Pharmacological activity and toxicity of some neurotropic agents under conditions of experimental hypodynamia

NASA Technical Reports Server (NTRS)

Kirichek, L. T.

1980-01-01

The indices of pharmacological range, risk coefficients, ED50, LD50, the size of the area of toxic activity, and maximal tolerated and absolute lethal doses were compared in hypodynamic mice. The pharmacological activity of the test neurotropic agents exhibiting a central action underwent change, but their toxicity remained unchanged.

A Quantitative Ethnopharmacological Documentation of Natural Pharmacological Agents Used by Pediatric Patients in Mauritius

PubMed Central

Mahomoodally, M. Fawzi; Sreekeesoon, D. Priyamka

2014-01-01

The pediatric population constitutes the most vulnerable patients due to a dearth of approved drugs. Consequently, there is a pressing need to probe novel natural pharmacological agents in an endeavour to develop new drugs to address pediatric illnesses. To date, no studies have explored the use of natural therapies for pediatric health care in Mauritius. Parents (n = 325) from different regions of the island were interviewed. Quantitative indexes such as fidelity level (FL), informant consensus factor (F IC), and use-value (UV) were calculated. Thirty-two plants were reported to be used by pediatric patients. Gastrointestinal disorders (F IC = 0.97) encompassing regurgitation, infantile colic, and stomach aches were the most common ailments managed with herbs. Matricaria chamomilla used for infantile colic and its pharmacological properties has previously been documented for pediatric patients. Product from A. mellifera (UV = 0.75) was the most utilized zootherapy for managing cough. Most plants and animal products reported in this study have bioactive constituents supported by existing scientific literature but their use for the pediatric population is scant. The present ethnopharmacological study has opened new perspectives for further research into their pharmacology, which can subsequently support and facilitate timely pediatric medicinal product development. PMID:24949418

Current Pharmacological Approaches to Reduce Chorea in Huntington's Disease.

PubMed

Coppen, Emma M; Roos, Raymund A C

2017-01-01

There are currently no effective pharmacological agents available to stop or prevent the progression of Huntington's disease (HD), a rare hereditary neurodegenerative disorder. In addition to psychiatric symptoms and cognitive impairments, HD causes progressive motor disturbances, in particular choreiform movements, which are characterized by unwanted contractions of the facial muscles, trunk and extremities. Management of choreiform movements is usually advised if chorea interferes with daily functioning, causes social isolation, gait instability, falls, or physical injury. Although drugs to reduce chorea are available, only few randomized controlled studies have assessed the efficacy of these drugs, resulting in a high variety of prescribed drugs in clinical practice. The current pharmacological treatment options to reduce chorea in HD are outlined in this review, including the latest results on deutetrabenazine, a newly developed pharmacological agent similar to tetrabenazine, but with suggested less peak dose side effects. A review of the existing literature was conducted using the PubMed, Cochrane and Medline databases. In conclusion, mainly tetrabenazine, tiapride (in European countries), olanzapine, and risperidone are the preferred first choice drugs to reduce chorea among HD experts. In the existing literature, these drugs also show a beneficial effect on motor symptom severity and improvement of psychiatric symptoms. Generally, it is recommended to start with a low dose and increase the dose with close monitoring of any adverse effects. New interesting agents, such as deutetrabenazine and pridopidine, are currently under development and more randomized controlled trials are warranted to assess the efficacy on chorea severity in HD.

Rewriting My Autobiography: The Legal and Ethical Implications of Memory-Dampening Agents

ERIC Educational Resources Information Center

Aoki, Cynthia R. A.

2008-01-01

The formation and recall of memories are fundamental aspects of life and help preserve the complex collection of experiences that provide us with a sense of identity and autonomy. Scientists have recently started to investigate pharmacological agents that inhibit or "dampen" the strength of memory formation and recall. The development of…

Biotechnology Research Requirements for Aeronautical Systems through the Year 2000. Volume 1

DTIC Science & Technology

1982-07-30

signature. Reducing the aero contain radic.?z,:"ve fallout. vehicle’s detectibility by reducing the optical, electro, acoustic, and infrared 0 Pulsed...arsenal devoted to agent doses. At this time, basic biochemical and chemical agents, reported use of mycotoxins and pharmacological data are minimal and...mass spectroscopy , quartz chemical agents must be developed. This research microbalances, Industrial hygiene dosimetry, damp should quantify human

Recent Advances in Attention Bias Modification for Substance Addictions

PubMed Central

Zhang, Melvyn Weibin; Ying, Jiang Bo; Song, Guo; Fung, Daniel S. S.; Smith, Helen E.

2018-01-01

Research on attentional bias modification has increased since 2014. A recent meta-analysis demonstrates evidence for bias modification for substance disorders, including alcohol and tobacco use disorders. Several pharmacological trials have shown that pharmacological agents can attenuate and modify such attentional bias. The pharmacological trials that have appeared to date have produced mixed results, which has clinical implications. Developments in Internet and mobile technologies have transformed how attention bias modification is currently being achieved. There remains great potential for further research that examines the efficacy of technology-aided attention bias interventions. PMID:29617325

Interventions for post-infectious irritable bowel syndrome: a systematic review of treatment efficacy.

PubMed

Torbicki, Emma; Oh, Justin; Mishra, Sharmistha; Page, Andrea V; Boggild, Andrea K

2015-01-01

Post-infectious irritable bowel syndrome (PI-IBS) due to traveler's diarrhea is the second most common illness seen in post-travel clinics, yet its optimal management remains unknown. We performed a systematic review to evaluate treatment efficacy in PI-IBS. We searched Medline, EMBASE, LILACS, CINAHL, CAB abstracts, and the Cochrane Library to February 3, 2014 for intervention studies of the pharmacologic and non-pharmacologic management of PI-IBS and examined the evidence according to a modified Grading of Recommendations Assessment, Development, and Evaluation (GRADE) scale. Of 336 records, 9 studies were included. Eight studies of pharmacologic interventions examined 5 agents (mesalazine or mesalamine, ondansetron, prednisolone, cholestyramine, and metronidazole). One study examined the non-pharmacologic intervention of different infant nutritional formulas following acute gastroenteritis. The quality of the evidence to date was low, with small sample size (fewer than 50 participants) and short duration of follow-up. Overall, the efficacy of pharmacological treatment ranged from no benefit (ondansetron and prednisolone) to moderately beneficial (cholestyramine and metronidazole). The evidence for mesalazine was equivocal: one study showed benefit, two others showed none. Heterogeneity in outcome measures and low strength of evidence preclude recommendations on the optimal management of PI-IBS by a specific agent. More comparative intervention research into PI-IBS treatment is needed for consistent best practice in PI-IBS management. Clinicians may elect to pursue therapeutic trials of mesalazine, cholestyramine, or metronidazole in individual patients, but should be aware that data supporting the efficacy of these agents is limited.

Stimuli-sensitive hydrogels: ideal carriers for chronobiology and chronotherapy.

PubMed

Peppas, Nicholas A; Leobandung, William

2004-01-01

The development of solid-phase peptide synthesis in the early 1960s and recombinant DNA technology in the early 1970s boosted the scientific interest of utilizing proteins and peptides as potential therapeutic agents to battle poorly controlled diseases. While there has been rapid progress in the development and synthesis of new proteins and peptides as potential therapeutic agents, the formulation and development of the associated delivery systems is lacking. The development of delivery systems is equally important due to the problems of stability, low bioavailability and short half-life of proteins and peptides. The main problem in this field is that low stability leads to low bioavailability. In this review we draw attention to chrono-pharmacological drug-delivery systems, which can be used to match the delivery of therapeutic agents with the biological rhythm. They are very important especially in endocrinology and in vaccine therapy. We show that the treatment of hypopituitary dwarfism by administration of human growth-hormone-releasing hormone (GHRH) is more effective when GHRH is administered in a pulsatile manner that exhibits a period characteristic of the patient's circadian rhythm. Here we examine how to design novel chrono-pharmacological drug-delivery systems that should be able to release the therapeutic agents at predetermined intervals.

Constellation Pharmacology: A new paradigm for drug discovery

PubMed Central

Schmidt, Eric W.; Olivera, Baldomero M.

2015-01-01

Constellation Pharmacology is a cell-based high-content phenotypic-screening platform that utilizes subtype-selective pharmacological agents to elucidate the cell-specific combinations (“constellations”) of key signaling proteins that define specific cell types. Heterogeneous populations of native cells, in which the different individual cell types have been identified and characterized, are the foundation for this screening platform. Constellation Pharmacology is useful for screening small molecules or for deconvoluting complex mixtures of biologically-active natural products. This platform has been used to purify natural products and discover their molecular mechanisms. In the on-going development of Constellation Pharmacology, there is a positive-feedback loop between the pharmacological characterization of cell types and screening for new drug candidates. As Constellation Pharmacology is used to discover compounds with novel targeting-selectivity profiles, those new compounds then further help to elucidate the constellations of specific cell types, thereby increasing the content of this high-content platform. PMID:25562646

Mechanisms of acetylcholine- and bradykinin-induced preconditioning.

PubMed

Critz, Stuart D; Cohen, Michael V; Downey, James M

2005-01-01

Acetylcholine (ACh) and bradykinin (BK) are potent pharmacological agents which mimic ischemic preconditioning (IPC) enabling hearts to resist infarction during a subsequent period of ischemia. The cardioprotective pathways activated by BK but not ACh may also protect when activated at reperfusion. ACh and BK stimulate Gi/o-linked receptors and ultimately mediate protection by opening mitochondrial ATP-sensitive potassium channels with the generation of reactive oxygen species that act as second messengers to activate protein kinase C (PKC). There appear to be key differences, however, in the pathways prior to potassium channel opening for these two receptors. This review aims to summarize what is currently known about pharmacological preconditioning by ACh and BK with an emphasis on differences that are seen in the signal transduction cascades. Understanding the cellular basis of protection by ACh and BK is a critical step towards developing pharmacological agents that will prevent infarction during ischemia resulting from coronary occlusion or heart attack.

Emerging Drugs and Indications for Cardio-Metabolic Disorders in People with Severe Mental Illness.

PubMed

Kouidrat, Youssef; Amad, Ali; De Hert, Marc

2015-01-01

Patients with severe mental illnesses, such as schizophrenia and bipolar disorder, are at increased risk of developing metabolic disorders including obesity, diabetes, and dyslipidemia. All of these comorbidities increase the risk of cardiovascular disease and mortality. Different approaches, including diet and lifestyle modifications, behavioral therapy and switching antipsychotic agents, have been proposed to manage these metabolic abnormalities. However, these interventions may be insufficient, impractical or fail to counteract the metabolic dysregulation. Consequently, a variety of pharmacological agents such as antidiabetic drugs, have been studied in an attempt to reverse the weight gain and metabolic abnormalities evident in these patients. Despite a significant effect, many of these treatments are used off-label. This qualitative review focuses on pharmacological agents that could offer significant benefits in the management of cardio-metabolic disorders associated with serious mental illness.

Scopolamine provocation-based pharmacological MRI model for testing procognitive agents.

PubMed

Hegedűs, Nikolett; Laszy, Judit; Gyertyán, István; Kocsis, Pál; Gajári, Dávid; Dávid, Szabolcs; Deli, Levente; Pozsgay, Zsófia; Tihanyi, Károly

2015-04-01

There is a huge unmet need to understand and treat pathological cognitive impairment. The development of disease modifying cognitive enhancers is hindered by the lack of correct pathomechanism and suitable animal models. Most animal models to study cognition and pathology do not fulfil either the predictive validity, face validity or construct validity criteria, and also outcome measures greatly differ from those of human trials. Fortunately, some pharmacological agents such as scopolamine evoke similar effects on cognition and cerebral circulation in rodents and humans and functional MRI enables us to compare cognitive agents directly in different species. In this paper we report the validation of a scopolamine based rodent pharmacological MRI provocation model. The effects of deemed procognitive agents (donepezil, vinpocetine, piracetam, alpha 7 selective cholinergic compounds EVP-6124, PNU-120596) were compared on the blood-oxygen-level dependent responses and also linked to rodent cognitive models. These drugs revealed significant effect on scopolamine induced blood-oxygen-level dependent change except for piracetam. In the water labyrinth test only PNU-120596 did not show a significant effect. This provocational model is suitable for testing procognitive compounds. These functional MR imaging experiments can be paralleled with human studies, which may help reduce the number of false cognitive clinical trials. © The Author(s) 2015.

The clinical pharmacology of alkylating agents in high-dose chemotherapy.

