregivers. Agitation, one of the most distressing NPS, lacks well-established long-term interventions that are both effective and safe. While non-pharmacological interventions are the suggested first-line treatment, it isn't effective in managing symptoms for every patient. In such cases, clinicians turn to the use of pharmacological interventions. Traditionally, these interventions consist of off-label use of antipsychotics, sedative/hypnotics, anxiolytics, acetylcholinesterase inhibitors, memantine and antidepressants, where the efficacy doesn't necessarily outweigh the associated risks. Gains made in understanding the neurobiological mechanisms underlying agitation have fueled several recent clinical trials. A comprehensive literature search for published articles evaluating pharmacologic interventions for agitation in AD was done. A review of some of these clinical trials was completed: dextromethorphan/quinidine, scyllo-inositol, brexpiprazole, prazosin, cannabinoids, dronabinol and citalopram show promise in treating agitation. Neurobiological findings and enhanced trial designs have re-ignited the area of pharmacological treatment of NPS. Although further research is needed to fully determine the safety, tolerability and efficacy of these treatments, the mission to finding effective treatments for NPS such as agitation in patients with dementia is well underway.

Treatment of toxicity from amphetamines, related derivatives, and analogues: a systematic clinical review.

PubMed

Richards, John R; Albertson, Timothy E; Derlet, Robert W; Lange, Richard A; Olson, Kent R; Horowitz, B Zane

2015-05-01

Overdose of amphetamine, related derivatives, and analogues (ARDA) continues to be a serious worldwide health problem. Patients frequently present to the hospital and require treatment for agitation, psychosis, and hyperadrenegic symptoms leading to pathologic sequelae and mortality. To review the pharmacologic treatment of agitation, psychosis, and the hyperadrenergic state resulting from ARDA toxicity. MEDLINE, PsycINFO, and the Cochrane Library were searched from inception to September 2014. Articles on pharmacologic treatment of ARDA-induced agitation, psychosis, and hyperadrenergic symptoms were selected. Evidence was graded using Oxford CEBM. Treatment recommendations were compared to current ACCF/AHA guidelines. The search resulted in 6082 articles with 81 eligible treatment involving 835 human subjects. There were 6 high-quality studies supporting the use of antipsychotics and benzodiazepines for control of agitation and psychosis. There were several case reports detailing the successful use of dexmedetomidine for this indication. There were 9 high-quality studies reporting the overall safety and efficacy of β-blockers for control of hypertension and tachycardia associated with ARDA. There were 3 high-quality studies of calcium channel blockers. There were 2 level I studies of α-blockers and a small number of case reports for nitric oxide-mediated vasodilators. High-quality evidence for pharmacologic treatment of overdose from ARDA is limited but can help guide management of acute agitation, psychosis, tachycardia, and hypertension. The use of butyrophenone and later-generation antipsychotics, benzodiazepines, and β-blockers is recommended based on existing evidence. Future randomized prospective trials are needed to evaluate new agents and further define treatment of these patients. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Molecular docking, synthesis and biological screening of mefenamic acid derivatives as anti-inflammatory agents.

PubMed

Savjani, Jignasa K; Mulamkattil, Suja; Variya, Bhavesh; Patel, Snehal

2017-04-15

Drug induced gastrointestinal ulceration, renal side effects and hepatotoxicity are the main causes of numerous Non-Steroidal Anti-inflammatory Drugs (NSAIDs). Cyclooxygenase-2 (COX-2) inhibitors discovered to decrease the gastrointestinal issues, but unfortunately, most of them are associated with major cardiovascular adverse effects. Along these lines, various new strategies and frameworks were developed wherein basic alterations of the present medications were accounted for. The aim of the study was to prepare derivatives of mefenamic acid to evaluate anti-inflammatory activity with fewer adverse reactions. In this study, molecular docking investigations of outlined derivatives were done utilizing Protein Data Bank (PDB ID-4PH9). Synthesis of heterocyclic compounds was carried out utilizing Dicyclohexylcarbodiimide/4-Dimethylaminopyridine (DCC/DMAP) coupling. Acute toxicity prediction was performed using free online GUSAR (General Unrestricted Structure-Activity Relationships) software. The study indicated most of the compounds under safe category. In-vitro pharmacological assessment of heterocyclic compounds was done for COX-1 and COX-2 enzymes for the determination of selectivity. In vivo pharmacological screening for anti-inflammatory activity and ED 50 value were determined utilizing carrageenan induced rat paw edema. Gastro intestinal safety study was carried out on selected compounds and found to be devoid of any gastric ulcer toxicity. Most of the compounds indicated high scores as compared to standard during molecular modelling, analysis and displayed interactions with active amino acids of a COX-2 enzyme. The pharmacological screening uncovered that compound substituted with p-bromophenyl indicated maximum potency. Copyright © 2017 Elsevier B.V. All rights reserved.

Pharmacological interventions for daytime sleepiness and sleep disorders in Parkinson's disease: Systematic review and meta-analysis.

PubMed

Rodrigues, Tiago Martins; Castro Caldas, Ana; Ferreira, Joaquim J

2016-06-01

Daytime sleepiness and sleep disorders are frequently reported in Parkinson's disease (PD). However, their impact on quality of life has been underestimated and few clinical trials have been performed. We aimed to assess the efficacy and safety of pharmacological interventions for daytime sleepiness and sleep disorders in PD. Systematic review of randomized controlled trials comparing any pharmacological intervention with no intervention or placebo for the treatment of daytime sleepiness and sleep problems in PD patients. Ten studies (n = 338 patients) were included. Four trials addressed interventions for excessive daytime sleepiness. Meta-analysis of the three trials evaluating modafinil showed a significant reduction in sleepiness, as assessed by the Epworth Sleepiness Scale (ESS) (- 2.24 points, 95% CI - 3.90 to - 0.57, p < 0.05). In one study, treatment with caffeine was associated with a non-significant improvement of 1.71 points in ESS (95% CI, - 3.57 to 0.13). The six remaining trials assessed interventions for insomnia and REM sleep Behaviour Disorder (RBD). Single study results suggest that doxepin and YXQN granules might be efficacious, while pergolide may be deleterious for insomnia and that rivastigmine may be used to treat RBD in PD patients. However, there is insufficient evidence to support or refute the efficacy of any of these interventions. No relevant side effects were reported. Whilst providing recommendations, this systematic review depicts the lack of a body of evidence regarding the treatment of sleep disorders in PD patients; hence, further studies are warranted. Copyright © 2016 Elsevier Ltd. All rights reserved.

Use of bispectral index system (BIS) to Monitor Enteral Conscious (moderate) sedation during general dental procedures.

PubMed

Donaldson, Mark; Goodchild, Jason H

2009-12-01

Although dental board regulations for the provision of in-office enteral conscious (oral) sedation vary widely with respect to training and pharmacologic strategies, they agree on the use of drugs that are inherently safe, the use of pulse oximetry and the availability of emergency equipment, including pharmacologic antagonists. Patient safety is of greatest concern and is best addressed by appropriate selection of patients, adequate training of personnel and appropriate monitoring of patients. Readings from bispectral index system (BIS) monitors, which use electroencephalographic signals, correlate accurately with depth of sedation during nondissociative general anesthesia of adults and children in the operating room setting. The usefulness of such monitoring as an adjunct to other forms of monitoring of in-office enteral sedation in the dental setting may represent the next important application of this tool, adding a further level of safety for the patient and another level of predictability for the practitioner. This paper reviews the current evidence supporting this new technique, presenting data from 20 procedures in which BIS monitoring during in-office enteral sedation was employed in a community dental practice.

[Advances in the treatment of secondary osteoporosis].

PubMed

Galindo Zavala, R; Núñez Cuadros, E; Díaz Cordovés-Rego, G; Urda Cardona, A L

2014-12-01

Osteoporosis is being increasingly recognised in paediatric practice as a consequence of the increasing life expectancy of children who suffer from chronic diseases and other factors. There are many non-pharmacological measures that can improve children' bone health, for example, avoiding inflammatory activity and osteotoxic treatments; increasing sun exposure and weight-bearing exercise, and maintaining an adequate nutritional status. Vitamin D and calcium supplements have been proposed as a measure to increase bone mass, but their effect and therapeutic indications are not completely clear. On the other hand, bisphosphonates are currently the only pharmacological alternative for the patients with infantile secondary osteoporosis. However, more studies are required on the therapeutic indications, posology, and long term secondary effects of biphosphonates. The aim of this article is to analyze the scientific evidence of the effectiveness of the therapeutic alternatives for childhood secondary osteoporosis and their safety in children. Copyright © 2014 Asociación Española de Pediatría. Published by Elsevier Espana. All rights reserved.

Combining Machine Learning Systems and Multiple Docking Simulation Packages to Improve Docking Prediction Reliability for Network Pharmacology

PubMed Central

Hsin, Kun-Yi; Ghosh, Samik; Kitano, Hiroaki

2013-01-01

Increased availability of bioinformatics resources is creating opportunities for the application of network pharmacology to predict drug effects and toxicity resulting from multi-target interactions. Here we present a high-precision computational prediction approach that combines two elaborately built machine learning systems and multiple molecular docking tools to assess binding potentials of a test compound against proteins involved in a complex molecular network. One of the two machine learning systems is a re-scoring function to evaluate binding modes generated by docking tools. The second is a binding mode selection function to identify the most predictive binding mode. Results from a series of benchmark validations and a case study show that this approach surpasses the prediction reliability of other techniques and that it also identifies either primary or off-targets of kinase inhibitors. Integrating this approach with molecular network maps makes it possible to address drug safety issues by comprehensively investigating network-dependent effects of a drug or drug candidate. PMID:24391846

Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders.

PubMed

Nguyen, Linda; Thomas, Kelan L; Lucke-Wold, Brandon P; Cavendish, John Z; Crowe, Molly S; Matsumoto, Rae R

2016-03-01

Dextromethorphan (DM) is a commonly used antitussive and is currently the only FDA-approved pharmaceutical treatment for pseudobulbar affect. Its safety profile and diverse pharmacologic actions in the central nervous system have stimulated new interest for repurposing it. Numerous preclinical investigations and many open-label or blinded clinical studies have demonstrated its beneficial effects across a variety of neurological and psychiatric disorders. However, the optimal dose and safety of chronic dosing are not fully known. This review summarizes the preclinical and clinical effects of DM and its putative mechanisms of action, focusing on depression, stroke, traumatic brain injury, seizure, pain, methotrexate neurotoxicity, Parkinson's disease and autism. Moreover, we offer suggestions for future research with DM to advance the treatment for these and other neurological and psychiatric disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

Focusing on cardiovascular disease in type 2 diabetes mellitus: an introduction to bromocriptine QR.

PubMed

Bell, David S

2012-09-01

Cardiovascular risk reduction is a key priority in patients with diabetes. The relationship between glycemic control and macrovascular outcomes, such as the benefit of intensive glucose control and the importance of postprandial or fasting blood glucose, is still under debate. A number of pharmacologic options are available to treat type 2 diabetes mellitus and these options have differing evidence for their cardiovascular safety. In this article, the novel agent bromocriptine quick release is discussed. Recently approved, this once-daily treatment provides glycemic control as monotherapy or in combination with other antihyperglycemic medications and has been shown in a prospective phase 3 safety study to not increase cardiovascular risk. Therefore, bromocriptine quick release increases the range of options available to treat patients with type 2 diabetes mellitus without increasing cardiovascular risk.

Pharmacological management of anticholinergic delirium - theory, evidence and practice.

PubMed

Dawson, Andrew H; Buckley, Nicholas A

2016-03-01

The spectrum of anticholinergic delirium is a common complication following drug overdose. Patients with severe toxicity can have significant distress and behavioural problems that often require pharmacological management. Cholinesterase inhibitors, such as physostigmine, are effective but widespread use has been limited by concerns about safety, optimal dosing and variable supply. Case series support efficacy in reversal of anticholinergic delirium. However doses vary widely and higher doses commonly lead to cholinergic toxicity. Seizures are reported in up to 2.5% of patients and occasional cardiotoxic effects are also recorded. This article reviews the serendipitous path whereby physostigmine evolved into the preferred anticholinesterase antidote largely without any research to indicate the optimal dosing strategy. Adverse events observed in case series should be considered in the context of pharmacokinetic/pharmacodynamic studies of physostigmine which suggest a much longer latency before the maximal increase in brain acetylcholine than had been previously assumed. This would favour protocols that use lower doses and longer re-dosing intervals. We propose based on the evidence reviewed that the use of cholinesterase inhibitors should be considered in anticholinergic delirium that has not responded to non-pharmacological delirium management. The optimal risk/benefit would be with a titrated dose of 0.5 to 1 mg physostigmine (0.01-0.02 mg kg(-1) in children) with a minimum delay of 10-15 min before re-dosing. Slower onset and longer acting agents such as rivastigmine would also be logical but more research is needed to guide the appropriate dose in this setting. © 2015 The British Pharmacological Society.

Ascending-dose study of noribogaine in healthy volunteers: pharmacokinetics, pharmacodynamics, safety, and tolerability.

PubMed

Glue, Paul; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, Cheung-Tak; Friedhoff, Lawrence

2015-02-01

Noribogaine is the active metabolite of the naturally occurring psychoactive substance ibogaine, and may help suppress withdrawal symptoms in opioid-dependent subjects. The objectives of this Phase I study were to assess the safety, tolerability, pharmacokinetic, and pharmacodynamic profiles of noribogaine. In this ascending single-dose, placebo-controlled, randomized, double-blind, parallel-group study in 36 healthy drug-free male volunteers, 4 cohorts (n = 9) received oral doses of 3, 10, 30, or 60 mg or matching placebo, with intensive safety and pharmacokinetic assessments out to 216 hours, along with pharmacodynamic assessments sensitive to the effects of mu-opioid agonists. Noribogaine was rapidly absorbed, with peak concentrations occurring 2-3 hours after oral dosing, and showed dose-linear increases of area under the concentration-time curve (AUC) and Cmax between 3 and 60 mg. The drug was slowly eliminated, with mean half-life estimates of 28-49 hours across dose groups. Apparent volume of distribution was high (mean 1417-3086 L across dose groups). No safety or tolerability issues were identified in any cohort. No mu-opioid agonist pharmacodynamic effects were noted in pupillometry or cold-pressor testing. Single oral doses of noribogaine 3-60 mg were safe and well tolerated in healthy volunteers. © 2014, The American College of Clinical Pharmacology.

Safety pharmacology of acute MDMA administration in healthy subjects.

PubMed

Vizeli, Patrick; Liechti, Matthias E

2017-05-01

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4-8.2 h). The 125 mg dose of MDMA produced greater 'good drug effect' ratings than 75 mg. MDMA produced moderate and transient 'bad drug effect' ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

Venetoclax: A First-in-Class Oral BCL-2 Inhibitor for the Management of Lymphoid Malignancies.

PubMed

King, Amber C; Peterson, Tim J; Horvat, Troy Z; Rodriguez, Mabel; Tang, Laura A

2017-05-01

To review the pharmacology, efficacy, and safety of venetoclax for treatment of lymphoid malignancies. A literature search was performed of PubMed and MEDLINE databases (2005 to September 2016), abstracts from the American Society of Hematology and the American Society of Clinical Oncology, and ongoing studies from clinicaltrials.gov. Searches were performed utilizing the following key terms: venetoclax, ABT-199, GDC-199, obatoclax, GX15-070, BCL-2 inhibitor, navitoclax, ABT-263, and Venclexta. Studies of pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety of venetoclax in lymphoid malignancies were identified. Recently, treatment of B-cell lymphoproliferative disorders has shifted from conventional cytotoxic chemotherapy to novel small-molecule inhibitors. The advent of recently Food and Drug Administration-approved oral agents ibrutinib and idelalisib has shifted the paradigm of chronic lymphocytic leukemia (CLL) treatment; however, complete remission is uncommon, and the outcome for patients progressing on these treatments remains poor. Attention has been focused on a novel target, the B-cell lymphoma-2 protein (BCL-2), which serves an essential role in regulation of apoptosis. Venetoclax has demonstrated efficacy in multiple subtypes of lymphoid malignancies, including patients with relapsed/refractory CLL harboring deletion 17p, with an overall response rate of nearly 80%. Venetoclax is generally well tolerated, with the significant adverse effect being tumor lysis syndrome, for which there are formal management recommendations. Venetoclax has demonstrated promising results in relapsed/refractory lymphoid malignancies, with an acceptable adverse effect profile. As the role of BCL-2 inhibition in various malignancies becomes further elucidated, venetoclax may offer benefit to a myriad other patient populations.

NMR-based urine analysis in rats: prediction of proximal tubule kidney toxicity and phospholipidosis.

PubMed

Lienemann, Kai; Plötz, Thomas; Pestel, Sabine

2008-01-01

The aim of safety pharmacology is early detection of compound-induced side-effects. NMR-based urine analysis followed by multivariate data analysis (metabonomics) identifies efficiently differences between toxic and non-toxic compounds; but in most cases multiple administrations of the test compound are necessary. We tested the feasibility of detecting proximal tubule kidney toxicity and phospholipidosis with metabonomics techniques after single compound administration as an early safety pharmacology approach. Rats were treated orally, intravenously, inhalatively or intraperitoneally with different test compounds. Urine was collected at 0-8 h and 8-24 h after compound administration, and (1)H NMR-patterns were recorded from the samples. Variation of post-processing and feature extraction methods led to different views on the data. Support Vector Machines were trained on these different data sets and then aggregated as experts in an Ensemble. Finally, validity was monitored with a cross-validation study using a training, validation, and test data set. Proximal tubule kidney toxicity could be predicted with reasonable total classification accuracy (85%), specificity (88%) and sensitivity (78%). In comparison to alternative histological studies, results were obtained quicker, compound need was reduced, and very importantly fewer animals were needed. In contrast, the induction of phospholipidosis by the test compounds could not be predicted using NMR-based urine analysis or the previously published biomarker PAG. NMR-based urine analysis was shown to effectively predict proximal tubule kidney toxicity after single compound administration in rats. Thus, this experimental design allows early detection of toxicity risks with relatively low amounts of compound in a reasonably short period of time.

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

PubMed

Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit clear discriminative effects when tested against classical drugs of abuse in drug discrimination studies, and were not self-administered by rats. However, these compounds did cause salient discriminative effects of their own in animals trained to discriminate them from no drug. Therefore, from a safety pharmacology perspective, novel compounds that do not cause discriminative effects similar to classical drugs of abuse, may still cause psychoactive effects in humans and carry the potential to maintain drug abuse, suggesting that proactive investigation of drug abuse potential is warranted (Swedberg, 2013). These and other findings will be discussed, and the application of drug discrimination procedures beyond the typical standard application of testing novel compounds against known and well characterized reference drugs will be addressed. Copyright © 2016 Elsevier Inc. All rights reserved.

Navigating the fine line between benefit and risk in chronic atrial fibrillation: rationale and design of the Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY).

PubMed

Carrington, Melinda J; Ball, Jocasta; Horowitz, John D; Marwick, Thomas H; Mahadevan, Gnanadevan; Wong, Chiew; Abhayaratna, Walter P; Haluska, Brian; Thompson, David R; Scuffham, Paul A; Stewart, Simon

2013-06-20

Health outcomes associated with atrial fibrillation (AF) continue to be poor and standard management often does not provide clinical stability. The Standard versus Atrial Fibrillation spEcific managemenT studY (SAFETY) compares the efficacy of a post-discharge, nurse-led, multi-disciplinary programme to optimise AF management with usual care. SAFETY is a prospective, multi-centre, randomised controlled trial with blinded-endpoint adjudication. A target of 320 hospitalised patients with a chronic form of AF will be randomised (stratified by "rate" versus "rhythm" control) to usual post-discharge care or the SAFETY Intervention (SI). The SI involves home-based assessment, extensive clinical profiling and the application of optimal gold-standard pharmacology which is individually tailored according to a "traffic light" framework based on clinical stability, risk profile and therapeutic management. The primary endpoint is event-free survival from all-cause death or unplanned readmission during 18-36 months follow-up. Secondary endpoints include rate of recurrent hospital stay, treatment success (i.e. maintenance of rhythm or rate control and/or application of anti-thrombotic therapy without a bleeding event) and cost-efficacy. With study recruitment to be completed in early 2012, the results of this study will be available in early 2014. If positive, SAFETY will represent a potentially cost-effective and readily applicable strategy to improve health outcomes in high risk individuals discharged from hospital with chronic AF. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

First-in-human study assessing safety, tolerability and pharmacokinetics of BI 409306, a selective phosphodiesterase 9A inhibitor, in healthy males.

PubMed

Moschetti, Viktoria; Boland, Katja; Feifel, Ulrich; Hoch, Anja; Zimdahl-Gelling, Heike; Sand, Michael

2016-11-01

The aim of the present study was to investigate the safety, tolerability, dose proportionality and relative bioavailability of tablet and oral solution formulations of BI 409306 in healthy male subjects, and to compare the safety and pharmacokinetics in subjects who were extensive metabolizers (EMs) or poor metabolizers (PMs) of cytochrome P450 (CYP)-2C19. The present randomized, double-blind, placebo-controlled, single-centre study evaluated single rising doses of BI 409306 (0.5-500 mg) administered as a tablet or oral solution to EMs or PMs. Of 80 enrolled subjects (mean age 36.7 years), 79 (CYP2C19 EMs, 71; CYP2C19 PMs, eight) received treatment and completed the study. Adverse events (AEs) were mild to moderate in intensity. Overall, 17/71 (23.9%) EMs and 6/8 (75.0%) PMs experienced 28 and eight AEs, respectively, of which, 25 and seven AEs, respectively, were considered to be drug related. The most frequently reported AEs were nervous system and eye disorders; all occurred shortly (20-30 min) after administration and mostly resolved within 1-2 h. No serious AEs occurred. BI 409306 systemic absorption and elimination were rapid; peak plasma concentration (C max ) was reached <1 h after drug administration, and the half-life ranged from 0.99 h to 2.71 h. Both the tablet and oral solution resulted in similar exposures. In PMs, at dose levels of 10 mg and 100 mg, C max was 2.2-2.3-fold higher, and the area under the plasma concentration-time curve over the time interval 0 extrapolated to infinity was 4.1-5.0-fold higher compared with EMs. In healthy male subjects, BI 409306 was generally safe and well tolerated, with rapid absorption and elimination. Systemic exposure was higher in CYP2C19 PMs than EMs at the same dose level. © 2016 Boehringer Ingelheim. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov.

PubMed

Stockmann, Chris; Sherwin, Catherine M T; Koren, Gideon; Campbell, Sarah C; Constance, Jonathan E; Linakis, Matthew; Balch, Alfred; Varner, Michael W; Spigarelli, Michael G

2014-04-01

Physiologic changes during pregnancy alter the pharmacokinetics, safety, and efficacy of many drugs. For clinicians, there is often uncertainty regarding the safety of these drugs due to a scarcity of published data. This study aimed to comprehensively evaluate the characteristics and publication patterns of obstetric studies registered in ClinicalTrials.gov from 2007 to 2012. Primary outcome measures, funding sources, inclusion criteria, and the reporting of study results were evaluated. A manual review of Medline/PubMed was performed to identify publications associated with studies registered in ClinicalTrials.gov. Of 93,709 total studies, there were 5,203 (6%) obstetric studies registered in ClinicalTrials.gov. Interventional studies accounted for 70% and 30% were observational. Clinical trials of drugs (49%), procedures (13%), and behavioral interventions (12%) were most common. Among interventional drug trials, 84% featured randomized allocation to study arms and 93% included measures of safety and/or efficacy as primary endpoints. Of 946 (18%) studies completed more than 2 years ago, only 11% had reported results and <7% had been published. In an area with a great need for evidence of safe and effective therapies, the low publication rate of completed studies incorporating elements of high-quality trial design is concerning. The sources of this trend should be closely investigated. © 2013, The American College of Clinical Pharmacology.

Greater Celandine's Ups and Downs−21 Centuries of Medicinal Uses of Chelidonium majus From the Viewpoint of Today's Pharmacology

PubMed Central

Zielińska, Sylwia; Jezierska-Domaradzka, Anna; Wójciak-Kosior, Magdalena; Sowa, Ireneusz; Junka, Adam; Matkowski, Adam M.

2018-01-01

As antique as Dioscorides era are the first records on using Chelidonium as a remedy to several sicknesses. Inspired by the “signatura rerum” principle and an apparent ancient folk tradition, various indications were given, such as anti-jaundice and cholagogue, pain-relieving, and quite often mentioned—ophthalmological problems. Central and Eastern European folk medicine has always been using this herb extensively. In this region, the plant is known under many unique vernacular names, especially in Slavonic languages, associated or not with old Greek relation to “chelidon”—the swallow. Typically for Papaveroidae subfamily, yellow-colored latex is produced in abundance and leaks intensely upon injury. Major pharmacologically relevant components, most of which were first isolated over a century ago, are isoquinoline alkaloids—berberine, chelerythrine, chelidonine, coptisine, sanguinarine. Modern pharmacology took interest in this herb but it has not ended up in gaining an officially approved and evidence-based herbal medicine status. On the contrary, the number of relevant studies and publications tended to drop. Recently, some controversial reports and sometimes insufficiently proven studies appeared, suggesting anticancer properties. Anticancer potential was in line with anecdotical knowledge spread in East European countries, however, in the absence of directly-acting cytostatic compounds, some other mechanisms might be involved. Other properties that could boost the interest in this herb are antimicrobial and antiviral activities. Being a common synanthropic weed or ruderal plant, C. majus spreads in all temperate Eurasia and acclimates well to North America. Little is known about the natural variation of bioactive metabolites, including several aforementioned isoquinoline alkaloids. In this review, we put together older and recent literature data on phytochemistry, pharmacology, and clinical studies on C. majus aiming at a critical evaluation of state-of-the-art from the viewpoint of historical and folk indications. The controversies around this herb, the safety and drug quality issues and a prospective role in phytotherapy are discussed as well. PMID:29713277

[Clinical and pharmacological aspects of rifaximin, local antibiotic therapy in intestinal disorders].

PubMed

Gasztonyi, Beáta; Hunyady, Béla

2004-10-24

The authors report pharmacokinetics and indications of rifaximin and the results of clinical studies. Rifaximin has a large antibacterial spectrum with a good therapeutic effect on both gram positive and gram negative aerob and anaerob bacteria. Practically there is no absorption (< 1%) following oral administration with a high concentration in gastrointestinal mucosa (8000 microg/g). No increase in absorption can be detected in intestinal damage caused by inflammatory bowel disease. The remarkable safety profile of rifaximin is due to its negligible quality of absorption. According to the clinical studies rifaximin could be an adequate therapeutic approach in all gastrointestinal diseases and interventions when antibacterial therapy is needed.

Pharmacology of biosimilar candidate drugs in rheumatology: a literature review.

PubMed

Araújo, F; Cordeiro, I; Teixeira, F; Gonçalves, J; Fonseca, J E

2014-01-01

To review current evidence concerning pharmacology of biosimilar candidates to be used in rheumatology. A PubMed search up to August 2013 was performed using relevant search terms to include all studies assessing pharmacological properties of biosimilar candidates to be used in rheumatology. Data on study characteristics, type of intervention, pharmacokinetics (PK), pharmacodynamics (PD) and bioequivalence ratios was extracted. Of 280 articles screened, 5 fulfilled our inclusion criteria. Two trials, PLANETAS and PLANETRA, compared CT-P13 and infliximab in patients with active ankylosing spondylitis and rheumatoid arthritis, respectively. PK bioequivalence was demonstrated in the phase 1 PLANETAS trial by highly comparable area under the curve (AUC) and maximum drug concentrations (Cmax), whose geometric mean ratios fell between the accepted bioequivalence range of 80-125%. Equivalence in efficacy and safety was demonstrated in the phase 3 PLANETRA trial. Two phase 1 trials comparing etanercept biosimilar candidates TuNEX and HD203 in healthy volunteers showed a high degree of similarity in AUC and Cmax, with respective geometric mean ratios between PK bioequivalence range. The last included trial referred to GP2013, a rituximab biosimilar candidate, which demonstrated PK and PD bioequivalence to reference product in three different dosing regimens in cynomolgus monkeys. Infliximab, etanercept and rituximab biosimilar candidates have demonstrated PK bioequivalence in the trials included in this review. CT-P13 has recently been approved for use in the European market and the remaining biosimilar candidates are currently being tested in patients with rheumatoid arthritis.

Traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis: A review.

PubMed

Gao, Shi-Man; Liu, Jiu-Shi; Wang, Min; Cao, Ting-Ting; Qi, Yao-Dong; Zhang, Ben-Gang; Sun, Xiao-Bo; Liu, Hai-Tao; Xiao, Pei-Gen

2018-06-12

Species of the genus Codonopsis are perennial herbs mainly distributed throughout East, Southeast and Central Asia. As recorded, they have been used as traditional Chinese medicines since the Qing Dynasty, where they were claimed for strengthening the spleen and tonifying the lung, as well as nourishing blood and engendering liquid. Some species are also used as food materials in southern China and Southeast Asia, such as tea, wine, soup, plaster, and porridge. The review aims to assess the ethnopharmacological uses, explicit the material basis and pharmacological action, promote the safety of medical use, and suggest the future research potentials of Codonopsis. Information on the studies of Codonopsis was collected from scientific journals, books, and reports via library and electronic data search (PubMed, Elsevier, Scopus, Google Scholar, Springer, Science Direct, Wiley, Researchgate, ACS, EMBASE, Web of Science and CNKI). Meanwhile, it was also obtained from published works of material medica, folk records, ethnopharmacological literatures, Ph.D. and Masters Dissertation. Plant taxonomy was confirmed to the database "The Plant List" (www.theplantlist.org). Codonopsis has been used for medicinal purposes all around the world. Some species are also used as food materials in southern China and Southeast Asia. The chemical constituents of Codonopsis mainly are polyacetylenes, polyenes, flavonoids, lignans, alkaloids, coumarins, terpenoids, steroids, organic acids, saccharides, and so on. Extract of Codonopsis exhibit extensive pharmacological activities, including immune function regulation, hematopoiesis improvement, cardiovascular protection, neuroprotection, gastrointestinal function regulation, endocrine function regulation, cytotoxic and antibacterial effects, anti-aging and anti-oxidation, etc. Almost no obvious toxicity or side effect are observed and recorded for Codonopsis. The traditional uses, phytochemistry, pharmacology and toxicology of Codonopsis are reviewed in this paper. Species of the genus have long been used as traditional medicines and food materials, they are reported with a large number of chemical constituents with different structures, extensive pharmacological activities in immune system, blood system, digestive system, etc. and almost no toxicity. More profound studies on less popular species, pharmacodynamic material basis and pharmacological mechanism, and quality assurance are suggested to be carried out to fulfil the research on the long-term clinical use and new drug research of Codonopsis. Copyright © 2018 Elsevier B.V. All rights reserved.

Immunotherapies to prevent mother-to-child transmission of HIV.

PubMed

Hicar, Mark D

2013-03-01

Although pharmacological interventions have been successful in reducing prevention of maternal to child transmission (PMTCT) of HIV, there is concern that complete elimination through this mode of transmission will require other measures. Immunotherapies in infants or pregnant mothers may be able to eradicate this form of transmission. A recent vaccine trial in adults showed encouraging results, but as in most HIV safety and efficacy vaccine trials, the question of MTCT was not addressed. Concentrating transmission studies and vaccine studies in the setting of MTCT offers several advantages. MTCT has a generally reproducible known transmission rate and has been successfully used to assess pharmacological interventions on decreasing transmission. Even in resource poor settings, the infrastructure for neonatal vaccination is already in place. Although rare, both passive and active vaccination trials have been successfully completed in pediatric populations. Unfortunately, little success in affecting MTCT has been shown. Largely, a correlate of protection in any type of transmission, including MTCT, is unknown. Data supports a role for antibodies in effecting strain and transmission during MTCT. The role of antibodies in MTCT is reviewed with a focus on recent passive immunization and considerations for future studies.

E-pharmacovigilance: development and implementation of a computable knowledge base to identify adverse drug reactions.

PubMed

Neubert, Antje; Dormann, Harald; Prokosch, Hans-Ulrich; Bürkle, Thomas; Rascher, Wolfgang; Sojer, Reinhold; Brune, Kay; Criegee-Rieck, Manfred

2013-09-01

Computer-assisted signal generation is an important issue for the prevention of adverse drug reactions (ADRs). However, due to poor standardization of patients' medical data and a lack of computable medical drug knowledge the specificity of computerized decision support systems for early ADR detection is too low and thus those systems are not yet implemented in daily clinical practice. We report on a method to formalize knowledge about ADRs based on the Summary of Product Characteristics (SmPCs) and linking them with structured patient data to generate safety signals automatically and with high sensitivity and specificity. A computable ADR knowledge base (ADR-KB) that inherently contains standardized concepts for ADRs (WHO-ART), drugs (ATC) and laboratory test results (LOINC) was built. The system was evaluated in study populations of paediatric and internal medicine inpatients. A total of 262 different ADR concepts related to laboratory findings were linked to 212 LOINC terms. The ADR knowledge base was retrospectively applied to a study population of 970 admissions (474 internal and 496 paediatric patients), who underwent intensive ADR surveillance. The specificity increased from 7% without ADR-KB up to 73% in internal patients and from 19.6% up to 91% in paediatric inpatients, respectively. This study shows that contextual linkage of patients' medication data with laboratory test results is a useful and reasonable instrument for computer-assisted ADR detection and a valuable step towards a systematic drug safety process. The system enables automated detection of ADRs during clinical practice with a quality close to intensive chart review. © 2013 The Authors. British Journal of Clinical Pharmacology © 2013 The British Pharmacological Society.

Pharmacokinetics and Safety of a Single Oral Dose of Mirogabalin in Japanese Subjects With Varying Degrees of Renal Impairment.

PubMed

Kato, Manabu; Tajima, Naoyuki; Shimizu, Takako; Sugihara, Masahiro; Furihata, Kenichi; Harada, Kazuhiro; Ishizuka, Hitoshi

2018-01-01

Mirogabalin (DS-5565) is a novel preferentially selective α 2 δ-1 ligand being developed for the treatment of diabetic peripheral neuropathic pain and postherpetic neuralgia. The current multicenter open-label study determined the effect of varying degrees of renal impairment on the pharmacokinetics and safety of a single dose of mirogabalin 5 mg in Japanese subjects. A total of 30 subjects (6 subjects per renal function category [normal, mild, moderate, or severe impairment; and end-stage renal disease (ESRD)]) were enrolled and completed the study. The AUC last increased with severity of renal impairment; the geometric least-squares mean ratios of AUC last compared with subjects with normal renal function were 1.3, 1.9, 3.6, and 5.3 for patients with mild, moderate, and severe impairment and ESRD, respectively. In accordance with this AUC last increase, apparent total body clearance (CL/F), renal clearance (CLr), and the cumulative percentage of mirogabalin dose excreted into urine all decreased with severity of renal impairment. There were no deaths and no severe treatment-related adverse events (TEAEs), serious TEAEs, or TEAEs resulting in study discontinuation. Mirogabalin was well tolerated in Japanese subjects with normal renal function and those with mild to severe renal impairment. It was also tolerated in subjects with ESRD but with a higher incidence of TEAEs. The most frequently reported TEAEs were dizziness (ESRD, n = 3), somnolence (ESRD, n = 2), and vomiting (ESRD, n = 2). Based on these data, a mirogabalin dose adjustment will be considered in Japanese subjects with moderate to severe renal impairment and those with ESRD. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

PubMed Central

Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela; Del Bel, Elaine Aparecida; Guimarães, Francisco Silveira

2012-01-01

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ9-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca2+) increase, etc.), on CBD behavioural effects. PMID:23108553

Impact of calcium-sensitive dyes on the beating properties and pharmacological responses of human iPS-derived cardiomyocytes using the calcium transient assay.

PubMed

Kopljar, Ivan; Hermans, An N; Teisman, Ard; Gallacher, David J; Lu, Hua Rong

Calcium-based screening of hiPS-CMs is a useful preclinical safety evaluation platform with the ability to generate robust signals that facilitates high-throughput screening and data analysis. However, due to the potential inherent toxicities, it is important to understand potential effects of different calcium-sensitive dyes on the hiPS-CMs model. We compared three calcium-sensitive fluorescence dyes (Cal520, ACTOne and Calcium 5) for their impact on the variability, the beating properties and the pharmacological responses of hiPS-CMs using the Hamamatsu FDSS/μCell imaging platform. Direct effects of three dyes on the electrophysiological properties of hiPS-CMs were evaluated with the multi-electrode array (MEA) Axion Maestro platform. We propose a specific experimental protocol for each dye which gives the most optimal assay conditions to minimize variability and possible adverse effects. We showed that Cal520 had the smallest effect on hiPS-CMs together with the longest-lasting stable amplitude signal (up to 4 h). Although all dyes had a (minor) acute effect on hiPS-CMs, in the form of reduced beat rate and prolonged field potential duration, the selection of the dye did not influence the pharmacological response of four cardioactive drugs (dofetilide, moxifloxacin, nimodipine and isoprenaline). In conclusion, we have documented that different calcium sensitive dyes have only minor direct (acute) effects on hiPS-CMs with Cal520 showing the least effects and the longest lasting signal amplitude. Importantly, drug-induced pharmacological responses in hiPS-CMs were comparable between the three dyes. These findings should help further improve the robustness of the hiPS-CMs-based calcium transient assay as a predictive, preclinical cardiac safety evaluation tool. Copyright © 2018 Elsevier Inc. All rights reserved.

Impact of Pharmacogenetics on Efficacy and Safety of Statin Therapy for Dyslipidemia.

PubMed

Maxwell, Whitney D; Ramsey, Laura B; Johnson, Samuel G; Moore, Kate G; Shtutman, Michael; Schoonover, John H; Kawaguchi-Suzuki, Marina

2017-09-01

Interindividual variability in response to 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, or statins, with regard to both efficacy and safety is an obvious target for pharmacogenetic research. Many genes have been identified as possible contributors to variability in statin response and safety. Genetic polymorphisms may alter the structure or expression of coded proteins, with potential impacts on lipid and statin absorption, distribution, metabolism, and elimination as well as response pathways related to the pharmacologic effect. Many studies have explored the variation in statins' pharmacokinetic and pharmacodynamic parameters; however, to our knowledge, few have established definitive relationships between the genetic polymorphisms and patient outcomes, such as cardiovascular events. In this review article, we provide a statin-based summary of available evidence describing pharmacogenetic associations that may be of clinical relevance in the future. Although currently available studies are often small or retrospective, and may have conflicting results, they may be useful in providing direction for future confirmatory studies and may point to associations that could be confirmed in the future when more patient outcomes-based studies are available. We also summarize the clinically relevant evidence currently available to assist clinicians with providing personalized pharmacotherapy for patients requiring statin therapy. © 2017 Pharmacotherapy Publications, Inc.

Nonclinical safety of mavrilimumab, an anti-GMCSF receptor alpha monoclonal antibody, in cynomolgus monkeys: Relevance for human safety

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

Ryan, Patricia C., E-mail: ryanp@medimmune.com; Sleeman, Matthew A.; Rebelatto, Marlon

Mavrilimumab (CAM-3001) is an investigational human IgG4 monoclonal antibody (MAb) targeting GM-CSF receptor alpha which is currently being developed for the treatment of RA. GM-CSF plays a central role in the pathogenesis of rheumatoid arthritis (RA) through the activation, differentiation, and survival of macrophages and neutrophils. To support clinical development, the nonclinical safety of mavrilimumab was evaluated in several studies with cynomolgus monkeys as the pharmacologically relevant species. Comprehensive toxicity parameters were assessed in each study, and treatment duration ranged from 4 to 26 weeks. Mavrilimumab has an acceptable safety profile in monkeys with no changes in any parameters othermore » than microscopic findings in lung. In several studies, minimal accumulation of foamy alveolar macrophages was observed. This finding was only seen in studies of at least 11 weeks duration, was reversible following a dose-free recovery period and was considered non-adverse. At higher dose levels (≥ 30 mg/kg/week), in a 26-week repeat-IV dose study, the presence of lung foreign material, cholesterol clefts, and granulomatous inflammation was also observed in a few animals and was considered adverse. The dose- and time-related accumulation of foamy macrophages in lung following exposure to mavrilimumab observed in several NHP studies was expected based upon the known role of GM-CSFRα signaling in the function of alveolar macrophages. Overall, a clean no-observed-adverse-effect-level (NOAEL) without any effects in lung was established and provided adequate clinical safety margins. In clinical studies in RA patients, mavrilimumab has demonstrated good clinical activity with adequate safety to support further clinical development. A Phase 2b study of mavrilimumab in subjects with RA is in progress. - Highlights: • Mavrilimumab is a MAB targeting GM-CSFRα being developed for RA therapy. • Mavrilimumab has an acceptable safety profile in cynomolgus monkeys. • Lung changes observed reflect role of GM-CSF in alveolar macrophage function. • High safety margins support continued clinical development of mavrilimumab.« less

Audience response technology: engaging and empowering non-medical prescribing students in pharmacology learning.

PubMed

Lymn, Joanne S; Mostyn, Alison

2010-10-27

Non-medical prescribing (NMP) is a six month course for nurses and certain allied health professionals. It is critical that these students develop a good understanding of pharmacology; however, many students are mature learners with little or no formal biological science knowledge and struggle with the pharmacology component. The implications for patient safety are profound, therefore we encourage students not just to memorise enough pharmacology to pass the exam but to be able to integrate it into clinical practice. Audience response technology (ART), such as the KeePad system (KS) has been shown to promote an active approach to learning and provide instant formative feedback. The aim of this project, therefore, was to incorporate and evaluate the use the KS in promoting pharmacology understanding in NMP students. Questions were incorporated into eight pharmacology lectures, comprising a mix of basic and clinical pharmacology, using TurningPoint software. Student (n = 33) responses to questions were recorded using the KS software and the percentage of students getting the question incorrect and correct was made immediately available in the lecture in graphical form. Survey data collected from these students investigated student perceptions on the use of the system generally and specifically as a learning tool. More in depth discussion of the usefulness of the KS was derived from a focus group comprising 5 students. 100% of students enjoyed using the KS and felt it promoted their understanding of key concepts; 92% stated that it helped identify their learning needs and 87% agreed that the technology was useful in promoting integration of concepts. The most prevalent theme within feedback was that of identifying their own learning needs. Analysis of data from the focus group generated similar themes, with the addition of improving teaching. Repeated questioning produced a significant increase (p < 0.05) in student knowledge of specific pharmacological concepts. The use of ART enhanced non-medical prescribing students' experience of pharmacology teaching. Student perceptions were that this system increased their ability to identify learning needs and promoted understanding and integration of concepts. Students also reported that the technology aided exam revision and reduced associated anxiety.

Audience response technology: Engaging and empowering non-medical prescribing students in pharmacology learning

PubMed Central

2010-01-01

Background Non-medical prescribing (NMP) is a six month course for nurses and certain allied health professionals. It is critical that these students develop a good understanding of pharmacology; however, many students are mature learners with little or no formal biological science knowledge and struggle with the pharmacology component. The implications for patient safety are profound, therefore we encourage students not just to memorise enough pharmacology to pass the exam but to be able to integrate it into clinical practice. Audience response technology (ART), such as the KeePad system (KS) has been shown to promote an active approach to learning and provide instant formative feedback. The aim of this project, therefore, was to incorporate and evaluate the use the KS in promoting pharmacology understanding in NMP students. Methods Questions were incorporated into eight pharmacology lectures, comprising a mix of basic and clinical pharmacology, using TurningPoint software. Student (n = 33) responses to questions were recorded using the KS software and the percentage of students getting the question incorrect and correct was made immediately available in the lecture in graphical form. Survey data collected from these students investigated student perceptions on the use of the system generally and specifically as a learning tool. More in depth discussion of the usefulness of the KS was derived from a focus group comprising 5 students. Results 100% of students enjoyed using the KS and felt it promoted their understanding of key concepts; 92% stated that it helped identify their learning needs and 87% agreed that the technology was useful in promoting integration of concepts. The most prevalent theme within feedback was that of identifying their own learning needs. Analysis of data from the focus group generated similar themes, with the addition of improving teaching. Repeated questioning produced a significant increase (p < 0.05) in student knowledge of specific pharmacological concepts. Conclusions The use of ART enhanced non-medical prescribing students' experience of pharmacology teaching. Student perceptions were that this system increased their ability to identify learning needs and promoted understanding and integration of concepts. Students also reported that the technology aided exam revision and reduced associated anxiety. PMID:20979620

Two Phase 1, Open-Label, Single-Dose, Randomized, Crossover Studies to Assess the Pharmacokinetics, Safety, and Tolerability of Orally Administered Granules of Secnidazole (2 g) in Healthy Female Volunteers Under Different Administration Conditions.

PubMed

Pentikis, Helen S; Adetoro, Nikki

2017-11-10

Bacterial vaginosis (BV) is the most common vaginal infection in reproductive-age women and a significant risk factor for sexually transmitted diseases and pregnancy complications. Standard 5- to 7-day antimicrobial treatments for BV are associated with high rates of recurrence and adverse events. SYM-1219 is a novel granule formulation containing 2 g of secnidazole, developed as an oral, single-dose BV treatment. Two phase 1, open-label, single-center, randomized, crossover trials (studies 102 and 103) assessed the pharmacokinetics and safety of SYM-1219 single doses (≥7-day washout between doses) in healthy, nonpregnant women aged 18 to 65 years inclusive. Study 102 compared SYM-1219 in applesauce in fasted vs fed states. Study 103 compared SYM-1219 (fasted) in pudding and yogurt vs applesauce. Studies 102 and 103 each dosed 24 subjects (mean [standard deviation] ages, 36 [1.8] and 40 [11.6] years, respectively). In both studies the 90% confidence intervals for all treatment comparisons of maximum plasma concentration, area under the concentration-time curve from 0 to last measurable concentration and to infinity, geometric mean ratios were within 80% to 125%, demonstrating bioequivalence. In both studies median fasted time to maximum plasma concentration was 4 hours (6 hours fed in study 102), and mean half-life ranged from 17 to 19 hours. Treatment-emergent adverse events occurred in 70.8% and 83.3% subjects in studies 102 and 103, respectively, most commonly headache (41.7% and 50.0%) and gastrointestinal treatment-emergent adverse events. The pharmacokinetics of SYM-1219 were similar in fed and fasted states and when administered in different foods. © 2017 The Authors. Clinical Pharmacology in Drug Development published by Wiley Periodicals, Inc. on behalf of The American College of Clinical Pharmacology.

Preschool ADHD: exploring uncertainties in diagnostic validity and utility, and treatment efficacy and safety.

PubMed

Sonuga-Barke, Edmund J S; Daley, David; Thompson, Margaret; Swanson, Jim

2003-07-01

The current scientific and clinical status of preschool attention deficit hyperactivity disorder and its management is reviewed. Recent clinical and neuropsychological research supporting the utility of the construct will be presented along with a critical analysis of diagnostic issues. The published literature on treatment efficacy (both pharmacological and nonpharmacological) will be reviewed with a special focus on the issue of the safety and side effects of psycho-stimulants. The need for early identification and preventative intervention is indicated but caution should be employed in the use of psychostimulants with this age group.

Drug safety is a barrier to the discovery and development of new androgen receptor antagonists.

PubMed

Foster, William R; Car, Bruce D; Shi, Hong; Levesque, Paul C; Obermeier, Mary T; Gan, Jinping; Arezzo, Joseph C; Powlin, Stephanie S; Dinchuk, Joseph E; Balog, Aaron; Salvati, Mark E; Attar, Ricardo M; Gottardis, Marco M

2011-04-01

Androgen receptor (AR) antagonists are part of the standard of care for prostate cancer. Despite the almost inevitable development of resistance in prostate tumors to AR antagonists, no new AR antagonists have been approved for over a decade. Treatment failure is due in part to mutations that increase activity of AR in response to lower ligand concentrations as well as to mutations that result in AR response to a broader range of ligands. The failure to discover new AR antagonists has occurred in the face of continued research; to enable progress, a clear understanding of the reasons for failure is required. Non-clinical drug safety studies and safety pharmacology assays were performed on previously approved AR antagonists (bicalutamide, flutamide, nilutamide), next generation antagonists in clinical testing (MDV3100, BMS-641988), and a pre-clinical drug candidate (BMS-501949). In addition, non-clinical studies with AR mutant mice, and EEG recordings in rats were performed. Non-clinical findings are compared to disclosures of clinical trial results. As a drug class, AR antagonists cause seizure in animals by an off-target mechanism and are found in vitro to inhibit GABA-A currents. Clinical trials of candidate next generation AR antagonists identify seizure as a clinical safety risk. Non-clinical drug safety profiles of the AR antagonist drug class create a significant barrier to the identification of next generation AR antagonists. GABA-A inhibition is a common off-target activity of approved and next generation AR antagonists potentially explaining some side effects and safety hazards of this class of drugs. Copyright © 2010 Wiley-Liss, Inc.

Pharmacokinetics, Safety, and Tolerability of Lamotrigine Chewable/Dispersible Tablet Following Repeat-Dose Administration in Healthy Chinese Volunteers.

PubMed

Li, Yan; Zhang, Fan; Xu, Yanmei; Hu, Joice; Li, Huafang

2018-03-26

In this open-label, single-center study, the pharmacokinetics, safety, and tolerability of lamotrigine chewable/dispersible tablets were assessed in healthy Chinese volunteers. Each volunteer (N = 16) received repeat doses of oral lamotrigine titrated from 25 mg to 50 mg to 100 mg over 42 days and was followed up for 10-17 days. Safety and tolerability were assessed throughout the study. Lamotrigine pharmacokinetic parameters were estimated using noncompartmental analysis. Overall, 15 (94%) volunteers completed the study. Lamotrigine serum concentrations peaked 2.5 hours postdose, with a mean terminal half-life of 36.8 hours. The apparent lamotrigine oral clearance was 1577.88 mL/h. The accumulation ratios (day 14 vs day 1) were 2.53 and 2.58 for area under the curve and peak concentration, respectively. Lamotrigine 25 to 100 mg once daily exhibited dose-proportional pharmacokinetics (based on area under the curve and peak concentration), following repeat dosing. Nine volunteers reported adverse events, 2 experienced oropharyngeal pain, each receiving 25 mg and 50 mg. One volunteer withdrew due to an increase in liver enzymes. No deaths, serious adverse effects, or skin rashes were reported during the study. No new safety concerns were observed. Overall, the pharmacokinetic profiles after repeat doses of lamotrigine chewable/dispersible tablets once daily in a Chinese population were similar to those observed in Western populations. © 2018, The American College of Clinical Pharmacology.

Dapagliflozin/Saxagliptin Fixed-Dose Tablets: A New Sodium-Glucose Cotransporter 2 and Dipeptidyl Peptidase 4 Combination for the Treatment of Type 2 Diabetes.

PubMed

Coppenrath, Valerie Azzopardi; Hydery, Tasmina

2018-01-01

To review the pharmacology, pharmacokinetics, efficacy, safety, and place in therapy of the fixed-dose combination (FDC) product, QTERN (dapagliflozin/saxagliptin) tablets. Searches of MEDLINE (1946 to July 1, 2017) were conducted using the keywords QTERN, saxagliptin, and dapagliflozin. Additional data were obtained from the prescribing information, the product dossier, and Clinicaltrials.gov . All English language articles related to pharmacology, pharmacokinetics, efficacy, or safety of the combination therapy in human subjects were reviewed. The pharmacokinetics of saxagliptin and dapagliflozin were not affected significantly when administered as an FDC product. Saxagliptin may suppress the increased secretion of glucagon associated with dapagliflozin. The combination dapagliflozin/saxagliptin has been studied as add-on therapy to metformin in patients with uncontrolled type 2 diabetes mellitus (T2DM). The difference in hemoglobin A 1C (A1C) between saxagliptin + dapagliflozin + metformin (triple therapy) and saxagliptin + metformin was -0.59 (95% CI = -0.81 to -0.37, P < 0.0001), and the difference between triple therapy and dapagliflozin + metformin was -0.27 (95% CI = -0.48 to -0.05, P = 0.0166). The combination was well tolerated when added to metformin. QTERN (dapagliflozin/saxagliptin) tablets are a reasonable option for patients with T2DM not controlled on metformin, but cost, insurance coverage, and a lackluster reduction in A1C will likely limit its use until more data regarding its effects on complications of diabetes and cardiovascular outcomes become available.

Risks and benefits of commonly used herbal medicines in Mexico.

PubMed

Rodriguez-Fragoso, Lourdes; Reyes-Esparza, Jorge; Burchiel, Scott W; Herrera-Ruiz, Dea; Torres, Eliseo

2008-02-15

In Mexico, local empirical knowledge about medicinal properties of plants is the basis for their use as home remedies. It is generally accepted by many people in Mexico and elsewhere in the world that beneficial medicinal effects can be obtained by ingesting plant products. In this review, we focus on the potential pharmacologic bases for herbal plant efficacy, but we also raise concerns about the safety of these agents, which have not been fully assessed. Although numerous randomized clinical trials of herbal medicines have been published and systematic reviews and meta-analyses of these studies are available, generalizations about the efficacy and safety of herbal medicines are clearly not possible. Recent publications have also highlighted the unintended consequences of herbal product use, including morbidity and mortality. It has been found that many phytochemicals have pharmacokinetic or pharmacodynamic interactions with drugs. The present review is limited to some herbal medicines that are native or cultivated in Mexico and that have significant use. We discuss the cultural uses, phytochemistry, pharmacological, and toxicological properties of the following plant species: nopal (Opuntia ficus), peppermint (Mentha piperita), chaparral (Larrea divaricata), dandlion (Taraxacum officinale), mullein (Verbascum densiflorum), chamomile (Matricaria recutita), nettle or stinging nettle (Urtica dioica), passionflower (Passiflora incarnata), linden flower (Tilia europea), and aloe (Aloe vera). We conclude that our knowledge of the therapeutic benefits and risks of some herbal medicines used in Mexico is still limited and efforts to elucidate them should be intensified.

Risks and benefits of commonly used herbal medicines in Mexico

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

Rodriguez-Fragoso, Lourdes; Reyes-Esparza, Jorge; Burchiel, Scott W.

In Mexico, local empirical knowledge about medicinal properties of plants is the basis for their use as home remedies. It is generally accepted by many people in Mexico and elsewhere in the world that beneficial medicinal effects can be obtained by ingesting plant products. In this review, we focus on the potential pharmacologic bases for herbal plant efficacy, but we also raise concerns about the safety of these agents, which have not been fully assessed. Although numerous randomized clinical trials of herbal medicines have been published and systematic reviews and meta-analyses of these studies are available, generalizations about the efficacymore » and safety of herbal medicines are clearly not possible. Recent publications have also highlighted the unintended consequences of herbal product use, including morbidity and mortality. It has been found that many phytochemicals have pharmacokinetic or pharmacodynamic interactions with drugs. The present review is limited to some herbal medicines that are native or cultivated in Mexico and that have significant use. We discuss the cultural uses, phytochemistry, pharmacological, and toxicological properties of the following plant species: nopal (Opuntia ficus), peppermint (Mentha piperita), chaparral (Larrea divaricata), dandlion (Taraxacum officinale), mullein (Verbascum densiflorum), chamomile (Matricaria recutita), nettle or stinging nettle (Urtica dioica), passionflower (Passiflora incarnata), linden flower (Tilia europea), and aloe (Aloe vera). We conclude that our knowledge of the therapeutic benefits and risks of some herbal medicines used in Mexico is still limited and efforts to elucidate them should be intensified.« less

Risks and Benefits of Commonly used Herbal Medicines in México

PubMed Central

Rodriguez-Fragoso, Lourdes; Reyes-Esparza, Jorge; Burchiel, Scott; Herrera-Ruiz, Dea; Torres, Eliseo

2008-01-01

In Mexico, local empirical knowledge about medicinal properties of plants is the basis for their use as home remedies. It is generally accepted by many people in Mexico and elsewhere in the world that beneficial medicinal effects can be obtained by ingesting plant products. In this review, we focus on the potential pharmacologic bases for herbal plant efficacy, but we also raise concerns about the safety of these agents, which have not been fully assessed. Although numerous randomized clinical trials of herbal medicines have been published and systematic reviews and meta-analyses of these studies are available, generalizations about the efficacy and safety of herbal medicines are clearly not possible. Recent publications have also highlighted the unintended consequences of herbal product use, including morbidity and mortality. It has been found that many phytochemicals have pharmacokinetic or pharmacodynamic interactions with drugs. The present review is limited to some herbal medicine that are native or cultivated in Mexico and that have significant use. We discuss the cultural uses, phytochemistry, pharmacological and toxicological properties of the following following plant species: Nopal (Opuntia ficus), Peppermint (Mentha piperita), Chaparral (Larrea divaricata), Dandlion (Taraxacum officinale), Mullein (Verbascum densiflorum), Chamomile (Matricaria recutita), Nettle or Stinging Nettle (Urtica dioica), Passionflower (Passiflora incarmata), Linden Flower (Tilia europea), and Aloa (Aloa vera). We conclude that our knowledge of the therapeutic benefits and risks of some herbal medicines used in Mexico is still limited and efforts to elucidate them should be intensified. PMID:18037151

Zoledronic acid in pediatric metabolic bone disorders.

PubMed

Bowden, Sasigarn A; Mahan, John D

2017-10-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted.

An unusual surgical indication for cerebral tuberculosis: status dystonicus. Case report.

PubMed

Franzini, Andrea; Franzini, Angelo; Levi, Vincenzo; Cordella, Roberto; Messina, Giuseppe

2018-05-15

Actual indications for surgery in tuberculosis are limited to obtaining a diagnosis, acquiring tissue for culture studies, treating hydrocephalus, aspiring a brain abscess, and reducing intracranial pressure in patients with multiple tuberculomas. Tuberculosis-related movement disorders are usually treated pharmacologically. We report on a child affected by post-tubercular generalized dystonia, who progressed to status dystonicus (SD) and underwent stereotactic bilateral pallidotomy. After surgery, SD resolved, and drugs were rapidly tapered. The successful reversal of SD and the motor improvement observed in our patient demonstrate the safety, feasibility, and clinical efficacy of pallidotomy in post-tuberculous-meningoencephalitis dystonia and SD.

Cassia fistula Linn: Potential candidate in the health management

PubMed Central

Rahmani, Arshad H.

2015-01-01

Cassia fistula Linn is known as Golden shower has therapeutics importance in health care since ancient times. Research findings over the last two decade have confirmed the therapeutics consequence of C. fistula in the health management via modulation of biological activities due to the rich source of antioxidant. Several findings based on the animal model have confirmed the pharmacologically safety and efficacy and have opened a new window for human health management. This review reveals additional information about C. fistula in the health management via in vivo and in vitro study which will be beneficial toward diseases control. PMID:26130932

[Medical-legal issues of physical and pharmacological restraint].

PubMed

Gómez-Durán, Esperanza L; Guija, Julio A; Ortega-Monasterio, Leopoldo

2014-03-01

The use of physical and pharmacological restraint is controversial but is currently accepted as inevitable. It is indicated for controlling behavioral disorders and psychomotor agitation that put patients and third parties at risk. Its indication should be medical, and we should opt for the least restrictive measure. Restraints represent a possible infringement of patients' fundamental rights and require understanding and strict respect for the medical-legal precepts by physicians and other practitioners involved in its application. This article reviews the current legal framework, as well as the medical-legal premises and aspects of applying restraints, with the objective of ensuring maximum respect for patients' rights and the appropriate legal safety in the activity of practitioners. Copyright © 2014 Elsevier España, S.L. All rights reserved.

Development of Safe and Effective Botanical Dietary Supplements

PubMed Central

2015-01-01

Regulated differently than drugs or foods, the market for botanical dietary supplements continues to grow worldwide. The recently implemented U.S. FDA regulation that all botanical dietary supplements must be produced using good manufacturing practice is an important step toward enhancing the safety of these products, but additional safeguards could be implemented, and unlike drugs, there are currently no efficacy requirements. To ensure a safe and effective product, botanical dietary supplements should be developed in a manner analogous to pharmaceuticals that involves identification of mechanisms of action and active constituents, chemical standardization based on the active compounds, biological standardization based on pharmacological activity, preclinical evaluation of toxicity and potential for drug–botanical interactions, metabolism of active compounds, and finally, clinical studies of safety and efficacy. Completing these steps will enable the translation of botanicals from the field to safe human use as dietary supplements. PMID:26125082

Guselkumab for the treatment of moderate-to-severe plaque psoriasis.

PubMed

Yang, Eric J; Sanchez, Isabelle M; Beck, Kristen; Sekhon, Sahil; Wu, Jashin J; Bhutani, Tina

2018-04-01

Guselkumab is a human monoclonal antibody targeting the p19 subunit of IL-23 that has been approved for the treatment of adult patients with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy. This medication blocks the IL-23/IL-17 axis, which has been implicated in playing a key role in the pathogenesis of psoriasis. Areas covered: This review outlines the pharmacologic properties, safety, and efficacy of guselkumab for the treatment of plaque psoriasis. Expert commentary: Guselkumab is the first IL-23 specific inhibitor to be approved for the treatment of plaque psoriasis. Phase II and III clinical trial results have demonstrated excellent safety and efficacy of guselkumab. IL-23 inhibitors may offer potential benefits over existing therapies for moderate-to-severe plaque psoriasis in terms of safety, frequency of administration, and efficacy. Long-term safety data will be critical in evaluating the role of guselkumab in the treatment of psoriasis.

The Influence of Safety, Efficacy, and Medical Condition Severity on Natural versus Synthetic Drug Preference.

PubMed

Meier, Brian P; Lappas, Courtney M

2016-11-01

Research indicates that there is a preference for natural v. synthetic products, but the influence of this preference on drug choice in the medical domain is largely unknown. We present 5 studies in which participants were asked to consider a hypothetical situation in which they had a medical issue requiring pharmacological therapy. Participants ( N = 1223) were asked to select a natural, plant-derived, or synthetic drug. In studies 1a and 1b, approximately 79% of participants selected the natural v. synthetic drug, even though the safety and efficacy of the drugs were identical. Furthermore, participants rated the natural drug as safer than the synthetic drug, and as that difference increased, the odds of choosing the natural over synthetic drug increased. In studies 2 and 3, approximately 20% of participants selected the natural drug even when they were informed that it was less safe (study 2) or less effective (study 3) than the synthetic drug. Finally, in study 4, approximately 65% of participants chose a natural over synthetic drug regardless of the severity of a specific medical condition (mild v. severe hypertension), and this choice was predicted by perceived safety and efficacy differences. Overall, these data indicate that there is a bias for natural over synthetic drugs. This bias could have implications for drug choice and usage. © The Author(s) 2015.

Dose-dependent acute liver injury with hypersensitivity features in humans due to a novel microsomal prostaglandin E synthase 1 inhibitor.

PubMed

Jin, Yan; Regev, Arie; Kam, Jeanelle; Phipps, Krista; Smith, Claire; Henck, Judith; Campanale, Kristina; Hu, Leijun; Hall, D Greg; Yang, Xiao Yan; Nakano, Masako; McNearney, Terry Ann; Uetrecht, Jack; Landschulz, William

2018-01-01

LY3031207, a novel microsomal prostaglandin E synthase 1 inhibitor, was evaluated in a multiple ascending dose study after nonclinical toxicology studies and a single ascending dose study demonstrated an acceptable toxicity, safety and tolerability profile. Healthy subjects were randomized to receive LY3031207 (25, 75 and 275 mg), placebo or celecoxib (400 mg) once daily for 28 days. The safety, tolerability and pharmacokinetic and pharmacodynamic profiles of LY3031207 were evaluated. The study was terminated when two subjects experienced drug-induced liver injury (DILI) after they had received 225 mg LY3031207 for 19 days. Liver biopsy from these subjects revealed acute liver injury with eosinophilic infiltration. Four additional DILI cases were identified after LY3031207 dosing had been stopped. All six DILI cases shared unique presentations of hepatocellular injury with hypersensitivity features and demonstrated a steep dose-dependent trend. Prompt discontinuation of the study drug and supportive medical care resulted in full recovery. Metabolites from metabolic activation of the imidazole ring were observed in plasma and urine samples from all subjects randomized to LY3031207 dosing. This study emphasized the importance of careful safety monitoring and serious adverse events management in phase I trials. Metabolic activation of the imidazole ring may be involved in the development of hepatotoxicity of LY3031207. © 2017 The British Pharmacological Society.

Subchronic and Genetic Safety Assessment of a New Medicinal Dendrobium Species: Dendrobium Taiseed Tosnobile in Rats

PubMed Central

Yang, Li-Chan; Liao, Jiunn-Wang; Wen, Chi-Luan

2018-01-01

Dendrobium Taiseed Tosnobile is a new species of herba dendrobii (Shi-Hu) that was developed by crossbreeding D. tosaense and D. nobile. Its pharmacological activity and active component have been reported, but its subchronic toxicity and genetic safety have not yet been investigated. This study assessed the 90-day oral toxicity and genetic safety of the aqueous extracts of D. Taiseed Tosnobile (DTTE) in male and female Sprague-Dawley (SD) rats. Eighty rats were divided into four groups, each consisting of ten male and ten female rats. DTTE was given orally to rats at 800, 1600, or 2400 mg/kg for 90 consecutive days, and distilled water was used for the control group. Genotoxicity studies were performed using a bacterial reverse mutation assay and in vivo mammalian cell micronucleus test in ICR mice and analyzed using flow cytometry. Throughout the study period, no abnormal changes were observed in clinical signs and body weight or on ophthalmological examinations. Additionally, no significant differences were found in urinalysis, hematology, and serum biochemistry parameters between the treatment and control groups. Necropsy and histopathological examination indicated no treatment-related changes. Based on results, the no-observed-adverse-effect level of DTTE is greater than 2400 mg/kg in SD rats. PMID:29541145

Pharmacologic intervention for retained placenta: a systematic review and meta-analysis.

PubMed

Duffy, James M N; Mylan, Sophie; Showell, Marian; Wilson, Matthew J A; Khan, Khalid S

2015-03-01

To assess the effectiveness and safety of pharmacologic interventions for the treatment of retained placenta (when the placenta remains undelivered after 30 minutes of active management of the third stage of labor). We searched: 1) Cochrane Central Register of Controlled Trials (CENTRAL), 2) Cochrane Pregnancy and Childbirth Group's Trials Register, 3) EMBASE, and 4) MEDLINE from inception to June 2014. Randomized controlled trials comparing a pharmacologic intervention(s) with a placebo for the treatment of retained placenta were included. Sixteen randomized controlled trials, including 1,683 participants, were included. Study characteristics and quality were recorded. The meta-analysis was based on random-effects methods for pooled data. There were no statistically significant differences in the requirement to perform manual removal of a placenta in patients treated with oxytocin (55% compared with 60%; relative risk [RR] 0.86, 95% confidence interval [CI] 0.73-1.02; 10 randomized controlled trials [RCTs]), prostaglandins (44% compared with 55%; RR 0.82, 95% CI 0.58-1.15; four RCTs), nitroglycerin (85% compared with 80%; RR 1.06, 95% CI 0.80-1.41; one RCT), or oxytocin and nitroglycerin (52% compared with 79%; RR 0.23, 95% CI 0.01-8.48; two RCTs) compared with placebo. There was limited reporting of secondary outcomes. As opposed to the use of oxytocin as part of the active management of the third stage of labor that has been shown to diminish bleeding in the third stage, once the diagnosis of retained placenta has been made, no pharmacologic treatment has been shown to be effective. When retained placenta is diagnosed, immediate manual removal of the placenta should be considered. PROSPERO International Prospective Register of Systematic Reviews, http://www.crd.york.ac.uk/PROSPERO/, CRD42014010641.

Commentary on recent therapeutic guidelines for osteoarthritis.

PubMed

Cutolo, Maurizio; Berenbaum, Francis; Hochberg, Marc; Punzi, Leonardo; Reginster, Jean-Yves

2015-06-01

Despite availability of international evidence-based guidelines for osteoarthritis (OA) management, agreement on the different treatment modalities is lacking. A symposium of European and US OA experts was held within the framework of the Annual European Congress of Rheumatology to discuss and compare guidelines and recommendations for the treatment of knee OA and to reach a consensus for management, particularly for areas in which there is no clear consensus: non-pharmacological therapy; efficacy and safety of analgesics and non-steroidal anti-inflammatory drugs (NSAIDs); intra-articular (i.a.) hyaluronates (HA); and the role of chondroitin sulfate (CS) and/or glucosamine sulfate (GS). All guidelines reviewed agree that knee OA is a progressive disease of the joint whose management requires non-pharmacological and pharmacological approaches. Discrepancies between guidelines are few and mostly reflect heterogeneity of expert panels involved, geographical differences in the availability of pharmacotherapies, and heterogeneity of the studies included. Panels chosen for guideline development should include experts with real clinical experience in drug use and patient management. Implementation of agreed guidelines can be thwarted by drug availability and reimbursement plans, resulting in optimal OA treatment being jeopardized, HA and symptomatic slow-acting drugs for osteoarthritis (SySADOAs) being clear examples of drugs whose availability and prescription can greatly vary geographically. In addition, primary care providers, often responsible for OA management (at least in early disease), may not adhere to clinical care guidelines, particularly for non-pharmacological OA treatment. Harmonization of the recommendations for knee OA treatment is challenging but feasible, as shown by the step-by-step therapeutic algorithm developed by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). More easily disseminated and implemented guidance for OA treatment in the primary care setting is key to improved management of OA. Copyright © 2015 Elsevier Inc. All rights reserved.

Forum for debate: Safety of allogeneic blood transfusion alternatives in the surgical/critically ill patient.

PubMed

Muñoz Gómez, M; Bisbe Vives, E; Basora Macaya, M; García Erce, J A; Gómez Luque, A; Leal-Noval, S R; Colomina, M J; Comin Colet, J; Contreras Barbeta, E; Cuenca Espiérrez, J; Garcia de Lorenzo Y Mateos, A; Gomollón García, F; Izuel Ramí, M; Moral García, M V; Montoro Ronsano, J B; Páramo Fernández, J A; Pereira Saavedra, A; Quintana Diaz, M; Remacha Sevilla, Á; Salinas Argente, R; Sánchez Pérez, C; Tirado Anglés, G; Torrabadella de Reinoso, P

2015-12-01

In recent years, several safety alerts have questioned or restricted the use of some pharmacological alternatives to allogeneic blood transfusion in established indications. In contrast, there seems to be a promotion of other alternatives, based on blood products and/or antifibrinolytic drugs, which lack a solid scientific basis. The Multidisciplinary Autotransfusion Study Group and the Anemia Working Group España convened a multidisciplinary panel of 23 experts belonging to different healthcare areas in a forum for debate to: 1) analyze the different safety alerts referred to certain transfusion alternatives; 2) study the background leading to such alternatives, the evidence supporting them, and their consequences for everyday clinical practice, and 3) issue a weighted statement on the safety of each questioned transfusion alternative, according to its clinical use. The members of the forum maintained telematics contact for the exchange of information and the distribution of tasks, and a joint meeting was held where the conclusions on each of the items examined were presented and discussed. A first version of the document was drafted, and subjected to 4 rounds of review and updating until consensus was reached (unanimously in most cases). We present the final version of the document, approved by all panel members, and hope it will be useful for our colleagues. Copyright © 2015 Elsevier España, S.L.U. and SEMICYUC. All rights reserved.

Safety and efficacy of Cardi-O-fix occluder for percutaneous closure of a patent foramen ovale

PubMed Central

Zhao, Enfa; Liu, Wenjuan; Zhang, Yushun; Cheng, Gesheng; Du, Yajuan; He, Lu; Wang, Xingye; He, Xumei

2017-01-01

Abstract Background: Amplatzer occluder and Cardio-O-fix occluder are currently used in percutaneous closure of patent foramen ovale. However, there is still a lack of relevant reports comparison the differences between them. The aim of this study was to evaluate the short-term and mid-term safety and efficacy of the Cardi-O-fix occluder in preventing recurrent cerebrovascular events in patients with a patent foramen ovale (PFO). Methods: We enrolled 246 patients (105 men) with a PFO from May 30, 2013 to March 30, 2015 in this single-center prospective study. All patients were treated by PFO interventional closure, with the Cardi-O-fix PFO occluder being used in 180 patients and the Amplatzer PFO occluder being utilized in the remaining 66 patients. After the procedure, we verified the safety and efficacy of different devices using contrast transthoracic echocardiography. Results: Neither recurrent stroke nor death was encountered during the follow-up of 12 months. Transient ischemic attack (TIA) was noted in 2 patients (1.1%) in the Cardi-O-fix PFO occluder group, and 1 patient suffered from TIA (1.5%) in the Amplatzer PFO occluder group. Among them, only 1 patient exhibited a small right to left shunt (RLS). There was no statistical difference in recurrent cerebral ischemic events. Three cases of paroxysmal atrial fibrillation were observed in the Cardi-O-fix PFO occluder group. One reverted spontaneously to sinus rhythm and the other 2 cases had pharmacologic conversion to sinus rhythm. One case of paroxysmal atrial fibrillation occurred in the Amplatzer group, which underwent pharmacologic conversion to sinus rhythm. There was no significant difference between the 2 groups regarding incidence of arrhythmia. No occluder translocation, erosion, pericardial effusion, and puncture site bleeding were observed in the 2 groups within 12 months of follow-up. The complete closure rates of the Cardi-O-fix and Amplatzer PFO occluder devices at the 12 months after the procedure were 73.9% and 63.6%, respectively, and the effective closure rates were 90.6% and 86.4%, respectively. There was no statistically significant difference in the complete closure rate and effective occlusion rate (P > 0.05) between the devices. Conclusions: There was no significant difference in the short- and mid-term efficacy and safety between the Cardi-O-fix PFO occluder and Amplatzer PFO occluder. The efficacy and safety of the Cardi-O-fix occluder were comparable to those of the Amplatzer PFO occluder. PMID:28383438

Teratology studies in the mouse.

PubMed

Marsden, Edward; Leroy, Mariline

2013-01-01

The rat is the routine species of choice as the rodent model for regulatory safety testing of xenobiotics such as medicinal products, food additives, and other chemicals. However, the rat is not always suitable for pharmacological, toxicological, immunogenic, pharmacokinetic, or even practical reasons. Under such circumstances, the mouse offers an alternative for finding a suitable rodent model acceptable to the regulatory authorities. Since all essential routes of administration are possible, the short reproductive cycle and large litter size of the mouse make it a species well adapted for use in teratology studies. Given that good quality animals, including virgin mated females, can be acquired relatively easily and inexpensively, the mouse has been used in reproductive toxicity studies for decades and study protocols are well established.

MicroRNAs as targets for dietary and pharmacological inhibitors of mutagenesis and carcinogenesis

PubMed Central

Izzotti, Alberto; Cartiglia, Cristina; Steele, Vernon E.; De Flora, Silvio

2012-01-01

MicroRNAs (miRNAs) have been implicated in many biological processes, cancer, and other diseases. In addition, miRNAs are dysregulated following exposure to toxic and genotoxic agents. Here we review studies evaluating modulation of miRNAs by dietary and pharmacological agents, which could potentially be exploited for inhibition of mutagenesis and carcinogenesis. This review covers natural agents, including vitamins, oligoelements, polyphenols, isoflavones, indoles, isothiocyanates, phospholipids, saponins, anthraquinones and polyunsaturated fatty acids, and synthetic agents, including thiols, nuclear receptor agonists, histone deacetylase inhibitors, antiinflammatory drugs, and selective estrogen receptor modulators. As many as 145 miRNAs, involved in the control of a variety of carcinogenesis mechanisms, were modulated by these agents, either individually or in combination. Most studies used cancer cells in vitro with the goal of modifying their phenotype by changing miRNA expression profiles. In vivo studies evaluated regulation of miRNAs by chemopreventive agents in organs of mice and rats, either untreated or exposed to carcinogens, with the objective of evaluating their safety and efficacy. The tissue specificity of miRNAs could be exploited for the chemoprevention of site-specific cancers, and the study of polymorphic miRNAs is expected to predict the individual response to chemopreventive agents as a tool for developing new prevention strategies. PMID:22683846

Aerospace Medicine and Biology: A continuing bibliography with indexes, supplement 212

NASA Technical Reports Server (NTRS)

1980-01-01

A bibliography listing 146 reports, articles, and other documents introduced into the NASA scientific and technical information system is presented. The subject coverage concentrates on the biological, psychological, and environmental factors involved in atmospheric and interplanetary flight. Related topics such as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, and exobiology are also given attention.

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae)

PubMed Central

Brinker, Anita M.; Ma, Jun; Lipsky, Peter E.; Raskin, Ilya

2013-01-01

Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook. f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-α (TNF-α), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-γ). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components. PMID:17250858

Medicinal chemistry and pharmacology of genus Tripterygium (Celastraceae).

PubMed

Brinker, Anita M; Ma, Jun; Lipsky, Peter E; Raskin, Ilya

2007-03-01

Plants in the genus Tripterygium, such as Tripterygium wilfordii Hook.f., have a long history of use in traditional Chinese medicine. In recent years there has been considerable interest in the use of Tripterygium extracts and of the main bioactive constituent, the diterpene triepoxide triptolide (1), to treat a variety of autoimmune and inflammation-related conditions. The main mode of action of the Tripterygium extracts and triptolide (1) is the inhibition of expression of proinflammatory genes such as those for interleukin-2 (IL-2), inducible nitric oxide synthase (iNOS), tumor necrosis factor-alpha (TNF-alpha), cyclooxygenase-2 (COX-2) and interferon-gamma (IFN-gamma). The efficacy and safety of certain types of Tripterygium extracts were confirmed in human clinical trials in the US and abroad. Over 300 compounds have been identified in the genus Tripterygium, and many of these have been evaluated for biological activity. The overall activity of the extract is based on the interaction between its components. Therefore, the safety and efficacy of the extract cannot be fully mimicked by any individual constituent. This review discusses the biochemical composition and biological and pharmacological activities of Tripterygium extracts, and their main bioactive components.

Doxylamine succinate-pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview.

PubMed

Nuangchamnong, Nina; Niebyl, Jennifer

2014-01-01

Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in part due to fears of adverse effects of medications on the fetus during early pregnancy. In April 2013, the US Food and Drug Administration (FDA) approved doxylamine succinate 10 mg and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination pill called Diclegis for the treatment of NVP. Diclegis is currently the only medication that is FDA-approved for the indication of NVP. This review addresses the historical context, safety, efficacy, pharmacology, and practical role of doxylamine and pyridoxine for the management of NVP. The reintroduction of this doxylamine-pyridoxine combination pill into the American market fills a therapeutic gap in the management of NVP left by the removal of the same active drugs marketed over 30 years ago in the form of Bendectin. The substantial amount of safety data accumulated over the years makes it one of the few drugs that qualify for FDA Pregnancy Category A status. In the hierarchical approach to pharmacological treatment of NVP, the combination of doxylamine and pyridoxine should thus be first-tier.

Doxylamine succinate–pyridoxine hydrochloride (Diclegis) for the management of nausea and vomiting in pregnancy: an overview

PubMed Central

Nuangchamnong, Nina; Niebyl, Jennifer

2014-01-01

Nausea and vomiting in pregnancy (NVP) is common and often undertreated, in part due to fears of adverse effects of medications on the fetus during early pregnancy. In April 2013, the US Food and Drug Administration (FDA) approved doxylamine succinate 10 mg and pyridoxine hydrochloride (a vitamin B6 analog) 10 mg as a delayed-release combination pill called Diclegis for the treatment of NVP. Diclegis is currently the only medication that is FDA-approved for the indication of NVP. This review addresses the historical context, safety, efficacy, pharmacology, and practical role of doxylamine and pyridoxine for the management of NVP. The reintroduction of this doxylamine–pyridoxine combination pill into the American market fills a therapeutic gap in the management of NVP left by the removal of the same active drugs marketed over 30 years ago in the form of Bendectin. The substantial amount of safety data accumulated over the years makes it one of the few drugs that qualify for FDA Pregnancy Category A status. In the hierarchical approach to pharmacological treatment of NVP, the combination of doxylamine and pyridoxine should thus be first-tier. PMID:24748822

Caffeine-based food supplements and beverages: Trends of consumption for performance purposes and safety concerns.

PubMed

Bessada, Sílvia M F; Alves, Rita C; Oliveira, M Beatriz P P

2018-07-01

Nowadays, daily food supplementation regarding the improvement of physical and mental performance is a growing trend in sport practitioners, young students and active people. Food supplements are foodstuffs, labeled under food law and not obliged to safety assessments before their commercialization. Several products are commercialized claiming ergogenic effects as marketing strategies. Caffeine is often one of their main ingredients, as it increases both physical performance and concentration. This manuscript presents a general overview of the current caffeine-based food supplements and energy drinks available in the Portuguese market, as well as the consuming trends regarding their ergogenic effects, performance purposes, and active ingredients. Product claims, recommended daily intakes, caffeine pharmacology, and safety concerns aspects are also discussed aspects. Copyright © 2018 Elsevier Ltd. All rights reserved.

Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)--a review of their phytochemistry, pharmacology, toxicology and traditional use.

PubMed

Jin, Gui-Lin; Su, Yan-Ping; Liu, Ming; Xu, Ying; Yang, Jian; Liao, Kai-Jun; Yu, Chang-Xi

2014-02-27

In the genus Gelsemium, Gelsemium elegans (Gardn. & Champ.) Benth. has been recognized as a toxic plant that is widely distributed in Southeast Asia and has been used as traditional Chinese medicine for the treatment of rheumatoid pain, neuropathic pain, spasticity, skin ulcers and cancers for many years. Gelsemium sempervirens (L.) J.St.-Hil. has been used since the nineteenth century in homeopathy for treating anxiety, neuralgia, migraine and spasmodic disorders, such as asthma and whooping cough in North America. This review aims to provide comprehensive information on the botany, traditional uses, phytochemistry, pharmacological research and toxicology of medicinal plants in the genus Gelsemium. The overall objective is to explore the evidence supporting its ethnopharmacological effectiveness. A literature survey was performed by searching the scientific databases Pubmed, Google Scholar, SciFinder, Scopus, Web of Science and the Chinese CNKI, in addition to traditional Chinese medicine and homeopathic texts for information on Gelsemium. Plants of the genus Gelsemium have been used in traditional medicine for the treatment of migraines, neuralgia, sciatica, cancer and various types of sores. Studies into the phytochemical composition of this genus have shown that all of the species are rich sources of monoterpene indole alkaloids and that they have attracted the attention of many researchers due to their markedly diverse and complex architecture. To date, a total of 121 alkaloids have been isolated and identified from the genus. The crude extracts, as well as the monomeric compounds, from the genus possess anti-tumor, analgesic, anxiolytic, anti-inflammatory and immunomodulating pharmacological activities. It is evident from the available literature that Gelsemium species possess potential for use as a beneficial therapeutic remedy. However, the analysis of previous pharmacological research suggests that a clear assignment of active molecules and mechanisms of action is remain lacking. Due to their high toxicity, the studies available on toxicity and safety are inadequate for providing information on clinical utilization. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

Synthesis, and anticonvulsant activity of new amides derived from 3-methyl- or 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetic acids.

PubMed

Obniska, Jolanta; Rapacz, Anna; Rybka, Sabina; Góra, Małgorzata; Kamiński, Krzysztof; Sałat, Kinga; Żmudzki, Paweł

2016-04-15

This paper describes the synthesis of the library of 22 new 3-methyl- and 3-ethyl-3-methyl-2,5-dioxo-pyrrolidin-1-yl-acetamides as potential anticonvulsant agents. The maximal electroshock (MES) and the subcutaneous pentylenetetrazole (scPTZ) seizure models were used for screening all the compounds. The 6 Hz model of pharmacoresistant limbic seizures was applied for studying selected derivatives. Six amides were chosen for pharmacological characterization of their antinociceptive activity in the formalin model of tonic pain as well as local anesthetic activity was assessed in mice. The pharmacological data indicate on the broad spectra of activity across the preclinical seizure models. Compounds 10 (ED50=32.08 mg/kg, MES test) and 9 (ED50=40.34 mg/kg, scPTZ test) demonstrated the highest potency. These compounds displayed considerably better safety profiles than clinically relevant antiepileptic drugs phenytoin, ethosuximide, or valproic acid. Several molecules showed antinociceptive and local anesthetic properties. The in vitro radioligand binding studies demonstrated that the influence on the sodium and calcium channels may be one of the essential mechanisms of action. Copyright © 2016. Published by Elsevier Ltd.

A cross-species translational pharmacokinetic-pharmacodynamic evaluation of core body temperature reduction by the TRPM8 blocker PF-05105679.

PubMed

Gosset, James R; Beaumont, Kevin; Matsuura, Tomomi; Winchester, Wendy; Attkins, Neil; Glatt, Sophie; Lightbown, Ian; Ulrich, Kristina; Roberts, Sonia; Harris, Jolie; Mesic, Emir; van Steeg, Tamara; Hijdra, Diana; van der Graaf, Piet H

2017-11-15

PF-05105679 is a moderately potent TRPM8 blocker which has been evaluated for the treatment of cold pain sensitivity. The TRPM8 channel is responsible for the sensation of cold environmental temperatures and has been implicated in regulation of core body temperature. Consequently, blockade of TRPM8 has been suggested to result in lowering of core body temperature. As part of the progression to human studies, the effect of PF-05105679 on core body temperature has been investigated in animals. Safety pharmacology studies showed that PF-05105679 reduced core body temperature in a manner that was inversely related to body weight of the species tested (greater exposure to PF-05105679 was required to lower temperature by 1°C in higher species). Based on an allometric (body weight) relationship, it was hypothesized that PF-05105679 would not lower core body temperature in humans at exposures that could exhibit pharmacological effects on cold pain sensation. On administration to humans, PF-05105679 was indeed effective at reversing the cold pain sensation associated with the cold pressor test in the absence of effects on core body temperature. Copyright © 2017 Elsevier B.V. All rights reserved.

Plant sterol enriched functional food and atherosclerosis.

PubMed

Köhler, Jürgen; Teupser, Daniel; Elsässer, Albrecht; Weingärtner, Oliver

2017-06-01

Hypercholesterolaemia is a major cardiovascular risk factor. A healthy diet and a healthy lifestyle reduces cardiovascular risk. 'Functional foods' supplemented with phytosterols are recommended for the management of hypercholesterolaemia and have become a widely used non-prescription approach to lower plasma cholesterol levels. Two billion euros are spent world-wide each year on various functional foods, which have regulator-approved health claims for the management of elevated cholesterol levels. While international societies, such as the European Atherosclerosis Society or the National Heart Foundation in Australia, still advise phytosterols as an additional dietary option in the management of hypercholesterolaemia, recently released guidelines such as those from the National Institute of Health and Clinical Excellence in the United Kingdom are more critical of food supplementation with phytosterols and draw attention to significant safety issues. This review challenges whether an intervention with phytosterol supplements is beneficial. We summarize the current evidence from genetic diseases, genetic association studies, clinical trial data and data from animal studies. This article is part of a themed section on Principles of Pharmacological Research of Nutraceuticals. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.11/issuetoc. © 2017 The British Pharmacological Society.

CYP2D6 predicted metabolizer status and safety in adult patients with attention-deficit hyperactivity disorder participating in a large placebo-controlled atomoxetine maintenance of response clinical trial.

PubMed

Fijal, Bonnie A; Guo, Yingying; Li, Si G; Ahl, Jonna; Goto, Taro; Tanaka, Yoko; Nisenbaum, Laura K; Upadhyaya, Himanshu P

2015-10-01

Atomoxetine, which is indicated for treatment of attention-deficit hyperactivity disorder (ADHD), is predominantly metabolized by genetically polymorphic cytochrome P450 2D6 (CYP2D6). Based on identified CYP2D6 genotypes, individuals can be categorized into 4 phenotypic metabolizer groups as ultrarapid, extensive, intermediate, and poor. Previous studies have focused on observed differences between poor and extensive metabolizers, but it is not well understood whether the safety profile of intermediate metabolizers differs from that of ultrarapid and extensive metabolizers. This study compared safety and tolerability among the different CYP2D6 metabolizer groups in the 12-week open-label phase of an atomoxetine study in adult patients with ADHD. Genotyping identified 1039 patients as extensive/ultrarapid metabolizers, 780 patients as intermediate metabolizers, and 117 patients as poor metabolizers. Common (≥5% frequency) treatment-emergent adverse events did not significantly differ between extensive/ultrarapid and intermediate metabolizers (odds ratios were <2.0 or >0.5). Poor metabolizers had higher frequencies of dry mouth, erectile dysfunction, hyperhidrosis, insomnia, and urinary retention compared with the other metabolizer groups. There were no significant differences between extensive/ultrarapid and intermediate metabolizers in changes from baseline in vital signs. These results suggest that data from CYP2D6 intermediate and extensive/ultrarapid metabolizers can be combined when considering safety analyses related to atomoxetine. © 2015, The American College of Clinical Pharmacology.