PubMed

Huitema, A D; Smits, K D; Mathôt, R A; Schellens, J H; Rodenhuis, S; Beijnen, J H

2000-08-01

Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.

Study of Efficacy and Safety of LEE011 in Men and Postmenopausal Women With Advanced Breast Cancer.

ClinicalTrials.gov

2017-10-12

Breast Neoplasms; Breast Diseases; Neoplasms; Neoplasms by Site; Fulvestrant; Antineoplastic Agents; Antineoplastic Agents, Hormonal; Estrogen Receptor Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Therapeutic Use

Emerging nonsurgical methods for the treatment of vitreomacular adhesion: a review

PubMed Central

Schneider, Eric W; Johnson, Mark W

2011-01-01

With the dissemination of optical coherence tomography over the past two decades, the role of persistent vitreomacular adhesion (VMA) in the development of numerous macular pathologies – including idiopathic macular hole, vitreomacular traction syndrome, cystoid and diabetic macular edema, neovascularization in diabetic retinopathy and retinal vein occlusion, exudative age-related macular degeneration, and myopic traction maculopathy – has been established. While invasive vitreoretinal procedures have long been utilized to address complications related to these disorders, such an approach is hampered by incomplete vitreoretinal separation and vitreous removal, surgical complications, and high costs. In light of such limitations, investigators have increasingly looked to nonsurgical means for the treatment of persistent pathologic VMA. Chief among these alternative measures is the intravitreal application of pharmacologic agents for the induction of vitreous liquefaction and/or vitreoretinal separation, an approach termed pharmacologic vitreolysis. This article aims to review the available evidence regarding the use of pharmacologic agents in the treatment of VMA-related pathology. In addition, a discussion of vitreous molecular organization and principles of physiologic posterior vitreous detachment is provided to allow for a consideration of vitreolytic agent mode of action and molecular targets. PMID:21887098

Pharmacological AMP Kinase Activators Target the Nucleolar Organization and Control Cell Proliferation

PubMed Central

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Aims Phenformin, resveratrol and AICAR stimulate the energy sensor 5′-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Methods Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. Results AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. Conclusions AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential biomarker for the development of drugs that diminish diabetic renal hypertrophy. PMID:24498249

Pharmacological AMP kinase activators target the nucleolar organization and control cell proliferation.

PubMed

Kodiha, Mohamed; Salimi, Ali; Wang, Yi Meng; Stochaj, Ursula

2014-01-01

Phenformin, resveratrol and AICAR stimulate the energy sensor 5'-AMP activated kinase (AMPK) and inhibit the first step of ribosome biogenesis, de novo RNA synthesis in nucleoli. Nucleolar activities are relevant to human health, because ribosome production is crucial to the development of diabetic complications. Although the function of nucleoli relies on their organization, the impact of AMPK activators on nucleolar structures is not known. Here, we addressed this question by examining four nucleolar proteins that are essential for ribosome biogenesis. Kidney cells were selected as model system, because diabetic nephropathy is one of the complications associated with diabetes mellitus. To determine the impact of pharmacological agents on nucleoli, we focused on the subcellular and subnuclear distribution of B23/nucleophosmin, fibrillarin, nucleolin and RPA194. This was achieved by quantitative confocal microscopy at the single-cell level in combination with cell fractionation and quantitative Western blotting. AMPK activators induced the re-organization of nucleoli, which was accompanied by changes in cell proliferation. Among the compounds tested, phenformin and resveratrol had the most pronounced impact on nucleolar organization. For B23, fibrillarin, nucleolin and RPA194, both agents (i) altered the nucleocytoplasmic distribution and nucleolar association and (ii) reduced significantly the retention in the nucleus. (iii) Phenformin and resveratrol also increased significantly the total concentration of B23 and nucleolin. AMPK activators have unique effects on the subcellular localization, nuclear retention and abundance of nucleolar proteins. We propose that the combination of these events inhibits de novo ribosomal RNA synthesis and modulates cell proliferation. Our studies identified nucleolin as a target that is especially sensitive to pharmacological AMPK activators. Because of its response to pharmacological agents, nucleolin represents a potential biomarker for the development of drugs that diminish diabetic renal hypertrophy.

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

Future pharmacological treatments for substance use disorders

PubMed Central

Forray, Ariadna; Sofuoglu, Mehmet

2014-01-01

Substance use disorders represent a serious public health and social issue worldwide. Recent advances in our understanding of the neurobiological basis of the addictive processes have led to the development of a growing number of pharmacological agents to treat addictions. Despite this progress, there are no approved pharmacological treatments for cocaine, methamphetamine and cannabis addiction. Moving treatment development to the next stage will require novel ways of approaching substance use disorders. One such novel approach is to target individual vulnerabilities, such as cognitive function, sex differences and psychiatric comorbidities. This review provides a summary of promising pharmacotherapies for alcohol, opiate, stimulant and nicotine addictions. Many medications that target positive and negative reinforcement of drugs, as well as individual vulnerabilities to addiction, are in different phases of development. Clinical trials testing the efficacy of these medications for substance use disorder are warranted. PMID:23039267

Molecular and clinical pharmacology of intranasal corticosteroids: clinical and therapeutic implications.

PubMed

Derendorf, H; Meltzer, E O

2008-10-01

Intranasal corticosteroids (INSs) are effective treatments for allergic rhinitis, rhinosinusitis, and nasal polyposis. In recent years, increased understanding of corticosteroid and glucocorticoid receptor pharmacology has enabled the development of molecules designed specifically to achieve potent, localized activity with minimal risk of systemic exposure. Pharmacologic potency studies using affinity and other assessments have produced similar rank orders of potency, with the most potent being mometasone furoate, fluticasone propionate, and its modification, fluticasone furoate. The furoate and propionate ester side chains render these agents highly lipophilic, which may facilitate their absorption through nasal mucosa and uptake across phospholipid cell membranes. These compounds demonstrate negligible systemic absorption. Systemic absorption rates are higher among the older corticosteroids (flunisolide, beclomethasone dipropionate, triamcinolone acetonide, and budesonide), which have bioavailabilities in the range of 34-49%. Studies, including 1-year studies with mometasone furoate, fluticasone propionate, and budesonide that evaluated potential systemic effects of INSs in children have generally found no adverse effects on hypothalamic-pituitary-adrenal axis function or growth. Clinical data suggest no significant differences in efficacy between the INSs. Theoretically, newer agents with lower systemic availability may be preferable, and may come closer to the pharmacokinetic/pharmacologic criteria for the ideal therapeutic choice.

Pharmacological Properties and Molecular Mechanisms of Thymol: Prospects for Its Therapeutic Potential and Pharmaceutical Development

PubMed Central

Nagoor Meeran, Mohamed Fizur; Javed, Hayate; Al Taee, Hasan; Azimullah, Sheikh; Ojha, Shreesh K.

2017-01-01

Thymol, chemically known as 2-isopropyl-5-methylphenol is a colorless crystalline monoterpene phenol. It is one of the most important dietary constituents in thyme species. For centuries, it has been used in traditional medicine and has been shown to possess various pharmacological properties including antioxidant, free radical scavenging, anti-inflammatory, analgesic, antispasmodic, antibacterial, antifungal, antiseptic and antitumor activities. The present article presents a detailed review of the scientific literature which reveals the pharmacological properties of thymol and its multiple therapeutic actions against various cardiovascular, neurological, rheumatological, gastrointestinal, metabolic and malignant diseases at both biochemical and molecular levels. The noteworthy effects of thymol are largely attributed to its anti-inflammatory (via inhibiting recruitment of cytokines and chemokines), antioxidant (via scavenging of free radicals, enhancing the endogenous enzymatic and non-enzymatic antioxidants and chelation of metal ions), antihyperlipidemic (via increasing the levels of high density lipoprotein cholesterol and decreasing the levels of low density lipoprotein cholesterol and low density lipoprotein cholesterol in the circulation and membrane stabilization) (via maintaining ionic homeostasis) effects. This review presents an overview of the current in vitro and in vivo data supporting thymol’s therapeutic activity and the challenges concerning its use for prevention and its therapeutic value as a dietary supplement or as a pharmacological agent or as an adjuvant along with current therapeutic agents for the treatment of various diseases. It is one of the potential candidates of natural origin that has shown promising therapeutic potential, pharmacological properties and molecular mechanisms as well as pharmacokinetic properties for the pharmaceutical development of thymol. PMID:28694777

Pharmacologic treatments for dry eye: a worthwhile investment?

PubMed

Novack, Gary D

2002-01-01

To determine whether investment in a novel pharmacologic agent for the treatment of dry eye would be worthwhile from a financial perspective. Estimates were made of the cost and time required to develop a novel pharmacologic treatment of dry eye and the potential revenues for the product. These estimates were used to compute the value of the investment, adjusting for the time value of money. Development was estimated to cost $42 million and to take 55 months from investigational new drug exemption filing to new drug application approval. The potential market for this treatment was estimated at $542 million per year at year 5. Adding in the cost of development and marketing as well as other costs, net present value was very positive at the 5, 8, 10, and 40% cost of financing. The internal rate of return was 90%. In summary, if there were a successful pharmacologic treatment of dry eye and if a firm could manage the cash flow during the development, then the market potential approaches that of other treatment of chronic ophthalmic conditions (e.g., glaucoma), and it would be a worthwhile investment.

Supercapacitive transport of pharmacologic agents using nanoporous gold electrodes.

PubMed

Gittard, Shaun D; Pierson, Bonnie E; Ha, Cindy M; Wu, Chung-An Max; Narayan, Roger J; Robinson, David B

2010-02-01

In this study, nanoporous gold supercapacitors were produced by electrochemical dealloying of gold-silver alloy. Scanning electron microscopy and energy dispersive X-ray spectroscopy confirmed completion of the dealloying process and generation of a porous gold material with approximately 10 nm diameter pores. Cyclic voltammetry and chronoamperometry of the nanoporous gold electrodes indicated that these materials exhibited supercapacitor behavior. The storage capacity of the electrodes measured by chronoamperometry was approximately 3 mC at 200 mV. Electrochemical storage and voltage-controlled delivery of two model pharmacologic agents, benzylammonium and salicylic acid, was demonstrated. These results suggest that capacitance-based storage and delivery of pharmacologic agents may serve as an alternative to conventional drug delivery methods.

Pharmacological Modulation of Lung Carcinogenesis in Smokers: Preclinical and Clinical Evidence

PubMed Central

De Flora, Silvio; Ganchev, Gancho; Iltcheva, Marietta; La Maestra, Sebastiano; Micale, Rosanna T.; Steele, Vernon E.; Balansky, Roumen

2016-01-01

Many drugs in common use possess pleiotropic properties that make them capable of interfering with carcinogenesis mechanisms. We discuss here the ability of pharmacological agents to mitigate the pulmonary carcinogenicity of mainstream cigarette smoke. The evaluated agents included antiinflammatory drugs (budesonide, celecoxib, aspirin, naproxen, licofelone), antidiabetic drugs (metformin, pioglitazone), antineoplastic agents (lapatinib, bexarotene, vorinostat), and other drugs and supplements (phenethyl isothiocyanate, myo-inositol, N-acetylcysteine, ascorbic acid, berry extracts). The drugs have been evaluated in mouse models mimicking interventions either in current smokers or in ex-smokers or a prenatal chemoprevention. They displayed a broad spectrum of activities by attenuating either smoke-induced preneoplastic lesions or benign tumors and/or malignant tumors. Together with epidemiological data, these findings provide useful information to predict the potential effects of pharmacological agents in smokers. PMID:26726119

Pharmacologic management of chronic neuropathic pain

PubMed Central

Mu, Alex; Weinberg, Erica; Moulin, Dwight E.; Clarke, Hance

2017-01-01

Abstract Objective To provide family physicians with a practical clinical summary of the Canadian Pain Society (CPS) revised consensus statement on the pharmacologic management of neuropathic pain. Quality of evidence A multidisciplinary interest group within the CPS conducted a systematic review of the literature on the current treatments of neuropathic pain in drafting the revised consensus statement. Main message Gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are the first-line agents for treating neuropathic pain. Tramadol and other opioids are recommended as second-line agents, while cannabinoids are newly recommended as third-line agents. Other anticonvulsants, methadone, tapentadol, topical lidocaine, and botulinum toxin are recommended as fourth-line agents. Conclusion Many pharmacologic analgesics exist for the treatment of neuropathic pain. Through evidence-based recommendations, the CPS revised consensus statement helps guide family physicians in the management of patients with neuropathic pain. PMID:29138154

Targeting Sphingosine Kinase-1 To Inhibit Melanoma

PubMed Central

Madhunapantula, SubbaRao V.; Hengst, Jeremy; Gowda, Raghavendra; Fox, Todd E.; Yun, Jong K; Robertson, Gavin P.

2012-01-01

SUMMARY Resistance to therapies develops rapidly for melanoma leading to more aggressive disease. Therefore, agents are needed that specifically inhibit proteins or pathways controlling the development of this disease, which can be combined, dependent on genes deregulated in a particular patient’s tumors. This study shows that elevated sphingosine-1-phosphate (S-1-P) levels resulting from increased activity of sphingosine kinase-1 (SPHK1) occur in advanced melanomas. Targeting SPHK1 using siRNA decreased anchorage dependent and independent growth as well as sensitized melanoma cells to apoptosis inducing agents. Pharmacological SPHK1 inhibitors SKI-I but not SKI-II decreased S-1-P content, elevated ceramide levels, caused a G2-M block and induced apoptotic cell death in melanomas. Targeting SPHK1 using siRNA or the pharmacological agent called SKI-I, decreased the levels of pAKT. Furthermore, SKI-I inhibited the expression of CYCLIN D1 protein and increased the activity of caspase-3/7, which in turn led to the degradation of PARP. In animals, SKI-I but not SKI-II retarded melanoma growth by 25-40%. Thus, targeting SPHK1 using siRNAs or SKI-I has therapeutic potential for melanoma treatment either alone or in combination with other targeted agents. PMID:22236408

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology

PubMed Central

Pirazzini, Marco; Rossetto, Ornella; Eleopra, Roberto

2017-01-01

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. PMID:28356439

Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology.

PubMed

Pirazzini, Marco; Rossetto, Ornella; Eleopra, Roberto; Montecucco, Cesare

2017-04-01

The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology. Copyright © 2017 by The Author(s).

Combining Pharmacological Countermeasures to Attenuate the Acute Radiation Syndrome-A Concise Review.

PubMed

Hofer, Michal; Hoferová, Zuzana; Depeš, Daniel; Falk, Martin

2017-05-19

The goal of combined pharmacological approaches in the treatment of the acute radiation syndrome (ARS) is to obtain an effective therapy producing a minimum of undesirable side effects. This review summarizes important data from studies evaluating the efficacy of combining radioprotective agents developed for administration prior to irradiation and therapeutic agents administered in a post-irradiation treatment regimen. Many of the evaluated results show additivity, or even synergism, of the combined treatments in comparison with the effects of the individual component administrations. It can be deduced from these findings that the research in which combined treatments with radioprotectors/radiomitigators are explored, tested, and evaluated is well-founded. The requirement for studies highly emphasizing the need to minimize undesirable side effects of the radioprotective/radiomitigating therapies is stressed.

Recent advances in cancer therapy.

PubMed

Mercado, I; Baez, L; Caceres, W

1997-01-01

The treatment of cancer has developed substantially from its conception in the first years of the 20th century. Since the introduction of alkylating agents during second World War, the oncology specialty has markedly grown. In the recent years, new drugs have been approved for the treatment of cancer. Such examples include the taxanes (Docetaxel and Paclitaxel), Vinorelbine, Irinotecan, Topotecan, Gemcitabine and Gliadel. We will discuss these new chemotherapuetic agents, their pharmacology, indications, toxicity and appropriate dosing. There is no doubt that further clinical research is needed to determine the optimal use of these agents.

Pharmacological strategies for protection of extrahepatic islet transplantation.

PubMed

Omori, K; Komatsu, H; Rawson, J; Mullen, Y

2015-06-01

The safety and effectiveness of islet transplantation has been proven through world-wide trials. However, acute and chronic islet loss has hindered the ultimate objective of becoming a widely used treatment option for type 1 diabetes. A large islet loss is attributed, in part, to the liver being a less-than-optimal site for transplantation. Over half of the transplanted islets are destroyed shortly after transplantation due to direct exposure to blood and non-specific inflammation. Successfully engrafted islets are continuously exposed to the liver micro-environment, a unique immune system, low oxygen tension, toxins and high glucose, which is toxic to islets, leading to premature islet dysfunction/death. Investigations have continued to search for alternate sites to transplant islets that provide a better environment for prolonged function and survival. This article gathers courses and conditions that lead to islet loss, from organ procurement through islet transplantation, with special emphasis on hypoxia, oxidative stress, and antigen non-specific inflammation, and reviews strategies using pharmacological agents that have shown effectiveness in protecting islets, including a new treatment approach utilizing siRNA. Pharmacological agents that support islet survival and promote β-cell proliferation are also included. Treatment of donor pancreata and/or islets with these agents should increase the effectiveness of islets transplanted into extrahepatic sites. Furthermore, the development of methods designed to release these agents over an extended period, will further increase their efficacy. This requires the combined efforts of both islet transplant biologists and bioengineers.

Pharmacologic management of chronic neuropathic pain: Review of the Canadian Pain Society consensus statement.

PubMed

Mu, Alex; Weinberg, Erica; Moulin, Dwight E; Clarke, Hance

2017-11-01

To provide family physicians with a practical clinical summary of the Canadian Pain Society (CPS) revised consensus statement on the pharmacologic management of neuropathic pain. A multidisciplinary interest group within the CPS conducted a systematic review of the literature on the current treatments of neuropathic pain in drafting the revised consensus statement. Gabapentinoids, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors are the first-line agents for treating neuropathic pain. Tramadol and other opioids are recommended as second-line agents, while cannabinoids are newly recommended as third-line agents. Other anticonvulsants, methadone, tapentadol, topical lidocaine, and botulinum toxin are recommended as fourth-line agents. Many pharmacologic analgesics exist for the treatment of neuropathic pain. Through evidence-based recommendations, the CPS revised consensus statement helps guide family physicians in the management of patients with neuropathic pain. Copyright© the College of Family Physicians of Canada.

Snake Venom L-Amino Acid Oxidases: Trends in Pharmacology and Biochemistry

PubMed Central

Izidoro, Luiz Fernando M.; Sobrinho, Juliana C.; Mendes, Mirian M.; Costa, Tássia R.; Grabner, Amy N.; Rodrigues, Veridiana M.; da Silva, Saulo L.; Zanchi, Fernando B.; Zuliani, Juliana P.; Fernandes, Carla F. C.; Calderon, Leonardo A.; Stábeli, Rodrigo G.; Soares, Andreimar M.

2014-01-01

L-amino acid oxidases are enzymes found in several organisms, including venoms of snakes, where they contribute to the toxicity of ophidian envenomation. Their toxicity is primarily due to enzymatic activity, but other mechanisms have been proposed recently which require further investigation. L-amino acid oxidases exert biological and pharmacological effects, including actions on platelet aggregation and the induction of apoptosis, hemorrhage, and cytotoxicity. These proteins present a high biotechnological potential for the development of antimicrobial, antitumor, and antiprotozoan agents. This review provides an overview of the biochemical properties and pharmacological effects of snake venom L-amino acid oxidases, their structure/activity relationship, and supposed mechanisms of action described so far. PMID:24738050

Have clinical studies demonstrated diabetes prevention or delay of diabetes through early treatment?

PubMed

Southwood, Robin L

2010-01-01

The incidence of type 2 diabetes continues to increase at alarming rates. Prediabetes is a state of abnormal glycemic values that are not abnormal enough to result in the diagnosis of type 2 diabetes. Significant interest in the prevention of diabetes has resulted in trials evaluating pharmacologic intervention and lifestyle intervention to prevent the development of diabetes. Controversy exists over the exact definition of diabetes prevention. Agents might possibly delay diagnosis of diabetes via pharmacologic lowering of blood glucose. Goals of diabetes prevention include decreased cardiovascular disease. Trials assessing diabetes prevention should assess 1) Impact of the study drug upon the incidence of diabetes, 2) Impact of the study drug upon diagnosis of diabetes after post-treatment washout phase, 3) Assessment of insulin sensitivity/@-cell function/insulin secretion and blood glucose, 4) Assessment of confounding factors, 5) Impact of the study drug on the occurrence of cardiovascular disease. The published studies were reviewed using these criteria. Six studies evaluating seven agents have been were reviewed. Six of the seven agents reduced diagnosis of diabetes during use, but only two demonstrated effect after washout phase. One of the two agents has been withdrawn from the market. The second agent had a short follow-up period making the results difficult to interpret. Assessment of insulin secretion at entry to trial was common, however ongoing reassessment was uncommon. All studies attempted to assess confounding factors, however stratification of drug benefit relative to amount of lifestyle modification benefit was not reported in trials. Cardiovascular benefit in the form of reduced hypertension was documented with three agents. Pharmacologic prevention of type 2 diabetes remains unproven, due in part to the difficulty distinguishing between prevention and delay. Reduction in cardiovascular benefit is unproven with most agents studied. Larger studies powered to detect cardiovascular endpoints are necessary to determine benefit of diabetes prevention.

Ibogaine, an anti-addictive drug: pharmacology and time to go further in development. A narrative review.

PubMed

Maciulaitis, R; Kontrimaviciute, V; Bressolle, F M M; Briedis, V

2008-03-01

Ibogaine is an indole alkaloid derived from the bark of the root of the African shrub Tabernanthe iboga. Psychoactive properties of ibogaine have been known for decades. More recently, based on experimental data from animals and anectodal reports in human, it has been found that this drug has anti-addictive effects. Several patents were published between 1969 and 1995. The pharmacology of ibogaine is quite complex, affecting many different neurotransmitter systems simultaneously. However, the pharmacological targets underlying the physiological and psychological actions of ibogaine are not completely understood. Ibogaine is rapidly metabolized in the body in noribogaine. The purpose of this article was to review data from the literature concerning physicochemical properties, bio-analytical methods, and pharmacology of ibogaine; this article will be focused on the use of this drug as anti-addictive agent.

Marine Pharmacology in 2005-6: Antitumour and Cytotoxic Compounds

PubMed Central

Mayer, Alejandro M.S.; Gustafson, Kirk R.

2009-01-01

During 2005 and 2006, marine pharmacology research directed towards the discovery and development of novel antitumour agents was reported in 171 peer-reviewed articles. The purpose of this article is to present a structured review of the antitumour and cytotoxic properties of 136 marine natural products, many of which are novel compounds that belong to diverse structural classes, including polyketides, terpenes, steroids, and peptides. The organisms yielding these bioactive marine compounds included invertebrate animals, algae, fungi and bacteria. Antitumour pharmacological studies were conducted with 42 structurally defined marine natural products in a number of experimental and clinical models which further defined their mechanisms of action. Particularly potent in vitro cytotoxicity data generated with murine and human tumour cell lines was reported for 94 novel marine chemicals with as yet undetermined mechanisms of action. Noteworthy is the fact that marine anticancer research was sustained by a global collaborative effort, involving researchers from Australia, Belgium, Benin, Brazil, Canada, China, Egypt, France, Germany, India, Indonesia, Italy, Japan, Mexico, the Netherlands, New Zealand, Panama, the Philippines, Slovenia, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, and the United States. Finally, this 2005-6 overview of the marine pharmacology literature highlights the fact that the discovery of novel marine antitumour agents continued at the same active pace as during 1998-2004. PMID:18701274

[Pharmacological management of rheumatoid arthritis: the state of the art and the future perspective].

PubMed

Kameda, Hideto; Takeuchi, Tsutomu

2013-07-01

Pharmacological management of rheumatoid arthritis (RA) has been rapidly progressed in recent years, which is appeared in the "treat to target" movement and the recommendations developed by some established international/domestic rheumatology associations. The baseline evaluation of poor prognostic factors as well as disease activity with composite measures is necessary for a personalized management. Methotrexate is currently the anchor drug, and other conventional or biological antirheumatic drugs should be added to it for refractory patients. The development of various novel agents including signal transduction inhibitors should promote further advances in the management of RA and other systemic autoimmune and/or inflammatory diseases.

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.

EXPERIMENTAL STUDIES ON THE PROTECTIVE EFFECT OF SEVERAL PHARMACOLOGICAL AGENTS AGAINST X-IRRADIATION (in Japanese)

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

Shakudo, Y.

The protective effects of several pharmacological agents against lethal radiation effects were tested in mice. Noradrenaline, phenylephrine, naphazoline, tetrahydrozoline, and methoxamine markedly reduced radiation mortality when injected 5 min before exposure. Adrenaline and phenylethylamine had little protective effect, while ephedrine had no effect. Cocain was moderately effective, while caffein had little effect. (C.H.)