Translating New Science Into the Drug Review Process

PubMed Central

Rouse, Rodney; Kruhlak, Naomi; Weaver, James; Burkhart, Keith; Patel, Vikram; Strauss, David G.

2017-01-01

In 2011, the US Food and drug Administration (FDA) developed a strategic plan for regulatory science that focuses on developing new tools, standards, and approaches to assess the safety, efficacy, quality, and performance of FDA-regulated products. In line with this, the Division of Applied Regulatory Science was created to move new science into the Center for Drug Evaluation and Research (CDER) review process and close the gap between scientific innovation and drug review. The Division, located in the Office of Clinical Pharmacology, is unique in that it performs mission-critical applied research and review across the translational research spectrum including in vitro and in vivo laboratory research, in silico computational modeling and informatics, and integrated clinical research covering clinical pharmacology, experimental medicine, and postmarket analyses. The Division collaborates with Offices throughout CDER, across the FDA, other government agencies, academia, and industry. The Division is able to rapidly form interdisciplinary teams of pharmacologists, biologists, chemists, computational scientists, and clinicians to respond to challenging regulatory questions for specific review issues and for longer-range projects requiring the development of predictive models, tools, and biomarkers to speed the development and regulatory evaluation of safe and effective drugs. This article reviews the Division’s recent work and future directions, highlighting development and validation of biomarkers; novel humanized animal models; translational predictive safety combining in vitro, in silico, and in vivo clinical biomarkers; chemical and biomedical informatics tools for safety predictions; novel approaches to speed the development of complex generic drugs, biosimilars, and antibiotics; and precision medicine. PMID:29568713

Pharmacology of the glucagon-like peptide-1 analog exenatide extended-release in healthy cats.

PubMed

Rudinsky, A J; Adin, C A; Borin-Crivellenti, S; Rajala-Schultz, P; Hall, M J; Gilor, C

2015-04-01

Exenatide extended-release (ER) is a microencapsulated formulation of the glucagon-like peptide 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once-weekly injection with comparable efficacy to insulin with an improved safety profile in type II diabetic people. Here, we studied the pharmacology of exenatide ER in 6 healthy cats. A single subcutaneous injection of exenatide ER (0.13 mg/kg) was administered on day 0. Exenatide concentrations were measured for 12 wk. A hyperglycemic clamp (target = 225 mg/dL) was performed on days -7 (clamp I) and 21 (clamp II) with measurements of insulin and glucagon concentrations. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the clamp. Continuous glucose monitoring was performed on weeks 0, 2, and 6 after injection. Plasma concentrations of exenatide peaked at 1 h and 4 wk after injection. Comparing clamp I with clamp II, fasting blood glucose decreased (mean ± standard deviation = -11 ± 8 mg/dL, P = 0.02), glucose tolerance improved (median [range] +33% [4%-138%], P = 0.04), insulin concentrations increased (+36.5% [-9.9% to 274.1%], P = 0.02), and glucagon concentrations decreased (-4.7% [0%-12.1%], P = 0.005). Compared with preinjection values on continuous glucose monitoring, glucose concentrations decreased and the frequency of readings <50 mg/dL increased at 2 and 6 wk after injection of exenatide ER. This did not correspond to clinical hypoglycemia. No other side effects were observed throughout the study. Exenatide ER was safe and effective in improving glucose tolerance 3 wk after a single injection. Further evaluation is needed to determine its safety, efficacy, and duration of action in diabetic cats. Copyright © 2015 Elsevier Inc. All rights reserved.

Efficacy and safety of topical NSAIDs in the management of osteoarthritis: Evidence from real-life setting trials and surveys.

PubMed

Rannou, François; Pelletier, Jean-Pierre; Martel-Pelletier, Johanne

2016-02-01

Topical non-steroidal anti-inflammatory drugs (NSAIDs) are recommended in international and national guidelines as an early treatment option for the symptomatic management of knee and hand osteoarthritis (OA), and may be used ahead of oral NSAIDs due to their superior safety profile. The European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) treatment algorithm recommends topical NSAIDs for knee OA in addition to the pharmacological background of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs) and rescue analgesia with paracetamol and non-pharmacological treatment, if the patient is still symptomatic. Topical NSAIDs have a moderate effect on pain relief, with efficacy similar to that of oral NSAIDs, with the advantage of a better risk:benefit ratio. In real-life studies, topical and oral NSAIDs demonstrate an equivalent effect on knee pain over 1 year of treatment, with fewer adverse events due to lower systemic absorption of topical NSAIDs compared with oral NSAIDs. As a result, topical NSAIDs may be the preferred treatment option, especially in OA patients aged ≥75 years, and those with co-morbidities or at an increased risk of cardiovascular, gastrointestinal, or renal side effects. Furthermore, using topical NSAIDs in inflammatory rheumatic diseases leads to a 40% reduction in the need for concomitant oral NSAIDs. When selecting a topical NSAID, absorption and bioavailability are important because of heterogeneity among topical drug formulations. Molecules like etofenamate have a bioavailability of >20% and evidence for accumulation in synovial tissues, with efficacy demonstrated as improvement in pain and function in real-life studies of OA patients. Diclofenac also shows good efficacy alongside evidence that diclofenac accumulates in the synovium. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

A Pharmacovigilance Study in First Episode of Psychosis: Psychopharmacological Interventions and Safety Profiles in the PEPs Project

PubMed Central

Bioque, Miquel; Llerena, Adrián; Cabrera, Bibiana; Mezquida, Gisela; Lobo, Antonio; González-Pinto, Ana; Díaz-Caneja, Covadonga M.; Corripio, Iluminada; Aguilar, Eduardo J.; Bulbena, Antoni; Castro-Fornieles, Josefina; Vieta, Eduard; Lafuente, Amàlia; Mas, Sergi; Parellada, Mara; Saiz-Ruiz, Jerónimo; Cuesta, Manuel J.

2016-01-01

Background: The characterization of the first episode of psychosis and how it should be treated are principal issues in actual research. Realistic, naturalistic studies are necessary to represent the entire population of first episode of psychosis attended in daily practice. Methods: Sixteen participating centers from the PEPs project recruited 335 first episode of psychosis patients, aged 7 to 35 years. This article describes and discusses the psychopharmacological interventions and safety profiles at baseline and during a 60-day pharmacovigilance period. Results: The majority of first episode of psychosis patients received a second-generation antipsychotic (96.3%), orally (95%), and in adjusted doses according to the product specifications (87.2%). A total of 24% were receiving an antipsychotic polytherapy pattern at baseline, frequently associated with lower or higher doses of antipsychotics than the recommended ones. Eight patients were taking clozapine, all in monotherapy. Males received higher doses of antipsychotic (P=.043). A total of 5.2% of the patients were being treated with long-acting injectable antipsychotics; 12.2% of the patients received anticholinergic drugs, 12.2% antidepressants, and 13.7% mood stabilizers, while almost 40% received benzodiazepines; and 35.52% reported at least one adverse drug reaction during the pharmacovigilance period, more frequently associated with higher antipsychotic doses and antipsychotic polytherapy (85.2% vs 45.5%, P<.001). Conclusions: These data indicate that the overall pharmacologic prescription for treating a first episode of psychosis in Spain follows the clinical practice guideline recommendations, and, together with security issues, support future research of determinate pharmacological strategies for the treatment of early phases of psychosis, such as the role of clozapine, long-acting injectable antipsychotics, antipsychotic combination, and the use of benzodiazepines. PMID:26506856

Efficacy and safety of acupuncture for dizziness and vertigo in emergency department: a pilot cohort study.

PubMed

Chiu, Chih-Wen; Lee, Tsung-Chieh; Hsu, Po-Chi; Chen, Chia-Yun; Chang, Shun-Chang; Chiang, John Y; Lo, Lun-Chien

2015-06-09

Dizziness and vertigo account for roughly 4% of chief symptoms in the emergency department (ED). Pharmacological therapy is often applied for these symptoms, such as vestibular suppressants, anti-emetics and benzodiazepines. However, every medication is accompanied with unavoidable side-effects. There are several research articles providing evidence of acupuncture treating dizziness and vertigo but few studies of acupuncture as an emergent intervention in ED. We performed a pilot cohort study to evaluate the efficacy and safety of acupuncture in treating patients with dizziness and vertigo in ED. A total of 60 participants, recruited in ED, were divided into acupuncture and control group. Life-threatening conditions or central nervous system disorders were excluded to ensure participants' safety. The clinical effect of treating dizziness and vertigo was evaluated by performing statistical analyses on data collected from questionnaires of Dizziness Handicap Inventory (DHI), Visual Analog Scale (VAS) of dizziness and vertigo, and heart rate variability (HRV). The variation of VAS demonstrated a significant decrease (p-value: 0.001 and p-value: 0.037) between two groups after two different durations: 30 mins and 7 days. The variation of DHI showed no significant difference after 7 days. HRV revealed a significant increase in high frequency (HF) in the acupuncture group. No adverse event was reported in this study. Acupuncture demonstrates a significant immediate effect in reducing discomforts and VAS of both dizziness and vertigo. This study provides clinical evidence on the efficacy and safety of acupuncture to treat dizziness and vertigo in the emergency department. ClinicalTrials.gov ID: NCT02358239 . Registered 5 February 2015.

Phase-0/microdosing studies using PET, AMS, and LC-MS/MS: a range of study methodologies and conduct considerations. Accelerating development of novel pharmaceuticals through safe testing in humans - a practical guide.

PubMed

Burt, Tal; John, Christy S; Ruckle, Jon L; Vuong, Le T

2017-05-01

Phase-0 studies, including microdosing, also called Exploratory Investigational New Drug (eIND) or exploratory clinical trials, are a regulatory framework for first-in-human (FIH) trials. Common to these approaches is the use and implied safety of limited exposures to test articles. Use of sub-pharmacological doses in phase-0/microdose studies requires sensitive analytic tools such as accelerator mass spectrometer (AMS), Positron Emission Tomography (PET), and Liquid Chromatography Tandem Mass Spectrometry (LC-MS/MS) to determine drug disposition. Areas covered: Here we present a practical guide to the range of methodologies, design options, and conduct strategies that can be used to increase the efficiency of drug development. We provide detailed examples of relevant developmental scenarios. Expert opinion: Validation studies over the past decade demonstrated the reliability of extrapolation of sub-pharmacological to therapeutic-level exposures in more than 80% of cases, an improvement over traditional allometric approaches. Applications of phase-0/microdosing approaches include study of pharmacokinetic and pharmacodynamic properties, target tissue localization, drug-drug interactions, effects in vulnerable populations (e.g. pediatric), and intra-target microdosing (ITM). Study design should take into account the advantages and disadvantages of each analytic tool. Utilization of combinations of these analytic techniques increases the versatility of study designs and the power of data obtained.

Epigenetic drug discovery for Alzheimer's disease.

PubMed

Cacabelos, Ramón; Torrellas, Clara

2014-09-01

It is assumed that epigenetic modifications are reversible and could potentially be targeted by pharmacological and dietary interventions. Epigenetic drugs are gaining particular interest as potential candidates for the treatment of Alzheimer's disease (AD). This article covers relevant information from over 50 different epigenetic drugs including: DNA methyltransferase inhibitors; histone deacetylase inhibitors; histone acetyltransferase modulators; histone methyltransferase inhibitors; histone demethylase inhibitors; non-coding RNAs (microRNAs) and dietary regimes. The authors also review the pharmacoepigenomics and the pharmacogenomics of epigenetic drugs. The readers will gain insight into i) the classification of epigenetic drugs; ii) the mechanisms by which these drugs might be useful in AD; iii) the pharmacological properties of selected epigenetic drugs; iv) pharmacoepigenomics and the influence of epigenetic drugs on genes encoding CYP enzymes, transporters and nuclear receptors; and v) the genes associated with the pharmacogenomics of anti-dementia drugs. Epigenetic drugs reverse epigenetic changes in gene expression and might open future avenues in AD therapeutics. Unfortunately, clinical trials with this category of drugs are lacking in AD. The authors highlight the need for pharmacogenetic and pharmacoepigenetic studies to properly evaluate any efficacy and safety issues.

[Advances in novel carrier systems of chemical constituents from spice volatile oils].

PubMed

Zhang, Jia-jia; Zhu, Yuan; Yu, Jiang-nan; Xu, Xi-ming

2015-10-01

Recent years, chemical constituents from spice volatile oils have gained worldwide concern owing to its multiple pharmacological effects and safety for using as the natural antibacterial agents. However, their poor dissolution, strong volatility, serious irritation, weak stability, easy oxidation and low bioavailability characteristics are the major obstacle in the preparation of effective oral formulation and practical application. Therefore, there is an urgent need to select a novel carrier system that can delivery the chemical constituents from spice volatile oils more efficiently with improving their stability as well as alleviating the irritation, and develop the functional food, health products and even medicine for exerting their pharmacological effects, which also is the focus and nodus of the research on their application. This review presents recent systematic studies on their novel carrier systems, including cyclodextrin inclusion complex, liposomes, nanoemulsions, nanoparticles, solid dispersion and so on, and summarizes the characteristics, application range and problems of each novel carrier systems, in order to provide some beneficial thoughts in further developing new products of chemical constituents from spice volatile oils.

LY3127760, a Selective Prostaglandin E4 (EP4) Receptor Antagonist, and Celecoxib: A Comparison of Pharmacological Profiles

PubMed Central

Smith, Claire; Hu, Leijun; Coutant, David E.; Whitehurst, Kelly; Phipps, Krista; McNearney, Terry Ann; Yang, Xiao; Ackermann, Bradley; Pottanat, Thomas; Landschulz, William

2017-01-01

Abstract Safety, tolerability, and pharmacology profiles of LY3127760, an EP4 antagonist, were explored in healthy subjects in a subject/investigator‐blind, parallel‐group, multiple‐ascending dose study. Cohorts consisted of 13 patients randomized to LY3127760, celecoxib (400 mg), or placebo (9:2:2 ratio) for 28 days. LY3127760 was well tolerated; the most commonly observed adverse events were gastrointestinal, similar to celecoxib. LY3127760 increased release of ex vivo tumor necrosis factor alpha after lipopolysaccharide/prostaglandin E2 stimulation when compared with placebo, suggesting a dose‐dependent blockade of the EP4 receptor. Compared with placebo, 24‐h urinary excretion of prostaglandin E metabolite was modestly increased; prostacyclin metabolite was inhibited; and thromboxane A2 metabolite was unchanged. Effects on sodium and potassium excretion were similar to those of celecoxib. We conclude that LY3127760 demonstrated similar effects on prostacyclin synthesis and renal sodium retention as celecoxib. These data support exploration of LY3127760 at daily doses of 60 mg to 600 mg in phase II trials. This trial's registration number: NCT01968070. PMID:28857461

The Virtual Anemia Trial: An Assessment of Model-Based In Silico Clinical Trials of Anemia Treatment Algorithms in Patients With Hemodialysis.

PubMed

Fuertinger, Doris H; Topping, Alice; Kappel, Franz; Thijssen, Stephan; Kotanko, Peter

2018-04-01

In silico approaches have been proposed as a novel strategy to increase the repertoire of clinical trial designs. Realistic simulations of clinical trials can provide valuable information regarding safety and limitations of treatment protocols and have been shown to assist in the cost-effective planning of clinical studies. In this report, we present a blueprint for the stepwise integration of internal, external, and ecological validity considerations in virtual clinical trials (VCTs). We exemplify this approach in the context of a model-based in silico clinical trial aimed at anemia treatment in patients undergoing hemodialysis (HD). Hemoglobin levels and subsequent anemia treatment were simulated on a per patient level over the course of a year and compared to real-life clinical data of 79,426 patients undergoing HD. The novel strategies presented here, aimed to improve external and ecological validity of a VCT, significantly increased the predictive power of the discussed in silico trial. © 2018 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Transdermal patches: history, development and pharmacology.

PubMed

Pastore, Michael N; Kalia, Yogeshvar N; Horstmann, Michael; Roberts, Michael S

2015-05-01

Transdermal patches are now widely used as cosmetic, topical and transdermal delivery systems. These patches represent a key outcome from the growth in skin science, technology and expertise developed through trial and error, clinical observation and evidence-based studies that date back to the first existing human records. This review begins with the earliest topical therapies and traces topical delivery to the present-day transdermal patches, describing along the way the initial trials, devices and drug delivery systems that underpin current transdermal patches and their actives. This is followed by consideration of the evolution in the various patch designs and their limitations as well as requirements for actives to be used for transdermal delivery. The properties of and issues associated with the use of currently marketed products, such as variability, safety and regulatory aspects, are then described. The review concludes by examining future prospects for transdermal patches and drug delivery systems, such as the combination of active delivery systems with patches, minimally invasive microneedle patches and cutaneous solutions, including metered-dose systems. © 2015 The British Pharmacological Society.

Pharmacological treatments and risks for the food chain.

PubMed

Girardi, C; Odore, R

2008-09-01

Veterinarians play a pivotal role in public health control, in particular in the management of risks deriving from pharmacological treatments of food-producing animals. Veterinary medicinal products can represent a risk for animal health and welfare (side effects, decreased efficacy), for farmers and practitioners administering the drug, for consumers of food of animal origin (presence of residues, occurrence of antibiotic resistance) and for the environment. According to pending European guidelines, risk management starts from marketing authorisation that must be based on risk evaluation and can be denied when the risk/benefit ratio is not favourable considering the advantages for animal health and welfare and for safety of consumers. Veterinarians can prevent and control risks by using correct pharmacological criteria to choose and administer medicinal products and undertaking risk-based inspection of residues of drugs in food of animal origin. Moreover, a major tool for veterinarians to prevent and control drug-borne risk is "pharmacovigilance". Risks for the environment are usually assessed during the pre-marketing approval process, however veterinarians, as risk managers, should educate farmers about correct drug handling and disposal, and periodically verify that suggested measures are applied.

Development and delivery of clinical pharmacology in regulatory agencies.

PubMed

Breckenridge, Alasdair

2012-06-01

Medicines regulation is based on a foundation of science, policy and judgement. It operates within several frameworks (scientific, legal and public health), which are interdependent. While safety, quality and efficacy remain the criteria by which medicines are assessed, the benefit-to-harm balance for any medicine or medical device is of paramount importance. While the regulator was hitherto the gatekeeper who allowed a medicine on to the market, payers now require, in addition, assessment of cost and clinical effectiveness before use. As regulatory frameworks develop, several changes will occur, as follows: (i) formal benefit-harm assessment will become an integral part of submission for marketing authorizations; (ii) there will be greater use of surveillance for adverse reactions to new medicines using methods other than voluntary reporting; (iii) risk management plans will become benefit-risk management plans; (iv) life-saving medicines will be approved earlier; and (v) regulation and health technology assessment will take place simultaneously. Clinical pharmacologists will play important roles in these developments. © 2012 The Author. British Journal of Clinical Pharmacology © 2012 The British Pharmacological Society.

Worldwide Distribution of Cytochrome P450 Alleles: A Meta-analysis of Population-scale Sequencing Projects.

PubMed

Zhou, Y; Ingelman-Sundberg, M; Lauschke, V M

2017-10-01

Genetic polymorphisms in cytochrome P450 (CYP) genes can result in altered metabolic activity toward a plethora of clinically important medications. Thus, single nucleotide variants and copy number variations in CYP genes are major determinants of drug pharmacokinetics and toxicity and constitute pharmacogenetic biomarkers for drug dosing, efficacy, and safety. Strikingly, the distribution of CYP alleles differs considerably between populations with important implications for personalized drug therapy and healthcare programs. To provide a global distribution map of CYP alleles with clinical importance, we integrated whole-genome and exome sequencing data from 56,945 unrelated individuals of five major human populations. By combining this dataset with population-specific linkage information, we derive the frequencies of 176 CYP haplotypes, providing an extensive resource for major genetic determinants of drug metabolism. Furthermore, we aggregated this dataset into spectra of predicted functional variability in the respective populations and discuss the implications for population-adjusted pharmacological treatment strategies. © 2017 The Authors Clinical Pharmacology & Therapeutics published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

Psychedelic Drugs in Biomedicine.

PubMed

Kyzar, Evan J; Nichols, Charles D; Gainetdinov, Raul R; Nichols, David E; Kalueff, Allan V

2017-11-01

Psychedelic drugs, such as lysergic acid diethylamide (LSD), mescaline, and psilocybin, exert profound effects on brain and behavior. After decades of difficulties in studying these compounds, psychedelics are again being tested as potential treatments for intractable biomedical disorders. Preclinical research of psychedelics complements human neuroimaging studies and pilot clinical trials, suggesting these compounds as promising treatments for addiction, depression, anxiety, and other conditions. However, many questions regarding the mechanisms of action, safety, and efficacy of psychedelics remain. Here, we summarize recent preclinical and clinical data in this field, discuss their pharmacological mechanisms of action, and outline critical areas for future studies of psychedelic drugs, with the goal of maximizing the potential benefits of translational psychedelic biomedicine to patients. Copyright © 2017 Elsevier Ltd. All rights reserved.

Efficacy and safety in pharmacological cardioversion of recent-onset atrial fibrillation: a propensity score matching to compare amiodarone vs class IC antiarrhythmic drugs.

PubMed

Bonora, Antonio; Turcato, Gianni; Franchi, Elena; Taioli, Gabriele; Dilda, Alice; Zerman, Germana; Maccagnani, Antonio; Pistorelli, Claudio; Olivieri, Oliviero

2017-09-01

The acute management of recent-onset (<48 h) atrial fibrillation (AF) is still debated. Aim of our study was to compare efficacy and safety of intravenously administered class IC antidysrhythmic agents vs amiodarone in a propensity score matched series of patients acutely treated for AF in the emergency department. During a 3-year period, we retrospectively evaluated all episodes of recent-onset (<48 h) AF pharmacologically treated for sinus rhythm restoration in the emergency department. By means of a propensity score matching considering the main statistically different covariates, we selected two accurately matched treatment groups. We analysed the differences between amiodarone and class IC group in terms of efficacy and safety that is conversion to sinus rhythm rates within 12 and 48 h after starting treatment, time to conversion, and adverse drug effects. An overall number of 817 episodes of recent-onset AF were collected (amiodarone group = 406, class IC group = 411). After matching, we obtained 358 episodes equally divided (amiodarone group = 179 and class IC group = 179). Conversion rates within 12 h were 139 (53.1 %) in amiodarone group and 95 (72.6 %) in class IC group (p < 0.05). Median time for cardioversion was 420 min (331.6-508.3 CI 95 %) in amiodarone and 55 min (44.9-65.1 CI 95 %) in class IC group (p < 0.05). The incidence of adverse events in both groups was very low and equally distributed (p = ns). Intravenously administration of class IC agents, when compared with amiodarone, proved to be more rapid and effective, and equally safe in the acute management of recent-onset AF.

Clinical pharmacology of lubiprostone, a chloride channel activator in defecation disorders.

PubMed

Ginzburg, Regina; Ambizas, Emily M

2008-08-01

Lubiprostone, a prostaglandin E1 derivative, was approved in January 2006 for the treatment of chronic idiopathic constipation (CIC) in adults and in April 2008 for the treatment of irritable bowel syndrome with constipation (IBS-C) in adult women. To review the pharmacology, efficacy and safety of lubiprostone and recommend its place in therapy for CIC and IBS-C. We conducted a literature search using PubMed/Medline (1966-April 2008) using the keywords lubiprostone, chronic constipation, and irritable bowel syndrome. Data provided by the manufacturer and the FDA were also reviewed. Available literature for lubiprostone is mostly available in abstract data making it difficult to evaluate the clinical evidence. Although this medication shows promise, more information is needed to determine its place in therapy.

[PCSK-9 inhibitors, effects on LDL-C and future implications: What you should know].

PubMed

Corral, P; Ruiz, A J

The discovery of proprotein convertase subtilisin/kexin type 9 (PCSK9) in 2003 in families with familial hypercholesterolemia (HF) later generated the development of pharmacological strategies in order to inhibit this protein. Twelve years after this discovery, the first two biological compounds (monoclonal antibodies) were approved, which have been shown to substantially decrease LDL-C and other lipid subfractions. The objective of the present article is to review the history of the discovery of PCSK9, its physiology and pathophysiology and subsequent pharmacological development. The objectives and goals reached to date and the pending questions regarding the efficacy and safety of its clinical use are presented. Copyright © 2017 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Ascending Single-Dose, Double-Blind, Placebo-Controlled Safety Study of Noribogaine in Opioid-Dependent Patients.

PubMed

Glue, Paul; Cape, Gavin; Tunnicliff, Donna; Lockhart, Michelle; Lam, Fred; Hung, Noelyn; Hung, C Tak; Harland, Sarah; Devane, Jane; Crockett, R S; Howes, John; Darpo, Borje; Zhou, Meijian; Weis, Holger; Friedhoff, Lawrence

2016-11-01

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine's active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled single ascending-dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST who had been switched to morphine during the previous week. Noribogaine doses were 60, 120, or 180 mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were noneuphoric changes in light perception ∼1 hour postdose, headache, and nausea. Noribogaine had dose-linear increases for AUC and C max and was slowly eliminated (mean t 1/2 range, 24-30 hours). There was a concentration-dependent increase in QTcI (0.17 ms/ng/mL), with the largest observed mean effect of ∼16, 28, and 42 milliseconds in the 60-, 120-, and 180-mg groups, respectively. Noribogaine showed a nonstatistically significant trend toward decreased total score in opioid withdrawal ratings, most notably at the 120-mg dose; however, the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues. © 2016, The American College of Clinical Pharmacology.

Review of Clinical Pharmacology of Aloe vera L. in the Treatment of Psoriasis.

PubMed

Miroddi, Marco; Navarra, Michele; Calapai, Fabrizio; Mancari, Ferdinando; Giofrè, Salvatore Vincenzo; Gangemi, Sebastiano; Calapai, Gioacchino

2015-05-01

Aloe vera L., is a plant used worldwide as folk remedy for the treatment of various ailments, including skin disorders. Its gel is present in cosmetics, medicinal products and food supplements. Psoriasis, an immune-mediated chronic inflammatory disease, involving mainly the skin, affects about the 2-3% of general population. Conventional pharmacological treatments for psoriasis can have limited effectiveness and can cause adverse reactions. For this reason often psoriatic patients look for alternative treatments based on natural products containing Aloe vera. We conducted a systematic review of clinical trials assessing effectiveness and safety of aloe for the treatment of psoriasis. Clinical studies published in English were considered; a total of four clinical trials met inclusion criteria. Studies were also evaluated by using the Jadad scale and Consort Statement in Reporting Clinical trials of Herbal Medicine Intervention. Quality and methodological accuracy of considered studies varied considerably, and some crucial information to reproduce clinical results was missing. We conclude that administration of aloe as cutaneous treatment is generally well tolerated, as no serious side effects were reported. Results on the effectiveness of Aloe vera are contradictory; our analysis reveals the presence of methodological gaps preventing to reach final conclusions. Copyright © 2015 John Wiley & Sons, Ltd.

Castor oil for induction of labour: a retrospective study.

PubMed

Neri, Isabella; Dante, Giulia; Pignatti, Lucrezia; Salvioli, Chiara; Facchinetti, Fabio

2018-08-01

The aim of this study is to investigate the safety and efficacy of castor oil to induce labour. A retrospective observational case control study was conducted over five years. Castor oil was proposed to women referred to the Birth Centre (Castor Oil group (COG)). They were compared to women who chose to be followed by the traditional doctor-led unit (control group (CG)). Castor oil was administered in a 60 ml single dose in 200 ml of warm water. Inclusion criteria were gestational age between 40 and 41 weeks plus premature rupture of membranes between 12 and 18 hours or amniotic fluid index ≤4 or Bishop Score of ≤4 or absence of spontaneous labour over 41 + 4 weeks. Pharmacological induction of labour was required for 18 women in the COG (45%) and 36 in the CG (90%) (p < .001). The mode of delivery differed significantly between groups: women assuming castor oil showed a higher incidence of vaginal delivery, whereas the incidence of caesarean section was lower in the COG, but no statistical significance was reached. The use of castor oil is related to a higher probability of labour initiation within 24 hours. Castor oil can be considered a safe non-pharmacological method for labour induction.

Recent advances in the management of neuropsychiatric symptoms in dementia.

PubMed

Forlenza, Orestes V; Loureiro, Júlia Cunha; Pais, Marcos Vasconcelos; Stella, Florindo

2017-03-01

The present article addresses intriguing questions related to the clinical intervention in distinct neuropsychiatric syndromes of patients with dementia. We reviewed 154 articles published between 2015 and 2016 targeting psychopharmacological and nonpharmacological interventions, and safety-tolerability concerns. We selected 115 articles addressing the purpose of this study. Of these, 33 were chosen because they were dedicated to subtopics: agitation (42), depression (33), apathy (18), sleep disorders/anxiety (8), and psychosis (4). Clinical studies using both pharmacological (70) and nonpharmacological (37) interventions were considered; others were included for theoretical support. Regarding the methodological design, we found double-blind RCTs (17), single-blinded RCTs (4), open-label studies (18), case reports (5), cross-sectional or cohort studies (25), epidemiological papers (2), and expert reviews (44). This observation raises concerns about the overall methodological adequacy of a substantial proportion of studies in this field, which limits the potential of generalization of the findings. Finally, 18 studies were designed to determine safety-tolerability issues of psychotropic medications (6 were discussed). Effective and well tolerated treatment of neuropsychiatric syndromes in dementia remains a critically unsolved challenge. We understand that this is an extremely important area of research, and critically required to guide clinical decisions in geriatric neuropsychiatry.

A Review of the Pharmacology and Clinical Uses of Ivermectin

PubMed Central

Barragry, Thomas B.

1987-01-01

The avermectins were introduced in 1981 and constitute a potent new class of anthelmintic agents. They are naturally-derived products of microbial action displaying an exceptionally wide range of antiparasitic efficacy against internal and external parasites of domestic animals. This paper reviews their isolation and chemistry, mechanism of action, chemical efficacy and safety in cattle, sheep, swine, horses and dogs. PMID:17422843

PCSK9 Inhibition With Monoclonal Antibodies: Modern Management of Hypercholesterolemia.

PubMed

Ito, Matthew K; Santos, Raul D

2017-01-01

Current guidelines for hypercholesterolemia treatment emphasize lifestyle modification and lipid-modifying therapy to reduce the risk for cardiovascular disease. Statins are the primary class of agents used for the treatment of hypercholesterolemia. Although statins are effective for many patients, they fail to achieve optimal reduction in lipids for some patients, including those who have or are at high risk for cardiovascular disease. The PCSK9 gene was identified in the past decade as a potential therapeutic target for the management of patients with hypercholesterolemia. Pharmacologic interventions to decrease PCSK9 levels are in development, with the most promising approach using monoclonal antibodies that bind to PCSK9 in the plasma. Two monoclonal antibodies, alirocumab and evolocumab, have recently been approved for the treatment of hypercholesterolemia, and a third one, bococizumab, is in phase 3 clinical development. All 3 agents achieve significant reductions in levels of low-density lipoprotein cholesterol, as well as reductions in non-high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a). Long-term outcome trials are under way to determine the sustained efficacy, safety, and tolerability of PCSK9 inhibitors and whether this novel class of agents decreases the risk for major cardiovascular events in patients on lipid-modifying therapy. Available data suggest that PCSK9 inhibitors provide a robust reduction in atherogenic cholesterol levels with a good safety profile, especially for patients who fail to obtain an optimal clinical response to statin therapy, those who are statin intolerant or have contraindications to statin therapy, and those with familial hypercholesterolemia. © 2016, The Authors. The Journal of Clinical Pharmacology Published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Pharmacological treatment for memory disorder in multiple sclerosis.

PubMed

He, Dian; Zhang, Yun; Dong, Shuai; Wang, Dongfeng; Gao, Xiangdong; Zhou, Hongyu

2013-12-17

This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10).Multiple sclerosis (MS) is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to people with MS and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in people with MS but the results were not consistent. To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults with MS. We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings. All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults with MS who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater. Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation. We included seven randomised controlled trials (RCTs) involving 625 people mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups. We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in patients with MS remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MS patients with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 366)

NASA Technical Reports Server (NTRS)

1992-01-01

This bibliography lists 248 reports, articles, and other documents introduced into the NASA Scientific and Technical Information System during Aug. 1992. Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Zoledronic acid in pediatric metabolic bone disorders

PubMed Central

Mahan, John D.

2017-01-01

Zoledronic acid (ZA), a highly potent intravenous bisphosphonate (BP), has been increasingly used in children with primary and secondary osteoporosis due to its convenience of shorter infusion time and less frequent dosing compared to pamidronate. Many studies have also demonstrated beneficial effects of ZA in other conditions such as hypercalcemia of malignancy, fibrous dysplasia (FD), chemotherapy-related osteonecrosis (ON) and metastatic bone disease. This review summarizes pharmacologic properties, mechanism of action, dosing regimen, and therapeutic outcomes of ZA in a variety of metabolic bone disorders in children. Several potential novel uses of ZA are also discussed. Safety concerns and adverse effects are also highlighted. PMID:29184807

Aerospace Medicine and Biology: A Continuing Bibliography with Indexes. Supplement 492

NASA Technical Reports Server (NTRS)

1999-01-01

This report lists reports, articles and other documents recently announced in the NASA STI Database. In its subject coverage, Aerospace Medicine and Biology concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Treatment options for rheumatoid arthritis: celecoxib, leflunomide, etanercept, and infliximab.

PubMed

Luong, B T; Chong, B S; Lowder, D M

2000-06-01

To review new pharmacologic agents approved for use in the management of rheumatoid arthritis (RA). A MEDLINE search (1966-January 2000) was conducted to identify English-language literature available on the pharmacotherapy of RA, focusing on celecoxib, leflunomide, etanercept, and infliximab. These articles, relevant abstracts, and data provided by the manufacturers were used to collect pertinent data. All controlled and uncontrolled trials were reviewed. Agents were reviewed with regard to mechanism of action, efficacy, drug interactions, pharmacokinetics, dosing, precautions/contraindications, adverse effects, and cost. Traditional pharmacologic treatments for RA have been limited by toxicity, loss of efficacy, or both. Increasing discoveries into the mechanisms of inflammation in RA have led to the development of new agents in hopes of addressing these limitations. With the development of celecoxib, a selective cyclooxygenase-2 inhibitor, the potential exists to minimize the gastrotoxicity associated with nonsteroidal antiinflammatory drugs. Leflunomide has been shown to be equal to or less efficacious than methotrexate, and may be beneficial as a second-line disease-modifying antirheumatic drug (DMARD). The biologic response modifiers, etanercept and infliximab, are alternatives that have shown benefit alone or in combination with methotrexate. However, they should be reserved for patients who fail to respond to DMARD therapy. Further studies should be conducted to evaluate the long-term safety and efficacy of these agents as well as their role in combination therapy. Celecoxib, leflunomide, etanercept, and infliximab are the newest agents approved for RA. Clinical trials have shown that these agents are beneficial in the treatment of RA; however, long-term safety and efficacy data are lacking.

Radiation exposure of the anesthesiologist in the neurointerventional suite.

PubMed

Anastasian, Zirka H; Strozyk, Dorothea; Meyers, Philip M; Wang, Shuang; Berman, Mitchell F

2011-03-01

Scatter radiation during interventional radiology procedures can produce cataracts in participating medical personnel. Standard safety equipment for the radiologist includes eye protection. The typical configuration of fluoroscopy equipment directs radiation scatter away from the radiologist and toward the anesthesiologist. This study analyzed facial radiation exposure of the anesthesiologist during interventional neuroradiology procedures. Radiation exposure to the forehead of the anesthesiologist and radiologist was measured during 31 adult neuroradiologic procedures involving the head or neck. Variables hypothesized to affect anesthesiologist exposure were recorded for each procedure. These included total radiation emitted by fluoroscopic equipment, radiologist exposure, number of pharmacologic interventions performed by the anesthesiologist, and other variables. Radiation exposure to the anesthesiologist's face averaged 6.5 ± 5.4 μSv per interventional procedure. This exposure was more than 6-fold greater (P < 0.0005) than for noninterventional angiographic procedures (1.0 ± 1.0) and averaged more than 3-fold the exposure of the radiologist (ratio, 3.2; 95% CI, 1.8-4.5). Multiple linear regression analysis showed that the exposure of the anesthesiologist was correlated with the number of pharmacologic interventions performed by the anesthesiologist and the total exposure of the radiologist. Current guidelines for occupational radiation exposure to the eye are undergoing review and are likely to be lowered below the current 100-150 mSv/yr limit. Anesthesiologists who spend significant time in neurointerventional radiology suites may have ocular radiation exposure approaching that of a radiologist. To ensure parity with safety standards adopted by radiologists, these anesthesiologists should wear protective eyewear.

Model-based analysis of thromboxane B₂ and prostaglandin E₂ as biomarkers in the safety evaluation of naproxen.

PubMed

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert; Della Pasqua, Oscar

2014-08-01

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., Cmax and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15, 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B₂ and prostaglandin E₂ were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB₂ and PGE₂ was described by direct inhibition models with maximum pharmacological effects achieved at doses >7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. Copyright © 2014 Elsevier Inc. All rights reserved.

Identifying medication error chains from critical incident reports: a new analytic approach.

PubMed

Huckels-Baumgart, Saskia; Manser, Tanja

2014-10-01

Research into the distribution of medication errors usually focuses on isolated stages within the medication use process. Our study aimed to provide a novel process-oriented approach to medication incident analysis focusing on medication error chains. Our study was conducted across a 900-bed teaching hospital in Switzerland. All reported 1,591 medication errors 2009-2012 were categorized using the Medication Error Index NCC MERP and the WHO Classification for Patient Safety Methodology. In order to identify medication error chains, each reported medication incident was allocated to the relevant stage of the hospital medication use process. Only 25.8% of the reported medication errors were detected before they propagated through the medication use process. The majority of medication errors (74.2%) formed an error chain encompassing two or more stages. The most frequent error chain comprised preparation up to and including medication administration (45.2%). "Non-consideration of documentation/prescribing" during the drug preparation was the most frequent contributor for "wrong dose" during the administration of medication. Medication error chains provide important insights for detecting and stopping medication errors before they reach the patient. Existing and new safety barriers need to be extended to interrupt error chains and to improve patient safety. © 2014, The American College of Clinical Pharmacology.

Effect of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of apixaban.

PubMed

Chang, Ming; Yu, Zhigang; Shenker, Andrew; Wang, Jessie; Pursley, Janice; Byon, Wonkyung; Boyd, Rebecca A; LaCreta, Frank; Frost, Charles E

2016-05-01

This open-label study evaluated apixaban pharmacokinetics, pharmacodynamics, and safety in subjects with mild, moderate, or severe renal impairment and in healthy subjects following a single 10-mg oral dose. The primary analysis determined the relationship between apixaban AUC∞ and 24-hour creatinine clearance (CLcr ) as a measure of renal function. The relationships between 24-hour CLcr and iohexol clearance, estimated CLcr (Cockcroft-Gault equation), and estimated glomerular filtration rate (modification of diet in renal disease [MDRD] equation) were also assessed. Secondary objectives included assessment of safety and tolerability as well as international normalized ratio (INR) and anti-factor Xa activity as pharmacodynamic endpoints. The regression analysis showed that decreasing renal function resulted in modestly increased apixaban exposure (AUC∞ increased by 44% in severe impairment with a 24-hour CLcr of 15 mL/min, compared with subjects with normal renal function), but it did not affect Cmax or the direct relationship between apixaban plasma concentration and anti-factor Xa activity or INR. The assessment of renal function measured by iohexol clearance, Cockcroft-Gault, and MDRD was consistent with that determined by 24-hour CLcr . Apixaban was well tolerated in this study. These results suggest that dose adjustment of apixaban is not required on the basis of renal function alone. © 2015, The American College of Clinical Pharmacology.

Safety of Traditional Arab Herbal Medicine

PubMed Central

Saad, Bashar; Azaizeh, Hassan; Abu-Hijleh, Ghassan; Said, Omar

2006-01-01

Herbal remedies are widely used for the treatment and prevention of various diseases and often contain highly active pharmacological compounds. Many medicinal herbs and pharmaceutical drugs are therapeutic at one dose and toxic at another. Toxicity related to traditional medicines is becoming more widely recognized as these remedies become popular in the Mediterranean region as well as worldwide. Most reports concerning the toxic effects of herbal medicines are associated with hepatotoxicity although reports of other toxic effects including kidney, nervous system, blood, cardiovascular and dermatologic effects, mutagenicity and carcinogenicity have also been published in the medical literature. This article presents a systematic review on safety of traditional Arab medicine and the contribution of Arab scholars to toxicology. Use of modern cell biological, biochemical, in vitro and in vivo techniques for the evaluation of medicinal plants safety is also discussed. PMID:17173106

A Review of Swertia chirayita (Gentianaceae) as a Traditional Medicinal Plant

PubMed Central

Kumar, Vijay; Van Staden, Johannes

2016-01-01

Swertia chirayita (Gentianaceae), a popular medicinal herb indigenous to the temperate Himalayas is used in traditional medicine to treat numerous ailments such as liver disorders, malaria, and diabetes and are reported to have a wide spectrum of pharmacological properties. Its medicinal usage is well-documented in Indian pharmaceutical codex, the British, and the American pharmacopeias and in different traditional medicine such as the Ayurveda, Unani, Siddha, and other conventional medical systems. This ethnomedicinal herb is known mostly for its bitter taste caused by the presence of different bioactive compounds that are directly associated with human health welfare. The increasing high usage of Swertia chirayita, mostly the underground tissues, as well as the illegal overharvesting combined with habitat destruction resulted in a drastic reduction of its populations and has brought this plant to the verge of extinction. The increasing national and international demand for Swertia chirayita has led to unscrupulous collection from the wild and adulteration of supplies. The aim of this review is to provide a synthesis of the current state of scientific knowledge on the medicinal uses, phytochemistry, pharmacological activities, safety evaluation as well as the potential role of plant biotechnology in the conservation of Swertia chirayita and to highlight its future prospects. Pharmacological data reported in literature suggest that Swertia chirayita shows a beneficial effect in the treatment of several ailments. However, there is lack of adequate information on the safety evaluation of the plant. The pharmacological usefulness of Swertia chirayita requires the need for conservation-friendly approaches in its utilization. Providing high-quality genetically uniform clones for sustainable use and thereby saving the genetic diversity of this species in nature is important. In this regard, plant biotechnological applications such as micropropagation, synthetic seed production, and hairy root technology can play a significant role in a holistic conservation strategy. In addition to micropropagation, storage of these valuable genetic resources is equally important for germplasm preservation. However, more advanced research is warranted to determine the activities of bioactive compounds in vitro and in vivo, establish their underlying mechanisms of action and commence the process of clinical research. PMID:26793105

A Review of Swertia chirayita (Gentianaceae) as a Traditional Medicinal Plant.

PubMed

Kumar, Vijay; Van Staden, Johannes

2015-01-01

Swertia chirayita (Gentianaceae), a popular medicinal herb indigenous to the temperate Himalayas is used in traditional medicine to treat numerous ailments such as liver disorders, malaria, and diabetes and are reported to have a wide spectrum of pharmacological properties. Its medicinal usage is well-documented in Indian pharmaceutical codex, the British, and the American pharmacopeias and in different traditional medicine such as the Ayurveda, Unani, Siddha, and other conventional medical systems. This ethnomedicinal herb is known mostly for its bitter taste caused by the presence of different bioactive compounds that are directly associated with human health welfare. The increasing high usage of Swertia chirayita, mostly the underground tissues, as well as the illegal overharvesting combined with habitat destruction resulted in a drastic reduction of its populations and has brought this plant to the verge of extinction. The increasing national and international demand for Swertia chirayita has led to unscrupulous collection from the wild and adulteration of supplies. The aim of this review is to provide a synthesis of the current state of scientific knowledge on the medicinal uses, phytochemistry, pharmacological activities, safety evaluation as well as the potential role of plant biotechnology in the conservation of Swertia chirayita and to highlight its future prospects. Pharmacological data reported in literature suggest that Swertia chirayita shows a beneficial effect in the treatment of several ailments. However, there is lack of adequate information on the safety evaluation of the plant. The pharmacological usefulness of Swertia chirayita requires the need for conservation-friendly approaches in its utilization. Providing high-quality genetically uniform clones for sustainable use and thereby saving the genetic diversity of this species in nature is important. In this regard, plant biotechnological applications such as micropropagation, synthetic seed production, and hairy root technology can play a significant role in a holistic conservation strategy. In addition to micropropagation, storage of these valuable genetic resources is equally important for germplasm preservation. However, more advanced research is warranted to determine the activities of bioactive compounds in vitro and in vivo, establish their underlying mechanisms of action and commence the process of clinical research.