Tri-partite complex for axonal transport drug delivery achieves pharmacological effect

PubMed Central

2010-01-01

Background Targeted delivery of pharmaceutical agents into selected populations of CNS (Central Nervous System) neurons is an extremely compelling goal. Currently, systemic methods are generally used for delivery of pain medications, anti-virals for treatment of dermatomal infections, anti-spasmodics, and neuroprotectants. Systemic side effects or undesirable effects on parts of the CNS that are not involved in the pathology limit efficacy and limit clinical utility for many classes of pharmaceuticals. Axonal transport from the periphery offers a possible selective route, but there has been little progress towards design of agents that can accomplish targeted delivery via this intraneural route. To achieve this goal, we developed a tripartite molecular construction concept involving an axonal transport facilitator molecule, a polymer linker, and a large number of drug molecules conjugated to the linker, then sought to evaluate its neurobiology and pharmacological behavior. Results We developed chemical synthesis methodologies for assembling these tripartite complexes using a variety of axonal transport facilitators including nerve growth factor, wheat germ agglutinin, and synthetic facilitators derived from phage display work. Loading of up to 100 drug molecules per complex was achieved. Conjugation methods were used that allowed the drugs to be released in active form inside the cell body after transport. Intramuscular and intradermal injection proved effective for introducing pharmacologically effective doses into selected populations of CNS neurons. Pharmacological efficacy with gabapentin in a paw withdrawal latency model revealed a ten fold increase in half life and a 300 fold decrease in necessary dose relative to systemic administration for gabapentin when the drug was delivered by axonal transport using the tripartite vehicle. Conclusion Specific targeting of selected subpopulations of CNS neurons for drug delivery by axonal transport holds great promise. The data shown here provide a basic framework for the intraneural pharmacology of this tripartite complex. The pharmacologically efficacious drug delivery demonstrated here verify the fundamental feasibility of using axonal transport for targeted drug delivery. PMID:20085661

Advances in the management of insomnia

PubMed Central

Bishop, Todd M.; Marcus, Jonathan A.

2014-01-01

Insomnia is highly prevalent and associated with considerable morbidity. Several very efficacious treatments, both pharmacologic and non-pharmacologic, exist for the management of insomnia. New modes of delivery and new formulations of existing sedative-hypnotic medications have been introduced. Novel agents are still being developed and tested to arrive at a hypnotic that has limited side effects while still being efficacious. Innovations with respect to behavioral interventions, which are drastically under-utilized, have focused mainly on making these interventions more widely available through dissemination efforts, briefer formats and more accessible platforms. PMID:24991425

Schools of pharmacology: retinoid update.

PubMed

Scheinfeld, Noah

2006-10-01

The most widely used retinoids include topical tretinoin (Retin-A), adapalene (Differin), topical tazarotene (Tazorac), isotretinoin (Accutane), and acitretin (Soriatane). This article will review new uses and developments in tazarotene (its failure to secure FDA approval in oral form for psoriasis), adapalene (its new 0.3% gel form and use in rosacea), alitretinoin (its use in photoaging), bexarotene (its use for psoriasis and chronic hand dermatitis), isotretinoin (the IPledge program, its use for neuroblastoma and branded formulation pharmacological superiority to generics), and retinoic acid metabolism-blocking agents (RAMBAs) (liarazole use for ichthyosis and psoriasis).

New approaches to pharmacological treatment of osteoporosis.

PubMed Central

Akesson, Kristina

2003-01-01

Osteoporosis has been recognized as a major public health problem for less than two decades. The increasing incidence of fragility fractures, such as vertebral, hip, and wrist fractures, first became apparent from epidemiological studies in the early and mid-1980s, when effective treatment was virtually unavailable. Pharmacological therapies that effectively reduce the number of fractures by improving bone mass are now available widely in countries around the world. Most current agents inhibit bone loss by reducing bone resorption, but emerging therapies may increase bone mass by directly promoting bone formation--as is the case with parathyroid hormone. Current treatment alternatives include bisphosphonates, calcitonin, and selective estrogen receptor modulators, but sufficient calcium and vitamin D are a prerequisite. The availability of evidence-based data that show reductions in the incidence of fractures of 30-50% during treatment has been a major step forward in the pharmacological prevention of fractures. With all agents, fracture reduction is most pronounced for vertebral fracture in high-risk individuals; alendronate and risedronate also may protect against hip fracture in the elderly. New approaches to pharmacological treatment will include further development of existing drugs, especially with regard to tolerance and frequency of dosing. New avenues for targeting the condition will emerge as our knowledge of the regulatory mechanisms of bone remodelling increases, although issues of tissue specificity may be difficult to solve. In the long term, information gained through knowledge of bone genetics may be used to adapt pharmacological treatments more precisely to each individual. PMID:14710507

PHARMACOLOGIC PROBING OF AMPHOTERICIN B-INDUCED RENAL DYSFUNCTION IN THE NEONATAL RAT

EPA Science Inventory

Pharmacologic Probing of Amphotericin B-Induced Renal Dysfunction in the Neonatal Rat. Gray, J.A., and Kavlock, R.J. (1988). Toxicol. Appl. Pharmacol. 93, 360-368. Acetazolamide, furosemide, chlorothiazide, and amiloride pharmacologic agents that act primarily in the proximal tub...

Investigational Antimicrobial Agents of 2013

PubMed Central

Pucci, Michael J.

2013-01-01

SUMMARY New antimicrobial agents are always needed to counteract the resistant pathogens that continue to be selected by current therapeutic regimens. This review provides a survey of known antimicrobial agents that were currently in clinical development in the fall of 2012 and spring of 2013. Data were collected from published literature primarily from 2010 to 2012, meeting abstracts (2011 to 2012), government websites, and company websites when appropriate. Compared to what was reported in previous surveys, a surprising number of new agents are currently in company pipelines, particularly in phase 3 clinical development. Familiar antibacterial classes of the quinolones, tetracyclines, oxazolidinones, glycopeptides, and cephalosporins are represented by entities with enhanced antimicrobial or pharmacological properties. More importantly, compounds of novel chemical structures targeting bacterial pathways not previously exploited are under development. Some of the most promising compounds include novel β-lactamase inhibitor combinations that target many multidrug-resistant Gram-negative bacteria, a critical medical need. Although new antimicrobial agents will continue to be needed to address increasing antibiotic resistance, there are novel agents in development to tackle at least some of the more worrisome pathogens in the current nosocomial setting. PMID:24092856

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.

Safe prescribing practices in pregnancy and lactation.

PubMed

Hansen, Wendy F; Peacock, Anne E; Yankowitz, Jerome

2002-01-01

Midwives and other health care providers face a dilemma when a pregnant woman develops a condition that usually is treated with a pharmacologic agent. Understanding of basic teratology associated with drugs as well as the FDA categorization of agents can assist professionals in recognizing which pharmaceuticals should be used or avoided. In addition to reviewing teratology, this article addresses the use of common drugs for the treatment of upper respiratory conditions, minor pain, gastrointestinal problems, psychiatric illnesses, and neurologic disorders. In each category, current evidence is presented pertaining to which agents should be recommended for pregnant women.

Renal Function and Diuretic Therapy in Infants and Children. Part i

ERIC Educational Resources Information Center

Loggie, Jennifer M. H.; And Others

1975-01-01

Included in the review are a description of the anatomic and functional development of the human kidney, a comparison of the renal physiology of the infant and adult, and a discussion of the pediatric clinical pharmacology of the most commonly used diuretic agents. (DB)

Introduction/overview: gender-based differences in pharmacologic and toxicologic responses.

PubMed

Christian, M S

2001-01-01

Gender may be the most important factor in mammalian development and response to exogenous agents. From believing sex-related differences required sheltering women to protect their reproductive capacity (Victorians thought exercise, education, train travel, and certain music neuro- and reprotoxic to females) to legislating a status of essential equality of the sexes may have increased women's health issues. Men and women often respond differently to drugs. Inclusion of women in phase I/II clinical trials is insufficient to identify gender-based differences in response; rather, animal models should be the basis for predicting gender-based differences in pharmacologic and toxicologic effects. Unfortunately, current animal models do not consistently demonstrate such differences. Use of commonly used species (e.g., rats and dogs) does not necessarily result in relevant evaluation of an agent in a species at appropriate development (age), physiological state, anatomy, metabolism, or kinetics for estimation of human risks. The need to test agents in relevant animal models and advances in metabolic, pharmacokinetic, and pharmacodynamic capabilities challenge us to improve methods by using the most relevant models for estimating human risk. We need to be concerned about gender-related differences and the dynamics of gender-based growth and development over the entire life cycle. We must also consider potential interactions of dietary supplements and other exogenous agents that can act as drugs or modulate the potential effects of drugs differently in men, women, and developing children of both sexes. To this end, the health benefits of genistein and the effects of this dietary agent in a multigeneration study in rats will be described. It is envisioned that this symposium will assist in re-recognition of the importance of gender-related differences in use and response to pharmaceuticals and result in optimization of nonclinical testing procedures to identify benefits and risks for human use of these agents.

Monoacylglycerol lipase – a target for drug development?

PubMed Central

Fowler, CJ

2012-01-01

The endocannabinoid (eCB) system is involved in processes as diverse as control of appetite, perception of pain and the limitation of cancer cell growth and invasion. The enzymes responsible for eCB breakdown are attractive pharmacological targets, and fatty acid amide hydrolase inhibitors, which potentiate the levels of the eCB anandamide, are now undergoing pharmaceutical development. ‘Drugable’ selective inhibitors of monoacylglycerol lipase, a key enzyme regulating the levels of the other main eCB, 2-arachidonoylglycerol, were however not identified until very recently. Their availability has resulted in a large expansion of our knowledge concerning the pharmacological consequences of monoacylglycerol lipase inhibition and hence the role(s) played by the enzyme in the body. In this review, the pharmacology of monoacylglycerol lipase will be discussed, together with an analysis of the therapeutic potential of monoacylglycerol lipase inhibitors as analgesics and anticancer agents. PMID:22428756

Experimental gastric ulcers induced by immobilization and electric shock of rats and their pharmacotherapy

NASA Technical Reports Server (NTRS)

Zabrodin, O. N.

1980-01-01

The mechanism of development of experimental gastric ulcers, induced in rats by combined immobilization and electric shock, was analyzed pharmacologically with peripheral neurotropic agents. It is concluded that: (1) The most marked preventive effect in the development of the experimentally induced gastric ulcers was displayed by agents capable of blocking the ascending activation system of the reticular formation. (2) Sympathetic fibers, which disrupt the trophism of the gastric wall, form the efferent portion of the reflex arc. (3) Gastric secretion does not appear to be the primary cause of ulceration.

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.

Available Resources | Division of Cancer Prevention

Cancer.gov

Preclinical pharmacology and efficacy studies Identification and evaluation of intermediate biomarkers Formulation optimization for enhanced bioavailability and clinical usefulness Analytical method development for investigational agents in bulk form and in biological fluids and tissues PK and PK-PD modeling to optimize dosing regimen Scale-up non-cGMP and cGMP production of

Molecular mechanisms in therapy of acid-related diseases

PubMed Central

Shin, J. M.; Vagin, O.; Munson, K.; Kidd, M.; Modlin, I. M.; Sachs, G.

2011-01-01

Inhibition of gastric acid secretion is the mainstay of the treatment of gastroesophageal reflux disease and peptic ulceration; therapies to inhibit acid are among the best-selling drugs worldwide. Highly effective agents targeting the histamine H2 receptor were first identified in the 1970s. These were followed by the development of irreversible inhibitors of the parietal cell hydrogen-potassium ATPase (the proton pump inhibitors) that inhibit acid secretion much more effectively. Reviewed here are the chemistry, biological targets and pharmacology of these drugs, with reference to their current and evolving clinical utilities. Future directions in the development of acid inhibitory drugs include modifications of current agents and the emergence of a novel class of agents, the acid pump antagonists. PMID:17928953

Pharmacological approaches to methamphetamine dependence: a focused review.