A Decade in the MIST: Learnings from Investigations of Drug Metabolites in Drug Development under the "Metabolites in Safety Testing" Regulatory Guidance.

PubMed

Schadt, Simone; Bister, Bojan; Chowdhury, Swapan K; Funk, Christoph; Hop, Cornelis E C A; Humphreys, W Griffith; Igarashi, Fumihiko; James, Alexander D; Kagan, Mark; Khojasteh, S Cyrus; Nedderman, Angus N R; Prakash, Chandra; Runge, Frank; Scheible, Holger; Spracklin, Douglas K; Swart, Piet; Tse, Susanna; Yuan, Josh; Obach, R Scott

2018-06-01

Since the introduction of metabolites in safety testing (MIST) guidance by the Food and Drug Administration in 2008, major changes have occurred in the experimental methods for the identification and quantification of metabolites, ways to evaluate coverage of metabolites, and the timing of critical clinical and nonclinical studies to generate this information. In this cross-industry review, we discuss how the increased focus on human drug metabolites and their potential contribution to safety and drug-drug interactions has influenced the approaches taken by industry for the identification and quantitation of human drug metabolites. Before the MIST guidance was issued, the method of choice for generating comprehensive metabolite profile was radio chromatography. The MIST guidance increased the focus on human drug metabolites and their potential contribution to safety and drug-drug interactions and led to changes in the practices of drug metabolism scientists. In addition, the guidance suggested that human metabolism studies should also be accelerated, which has led to more frequent determination of human metabolite profiles from multiple ascending-dose clinical studies. Generating a comprehensive and quantitative profile of human metabolites has become a more urgent task. Together with technological advances, these events have led to a general shift of focus toward earlier human metabolism studies using high-resolution mass spectrometry and to a reduction in animal radiolabel absorption/distribution/metabolism/excretion studies. The changes induced by the MIST guidance are highlighted by six case studies included herein, reflecting different stages of implementation of the MIST guidance within the pharmaceutical industry. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Finnish nurses' and nursing students' pharmacological skills.

PubMed

Grandell-Niemi, Heidi; Hupli, Maija; Leino-Kilpi, Helena; Puukka, Pauli

2005-07-01

PURPOSES AND OBJECTIVES: The purposes of this study were to investigate the pharmacological skills of Finnish nurses and graduating nursing students, to determine how pharmacological skills are related to background factors and to identify differences between nurses and students and, finally, to examine how the instrument used, the Medication Calculation Skills Test, works. Pharmacology is a relevant and topical subject. In several studies, however, pharmacological skills of nurses and nursing students have been found insufficient. In addition, pharmacology as a subject is found to be difficult for both nursing students and nurses. The study was evaluative in nature; the data were collected using the Medication Calculation Skills Test, developed for the purposes of this study. The instrument was used to gather information on background factors and self-rated pharmacological and mathematical skills and to test actual skills in these areas. Results concerning pharmacological skills are reported in this paper. The maximum Medication Calculation Skills Test score was 24 points. The mean score for nurses was 18.6 and that for students 16.3. Half of (50%) the students attained a score of 67% and 57% of nurses attained a score of 79%. Nurses and students had some deficiencies in their pharmacological skills. Nurses had better pharmacological skills than students according to both self-ratings and actual performance on the test. It is vitally important that nurses have adequate pharmacological skills to administer medicines correctly. This study showed that the Medication Calculation Skills Test seems to work well in measuring pharmacological skills, even though it needs further evaluation. Findings from this study can be used when planning the nursing curriculum and further education for Registered Nurses.

Nanodrugs: pharmacokinetics and safety

PubMed Central

Onoue, Satomi; Yamada, Shizuo; Chan, Hak-Kim

2014-01-01

To date, various nanodrug systems have been developed for different routes of administration, which include dendrimers, nanocrystals, emulsions, liposomes, solid lipid nanoparticles, micelles, and polymeric nanoparticles. Nanodrug systems have been employed to improve the efficacy, safety, physicochemical properties, and pharmacokinetic/pharmacodynamic profile of pharmaceutical substances. In particular, functionalized nanodrug systems can offer enhanced bioavailability of orally taken drugs, prolonged half-life of injected drugs (by reducing immunogenicity), and targeted delivery to specific tissues. Thus, nanodrug systems might lower the frequency of administration while providing maximized pharmacological effects and minimized systemic side effects, possibly leading to better therapeutic compliance and clinical outcomes. In spite of these attractive pharmacokinetic advantages, recent attention has been drawn to the toxic potential of nanodrugs since they often exhibit in vitro and in vivo cytotoxicity, oxidative stress, inflammation, and genotoxicity. A better understanding of the pharmacokinetic and safety characteristics of nanodrugs and the limitations of each delivery option is necessary for the further development of efficacious nanodrugs with high therapeutic potential and a wide safety margin. This review highlights the recent progress in nanodrug system development, with a focus on the pharmacokinetic advantages and safety challenges. PMID:24591825

The need for a comprehensive medication safety module in medical education.

PubMed

Chandy, Sujith John

2016-10-01

A rising number of medicines and minimal emphasis on rational prescribing in the medical curriculum may compromise medication safety. There is no focused module in the curriculum dealing with factors affecting safety such as quality, medicines management, rational use, and approach to adverse effects. Creating awareness of these issues would hopefully plant a seed of safe prescribing and encourage pharmacovigilance. A study was therefore done to determine the need for such a module. A quasi-experimental pre-post module study. Medical students ( n = 88) completing pharmacology term were recruited after informed consent. A questionnaire containing 20 questions on various themes was administered and scored. Subsequently a module was developed and relevant safety themes taught to the students. After one month, the questionnaire was re-administered. The pre module score was 9.52/20. Knowledge about the various themes, adverse effects, medication management, quality issues and rational use were similar though poor knowledge was evident in specific areas such as clinical trials, look alike-sound alike medicines (LASA) and medicine storage. The post module score was 12.24/20. The improvement of score was statistically significant suggesting the effectiveness of the module. The relatively poor knowledge and improvement with a specific educational module emphasizes the need of such a module within the medical curriculum to encourage safe use of medicines by Indian Medical Graduates (IMG). It is hoped that the policy makers in medical education will introduce such a module within the medical curriculum.

Denosumab for the Treatment of Osteoporosis

PubMed Central

Zaheer, Sarah; LeBoff, Meryl; Lewiecki, E. Michael

2015-01-01

Introduction Low trauma fractures due to osteoporosis are a major health concern worldwide. Despite the availability of many therapeutic compounds to reduce fracture risk, osteoporosis remains undertreated and the burden of osteoporotic fractures remains high. Denosumab is a novel agent that acts to reduce bone turnover, improve bone mineral density, and reduce fracture risk, offering a favorable efficacy and safety profile. Areas covered This review covers the pharmacology and major clinical trials with extension/post-marketing follow-up, including trials for all FDA-approved indications of denosumab to date. Expert Opinion Denosumab is an efficacious and safe osteoporosis treatment option, with current data up to 8 years of continued use showing continued improvement in bone density with sustained fracture risk reduction. Safety profiles overall are similar to placebo, with no new safety concerns in extension trials, though a theoretical increased risk of infection exists with RANKL inhibition. Future considerations include safety of prolonged treatment beyond 8 years, and efficacy/fracture risk after discontinuation or with non-adherence, given the characteristic pharmacodynamic profile of denosumab. PMID:25614274

Studies in neuroendocrine pharmacology

NASA Technical Reports Server (NTRS)

Maickel, R. P.

1976-01-01

The expertise and facilities available within the Medical Sciences Program section on Pharmacology were used along with informational input from various NASA sources to study areas relevant to the manned space effort. Topics discussed include effects of drugs on deprivation-induced fluid consumption, brain biogenic amines, biochemical responses to stressful stimuli, biochemical and behavioral pharmacology of amphetamines, biochemical and pharmacological studies of analogues to biologically active indole compounds, chemical pharmacology: drug metabolism and disposition, toxicology, and chemical methodology. Appendices include a bibliography, and papers submitted for publication or already published.

Safety and efficacy of chastetree (Vitex agnus-castus) during pregnancy and lactation.

PubMed

Dugoua, Jean-Jacques; Seely, Dugald; Perri, Daniel; Koren, Gideon; Mills, Edward

2008-01-01

There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbs used during pregnancy and lactation. This is one article in a series that systematically reviews the evidence for herbs commonly used during pregnancy and lactation. To systematically review the literature for evidence on the use, safety and pharmacology of chastetree, focusing on issues pertaining to pregnancy and lactation. We searched 7 electronic databases and compiled data according to the grade of evidence found. RESULTS In pregnancy, there is poor evidence based on theoretical and expert opinion and in vitro studies that chastetree may have estrogenic and progesteronic activity, uterine stimulant activity, emmenagogue activity and prevent miscarriages. In lactation, theoretical and expert opinion conflict as to whether chastetree increases or decreases lactation. Given its relatively common use amongst women of childbearing age, it is likely that some women may consume chastetree while unknowingly pregnant. Complementary and alternative medicine, midwifery and medical practitioners should be aware of this fact when prescribing chastetree to women of childbearing age, particularly when the patient is planning a family. Key words: Chastetree, vitex agnus-castus, pregnancy, lactation, breastfeeding, systematic review.

Pharmacokinetics, efficacy and safety of glyburide for treatment of gestational diabetes mellitus.

PubMed

Malek, Rana; Davis, Stephen N

2016-06-01

Gestational diabetes mellitus (GDM) complicates 10% of all pregnancies and is defined as hyperglycemia first noted during pregnancy. Rates of GDM are rising and untreated GDM results in complications for both mother and fetus. GDM is often managed by diet and exercise but 30-40% of women will require pharmacological intervention. Insulin has traditionally been the treatment of choice but since 2007, glyburide, a second generation sulfonylurea has become the most prescribed medication for GDM. This review will cover the pharmacokinetics, efficacy, and safety of glyburide for the management of GDM. Management of GDM is challenging secondary to the stringent glycemic goals that mimic the lower glucose levels in pregnancy. Glyburide is generally effective in treating hyperglycemia. However, several studies have raised safety concerns showing higher neonatal intensive care unit (NICU) admissions, higher rates of macrosomia, large for gestational age and pre-eclampsia in the mother. For this reason, insulin should be first-line therapy for GDM. In areas of limited resources where the self-monitoring needed for accurate insulin dosing is not possible, where access to refrigeration for insulin storage is not universal, or severe needle phobia then the benefits of glyburide (controlling hyperglycemia) outweighs the harm of NICU admissions and macrosomia.

Ethnobotany, phytochemistry, and pharmacology of the genus Litsea: An update.

PubMed

Wang, Yun-Song; Wen, Zheng-Qi; Li, Bi-Tao; Zhang, Hong-Bin; Yang, Jing-Hua

2016-04-02

The genus Litsea is one of the most diverse genera of evergreen trees or shrubs belong to Lauraceae, and comprises roughly 400 species of tree that are distributed abundantly throughout tropical and subtropical Asia, North and South America. Litsea species have been used globally in traditional medicine for the treatment of various diseases including influenza, stomach aches, diarrhea, diabetes, vomiting, bone pain, inflammation, illness related to the central nervous system and other ailments. The purpose of this review is to provide updated, comprehensive and categorized information on the ethnobotany, phytochemistry and pharmacological research of Litsea species in order to explore their therapeutic potential and evaluate future research opportunities. All the available information on Litsea species was actualised by systematically searching the scientific literatures including Chinese, Korean, Japanese, Indian, and South American herbal classics, library catalogs and scientific databases (PubMed, SciFinder, Web of Science, Google Scholar, VIP and Wanfang). The Plant List, International Plant Name index and Scientific Database of China Plant Species were used to validate scientific names. 407 secondary metabolites have been reported from Litsea species. Litsea Species are sources of secondary metabolites with interesting chemical structures (alkaloids, lactones, sesquiterpenes, flavonoids, lignans, and essential oils) and significant bioactivities. Crude extracts, fractions and phytochemical constituents isolated from Litsea show a wide spectrum of in vitro and in vivo pharmacological activities including anticancer, anti-inflammatory, antimicrobial, antioxidant, antidiabetic, anti-HIV, insecticidal, etc. From data collected in this review, the genus Litsea comprises a wide range of therapeutically promising and valuable plants, and has attracted much attention owing to its multiple functions. Many traditional uses of Litsea species have now been validated by modern pharmacology research. Deep and systematic phytochemical investigation of the genus Litsea and the pharmacological properties, especially its mechanism of action and toxicology, to illustrate its ethnomedicinal use, explore the therapeutic potential and support further health-care product development will undoubtedly be the focus of further research. Therefore, detailed and extensive studies and clinical evaluation of Litsea species should be carried out in future for the safety approval of therapeutic applications. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Preclinical safety assessment of the 5-HT2A receptor agonist PET radioligand [ 11C]Cimbi-36.

PubMed

Ettrup, Anders; Holm, Søren; Hansen, Martin; Wasim, Muhammad; Santini, Martin Andreas; Palner, Mikael; Madsen, Jacob; Svarer, Claus; Kristensen, Jesper Langgaard; Knudsen, Gitte Moos

2013-08-01

[11C]Cimbi-36 was recently developed as an agonist radioligand for brain imaging of serotonin 2A receptors (5-HT2A) with positron emission tomography (PET). This may be used to quantify the high-affinity state of 5-HT2A receptors and may have the potential to quantify changes in cerebral 5-HT levels in vivo. We here investigated safety aspects related to clinical use of [11C]Cimbi-36, including radiation dosimetry and in vivo pharmacology. [11C]Cimbi-36 was injected in rats or pigs, and radiation dosimetry was examined by ex vivo dissection or with PET scanning, respectively. Based on animal data, the Organ Level INternal Dose Assessment software was used to estimate extrapolated human dosimetry for [11C]Cimbi-36. The 5-HT2A receptor agonist actions of [11C]Cimbi-36 in vivo pharmacological effects in mice elicited by increasing doses of Cimbi-36 were assessed with the head-twitch response (HTR). The effective dose as extrapolated from both rat and pig data was low, 7.67 and 4.88 μSv/MBq, respectively. In addition, the estimated absorbed radiation dose to human target organs did not exceed safety levels. Administration of 0.5 mg/kg Cimbi-36 leads to significant HTR compared to saline, whereas 0.05 mg/kg Cimbi-36 (doses much larger than those given in conjunction with a PET scan) did not elicit a significant HTR. Administration of tracer doses of [11C]Cimbi-36 does not seem to be associated with unusual radiation burden or adverse clinical effects.

Safety and efficacy of cranberry (vaccinium macrocarpon) during pregnancy and lactation.

PubMed

Dugoua, Jean-Jacques; Seely, Dugald; Perri, Daniel; Mills, Edward; Koren, Gideon

2008-01-01

There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbs used during pregnancy and lactation. This is one article in a series that systematically reviews the evidence for herbs commonly used during pregnancy and lactation. To systematically review the literature for evidence on the use, safety and pharmacology of cranberry, focusing on issues pertaining to pregnancy and lactation. We searched 7 electronic databases and compiled data according to the grade of evidence found. There is no direct evidence of safety or harm to the mother or fetus as a result of consuming cranberry during pregnancy. Indirectly, there is good scientific evidence that cranberry may be of minimal risk, where a survey of 400 pregnant women did not uncover any adverse events when cranberry was regularly consumed. In lactation, the safety or harm of cranberry is unknown. Women experience urinary tract infections with greater frequency during pregnancy. Given the evidence to support the use of cranberry for urinary tract infections (UTIs) and its safety profile, cranberry supplementation as fruit or fruit juice may be a valuable therapeutic choice in the treatment of UTIs during pregnancy.

[Azilsartan: a new angiotensin receptor blocker].

PubMed

Rakugi, Hiromi; Enya, Kazuaki

2012-09-01

Azilsartan is a new ARB with the specific and potent angiotensin II receptor binding-inhibitory effect and more continuous angiotensin II antagonistic and antihypertensive actions in pre-clinical studies compared with other ARBs. The controlled clinical study in Japanese hypertensive patients indicates that once-daily azilsartan dose provides more potent 24-hour sustained antihypertensive effect than that of candesartan but with equivalent safety. Azilsartan was confirmed to improve more potently the insulin-resistance in SHR and type 2 diabetic mice and suppress more prominently the urinary albumin excretion in type 2 diabetic fatty rats than other ARBs. Thus, azilsartan is a unique antihypertensive agent with the profile of more beneficial pharmacological activity, and could provide higher rates of hypertension control over 24-hour following once daily administration.

Safety assessment of hydroethanolic rambutan rind extract: acute and sub-chronic toxicity studies.

PubMed

Thinkratok, Aree; Suwannaprapha, Parin; Srisawat, Rungrudee

2014-10-01

This study evaluated the safety of rambutan rind extract (RRE) in male Wistar rats. While acute toxicity was evaluated by feeding the rats with single doses of RRE (1000, 2000, 3000, 4000, and 5000 mg/kg) and its sub-chronic toxicity was observed in rats orally administered with RRE (500, 1000, and 2000 mg/kg) daily for 30 days. In acute toxicity study, the LD50 was found to be greater than 5000 mg/kg of RRE. In sub-chronic toxicity study, no mortality and sign of toxicity was found up to 1000 mg/kg/day of RRE. At 2000 mg/kg/day dose, the mortality rate was 12.5%. Significant decreases in body weight gain and food consumption were found in both acute and sub-chronic toxicity studies. In acute toxicity study, all the studied doses of RRE did not alter serum levels of triglyceride (TG), aspartate aminotransferase (AST) andalanine aminotransferase (ALT). In sub-chronic toxicity study, all studied doses of RRE significantly decreased plasma levels of TG and blood urea nitrogen, but did not alter plasma levels of AST and ALT. TC levels did not show any significant change in both the studies. The obtained results provide basic information for in vivo experimental studies of the pharmacological potentiality of RRE.

Safety profile of bilastine: 2nd generation H1-antihistamines.

PubMed

Scaglione, F

2012-12-01

Bilastine is a new H1 antagonist with no sedative side effects, no cardiotoxic effects, and no hepatic metabolism. In addition, bilastine has proved to be effective for the symptomatic treatment of allergic rhinoconjunctivitis and urticaria. Pharmacological studies have shown that bilastine is highly selective for the H1 receptor in both in vivo and in vitro studies, and with no apparent affinity for other receptors. The absorption of bilastine is fast, linear and dose-proportional; it appears to be safe and well tolerated at all doses levels in healthy population. Multiple administration of bilastine has confirmed the linearity of the kinetic parameters. The distribution in the brain is undetectable. The safety profile in terms of adverse effects is very similar to placebo in all Phase I, II and III clinical trials. Bilastine (20 mg), unlike cetirizine, does not increase alcohol effects on the CNS. Bilastine 20 mg does not increase the CNS depressant effect of lorazepam. Bilastine 20 mg is similar to placebo in the driving test. Therefore, it meets the current criteria for medication used in the treatment of allergic rhinitis and urticaria.

The use of tramadol "on-demand" for premature ejaculation: a systematic review.

PubMed

Wong, Billy L K; Malde, Sachin

2013-01-01

To determine the efficacy and safety of tramadol in the treatment of premature ejaculation (PE) by systematically reviewing the results of randomized controlled trials. All studies evaluating the efficacy of tramadol for the treatment of PE published in peer reviewed medical journals between 2006 and March 2012 were identified by searching for the keywords "premature ejaculation" and "tramadol" in the PubMed database. Only randomized controlled trials published in the English language were included. A total of 5 articles, comprising 823 patients, met the inclusion criteria for further analysis. Overall, tramadol on-demand results in a significant improvement in mean intravaginal ejaculatory latency time and symptom scores compared with placebo and in an improvement in partner sexual satisfaction scores. The rate of short-term adverse effects is low. Tramadol is an effective treatment for patients with PE and represents a promising alternative to the currently used oral pharmacologic agents. Longer-term safety studies, and those comparing tramadol with the selective serotonin receptor inhibitors, are essential to determine the place of tramadol in the treatment of this distressing condition. Copyright © 2013 Elsevier Inc. All rights reserved.

Safety assessment of the Cistanche tubulosa health food product Memoregain®: Genotoxicity and 28-day repeated dose toxicity test.

PubMed

Liao, Po-Lin; Li, Ching-Hao; Tse, Ling-Shan; Kang, Jaw-Jou; Cheng, Yu-Wen

2018-06-07

The pharmacological effects of Cistanches Herba, known as "Ginseng of the desert", have been extensively studied. In this study, we aimed to assess the genotoxic and oral toxic effects of the Cistanche tubulosa health food product Memoregain ® using in vitro and in vivo tests. Ames tests using five strains of Salmonella typhimurium showed no signs of increased reverse mutation upon exposure to Memoregain ® up to a concentration of 5 mg/plate. Exposure of Chinese hamster ovary (CHO-K1) cells to Memoregain ® did not increase the frequency of chromosomal aberrations in vitro. Moreover, Memoregain ® treatment did not affect the proportions of immature to total erythrocytes or the number of micronuclei in the immature erythrocytes of ICR mice. Additionally, after 28-day repeated oral dose toxicity tests (0, 0.15, 0.3, and 0.5g/kg body weight) in rats, no observable adverse effects were found. These toxicological assessments supported the safety of Memoregain ® for human consumption. Copyright © 2018 Elsevier Ltd. All rights reserved.

Experiences of nurses as postgraduate students of pharmacology and therapeutics: a multiple case narrative study.

PubMed

Lim, Anecita Gigi; North, Nicola; Shaw, John

2014-06-01

Pharmacology and therapeutics are essential components of educational programmes in prescribing, yet little is known about students' experiences in studying these subjects for a prescribing role. To investigate the views and experiences of nurses as postgraduate students who were studying pharmacology and therapeutics in preparation for a prescribing role. Qualitative study using a multiple case narrative approach. The participants were undertaking or had recently completed a Master's degree programme; they worked in a range of clinical areas and services in the Auckland region. Twenty nurses, with advanced clinical backgrounds and experience engaged in postgraduate studies in pharmacology and therapeutics. A semi-structured interview of approximately 1h was undertaken with each participant. Transcripts were analysed within and across cases using Narralizer software to support thematic analysis. There were four broad thematic areas. In the first, 'prescribing in the context of advanced nursing practice', participants reflected on why prescribing authority was important to them. In the second theme, 'adequacy of prior pharmacology knowledge' they discussed the relative lack of pharmacology in their undergraduate programmes and in nursing practice. In the third, 'drawing on clinical experience in acquiring pharmacology knowledge', participants discussed how, as they grappled with new pharmacological science, they drew on clinical experience which facilitated their learning. In the fourth theme, 'benefits of increased pharmacology knowledge' they discussed how their studies improved their interactions with patients, medical colleagues and as members of multi-disciplinary teams. All nurses viewed their studies in pharmacology as fundamental to their roles as prescribers, through knowledge development and an increase in confidence. Although pharmacology theory was new to many participants, their learning was facilitated because they were able to reflect on previous clinical experience and apply this to theory. Copyright © 2014 Elsevier Ltd. All rights reserved.

Toxic Hazards Research Unit Annual Technical Report: 1984

DTIC Science & Technology

1984-09-01

exposed to TOCP exhibited the classic lesions of delayed neuropathy (Smith and Lillie, 1931; Barnes and Denz, 1953; (avanagh, 1954; and Fenton , 1955...Safety of *.i Chemicals in Food, Drugs, and Cosmetics , The staff of the Divi- sion of Pharmacology of the Federal Food and Drug Administration, Austin...Annual Technical Report: 1967, AMRL-TR-67-137 (AD 834723), Aerospace Medical Research Laboratory, Wright-Patterson Air Force Base, Ohio. Fenton , J. C

An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration.

PubMed

Ulbricht, Catherine; Basch, Ethan; Cheung, Lisa; Goldberg, Harley; Hammerness, Paul; Isaac, Richard; Khalsa, Karta Purkh Singh; Romm, Aviva; Rychlik, Idalia; Varghese, Minney; Weissner, Wendy; Windsor, Regina C; Wortley, Jayme

2014-03-01

An evidence-based systematic review of elderberry and elderflower (Sambucus nigra) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Implementing a pediatric obesity care guideline in a freestanding children's hospital to improve child safety and hospital preparedness.

PubMed

Porter, Renee M; Thrasher, Jodi; Krebs, Nancy F

2012-12-01

Medical and surgical care of children with severe obesity is complicated and requires recognition of the problem, appropriate equipment, and safe management. There is little literature describing patient, provider, and institutional needs for the severely obese pediatric patient. Nonetheless, the limited data suggest 3 broad categories of needs unique to this population: (a) airway management, (b) drug dosing and pharmacology, and (c) equipment and infrastructure. We describe an opportunity at the Children's Hospital Colorado to better prepare and optimize care for this patient population by creation of a Pediatric Obesity Care Guideline that focused on key areas of quality and safety. Copyright © 2012 Elsevier Inc. All rights reserved.

[Preclinical evaluation of the safety of biotechnology products: specific aspects].

PubMed

Descotes, Jacques; Ravel, Guillaume; Vial, Thierry

2003-01-01

Biotechnology-derived products represent a class of increasingly numerous drugs. One of their major characteristics is extreme diversity, which requires specific approaches for the preclinical evaluation of their safety. The selection of relevant animal species is not easy, as most of these products are human-specific. Thus, only one species will often be used, i.e. primates. As most of these products are large molecules, they can be directly immunogenic. When they are human-specific, no animal model is available to predict the risk. Many biotechnology-derived products have an expected influence on the immune system. This must be taken into account in the preclinical strategy of immunotoxicity evaluation that is now required for every new drug. As conventional toxicity testing is generally limited, safety pharmacology studies should include more than the core battery of assays required by current guidelines in order to complement missing data as much as possible. Because of these particularities, a comprehensive investigation of metabolism and pharmacokinetics is not usually needed. Some products can cross-react with cellular components not intended as therapeutic targets. It is, therefore, essential to rule out the risk of possible cross-reactions that can result in adverse effects. Finally, viral safety is a crucial component of the preclinical safety evaluation of these products. Overall, biotechnology-derived products raise specific issues because of their innovative and original characteristics, and it is difficult to address all these issues if not by using a case-by-case approach.

An Algorithm-Based Approach for Behavior and Disease Management in Children.

PubMed

Meyer, Beau D; Lee, Jessica Y; Thikkurissy, S; Casamassimo, Paul S; Vann, William F

2018-03-15

Pharmacologic behavior management for dental treatment is an approach to provide invasive yet compassionate care for young children; it can facilitate the treatment of children who otherwise may not cooperate for traditional in-office care. Some recent highly publicized procedural sedation-related tragedies have drawn attention to risks associated with pharmacologic management. However, it remains widely accepted that, by adhering to proper guidelines, procedural sedation can assist in the provision of high-quality dental care while minimizing morbidity and mortality from the procedure. The purpose of this paper was to propose an algorithm for clinicians to consider when selecting a behavior and disease management strategy for early childhood caries. This algorithm will not ensure a positive outcome but can assist clinicians when counseling caregivers about risks, benefits, and alternatives. It also emphasizes and underscores best-safety practices.

Drug development strategies for the treatment of obesity: how to ensure efficacy, safety, and sustainable weight loss

PubMed Central

Barja-Fernandez, S; Leis, R; Casanueva, FF; Seoane, LM

2014-01-01

The prevalence of obesity has increased worldwide, and approximately 25%–35% of the adult population is obese in some countries. The excess of body fat is associated with adverse health consequences. Considering the limited efficacy of diet and exercise in the current obese population and the use of bariatric surgery only for morbid obesity, it appears that drug therapy is the only available method to address the problem on a large scale. Currently, pharmacological obesity treatment options are limited. However, new antiobesity drugs acting through central nervous system pathways or the peripheral adiposity signals and gastrointestinal tract are under clinical development. One of the most promising approaches is the use of peptides that influence the peripheral satiety signals and brain–gut axis such as GLP-1 analogs. However, considering that any antiobesity drug may affect one or several of the systems that control food intake and energy expenditure, it is unlikely that a single pharmacological agent will be effective as a striking obesity treatment. Thus, future strategies to treat obesity will need to be directed at sustainable weight loss to ensure maximal safety. This strategy will probably require the coadministration of medications that act through different mechanisms. PMID:25489237

Safety of intravenous tranexamic acid in patients undergoing majororthopaedic surgery: a meta-analysis of randomised controlled trials

PubMed Central

Franchini, Massimo; Mengoli, Carlo; Marietta, Marco; Marano, Giuseppe; Vaglio, Stefania; Pupella, Simonetta; Mannucci, Pier Mannuccio; Liumbruno, Giancarlo M.

2018-01-01

Among the various pharmacological options to decrease peri-operative bleeding, tranexamic acid appears to be one of the most interesting. Several trials have consistently documented the efficacy of this synthetic drug in reducing the risk of blood loss and the need for allogeneic blood transfusion in patients undergoing total hip and knee arthroplasty. The safety of intravenous tranexamic acid in major orthopaedic surgery, particularly regarding the risk of venous thromboembolism, was systematically analysed in this review. A systematic search of the literature identified 73 randomised controlled trials involving 4,174 patients and 2,779 controls. The raw overall incidence of venous thromboembolism was 2.1% in patients who received intravenous tranexamic acid and 2.0% in controls. A meta-analytic pooling showed that the risk of venous thromboembolism in tranexamic acid-treated patients was not significantly different from that of controls (risk difference: 0.01%, 95% confidence interval [CI]: −0.05%, 0.07%; risk ratio: 1.067, 95% CI: 0.760–1.496). Other severe drug-related adverse events occurred very rarely (0.1%). In conclusion, the results of this systematic review and meta-analysis show that intravenous tranexamic acid is a safe pharmacological treatment to reduce blood loss and transfusion requirements in patients undergoing major orthopaedic surgery. PMID:29337665

Choosing between GLP-1 Receptor Agonists and DPP-4 Inhibitors: A Pharmacological Perspective

PubMed Central

Brown, Dominique Xavier; Evans, Marc

2012-01-01

In recent years the incretin therapies have provided a new treatment option for patients with type 2 diabetes mellitus (T2DM). The incretin therapies focus on the increasing levels of the two incretin hormones, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP). This results in increased glucose dependent insulin synthesis and release. GLP-1 receptor agonists such as liraglutide and exenatide exert an intrinsic biological effect on GLP-1 receptors directly stimulating the release of insulin from pancreatic beta cells. DPP-4 inhibitors such as sitagliptin and linagliptin prevent the inactivation of endogenous GLP-1 and GIP through competitive inhibition of the DPP-4 enzyme. Both incretin therapies have good safety and tolerability profiles and interact minimally with a number of medications commonly prescribed in T2DM. This paper focuses on the pharmacological basis by which the incretin therapies function and how this knowledge can inform and benefit clinical decisions. Each individual incretin agent has benefits and pitfalls relating to aspects such as glycaemic and nonglycaemic efficacy, safety and tolerability, ease of administration, and cost. Overall, a personalized medicine approach has been found to be favourable, tailoring the incretin agent to benefit and suit patient's needs such as renal impairment (RI) or hepatic impairment (HI). PMID:23125920

Prevention of exacerbations in patients with stable non-cystic fibrosis bronchiectasis: a systematic review and meta-analysis of pharmacological and non-pharmacological therapies.

PubMed

Abu Dabrh, Abd Moain; Hill, Adam T; Dobler, Claudia C; Asi, Noor; Farah, Wigdan H; Haydour, Qusay; Wang, Zhen; Benkhadra, Khalid; Prokop, Larry J; Murad, Mohammad Hassan

2018-04-20

Several pharmacological and non-pharmacological therapies are used to treat stable bronchiectasis of non-cystic fibrosis (CF) aetiology. We conducted a systematic review and meta-analysis to assess the evidence of the effectiveness of pharmacological and non-pharmacological treatment options in patients with stable non-CF bronchiectasis with a focus on reducing exacerbations. Multiple databases were searched through September 2017. Outcomes included the number of patients with exacerbation events, mean number of exacerbations, hospitalisations, mortality, quality of life measures, and safety and adverse effects. Meta-analysis was conducted using the random effects model. 30 randomised controlled trials enrolled subjects with non-CF bronchiectasis using different interventions. Moderate-quality evidence supported the effect of long-term antibiotics (≥3 months) on lowering the number of patients experiencing exacerbation events (relative risk 0.77 (95% CI 0.68 to 0.89)), reducing number of exacerbations (incidence rate ratio 0.62 (95% CI 0.49 to 0.78)), improving forced expiratory volume (litre) in the first second (FEV 1 ) (weighted mean difference (WMD); 0.02 (95% CI 0.00 to 0.04)), decreasing sputum purulence scores (numerical scale of 1-8) (WMD -0.90 (95% CI -1.58 to -0.22)) and improving quality of life scores assessed by the St George's Respiratory Questionnaire (WMD -6.07 (95% CI -10.7 to -1.43)). Bronchospasm increased with inhaled antibiotics while diarrhoea increased particularly with oral macrolide therapy. Moderate-quality evidence supports long-term antibiotic therapy for preventing exacerbations in stable non-CF bronchiectasis. However, data about the optimum agent, mode of therapy and length of treatment are limited. There is paucity of high-quality evidence to support the management of stable non-CF bronchiectasis including prevention of exacerbations. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Quality and safety of herbal medical products: regulation and the need for quality assurance along the value chains.

PubMed

Heinrich, Michael

2015-07-01

Herbal medicines and products derived from them are a diverse group of products for which different (and often limited) levels of evidence are available. As importantly, such products generally vary in their composition and are at the end of an often poorly understood value chain, which often links producers in biodiversity rich countries with the large markets in the North. This paper discusses the current regulatory framework of such herbal medical products (with a focus on the UK) and using examples from our own metabolomic research on Curcumal longa L. (turmeric, Zingiberaceae) how value chains impact on the composition and quality (and thus the safety) of such products. Overall, our recent research demonstrates the need for studying the links between producers and consumers of commodities produced in provider countries and that plant metabolomics offer a novel way of assessing the chemical variability along a value chain. © 2015 The British Pharmacological Society.

The pharmacokinetics, efficacy, safety, and ease of use of a novel portable metered-dose cannabis inhaler in patients with chronic neuropathic pain: a phase 1a study.

PubMed

Eisenberg, Elon; Ogintz, Miri; Almog, Shlomo

2014-09-01

Chronic neuropathic pain is often refractory to standard pharmacological treatments. Although growing evidence supports the use of inhaled cannabis for neuropathic pain, the lack of standard inhaled dosing plays a major obstacle in cannabis becoming a "main stream" pharmacological treatment for neuropathic pain. The objective of this study was to explore the pharmacokinetics, safety, tolerability, efficacy, and ease of use of a novel portable thermal-metered-dose inhaler (tMDI) for cannabis in a cohort of eight patients suffering from chronic neuropathic pain and on a stable analgesic regimen including medicinal cannabis. In a single-dose, open-label study, patients inhaled a single 15.1 ± 0.1 mg dose of cannabis using the Syqe Inhaler device. Blood samples for Δ(9)-tetrahydrocannabinol (THC) and 11-hydroxy-Δ(9)-THC were taken at baseline and up to 120 minutes. Pain intensity (0-10 VAS), adverse events, and satisfaction score were monitored following the inhalation. A uniform pharmacokinetic profile was exhibited across all participants (Δ(9)-THC plasma Cmax ± SD was 38 ± 10 ng/mL, Tmax ± SD was 3 ± 1 minutes, AUC₀→infinity ± SD was 607 ± 200 ng·min/mL). Higher plasma Cmax increase per mg Δ(9)-THC administered (12.3 ng/mL/mg THC) and lower interindividual variability of Cmax (25.3%), compared with reported alternative modes of THC delivery, were measured. A significant 45% reduction in pain intensity was noted 20 minutes post inhalation (P = .001), turning back to baseline within 90 minutes. Tolerable, lightheadedness, lasting 15-30 minutes and requiring no intervention, was the only reported adverse event. This trial suggests the potential use of the Syqe Inhaler device as a smokeless delivery system of medicinal cannabis, producing a Δ(9)-THC pharmacokinetic profile with low interindividual variation of Cmax, achieving pharmaceutical standards for inhaled drugs.

Child/Adolescent Anxiety Multimodal Study (CAMS): rationale, design, and methods

PubMed Central

2010-01-01

Objective To present the design, methods, and rationale of the Child/Adolescent Anxiety Multimodal Study (CAMS), a recently completed federally-funded, multi-site, randomized placebo-controlled trial that examined the relative efficacy of cognitive-behavior therapy (CBT), sertraline (SRT), and their combination (COMB) against pill placebo (PBO) for the treatment of separation anxiety disorder (SAD), generalized anxiety disorder (GAD) and social phobia (SoP) in children and adolescents. Methods Following a brief review of the acute outcomes of the CAMS trial, as well as the psychosocial and pharmacologic treatment literature for pediatric anxiety disorders, the design and methods of the CAMS trial are described. Results CAMS was a six-year, six-site, randomized controlled trial. Four hundred eighty-eight (N = 488) children and adolescents (ages 7-17 years) with DSM-IV-TR diagnoses of SAD, GAD, or SoP were randomly assigned to one of four treatment conditions: CBT, SRT, COMB, or PBO. Assessments of anxiety symptoms, safety, and functional outcomes, as well as putative mediators and moderators of treatment response were completed in a multi-measure, multi-informant fashion. Manual-based therapies, trained clinicians and independent evaluators were used to ensure treatment and assessment fidelity. A multi-layered administrative structure with representation from all sites facilitated cross-site coordination of the entire trial, study protocols and quality assurance. Conclusions CAMS offers a model for clinical trials methods applicable to psychosocial and psychopharmacological comparative treatment trials by using state-of-the-art methods and rigorous cross-site quality controls. CAMS also provided a large-scale examination of the relative and combined efficacy and safety of the best evidenced-based psychosocial (CBT) and pharmacologic (SSRI) treatments to date for the most commonly occurring pediatric anxiety disorders. Primary and secondary results of CAMS will hold important implications for informing practice-relevant decisions regarding the initial treatment of youth with anxiety disorders. Trial registration ClinicalTrials.gov NCT00052078. PMID:20051130

Clinical Pharmacology of Delafloxacin in Patients With Hepatic Impairment.

PubMed

Hoover, Randall; Marbury, Thomas C; Preston, Richard A; Quintas, Megan; Lawrence, Laura E; Paulson, Susan K; Luke, David R; Cammarata, Sue K

2017-03-01

Delafloxacin is a novel anionic fluoroquinolone with robust activity against Gram-positive, Gram-negative, atypical, and anaerobic bacteria, including methicillin-resistant S aureus. Delafloxacin is currently being studied for the treatment of acute bacterial skin and skin structure infections and community-acquired pneumonia. This was a phase 1, open-label pharmacokinetic and safety study of a single intravenous dose of 300 mg delafloxacin in subjects with mild, moderate, and severe hepatic impairment (Child-Pugh class A, B, and C, respectively) compared with matched healthy controls. The effects of hepatic impairment were assessed by ANOVA of log-transformed values for AUC 0-∞ , C max , and systemic clearance, with hepatic group as a fixed effect. Mean AUC 0-∞ and C max in each impairment group were not significantly different from those of the pooled healthy subjects (P > 0.05). The 90% confidence interval (CI) of the percentage ratios of least-squares means of AUC 0-∞ did not indicate significant differences between the impairment groups and pooled healthy controls: Child-Pugh class A (mild) 114.4 (CI: 95.6, 137.0), Child-Pugh class B (moderate) 114.8 (CI: 95.9, 137.4), and Child-Pugh class C (severe) 115.1 (CI: 96.1, 137.8). A single IV infusion of delafloxacin was generally well tolerated in all treatment groups. The exposure and clearance of delafloxacin in subjects with mild, moderate, or severe hepatic impairment did not significantly differ from those of pooled, matched healthy subjects. Based on these pharmacokinetic data, dose adjustment of delafloxacin in the presence of hepatic impairment is not needed. © 2016, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Patterns of glucose-lowering therapies and neonatal outcomes in the treatment of gestational diabetes in Canada, 2009-2014.

PubMed

Bowker, S L; Savu, A; Yeung, R O; Johnson, J A; Ryan, E A; Kaul, P

2017-09-01

To examine patterns of use of different glycaemic control agents for treating gestational diabetes mellitus. This was a large, retrospective, population-based cohort study of pregnant women with gestational diabetes from Alberta, Canada. We linked data from the Alberta Vital Statistics - Birth database with administrative claims data. Alberta Vital Statistics - Birth data were used to identify births that occurred between 1 January 2009 and 31 December 2014. We used International Classification of Diseases version 9/10 codes to identify women with gestational diabetes, and we excluded women with pre-existing diabetes. Our cohort consisted of 16 857 women with gestational diabetes, with a total of 18 761 birth events between 2009 and 2014. Over the study period, the proportion of women with gestational diabetes who were treated with glycaemic control therapies increased from 25.0% to 31.4% (P<0.0001). The number of pregnancies treated with insulin only increased (from 23.6% to 28.3%; P<0.0001), as did the number treated with metformin, +/- insulin (from 1.4% to 3.2%; P<0.0001). Rates of large-for-gestational-age infants were significantly higher among pregnancies treated with insulin only (17%) or metformin (16.5%) than among pregnancies that did not receive any pharmacological treatment (12.8%). Our findings show increasing use of insulin and metformin in women with gestational diabetes. Rates of large-for-gestational-age infants were similar among pregnant women receiving either pharmacological treatment, and higher than among pregnant women who did not receive any pharmacological treatment. Future research should explore the long-term outcomes and safety of metformin as an alternative for treating gestational diabetes. © 2017 Diabetes UK.

A review on phytochemistry, pharmacology and toxicology studies of Aconitum.

PubMed

Nyirimigabo, Eric; Xu, Yanyan; Li, Yubo; Wang, Yuming; Agyemang, Kojo; Zhang, Yanjun

2015-01-01

A number of species belonging to herbal genus Aconitum are well-known and popular for their medicinal benefits in Indian, Vietnamese, Korean, Japanese, Tibetan and Chinese systems of medicine. It is a valuable drug as well as an unpredictable toxic material. It is therefore imperative to understand and control the toxic potential of herbs from this genus. In this review, the ethnomedicinal, phytochemistry, pharmacology, structure activity relationship and toxicology studies of Aconitum were presented to add to knowledge for their safe application. A total of about 76 of all aconite species growing in China and surrounding far-east and Asian countries are used for various medical purposes. The main ingredients of aconite species are alkaloids, flavonoids, free fatty acids and polysaccharides. The tuberous roots of genus Aconitum are commonly applied for various diseases such as rheumatic fever, painful joints and some endocrinal disorders. It stimulates the tip of sensory nerve fibres. These tubers of Aconitum are used in the herbal medicines only after processing. There remain high toxicological risks of the improper medicinal applications of Aconitum. The cardio and neurotoxicities of this herb are potentially lethal. Many analytical methods have been reported for quantitatively and qualitatively characterization of Aconitum. Aconitum is a plant of great importance both in traditional medicine in general and in TCM in particular. Much attention should be put on Aconitum because of its narrow therapeutic range. However, Aconitum's toxicity can be reduced using different techniques and then benefit from its pharmacological activities. New methods, approaches and techniques should be developed for chemical and toxicological analysis to improve its quality and safety. © 2014 Royal Pharmaceutical Society.

Do final-year medical students have sufficient prescribing competencies? A systematic literature review.