PubMed

Karila, Laurent; Weinstein, Aviv; Aubin, Henri-Jean; Benyamina, Amine; Reynaud, Michel; Batki, Steven L

2010-06-01

Methamphetamine dependence is a serious worldwide public health problem with major medical, psychiatric, socioeconomic and legal consequences. Various neuronal mechanisms implicated in methamphetamine dependence have suggested several pharmacological approaches. A literature search from a range of electronic databases (PubMed, EMBASE, PsycInfo, the NIDA research monograph index and the reference list of clinicaltrials.gov) was conducted for the period from January 1985 to October 2009. There were no restrictions on the identification or inclusion of studies in terms of publication status, language and design type. A variety of medications have failed to show efficacy in clinical trials, including a dopamine partial agonist (aripiprazole), GABAergic agents (gabapentin) and serotonergic agents (SSRI, ondansetron, mirtazapine). Three double-blind placebo-controlled trials using modafinil, bupropion and naltrexone have shown positive results in reducing amphetamine or methamphetamine use. Two studies employing agonist replacement medications, one with d-amphetamine and the other with methylphenidate, have also shown promise. Despite the lack of success in most studies to date, increasing efforts are being made to develop medications for the treatment of methamphetamine dependence and several promising agents are targets of further research.

Neuropharmacology of Poststroke Motor and Speech Recovery.

PubMed

Keser, Zafer; Francisco, Gerard E

2015-11-01

Almost 7 million adult Americans have had a stroke. There is a growing need for more effective treatment options as add-ons to conventional therapies. This article summarizes the published literature for pharmacologic agents used for the enhancement of motor and speech recovery after stroke. Amphetamine, levodopa, selective serotonin reuptake inhibitors, and piracetam were the most commonly used drugs. Pharmacologic augmentation of stroke motor and speech recovery seems promising but systematic, adequately powered, randomized, and double-blind clinical trials are needed. At this point, the use of these pharmacologic agents is not supported by class I evidence. Copyright © 2015 Elsevier Inc. All rights reserved.

Pharmacological treatment of diabetes in older people.

PubMed

Valencia, W M; Florez, H

2014-12-01

The pharmacological management of diabetes in older people is complex and challenging. It requires a comprehensive understanding of the individual beyond the diabetes itself. Through the ageing years, the older individual presents with diabetes-related and non-related comorbidities and complications, develops functional limitations and psychological issues, and may lack social support and access to care. A disturbance in these categories, known as the four geriatric domains, will negatively affect diabetes self-management and self-efficacy, leading to poor outcomes and complications. Furthermore, older people with diabetes may be more interested in the management of other chronic conditions such as pain or impaired mobility, and diabetes may be lower in their list of priorities. Proper education must be provided to the older individual and caregivers, with continuous monitoring and counselling, especially when pharmacological interventions offer risks of side effects, adverse reactions and interactions with other medications. Informed shared medical decisions will help to improve adherence to the regimen; however, such discussions ought to be based on the best evidence available, which is unfortunately limited in this age group. We performed a review focused on pharmacological agents and summarize current evidence on their use for the treatment of diabetes in older people. We encourage clinicians to investigate and incorporate the four geriatrics domains in the selection and monitoring of these agents. © 2014 John Wiley & Sons Ltd.

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

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.

Mechanisms of chemoresistance to alkylating agents in malignant glioma.

PubMed

Sarkaria, Jann N; Kitange, Gaspar J; James, C David; Plummer, Ruth; Calvert, Hilary; Weller, Michael; Wick, Wolfgang

2008-05-15

Intrinsic or acquired chemoresistance to alkylating agents is a major cause of treatment failure in patients with malignant brain tumors. Alkylating agents, the mainstay of treatment for brain tumors, damage the DNA and induce apoptosis, but the cytotoxic activity of these agents is dependent on DNA repair pathways. For example, O6-methylguanine DNA adducts can cause double-strand breaks, but this is dependent on a functional mismatch repair pathway. Thus, tumor cell lines deficient in mismatch repair are resistant to alkylating agents. Perhaps the most important mechanism of resistance to alkylating agents is the DNA repair enzyme O6-methylguanine methyltransferase, which can eliminate the cytotoxic O6-methylguanine DNA adduct before it causes harm. Another mechanism of resistance to alkylating agents is the base excision repair (BER) pathway. Consequently, efforts are ongoing to develop effective inhibitors of BER. Poly(ADP-ribose)polymerase plays a pivotal role in BER and is an important therapeutic target. Developing effective strategies to overcome chemoresistance requires the identification of reliable preclinical models that recapitulate human disease and which can be used to facilitate drug development. This article describes the diverse mechanisms of chemoresistance operating in malignant glioma and efforts to develop reliable preclinical models and novel pharmacologic approaches to overcome resistance to alkylating agents.

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.

Identification of Novel G Protein–Coupled Receptor 143 Ligands as Pharmacologic Tools for Investigating X-Linked Ocular Albinism

PubMed Central

De Filippo, Elisabetta; Manga, Prashiela; Schiedel, Anke C.

2017-01-01

Purpose GPR143 regulates melanosome biogenesis and organelle size in pigment cells. The mechanisms underlying receptor function remain unclear. G protein–coupled receptors (GPCRs) are excellent pharmacologic targets; thus, we developed and applied a screening approach to identify potential GPR143 ligands and chemical modulators. Methods GPR143 interacts with β-arrestin; we therefore established a β-arrestin recruitment assay to screen for compounds that modulate activity. Because GPR143 is localized intracellularly, screening with the wild-type receptor would be restricted to agents absorbed by the cell. For the screen we used a mutant receptor, which shows similar basal activity as the wild type but traffics to the plasma membrane. We tested two compound libraries and investigated validated hits for their effects on melanocyte pigmentation. Results GPR143, which showed high constitutive activity in the β-arrestin assay, was inhibited by several compounds. The three validated inhibitors (pimozide, niclosamide, and ethacridine lactate) were assessed for impact on melanocytes. Pigmentation and expression of tyrosinase, a key melanogenic enzyme, were reduced by all compounds. Because GPR143 appears to be constitutively active, these compounds may turn off its activity. Conclusions X-linked ocular albinism type I, characterized by developmental eye defects, results from GPR143 mutations. Identifying pharmacologic agents that modulate GPR143 activity will contribute significantly to our understanding of its function and provide novel tools with which to study GPCRs in melanocytes and retinal pigment epithelium. Pimozide, one of three GPR143 inhibitors identified in this study, maybe be a good lead structure for development of more potent compounds and provide a platform for design of novel therapeutic agents. PMID:28632878

Advancements in Pharmacotherapy for Angina

PubMed Central

Jain, Ankur; Elgendy, Islam Y.; Al-Ani, Mohammad; Agarwal, Nayan; Pepine, Carl J.

2017-01-01

Introduction Angina pectoris is the most prevalent symptomatic manifestation of ischemic heart disease, frequently leads to a poor quality of life, and is a major cause of medical resource consumption. Since the early descriptions of nitrite and nitrate in the 19th century, there has been considerable advancement in the pharmacologic management of angina. Areas covered Management of chronic angina is often challenging for clinicians. Despite introduction of several pharmacological agents in last few decades, a significant proportion of patients continue to experience symptoms (i.e., refractory angina) with subsequent disability. For the purpose of this review, we searched PubMed and Cochrane databases from inception to August 2016 for the most clinically relevant publications that guide current practice in angina therapy and its development. In this article, we briefly review the pathophysiology of angina and mechanism-based classification of current therapy. This is followed by evidence-based insight into the traditional and novel pharmacotherapeutic agents, highlighting their clinical usefulness. Expert opinion Considering the wide array of available therapies with different mechanism efficacy and limiting factors, a personalized approach is essential, particularly for patients with refractory angina. Ongoing research with novel pharmacologic modalities is likely to provide new options for management of angina. PMID:28264619

Glycogen Synthase Kinase-3 Inhibitors as Potent Therapeutic Agents for the Treatment of Parkinson Disease.

PubMed Central

2012-01-01

Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by degeneration of the nigrostriatal dopaminergic pathway. Because the current therapies only lead to temporary, limited improvement and have severe side effects, new approaches to treat PD need to be developed. To discover new targets for potential therapeutic intervention, a chemical genetic approach involving the use of small molecules as pharmacological tools has been implemented. First, a screening of an in-house chemical library on a well-established cellular model of PD was done followed by a detailed pharmacological analysis of the hits. Here, we report the results found for the small heterocyclic derivative called SC001, which after different enzymatic assays was revealed to be a new glycogen synthase kinase-3 (GSK-3) inhibitor with IC50 = 3.38 ± 0.08 μM. To confirm that GSK-3 could be a good target for PD, the evaluation of a set of structurally diverse GSK-3 inhibitors as neuroprotective agents for PD was performed. Results show that inhibitors of GSK-3 have neuroprotective effects in vitro representing a new pharmacological option for the disease-modifying treatment of PD. Furthermore, we show that SC001 is able to cross the blood–brain barrier, protects dopaminergic neurons, and reduces microglia activation in in vivo models of Parkinson disease, being a good candidate for further drug development. PMID:23421686

Pharmacology of dimethanesulfonate alkylating agents: busulfan and treosulfan.

PubMed

Galaup, Ariane; Paci, Angelo

2013-03-01

Among the dimethanesulfonates, busulfan, in combination with other alkylating agents or nucleoside analogues, is the cornerstone of high-dose chemotherapy. It is used, and followed hematopoietic stem cell transplantation, for the treatment of various hematologic malignancies and immunodeficiencies. Treosulfan, which is a hydrophilic analogue of busulfan, was the first dimethanesufonate registered for the treatment of ovarian cancer. Recently, treosulfan has been investigated for the treatment of hematologic malignancies in combination with the same second agents before hematopoietic stem cell transplantation. This work reviews the pharmacological data of these two dimethanesulfonates alkylating agents. Specifically, the article looks at their chemistry, metabolism, anticancer activity, and their pharmacokinetics and pharmacodynamics. Busulfan has been investigated widely for more than three decades leading to a large and precise handling of this agent with numerous studies on activity and pharmacokinetics and pharmacodynamics. In contrast, the behavior of treosulfan is still under investigation and not fully described. The complexity of treosulfan's metabolism and mechanism of action gives rise to the need of a deeper understanding of its pharmacological activity in a context of high-dose chemotherapy. Specifically, there is a great need to better understand its pharmacokinetics/pharmacodynamics relationship.

Traditional and Alternative Therapies for Refractory Angina.

PubMed

Kocyigit, Duygu; Gurses, Kadri Murat; Yalcin, Muhammed Ulvi; Tokgozoglu, Lale

2017-01-01

Refractory angina (RFA) is an unfavourable condition that is characterized with persistent angina due to reversible myocardial ischemia in patients with coronary artery disease that remains uncontrollable despite an optimal combination of pharmacological agents and revascularization. Despite significant advances in revascularization techniques and agents used in pharmacological therapy, there is still a significant population suffering from RFA and the global prevalence is even increasing. Anti- anginal treatment and secondary risk-factor modification are the traditional approaches for this group of patients. Furthermore, now there is still a large number of alternative treatment options. In order to review traditional and alternative treatment strategies in patients with RFA, we searched Pubmed for articles in English using the search terms "pharmacological therapy, refractory angina", "alternative therapy, refractory angina" between inception to June 2016. We also went through separately for each alternative treatment modality on Pubmed. To identify further articles, we handsearched related citations in review articles and commentaries. We also included data from the European Society of Cardiology (2013), and the Canadian Society of Cardiology/ Canadian Pain Society (2012) guidelines. Data show that besides traditional pharmacological agents, such as nitrates, beta- blockers or calcium channel blockers, novel antiischemic drugs and if symptoms persist, several non- invasive and/ or invasive alternative strategies may be considered. Impact of some pharmacological agents, such as rho- kinase inhibitors, and novel alternative treatment modalities, such as coronary sinus reducers, stem cell therapy, gene and protein therapy, on outcomes are still under investigation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacology and pharmacogenetics of chemotherapeutic agents.

PubMed

Dawood, Shaheenah; Leyland-Jones, Brian

2009-06-01

The last decade the field of oncology has seen the introduction of several efficacious chemotherapeutic agents. However the benefits achieved have been modest at best. The choice of chemotherapeutic agent is often empirical and geared to fit the average patient with the result that approximately 40% of patients may be receiving the wrong drug. With greater understanding of the mechanisms behind the heterogeneity observed across patient populations, both in terms of efficacy and toxicity of a variety of therapeutic agents, research has now focused on individualizing treatment strategies by incorporating a combination of physiological variables, genetic characteristics and environmental factors together with the traditional tumor characteristics that currently drives clinical decision making. This review focuses on defining some of the principle components of personalized medicine. In addition we will review the pharmacological and pharmacogenetic predictors of toxic effects of chemotherapeutic agents drawing on examples of commonly used agents in oncology.

PTSD: from neurobiology to pharmacological treatments

PubMed Central

Kelmendi, Benjamin; Adams, Thomas G.; Yarnell, Stephanie; Southwick, Steven; Abdallah, Chadi G.; Krystal, John H.

2016-01-01

Posttraumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder characterized by symptoms of re-experience, avoidance, and hyperarousal that can arise immediately or many years after exposure to a traumatic event and injury. Although extensive research has been done over the past 30 years, the etiology of PTSD remains largely unknown. Several neurobiological systems have been implicated in the pathophysiology and vulnerability for developing PTSD; however, first-line pharmacotherapies are limited. Less than 30% achieve full remission, and even then, approved pharmacological treatments often take weeks for therapeutic effect. This article aims to review the pathophysiology of PTSD within multiple neurobiological systems and how these mechanisms are used as pharmacologic targets of treatment, as well as their potential for future targets of intervention. Highlights of the article We reviewed the neurobiological abnormalities in PTSD as they relate to well-established, preliminary, and future targets for pharmacological interventions. Abnormalities across different neurotransmitter systems have been implicated in the pathophysiology of PTSD but none of these systems function uniformly among all patients with PTSD First-line pharmacotherapy for PTSD provides a suboptimal response rates. Future pharmacological targets for PTSD include the cannabinoid and oxytocin systems, as well glutamatergic modulating agents. Drug development for PTSD should specifically address various dimensions of PTSD symptomatology. PMID:27837583

Emerging Potential of Natural Products as an Alternative Strategy to Pharmacological Agents Used Against Metabolic Disorders.

PubMed

Dias, Tânia R; Bernardino, Raquel L; Meneses, Maria J; Sousa, Mário; Sá, Rosália; Alves, Marco G; Silva, Branca M; Oliveira, Pedro F

2016-01-01

Human metabolism is an essential biological process that involves the consumption of different substrates to ensure the nutritional and energetic needs of cells. The disruption of this highly regulated system constitutes the onset of several disorders/dysfunctions such as diabetes mellitus, cardiovascular diseases and hypertension. In this review, we propose to discuss promising natural products that can act as modulators of cell metabolism and point towards possible targets to take into account in the development of new therapies against metabolic diseases. After having defined our main focus, we undertook an intensive search of bibliographic databases to select the peer-reviewed papers that fits within the review thematic. The information of the screened papers was described in an organized manner through the review and different types of studies were included. Two hundred and seventy papers were included in the review, as well as one reliable website from the World Health Organization. Several articles described that pharmacological agents are commonly used to counteract metabolic disorders. However, in many cases these products are insufficient, represent high costs to health care systems and are associated with several undesirable effects, highlighting the need to search for new therapies. Notably, many papers reported the promising results of natural products in the treatment of several metabolic disorders, constituting a possible alternative or complementary strategy to pharmacological agents. The findings of this review confirm that the currently available treatments for metabolic disorders and its associated complications remain far below the expected results.

Cyclodextrins as new formulation entities and therapeutic agents.

PubMed

Sikharam, Sreevalli; Egan, Talmage D; Kern, Steven E

2005-08-01

This review is focused on recent advances in the application of cyclodextrins to new drug formulations, with emphasis on the field of anesthesia. Cyclodextrins are well-known excipients in the pharmaceutical industry. Their recent application to the anesthetic induction agent propofol as a means of creating a non-lipid formulation may lead to their introduction into anesthesia pharmacology. The development of a novel cyclodextrin as specific reversal agent for the neuromuscular blocker rocuronium (that acts as an in-vivo scavenging system to bind free rocuronium in the circulation) will also increase the likelihood that cyclodextrins will have a greater clinical presence in anesthesiology in the future. Cyclodextrin-containing polymers are also finding a role in the delivery of nucleic acids and protein therapeutic agents. Recent developments in cyclodextrins as excipients for anesthetics may soon culminate in their introduction into anesthesiology, although more research is necessary to better define their potential.

Mechanism of action of recombinant activated factor VII: an update.

PubMed

Hedner, Ulla

2006-01-01

Bleeding episodes in patients with hemophilia and inhibitors must be managed using agents that are hemostatically active in the absence of factor VIII or IX. Activated prothrombin complex concentrates have long been used in this context. However, the search for safer and more effective agents has led to the development of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). This paper presents an update on the mechanism of action of rFVIIa, and describes how pharmacologic doses of this agent enhance thrombin production and thus contribute to the development of a stable, lysis-resistant fibrin plug at the site of vessel damage. This mechanism explains the reported efficacy of rFVIIa in a range of clinical situations characterized by impaired thrombin generation.

Medicinal Cannabis: History, Pharmacology, And Implications for the Acute Care Setting.

PubMed

Bridgeman, Mary Barna; Abazia, Daniel T

2017-03-01

The authors review the historical use of medicinal cannabis and discuss the agent's pharmacology and pharmacokinetics, select evidence on medicinal uses, and the implications of evolving regulations on the acute care hospital setting.

Stinging plants: as future bio-weapon.

PubMed

Gupta, Sanjay Mohan; Kumar, Kamal

2016-09-01

In the present opinion paper, we have been introducing for the first time the stinging plants and/or their biological toxins as novel bio-threat agents that may be used for the development of bio-weapons for self-defence purpose. The selected studied stinging plants are having dual role as nutraceutical and ethno-pharmacological uses apart from their less explored stinging property. However, future detailed work is required for identification and characterization of the precise stinging chemical components that will be used for the formulation of novel bio-warfare agents for self-defence purpose.

New Simulation Methods to Facilitate Achieving a Mechanistic Understanding of Basic Pharmacology Principles in the Classroom

ERIC Educational Resources Information Center

Grover, Anita; Lam, Tai Ning; Hunt, C. Anthony

2008-01-01

We present a simulation tool to aid the study of basic pharmacology principles. By taking advantage of the properties of agent-based modeling, the tool facilitates taking a mechanistic approach to learning basic concepts, in contrast to the traditional empirical methods. Pharmacodynamics is a particular aspect of pharmacology that can benefit from…

Marine pharmacology in 2005–6: Marine Compounds with Anthelmintic, Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiprotozoal, Antituberculosis, and Antiviral Activities; affecting the Cardiovascular, Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M. S.; Rodriguez, Abimael D.; Berlinck, Roberto G. S.; Hamann, Mark T.

2009-01-01

BACKGROUND The review presents the 2005–2006 peer-reviewed marine pharmacology literature, and follows a similar format to the authors’ 1998–2004 reviews. The preclinical pharmacology of chemically characterized marine compounds isolated from marine animals, algae, fungi and bacteria is systematically presented. RESULTS Anthelminthic, antibacterial, anticoagulant, antifungal, antimalarial, antiprotozoal, antituberculosis and antiviral activities were reported for 78 marine chemicals. Additionally 47 marine compounds were reported to affect the cardiovascular, immune and nervous system as well as possess anti-inflammatory effects. Finally, 58 marine compounds were shown to bind to a variety of molecular targets, and thus could potentially contribute to several pharmacological classes. CONCLUSIONS Marine pharmacology research during 2005–2006 was truly global in nature, involving investigators from 32 countries, and the United States, and contributed 183 marine chemical leads to the research pipeline aimed at the discovery of novel therapeutic agents. SIGNIFICANCE Continued preclinical and clinical research with marine natural products demonstrating a broad spectrum of pharmacological activity and will probably result in novel therapeutic agents for the treatment of multiple disease categories. PMID:19303911

CancerHSP: anticancer herbs database of systems pharmacology

NASA Astrophysics Data System (ADS)

Tao, Weiyang; Li, Bohui; Gao, Shuo; Bai, Yaofei; Shar, Piar Ali; Zhang, Wenjuan; Guo, Zihu; Sun, Ke; Fu, Yingxue; Huang, Chao; Zheng, Chunli; Mu, Jiexin; Pei, Tianli; Wang, Yuan; Li, Yan; Wang, Yonghua

2015-06-01

The numerous natural products and their bioactivity potentially afford an extraordinary resource for new drug discovery and have been employed in cancer treatment. However, the underlying pharmacological mechanisms of most natural anticancer compounds remain elusive, which has become one of the major obstacles in developing novel effective anticancer agents. Here, to address these unmet needs, we developed an anticancer herbs database of systems pharmacology (CancerHSP), which records anticancer herbs related information through manual curation. Currently, CancerHSP contains 2439 anticancer herbal medicines with 3575 anticancer ingredients. For each ingredient, the molecular structure and nine key ADME parameters are provided. Moreover, we also provide the anticancer activities of these compounds based on 492 different cancer cell lines. Further, the protein targets of the compounds are predicted by state-of-art methods or collected from literatures. CancerHSP will help reveal the molecular mechanisms of natural anticancer products and accelerate anticancer drug development, especially facilitate future investigations on drug repositioning and drug discovery. CancerHSP is freely available on the web at http://lsp.nwsuaf.edu.cn/CancerHSP.php.

Systems Pharmacology Dissection of the Anti-Inflammatory Mechanism for the Medicinal Herb Folium Eriobotryae

PubMed Central

Zhang, Jingxiao; Li, Yan; Chen, Su-Shing; Zhang, Lilei; Wang, Jinghui; Yang, Yinfeng; Zhang, Shuwei; Pan, Yanqiu; Wang, Yonghua; Yang, Ling

2015-01-01

Inflammation is a hallmark of many diseases like diabetes, cancers, atherosclerosis and arthritis. Thus, lots of concerns have been raised toward developing novel anti-inflammatory agents. Many alternative herbal medicines possess excellent anti-inflammatory properties, yet their precise mechanisms of action are yet to be elucidated. Here, a novel systems pharmacology approach based on a large number of chemical, biological and pharmacological data was developed and exemplified by a probe herb Folium Eriobotryae, a widely used clinical anti-inflammatory botanic drug. The results show that 11 ingredients of this herb with favorable pharmacokinetic properties are predicted as active compounds for anti-inflammatory treatment. In addition, via systematic network analyses, their targets are identified to be 43 inflammation-associated proteins including especially COX2, ALOX5, PPARG, TNF and RELA that are mainly involved in the mitogen-activated protein kinase (MAPK) signaling pathway, the rheumatoid arthritis pathway and NF-κB signaling pathway. All these demonstrate that the integrated systems pharmacology method provides not only an effective tool to illustrate the anti-inflammatory mechanisms of herbs, but also a new systems-based approach for drug discovery from, but not limited to, herbs, especially when combined with further experimental validations. PMID:25636035

Building Evidence-Based Tobacco Treatment in the Eastern Mediterranean Region: Lessons Learned by the Syrian Center for Tobacco Studies

PubMed Central

Asfar, Taghrid; Ward, Kenneth D.; Al-Ali, Radwan; Maziak, Wasim

2016-01-01

The tobacco epidemic in Syria is characterized by high rates of cigarettes smoking in men and dramatic reemergence of waterpipe smoking, especially among youths and women. The Syrian Center for Tobacco Studies (SCTS), an NIH-funded pioneer research and capacity building institution, has developed a research infrastructure and conducted three randomized clinical trials to develop and rigorously test culturally-appropriate tobacco treatment programs integrated into primary healthcare (PHC) centers. This review aimed to discuss challenges and lessons learned from the Syrian experience. Addressing these challenges may inform future cessation research activities in Syria and other developing countries. To develop a research infrastructure, the SCTS has established Syria’s first IRB and trained physicians/medical students in both tobacco treatment and research methods. Main challenges to conduct the cessation trials were difficulties of coordination between the local and international collaborators; high Smoking Rates among PHC providers; lack of pharmacological agents used in tobacco treatment; and difficulties of conducting research in a politically volatile region. Strategies to overcome these challenges were ensuring an active and regular involvement of all investigator; and advocating for a national smoking-cessation plan that involves training health care providers in smoking cessation treatment and make pharmacological agents used in smoking cessation available. PMID:27563356

Evidence-Based Pharmacologic Treatment of Pediatric Bipolar Disorder.

PubMed

Findling, Robert L

2016-01-01

Pharmacotherapy is an important component of treatment for children and adolescents with bipolar disorder. The body of evidence supporting safe and effective treatments in this population is growing. Available data provide information on the risks and benefits of pharmacologic agents used for acute manic, mixed, and depressive episodes as well as for maintenance treatment. Lithium, anticonvulsants, and antipsychotics comprise the armamentarium for treating pediatric bipolar disorder. When selecting treatment, clinicians must consider the efficacy and side effect profile of potential pharmacotherapies, as well as the patient's history, including the presence of comorbidities, in order to develop a treatment plan that will ensure optimal outcomes. © Copyright 2016 Physicians Postgraduate Press, Inc.

The pharmacology and toxicology of three new biologic agents used in pulmonary medicine.