PubMed

Brinkman, David J; Tichelaar, Jelle; Graaf, Sanne; Otten, René H J; Richir, Milan C; van Agtmael, Michiel A

2018-04-01

Prescribing errors are an important cause of patient safety incidents and are frequently caused by junior doctors. This might be because the prescribing competence of final-year medical students is poor as a result of inadequate clinical pharmacology and therapeutic (CPT) education. We reviewed the literature to investigate which prescribing competencies medical students should have acquired in order to prescribe safely and effectively, and whether these have been attained by the time they graduate. PubMed, EMBASE and ERIC databases were searched from the earliest dates up to and including January 2017, using the terms 'prescribing', 'competence' and 'medical students' in combination. Articles describing or evaluating essential prescribing competencies of final-year medical students were included. Twenty-five articles describing, and 47 articles evaluating, the prescribing competencies of final-year students were included. Although there seems to be some agreement, we found no clear consensus among CPT teachers on which prescribing competencies medical students should have when they graduate. Studies showed that students had a general lack of preparedness, self-confidence, knowledge and skills, specifically regarding general and antimicrobial prescribing and pharmacovigilance. However, the results should be interpreted with caution, given the heterogeneity and methodological weaknesses of the included studies. There is considerable evidence that final-year students have insufficient competencies to prescribe safely and effectively, although there is a need for a greater consensus among CPT teachers on the required competencies. Changes in undergraduate CPT education are urgently required in order to improve the prescribing of future doctors. © 2018 VU University Medical Centre. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Canadian Network for Mood and Anxiety Treatments (CANMAT) 2016 Clinical Guidelines for the Management of Adults with Major Depressive Disorder

PubMed Central

Lam, Raymond W.; McIntyre, Roger S.; Tourjman, S. Valérie; Bhat, Venkat; Blier, Pierre; Hasnain, Mehrul; Jollant, Fabrice; Levitt, Anthony J.; MacQueen, Glenda M.; McInerney, Shane J.; McIntosh, Diane; Milev, Roumen V.; Müller, Daniel J.; Parikh, Sagar V.; Pearson, Norma L.; Ravindran, Arun V.; Uher, Rudolf

2016-01-01

Background: The Canadian Network for Mood and Anxiety Treatments (CANMAT) conducted a revision of the 2009 guidelines by updating the evidence and recommendations. The scope of the 2016 guidelines remains the management of major depressive disorder (MDD) in adults, with a target audience of psychiatrists and other mental health professionals. Methods: Using the question-answer format, we conducted a systematic literature search focusing on systematic reviews and meta-analyses. Evidence was graded using CANMAT-defined criteria for level of evidence. Recommendations for lines of treatment were based on the quality of evidence and clinical expert consensus. “Pharmacological Treatments” is the third of six sections of the 2016 guidelines. With little new information on older medications, treatment recommendations focus on second-generation antidepressants. Results: Evidence-informed responses are given for 21 questions under 4 broad categories: 1) principles of pharmacological management, including individualized assessment of patient and medication factors for antidepressant selection, regular and frequent monitoring, and assessing clinical and functional outcomes with measurement-based care; 2) comparative aspects of antidepressant medications based on efficacy, tolerability, and safety, including summaries of newly approved drugs since 2009; 3) practical approaches to pharmacological management, including drug-drug interactions and maintenance recommendations; and 4) managing inadequate response and treatment resistance, with a focus on switching antidepressants, applying adjunctive treatments, and new and emerging agents. Conclusions: Evidence-based pharmacological treatments are available for first-line treatment of MDD and for management of inadequate response. However, given the limitations of the evidence base, pharmacological management of MDD still depends on tailoring treatments to the patient. PMID:27486148

Retrospective comparison of mechanical percutaneous thrombectomy of hemodialysis arteriovenous grafts with the Arrow-Trerotola device and the lyse and wait technique.

PubMed

Vashchenko, Natalia; Korzets, Asher; Neiman, Chaim; Bachar, Gil N; Ori, Yaacov; Belenky, Alexander; Atar, Eli

2010-06-01

The purpose of our study was to determine whether pharmacologic thrombolysis with urokinase in the lyse and wait (L&W) technique compared with mechanical declotting using the Arrow-Trerotola percutaneous thrombectomy device is more efficient, safer, or less expensive in treating thrombosed hemodialysis grafts. The files of 157 patients who underwent arteriovenous graft declotting from 2000 to 2007 at one tertiary care center were reviewed. The study group included 83 women and 74 men with a mean age of 68 +/- 12 years (range, 27-95 years). A total of 563 procedures were performed: 427 with the L&W technique and 136 with mechanical percutaneous thrombectomy using the percutaneous thrombectomy device. The two types of procedures were compared for success rate, complications, average patency time, and cost. There were no statistically significant differences between the pharmacologic and mechanical procedures in immediate success rate (99% and 98%, respectively) or average patency time (5.44 months and 5.40 months, respectively). The L&W technique was considerably less expensive. Given its lower cost and equal efficacy and safety, L&W appears to be preferable to mechanical thrombolysis with a percutaneous thrombectomy device for initial arteriovenous hemodialysis graft declotting.

Perspectives on the recent developments with green tea polyphenols in drug discovery.

PubMed

Li, Feng; Wang, Yongli; Li, Dapeng; Chen, Yilun; Qiao, Xuguang; Fardous, Rania; Lewandowski, Ashton; Liu, Jinbao; Chan, Tak-Hang; Dou, Q Ping

2018-04-24

Increasing evidence has expanded the role of green tea from a traditional beverage to a source of pharmacologically active molecules with diverse health benefits. However, conclusive clinical results are needed to better elucidate the cancer-preventive and therapeutic effects of green tea polyphenols (GTPs). Areas covered: The authors describe GTPs' chemical compositions and metabolic biotransformations, and their recent developments in drug discovery, focusing on their cancer chemopreventive and therapeutic effects. They then review the recent development of GTP-loaded nanoparticles and GTP prodrugs. Expert opinion: GTPs possess potent anticarcinogenic activities through interfering with the initiation, development and progression phases of cancer. There are several challenges (e.g. poor bioavailability) in developing GTPs as therapeutic agents. Use of nanoparticle-based delivery systems has provided unique advantages over purified GTPs. However, there is still a need to determine the actual magnitude and pharmacological mechanisms of GTPs encapsulated in nanoparticles, in order to address newly emerging safety issues associated with the potential 'local overdose' effect. The use of Pro- epigallocatechin gallate (Pro-EGCG) as a prodrug appears to offer improved in vitro stability as well as better in vivo bioavailability and efficacies in a number of animal studies, suggesting its potential as a therapeutic agent for further study and development.

[Clinical evaluation of the efficacy of the paracetamol and caffeine combination in the treatment of tension headache].

PubMed

Rabello, G D; Forte, L V; Galvão, A C

2000-03-01

Tension type headache in both its forms, episodic and chronic, is the most common type of headache experienced by the population. The headache attack or the prevention of new crises may be treated with pharmacological as well as non-pharmacological measures. This study included 5,490 patients from out-patient clinics and medical offices covering various regions of Brazil. Approximately 95% of the subjects had episodic tension type headache, while 5% had chronic tension type headache. The majority of the patients presented with crisis of moderate intensity (62.19%). In 5,419 patients a tension type headache crisis was treated with acetaminophen 1000 mg and caffeine 130 mg. In 93.98%, onset of relief occurred within 2 hours of taking the medication. In 77.61%, complete reversion of the crisis occurred within 2 hours. Good/excellent efficacy ratings were achieved in 61.93%/37.80% of the cases according to the physician's assessment and in 48.51%/40.29% according to the patients' assessment. Adverse events, commonly gastrointestinal manifestations, were reported by 5.57% of the patients. This is a Brazilian study of the efficacy and safety of the combined use of acetaminophen-caffeine for the treatment of tension type headache.

Adverse events analysis as an educational tool to improve patient safety culture in primary care: A randomized trial

PubMed Central

2011-01-01

Background Patient safety is a leading item on the policy agenda of both major international health organizations and advanced countries generally. The quantitative description of the phenomena has given rise to intense concern with the issue in institutions and organizations, leading to a number of initiatives and research projects and the promotion of patient safety culture, with training becoming a priority both in Spain and internationally. To date, most studies have been conducted in a hospital setting, even though primary care is the type most commonly used by the public, in our experience. Our study aims to achieve the following: - Assess the registry of adverse events as an education tool to improve patient safety culture in the Family and Community Teaching Units of Galicia. - Find and analyze educational tools to improve patient safety culture in primary care. - Evaluate the applicability of the Hospital Survey on Patient Safety Culture by the Agency for Healthcare Research and Quality, Spanish version, in the context of primary health care. Design and methods Design Experimental unifactorial study of two groups, control and intervention. Study population Tutors and residents in Family and Community Medicine in last year of studies in Galicia, Spain. Sample From the population universe through voluntary participation. Twenty-seven tutor-resident units in each group required, randomly assigned. Intervention Residents and their respective tutor (tutor-resident pair) in teaching units on Family and Community Medicine from throughout Galicia will be invited to participate. Tutor-resident pair that agrees to participate will be sent the Hospital Survey on Patient Safety Culture. Then, tutor-resident pair will be assigned to each group-either intervention or control-through simple random sampling. The intervention group will receive specific training to record the adverse effects found in patients under their care, with subsequent feedback, after receiving instruction on the process. No action will be taken in the control group. After the intervention has ended, the survey will once again be provided to all participants. Outcome measures Change in safety culture as measured by Hospital Survey on Patient Safety Culture CONSORT Extension for Non-Pharmacologic Treatments 2008 was applied. Discussion The most significant limitations on the project are related to selecting a tool to measure the safety environment, the training calendar of residents in Family and Community Medicine in last year of studies and the no-answer bias inherent to research conducted through self-administered surveys. The development and application of a safety culture in the health sector, specifically in primary care, is as yet limited. Thus, identifying the strengths and weaknesses in the safety environment may assist in designing strategies for improvement in the primary care health centers of our region. Trial registration ISRCTN: ISRCTN41911128 PMID:21672197

Safety of pharmacotherapy options for bulimia nervosa and binge eating disorder.

PubMed

Bello, Nicholas T; Yeomans, Bryn L

2018-01-01

Eating disorders represent a set of psychiatric illnesses with lifelong complications and high relapse rates. Individuals with eating disorders are often stigmatized and clinicians have a limited set of treatments options. Pharmacotherapy has the potential to improve long term compliance and patient commitment to treatment for eating disorders. Areas covered: This review will examine the efficacy and safety profile of the FDA-approved medications for the treatment of bulimia nervosa (BN) and binge eating disorder (BED). This will include the evaluation of fluoxetine for BN, and lisdexamfetamine for BED. Safety information will be review from randomized control trials (RCT), open label trials, and case reports. Expert opinion: Fluoxetine for BN and lisdexamfetamine for BED are relatively safe and well-tolerated. Despite these properties, these two medications represent a limited arsenal for the pharmacological treatment of eating disorders. Thus, more research-based strategies are needed to develop safe, effective, and more targeted therapies for eating disorders.

Medical Application of Spirulina platensis Derived C-Phycocyanin

PubMed Central

Liu, Qian; Huang, Yinghong; Zhang, Ronghua; Cai, Tiange; Cai, Yu

2016-01-01

Along with the development of marine biological pharmaceutical research, high-effective and low-toxic drugs and functional foods isolated from marine organisms have become a new field of pharmacy and bromatology. The pharmacological actions, such as anti-inflammation, antioxidation, antitumor, immunological enhancement, and hepatorenal protection of C-phycocyanin (C-PC) from Spirulina platensis, have been reported, and C-PC has important value of development and utilization either as drug or as functional food. There are many researches about the various pharmacological actions and mechanisms of C-PC, but related reports are only to some extent integrated deeply and accurately enough, which put some limitations to the further application of C-PC in medicine. Particularly, with the improvement of living standards and attention to health issues, C-PC being a functional food is preferred by more and more people. C-PC is easy to get, safe, and nontoxic; thus, it has a great potential of research and development as a drug or functional food. Here, the separation and purification, physicochemical properties, physiological and pharmacological activities, safety, and some applications are reviewed to provide relevant basis for the development of natural medicine and applied products. PMID:27293463

Efficacy, Safety, and Tolerability of Armodafinil Therapy for Hypersomnia Associated With Dementia With Lewy Bodies: A Pilot Study

PubMed Central

Lapid, Maria I.; Kuntz, Karen M.; Mason, Sara S.; Aakre, Jeremiah A.; Lundt, Emily S.; Kremers, Walter; Allen, Laura A.; Drubach, Daniel A.; Boeve, Bradley F.

2017-01-01

Background/Aims Hypersomnia is common in dementia with Lewy bodies (DLB). We assessed the efficacy, safety, and tolerability of armodafinil for hypersomnia associated with DLB. Methods We performed a 12-week pilot trial of armodafinil therapy (125–250 mg orally daily) in DLB outpatients with hypersomnia. Patients underwent neurologic examinations, neuropsychological battery, laboratory testing, electrocardiography, and polysomnography. Efficacy was assessed at 2, 4, 8, and 12 weeks. Safety assessment included laboratory examinations, QTc interval, and heart rate. Tolerability was assessed by analysis of adverse events. Data were analyzed using the last-observation-carried-forward method. Results Of 20 participants, 17 completed the protocol. Median age was 72 years, most were men (80%), and most had spouses as caregivers. Epworth Sleepiness Scale (P<.001), Maintenance of Wakefulness Test (P=.003), and Clinical Global Impression of Change (P<.001) scores improved at week 12. Neuropsychiatric Inventory total score (P=.003), visual hallucinations (P=.003), and agitation (P=.02) improved at week 4. Caregiver overall quality of life improved at week 12 (P=.004). No adverse events occurred. Conclusion These pilot data suggest improvements in hypersomnia and wakefulness and reasonable safety and tolerability of armodafinil therapy in hypersomnolent patients with DLB. Our findings inform the use of pharmacologic strategies to manage hypersomnolence in these patients. PMID:28448998

Preclinical safety and efficacy of a new recombinant FIX drug product for treatment of hemophilia B.

PubMed

Dietrich, Barbara; Schiviz, Alexandra; Hoellriegl, Werner; Horling, Frank; Benamara, Karima; Rottensteiner, Hanspeter; Turecek, Peter L; Schwarz, Hans Peter; Scheiflinger, Friedrich; Muchitsch, Eva-Maria

2013-11-01

Baxter has developed a new recombinant factor IX (rFIX) drug product (BAX326) for treating patients with hemophilia B, or congenital FIX deficiency. An extensive preclinical program evaluated the pharmacokinetics, efficacy, and safety of BAX326 in different species. The efficacy of BAX326 was tested in three mouse models of primary pharmacodynamics: tail-tip bleeding, carotid occlusion, and thrombelastography. The pharmacokinetics was evaluated after a single intravenous bolus injection in mice, rats, and macaques. Toxicity was assessed in rats and macaques, safety pharmacology in rabbits and macaques, and immunogenicity in mice. BAX326 was shown to be efficacious in all three primary pharmacodynamic studies (P ≤ 0.0076). Hemostatic efficacy was dose related and similar for the three lots tested. Pharmacokinetic results showed that rFIX activity and rFIX antigen concentrations declined in a bi-phasic manner, similar to a previously licensed rFIX product. BAX326 was well tolerated in rabbits and macaques at all dose levels; no thrombogenic events and no adverse clinical, respiratory, or cardiovascular effects occurred. BAX326 was also shown to have a similar immunogenicity profile to the comparator rFIX product in mice. These results demonstrate that BAX326 has a favorable preclinical safety and efficacy profile, predictive of a comparable effect to that of the previously licensed rFIX in humans.

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

Vamathevan, Jessica J., E-mail: jessica.j.vamathevan@gsk.com; Hall, Matthew D.; Hasan, Samiul

Improving drug attrition remains a challenge in pharmaceutical discovery and development. A major cause of early attrition is the demonstration of safety signals which can negate any therapeutic index previously established. Safety attrition needs to be put in context of clinical translation (i.e. human relevance) and is negatively impacted by differences between animal models and human. In order to minimize such an impact, an earlier assessment of pharmacological target homology across animal model species will enhance understanding of the context of animal safety signals and aid species selection during later regulatory toxicology studies. Here we sequenced the genomes of themore » Sus scrofa Göttingen minipig and the Canis familiaris beagle, two widely used animal species in regulatory safety studies. Comparative analyses of these new genomes with other key model organisms, namely mouse, rat, cynomolgus macaque, rhesus macaque, two related breeds (S. scrofa Duroc and C. familiaris boxer) and human reveal considerable variation in gene content. Key genes in toxicology and metabolism studies, such as the UGT2 family, CYP2D6, and SLCO1A2, displayed unique duplication patterns. Comparisons of 317 known human drug targets revealed surprising variation such as species-specific positive selection, duplication and higher occurrences of pseudogenized targets in beagle (41 genes) relative to minipig (19 genes). These data will facilitate the more effective use of animals in biomedical research. - Highlights: • Genomes of the minipig and beagle dog, two species used in pharmaceutical studies. • First systematic comparative genome analysis of human and six experimental animals. • Key drug toxicology genes display unique duplication patterns across species. • Comparison of 317 drug targets show species-specific evolutionary patterns.« less

Safety profile of biologic drugs in the therapy of Crohn disease: A systematic review and network meta-analysis.

PubMed

Moćko, Paweł; Kawalec, Paweł; Pilc, Andrzej

2016-12-01

Crohn disease (CD) is an inflammatory bowel disease which occurs especially in developed countries of Western Europe and North America. The aim of the study was to compare the safety profile of biologic drugs in patients with CD. A systematic literature search was performed using PubMed, Embase, and CENTRAL databases, until April 27, 2016. We included randomized controlled trials (RCTs) that compared the safety of biologic drugs (infliximab, adalimumab, vedolizumab, certolizumab pegol, and ustekinumab) with one another or with placebo in patients with CD. The network meta-analysis (NMA) was conducted for an induction phase (6-10 weeks) and maintenance phase (52-56 weeks) with a Bayesian hierarchical random effects model in the ADDIS ® software. The PROSPERO registration number was CRD42016032606. Ten RCTs were included in the systematic review with NMA. In the case of the induction phase, the NMA could be conducted for the assessment of the relative safety profile of adalimumab, vedolizumab, certolizumab pegol, and ustekinumab, and in the case of the maintenance phase-of infliximab, adalimumab, and vedolizumab. There were no significant differences in the rate of adverse events in patients treated with biologics. Statistical analysis revealed that vedolizumab had the greatest probability of being the safest treatment in most endpoints in the induction phase and adalimumab-in the maintenance phase. No significant differences between the biologics in the relative safety profile analysis were observed. Further studies are needed to confirm our findings, including head-to-head comparisons between the analyzed biologics. Copyright © 2016 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

The medication reconciliation process and classification of discrepancies: a systematic review.

PubMed

Almanasreh, Enas; Moles, Rebekah; Chen, Timothy F

2016-09-01

Medication reconciliation is a part of the medication management process and facilitates improved patient safety during care transitions. The aims of the study were to evaluate how medication reconciliation has been conducted and how medication discrepancies have been classified. We searched MEDLINE, EMBASE, CINAHL, PubMed, International Pharmaceutical Abstracts (IPA), and Web of Science (WOS), in accordance with the PRISMA statement up to April 2016. Studies were eligible for inclusion if they evaluated the types of medication discrepancy found through the medication reconciliation process and contained a classification system for discrepancies. Data were extracted by one author based on a predefined table, and 10% of included studies were verified by two authors. Ninety-five studies met the inclusion criteria. Approximately one-third of included studies (n = 35, 36.8%) utilized a 'gold' standard medication list. The majority of studies (n = 57, 60%) used an empirical classification system and the number of classification terms ranged from 2 to 50 terms. Whilst we identified three taxonomies, only eight studies utilized these tools to categorize discrepancies, and 11.6% of included studies used different patient safety related terms rather than discrepancy to describe the disagreement between the medication lists. We suggest that clear and consistent information on prevalence, types, causes and contributory factors of medication discrepancy are required to develop suitable strategies to reduce the risk of adverse consequences on patient safety. Therefore, to obtain that information, we need a well-designed taxonomy to be able to accurately measure, report and classify medication discrepancies in clinical practice. © 2016 The British Pharmacological Society.

Extinction of avoidance behavior by safety learning depends on endocannabinoid signaling in the hippocampus.

PubMed

Micale, Vincenzo; Stepan, Jens; Jurik, Angela; Pamplona, Fabricio A; Marsch, Rudolph; Drago, Filippo; Eder, Matthias; Wotjak, Carsten T

2017-07-01

The development of exaggerated avoidance behavior is largely responsible for the decreased quality of life in patients suffering from anxiety disorders. Studies using animal models have contributed to the understanding of the neural mechanisms underlying the acquisition of avoidance responses. However, much less is known about its extinction. Here we provide evidence in mice that learning about the safety of an environment (i.e., safety learning) rather than repeated execution of the avoided response in absence of negative consequences (i.e., response extinction) allowed the animals to overcome their avoidance behavior in a step-down avoidance task. This process was context-dependent and could be blocked by pharmacological (3 mg/kg, s.c.; SR141716) or genetic (lack of cannabinoid CB1 receptors in neurons expressing dopamine D1 receptors) inactivation of CB1 receptors. In turn, the endocannabinoid reuptake inhibitor AM404 (3 mg/kg, i.p.) facilitated safety learning in a CB1-dependent manner and attenuated the relapse of avoidance behavior 28 days after conditioning. Safety learning crucially depended on endocannabinoid signaling at level of the hippocampus, since intrahippocampal SR141716 treatment impaired, whereas AM404 facilitated safety learning. Other than AM404, treatment with diazepam (1 mg/kg, i.p.) impaired safety learning. Drug effects on behavior were directly mirrored by drug effects on evoked activity propagation through the hippocampal trisynaptic circuit in brain slices: As revealed by voltage-sensitive dye imaging, diazepam impaired whereas AM404 facilitated activity propagation to CA1 in a CB1-dependent manner. In line with this, systemic AM404 enhanced safety learning-induced expression of Egr1 at level of CA1. Together, our data render it likely that AM404 promotes safety learning by enhancing information flow through the trisynaptic circuit to CA1. Copyright © 2017 Elsevier Ltd. All rights reserved.

Cost-effectiveness of Maintaining Daily Intake of Oat β-Glucan for Coronary Heart Disease Primary Prevention.

PubMed

Earnshaw, Stephanie R; McDade, Cheryl L; Chu, YiFang; Fleige, Lisa E; Sievenpiper, John L

2017-04-01

Oat β-glucan reduces cholesterol levels and thus reduces the risk for coronary heart disease (CHD). However, its economic impact has not been well studied. We examined the economic impact of daily intake of ≥3 g of oat β-glucan in primary prevention of CHD in patients receiving statins or no pharmacologic treatment. A decision model was developed to compare costs and outcomes associated with lowering cholesterol levels with no pharmacologic treatment and normal diet, no pharmacologic treatment plus ≥3 g/d of oat β-glucan, and statin therapy plus ≥3 g/d of oat β-glucan. The population comprised men 45, 55, or 65 years of age with no history of cardiovascular disease and a 10-year risk for CHD of 5%, 7.5%, or 10%. Clinical efficacy data were gathered from meta-analyses; safety data, costs, and utilities were gathered from published literature. Cost per quality-adjusted life years and number of first events were reported. Maintaining ≥3 g/d of β-glucan may be cost-effective in men aged 45, 55, and 65 years with 10-year CHD risks of 5.0%, 7.5%, and 10.0% taking no pharmacologic treatment or on statins. It may also reduce first events of myocardial infarction and CHD death. Results are sensitive to oat β-glucan cost but insensitive to changes in other parameters. Maintaining ≥3 g of oat β-glucan daily remains cost-effective within plausible range of values. β-glucan may be cost-effective for preventing CHD events in middle-aged men with no history of cardiovascular events whose 10-year CHD risk is ≥5%. Maintaining daily β-glucan intake may have considerable impact on first events. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

Treatment of infertility in women with polycystic ovary syndrome: approach to clinical practice

PubMed Central

Melo, Anderson Sanches; Ferriani, Rui Alberto; Navarro, Paula Andrea

2015-01-01

Polycystic ovary syndrome represents 80% of anovulatory infertility cases. Treatment initially includes preconception guidelines, such as lifestyle changes (weight loss), folic acid therapy to prevent the risk of fetal neural tube defects and halting the consumption of tobacco and alcohol. The first-line pharmacological treatment for inducing ovulation consists of a clomiphene citrate treatment for timed intercourse. The second-line pharmacological treatment includes the administration of exogenous gonadotropins or laparoscopic ovarian surgery (ovarian drilling). Ovulation induction using clomiphene citrate or gonadotropins is effective with cumulative live birth rates of approximately 70%. Ovarian drilling should be performed when laparoscopy is indicated; this procedure is typically effective in approximately 50% of cases. Finally, a high-complexity reproduction treatment (in vitro fertilization or intracytoplasmic sperm injection) is the third-line treatment and is recommended when the previous interventions fail. This option is also the first choice in cases of bilateral tubal occlusion or semen alterations that impair the occurrence of natural pregnancy. Evidence for the routine use of metformin in infertility treatment of anovulatory women with polycystic ovary syndrome is not available. Aromatase inhibitors are promising and longer term studies are necessary to prove their safety. PMID:26602525

A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment.

PubMed

Burdick, Brittany Vasae; Adinoff, Bryon

2013-09-01

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.

Treatment of Established Status Epilepticus.

PubMed

Falco-Walter, Jessica J; Bleck, Thomas

2016-04-25

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE.

Treatment of Established Status Epilepticus

PubMed Central

Falco-Walter, Jessica J.; Bleck, Thomas

2016-01-01

Status epilepticus is the most severe form of epilepsy, with a high mortality rate and high health care costs. Status epilepticus is divided into four stages: early, established, refractory, and super-refractory. While initial treatment with benzodiazepines has become standard of care for early status epilepticus, treatment after benzodiazepine failure (established status epilepticus (ESE)) is incompletely studied. Effective treatment of ESE is critical as morbidity and mortality increases dramatically the longer convulsive status epilepticus persists. Phenytoin/fosphenytoin, valproic acid, levetiracetam, phenobarbital, and lacosamide are the most frequently prescribed antiseizure medications for treatment of ESE. To date there are no class 1 data to support pharmacologic recommendations of one agent over another. We review each of these medications, their pharmacology, the scientific evidence in support and against each in the available literature, adverse effects and safety profiles, dosing recommendations, and limitations of the available evidence. We also discuss future directions including the established status epilepticus treatment trial (ESETT). Substantial further research is urgently needed to identify these patients (particularly those with non-convulsive status epilepticus), elucidate the most efficacious antiseizure treatment with head-to-head randomized prospective trials, and determine whether this differs for convulsive vs. non-convulsive ESE. PMID:27120626

Psidium guajava L., from ethnobiology to scientific evaluation: Elucidating bioactivity against pathogenic microorganisms.

PubMed

Morais-Braga, Maria Flaviana B; Carneiro, Joara Nalyda P; Machado, Antonio Júdson T; Dos Santos, Antonia Thassya L; Sales, Débora L; Lima, Luciene F; Figueredo, Fernando G; Coutinho, Henrique Douglas M

2016-12-24

The use of popular plants has guided pharmaceutical research aimed at combating pathogenic microorganisms. Psidium guajava L. is a plant of great versatility and it has been used both as food and as a therapeutic agent. Root, bark, leaves, fruits, flowers and seeds are used for medicinal purposes, especially in infusions and decoctions for oral and topical use. P. guajava is utilized in symptomatology treatment related to organ malfunction and of diseases caused by the action of pathogenic and/or opportunistic microorganisms. Many pharmacological studies have been conducted to scientifically assess its therapeutic potential. The aim of the current study is to relate the popular use of this plant and its bioscientific assessment as a therapeutic agent in the treatment of diseases and symptoms caused by the action of protozoa, fungi, bacteria and viruses, and also evaluate the safety for the usage and the interaction with drugs. A bibliographic database the ethnobiology of Psidium guajava (2005-2015) and the pharmacological infections and parasitic diseases (2010-2015). Searches were done in scientific disclosure databases such as PubMed, Web of Science, and Scopus. P. guajava leaf extracts were scientifically investigated for the treatment of diseases caused by protozoa (leishmaniasis, malaria, giardiasis, amoebiasis and trichomoniasis), fungi (dermatosis, systemic and mucocutaneous diseases), bacteria (respiratory, mucocutaneous and gastrointestinal infections, cholera, gastritis and stomach ulcers, oral and periodontal infections, venereal diseases and urinary infections) and viruses (herpes, influenza, rotavirus disease and AIDS). The toxicity assays indicates the safet for usage. Highlight and elucidate the therapeutic potential and versatility of P. guajava. They also justify using ethnobiology efficiency to guide pharmacological studies. Some limitations can be observed in this kind of study, as the lack for ethnobiological informations and the absence of some controls in the assays. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Cardiovascular toxicity of nicotine: Implications for electronic cigarette use.

PubMed

Benowitz, Neal L; Burbank, Andrea D

2016-08-01

The cardiovascular safety of nicotine is an important question in the current debate on the benefits vs. risks of electronic cigarettes and related public health policy. Nicotine exerts pharmacologic effects that could contribute to acute cardiovascular events and accelerated atherogenesis experienced by cigarette smokers. Studies of nicotine medications and smokeless tobacco indicate that the risks of nicotine without tobacco combustion products (cigarette smoke) are low compared to cigarette smoking, but are still of concern in people with cardiovascular disease. Electronic cigarettes deliver nicotine without combustion of tobacco and appear to pose low-cardiovascular risk, at least with short-term use, in healthy users. Copyright © 2016 Elsevier Inc. All rights reserved.

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 368)

NASA Technical Reports Server (NTRS)

1992-01-01

This bibliography lists 305 reports, articles, and other documents introduced into the NASA Scientific and Technical Information System during Sep. 1992. The subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Aerospace Medicine and Biology: A Continuing Bibliography With Indexes. Supplement 486

NASA Technical Reports Server (NTRS)

1999-01-01

In its subject coverage, Aerospace Medicine and Biology concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion. Each entry in the publication consists of a standard bibliographic citation accompanied, in most cases, by an abstract.

Real-World Evidence: What It Is and What It Can Tell Us According to the International Society for Pharmacoepidemiology (ISPE) Comparative Effectiveness Research (CER) Special Interest Group (SIG).

PubMed

Yuan, Hongbo; Ali, M Sanni; Brouwer, Emily S; Girman, Cynthia J; Guo, Jeff J; Lund, Jennifer L; Patorno, Elisabetta; Slaughter, Jonathan L; Wen, Xuerong; Bennett, Dimitri

2018-05-07

On December 8, 2016, the New England Journal of Medicine published a sounding board on Real World Evidence (RWE) 1 by the US Food and Drug Administration (FDA) leadership. While the value of RWE based on nonrandomized observational studies was appreciated, such as for hypothesis generating, safety, and measuring quality in healthcare delivery, the authors expressed concerns on the quality of data sources and the ability of methodologies to control for confounding. In response, we offer a few considerations regarding these concerns. © 2018, The American Society for Clinical Pharmacology and Therapeutics.

Clinical trials in drug development: a minimalistic approach.

PubMed

Verweij, Jaap

2012-05-01

Drug development in oncology finds itself at the crossroad of unique opportunities and major challenges. The old paradigms should and can be replaced by a system that better matches the right patients to the right compounds and puts much more emphasis on the early stages of drug development. The clinical phases of drug development will no longer be split into phase I, II, and III studies, but rather into 'functional target pharmacology studies', followed by 'proof of concept studies'. The resulting development flow becomes Apollo-capsule shaped. Although randomized studies will still be needed for drugs using targets in the tumor environment, or for combinations of agents, drug registration might proceed without these if all of the following criteria are met in early development: availability of preclinical convincing evidence that the drug's target is the functional driver behind the disease phenotype, availability of a predictive biomarker that enables appropriate and actual patient selection in early pharmacology studies, a Response Evaluation Criteria In Solid Tumors (RECIST)-based single agent response rate of at least 50%, and/or a progression at first tumor assessment rate of 15% or less, a duration of absence of progression (stable disease) beyond doubt and considered clinically relevant, and no major safety concern. This set is not yet mature, but may be adapted over time. The concerns related to registering agents on the basis of small datasets can be adequately addressed by obligatory postmarketing hypothesis driven studies.

Pharmacological effects of saw palmetto extract in the lower urinary tract

PubMed Central

Suzuki, Mayumi; Ito, Yoshihiko; Fujino, Tomomi; Abe, Masayuki; Umegaki, Keizo; Onoue, Satomi; Noguchi, Hiroshi; Yamada, Shizuo

2009-01-01

Saw palmetto extract (SPE), an extract from the ripe berries of the American dwarf palm, has been widely used as a therapeutic remedy for urinary dysfunction due to benign prostatic hyperplasia (BPH) in Europe. Numerous mechanisms of action have been proposed for SPE, including the inhibition of 5α-reductase. Today, α1-adrenoceptor antagonists and muscarinic cholinoceptor antagonists are commonly used in the treatment of men with voiding symptoms secondary to BPH. The improvement of voiding symptoms in patients taking SPE may arise from its binding to pharmacologically relevant receptors in the lower urinary tract, such as α1-adrenoceptors, muscarinic cholinoceptors, 1,4-dihyropyridine receptors and vanilloid receptors. Furthermore, oral administration of SPE has been shown to attenuate the up-regulation of α1-adrenoceptors in the rat prostate induced by testosterone. Thus, SPE at clinically relevant doses may exert a direct effect on the pharmacological receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and an overactive bladder. SPE does not have interactions with co-administered drugs or serious adverse events in blood biochemical parameters, suggestive of its relative safety, even with long-term intake. Clinical trials (placebo-controlled and active-controlled trials) of SPE conducted in men with BPH were also reviewed. This review should contribute to the understanding of the pharmacological effects of SPE in the treatment of patients with BPH and associated lower urinary tract symptoms (LUTS). PMID:19262550

Pharmacological effects of saw palmetto extract in the lower urinary tract.

PubMed

Suzuki, Mayumi; Ito, Yoshihiko; Fujino, Tomomi; Abe, Masayuki; Umegaki, Keizo; Onoue, Satomi; Noguchi, Hiroshi; Yamada, Shizuo

2009-03-01

Saw palmetto extract (SPE), an extract from the ripe berries of the American dwarf palm, has been widely used as a therapeutic remedy for urinary dysfunction due to benign prostatic hyperplasia (BPH) in Europe. Numerous mechanisms of action have been proposed for SPE, including the inhibition of 5alpha-reductase. Today, alpha(1)-adrenoceptor antagonists and muscarinic cholinoceptor antagonists are commonly used in the treatment of men with voiding symptoms secondary to BPH. The improvement of voiding symptoms in patients taking SPE may arise from its binding to pharmacologically relevant receptors in the lower urinary tract, such as alpha(1)-adrenoceptors, muscarinic cholinoceptors, 1,4-dihyropyridine receptors and vanilloid receptors. Furthermore, oral administration of SPE has been shown to attenuate the up-regulation of alpha(1)-adrenoceptors in the rat prostate induced by testosterone. Thus, SPE at clinically relevant doses may exert a direct effect on the pharmacological receptors in the lower urinary tract, thereby improving urinary dysfunction in patients with BPH and an overactive bladder. SPE does not have interactions with co-administered drugs or serious adverse events in blood biochemical parameters, suggestive of its relative safety, even with long-term intake. Clinical trials (placebo-controlled and active-controlled trials) of SPE conducted in men with BPH were also reviewed. This review should contribute to the understanding of the pharmacological effects of SPE in the treatment of patients with BPH and associated lower urinary tract symptoms (LUTS).

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

Pruss, T.; Wolf, P.S.

Indapamide is a new indoline antihypertensive diuretic agent whose chemical structure differs substantially from those of the thiazides. The hydrophobic indoline moiety of indapamide confers a lipid solubility to the molecule that is 5 to 80 times greater than that of the thiazide diuretics. Thus indapamide accumulates in vascular smooth muscle at a concentration 10 times higher than that of protein-free perfusate. The affinity of indapamide for vascular smooth muscle manifests itself in vitro and in vivo as a decrease in reactivity following various pharmacologic interventions. Moreover, in vitro studies have demonstrated that indapamide decreases the inward calcium current andmore » the transmembrane influx of calcium. The diuretic effect of indapamide is predominantly due to inhibition of sodium reabsorption at the cortical diluting segment of the distal convoluted tubule. In animal studies, intravenous indapamide has no effect on glomerular filtration rate or renal blood flow. Indapamide is well absorbed and extensively metabolized in animals and humans, with biliary excretion being the predominant route of elimination in animals. Most important, repeat administration of indapamide to dogs with both kidneys removed produces no accumulation of intact indapamide or its metabolites. Extensive drug safety studies in animals indicate that indapamide produces no overt toxicity and exhibits a good margin of safety.« less

Therapeutic use of traditional Chinese herbal medications for chronic kidney diseases

PubMed Central

Zhong, Yifei; Deng, Yueyi; Chen, Yiping; Chuang, Peter Y; He, John Cijiang

2013-01-01

Traditional Chinese herbal medications (TCHM) are frequently used in conjunction with western pharmacotherapy for treatment of chronic kidney diseases (CKD) in China and many other Asian countries. The practice of traditional Chinese medicine is guided by cumulative empiric experience. Recent in vitro and animal studies have confirmed the biological activity and therapeutic effects of several TCHM in CKD. However, the level of evidence supporting TCHM is limited to small, non-randomized trials. Due to variations in the prescription pattern of TCHM and the need for frequent dosage adjustment, which are inherent to the practice of traditional Chinese medicine, it has been challenging to design and implement large randomized clinical trials of TCHM. Several TCHM are associated with significant adverse effects, including nephrotoxicity. However, reporting of adverse effects associated with TCHM has been inadequate. To fully realize the therapeutic use of TCHM in CKD we need molecular studies to identify active ingredients of TCHM and their mechanism of action, rigorous pharmacologic studies to determine the safety and meet regulatory standards required for clinical therapeutic agents, and well-designed clinical trials to provide evidence-based support of their safety and efficacy. PMID:23868014

Safety, Pharmacokinetics, and Pharmacodynamics in Healthy Volunteers Treated With GDC-0853, a Selective Reversible Bruton's Tyrosine Kinase Inhibitor.

PubMed

Herman, Ann E; Chinn, Leslie W; Kotwal, Shweta G; Murray, Elaine R; Zhao, Rui; Florero, Marilyn; Lin, Alyse; Moein, Anita; Wang, Rena; Bremer, Meire; Kokubu, Serika; Serone, Adrian P; Hanze, Eva L; Viberg, Anders; Morimoto, Alyssa M; Winter, Helen R; Katsumoto, Tamiko R

2018-06-01

GDC-0853 is a small molecule inhibitor of Bruton's tyrosine kinase (BTK) that is highly selective and noncovalent, leading to reversible binding. In double-blind, randomized, and placebo-controlled phase I healthy volunteer studies, GDC-0853 was well tolerated, with no dose-limiting adverse events (AEs) or serious AEs. The maximum tolerated dose was not reached during dose escalation (≤600 mg, single ascending dose (SAD) study; ≤250 mg twice daily (b.i.d.) and ≤500 mg once daily, 14-day multiple ascending dose (MAD) study). Plasma concentrations peaked 1-3 hours after oral administration and declined thereafter, with a steady-state half-life ranging from 4.2-9.9 hours. Independent assays demonstrated dose-dependent BTK target engagement. Based on pharmacokinetic/pharmacodynamic (PK/PD) simulations, a once-daily dosing regimen (e.g., 100 mg, q.d.) is expected to maintain a high level of BTK inhibition over the dosing interval. Taken together, the safety and PK/PD data support GDC-0853 evaluation in rheumatoid arthritis, lupus, and other autoimmune or inflammatory indications. © 2018 American Society for Clinical Pharmacology and Therapeutics.

Synthesis, antimalarial activity, and preclinical pharmacology of a novel series of 4'-fluoro and 4'-chloro analogues of amodiaquine. Identification of a suitable "back-up" compound for N-tert-butyl isoquine.

PubMed

O'Neill, Paul M; Shone, Alison E; Stanford, Deborah; Nixon, Gemma; Asadollahy, Eghbaleh; Park, B Kevin; Maggs, James L; Roberts, Phil; Stocks, Paul A; Biagini, Giancarlo; Bray, Patrick G; Davies, Jill; Berry, Neil; Hall, Charlotte; Rimmer, Karen; Winstanley, Peter A; Hindley, Stephen; Bambal, Ramesh B; Davis, Charles B; Bates, Martin; Gresham, Stephanie L; Brigandi, Richard A; Gomez-de-Las-Heras, Federico M; Gargallo, Domingo V; Parapini, Silvia; Vivas, Livia; Lander, Hollie; Taramelli, Donatella; Ward, Stephen A

2009-04-09

On the basis of a mechanistic understanding of the toxicity of the 4-aminoquinoline amodiaquine (1b), three series of amodiaquine analogues have been prepared where the 4-aminophenol "metabolic alert" has been modified by replacement of the 4'-hydroxy group with a hydrogen, fluorine, or chlorine atom. Following antimalarial assessment and studies on mechanism of action, two candidates were selected for detailed ADME studies and in vitro and in vivo toxicological assessment. 4'-Fluoro-N-tert-butylamodiaquine (2k) was subsequently identified as a candidate for further development studies based on potent activity versus chloroquine-sensitive and resistant parasites, moderate to excellent oral bioavailability, low toxicity in in vitro studies, and an acceptable safety profile.

The use of methylphenidate to relieve fatigue.

PubMed

Rojí, Rocío; Centeno, Carlos

2017-12-01

To review recent evidence on the efficacy and safety of methylphenidate as a symptomatic treatment of patients with cancer-related fatigue (CRF). Five clinical trials published since 2011 were identified. Two of these concluded that methylphenidate is more efficacious than placebo in providing relief from CRF, but the remaining three showed no difference in favour of methylphenidate. The studies were heterogeneous as per the dosage, scales used for evaluating fatigue and the target group studied. None of the studies detected serious reactions, and only mild and infrequent side-effects of methylphenidate were reported. Three new metanalyses show the slightly superior effect of methylphenidate compared to placebo in CRF. Overall, literature supports the existence of moderate benefit of methylphenidate in CRF, backed up by weak evidence. Future studies should aim at better identifying the profile of patients who would benefit most from this pharmacological intervention.

Pharmacologic and non-pharmacologic treatments for chronic pain in individuals with HIV: a systematic review

PubMed Central

Merlin, Jessica S.; Bulls, Hailey W.; Vucovich, Lee A.; Edelman, E. Jennifer; Starrels, Joanna L.

2016-01-01

Chronic pain occurs in as many as 85% of individuals with HIV and is associated with substantial functional impairment. Little guidance is available for HIV providers seeking to address their patients’ chronic pain. We conducted a systematic review to identify clinical trials and observational studies that examined the impact of pharmacologic or non-pharmacologic interventions on pain and/or functional outcomes among HIV-infected individuals with chronic pain in high-development countries. Eleven studies met inclusion criteria and were mostly low or very low quality. Seven examined pharmacologic interventions (gabapentin, pregabalin, capsaicin, analgesics including opioids) and four examined non-pharmacologic interventions (cognitive behavioral therapy, self-hypnosis, smoked cannabis). The only controlled studies with positive results were of capsaicin and cannabis, and had short-term follow-up (≤12 weeks). Among the seven studies of pharmacologic interventions, five had substantial pharmaceutical industry sponsorship. These findings highlight several important gaps in the HIV/chronic pain literature that require further research. PMID:27267445

The Effect of Pain on Task Performance: A Review of the Literature.

DTIC Science & Technology

1992-07-01

Pharmacology. 11 (2), 123-127 (1989) 8. J. D. Benson, Application of manual handling task in the control of low back pain. In Trends in Ergonomics /Human...Factors IV. Proceedings of the Annual International Industrial Ergonomics and Safety Conference. Amsterdam: Elsevier Science Publishers (1987). 9. T...development of a motor performance method for the measurement of pain. Ergonomics . 32 (3), 307-316 (1989) 67. K. Sedlak, Low-back pain perception and

Drugs in pregnancy--the issues for 2010.

PubMed

Davis, Donald B

2010-01-01

A Motherisk symposium on establishing benchmarks for the evaluation of medications during pregnancy, was held on May 10, 2006, under the auspices of the Canadian Society of Pharmacology and Therapeutics. From that symposium came a consensus on the need for collection and analysis of data on fetal safety and ongoing post-marketing surveillance, which in turn led to the establishment of CaseMed-Pregnancy--the Canadian Alliance for Safe and Effective Medication During Pregnancy and Breastfeeding.

[Tetrahydrocannabinol pharmacokinetics; new synthetic cannabinoids; road safety and cannabis].

PubMed

Goullé, Jean-Perre; Guerbet, Michel

2014-03-01

Delta-9-tetrahydrocannabinol (THC) is the main psychoactive ingredient of cannabis, a drug which is commonly smoked This paper focuses on the pharmacokinetics of THC. The average THC content in cannabis plant material has risen by a factor offour over the past 20 years, from 4% to 16%. This increase has important implications not only for the pharmacokinetics but also for the pharmacology of THC The mean bioavailability of THC in smoked cannabis is about 25%. In a cigarette containing 3.55% of THC, a peak plasma level of about 160 ng/mL occurs approximately 10 min after inhalation. THC is quickly cleared from plasma in a multiphasic manner and is widely distributed to tissues, leading to its pharmacologic effects. Body fat is a long-term storage site. This particular pharmacokinetic behavior explains the lack of correlation between the THC blood level and clinical effects, contrary to ethanol. The main THC metabolites are 11-OH-THC (the only active metabolite) and THC-COOH, which is eliminated in feces and urine over several weeks. Therefore, abstinence can be established by analyzing THC-COOH in urine, while blood THC analysis is used to confirm recent exposure. Cannabis is the main illicit drug found among vehicle drivers. Various traffic safety studies indicate that recent use of this drug at least doubles the risk of causing an accident, and that simultaneous alcohol consumption multiplies this risk by afactor of 14. Since 2009, synthetic cannabinoids have emerged on the illicit drug market. These substances act on the same CB1 receptors as THC, but with higher afinity. Their pharmacokinetics differs from that of THC, as they are metabolized into multiple derivatives, most of which are more active than THC itself.

Medicinal properties of Peganum harmala L. in traditional Iranian medicine and modern phytotherapy: a review.

PubMed

Mina, Cheraghi Niroumand; Farzaei, Mohammad Hosein; Gholamreza, Amin

2015-02-01

To review the pharmacological activities of Peganum harmala L. (P. harmala, Nitrariaceae) in traditional Iranian medicine (TIM) and modern phytotherapy. Opinions of TIM and modern phytotherapy about safety and acceptable dosage of this plant are discussed. Various medical properties of P. harmala were collected from important TIM references and added to scientific reports derived from modern medical databases like PubMed, Scirus, ScienceDirect and Scopus. The main medicinal part of the plant is the seed. In TIM resources, this plant possesses various Pharmacological activities such as carminative, galactagogue, diuretic, emmenagogue, antithrombotic and analgesic. In modern phytotherapy, P. harmala demonstrated numerous medicinal effects including cardiovascular, neurologic, antimicrobial, insecticidal, antineoplasmic, antiproliferative, gastrointestinal and antidiabetic effects. Adverse events such as neuro-sensorial symptoms, visual hallucination, bradycardia, hypotension, agitation, tremors, ataxia, abortion and vomiting cause people to use this plant cautiously. P. harmala is contraindicated during pregnancy, due to its abortive and mutagenic activities. Because of increasing the expression of CYP1A2, 2C19, and 3A4 and inhibition of monoamine oxidase, the pharmacokinetic parameters of drugs which are mainly metabolized by these enzymes may be affected by P. harmala. The medicinal properties declared for this plant in TIM are compared with those showed in modern phytotherapy. Some of the TIM properties were confirmed in modern phytotherapy like emetic and analgesic activities and some have not been evaluated in modern phytotherapy such as its therapeutic effects on paralysis, epilepsy and numbness. Finally, the current review provides the evidence for other researchers to use TIM properties of P. harmala as an efficacious natural drug. Further preclinical and clinical studies for adequate evaluating safety and therapeutic efficacy are recommended.

One-year prospective follow-up of pharmacological treatment in children with attention-deficit/hyperactivity disorder.

PubMed

Didoni, Anna; Sequi, Marco; Panei, Pietro; Bonati, Maurizio

2011-10-01

To delineate the safety and tolerability profile of methylphenidate and atomoxetine in children and adolescents with attention deficit hyperactivity disorder (ADHD) monitored for more than 1 year. A cohort study analyzing data from the national ADHD register on patients from the Lombardy Region treated with MPH or atomoxetine. A total of 229 children (median age 11 years, range 6-17), enrolled in 15 regional centers between June 2007 and May 2010. The prevalence rate of pharmacological treatment for ADHD was 0.23%, whereas the estimated ADHD prevalence in the population was 0.95%. In total, 73.8% of patients had been treated with atomoxetine (10-90 mg daily) or MPH (10-75 mg daily); 22% of patients also received an additional psychotropic drug. Of the treated children, 26.9% discontinued the drug prior to 1 year of treatment, mostly because of adverse effects (28.6%). No new or unexpected adverse events (rate 39.2%) were encountered. Decreased appetite, headache, and unstable mood were the leading events. The most severe events occurred in two boys: one experienced absence seizures for the first time with MPH, the other experienced hallucinations with atomoxetine. Therapy was discontinued in ten male patients (7.7%) because of adverse events. All patients with adverse effects recovered well. A very low rate of ADHD prevalence was estimated in Italian children compared to that reported in other countries. Although the medications for ADHD are generally well tolerated, with only mild or minor adverse effects in most cases, their rational use can only be guaranteed by disseminating and monitoring evidence-based practices and by monitoring the safety and efficacy of treatments in both the short and long terms with appropriate tools and approaches.

The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease.

PubMed

Edwards, Nicola C; Steeds, Richard P; Chue, Colin D; Stewart, Paul M; Ferro, Charles J; Townend, Jonathan N

2012-03-01

Mineralocorticoid receptor blockade (MRBs) in combination with angiotensin converting enzyme (ACE) inhibitors and angiotensin-II receptor blockade (ARBs) improve prognostic markers of cardiovascular and renal disease in early stage chronic kidney disease (CKD). Concerns relating to the safety and tolerability of MRBs in CKD may limit their use in a non clinical trial setting. METHODS In the Chronic Renal Impairment in Birmingham II study, 115 patients with non-diabetic early stage CKD (eGFR 30-89ml/min/1.73m(2) ) received 25mg daily of spironolactone for 4 weeks before randomization to continuing treatment or placebo for a further 36 weeks. All patients were on ACE inhibitors and/or ARB therapy. Potassium and renal function were checked at weeks 1, 2, 4, 8, 16, 28 and 40. The incidence of hyperkalaemia, significant renal dysfunction (reduction eGFR ≥25%) and adverse effects was assessed. After 40 weeks of treatment the incidence of serious hyperkalaemia (K(+) ≥6.0mmol/L) was <1%. A potassium 5.5-5.9mmol/L occurred on ≥1 occasion over follow-up in 11 patients (nine on spironolactone) and was predicted by baseline potassium ≥5.0mmol/L and eGFR ≤45 ml/min/1.73m(2) . Over follow-up, three patients experienced significant renal dysfunction but no patients withdrew due to intolerance or side effects. Changes in potassium, eGFR and systolic blood pressure were most apparent in the first 4 eeks. Spironolactone was well tolerated in selected patients with early stage CKD. Strict monitoring over the first month of treatment followed by standard surveillance as for ACE inhibitors and ARBs is suggested. © 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.

Incorporating Natural Products, Pharmaceutical Drugs, Self-Care and Digital/Mobile Health Technologies into Molecular-Behavioral Combination Therapies for Chronic Diseases.

PubMed

Bulaj, Grzegorz; Ahern, Margaret M; Kuhn, Alexis; Judkins, Zachary S; Bowen, Randy C; Chen, Yizhe

2016-01-01

Merging pharmaceutical and digital (mobile health, mHealth) ingredients to create new therapies for chronic diseases offers unique opportunities for natural products such as omega-3 polyunsaturated fatty acids (n-3 PUFA), curcumin, resveratrol, theanine, or α-lipoic acid. These compounds, when combined with pharmaceutical drugs, show improved efficacy and safety in preclinical and clinical studies of epilepsy, neuropathic pain, osteoarthritis, depression, schizophrenia, diabetes and cancer. Their additional clinical benefits include reducing levels of TNFα and other inflammatory cytokines. We describe how pleiotropic natural products can be developed as bioactive incentives within the network pharmacology together with pharmaceutical drugs and self-care interventions. Since approximately 50% of chronically-ill patients do not take pharmaceutical drugs as prescribed, psychobehavioral incentives may appeal to patients at risk for medication non-adherence. For epilepsy, the incentive-based network therapy comprises anticonvulsant drugs, antiseizure natural products (n-3 PUFA, curcumin or/and resveratrol) coupled with disease-specific behavioral interventions delivered by mobile medical apps. The add-on combination of antiseizure natural products and mHealth supports patient empowerment and intrinsic motivation by having a choice in self-care behaviors. The incentivized therapies offer opportunities: (1) to improve clinical efficacy and safety of existing drugs, (2) to catalyze patient-centered, disease self-management and behavior-changing habits, also improving health-related quality-of-life after reaching remission, and (3) merging copyrighted mHealth software with natural products, thus establishing an intellectual property protection of medical treatments comprising the natural products existing in public domain and currently promoted as dietary supplements. Taken together, clinical research on synergies between existing drugs and pleiotropic natural products, and their integration with self-care, music and mHealth, expands precision/personalized medicine strategies for chronic diseases via pharmacological-behavioral combination therapies.

Role of Quantitative Clinical Pharmacology in Pediatric Approval and Labeling.

PubMed

Mehrotra, Nitin; Bhattaram, Atul; Earp, Justin C; Florian, Jeffry; Krudys, Kevin; Lee, Jee Eun; Lee, Joo Yeon; Liu, Jiang; Mulugeta, Yeruk; Yu, Jingyu; Zhao, Ping; Sinha, Vikram

2016-07-01

Dose selection is one of the key decisions made during drug development in pediatrics. There are regulatory initiatives that promote the use of model-based drug development in pediatrics. Pharmacometrics or quantitative clinical pharmacology enables development of models that can describe factors affecting pharmacokinetics and/or pharmacodynamics in pediatric patients. This manuscript describes some examples in which pharmacometric analysis was used to support approval and labeling in pediatrics. In particular, the role of pharmacokinetic (PK) comparison of pediatric PK to adults and utilization of dose/exposure-response analysis for dose selection are highlighted. Dose selection for esomeprazole in pediatrics was based on PK matching to adults, whereas for adalimumab, exposure-response, PK, efficacy, and safety data together were useful to recommend doses for pediatric Crohn's disease. For vigabatrin, demonstration of similar dose-response between pediatrics and adults allowed for selection of a pediatric dose. Based on model-based pharmacokinetic simulations and safety data from darunavir pediatric clinical studies with a twice-daily regimen, different once-daily dosing regimens for treatment-naïve human immunodeficiency virus 1-infected pediatric subjects 3 to <12 years of age were evaluated. The role of physiologically based pharmacokinetic modeling (PBPK) in predicting pediatric PK is rapidly evolving. However, regulatory review experiences and an understanding of the state of science indicate that there is a lack of established predictive performance of PBPK in pediatric PK prediction. Moving forward, pharmacometrics will continue to play a key role in pediatric drug development contributing toward decisions pertaining to dose selection, trial designs, and assessing disease similarity to adults to support extrapolation of efficacy. Copyright © 2016 U.S. Government work not protected by U.S. copyright.

Outcome of Radiofrequency Catheter Ablation as a non-pharmacological therapy for idiopathic Ventricular Tachycardia.

PubMed

Samore, Naseer Ahmed; Imran Majeed, Syed Muhammad; Kayani, Azhar Mahmud; Bhalli, Muhammad Asif; Shabbir, Muhammad

2009-09-01

To determine the outcome of Radiofrequency Catheter Ablation (RFCA) as a non-pharmacological curative therapy for idiopathic Ventricular Tachycardia (VT) and to identify procedure-related complications. Descriptive study. The Armed Forces Institute of Cardiology and National Institute of Heart Diseases, Rawalpindi, from February 2001 to October 2008. Ninety eight consecutive patients with idiopathic VT, resistant to drug therapy, who underwent Electrophysiology Studies (EPS) radiofrequency catheter ablation were enrolled. Clinical and electrophysiological variables were recorded and a descriptive analysis was done. Out of the 98 patients, 79 were males (80.6%). The mean age was 33.29+11.93 years. Modes of presentation were sustained VT, Repetitive Monomorphic VT (RMVT), Non-sustained VT (NSVT) and Ventricular Premature Beats (VPBs). Right Ventricular Outflow Tract (RVOT) VT was found in 37 patients, 37 had Idiopathic Left Ventricular Tachycardia (ILVT), 20 had Left Ventricular Outflow Tract (LVOT) VT, and Inflow Right Ventricular Tachycardia (IRVT) was found in 7 patients. Other sites of origin of VT were infrequent. Eight patients had dual morphologies of VT. Atrioventricular Nodal Re-entry Tachycardia (AVNRT) was found in 8 patients. RFCA was successful in abolishing inducible VT in 88 patients. One patient developed complete AV block requiring a permanent pacemaker. Results of this study confirm a high degree of success and safety of radiofrequency catheter ablation as curative therapy for idiopathic ventricular tachycardia.

A critical review of the antipsychotic effects of cannabidiol: 30 years of a translational investigation.

PubMed

Zuardi, Antonio Waldo; Crippa, Jose Alexandre S; Hallak, Jaime E C; Bhattacharyya, Sagnik; Atakan, Zerrin; Martin-Santos, Rocio; McGuire, Philip K; Guimarães, Francisco Silveira

2012-01-01

Δ(9)-tetrahydrocannabinol (Δ(9)-THC) is the main compound of the Cannabis Sativa responsible for most of the effects of the plant. Another major constituent is cannabidiol (CBD), formerly regarded to be devoid of pharmacological activity. However, laboratory rodents and human studies have shown that this cannabinoid is able to prevent psychotic-like symptoms induced by high doses of Δ(9)- THC. Subsequent studies have demonstrated that CBD has antipsychotic effects as observed using animal models and in healthy volunteers. Thus, this article provides a critical review of the research evaluating antipsychotic potential of this cannabinoid. CBD appears to have pharmacological profile similar to that of atypical antipsychotic drugs as seem using behavioral and neurochemical techniques in animal models. Additionally, CBD prevented human experimental psychosis and was effective in open case reports and clinical trials in patients with schizophrenia with a remarkable safety profile. Moreover, fMRI results strongly suggest that the antipsychotic effects of CBD in relation to the psychotomimetic effects of Δ(9)-THC involve the striatum and temporal cortex that have been traditionally associated with psychosis. Although the mechanisms of the antipsychotic properties are still not fully understood, we propose a hypothesis that could have a heuristic value to inspire new studies. These results support the idea that CBD may be a future therapeutic option in psychosis, in general and in schizophrenia, in particular.

The genus Sida L. - A traditional medicine: Its ethnopharmacological, phytochemical and pharmacological data for commercial exploitation in herbal drugs industry.

PubMed

Dinda, Biswanath; Das, Niranjan; Dinda, Subhajit; Dinda, Manikarna; SilSarma, Indrajit

2015-12-24

Sida L. (Malvaceae) has been used for centuries in traditional medicines in different countries for the prevention and treatment of different diseases such as diarrhea, dysentery, gastrointestinal and urinary infections, malarial and other fevers, childbirth and miscarriage problems, skin ailments, cardiac and neural problems, asthma, bronchitis and other respiratory problems, weight loss aid, rheumatic and other inflammations, tuberculosis, etc. To assess the scientific evidence for therapeutic potential of Sida L. and to identify the gaps of future research needs. The available information on the ethnomedicinal uses, phytochemistry, pharmacology and toxicology of Sida species was collected via a library and electronic searches in SciFinder, PubMed, ScienceDirect, Google Scholar for the period, 1933-2015. A variety of ethnomedicinal uses of Sida species have been found in India, China, Afrian and American countries. Phytochemical investigation of this genus has resulted in identification of about 142 chemical constituents, among which alkaloids, flavonoids and ecdysteroids are the predominant groups. The crude extracts and isolates have exhibited a wide spectrum of in vitro and in vivo pharmacological effects involving antimicrobial, analgesic, anti-inflammatory, abortifacient, neuroprotective, cardiovascular and cardioprotective, antimalarial, antitubercular, antidiabetic and antiobesity, antioxidant and nephroprotective activities among others. Ethnopharmacological preparations containing Sida species as an ingredient in India, African and American countries possess good efficacy in health disorders. From the toxicity perspective, only three Sida species have been assessed and found safe for oral use in rats. Pharmacological results supported some of the uses of Sida species in the traditional medicine. Alkaloids, flavonoids, other phenolics and ecdysteroids were perhaps responsible for the activities of extracts of the plants of this genus. No clinical study was reported. The detailed study on mechanism of action of isolates and extracts and their clinical study are needed for their use in modern medicine. More attention should be paid to Sida acuta, Sida cordifolia, Sida spinosa, Sida rhombifolia and Sida veronicaefolia in the domain of diarrhea, dysentery, gastrointestinal and urinary infections, skin ailments, asthma, bronchitis and other respiratory problems, malaria, childbirth and miscarriage problems, cardiac and neural problems, weight loss aid, and rheumatic and other inflammations, etc. Furthermore, detailed study on quality and safety assurance data on available ethnopharmacological preparations is needed for their commercial exploitation in local and global markets. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Adverse events analysis as an educational tool to improve patient safety culture in primary care: a randomized trial.

PubMed

González-Formoso, Clara; Martín-Miguel, María Victoria; Fernández-Domínguez, Ma José; Rial, Antonio; Lago-Deibe, Fernando Isidro; Ramil-Hermida, Luis; Pérez-García, Margarita; Clavería, Ana

2011-06-14

Patient safety is a leading item on the policy agenda of both major international health organizations and advanced countries generally. The quantitative description of the phenomena has given rise to intense concern with the issue in institutions and organizations, leading to a number of initiatives and research projects and the promotion of patient safety culture, with training becoming a priority both in Spain and internationally. To date, most studies have been conducted in a hospital setting, even though primary care is the type most commonly used by the public, in our experience. Our study aims to achieve the following:--Assess the registry of adverse events as an education tool to improve patient safety culture in the Family and Community Teaching Units of Galicia.--Find and analyze educational tools to improve patient safety culture in primary care.--Evaluate the applicability of the Hospital Survey on Patient Safety Culture by the Agency for Healthcare Research and Quality, Spanish version, in the context of primary health care. Experimental unifactorial study of two groups, control and intervention. Tutors and residents in Family and Community Medicine in last year of studies in Galicia, Spain. From the population universe through voluntary participation. Twenty-seven tutor-resident units in each group required, randomly assigned. Residents and their respective tutor (tutor-resident pair) in teaching units on Family and Community Medicine from throughout Galicia will be invited to participate. Tutor-resident pair that agrees to participate will be sent the Hospital Survey on Patient Safety Culture. Then, tutor-resident pair will be assigned to each group--either intervention or control--through simple random sampling. The intervention group will receive specific training to record the adverse effects found in patients under their care, with subsequent feedback, after receiving instruction on the process. No action will be taken in the control group. After the intervention has ended, the survey will once again be provided to all participants. Change in safety culture as measured by Hospital Survey on Patient Safety CultureCONSORT Extension for Non-Pharmacologic Treatments 2008 was applied. The most significant limitations on the project are related to selecting a tool to measure the safety environment, the training calendar of residents in Family and Community Medicine in last year of studies and the no-answer bias inherent to research conducted through self-administered surveys.The development and application of a safety culture in the health sector, specifically in primary care, is as yet limited. Thus, identifying the strengths and weaknesses in the safety environment may assist in designing strategies for improvement in the primary care health centers of our region. ISRCTN: ISRCTN41911128.

Efficacy and safety of renal denervation for Chinese patients with resistant hypertension using a microirrigated catheter: study design and protocol for a prospective multicentre randomised controlled trial.

PubMed

Liu, Zongjun; Shen, Li; Huang, Weijian; Zhao, Xianxian; Fang, Weiyi; Wang, Changqian; Yin, Zhaofang; Wang, Jianan; Fu, Guosheng; Liu, Xuebo; Jiang, Jianjun; Zhang, Zhihui; Li, Jingbo; Lu, Yingmin; Ge, Junbo

2017-09-01

Available data show that approximately 8%-18% of patients with primary hypertension will develop resistant hypertension. In recent years, catheter-based renal denervation (RDN) has emerged as a potential treatment option for resistant hypertension. A number of observational studies and randomised controlled trials among non-Chinese patients have demonstrated its potential safety and efficacy. This is a multicentre, randomised, open-label, parallel-group, active controlled trial that will investigate the efficacy and safety of a 5F saline-irrigated radiofrequency ablation (RFA) used for RDN in the treatment of Chinese patients with resistant hypertension. A total of 254 patients who have failed pharmacological therapy will be enrolled. Eligible subjects will be randomised in a 1:1 ratio to undergo RDN using the RFA plus antihypertensive medication or to receive treatment with antihypertensive medication alone. The primary outcome measure is the change in 24 hours average ambulatory systolic blood pressure from baseline to 3 months, comparing the RDN-plus-medication group with the medication-alone group. Important secondary endpoints include the change in office blood pressure from baseline to 6 months after randomisation. Safety endpoints such as changes in renal function will also be evaluated. The full analysis set, according to the intent-to-treat principle, will be established as the primary analysis population. All participants will provide informed consent; the study protocol has been approved by the Independent Ethics Committee for each site. This study is designed to investigate the efficacy and safety of RDN using a 5F saline microirrigated RFA. Findings will be shared with participating hospitals, policymakers and the academic community to promote the clinical management of resistant hypertension in China. ClinicalTrials.gov ID: NCT02900729; pre-results. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Application of the SEIPS Model to Analyze Medication Safety in a Crisis Residential Center.

PubMed

Steele, Maria L; Talley, Brenda; Frith, Karen H

2018-02-01

Medication safety and error reduction has been studied in acute and long-term care settings, but little research is found in the literature regarding mental health settings. Because mental health settings are complex, medication administration is vulnerable to a variety of errors from transcription to administration. The purpose of this study was to analyze critical factors related to a mental health work system structure and processes that threaten safe medication administration practices. The Systems Engineering Initiative for Patient Safety (SEIPS) model provides a framework to analyze factors affecting medication safety. The model approach analyzes the work system concepts of technology, tasks, persons, environment, and organization to guide the collection of data. In the study, the Lean methodology tools were used to identify vulnerabilities in the system that could be targeted later for improvement activities. The project director completed face-to-face interviews, asked nurses to record disruptions in a log, and administered a questionnaire to nursing staff. The project director also conducted medication chart reviews and recorded medication errors using a standardized taxonomy for errors that allowed categorization of the prevalent types of medication errors. Results of the study revealed disruptions during the medication process, pharmacology training needs, and documentation processes as the primary opportunities for improvement. The project engaged nurses to identify sustainable quality improvement strategies to improve patient safety. The mental health setting carries challenges for safe medication administration practices. Through analysis of the structure, process, and outcomes of medication administration, opportunities for quality improvement and sustainable interventions were identified, including minimizing the number of distractions during medication administration, training nurses on psychotropic medications, and improving the documentation system. A task force was created to analyze the descriptive data and to establish objectives aimed at improving efficiency of the work system and care process involved in medication administration at the end of the project. Copyright © 2017 Elsevier Inc. All rights reserved.

Clinical pharmacology review of safinamide for the treatment of Parkinson's disease.

PubMed

Fabbri, Margherita; Rosa, Mario M; Abreu, Daisy; Ferreira, Joaquim J

2015-12-01

Safinamide (Xadago™) is an oral α-aminoamide derivative marketed for the treatment of Parkinson's disease (PD). The drug has both dopaminergic properties, namely highly selective and reversible inhibition of monoamine oxidase B, and nondopamimetic properties, namely selective sodium channel blockade and calcium channel modulation, with consequent inhibition of excessive glutamate release. In 2014, safinamide was approved in the European Economic Area, as "an add-on therapy to stable dose levodopa, alone or in combination with other PD therapies in mid- to late-stage-fluctuating PD patients." In addition, evidence has been provided for safinamide in the treatment of motor symptoms in early PD patients. This article summarizes the pharmacological properties, development program, clinical indications for PD treatment, stratified according to several disease's stages and the safety profile of safinamide. A meta-analysis of the most frequent adverse events among Phase III trials has been also performed.

New antiobesity agents: lorcaserin (Belviq) and phentermine/topiramate ER (Qsymia).

PubMed

Shyh, Grace; Cheng-Lai, Angela

2014-01-01

Obesity is a risk factor for a wide range of conditions, including cardiovascular disease. Although lifestyle modifications remain the cornerstone for the management of obesity, pharmacologic agents may be a helpful addition to patients who have comorbidities and do not respond adequately to diet and exercise. Lorcaserin and phentermine/topiramate ER are 2 long-awaited agents, approved in 2012 for obesity management, 13 years since orlistat received US Food and Drug Administration approval in 1999. Lorcaserin is a serotonin agonist, whereas phentermine/topiramate is a combination of a sympathomimetic agent and an antiepileptic drug; both these agents have been shown to reduce weight significantly and improve cardiovascular and metabolic parameters, such as blood pressure, lipids, and HbA1C. This article reviews the pharmacology and clinical efficacy and safety of each of these agents. The differences among the three available agents for long-term management of obesity will also be examined.

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.

Safety, tolerability, and pharmacokinetics of single oral doses of tofacitinib, a Janus kinase inhibitor, in healthy volunteers.

PubMed

Krishnaswami, Sriram; Boy, Mary; Chow, Vincent; Chan, Gary

2015-03-01

Tofacitinib is an oral Janus kinase inhibitor. This randomized, double-blind, parallel-group, placebo-controlled study was the first evaluation of tofacitinib in humans. The objectives were to characterize the safety and tolerability, pharmacokinetics (PK), and pharmacodynamics of escalating single tofacitinib doses in healthy subjects. Tofacitinib (0.1, 0.3, 1, 3, 10, 30, 60, and 100 mg) or placebo was administered as oral powder for constitution. For each dose, 7-9 subjects were randomized to tofacitinib and 3-5 subjects to placebo. Ninety-five males and females (age range 19-45) completed the study. Forty-nine treatment-emergent all-causality adverse events (AEs) were observed; nausea and headache were the most frequently reported. Tofacitinib PK was characterized by rapid absorption (time to peak serum concentration [Tmax ] 0.5-1 hour), rapid elimination (mean terminal half-lives 2.3-3.1 hours), and dose-proportional systemic exposures (peak serum concentration [Cmax ] and area under the serum concentration-time curve from time zero to infinity [AUC0-∞ ]). No appreciable correlation was observed between tofacitinib dose and lymphocyte subset counts. Single-dose tofacitinib up to 100 mg in healthy subjects had a safety profile of mostly mild AEs, and no deaths, serious AEs, severe AEs or discontinuations due to AEs. © 2014, The American College of Clinical Pharmacology.

Low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy: Rationale and design of the Highlow study, a randomised trial of two doses.

PubMed

Bleker, Suzanne M; Buchmüller, Andrea; Chauleur, Céline; Ní Áinle, Fionnuala; Donnelly, Jennifer; Verhamme, Peter; Jacobsen, Anne Flem; Ganzevoort, Wessel; Prins, Martin; Beyer-Westendorf, Jan; DeSancho, Maria; Konstantinides, Stavros; Pabinger, Ingrid; Rodger, Marc; Decousus, Hervé; Middeldorp, Saskia

2016-08-01

Women with a history of venous thromboembolism (VTE) have a 2% to 10% absolute risk of VTE recurrence during subsequent pregnancies. Therefore, current guidelines recommend that all pregnant women with a history of VTE receive pharmacologic thromboprophylaxis. The optimal dose of low-molecular-weight heparin (LMWH) for thromboprophylaxis is unknown. In the Highlow study (NCT 01828697; www.highlowstudy.org), we compare a fixed low dose of LMWH with an intermediate dose of LMWH for the prevention of pregnancy-associated recurrent VTE. We present the rationale and design features of this study. The Highlow study is an investigator-initiated, multicentre, international, open-label, randomised trial. Pregnant women with a history of VTE and an indication for ante- and postpartum pharmacologic thromboprophylaxis are included before 14weeks of gestation. The primary efficacy outcome is symptomatic recurrent VTE during pregnancy and 6weeks postpartum. The primary safety outcomes are clinically relevant bleeding, blood transfusions before 6weeks postpartum and mortality. Patients are closely monitored to detect cutaneous reactions to LMWH and are followed for 3months after delivery. A central independent adjudication committee adjudicates all suspected outcome events. The Highlow study is the first large randomised controlled trial in pregnancy that will provide high-quality evidence on the optimal dose of LWMH thromboprophylaxis for the prevention of recurrent VTE in pregnant women with a history of VTE. Copyright © 2016 Elsevier Ltd. All rights reserved.

Listen to the public and fulfil their information interests - translating vaccine communication research findings into guidance for regulators.

PubMed

Bahri, Priya; Castillon Melero, Mireia

2018-03-24

Regulatory authorities have a crucial role in communicating about the vaccines they license. In terms of content and timing, their communication to the public is usually driven by data on quality, safety and efficacy. However, concerns over safety and vaccine hesitancy have emerged in some communities in various countries, and this demands a new approach to communication, starting with listening to the public debate. Reviewing communication research findings, coming in particular from the cognitive, decision-making and media sciences, constitutes one mechanism of listening and has led the European Union (EU) regulatory network to developing guidance about which common concerns and information needs of the public to address through proactive and prepared communication. The guidance has been welcomed by EU and international fora. The current article summarizes the recommendations and shares the underlying research findings, as well as a proof of concept that communication research can be valuable for regulators. It is critical that regulators integrate the communication process with product risk assessment in the framework of pharmacovigilance, to ensure that public concerns are addressed in the assessments and that information about evidence and uncertainty relating to safety is provided to the public and vaccination policy makers in a specific, clear and accurate manner. Additionally, information from regulatory authorities should support healthcare professionals in their communication with patients. Meeting the information interests of the public is the principal prerequisite for informed decisions as well as safe and effective use of vaccines and medicines overall. This is also fundamental for trust in the authorities' commitment to patient and population health. © 2018 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy

PubMed Central

Angeloni, Emiliano

2016-01-01

Background Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). Objective To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. Methods PubMed, Embase, and Cochrane Library were searched using search terms “ azilsartan”, “chlorthalidone,” “pharmacology,” “pharmacokinetics,” “pharmacodynamics,” “pharmacoeconomics,” and “cost-effectiveness.” To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Results Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Conclusion Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo. PMID:27103882

Azilsartan medoxomil in the management of hypertension: an evidence-based review of its place in therapy.

PubMed

Angeloni, Emiliano

2016-01-01

Azilsartan (AZI) is a relatively new angiotensin receptor blocker available for the treatment of any stage of hypertension, which was eventually given in combination with chlorthalidone (CLT). To review pharmacology and clinical role of AZI monotherapy and AZI/CLT or AZI/amlodipine combination therapies for hypertension management. PubMed, Embase, and Cochrane Library were searched using search terms " azilsartan", "chlorthalidone," "pharmacology," "pharmacokinetics," "pharmacodynamics," "pharmacoeconomics," and "cost-effectiveness." To obtain other relevant information, US Food and Drug Association as well as manufacturer prescribing information were also reviewed. Randomized controlled trials demonstrated AZI to be superior to other sartans, such as valsartan, olmesartan, and candesartan, in terms of 24-hour ambulatory blood pressure monitoring (ABPM) reduction with respect. That beneficial effect of azilsartan was also associated with similar safety profiles. When compared to other antihypertensive drugs, azilsartan was found to be superior to any angiotensin-converting enzyme inhibitor, including ramipril, in terms of ABPM results, and noninferior to amlodipine in terms of sleep-BP control. The association of AZI and CLT was then found to be superior to other sartans + thiazide combination therapies in terms of both BP lowering and goal achievement. The combination of AZI and amlodipine has also been tested in clinical trials, but compared only with placebo, demonstrating its superiority in terms of efficacy and similarity in terms of safety. Azilsartan is a safe and effective treatment option for every stage of hypertension, both alone or in fixed-dose combination tablets with chlorthalidone or amlodipine. Beneficial effects of AZI were also noted in patients with any degree of renal impairment. In addition, safety profiles of AZI were similar to that of the placebo.

The Canadian Pharmacogenomics Network for Drug Safety: a model for safety pharmacology.

PubMed

Ross, Colin J D; Visscher, Henk; Sistonen, Johanna; Brunham, Liam R; Pussegoda, Kusala; Loo, Tenneille T; Rieder, Michael J; Koren, Gideon; Carleton, Bruce C; Hayden, Michael R

2010-07-01

Adverse drug reactions (ADRs) rank as one of the top 10 leading causes of death in the developed world, and the direct medical costs of ADRs exceed $100 billion annually in the United States alone. Pharmacogenomics research seeks to identify genetic factors that are responsible for individual differences in drug efficacy and susceptibility to ADRs. This has led to several genetic tests that are currently being used to provide clinical recommendations. The Canadian Pharmacogenomics Network for Drug Safety is a nation-wide effort established in Canada to identify novel predictive genomic markers of severe ADRs in children and adults. A surveillance network has been established in 17 of Canada's major hospitals to identify patients experiencing specific ADRs and to collect biological samples and relevant clinical history for genetic association studies. To identify ADR-associated genetic markers that could be incorporated into predictive tests that will reduce the occurrence of serious ADRs, high-throughput genomic analyses are conducted with samples from patients that have suffered serious ADRs and matched control patients. ADRs represent a significant unmet medical problem with significant morbidity and mortality, and Canadian Pharmacogenomics Network for Drug Safety is a nation-wide network in Canada that seeks to identify genetic factors responsible for interindividual differences in susceptibility to serious ADRs. Active ADR surveillance is necessary to identify and recruit patients who suffer from serious ADRs. National and international collaborations are required to recruit sufficient patients for these studies. Several pharmacogenomics tests are currently in clinical use to provide dosing recommendations, and the number of pharmacogenomics tests is expected to significantly increase in the future.

Safety Assessment of Acyl Glucuronides-A Simplified Paradigm.

PubMed

Smith, Dennis A; Hammond, Timothy; Baillie, Thomas A

2018-06-01

While simple O - (ether-linked) and N -glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of the parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging. In this Commentary, we discuss alternative (non-acyl glucuronide) mechanisms by which carboxylic acids may cause serious adverse reactions, and propose a novel, practical approach to compare systemic exposure to acyl glucuronide metabolites in humans to that in animal species used in preclinical safety assessment based on relative estimates of the total body burden of these circulating conjugates. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

Safety Concerns Surrounding Quinolone Use in Children

PubMed Central

Patel, Karisma; Goldman, Jennifer L.

2016-01-01

Fluoroquinolones are highly effective antibiotics with many desirable pharmacokinetic and pharmacodynamic properties including high bioavailability, large volume of distribution, and a broad spectrum of antimicrobial activity. Despite their attractive profile as anti-infective agents, their use in children is limited, primarily due to safety concerns. In this review we highlight the pharmacological properties of fluoroquinolones and describe their current use in pediatrics. In addition, we provide a comprehensive assessment of the safety data associated with fluoroquinolone use in children. Although permanent or destructive arthropathy remains a significant concern, currently available data demonstrate that arthralgia and arthropathy are relatively uncommon in children and resolve following cessation of fluoroquinolone exposure without resulting in long-term sequelae. The concern for safety and risk of adverse events associated with pediatric fluoroquinolone use is likely driving the limited prescribing of this drug class in pediatrics. However, in adults, fluoroquinolones are the most commonly prescribed broad-spectrum antibiotics, resulting in the development of drug-resistant bacteria that can be challenging to treat effectively. The consequence of misuse and overuse of fluoroquinolones leading to drug resistance is a greater, but frequently overlooked, safety concern that applies to both children and adults and one that should be considered at the point of prescribing. PMID:26865283

Implications of the cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial and associated FDA public safety alert.

PubMed

Choi, Hyon; Neogi, Tuhina; Stamp, Lisa; Dalbeth, Nicola; Terkeltaub, Robert

2018-06-05

Recently, the FDA issued a public safety alert, responding to results of the now-published Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial. CARES showed no significant difference between allopurinol and febuxostat in the primary composite endpoint of cardiovascular (CV) events in subjects with gout and established cardiovascular comorbidities at baseline. However, there was significantly increased risk of cardiac and all-cause mortality with febuxostat. Urate lowering therapy (ULT) is central to long-term management of gout, and xanthine oxidoreductase inhibitor (XOI) therapy is the consensus first line approach. Allopurinol is generally the first XOI employed, but febuxostat is an effective XOI option, and is commonly used when allopurinol is not tolerated. These data are further relevant since CV co-morbidities are common in gout. Here, we examine why the CARES trial was done, and discuss other, ongoing comparative studies of febuxostat and allopurinol whose results are awaited. We assess strengths and limitations of CARES, and appraise robustness and biologic plausibility of the results. CARES does not prove that febuxostat raises CV mortality risk, but suggests greater risk with febuxostat than allopurinol. CARES results do not support first line use of febuxostat ULT, and raise questions on febuxostat placement at various pharmacologic ULT decision tree branches. Alternatives to febuxostat that are frequently effective include allopurinol dose-escalation, and uricosuric therapy alone or combined with allopurinol. The FDA safety alert highlights the need for shared ULT medical decision with gout patients, including discussion of CV safety of febuxostat. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

Post-approval safety issues with innovative drugs: a European cohort study.

PubMed

Mol, Peter G M; Arnardottir, Arna H; Motola, Domenico; Vrijlandt, Patrick J; Duijnhoven, Ruben G; Haaijer-Ruskamp, Flora M; de Graeff, Pieter A; Denig, Petra; Straus, Sabine M J M

2013-11-01

At time of approval, knowledge of the full benefit risk of any drug is limited, in particular with regards to safety. Post-approval surveillance of potential drug safety concerns is recognized as an important task of regulatory agencies. For innovative, often first-in-class drugs, safety knowledge at time of approval is often even less extensive and these may require tighter scrutiny post approval. We evaluated whether more post-approval serious safety issues were identified for drugs with a higher level of innovation. A cohort study was performed that included all new active substances approved under the European Centralized Procedure and for which serious safety issues were identified post-approval from 1 January 1999 to 1 January 2012. Serious safety issues were defined as issues requiring a Direct Healthcare Professional Communication to alert individual healthcare professionals of a new serious safety issue, or a safety-related drug withdrawal. Data were retrieved from publicly available websites of the Dutch Medicines Evaluation Board and the European Medicines Agency. The level of innovation was scored using a validated algorithm, grading drugs as important (A), moderate (B) or modest (C) innovations or as pharmacological or technological (pharm/tech) innovations. The data were analyzed using appropriate descriptive statistics and Kaplan-Meier analysis, with a Mantel-Cox log-rank test, and Cox-regression models correcting for follow-up duration, to identify a possible trend in serious safety issues with an increasing level of innovation. In Europe, 279 new drugs were approved between 1999 and 2011. Fifty-nine (21 %) were graded as important, 63 (23 %) moderate, or 34 (12 %) modest innovations and 123 (44 %) as non-innovative (pharm/tech), while 15 (25 %), 13 (21 %), 8 (24 %) and 17 (14 %) had post-approval safety issues, respectively (p = 0.06, linear-by-linear test). Five drugs were withdrawn from the market. The Kaplan-Meier-derived probability for having a first serious safety issue was statistically significant, log-rank (Mantel-Cox) p = 0.036. In the final adjusted Cox proportional hazard model there was no statistically significant difference in occurrence of a first serious safety issue for important, moderate and modest innovations versus non-innovative drugs; hazard ratios 1.76 (95 % CI 0.82-3.77), 1.61 (95 % CI 0.76-3.41)], and 1.25 (95 % CI 0.51-3.06), respectively. A higher level of innovation was not clearly related to an increased risk of serious safety issues identified after approval.

Fexinidazole--a new oral nitroimidazole drug candidate entering clinical development for the treatment of sleeping sickness.

PubMed

Torreele, Els; Bourdin Trunz, Bernadette; Tweats, David; Kaiser, Marcel; Brun, Reto; Mazué, Guy; Bray, Michael A; Pécoul, Bernard

2010-12-21

Human African trypanosomiasis (HAT), also known as sleeping sickness, is a fatal parasitic disease caused by trypanosomes. Current treatment options for HAT are scarce, toxic, no longer effective, or very difficult to administer, in particular for the advanced, fatal stage of the disease (stage 2, chronic HAT). New safe, effective and easy-to-use treatments are urgently needed. Here it is shown that fexinidazole, a 2-substituted 5-nitroimidazole rediscovered by the Drugs for Neglected Diseases initiative (DNDi) after extensive compound mining efforts of more than 700 new and existing nitroheterocycles, could be a short-course, safe and effective oral treatment curing both acute and chronic HAT and that could be implemented at the primary health care level. To complete the preclinical development and meet the regulatory requirements before initiating human trials, the anti-parasitic properties and the pharmacokinetic, metabolic and toxicological profile of fexinidazole have been assessed. Standard in vitro and in vivo anti-parasitic activity assays were conducted to assess drug efficacy in experimental models for HAT. In parallel, a full range of preclinical pharmacology and safety studies, as required by international regulatory guidelines before initiating human studies, have been conducted. Fexinidazole is moderately active in vitro against African trypanosomes (IC₅₀ against laboratory strains and recent clinical isolates ranged between 0.16 and 0.93 µg/mL) and oral administration of fexinidazole at doses of 100 mg/kg/day for 4 days or 200 mg/kg/day for 5 days cured mice with acute and chronic infection respectively, the latter being a model for the advanced and fatal stage of the disease when parasites have disseminated into the brain. In laboratory animals, fexinidazole is well absorbed after oral administration and readily distributes throughout the body, including the brain. The absolute bioavailability of oral fexinidazole was 41% in mice, 30% in rats, and 10% in dogs. Furthermore, fexinidazole is rapidly metabolised in vivo to at least two biologically active metabolites (a sulfoxide and a sulfone derivative) that likely account for a significant portion of the therapeutic effect. Key pharmacokinetic parameter after oral absorption in mice for fexinidazole and its sulfoxide and sulfone metabolites are a C(max) of 500, 14171 and 13651 ng/mL respectively, and an AUC₀₋₂₄ of 424, 45031 and 96286 h.ng/mL respectively. Essentially similar PK profiles were observed in rats and dogs. Toxicology studies (including safety pharmacology and 4-weeks repeated-dose toxicokinetics in rat and dog) have shown that fexinidazole is well tolerated. The No Observed Adverse Event Levels in the 4-weeks repeated dose toxicity studies in rats and dogs was 200 mg/kg/day in both species, with no issues of concern identified for doses up to 800 mg/kg/day. While fexinidazole, like many nitroheterocycles, is mutagenic in the Ames test due to bacterial specific metabolism, it is not genotoxic to mammalian cells in vitro or in vivo as assessed in an in vitro micronucleus test on human lymphocytes, an in vivo mouse bone marrow micronucleus test, and an ex vivo unscheduled DNA synthesis test in rats. The results of the preclinical pharmacological and safety studies indicate that fexinidazole is a safe and effective oral drug candidate with no untoward effects that would preclude evaluation in man. The drug has entered first-in-human phase I studies in September 2009. Fexinidazole is the first new clinical drug candidate with the potential for treating advanced-stage sleeping sickness in thirty years.

Antipsychotic interventions in prodromal psychosis: safety issues.

PubMed

Liu, Chen-Chung; Demjaha, Arsime

2013-03-01

In recent years, psychopharmacological intervention in prodromal psychosis, also known as the ultra-high risk (UHR) mental state for psychosis, has attracted much attention. Whilst it has been shown that antipsychotic use in UHR individuals may be effective in potentially delaying or even averting progression to frank psychosis, their use in subjects that do not necessarily convert to psychosis has raised considerable ethical concerns because of their adverse effects. Recent treatment guidelines for patients at UHR for psychosis recommend the use of antipsychotics only in exceptional conditions and with great precautions. To date only a few studies have investigated the use of antipsychotic medications in UHR patients and the potential benefits and risks related to their use in prodromal psychosis remain unclear. We review here all published studies that included UHR patients treated with antipsychotics, regardless of study design. These studies were all of second-generation antipsychotics, given that first-generation antipsychotics cannot be recommended because of their adverse drug reactions. We specifically examine the available descriptions of adverse reactions of the individual antipsychotic medication in each study and discuss the potential effects of various demographic and clinical factors that may impact on safety issues of pharmacological interventions in UHR patients. Clinical trials to date investigating potential benefits of antipsychotic treatments in preventing transition to psychosis were of relatively short duration and have involved a small number of patients. Whilst it appears that pharmacological intervention at this stage may be effective in both reducing the psychopathology and decreasing transition rates, and is potentially safe, in the absence of sufficient evidence-based knowledge to guide treatment, definitive clinical recommendations and guidelines cannot be derived. Certain adverse events take time to develop, such as metabolic syndrome and endocrine-related effects, thus longer term clinical trials with a larger number of patients are needed to determine the effectiveness of antipsychotic intervention and the relationship of its duration to emergence of adverse events. This can inform the development of timely strategies to prevent serious negative impacts and thus maximize the benefits of antipsychotic intervention in UHR patients that outweigh the risks associated with their use.

Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog.