PubMed

Albertson, T E; Walby, W F; Allen, R P; Tharratt, R S

1995-01-01

Biological agents have played an important role in the evolution of modern medical therapeutics. Recent advances in biologicals have in part been stimulated by the biotechnology revolution seen over the last several years. Toxicologists need to be aware of the proposed mechanisms and approved and experimental uses of these new biologic agents. Further, controversies about their use, efficacy, cost issues and potential toxicities should be known. Often these drugs are designed for small patient populations thus limiting the availability of human toxicological data bases. This paper reviews the pharmacology and toxicology of three new biologics (recombinant human DNase I, alpha 1-protease inhibitor, and nitric oxide). These agents appear to have important roles in treating specific diseases or disease states seen in pulmonary medicine.

Design, Synthesis and Pharmacological Evaluation of Novel Vanadium-Containing Complexes as Antidiabetic Agents

PubMed Central

Fedorova, Elena V.; Buryakina, Anna V.; Zakharov, Alexey V.; Filimonov, Dmitry A.; Lagunin, Alexey A.; Poroikov, Vladimir V.

2014-01-01

Based on the data about structure and antidiabetic activity of twenty seven vanadium and zinc coordination complexes collected from literature we developed QSAR models using the GUSAR program. These QSAR models were applied to 10 novel vanadium coordination complexes designed in silico in order to predict their hypoglycemic action. The five most promising substances with predicted potent hypoglycemic action were selected for chemical synthesis and pharmacological evaluation. The selected coordination vanadium complexes were synthesized and tested in vitro and in vivo for their hypoglycemic activities and acute rat toxicity. Estimation of acute rat toxicity of these five vanadium complexes was performed using a freely available web-resource (http://way2drug.com/GUSAR/acutoxpredict.html). It has shown that the selected compounds belong to the class of moderate toxic pharmaceutical agents, according to the scale of Hodge and Sterner. Comparison with the predicted data has demonstrated a reasonable correspondence between the experimental and predicted values of hypoglycemic activity and toxicity. Bis{tert-butyl[amino(imino)methyl]carbamato}oxovanadium (IV) and sodium(2,2′-Bipyridyl)oxo-diperoxovanadate(V) octahydrate were identified as the most potent hypoglycemic agents among the synthesized compounds. PMID:25057899

Pharmacological action of Panax ginseng on the behavioral toxicities induced by psychotropic agents.

PubMed

Kim, Hyoung-Chun; Shin, Eun-Joo; Jang, Choon-Gon; Lee, Myung-Koo; Eun, Jae-Soon; Hong, Jin-Tae; Oh, Ki-Wan

2005-09-01

Morphine-induced analgesia has been shown to be antagonized by ginseng total saponins (GTS), which also inhibit the development of analgesic tolerance to and physical dependence on morphine. GTS is involved in both of these processes by inhibiting morphine-6-dehydrogenase, which catalyzes the synthesis of morphinone from morphine, and by increasing the level of hepatic glutathione, which participates in the toxicity response. Thus, the dual actions of ginseng are associated with the detoxification of morphine. In addition, the inhibitory or facilitated effects of GTS on electrically evoked contractions in guinea pig ileum (mu-receptors) and mouse vas deferens (delta-receptors) are not mediated through opioid receptors, suggesting the involvement of non-opioid mechanisms. GTS also attenuates hyperactivity, reverse tolerance (behavioral sensitization), and conditioned place preference induced by psychotropic agents, such as methamphetamine, cocaine, and morphine. These effects of GTS may be attributed to complex pharmacological actions between dopamine receptors and a serotonergic/adenosine A2A/ delta-opioid receptor complex. Ginsenosides also attenuate the morphine-induced cAMP signaling pathway. Together, the results suggest that GTS may be useful in the prevention and therapy of the behavioral side effects induced by psychotropic agents.

Clinical presentation, diagnosis, and pharmacotherapy of patients with primary brain tumors.

PubMed

Newton, H B; Turowski, R C; Stroup, T J; McCoy, L K

1999-01-01

To briefly review the clinical presentation and diagnosis of patients with primary brain tumors, followed by an in-depth survey of the pertinent pharmacotherapy. A detailed search of the neurologic, neurosurgical, and oncologic literature for basic science research, clinical studies, and review articles related to chemotherapy and pharmacotherapy of primary brain tumors. Relevant studies on tissue culture systems, animals, and humans examining the mechanisms of action, pharmacokinetics, clinical pharmacology, and treatment results of chemotherapeutic agents for primary brain tumors. In addition, studies of pharmacologic agents administered for supportive care and symptom control are reviewed. Primary brain tumors derive from cells within the intracranial cavity and generally present with headache, seizure activity, cognitive changes, and weakness. They are diagnosed most efficiently with magnetic resonance imaging. After diagnosis, the most common supportive medications include corticosteroids, gastric acid inhibitors, and anticonvulsants. Chemotherapy is adjunctive treatment for patients with malignant tumors and selected recurrent or progressive benign neoplasms. In general, the most effective chemotherapeutic drugs are alkylating agents such as the nitrosoureas, procarbazine, cisplatin, and carboplatin. Other agents used include cyclophosphamide, methotrexate, vincristine, and etoposide. Angiogenesis inhibitors and gene therapy comprise some of the novel therapeutic strategies under investigation. The efficacy of chemotherapy for primary brain tumors remains modest. Novel agents must be discovered that are more specific and attack tumor cells at the molecular level of tumorigenesis. Furthermore, strategies must be developed to counteract the pervasive problem of brain tumor chemoresistance.

Behavioral Tolerance to Anticholinergic Agents

DTIC Science & Technology

1986-11-20

Medicine , 47, 137-141. 7. Kurtz, P.J. (1977) Behavioral and biochemical effects of the carbamate insecticide, mobam. Pharmacology Biochemistry & Behavior...tolerance to marihuana in rats. Pharmacology Biochemistry and Behavior, 1, 73-76. 43 40. Olson, J. and Carder, B. (1974) Behavioral tolerance to... marihuana as a function of amount of prior training. Pharmacology Biochemistry and Behavior, 2, 243-247. 41. Sidman, M. (1960) Tactics of Scientific

Medicinal Plants for the Treatment of Local Tissue Damage Induced by Snake Venoms: An Overview from Traditional Use to Pharmacological Evidence

PubMed Central

Félix-Silva, Juliana; Silva-Junior, Arnóbio Antônio; Zucolotto, Silvana Maria

2017-01-01

Snakebites are a serious problem in public health due to their high morbimortality. Most of snake venoms produce intense local tissue damage, which could lead to temporary or permanent disability in victims. The available specific treatment is the antivenom serum therapy, whose effectiveness is reduced against these effects. Thus, the search for complementary alternatives for snakebite treatment is relevant. There are several reports of the popular use of medicinal plants against snakebites worldwide. In recent years, many studies have been published giving pharmacological evidence of benefits of several vegetal species against local effects induced by a broad range of snake venoms, including inhibitory potential against hyaluronidase, phospholipase, proteolytic, hemorrhagic, myotoxic, and edematogenic activities. In this context, this review aimed to provide an updated overview of medicinal plants used popularly as antiophidic agents and discuss the main species with pharmacological studies supporting the uses, with emphasis on plants inhibiting local effects of snake envenomation. The present review provides an updated scenario and insights into future research aiming at validation of medicinal plants as antiophidic agents and strengthens the potentiality of ethnopharmacology as a tool for design of potent inhibitors and/or development of herbal medicines against venom toxins, especially local tissue damage. PMID:28904556

Medicinal Plants for the Treatment of Local Tissue Damage Induced by Snake Venoms: An Overview from Traditional Use to Pharmacological Evidence.

PubMed

Félix-Silva, Juliana; Silva-Junior, Arnóbio Antônio; Zucolotto, Silvana Maria; Fernandes-Pedrosa, Matheus de Freitas

2017-01-01

Snakebites are a serious problem in public health due to their high morbimortality. Most of snake venoms produce intense local tissue damage, which could lead to temporary or permanent disability in victims. The available specific treatment is the antivenom serum therapy, whose effectiveness is reduced against these effects. Thus, the search for complementary alternatives for snakebite treatment is relevant. There are several reports of the popular use of medicinal plants against snakebites worldwide. In recent years, many studies have been published giving pharmacological evidence of benefits of several vegetal species against local effects induced by a broad range of snake venoms, including inhibitory potential against hyaluronidase, phospholipase, proteolytic, hemorrhagic, myotoxic, and edematogenic activities. In this context, this review aimed to provide an updated overview of medicinal plants used popularly as antiophidic agents and discuss the main species with pharmacological studies supporting the uses, with emphasis on plants inhibiting local effects of snake envenomation. The present review provides an updated scenario and insights into future research aiming at validation of medicinal plants as antiophidic agents and strengthens the potentiality of ethnopharmacology as a tool for design of potent inhibitors and/or development of herbal medicines against venom toxins, especially local tissue damage.

PARADIGM - HF: The Rise of the Arnis.

PubMed

Guha, Kaushik; Varkey, Sneha; Sharma, Rakesh

2016-01-01

Heart failure remains a widespread commonly encountered clinical condition. It is responsible for increased healthcare expenditure, driven by frequent and often prolonged hospital admissions associated with an increased mortality. A clinically useful classification of the syndrome is, patients with left ventricular systolic impairment (Heart Failure and reduced ejection fraction, HFREF) and patients with preserved left ventricular systolic function (HFPEF). The pharmacological treatment for patients with HFREF has evolved over the last twenty five years, focusing on modulation of the neurohormonal activation which represents a hallmark of this condition. This has led to the development of a stepwise treatment algorithm predominately based on inhibition of the renin angiotensin aldosterone pathway and counteracting sympathetic over-activation. In particular since the early trials in chronic heart failure (CHF) demonstrated a significant mortality benefit with ACE-inhibitors, subsequent studies have been conducted in conjunction with these drugs. The rationale being that it would be unethical to trial any new agent without the concomitant use of ACE-inhibitors. The recent publication of the PARADIGM -HF study has challenged this convention by trialling a novel pharmacological agent against an ACE-inhibitor in a landmark trial. The review sets out the current pharmacological treatment for patients with heart failure and discusses the recent findings with this novel class of medication.

[The development of neurotoxic agents as chemical weapons during the National Socialist period in Germany].

PubMed

López-Muñoz, F; Alamo, C; Guerra, J A; García-García, P

The discovery and development of the so-called 'nerve agents' (neurotoxic substances to be used as weapons) took place in the Third Reich, largely thanks to the vast amount of progress being made in pharmacology in Germany at that time, both in academic and industrial terms. Furthermore, successive National Socialist governments set up a collaborative network made up of the academia, the chemical industry and military chiefs that also favoured this line of research. The first neurotoxic substance to be incorporated into the category of 'chemical warfare agent' did so almost wholly by chance. As part of the work being carried out on organophosphate-type pesticides and insecticides, Gerald Schrader, a chemist at the I.G. Farben company, synthesised tabun (ethyl N,N-dimethylphosphoramidocyanidate) and an incident involving accidental contamination of laboratory staff with this substance highlighted its potential toxicity. The same group of researchers later synthesised another substance with the same properties, sarin (isopropyl methylphosphonofluoridate). Both agents were studied for use as chemical weapons by Wolfgang Wirth. At the same time, a group led by Richard Kuhn, who won the Nobel Prize in Chemistry in 1938, synthesised pinacolyl methylphosphonofluoridate, otherwise known as soman. Pharmacological studies confirmed that the neurotoxic mechanism of action of these substances was the irreversible inhibition of the enzyme acetylcholinesterase, which is responsible for metabolising acetylcholine. Results also showed that an excess of this neurotransmitter led to a continuous over-stimulation of the cholinergic (nicotinic and muscarinic) receptors, which is what triggers the appearance of the wide range of symptoms of poisoning and their swift fatal effect.

Respiratory health of elite athletes – preventing airway injury: a critical review

PubMed Central

Kippelen, Pascale; Fitch, Kenneth D; Anderson, Sandra Doreen; Bougault, Valerie; Boulet, Louis-Philippe; Rundell, Kenneth William; Sue-Chu, Malcolm; McKenzie, Donald C

2012-01-01

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established. PMID:22522585

Celecoxib: a potent cyclooxygenase-2 inhibitor in cancer prevention.