PubMed

Knudsen, T; Kristensen, A T; Nichols, T C; Agersø, H; Jensen, A L; Kjalke, M; Ezban, M; Tranholm, M

2011-11-01

Recombinant human FVIIa (rhFVIIa) corrects the coagulopathy in hemophilia A and B as well as FVII deficiency. This is also the case in dogs until canine anti-human FVIIa antibodies develop (~2 weeks). Recombinant canine factor VIIa (rcFVIIa), successfully over-expressed by gene transfer in haemophilia dogs, has provided long-term haemostasis (>2 years). However, pharmacokinetics (PK), pharmacodynamics (PD) and safety of rcFVIIa after pharmacological administration have not been reported. We therefore wanted to explore the safety, PK and PD of rcFVIIa in dogs. A pilot study was set up to evaluate the safety as well as PK and PD of rcFVIIa after a single intravenous dose of 270 μg kg(-1) to one HA and one haemostatically normal dog and to directly compare rcFVIIa with rhFVIIa in these two dogs. Single doses of rcFVIIa and rhFVIIa were well tolerated. No adverse events were observed. Pharmacokinetic characteristics including half-life (FVIIa activity: 1.2-1.8 h; FVIIa antigen 2.8-3.7 h) and clearance were comparable for rcFVIIa and rhFVIIa. Kaolin-activated thromboelastography approached normal in the HA dog with the improvement being most pronounced after rcFVIIa. This study provided the first evidence that administering rcFVIIa intravenously is feasible, safe, well tolerated and efficacious in correcting the haemophilic coagulopathy in canine HA and that rcFVIIa exhibits pharmacokinetic characteristics comparable to rhFVIIa in haemophilic and haemostatically competent dogs. This strengthens the hypothesis that rcFVIIa can be administered to dogs to mimic the administration of rhFVIIa to humans. © 2011 Blackwell Publishing Ltd.

Population pharmacokinetics and exposure-response of osimertinib in patients with non-small cell lung cancer.

PubMed

Brown, Kathryn; Comisar, Craig; Witjes, Han; Maringwa, John; de Greef, Rik; Vishwanathan, Karthick; Cantarini, Mireille; Cox, Eugène

2017-06-01

To develop a population (pop) pharmacokinetic (PK) model for osimertinib (AZD9291) and its metabolite (AZ5104) and investigate the exposure-response relationships for selected efficacy and safety parameters. PK, safety and efficacy data were collected from two non-small cell lung cancer (NSCLC) patient studies (n = 748) and one healthy volunteer study (n = 32), after single or multiple once-daily dosing of 20-240 mg osimertinib. Nonlinear mixed effects modelling was used to characterise the popPK. Individual exposure values were used to investigate the relationship with response evaluation criteria in solid tumours (RECIST 1.1) efficacy parameters and key safety parameters (rash, diarrhoea, QTcF). A popPK model that adequately described osimertinib and its metabolite AZ5104 in a joint manner was developed. Body weight, serum albumin and ethnicity were identified as significant covariates on PK in the analysis, but were not found to have a clinically relevant impact on osimertinib exposure. No relationship was identified between exposure and efficacy over the dose range studied. A linear relationship was observed between exposure and the occurrence of rash or diarrhoea, and between concentration and QTcF, with a predicted mean (upper 90% confidence interval) increase of 14.2 (15.8) ms at the maximum concentration for an 80 mg once-daily dose at steady state. PopPK and exposure-response models were developed for osimertinib and AZ5104. There was no relationship between exposure and efficacy but a linear relationship between exposure and safety endpoints (rash, diarrhoea and QTcF) was observed. © 2016 The British Pharmacological Society.

A randomized, controlled phase I/II study to evaluate the safety and efficacy of MGV354 for ocular hypertension or glaucoma.

PubMed

Stacy, Rebecca; Huttner, Kenneth; Watts, Jen; Peace, James; Wirta, David; Walters, Tom; Sall, Kenneth; Seaman, John; Ni, Xiao; Prasanna, Ganesh; Mogi, Muneto; Adams, Christopher; Yan, Jing-He; Wald, Michael; He, Yunsheng; Newton, Ronald; Kolega, Randall; Grosskreutz, Cynthia

2018-05-23

To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma DESIGN: Double-masked, randomized, and vehicle-controlled study METHODS: Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multi-site trial that evaluated IOP-lowering efficacy of the MTD administered nightly for one week in 50 patients with minimum IOP of 24mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at Day 8 compared to baseline (ClinicalTrials.gov NCT02743780). There was no difference in favor of MGV354 for IOP lowering; change from Baseline to Day 8 in mean diurnal IOP was -0.6 mmHg for MGV354-treated patients and -1.1 mmHg for Vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia. Overall, MGV354 0.1% demonstrated no statistically significant effect compared to Vehicle in lowering IOP based upon the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology. Copyright © 2018 Elsevier Inc. All rights reserved.

Need of the regulation for profit percentage investment by pharmaceutical companies in new drug discovery research from the various local traditional medicinal and plant systems.

PubMed

Bhattarai, M D

2012-01-01

In the modern medical systems the active pharmacological ingredients, effective against any disease is identified, purified and studied for its various effects and side-effects whereas it is not so in the traditional systems. Therefore, it is not surprising that safety concerns have often been raised about the traditional medical products. The major issue now, is to make appropriate situation with basic supports to bring all the available experts and resources together for the identification, purification, and study of efficacy and safety of the active molecules of the popular traditional medicines. Government and public sectors in the countries with such rich traditional medicinal and plant systems have related experts, but they also have much hurdle regarding recruitment and retention of expert human resources, getting fund, purchase and maintenance of equipment, bureaucratic formalities and others. The pharmaceutical companies have basic laboratories with related infrastructure and human resources as well as interest about bringing the drug molecules. To bridge the gap, there is a need of the regulation which will make the pharmaceutical companies to invest certain percentage of their profit in the field of research to identify new drug molecules and to study their effects. It is just not an issue of discovering the active molecule but also of creating the concept and culture of research, purity and quality of drugs, safety of people, and future direction of the human society.

Safety and efficacy of blue cohosh (Caulophyllum thalictroides) during pregnancy and lactation.

PubMed

Dugoua, Jean-Jacques; Perri, Daniel; Seely, Dugald; Mills, Edward; Koren, Gideon

2008-01-01

There is a lack of basic knowledge on the part of both clinicians and patients as to the indications for use and safety of herbal medicines in pregnancy and lactation. This is one article in a series that systematically reviews the evidence for commonly used herbs during pregnancy and lactation. To systematically review the literature for evidence on the use, safety and pharmacology of blue cohosh, focusing on issues pertaining to pregnancy and lactation. We searched 7 electronic databases and compiled data according to the grade of evidence found. According to a survey of midwives in the United States, approximately 64% of midwives reported using blue cohosh as a labour-inducing aid. There are three case reports in the scientific literature that blue cohosh taken at the time of delivery may cause; 1) perinatal stroke, 2) acute myocardial infarction, profound congestive heart failure and shock and 3) severe multi-organ hypoxic injury. There is one case report that blue cohosh possesses abortifacient properties. There is in vitro evidence that blue cohosh may have teratogenic, embryotoxic and oxytoxic effects. In lactation, the safety of blue cohosh is unknown. Based on the available scientific information, blue cohosh should; 1) be used with extreme caution during pregnancy, 2) be used only under medical professional supervision and 3) not be available to the public as an over-the-counter product. There is an urgent need to conduct a retrospective or prospective cohort study of midwifes using blue cohosh in order to determine its safety. Key words: Blue cohosh, caulophyllum thalictroides, pregnancy, lactation, breastfeeding, systematic review.

Medicinal plants of the Russian Pharmacopoeia; their history and applications.

PubMed

Shikov, Alexander N; Pozharitskaya, Olga N; Makarov, Valery G; Wagner, Hildebert; Verpoorte, Rob; Heinrich, Michael

2014-07-03

Due to the location of Russia between West and East, Russian phytotherapy has accumulated and adopted approaches that originated in European and Asian traditional medicine. Phytotherapy is an official and separate branch of medicine in Russia; thus, herbal medicinal preparations are considered official medicaments. The aim of the present review is to summarize and critically appraise data concerning plants used in Russian medicine. This review describes the history of herbal medicine in Russia, the current situation and the pharmacological effects of specific plants in the Russian Pharmacopoeia that are not included in the European Pharmacopoeia. Based on the State Pharmacopoeia of the USSR (11(th) edition), we selected plant species that have not yet been adopted in Western and Central Europe (e.g., selected for inclusion in the European Pharmacopoeia) and systematically searched the scientific literature for data using library catalogs, the online service E-library.ru, and databases such as Medline/Pubmed, Scopus, and the Web of Science regarding species, effectiveness, pharmacological effects, and safety. The Russian Federation follows the State Pharmacopoeia of the USSR (11(th) edition), which contains 83 individual plant monographs. Fifty-one of these plants are also found in the European Pharmacopoeia and have been well studied, but 32 plants are found only in the Pharmacopoeia of the USSR. Many articles about these medicinal plants were never translated in English, and much of the information collected by Russian scientists has never been made available to the international community. Such knowledge can be applied in future studies aimed at a safe, evidence-based use of traditional Russian medicinal plants in European and global phytopharmacotherapy as well as for the discovery of novel leads for drug development. The review highlights the therapeutic potential of these Russian phytopharmaceuticals but also highlights cases where concern has been raised about product safety and tolerability, which would aid in supporting their safe use. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Results From the First-in-Human Study With Ozanimod, a Novel, Selective Sphingosine-1-Phosphate Receptor Modulator.

PubMed

Tran, Jonathan Q; Hartung, Jeffrey P; Peach, Robert J; Boehm, Marcus F; Rosen, Hugh; Smith, Heather; Brooks, Jennifer L; Timony, Gregg A; Olson, Allan D; Gujrathi, Sheila; Frohna, Paul A

2017-08-01

The sphingosine-1-phosphate 1 receptor (S1P 1R ) is expressed by lymphocytes, dendritic cells, and vascular endothelial cells and plays a role in the regulation of chronic inflammation and lymphocyte egress from peripheral lymphoid organs. Ozanimod is an oral selective modulator of S1P 1R and S1P 5R receptors in clinical development for the treatment of chronic immune-mediated, inflammatory diseases. This first-in-human study characterized the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ozanimod in 88 healthy volunteers using a range of single and multiple doses (7 and 28 days) and a dose-escalation regimen. Ozanimod was generally well tolerated up to a maximum single dose of 3 mg and multiple doses of 2 mg/d, with no severe adverse events (AEs) and no dose-limiting toxicities. The most common ozanimod-related AEs included headache, somnolence, dizziness, nausea, and fatigue. Ozanimod exhibited linear PK, high steady-state volume of distribution (73-101 L/kg), moderate oral clearance (204-227 L/h), and an elimination half-life of approximately 17 to 21 hours. Ozanimod produced a robust dose-dependent reduction in total peripheral lymphocytes, with a median decrease of 65% to 68% observed after 28 days of dosing at 1 and 1.5 mg/d, respectively. Ozanimod selectivity affected lymphocyte subtypes, causing marked decreases in cells expressing CCR7 and variable decreases in subsets lacking CCR7. A dose-dependent negative chronotropic effect was observed following the first dose, with the dose-escalation regimen attenuating the first-dose negative chronotropic effect. Ozanimod safety, PK, and PD properties support the once-daily regimens under clinical investigation. © 2017, The Authors. The Journal of Clinical Pharmacology published by Wiley Periodicals, Inc. on behalf of American College of Clinical Pharmacology.

Tithonia diversifolia (Hemsl.) A. Gray as a medicinal plant: A comprehensive review of its ethnopharmacology, phytochemistry, pharmacotoxicology and clinical relevance.

PubMed

Mabou Tagne, Alex; Marino, Franca; Cosentino, Marco

2018-06-28

Tithonia diversifolia (TD) is widely valued in several cultures for its medicinal properties. A comprehensive review of the current understanding of this plant species is required due to emerging concerns over its efficacy, toxicity and allergenic potential. We critically summarized the current evidence on the botany, traditional use, phytochemistry, pharmacology and safety of TD, with the view to provide perspectives for developing more attractive pharmaceuticals of plant origin, but also to lay a new foundation for further investigations on this plant. A preliminary consultation of search engines such as Web of Science, PubMed, ScienceDirect and other published/unpublished resources provided an overview of extant literature on TD. Then, we meticulously screened all titles, abstracts and full-texts to establish consistency in the application of inclusion criteria. Studies were considered for inclusion if they dealt with taxonomy, global distribution, local and traditional knowledge, phytochemistry, toxicity and biological effects. 1856 articles were retrieved among which 168 were revised and included. Several studies conducted on cell lines and animals provided supporting evidence for some ethnomedicinal claims of extracts from TD. Short-term use of Tithonia extracts were effective and well-tolerated in animals when taken at lower doses. Both the toxic and therapeutic effects were attributed to bioactive principles naturally occurring in this species including sesquiterpene lactones, chlorogenic acid and flavonoids. T. diversifolia is a valuable source of bioactive compounds with significant therapeutic implications and favourable safety index. However, more rigorously designed investigations are needed to recommend the whole plant or its active ingredients as a medication, and should focus on understanding the multi-target network pharmacology of the plant, clarifying the effective doses as well as identifying the potential interactions with prescribed drugs or other chemicals. Copyright © 2018 Elsevier B.V. All rights reserved.

Safety and tolerability of new-generation anti-obesity medications: a narrative review.

PubMed

Patel, Dhiren K; Stanford, Fatima Cody

2018-03-01

The prevalence of obesity and associated comorbidities is rising. Despite their weight-loss efficacy, new generation anti-obesity medications are only prescribed to a minority of adults with obesity, possibly, which in part may be due to safety concerns. This review presents detailed safety profiles for orlistat, phentermine/topiramate, lorcaserin, naltrexone/bupropion and liraglutide 3.0 mg, and discusses the associated risk-benefit profiles. Two anti-obesity medications presented safety issues that warranted further discussion; phentermine/topiramate (fetal toxicity) and liraglutide 3.0 mg (risk of gallstone disease and mild, acute pancreatitis), whereas the adverse events associated with orlistat, lorcaserin, and naltrexone/bupropion were mostly transient tolerability issues. The difficulties surrounding the objective determination of risk-benefit for anti-obesity medications is discussed. The need for more long-term data, thorough patient assessment, individualization of pharmacological interventions and adherence to stopping rules to maximize risk-benefit are highlighted. Overall, the majority of new generation anti-obesity medications present encouraging tolerability profiles; however, in some cases a lack of long-term clinical trials confounds the accurate determination of risk-benefit.

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity

PubMed Central

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD. PMID:28740389

Methylphenidate dose optimization for ADHD treatment: review of safety, efficacy, and clinical necessity.

PubMed

Huss, Michael; Duhan, Praveen; Gandhi, Preetam; Chen, Chien-Wei; Spannhuth, Carsten; Kumar, Vinod

2017-01-01

Attention-deficit/hyperactivity disorder (ADHD) is a chronic psychiatric disorder characterized by hyperactivity and/or inattention and is often associated with a substantial impact on psychosocial functioning. Methylphenidate (MPH), a central nervous system stimulant, is commonly used for pharmacological treatment of adults and children with ADHD. Current practice guidelines recommend optimizing MPH dosage to individual patient needs; however, the clinical benefits of individual dose optimization compared with fixed-dose regimens remain unclear. Here we review the available literature on MPH dose optimization from clinical trials and real-world experience on ADHD management. In addition, we report safety and efficacy data from the largest MPH modified-release long-acting Phase III clinical trial conducted to examine benefits of dose optimization in adults with ADHD. Overall, MPH is an effective ADHD treatment with a good safety profile; data suggest that dose optimization may enhance the safety and efficacy of treatment. Further research is required to establish the extent to which short-term clinical benefits of MPH dose optimization translate into improved long-term outcomes for patients with ADHD.

Model-based analysis of thromboxane B{sub 2} and prostaglandin E{sub 2} as biomarkers in the safety evaluation of naproxen

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

Sahota, Tarjinder; Sanderson, Ian; Danhof, Meindert

The assessment of safety in traditional toxicology protocols relies on evidence arising from observed adverse events (AEs) in animals and on establishing their correlation with different measures of drug exposure (e.g., C{sub max} and AUC). Such correlations, however, ignore the role of biomarkers, which can provide further insight into the underlying pharmacological mechanisms. Here we use naproxen as a paradigm drug to explore the feasibility of a biomarker-guided approach for the prediction of AEs in humans. A standard toxicology protocol was set up for the evaluation of effects of naproxen in rat, in which four doses were tested (7.5, 15,more » 40 and 80 mg/kg). In addition to sparse blood sampling for the assessment of exposure, thromboxane B{sub 2} and prostaglandin E{sub 2} were also collected in satellite groups. Nonlinear mixed effects modelling was used to evaluate the predictive performance of the approach. A one-compartmental model with first order absorption was found to best describe the pharmacokinetics of naproxen. A nonlinear relationship between dose and bioavailability was observed which leads to a less than proportional increase in naproxen concentrations with increasing doses. The pharmacodynamics of TXB{sub 2} and PGE{sub 2} was described by direct inhibition models with maximum pharmacological effects achieved at doses > 7.5 mg/kg. The predicted PKPD relationship in humans was within 10-fold of the values previously published. Moreover, our results indicate that biomarkers can be used to assess interspecies differences in PKPD and extrapolated data from animals to humans. Biomarker sampling should be used systematically in general toxicity studies. - Highlights: • Prediction of a drug's safety profile from preclinical protocols remains challenging. • Pharmacokinetic measures of safe exposure (e.g., AUC) ignore the role of biomarkers. • PKPD relationships enable the evaluation of adverse events in a mechanistic manner. • Major differences exist between rats and humans in the effects of naproxen on TXB{sub 2}. • A biomarker-guided approach may facilitate the prediction of adverse events in humans.« less

Pharmacokinetic drivers of toxicity for basic molecules: Strategy to lower pKa results in decreased tissue exposure and toxicity for a small molecule Met inhibitor

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

Diaz, Dolores, E-mail: diaz.dolores@gene.com; Ford, Kevin A.; Hartley, Dylan P.

Several toxicities are clearly driven by free drug concentrations in plasma, such as toxicities related to on-target exaggerated pharmacology or off-target pharmacological activity associated with receptors, enzymes or ion channels. However, there are examples in which organ toxicities appear to correlate better with total drug concentrations in the target tissues, rather than with free drug concentrations in plasma. Here we present a case study in which a small molecule Met inhibitor, GEN-203, with significant liver and bone marrow toxicity in preclinical species was modified with the intention of increasing the safety margin. GEN-203 is a lipophilic weak base as demonstratedmore » by its physicochemical and structural properties: high LogD (distribution coefficient) (4.3) and high measured pKa (7.45) due to the basic amine (N-ethyl-3-fluoro-4-aminopiperidine). The physicochemical properties of GEN-203 were hypothesized to drive the high distribution of this compound to tissues as evidenced by a moderately-high volume of distribution (Vd > 3 l/kg) in mouse and subsequent toxicities of the compound. Specifically, the basicity of GEN-203 was decreased through addition of a second fluorine in the 3-position of the aminopiperidine to yield GEN-890 (N-ethyl-3,3-difluoro-4-aminopiperidine), which decreased the volume of distribution of the compound in mouse (Vd = 1.0 l/kg), decreased its tissue drug concentrations and led to decreased toxicity in mice. This strategy suggests that when toxicity is driven by tissue drug concentrations, optimization of the physicochemical parameters that drive tissue distribution can result in decreased drug concentrations in tissues, resulting in lower toxicity and improved safety margins. -- Highlights: ► Lower pKa for a small molecule: reduced tissue drug levels and toxicity. ► New analysis tools to assess electrostatic effects and ionization are presented. ► Chemical and PK drivers of toxicity can be leveraged to improve safety.« less

The effect of learning styles and study behavior on success of preclinical students in pharmacology.

PubMed

Asci, Halil; Kulac, Esin; Sezik, Mekin; Cankara, F Nihan; Cicek, Ekrem

2016-01-01

To evaluate the effect of learning styles and study behaviors on preclinical medical students' pharmacology exam scores in a non-Western setting. Grasha-Reichmann Student Learning Study Scale and a modified Study Behavior Inventory were used to assess learning styles and study behaviors of preclinical medical students (n = 87). Logistic regression models were used to evaluate the independent effect of gender, age, learning style, and study behavior on pharmacology success. Collaborative (40%) and competitive (27%) dominant learning styles were frequent in the cohort. The most common study behavior subcategories were study reading (40%) and general study habits (38%). Adequate listening and note-taking skills were associated with pharmacology success, whereas students with adequate writing skills had lower exam scores. These effects were independent of gender. Preclinical medical students' study behaviors are independent predictive factors for short-term pharmacology success.

Safety, Tolerability, and Pharmacokinetics of Therapeutic and Supratherapeutic Doses of Tramadol Hydrochloride in Healthy Adults: A Randomized, Double-Blind, Placebo-Controlled Multiple-Ascending-Dose Study.

PubMed

DeLemos, Byron; Richards, Henry M; Vandenbossche, Joris; Ariyawansa, Jay; Natarajan, Jaya; Alexander, Binu; Ramakrishna, Tage; Murtaugh, Thomas; Stahlberg, Hans-Jürgen

2017-11-01

This randomized, double-blind, parallel-group multiple-ascending-dose study evaluated the safety, tolerability, and pharmacokinetics of tramadol hydrochloride in healthy adults to inform dosage and design for a subsequent QT/QTc study. Healthy men and women, 18 to 45 years old (inclusive), were sequentially assigned to the tramadol 200, 400, or 600 mg/day treatment cohort and within each cohort, randomized (4:1) to either tramadol or placebo every 6 hours for 9 oral doses. Of the 24 participants randomized to tramadol (n = 8/cohort), 22 (91.7%) completed the study. The AUC tau,ss of tramadol increased approximately 2.2- and 3.6-fold for the (+) enantiomer and 2.0- and 3.5-fold for the (-) enantiomer with increasing dose from 200 to 400  and 600 mg/day, whereas the C max,ss increased 2.1- and 3.3-fold for the (+) enantiomer and 2.0- and 3.2-fold for the (-) enantiomer. Overall, 21 participants (87.5%) participants reported ≥1 treatment-emergent adverse event; most frequent were nausea (17 of 24, 70.8%) and vomiting (7 of 24, 29.2%). Vomiting (affected participants and events) increased with increasing dose from 200 to 600 mg/day but was mild (5 of 24) or moderate (2 of 24) in severity. All tested dosage regimens of tramadol showed acceptable safety and tolerability profile for further investigation in a thorough QT/QTc study. © 2017, The American College of Clinical Pharmacology.

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 97

NASA Technical Reports Server (NTRS)

1972-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 94)

NASA Technical Reports Server (NTRS)

1971-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

Aerospace medicine and biology: A continuing bibliography with indexes, supplement 96

NASA Technical Reports Server (NTRS)

1971-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

Aerospace medicine and biology: A continuing bibliography with indexes, supplement

NASA Technical Reports Server (NTRS)

1972-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

Aerospace medicine and biology: A continuing bibliography with indexes (supplement 100)

NASA Technical Reports Server (NTRS)

1972-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. Reference describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

An Evidence-Based Systematic Review of Beta-Sitosterol, Sitosterol (22,23- dihydrostigmasterol, 24-ethylcholesterol) by the Natural Standard Research Collaboration.

PubMed

Ulbricht, Catherine E

2016-01-01

An evidence-based systematic review of beta-sitosterol, sitosterol (22,23-dihydrostigmasterol, 24-ethylcholesterol) by the Natural Standard Research Collaboration consolidates the safety and efficacy data available in the scientific literature using a validated, reproducible grading rationale. This article includes written and statistical analysis of clinical trials, plus a compilation of expert opinion, folkloric precedent, history, pharmacology, kinetics/dynamics, interactions, adverse effects, toxicology, and dosing.

Classics in Chemical Neuroscience: Diazepam (Valium)

PubMed Central

2014-01-01

Diazepam (Valium) is among the most successful drugs from the onset of the psychopharmacological revolution that began during the 1950s. Efficacious in treating a wide-spectrum of CNS disorders, including anxiety and epilepsy, it set the standard for pharmacotherapy in terms of potency, onset of action, and safety. In this Review, the legacy of diazepam to chemical neuroscience will be considered along with its synthesis, pharmacology, drug metabolism, adverse events and dependence, clinical use, and regulatory issues. PMID:24552479

[Study on characteristics of pharmacological effects of traditional Chinese medicines distributing along stomach meridian based on medicinal property combination].

PubMed

Zhang, Bai-Xia; Gu, Hao; Guo, Hong-Ling; Ma, Li; Wang, Yun; Qiao, Yan-Jiang

2014-07-01

At present, studies on traditional Chinese medicine (TCM) properties are mostly restricted to a single or two kinds of medicinal properties, but deviated from the holism of the theoretical system of TCMs. In this paper, the characteristics of pharmacological effects of different property combinations of TCMs distributing in the stomach meridian were take as the study objective. The data of properties of TCMs distributing in the stomach meridian was collected from the Pharmacopoeia of the People's Republic of China (2005). The data of pharmacological effects of TCMs distributing in the stomach meridian was collected from all of literatures recorded in Chinese Journal Full-text Database (CNKI) since 1980, Science of Chinese Materia Medica (Yan Zhenghua, People's Medical Publishing House, 2006) and Clinical Science of Chinese Materia Medica (Gao Xuemin, Zhong Gansheng, Hebei Science and Technology Publishing House, 2005). The corresponding pharmacological effects of property combinations of TCMs distributing in the stomach meridian was mined by the method of association rules. The results of the association rules were consistent with the empirical knowledge, and showed that different medicinal property combinations had respective pharmacological characteristics, including differences and similarities in pharmacological effects of different medicinal property combinations. Medicinal property combinations with identical four properties or five tastes showed similar pharmacological effects; whereas medicinal property combinations with different four properties or five tastes showed differentiated pharmacological effects. However, medicinal property combinations with different four properties or five tastes could also show similar pharmacological effects. In this study, the medicinal property theory and the pharmacological effects of TCMs were combined to reveal the main characteristics and regularity of pharmacological effects of TCMs distributing in the stomach meridian and provide a new way of thinking and method for revealing the mechanism action of TCMs distributing in the stomach meridian and discovering the pharmacological effects of TCMs distributing in the stomach meridian.

Performance of Clinical Nurse Educators in Teaching Pharmacology and Medication Management: Nursing Students’ Perceptions

PubMed Central

Ghamari Zare, Zohre; Adib-Hajbaghery, Mohsen

2016-01-01

Background Pharmacological knowledge and medication management skills of student nurses greatly depend on the clinical nurse educators’ performance in this critical issue. However, the Iranian nurse educators’ performance in teaching pharmacology and medication management are not adequately studied. Objectives The current study aimed to investigate the nursing students’ perceptions on the status of clinical pharmaceutical and medication management education. Materials and Methods A cross-sectional study was conducted on all 152 nursing students registered in the seventh and eighth semesters at the Qom and Naragh branches of Islamic Azad University, and Kashan University of Medical Sciences in 2013 - 2014 academic year. The students’ perceptions on the performance of clinical nurse educators in teaching pharmacology and medication management were assessed using a researcher made questionnaire. The questionnaire consisted of 31 items regarding clinical educators’ performance in teaching pharmacology and medication management and two questions about students’ satisfaction with their level of knowledge and skills in pharmacology and medication management. Descriptive statistics was employed and analysis of variance was performed to compare the mean of scores of teaching pharmacology and medication management in the three universities. Results Among a total of 152 subjects, 82.9% were female and their mean age was 22.57 ± 1.55 years. According to the students, instructors had the weakest performance in the three items of teaching pharmacology and medication management based on the students’ learning needs, teaching medication management through a patient-centered method and teaching pharmacology and medication management based on the course plan. The students’ satisfaction regarding their own knowledge and skill of pharmacology and medication management was at medium level. Conclusions Nursing students gave a relatively low score in several aspects of their instructors’ performance regarding teaching pharmacology and medication management. It seems that many clinical nurse educators in the studied settings were incompetent especially in teaching pharmacology and medication management, while these are critical areas and need special attention. PMID:27331055

Performance of Clinical Nurse Educators in Teaching Pharmacology and Medication Management: Nursing Students' Perceptions.

PubMed

Ghamari Zare, Zohre; Adib-Hajbaghery, Mohsen

2016-03-01

Pharmacological knowledge and medication management skills of student nurses greatly depend on the clinical nurse educators' performance in this critical issue. However, the Iranian nurse educators' performance in teaching pharmacology and medication management are not adequately studied. The current study aimed to investigate the nursing students' perceptions on the status of clinical pharmaceutical and medication management education. A cross-sectional study was conducted on all 152 nursing students registered in the seventh and eighth semesters at the Qom and Naragh branches of Islamic Azad University, and Kashan University of Medical Sciences in 2013 - 2014 academic year. The students' perceptions on the performance of clinical nurse educators in teaching pharmacology and medication management were assessed using a researcher made questionnaire. The questionnaire consisted of 31 items regarding clinical educators' performance in teaching pharmacology and medication management and two questions about students' satisfaction with their level of knowledge and skills in pharmacology and medication management. Descriptive statistics was employed and analysis of variance was performed to compare the mean of scores of teaching pharmacology and medication management in the three universities. Among a total of 152 subjects, 82.9% were female and their mean age was 22.57 ± 1.55 years. According to the students, instructors had the weakest performance in the three items of teaching pharmacology and medication management based on the students' learning needs, teaching medication management through a patient-centered method and teaching pharmacology and medication management based on the course plan. The students' satisfaction regarding their own knowledge and skill of pharmacology and medication management was at medium level. Nursing students gave a relatively low score in several aspects of their instructors' performance regarding teaching pharmacology and medication management. It seems that many clinical nurse educators in the studied settings were incompetent especially in teaching pharmacology and medication management, while these are critical areas and need special attention.

Interleukin-21: updated review of Phase I and II clinical trials in metastatic renal cell carcinoma, metastatic melanoma and relapsed/refractory indolent non-Hodgkin's lymphoma.

PubMed

Hashmi, Mehmood H; Van Veldhuizen, Peter J

2010-05-01

In advanced renal cell cancer and malignant melanoma, the current FDA approved immune modulators, such as IL-2, are the only agents which provide a durable complete remission. These responses, however, occur in < 10% of treated patients and their applicability is limited to selected patients because of their toxicity. The identification of new immunotherapeutic agents with an improved response rate and toxicity profile would represent a significant advancement in the treatment of these malignancies. This is a comprehensive review of IL-21 including its pharmacology and current developmental status. A literature review was performed using all PubMed listed publications involving IL-21, including original research articles, reviews and abstracts. It also includes a review of current ongoing trials and information from the official product website. Recombinant IL-21 (rIL-21) is a new immune modulator currently undergoing Phase I and II testing. It is a cytokine with a four helix structure that has structural and sequence homology to IL-2 and -15, but also possesses many unique biological properties. In this review, we evaluate the development, pharmacologic properties, safety profile and current clinical efficacy of rIL-21. rIL-21 has an acceptable safety profile and encouraging single agent activity in early phase renal cell carcinoma and melanoma clinical trials.

Recommendations for the proper use of nonprescription cough suppressants and expectorants in solid-organ transplant recipients.

PubMed

Gabardi, Steven; Carter, Danielle; Martin, Spencer; Roberts, Keri

2011-03-01

To describe the pharmacology and safety of oral over-the-counter cough suppressants and expectorants and to present recommendations for the use of these agents in solid-organ transplant recipients based on the potential for adverse drug reactions or drug-disease interactions. Data from journal articles and other sources describing the pharmacology and safety of over-the-counter cough suppressants and expectorants, drug-drug interactions with immunosuppressive agents, and drug-disease state interactions are reviewed. Potential and documented drug-drug interactions between immunosuppressive agents and over-the-counter cough medications guaifenesin, dextromethorphan, diphenhydramine, and codeine were evaluated on the basis of pharmacokinetic and pharmacodynamic principles. Interactions between these cough medications and the physiological changes in the body following transplantation also were examined. Diphenhydramine requires additional monitoring when used to treat cough in transplant recipients owing to its anticholinergic properties and the potential for interactions with cyclosporine. Dextromethorphan can be used in most transplant recipients, although greater caution should be exercised if the patient has undergone liver transplant or has liver impairment. Guaifenesin can be used in transplant recipients but should be used with caution in patients receiving kidney or lung transplants and in patients with renal impairment. Codeine combined with guaifenesin is another option for cough and can be used in most transplant patients although those with reduced renal function should be monitored carefully for adverse events.

Exploring Opioid-Sparing Multimodal Analgesia Options in Trauma: A Nursing Perspective

PubMed Central

Lyons, Mary; Montgomery, Robert; Quinlan-Colwell, Ann

2016-01-01

Challenges with opioids (e.g., adverse events, misuse and abuse with long-term administration) have led to a renewed emphasis on opioid-sparing multimodal management of trauma pain. To assess the extent to which currently available evidence supports the efficacy and safety of various nonopioid analgesics and techniques to manage trauma pain, a literature search of recently published references was performed. Additional citations were included on the basis of authors' knowledge of the literature. Effective options for opioid-sparing analgesics include oral and intravenous (IV) acetaminophen; nonsteroidal anti-inflammatory drugs available via multiple routes; and anticonvulsants, which are especially effective for neuropathic pain associated with trauma. Intravenous routes (e.g., IV acetaminophen, IV ketorolac) may be associated with a faster onset of action than oral routes. Additional adjuvants for the treatment of trauma pain are muscle relaxants and alpha-2 adrenergic agonists. Ketamine and regional techniques play an important role in multimodal therapy but require medical and nursing support. Nonpharmacologic treatments (e.g., cryotherapy, distraction techniques, breathing and relaxation, acupuncture) supplement pharmacologic analgesics and can be safe and easy to implement. In conclusion, opioid-sparing multimodal analgesia addresses concerns associated with high doses of opioids, and many pharmacologic and nonpharmacologic options are available to implement this strategy. Nurses play key roles in comprehensive patient assessment; administration of patient-focused, opioid-sparing, multimodal analgesia in trauma; and monitoring for safety concerns. PMID:27828892

Exploring Opioid-Sparing Multimodal Analgesia Options in Trauma: A Nursing Perspective.

PubMed

Sullivan, Denise; Lyons, Mary; Montgomery, Robert; Quinlan-Colwell, Ann

Challenges with opioids (e.g., adverse events, misuse and abuse with long-term administration) have led to a renewed emphasis on opioid-sparing multimodal management of trauma pain. To assess the extent to which currently available evidence supports the efficacy and safety of various nonopioid analgesics and techniques to manage trauma pain, a literature search of recently published references was performed. Additional citations were included on the basis of authors' knowledge of the literature. Effective options for opioid-sparing analgesics include oral and intravenous (IV) acetaminophen; nonsteroidal anti-inflammatory drugs available via multiple routes; and anticonvulsants, which are especially effective for neuropathic pain associated with trauma. Intravenous routes (e.g., IV acetaminophen, IV ketorolac) may be associated with a faster onset of action than oral routes. Additional adjuvants for the treatment of trauma pain are muscle relaxants and alpha-2 adrenergic agonists. Ketamine and regional techniques play an important role in multimodal therapy but require medical and nursing support. Nonpharmacologic treatments (e.g., cryotherapy, distraction techniques, breathing and relaxation, acupuncture) supplement pharmacologic analgesics and can be safe and easy to implement. In conclusion, opioid-sparing multimodal analgesia addresses concerns associated with high doses of opioids, and many pharmacologic and nonpharmacologic options are available to implement this strategy. Nurses play key roles in comprehensive patient assessment; administration of patient-focused, opioid-sparing, multimodal analgesia in trauma; and monitoring for safety concerns.

Safety, Tolerability, and Antihypertensive Effect of SER100, an Opiate Receptor-Like 1 (ORL-1) Partial Agonist, in Patients With Isolated Systolic Hypertension.

PubMed

Kantola, Ilkka; Scheinin, Mika; Gulbrandsen, Trygve; Meland, Nils; Smerud, Knut T

2017-11-01

The purpose of the present trial was to evaluate safety, tolerability, and effect on systolic blood pressure (SBP) of SER100 in a small group of patients with isolated systolic hypertension (ISH) in treatment with at least 1 antihypertensive drug. Eligible patients were randomized to either SER100 (10 mg) or placebo in a crossover design, and 2 doses were given subcutaneously (SC), 8 hours apart, on 2 consecutive days. On all treatment days patients were monitored with an ambulatory blood pressure measurement device for 12 daytime hours. Seventeen patients completed treatment. There were no serious or severe adverse events. Relative to placebo SER100 induced an average reduction of SBP during the 2 treatment days of 7.0 mm Hg (P = 0.0032), whereas the average reduction of diastolic blood pressure (DBP) over the same period was 3.8 mm Hg (P = 0.0011). For patients with ISH, this short-term cross-over study of SC SER100 demonstrated an acceptable safety profile and consistent, significant lowering of SBP and DBP. As initial clinical proof of concept for a new class of drugs, a nociceptin agonist peptide, the results were encouraging and warrant further research. © 2016, The American College of Clinical Pharmacology.

From a Viewpoint of Clinical Settings: Pharmacoepidemiology as Reverse Translational Research (rTR).

PubMed

Kawakami, Junichi

2017-01-01

Clinical pharmacology and pharmacoepidemiology research may converge in practise. Pharmacoepidemiology is the study of pharmacotherapy and risk management in patient groups. For many drugs, adverse reaction(s) that were not seen and/or clarified during research and development stages have been reported in the real world. Pharmacoepidemiology can detect and verify adverse drug reactions as reverse translational research. Recently, development and effective use of medical information databases (MID) have been conducted in Japan and elsewhere for the purpose of post-marketing safety of drugs. The Ministry of Health, Labour and Welfare, Japan has been promoting the development of 10-million scale database in 10 hospitals and hospital groups as "the infrastructure project of medical information database (MID-NET)". This project enables estimation of the frequency of adverse reactions, the distinction between drug-induced reactions and basal health-condition changes, and usefulness verification of administrative measures of drug safety. However, because the database information is different from detailed medical records, construction of methodologies for the detection and evaluation of adverse reactions is required. We have been performing database research using medical information system in some hospitals to establish and demonstrate useful methods for post-marketing safety. In this symposium, we aim to discuss the possibility of reverse translational research from clinical settings and provide an introduction to our research.

Treatment of Post-Traumatic Stress Disorders with the Alpha-1 Adrenergic Antagonist Prazosin.

PubMed

Simon, Philippe Yves Rémy; Rousseau, Pierre-François

2017-03-01

The present review aims to assess the clinical efficacy and safety of the α-1-adrenergic antagonist prazosin as primary pharmacologic treatment for post-traumatic stress disorder (PTSD). A systematic review was performed using keywords (i.e., prazosin, α-1-adrenergic antagonist, α-1-blocker, post-traumatic stress disorder) in the databases PubMed/Medline (1966-May 2016), Embase (1966-May 2016), ScienceDirect (1823-May 2016), OvidSP (1946-May 2016) and Nature (1845-May 2016). To be considered for inclusion, studies had to test the efficacy of prazosin either alone or added to ongoing treatment in adults with PTSD, use validated tools to assess and monitor the disorders, allow comparisons on the basis of univariate analyses (i.e., p-values of t-tests and effect sizes) and list the identified adverse reactions. 12 studies were included: 5 randomized controlled trials, 4 open-label prospective trials and 3 retrospective file reviews. The evaluation concerned 276 patients exposed to civilian trauma (19%) or war trauma (81%). Prazosin significantly decreases trauma nightmares, avoidance, hypervigilance and improves patient status in all studies. No significant difference of blood pressure was observed at the end of trials. Beyond the methodological and clinical biases of these studies, the present review not only confirms the effectiveness and good tolerability of prazosin, but also suggests its possible use as primary pharmacologic treatment for PTSD. Uncertainties remain, however, regarding the prescription modalities and dosages.

Ethnopharmacological reports on anti-Buruli ulcer medicinal plants in three West African countries.

PubMed

Tsouh Fokou, Patrick Valere; Nyarko, Alexander Kwadwo; Appiah-Opong, Regina; Tchokouaha Yamthe, Lauve Rachel; Addo, Phyllis; Asante, Isaac K; Boyom, Fabrice Fekam

2015-08-22

Buruli ulcer (BU) is the third most common mycobacterial infection in the world, after tuberculosis and leprosy and has recently been recognized as an important emerging disease. This disease is common in West Africa where more than 99% of the burden is felt and where most affected people live in remote areas with traditional medicine as primary or only option. Reports indicate that the ethnopharmacological control approach of the disease in such settings has shown promise. However, no or very few compilations of traditional knowledge in using medicinal plants to treat BU have been attempted so far. This review aimed to record medicinal plants used traditionally against BU in three countries in West Africa: Ivory Coast, Ghana and Benin and for which ethnopharmacological knowledge supported by pharmacological investigations has been reported. The information recorded in this review will support further pharmacological research to develop appropriate drugs for a better BU control. A systematic review of the literature on ethnobotanical use and anti-BU activity of plants reported for BU treatment was performed. The approach consisted to search several resources, including Technical Reports, Books, Theses, Conference proceedings, web-based scientific databases such as publications on PubMed, Science direct, Springer, ACS, Scielo, PROTA, Google and Google scholar reporting ethnobotanical surveys and screening of natural products against Mycobacterium ulcerans. This study was limited to papers and documents published either in English or French reporting ethnopharmacological knowledge in BU treatment or pharmacological potency in vitro. This review covered the available literature up to December 2014. The majority of reports originated from the three most affected West African countries (Cote d'Ivoire, Ghana and Benin). Though, 98 plant species belonging to 48 families have been identified as having anti-BU use, many have received no or little attention. Most of the pharmacological studies were performed only on 54 species. To a lesser extent, ethnopharmacological knowledge was validated in vitro for only 13 species. Of those, seven species including Ricinus comminus, Cyperus cyperoides (cited as Mariscus alternifolius), Nicotiana tabacum, Mangifera indica, Solanum rugosum, Carica papaya, and Moringa oleifera demonstrated efficacy in hospitalised BU patients. Four isolated and characterized compounds were reported to have moderate bioactivity in vitro against M. ulcerans. This review compiles for the first time ethnopharmacologically useful plants against BU. The phamacological potential of 13 of them has been demonstrated in vitro and support BU evidence-based traditional medicines. In addition, 7 species showed activity in BU patients and have emerged as a promising source of the traditional medicine for treatment of BU. Yet, further safety and efficacy study should be initiated prior any approval as alternative therapy. Overall, a huge gap in knowledge appeared, suggesting further well-planned and detailed investigations of the in vitro, in vivo, and safety properties of the claimed anti-BU plants. Therefore, plants with medicinal potential should be scrutinized for biologically active compounds, using bioassay-guided fractionation approach to provide new insights to find novel therapeutics for BU control. Copyright © 2015. Published by Elsevier Ireland Ltd.

[Clinical-pharmacological aspects to accelerate the development process from the preclinical to the clinical phase/1st communication: The contribution of clinical pharmacology].

PubMed

Kuhlmann, Jochen

2004-01-01

To improve the transition from research to development a critical evaluation of the individual project by research and disease area teams is required to include input from pharmacology, toxicology, pharmacokinetics, galenics, clinical pharmacology, clinical as well as regulatory experts and marketing. Decisions on the individual development strategy should be made prior to the start of development and all projects should be reviewed at predefined stages throughout the product development life cycle. This ensures consistency of decision-making not only during the development of individual products but throughout the entire development pipeline. Studies in the exploratory stage of drug development should be designed for decision making in contrast to later clinical trials in the confirmatory stage that require power for proof-of-safety and proof-of-efficacy. The more thorough and profound studies have been carried out during this exploratory stage of drug development, the earlier a decision can be made on the continuation or discontinuation of further development, thus saving development time and money and assessing and considerably reducing the risk for the patients and increasing the success rate of the project in the later confirmatory effectiveness trial with an adequate number of subjects receiving the new therapy under typical conditions of use. Strategies which may be helpful to improve the quality of decisions in drug discovery and drug development are: discovery experiments should be done to critically evaluate the compound, the "killer" experiments should be done as early as possible, continuous effort on preclinical disease models is necessary to improve predictability of efficacy in patients ("humanized" research): genomic technology should be used to identify novel, disease-related targets and to characterise preclinical test systems, improvement of knowledge and experience concerning the relevance of new technologies for the clinical picture; genotyping of clinical trial patients to select patient groups which are likely to respond to treatment (pharmacogenomics), modelling and simulation of preclinical and clinical trials, integration of pharmacokinetic and pharmacodynamic principles into drug development, assessment of the interaction potential (CYP-450, trasporter proteins and others), increasing use of biomarker/surrogate marker for rapid clinical feedback, involvement of the target population as soon as possible, applying statistical data analysis techniques for proving effectiveness, co-operation with high quality centers. To reach this goal clinical pharmacology must be fully integrated in the whole process from the candidate selection to its positioning within the market.

Deferasirox for the treatment of chronic iron overload in transfusional hemosiderosis.

PubMed

Shashaty, George; Frankewich, Raymond; Chakraborti, Tamal; Choudary, Jasti; Al-Fayoumi, Suliman; Kacuba, Alice; Castillo, Sonia; Robie-Suh, Kathy; Rieves, Dwaine; Weiss, Karen; Pazdur, Richard

2006-12-01

This report describes the Food and Drug Administration's review of data and analyses leading to the approval of the oral iron chelator, deferasirox for the treatment of chronic iron overload due to transfusional hemosiderosis. The FDA reviewed findings of a controlled, open-label, randomized multicenter phase III study of deferasirox vs. deferoxamine in 586 patients with beta-thalessemia and transfusional hemosiderosis. The study results as well as the results of the FDA review of chemistry, preclinical pharmacology, and supportive studies are described. Following 48 weeks of treatment in the phase III study, patients' liver iron concentrations (a key endpoint variable) had decreased an average of 2.4 mg of iron (Fe)/g dry weight (dw) and 2.9 mg Fe/g dw in the deferasirox and deferoxamine groups, respectively, despite continued blood transfusions in both cohorts. Deferasirox was associated with serum creatinine increases in approximately a third of patients. Common adverse events included gastrointestinal symptoms and skin rash. Other data provided supportive evidence of deferasirox safety and efficacy. The FDA granted deferasirox accelerated approval on November 2, 2005, for use in treating chronic iron overload due to transfusional hemosiderosis in patients > or =2 years of age. The sponsor must obtain clinical data demonstrating the drug's long-term safety and effectiveness.

Comparison of multiple interventions for older adults with Alzheimer disease or mild cognitive impairment: A PRISMA-compliant network meta-analysis.

PubMed

Liang, Jing-Hong; Xu, Yong; Lin, Lu; Jia, Rui-Xia; Zhang, Hong-Bo; Hang, Lei

2018-05-01

The increasing prevalence of Alzheimer disease (AD) emphasizes the need for effective treatments. Both pharmacological therapies such as nutrition therapy (NT) and nonpharmacologic therapies including traditional treatment or personalized treatment (e.g., physical exercise, music therapy, computerized cognitive training) have been approved for the treatment of AD or mild cognitive impairment (MCI) in numerous areas. The aim of this study was to compare 4 types of interventions, physical exercise (PE), music therapy (MT), computerized cognitive training (CCT), and NT, in older adults with mild to moderate AD or MCI and identify the most effective intervention for their cognitive function. We used a system of search strategies to identify relevant studies and include randomized controlled trials (RCTs), placebo-controlled trials evaluating the efficacy and safety of 4 interventions in patients with AD or MCI. We updated the relevant studies which were published before March 2017 as a full-text article. Using Bayesian network meta-analysis (NMA), we ranked cognitive ability based objectively on Mini-Mental State Examination (MMSE), and assessed neuropsychiatric symptoms based on Neuropsychiatric Inventory (NPI). Pairwise and network meta-analyses were sequentially performed for efficacy and safety of intervention compared to control group through RCTs included. We included 17 RCTs. Fifteen trials (n = 1747) were pooled for cognition and no obvious heterogeneity was found (I = 21.7%, P = .212) in NMA, the mean difference (MD) of PE (MD = 2.1, confidence interval [CI]: 0.44-3.8) revealed that PE was significantly efficacious in the treatment group in terms of MMSE. Five trials (n = 660) assessed neuropsychiatric symptoms with an obvious heterogeneity (I = 61.6%, P = .034), the MD of CCT (MD = -7.7, CI: -14 to -2.4), revealing that CCT was significantly efficacious in NPI. As the first NMA comparing different interventions for AD and MCI, our study suggests that PE and CCT might have a significant improvement in cognition and neuropsychiatric symptoms respectively. Moreover, nonpharmacological therapies might be better than pharmacological therapies.

Helichrysum italicum: from traditional use to scientific data.

PubMed

Antunes Viegas, Daniel; Palmeira-de-Oliveira, Ana; Salgueiro, Lígia; Martinez-de-Oliveira, José; Palmeira-de-Oliveira, Rita

2014-01-01

Helichrysum italicum (Roth) G. Don fil. (family Asteraceae) has been used for its medicinal properties for a long time and, even nowadays, continues to play an important role in the traditional medicine of Mediterranean countries. Based on this traditional knowledge, its different pharmacological activities have been the focus of active research. This review aims to provide an overview of the current state of knowledge of the pharmacological activities of Helichrysum italicum, as well as its traditional uses, toxicity, drug interactions and safety. The selection of relevant data was made through a search using the keywords "Helichrysum italicum" and "H. italicum" in "Directory of Open Access Journals", "Google Scholar", "ISI Web of Knowledge", "PubMed", "ScienceDirect" and "Wiley Online Library". Information obtained in local and foreign books and other sources was also included. There are reports on the traditional use of Helichrysum italicum in European countries, particularly Italy, Spain, Portugal and Bosnia and Herzegovina. In these countries, its flowers and leaves are the most used parts in the treatment of health disorders such as allergies, colds, cough, skin, liver and gallbladder disorders, inflammation, infections and sleeplessness. In order to validate some of the traditional uses of Helichrysum italicum and highlight other potential applications for its extracts and isolated compounds, several scientific studies have been conducted in the last decades. In vitro studies characterized Helichrysum italicum as an antimicrobial and anti-inflammatory agent. Its flavonoids and terpenes were effective against bacteria (e.g. Staphylococcus aureus), its acetophenones, phloroglucinols and terpenoids displayed antifungal action against Candida albicans and its flavonoids and phloroglucinols inhibited HSV and HIV, respectively. Helichrysum italicum acetophenones, flavonoids and phloroglucinols demonstrated inhibitory action in different pathways of arachidonic acid metabolism and other pro-inflammatory mediators. Regarding Helichrysum italicum in vivo activity, the highlight goes to the anti-erythematous and photoprotective activities of its flavonoids, demonstrated both in animals and humans, and to the anti-inflammatory properties exhibited by its flavonoids, acetophenones and phloroglucinols, as seen in animal models. Concerning its safety and adverse effects, while Helichrysum italicum does not display significant levels of cytotoxicity or genotoxicity, it should be noticed that one of its flavonoids inhibited some CYP isoforms and a case has been reported of an allergic reaction to its extracts. Helichrysum italicum is a medicinal plant with promising pharmacological activities. However, most of its traditionally claimed applications are not yet scientifically proven. Clinical trials are needed to further confirm these data and promote Helichrysum italicum as an important tool in the treatment of several diseases. © 2013 Published by Elsevier Ireland Ltd.

Indiplon in the management of insomnia

PubMed Central

Lemon, Michael D; Strain, Joe D; Hegg, Annie M; Farver, Debra K

2009-01-01

Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine γ-aminobutyric acid (GABA) agonist studied for the treatment of insomnia. This article reviews the chemistry, pharmacology, clinical pharmacokinetics, drug interactions, clinical trials, safety, tolerability, contraindications, use in special populations, and dosing of indiplon. OVID, International Pharmaceutical Abstracts (IPA), and PubMed databases were searched (1966 to February 2009) for the keywords indiplon, NBI-34060, and insomnia. References of key articles were also reviewed to identify additional publications. Only English language articles were selected for review. Indiplon has been shown to have high affinity and selectivity for the GABAα1 receptor subunit associated with sedation. In clinical studies, indiplon has demonstrated efficacy in improving latency to sleep onset, latency to persistent sleep, total sleep time, wake time after sleep onset, number of awakenings after sleep onset, and overall sleep quality when compared to placebo. Indiplon has a favorable safety profile with limited rebound insomnia and no tolerance. Neurocrine Biosciences, Incorporated received an Approvable Letter from the United States Food and Drug Administration in December 2007 for the indiplon IR 5 mg and 10 mg capsules based on meeting three additional requirements. At the time of this writing, indiplon remains unapproved. PMID:19920929

Indiplon in the management of insomnia.

PubMed

Lemon, Michael D; Strain, Joe D; Hegg, Annie M; Farver, Debra K

2009-09-21

Indiplon is a novel pyrazolopyrimidine, nonbenzodiazepine gamma-aminobutyric acid (GABA) agonist studied for the treatment of insomnia. This article reviews the chemistry, pharmacology, clinical pharmacokinetics, drug interactions, clinical trials, safety, tolerability, contraindications, use in special populations, and dosing of indiplon. OVID, International Pharmaceutical Abstracts (IPA), and PubMed databases were searched (1966 to February 2009) for the keywords indiplon, NBI-34060, and insomnia. References of key articles were also reviewed to identify additional publications. Only English language articles were selected for review. Indiplon has been shown to have high affinity and selectivity for the GABAalpha(1) receptor subunit associated with sedation. In clinical studies, indiplon has demonstrated efficacy in improving latency to sleep onset, latency to persistent sleep, total sleep time, wake time after sleep onset, number of awakenings after sleep onset, and overall sleep quality when compared to placebo. Indiplon has a favorable safety profile with limited rebound insomnia and no tolerance. Neurocrine Biosciences, Incorporated received an Approvable Letter from the United States Food and Drug Administration in December 2007 for the indiplon IR 5 mg and 10 mg capsules based on meeting three additional requirements. At the time of this writing, indiplon remains unapproved.

Evaluation of Stability and In Vitro Security of Nanoemulsions Containing Eucalyptus globulus Oil

PubMed Central

Quatrin, Priscilla Maciel; Sagrillo, Michele Rorato; Nascimento, Kátia

2017-01-01

Essential oil of Eucalyptus globulus presents several pharmacological properties. However, their therapeutic efficacy may be affected by limitations due to several conditions, rendering it difficult to obtain stable and effective pharmaceutical formulations. The use of nanotechnology is an alternative to improve their characteristics aiming to ensure their stability and effectiveness. Furthermore, studies about the possible toxic effects of nanostructures are necessary to evaluate safety when the formulation comes into contact with human cells. Hence, in this paper, we evaluate for the first time the stability and in vitro cytogenotoxicity of nanoemulsions containing Eucalyptus globulus in peripheral blood mononuclear cells. As a result, the stability study found that the best condition for storage up to 90 days was refrigeration (4°C); it was the condition that best preserved the nanometric features. The content of the major compounds of oil was maintained after nanoencapsulation and preserved over time. In tests to evaluate the safety of this formulation, we can conclude that, at a low concentration (approximately 0.1%), Eucalyptus globulus nanoemulsion did not cause toxicity in peripheral blood mononuclear cells and also showed a protective effect in cells against possible damage when compared to oil in free form. PMID:28691021

Enteric-coated mycophenolate sodium.

PubMed

Gabardi, Steven; Tran, Jennifer L; Clarkson, Michael R

2003-11-01

To review the pharmacology, pharmacokinetics, efficacy, and safety of mycophenolate sodium. Primary literature was obtained via a MEDLINE search (1966-June 2003). Abstracts were obtained from the manufacturer and included in the analysis. All studies and abstracts evaluating mycophenolate sodium in solid organ transplantation were considered for inclusion. English-language studies and abstracts were selected for inclusion, but were limited to those consisting of human subjects. Mycophenolate sodium, a mycophenolic acid prodrug, is an inhibitor of T-lymphocyte proliferation. Mycophenolic acid reduces the incidence of acute rejection in renal transplantation. Mycophenolate sodium is enteric coated and has been suggested as a potential method to reduce the gastrointestinal adverse events seen with mycophenolate mofetil. Both mycophenolate mofetil and mycophenolate sodium have been shown to be therapeutically equivalent at decreasing the incidence of allograft rejection and loss. The frequency of adverse events is similar between both compounds, with the most common events being diarrhea and leukopenia. Mycophenolate sodium is effective in preventing acute rejection in renal transplant recipients. At doses of 720 mg twice daily, the efficacy and safety profiles are similar to those of mycophenolate mofetil 1000 mg twice daily. Mycophenolate sodium has been approved in Switzerland; approval in the US is pending.

Evidence-based treatment of atopic dermatitis with topical moisturizers.

PubMed

Micali, Giuseppe; Paternò, Valentina; Cannarella, Rossella; Dinotta, Franco; Lacarrubba, Francesco

2018-06-01

Skin barrier restoration represents the mainstay of the treatment of atopic dermatitis and the use of moisturizers is recommended by several international guidelines. The aim of the study was to investigate through an evidence-based medicine analysis the effectiveness and safety of different moisturizing products available for a non-pharmacological treatment of atopic dermatitis. A total of 92 randomized controlled trials (RCTs) have been identified and analyzed. The results confirm the presence of a reasonable number of studies highlighting moisturizers safety and effectiveness in the treatment of atopic dermatitis by improving disease severity, increasing the time of relapse and reducing the time of flares. Moisturizers containing urea, glycerin or glycyrrhetinic acid seem to show the greater evidence of efficacy being supported by more clinical trials. Among the existing moisturizers, those containing a single agent generally work although the heterogeneity of RCTs does not allow reaching more definitive conclusions. Moisturizers made of a mixture of substances seem to be more effective thanks to the presence of different active substances that may exert a synergistic effect. A meta-analysis of 4 RCTs confirms the efficacy of a medical device containing glycyrrhetinic acid, hyaluronic acid, shea butter, telmesteine, and vitis vinifera in the treatment of atopic dermatitis.

Efficacy, pharmacokinetic and pharmacodynamic profile of ceftolozane + tazobactam in the treatment of complicated urinary tract infections.

PubMed

Wagenlehner, Florian M; Alidjanov, Jakhongir F

2016-08-01

Urinary tract infections (UTIs) are the second most common nosocomially acquired infections, responsible for approximately 21% of healthcare-associated pyelonephritis and 10.5% of urosepsis. Worldwide trends of increasing resistance resulted in the urgent need for novel antimicrobials that would be active against bacterial resistance mechanisms as an alternative to carbapenems, which are considered last resort antibiotics. The current review is based on a Medline search of published English language literature and contains summary information regarding the evaluation of pharmacologic properties, efficacy, safety and activity of ceftolozane+tazobactam against common bacterial resistance mechanisms. In vivo and vitro studies demonstrated high activity of ceftolozane+tazobactam in the combination of 2:1 against a variety of uropathogens, including ESBL-producers. Phase II and Phase III studies performed in patients with complicated UTIs showed good tolerability and safety of ceftolozane+tazobactam when prescribed intravenously 1.5 g every 8 h for 7 days and at least non-inferiority to a high dose (750 mg) of levofloxacin. The pharmacokinetics of ceftolozane+tazobactam makes it a worthy alternative to carbapenems in cases of complicated UTIs, also caused by multidrug resistant uropathogens.

Management of beta-thalassemia-associated osteoporosis.

PubMed

Giusti, Andrea; Pinto, Valeria; Forni, Gian Luca; Pilotto, Alberto

2016-03-01

Beta-Thalassemia-associated osteoporosis is a multifactorial and complex condition. Different acquired and genetic factors are involved in its pathogenesis. These factors produce an imbalance in bone remodeling by inhibiting osteoblast activity and increasing osteoclast function, leading to bone loss and increased fracture risk. The management of patients presenting with thalassemia-associated osteoporosis should consist of the implementation of general measures and the prescription of a specific pharmacological agent, with the aim of reducing fracture risk and preventing disability and deterioration of quality of life. General measures include control of anemia, adequate chelation therapy, healthy nutrition and lifestyle, regular exercise, adequate management of comorbid conditions, hormone replacement therapy in patients with hypogonadism, and vitamin D supplementation/therapy. Among the pharmacological agents currently available for the management of osteoporosis in postmenopausal women and men, bisphosphonates have been shown to improve bone mineral density, to reduce bone turnover, and to decrease bone/back pain in patients with thalassemia-associated osteoporosis, with a good profile of safety and tolerability. On the other hand, there are limited experiences with other pharmacological agents (e.g., denosumab or teriparatide). The complexity of this condition presents diagnostic and therapeutic challenges and underscores the importance of a comprehensive and multidisciplinary approach. © 2016 New York Academy of Sciences.

Pharmacological and Toxicological Profile of Harmane-β-Carboline Alkaloid: Friend or Foe.

PubMed

Khan, Haroon; Patel, Seema; Kamal, Mohammad A

2017-01-01

The plant secondary metabolites have an outstanding therapeutic potential and success over the years. In fact, it is the foundation of numerous clinically used drugs. Similarly, these is a general perception that these products are inherent safety. However, such products might have toxic/unwanted lethal effects therefore, along with biological relevance, toxicological evaluation is equally important for clinical applications. Therefore, harmane- β-carboline alkaloid was investigated for both therapeutic and toxicological potential. The literature related to the therapeutic/toxicological effects of the alkaloid was searched using various scientific data bases including Google, ScienceDirect, PubMed, SpringerLink, ASC. The peer reviewed articles were only selected. The harmane-β-carboline alkaloid has shown several pharmacological activities such as antianxiety, antidepressant, antiplatelet, antidiabetic, acetylcholinesterase and myeloperoxidase inhibition, antioxidant, antiparasitic, hypotensive, morphine withdrawal syndrome alleviation, and antinociceptive effects. On the other hand, it exhibited tremorogenic effect, for a symptom of Parkinson's disease. Adverse effect of the alkaloid on learning and memory have also been observed. All together, it is, concluded in this review that harmane elicited marked pharmacological effects but simultaneously, it possessed some serious side effects that could be the primary hurdle in the way of its clinical testing. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Advancements in drug development for diarrhea-predominant irritable bowel syndrome.

PubMed

Dothel, Giovanni; Barbaro, Maria Raffaella; Raschi, Emanuel; Barbara, Giovanni; De Ponti, Fabrizio

2018-03-01

Diarrhea-predominant irritable bowel syndrome (IBS-D) is a common disorder characterized by a complex pathophysiology hampering optimal targeted drug development. Recent advances in our understanding of key underlying mechanisms prompted novel therapeutics including novel pharmacological approaches. Areas covered: This review summarizes the latest advancements in the pipeline of IBS-D drugs focusing on new pharmacological targets, efficacy and safety of medicinal products considering the recent harmonization of regulatory requirements by the FDA and the EMA. Expert opinion: The new 5-HT 3 receptor antagonist ramosetron appears a promising therapeutic approach devoid of significant adverse events, although it is presently unavailable in Western countries, most likely because of the precautionary approach taken by regulatory agencies with this drug class. New pharmacological concepts on full agonists/antagonists, mixed-receptor activity and novel drug targets may streamline the present drug pipeline along with the adherence on new regulatory guidelines on outcome measures. Eluxadoline can be taken as an example of this paradigm shift. It has now been granted marketing authorization for IBS-D on both sides of the Atlantic, but it is still considered as a second-line agent by the NICE. There is still much work to be done to fully cover clinical needs of patients with IBS-D.

[Pharmacological Basis for Therapeutics. Pharmacological Analysis of Summary of Product Characteristics (SPC) for Physicians].

PubMed

Lechat, Philippe

2015-01-01

The summary of product characteristics, the SPC, is the major annex document of Marketing Authorisation (MA) dossier for a medicine. This document is the reference document for health care professionnals since it contains all necessary and opposable information for its therapeutic use. The SPC is initially submitted by the MA applicant and deeply revised in details by regulatory authorities, the national agencies for national MA, and the European Medicine Agency (EMA) for the european centralized procedures. The SPC presents with 12 sections each one being divided into several paragraphs. Sections 1-3 present the name, dosage, qualitative and quantitative composition, the pharmaceutical form of the medicine. Section 4 contains all the clinical particulars: Therapeutic indications, posology and methods of administration, contra-indications, special warnings and precautions for use, interactions, impact on fertility, contraception, pregnancy, lactation, effects on ability to drive and use machines, undesirable effects and risk associated with overdose. Section 5 describes pharmacological properties (pharmacodynamics and pharmacokinetics) and preclinical safety data. Section 6 describes the pharmaceutical particulars: excipients, incompatibilities, shelf live, nature and content of container, special precautions for disposal. Sections 7-10 are administrative ones (date of MA, MA holder), sections 11 and 12 are specific to radiopharmaceuticals (dosimetry and modalities of preparation). SPC is available free of charge on national regulatory agency websites and on EMA website. Sections of SPC finally have to be considered as the pharmacological basis of therapeutic use for each medicine. © 2015 Société Française de Pharmacologie et de Thérapeutique.

Pharmacokinetic interactions and safety evaluations of coadministered tafenoquine and chloroquine in healthy subjects.

PubMed

Miller, Ann K; Harrell, Emma; Ye, Li; Baptiste-Brown, Sharon; Kleim, Jőrg-Peter; Ohrt, Colin; Duparc, Stephan; Möhrle, Jörg J; Webster, Alison; Stinnett, Sandra; Hughes, Arlene; Griffith, Sandy; Beelen, Andrew P

2013-12-01

The long-acting 8-aminoquinoline tafenoquine (TQ) coadministered with chloroquine (CQ) may radically cure Plasmodium vivax malaria. Coadministration therapy was evaluated for a pharmacokinetic interaction and for pharmacodynamic, safety and tolerability characteristics. Healthy subjects, 18-55 years old, without documented glucose-6-phosphate dehydrogenase deficiency, received CQ alone (days 1-2, 600 mg; and day 3, 300 mg), TQ alone (days 2 and 3, 450 mg) or coadministration therapy (day 1, CQ 600 mg; day 2, CQ 600 mg + TQ 450 mg; and day 3, CQ 300 mg + TQ 450 mg) in a randomized, double-blind, parallel-group study. Blood samples for pharmacokinetic and pharmacodynamic analyses and safety data, including electrocardiograms, were collected for 56 days. The coadministration of CQ + TQ had no effect on TQ AUC0-t , AUC0-∞ , Tmax or t1/2 . The 90% confidence intervals of CQ + TQ vs. TQ for AUC0-t , AUC0-∞ and t1/2 indicated no drug interaction. On day 2 of CQ + TQ coadministration, TQ Cmax and AUC0-24 increased by 38% (90% confidence interval 1.27, 1.64) and 24% (90% confidence interval 1.04, 1.46), respectively. The pharmacokinetics of CQ and its primary metabolite desethylchloroquine were not affected by TQ. Coadministration had no clinically significant effect on QT intervals and was well tolerated. No clinically significant safety or pharmacokinetic/pharmacodynamic interactions were observed with coadministered CQ and TQ in healthy subjects. © 2013 The British Pharmacological Society.

Long-term effectiveness of ranibizumab for age-related macular degeneration and diabetic macular edema

PubMed Central

Fong, Angie HC; Lai, Timothy YY

2013-01-01

Neovascular age-related macular degeneration (AMD) and diabetic macular edema (DME) are major causes of visual impairment in the elderly population worldwide. With the aging population, the prevalence of neovascular AMD and DME has increased substantially over the recent years. Vascular endothelial growth factor (VEGF) has been implicated as playing an important role in the pathogenesis of both neovascular AMD and DME. Since its introduction in 2006, ranibizumab, a recombinant, humanized, monoclonal antibody fragment against all isoforms of VEGF-A, has revolutionized the treatment of neovascular AMD and DME. The efficacy and safety of ranibizumab in neovascular AMD has been demonstrated in the ANCHOR and MARINA trials. Further studies including the PIER, PrONTO, and SUSTAIN trials have also evaluated the optimal dosing regimen of ranibizumab in neovascular AMD. The CATT and IVAN trials compared the safety and efficacy of ranibizumab with off-label use of bevacizumab. Studies such as SUSTAIN and HORIZON have shown that ranibizumab has a good safety profile and is well tolerated for over 4 years with very few serious ocular and systemic adverse events. For DME, Phase II RESOLVE study and Phase III RISE and RIDE studies have demonstrated superiority of ranibizumab treatment in improving vision over placebo controls. Phase II READ and Phase III RESOLVE and REVEAL studies have shown that ranibizumab is more effective both as monotherapy and in combination with laser compared with laser monotherapy. The 3-year results from the DRCRnet protocol I study found that ranibizumab with deferred laser resulted in better long-term visual outcome compared with ranibizumab with prompt laser. This review summarizes various important clinical trials on the long-term efficacy and safety of ranibizumab in the treatment of neovascular AMD and DME. The pharmacological properties of ranibizumab, its cost effectiveness, and impact on quality of life will also be discussed. PMID:23766636

Ayurvedic Medicine for the Treatment of Dementia: Mechanistic Aspects

PubMed Central

Farooqui, Akhlaq A.; Farooqui, Tahira; Madan, Anil; Ong, Jolin Hwee-Jing

2018-01-01

Ayurvedic medicine is a personalized system of traditional medicine native to India and the Indian subcontinent. It is based on a holistic view of treatment which promotes and supports equilibrium in different aspects of human life: the body, mind, and soul. Popular Ayurvedic medicinal plants and formulations that are used to slow down brain aging and enhance memory include Ashwagandha (Withania somnifera), Turmeric (Curcuma longa), Brahmi (Bacopa monnieri), Shankhpushpi (Convolvulus pluricaulis, Evolvulus alsinoides, and other species), gotu kola (Centella asiatica), and guggulu (Commiphora mukul and related species) and a formulation known as Brāhmī Ghṛita, containing Brahmi, Vacā (Acorus calamus), Kuṣṭha (Saussurea lappa), Shankhpushpi, and Purāṇa Ghṛita (old clarified butter/old ghee). The rationale for the utilization of Ayurvedic medicinal plants has depended mostly on traditional usage, with little scientific data on signal transduction processes, efficacy, and safety. However, in recent years, pharmacological and toxicological studies have begun to be published and receive attention from scientists for verification of their claimed pharmacological and therapeutic effects. The purpose of this review is to outline the molecular mechanisms, signal transduction processes, and sites of action of some Ayurvedic medicinal plants. It is hoped that this description can be further explored with modern scientific methods, to reveal new therapeutic leads and jump-start more studies on the use of Ayurvedic medicine for prevention and treatment of dementia. PMID:29861767

A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831)

PubMed Central

Kean, James D.; Kaufman, Jordy; Lomas, Justine; Goh, Antionette; White, David; Simpson, David; Scholey, Andrew; Singh, Hemant; Sarris, Jerome; Zangara, Andrea; Stough, Con

2015-01-01

Clinical diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) and the use of prescription medications for its treatment have increased in recent years. Current treatments may involve the administration of amphetamine-type substances, a treatment path many parents are apprehensive to take. Therefore, alternative pharmacological treatments are required. Few nutritional or pharmacological alternatives that reduce ADHD associated symptoms (hyperactivity and inattention) have been subjected to rigorous clinical trials. Bacopa monnieri is a perennial creeping herb. CDRI 08 is a special extract of Bacopa monnieri which has been subjected to hundreds of scientific studies and has been shown in human randomized controlled trials (RCTs) to improve memory, attention, and mood. It is hypothesised that chronic administration of CDRI 08 will improve attention, concentration and behaviour in children with high levels of hyperactivity and/or inattention. This paper reports the protocol for the first 16-week, randomized, placebo-controlled, double-blind, parallel groups trial examining the efficacy and safety of CDRI 08 in male children aged 6–14 years with high levels of inattention and hyperactivity. The primary outcome variable will be the level of hyperactivity and inattention measured by the Conners’ Parent Rating Scale (CPRS). Secondary outcome variables include cognition, mood, sleep, and EEG. Trial registration: Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000827831. PMID:26633481

Ayurvedic Medicine for the Treatment of Dementia: Mechanistic Aspects.

PubMed

Farooqui, Akhlaq A; Farooqui, Tahira; Madan, Anil; Ong, Jolin Hwee-Jing; Ong, Wei-Yi

2018-01-01

Ayurvedic medicine is a personalized system of traditional medicine native to India and the Indian subcontinent. It is based on a holistic view of treatment which promotes and supports equilibrium in different aspects of human life: the body, mind, and soul. Popular Ayurvedic medicinal plants and formulations that are used to slow down brain aging and enhance memory include Ashwagandha (Withania somnifera) , Turmeric (Curcuma longa) , Brahmi (Bacopa monnieri) , Shankhpushpi ( Convolvulus pluricaulis, Evolvulus alsinoides , and other species), gotu kola (Centella asiatica) , and guggulu ( Commiphora mukul and related species) and a formulation known as Brāhmī Gh ṛ ita, containing Brahmi, Vacā (Acorus calamus) , Ku ṣṭ ha (Saussurea lappa) , Shankhpushpi, and Purāṇa Gh ṛ ita (old clarified butter/old ghee). The rationale for the utilization of Ayurvedic medicinal plants has depended mostly on traditional usage, with little scientific data on signal transduction processes, efficacy, and safety. However, in recent years, pharmacological and toxicological studies have begun to be published and receive attention from scientists for verification of their claimed pharmacological and therapeutic effects. The purpose of this review is to outline the molecular mechanisms, signal transduction processes, and sites of action of some Ayurvedic medicinal plants. It is hoped that this description can be further explored with modern scientific methods, to reveal new therapeutic leads and jump-start more studies on the use of Ayurvedic medicine for prevention and treatment of dementia.

A Randomized Controlled Trial Investigating the Effects of a Special Extract of Bacopa monnieri (CDRI 08) on Hyperactivity and Inattention in Male Children and Adolescents: BACHI Study Protocol (ANZCTRN12612000827831).

PubMed

Kean, James D; Kaufman, Jordy; Lomas, Justine; Goh, Antionette; White, David; Simpson, David; Scholey, Andrew; Singh, Hemant; Sarris, Jerome; Zangara, Andrea; Stough, Con

2015-12-02

Clinical diagnoses of Attention Deficit Hyperactivity Disorder (ADHD) and the use of prescription medications for its treatment have increased in recent years. Current treatments may involve the administration of amphetamine-type substances, a treatment path many parents are apprehensive to take. Therefore, alternative pharmacological treatments are required. Few nutritional or pharmacological alternatives that reduce ADHD associated symptoms (hyperactivity and inattention) have been subjected to rigorous clinical trials. Bacopa monnieri is a perennial creeping herb. CDRI 08 is a special extract of Bacopa monnieri which has been subjected to hundreds of scientific studies and has been shown in human randomized controlled trials (RCTs) to improve memory, attention, and mood. It is hypothesised that chronic administration of CDRI 08 will improve attention, concentration and behaviour in children with high levels of hyperactivity and/or inattention. This paper reports the protocol for the first 16-week, randomized, placebo-controlled, double-blind, parallel groups trial examining the efficacy and safety of CDRI 08 in male children aged 6-14 years with high levels of inattention and hyperactivity. The primary outcome variable will be the level of hyperactivity and inattention measured by the Conners' Parent Rating Scale (CPRS). Secondary outcome variables include cognition, mood, sleep, and EEG. Australia and New Zealand Clinical Trials Register (ANZCTR): ACTRN12612000827831.

Aerospace Medicine and Biology: A Continuing Bibliography With Indexes

NASA Technical Reports Server (NTRS)

1997-01-01

This issue of Aerospace Medicine and Biology, A Continuing Bibliography with Indexes NASA SP-7O11 lists reports, articles, and other documents recently announced in the NASA STI Database. In its subject coverage, Aerospace Medicine and Biology concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Biological activities and medicinal properties of Gokhru (Pedalium murex L.)

PubMed Central

Rajashekar, V; Rao, E Upender; P, Srinivas

2012-01-01

Bada Gokhru (Pedalium murex L.) is perhaps the most useful traditional medicinal plant in India. Each part of the neem tree has some medicinal property and is thus commercially exploitable. During the last five decades, apart from the chemistry of the Pedalium murex compounds, considerable progress has been achieved regarding the biological activity and medicinal applications of this plant. It is now considered as a valuable source of unique natural products for development of medicines against various diseases and also for the development of industrial products. This review gives a bird's eye view mainly on the biological activities of some of this compounds isolated, pharmacological actions of the extracts, clinical studies and plausible medicinal applications of gokharu along with their safety evaluation. PMID:23569975

Aerospace Medicine and Biology: A Continuing Bibliography. Supplement 475

NASA Technical Reports Server (NTRS)

1998-01-01

This supplemental issue of Aerospace Medicine and Biology, A Continuing Bibliography with Indexes lists reports, articles, and other documents recently announced in the NASA STI Database. In its subject coverage, Aerospace Medicine and Biology concentrates on the biological, physiological, psychological, and environmental effects to which humans are subjected during and following simulated or actual flight in the Earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Applied research receives the most emphasis, but references to fundamental studies and theoretical principles related to experimental development also qualify for inclusion.

Bitter melon (Momordica charantia): a review of efficacy and safety.

PubMed

Basch, Ethan; Gabardi, Steven; Ulbricht, Catherine

2003-02-15

The pharmacology, clinical efficacy, adverse effects, drug interactions, and place in therapy of bitter melon are described. Bitter melon (Momordica charantia) is an alternative therapy that has primarily been used for lowering blood glucose levels in patients with diabetes mellitus. Components of bitter melon extract appear to have structural similarities to animal insulin. Antiviral and antineoplastic activities have also been reported in vitro. Four clinical trials found bitter melon juice, fruit, and dried powder to have a moderate hypoglycemic effect. These studies were small and were not randomized or double-blind, however. Reported adverse effects of bitter melon include hypoglycemic coma and convulsions in children, reduced fertility in mice, a favism-like syndrome, increases in gamma-glutamyltransferase and alkaline phosphatase levels in animals, and headaches. Bitter melon may have additive effects when taken with other glucose-lowering agents. Adequately powered, randomized, placebo-controlled trials are needed to properly assess safety and efficacy before bitter melon can be routinely recommended. Bitter melon may have hypoglycemic effects, but data are not sufficient to recommend its use in the absence of careful supervision and monitoring.

Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe?

PubMed

Kruse, David W

2008-12-01

Osteoarthritis of the hip is a significant source of morbidity in the elderly. Treatment guidelines are available for the management of hip osteoarthritis, but these do not address the application of intraarticular corticosteroid injection. The intraarticular injection of corticosteroid is used in the management of other large joint osteoarthritic diseases and is well studied in the knee, however, this data cannot be used to make sound clinical decisions regarding its use for hip osteoarthritis. There are also concerns regarding the safety of this modality. Review of the published literature reveals that there are eight trials examining the efficacy of intraarticular corticosteroid injection for hip osteoarthritis and of these only four are randomized controlled trials. In general, the available literature demonstrates a short-term reduction of pain with corticosteroid injection and is indicated for patients refractory to non-pharmacologic or analgesic and NSAID therapy. The use of radiologic-guidance is recommended and, with proper sterile technique, the risk of adverse outcomes is very low. Future randomized controlled trials are needed to further examine the efficacy and safety of intraarticular corticosteroid injection for hip osteoarthritis.

Hibiscus sabdariffa L., roselle calyx, from ethnobotany to pharmacology.

PubMed

Carvajal-Zarrabal, Octavio; Barradas-Dermitz, Dulce María; Orta-Flores, Zaida; Hayward-Jones, Patricia Margaret; Nolasco-Hipólito, Cirilo; Aguilar-Uscanga, M Guadalupe; Miranda-Medina, Anilú; Bujang, Kopli Bin

2012-01-01

Using MEDLINE and SCOPUS databases, a review of the literature from the pioneering study of 1991 until 2010 was performed on the effects on biological models of Hibiscus sabdariffa L. roselle calyx, its extracts mainly in polar solvents, or pure components found in extracts, as well as their possible relationship to these effects. Three relevant effects on lipid metabolism, antihypertensive activity, and apoptosis were observed. Our chronological review of the studies mentioned in the literature provides another opportunity to see how humans compile scientific knowledge of a chemical structure-physiological activity relationship starting from an ethnobotanical-ethnopharmagognosy contribution. The chemical components that are the main active principles in the physiological activities of Hibiscus sabdariffa L. calyx are anthocyanins and polyphenols (protocatechuic acid and quercetin). Advances have also been made in the elucidation of action mechanisms. Additionally, it has become clear that the lack of standardization in terms of chemical components of the material arising from Hibiscus sabdariffa L. used in testing on biological models imposes limits on the possibility of carrying out comparative analyses between studies. Fortunately, more recent studies are overcoming this obstacle by reporting component concentrations of assumed active principles; however, complete analysis of the extract, if this is to be considered as a therapeutic agent, is not commonly reported in the aforesaid studies. If one of the eventual scenarios for Hibiscus sabdariffa L. calyx is as a therapeutic agent in communities with economic limitations, then studies of a pharmacological nature should guarantee the effectiveness, safety, and tolerability of this material, which is widely accepted to be associated with chemical complexity, thus making this knowledge necessary.

Hibiscus sabdariffa L., roselle calyx, from ethnobotany to pharmacology

PubMed Central

Carvajal-Zarrabal, Octavio; Barradas-Dermitz, Dulce María; Orta-Flores, Zaida; Hayward-Jones, Patricia Margaret; Nolasco-Hipólito, Cirilo; Aguilar-Uscanga, M Guadalupe; Miranda-Medina, Anilú; Bujang, Kopli Bin

2012-01-01

Using MEDLINE and SCOPUS databases, a review of the literature from the pioneering study of 1991 until 2010 was performed on the effects on biological models of Hibiscus sabdariffa L. roselle calyx, its extracts mainly in polar solvents, or pure components found in extracts, as well as their possible relationship to these effects. Three relevant effects on lipid metabolism, antihypertensive activity, and apoptosis were observed. Our chronological review of the studies mentioned in the literature provides another opportunity to see how humans compile scientific knowledge of a chemical structure–physiological activity relationship starting from an ethnobotanical–ethnopharmagognosy contribution. The chemical components that are the main active principles in the physiological activities of Hibiscus sabdariffa L. calyx are anthocyanins and polyphenols (protocatechuic acid and quercetin). Advances have also been made in the elucidation of action mechanisms. Additionally, it has become clear that the lack of standardization in terms of chemical components of the material arising from Hibiscus sabdariffa L. used in testing on biological models imposes limits on the possibility of carrying out comparative analyses between studies. Fortunately, more recent studies are overcoming this obstacle by reporting component concentrations of assumed active principles; however, complete analysis of the extract, if this is to be considered as a therapeutic agent, is not commonly reported in the aforesaid studies. If one of the eventual scenarios for Hibiscus sabdariffa L. calyx is as a therapeutic agent in communities with economic limitations, then studies of a pharmacological nature should guarantee the effectiveness, safety, and tolerability of this material, which is widely accepted to be associated with chemical complexity, thus making this knowledge necessary. PMID:27186114

Weighing the potential effectiveness of various treatments for sleep bruxism.

PubMed

Huynh, Nelly; Manzini, Christiane; Rompré, Pierre H; Lavigne, Gilles J

2007-10-01

Sleep bruxism may lead to a variety of problems, but its pathophysiology has not been completely elucidated. As such, there is no definitive treatment, but certain preventive measures and/or drugs may be used in acute cases, particularly those involving pain. This article is intended to guide clinician scientists to the treatment most appropriate for future clinical studies. To determine the best current treatment, 2 measures were used to compare the results of 10 clinical studies on sleep bruxism, 3 involving oral devices and 7 involving pharmacologic therapy. The first measure, the number needed to treat (NNT), allows several randomized clinical studies to be compared and a general conclusion to be drawn. The second measure, effect size, allows evaluation of the impact of treatment relative to a placebo using different studies of similar design. Taking into account the NNT, the effect size and the power of each study, it can be concluded that the following treatments reduce sleep bruxism: mandibular advancement device, clonidine and occlusal splint. However, the first 2 of these have been linked to adverse effects. The occlusal splint is therefore the treatment of choice, as it reduces grinding noise and protects the teeth from premature wear with no reported adverse effects. The NNT could not be calculated for an alternative pharmacologic treatment, short-term clonazepam therapy, which had a large effect size and reduced the average bruxism index. However, the risk of dependency limits its use over long periods. Assessment of efficacy and safety of the most promising treatments will require studies with larger sample sizes over longer periods.

Safety of nicergoline as an agent for management of cognitive function disorders.

PubMed

Saletu, Bernd; Garg, Amit; Shoeb, Ahsan

2014-01-01

Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency's (EMEA's) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders.

Safety of Nicergoline as an Agent for Management of Cognitive Function Disorders

PubMed Central

2014-01-01

Nicergoline is a semisynthetic ergot derivative and has a selective alpha-1A adrenergic receptor blocking property and also other additional mechanisms of actions, both in the brain and in the periphery. It is in clinical use for over three decades in over fifty countries for conditions such as cerebral infarction, acute and chronic peripheral circulation disorders, vascular dementia, and Alzheimer's disease and has been found to be beneficial in a variety of other conditions. However, concerns about its safety have been raised, especially after the European medicines agency's (EMEA's) restriction in the use of all ergot derivatives including nicergoline. But, most of the available literature and data suggest that the adverse events with nicergoline are mild and transient. Further, none of the available treatment options for cognitive disorders afford definitive resolution of symptoms. In this backdrop, we discuss the pharmacology of nicergoline with special emphasis on the safety of this compound, especially when used in patients suffering from cognitive function disorders. PMID:25243157

Sedatives for opiate withdrawal in newborn infants.

PubMed

Osborn, David A; Jeffery, Heather E; Cole, Michael J

2010-10-06

Neonatal abstinence syndrome (NAS) due to opiate withdrawal may result in disruption of the mother-infant relationship, sleep-wake abnormalities, feeding difficulties, weight loss and seizures. Treatments used to ameliorate symptoms and reduce morbidity include opiates, sedatives and non-pharmacological treatments. To assess the effectiveness and safety of using a sedative compared to a non-opiate control for NAS due to withdrawal from opiates, and to determine which type of sedative is most effective and safe. This update included searches of the Cochrane Central Register of Controlled Trials (Issue 1, 2010), MEDLINE 1966 to April 2010 and abstracts of conference proceedings. Trials enrolling infants with NAS born to mothers with an opiate dependence with > 80% follow-up and using random or quasi-random allocation to sedative or control. Control could include another sedative or non-pharmacological treatment. Each author assessed study quality and extracted data independently. Seven studies enrolling 385 patients were included. There were substantial methodological concerns for most studies including the use of quasi-random allocation methods and sizeable, largely unexplained differences in reported numbers allocated to each group.One study reported phenobarbitone compared to supportive care alone did not reduce treatment failure or time to regain birthweight, but resulted in a significant reduction in duration of supportive care (MD -162.1 min/day, 95% CI -249.2, -75.1). Comparing phenobarbitone to diazepam, meta-analysis of two studies found phenobarbitone resulted in a significant reduction in treatment failure (typical RR 0.39, 95% CI 0.24, 0.62). Comparing phenobarbitone with chlorpromazine, one study reported no significant difference in treatment failure.In infants treated with an opiate, one study reported addition of clonidine resulted in no significant difference in treatment failure, seizures or mortality. In infants treated with an opiate, one study reported addition of phenobarbitone significantly reduced the proportion of time infants had a high abstinence severity score, duration of hospitalisation and maximal daily dose of opiate. Infants with NAS due to opiate withdrawal should receive initial treatment with an opiate. Where a sedative is used, phenobarbitone should be used in preference to diazepam. In infants treated with an opiate, the addition of phenobarbitone or clonidine may reduce withdrawal severity. Further studies are needed to determine the role of sedatives in infants with NAS due to opiate withdrawal and the safety and efficacy of adding phenobarbitone or clonidine in infants treated with an opiate for NAS.

Aeromedical decision making in attention-deficit/hyperactivity disorder.

PubMed

Fitzgerald, David J P; Navathe, Pooshan D; Drane, A Michael

2011-05-01

Attention-deficit/hyperactivity disorder is a problematic diagnosis in the context of aeromedical certification. Certain characteristics of the disorder such as impaired attention potentially affect the safe conduct of flying. Pharmacological treatment with stimulants also has issues surrounding short half-lives and effects on the recognition of fatigue. This article gives a broad overview of the issues involved and provides certification guidelines as adopted in the Australian Civil Aviation Safety Authority which may be helpful if adopted by other certification bodies.

A cumulative index to a continuing bibliography on aerospace medicine and biology, January 1972

NASA Technical Reports Server (NTRS)

1972-01-01

Subject coverage concentrates on the biological, physiological, psychological, and environmental effects to which man is subjected during and following simulated or actual flight in the earth's atmosphere or in interplanetary space. References describing similar effects on biological organisms of lower order are also included. Such related topics as sanitary problems, pharmacology, toxicology, safety and survival, life support systems, exobiology, and personnel factors receive appropriate attention. Each entry consists of a standard citation accompanied by its abstract.

[Medicinal cannabis].

PubMed

Van der Meersch, H; Verschuere, A P; Bottriaux, F

2006-01-01

Pharmaceutical grade cannabis is available to Dutch patients from public pharmacies in the Netherlands. The first part of this paper reviews the pharmaceutical and pharmacological properties of medicinal cannabis. Detailed information about its composition and quality, potential applications, methods of administration, adverse reactions, drug interactions and safety during pregnancy or breastfeeding are given. The second part deals with the legal aspects of dispensing medicinal cannabis through pharmacies in view of the Belgian and Dutch legislation. The last part discusses the present Belgian regulation about the possession of cannabis.