PubMed

Kismet, Kemal; Akay, M Turan; Abbasoglu, Osman; Ercan, Aygün

2004-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are the most widely used therapeutic agents in the treatment of pain, inflammation and fever. They may also have a role in the management of cancer prevention, Alzheimer's disease and prophylaxis against cardiovascular disease. These drugs act primarily by inhibiting cyclooxygenase enzyme, which has two isoforms, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2). Selective COX-2 inhibitors provide potent anti-inflammatory and analgesic effects without the side effects of gastric and renal toxicity and inhibition of platelet function. Celecoxib is a potent COX-2 inhibitor being developed for the treatment of rheumatoid arthritis and osteoarthritis. Chemoprevention is the use of pharmacological or natural agents to prevent, suppress, interrupt or reverse the process of carcinogenesis. For this purpose, celecoxib is being used for different cancer types. The effects of NSAIDs on tumor growth remain unclear, but are most likely to be multifocal. In this article, we reviewed COX-2 selectivity, the pharmacological properties of celecoxib, the use of celecoxib for cancer prevention and the mechanisms of chemoprevention.

Respiratory health of elite athletes - preventing airway injury: a critical review.

PubMed

Kippelen, Pascale; Fitch, Kenneth D; Anderson, Sandra Doreen; Bougault, Valerie; Boulet, Louis-Philippe; Rundell, Kenneth William; Sue-Chu, Malcolm; McKenzie, Donald C

2012-06-01

Elite athletes, particularly those engaged in endurance sports and those exposed chronically to airborne pollutants/irritants or allergens, are at increased risk for upper and lower airway dysfunction. Airway epithelial injury may be caused by dehydration and physical stress applied to the airways during severe exercise hyperpnoea and/or by inhalation of noxious agents. This is thought to initiate an inflammatory cascade/repair process that, ultimately, could lead to airway hyperresponsiveness (AHR) and asthma in susceptible athletes. The authors review the evidence relating to prevention or reduction of the risk of AHR/asthma development. Appropriate measures should be implemented when athletes exercise strenuously in an attempt to attenuate the dehydration stress and reduce the exposure to noxious airborne agents. Environmental interventions are the most important. Non-pharmacological strategies can assist, but currently, pharmacological measures have not been demonstrated to be effective. Whether early prevention of airway injury in elite athletes can prevent or reduce progression to AHR/asthma remains to be established.

Pharmacology in space. Part 2. Controlling motion sickness

NASA Technical Reports Server (NTRS)

Lathers, C. M.; Charles, J. B.; Bungo, M. W.

1989-01-01

In this second article in the two-part series on pharmacology in space, Claire Lathers and colleagues discuss the pharmacology of drugs used to control motion sickness in space and note that the pharmacology of the 'ideal' agent has yet to be worked out. That motion sickness may impair the pharmacological action of a drug by interfering with its absorption and distribution because of alteration of physiology is a problem unique to pharmacology in space. The authors comment on the problem of designing suitable ground-based studies to evaluate the pharmacological effect of drugs to be used in space and discuss the use of salivary samples collected during space flight to allow pharmacokinetic evaluations necessary for non-invasive clinical drug monitoring.

The pharmacological treatment and management of obesity.

PubMed

Hussain, Syed Sufyan; Bloom, Stephen Robert

2011-01-01

Obesity is a pandemic with many complications that increase the societal disease burden and cost of health care, and decrease longevity and quality of life. Currently, 1 in 3 adults in the United States is obese. Physicians must therefore regularly confront obesity and its consequent diseases, and develop strategies for effective treatment and management. This article summarizes current lifestyle modifications, pharmacological treatment, and surgical options for the management of obesity and discusses the benefits, limitations, and risks of each. As insights are gained into the pathophysiology of a gut-brain neurochemical feedback axis governing satiety and feeding behavior, targets for new pharmacotherapies are being developed. In particular, gut hormone analogs are an attractive antiobesity therapy because they appear to lack the adverse effects historically associated with central nervous system-acting agents.

Pharmacotherapeutic agents in the treatment of methamphetamine dependence.

PubMed

Morley, Kirsten C; Cornish, Jennifer L; Faingold, Alon; Wood, Katie; Haber, Paul S

2017-05-01

Methamphetamine use is a serious public health concern in many countries and is second to cannabis as the most widely abused illicit drug in the world. Effective management for methamphetamine dependence remains elusive and the large majority of methamphetamine users relapse following treatment. Areas covered: Progression in the understanding of the pharmacological basis of methamphetamine use has provided us with innovative opportunities to develop agents to treat dependence. The current review summarizes relevant literature on the neurobiological and clinical correlates associated with methamphetamine use. We then outline agents that have been explored for potential treatments in preclinical studies, human laboratory phase I and phase II trials over the last ten years. Expert opinion: No agent has demonstrated a broad and strong effect in achieving MA abstinence in Phase II trials. Agents with novel therapeutic targets appear promising. Advancement in MA treatment, including translation into practice, faces several clinical challenges.

Advances in antiplatelet therapy for acute coronary syndromes.

PubMed

Contractor, Hussain; Ruparelia, Neil

2012-07-01

Admissions to emergency care centres with acute coronary syndromes remain one of the principal burdens on healthcare systems in the Western world. Early pharmacological treatment in these patients is crucial, lessening the impact on both morbidity and mortality, with the cornerstone of management being antiplatelet agents. While aspirin and clopidogrel have been the drugs of choice for nearly a decade, an array of newer, more potent antiplatelet agents are now available or in late stage development. Data are rapidly gathering suggesting these agents have superior anti-ischaemic properties, improving patient outcomes, but that for some agents increased vigilance and appropriate patient selection may be necessary to guard against bleeding complications. In this review, the authors aim to deliver an overview of the changing field of antiplatelet therapy and provide information about the relative risks and benefits of these newer agents, many of which will be entering widespread clinical use imminently.

Neuroprotective "agents" in surgery. Secret "agent" man, or common "agent" machine?

NASA Technical Reports Server (NTRS)

Andrews, R. J.

1999-01-01

The search for clinically-effective neuroprotective agents has received enormous support in recent years--an estimated $200 million by pharmaceutical companies on clinical trials for traumatic brain injury alone. At the same time, the pathophysiology of brain injury has proved increasingly complex, rendering the likelihood of a single agent "magic bullet" even more remote. On the other hand, great progress continues with technology that makes surgery less invasive and less risky. One example is the application of endovascular techniques to treat coronary artery stenosis, where both the invasiveness of sternotomy and the significant neurological complication rate (due to microemboli showering the cerebral vasculature) can be eliminated. In this paper we review aspects of intraoperative neuroprotection both present and future. Explanations for the slow progress on pharmacologic neuroprotection during surgery are presented. Examples of technical advances that have had great impact on neuroprotection during surgery are given both from coronary artery stenosis surgery and from surgery for Parkinson's disease. To date, the progress in neuroprotection resulting from such technical advances is an order of magnitude greater than that resulting from pharmacologic agents used during surgery. The progress over the last 20 years in guidance during surgery (CT and MRI image-guidance) and in surgical access (endoscopic and endovascular techniques) will soon be complemented by advances in our ability to evaluate biological tissue intraoperatively in real-time. As an example of such technology, the NASA Smart Probe project is considered. In the long run (i.e., in 10 years or more), pharmacologic "agents" aimed at the complex pathophysiology of nervous system injury in man will be the key to true intraoperative neuroprotection. In the near term, however, it is more likely that mundane "agents" based on computers, microsensors, and microeffectors will be the major impetus to improved intraoperative neuroprotection.

Potential Antiosteoporotic Agents from Plants: A Comprehensive Review

PubMed Central

Jia, Min; Nie, Yan; Cao, Da-Peng; Xue, Yun-Yun; Wang, Jie-Si; Zhao, Lu; Rahman, Khalid; Zhang, Qiao-Yan; Qin, Lu-Ping

2012-01-01

Osteoporosis is a major health hazard and is a disease of old age; it is a silent epidemic affecting more than 200 million people worldwide in recent years. Based on a large number of chemical and pharmacological research many plants and their compounds have been shown to possess antiosteoporosis activity. This paper reviews the medicinal plants displaying antiosteoporosis properties including their origin, active constituents, and pharmacological data. The plants reported here are the ones which are commonly used in traditional medical systems and have demonstrated clinical effectiveness against osteoporosis. Although many plants have the potential to prevent and treat osteoporosis, so far, only a fraction of these plants have been thoroughly investigated for their physiological and pharmacological properties including their mechanism of action. An attempt should be made to highlight plant species with possible antiosteoporosis properties and they should be investigated further to help with future drug development for treating this disease. PMID:23365596

The Mind Bending Quest for Cognitive Enhancers

PubMed Central

Arce, E

2016-01-01

Adequate cognitive functioning is essential for daily activities. When there is an insult to the brain, cognitive abilities can suffer, which, in turn, produce substantial medical and functional impairment. Advances in neurobiology, circuit neuroscience, and clinical assessment technology are converging in a manner that holds promise for the development of new pharmacological agents for cognitive enhancement in neuropsychiatric disease. PMID:27706806

Emerging drugs for neuropathic pain.

PubMed

Gilron, Ian; Dickenson, Anthony H

2014-09-01

Neuropathic pain is a costly and disabling condition, which affects up to 8% of the population. Available therapies often provide incomplete pain relief and treatment-related side effects are common. Preclinical neuropathic pain models have facilitated identification of several promising targets, which have progressed to human clinical phases of evaluation. A systematic database search yielded 25 new molecular entities with specified pharmacological mechanisms that have reached Phase II or III clinical trials. These include calcium channel antagonists, vanilloid receptor antagonists, potassium channel agonists, NMDA antagonists, novel opioid receptor agonists, histamine H3 receptor antagonists, a novel sodium channel antagonist, serotonin modulators, a novel acetylcholine receptor agonist, α-2b adrenoreceptor agonist, cannabinoid CB2 receptor agonist, nitric oxide synthase inhibitor, orexin receptor antagonist, angiotensin II 2 antagonist, imidazoline I2 receptor agonist, apoptosis inhibitor and fatty acid amide hydrolase inhibitor. Although the diversity of pharmacological mechanisms of interest emphasise the complexity of neuropathic pain transmission, the considerable number of agents under development reflect a continued enthusiasm in drug development for neuropathic pain. Ongoing enhancements in methodology of both preclinical and clinical research and closer translation in both directions are expected to more efficiently identify new agents, which will improve the management of neuropathic pain.

Use of bedaquiline and delamanid in diabetes patients: clinical and pharmacological considerations.

PubMed

Hu, Minhui; Zheng, Chunlan; Gao, Feng

2016-01-01

Antituberculosis (anti-TB) treatment may be affected by both diabetes and hypoglycemic agents in patients with these 2 comorbidities. However, data supporting this conclusion relate only to standard anti-TB therapies. Sirturo ® (bedaquiline) and Deltyba ® (delamanid), novel drugs for multidrug-resistant tuberculosis (MDR-TB), are recommended for diabetes patients when another effective treatment regimen cannot be provided. Currently, there are no clinical data related to the use of these agents in diabetes patients. Possible alterations in the pharmacokinetics of these novel drugs induced by changes in subcutaneous adipose blood flow, gastric emptying, or nephropathy in diabetes patients, and possible drug-drug interactions with hypoglycemic agents, are of special interest, since the efficacy of bedaquiline and delamanid is concentration dependent. Moreover, it is of fundamental importance to avoid possible additive or synergistic effects of adverse drug reactions in this already vulnerable patient group. We reviewed clinical particularities related to the use of bedaquiline and delamanid in patients with type 1 and 2 diabetes mellitus (DM), as well as pharmacological aspects of the concurrent use of these agents with oral and injectable hypoglycemic agents. Bedaquiline shares liver metabolic pathways with several oral hypoglycemic agents, whereas delamanid may compete with several oral hypoglycemic agents and insulin analogs at protein-binding sites. Special concern exists regarding the use of bedaquiline and delamanid in diabetes patients aged >65 years and patients with severe renal or hepatic impairment or electrolyte disturbances. Concurrent use of bedaquiline and delamanid with insulin analogs, and other hypoglycemic agents that prolong the heart rate-corrected QT interval, such as sulfonylureas and glinides, may enhance this adverse reaction. Hepatic-related adverse reactions may develop more frequently when these drugs are combined with thiazolidinediones and acarbose. Data from Phase III and postmarketing studies are needed to elucidate the effect of DM and hypoglycemic agents on bedaquiline and delamanid effects in MDR-TB patients.

Current concepts in the pharmacological management of obesity.

PubMed

Carek, P J; Dickerson, L M

1999-06-01

The pharmacological management of obesity has gained increasing attention as new weight loss treatments are approved and a significant proportion of the public strives to lose weight. Obesity is associated with a high mortality rate, multiple chronic medical conditions, and carries an enormous financial burden. Obesity is a multifactorial condition, most often due to an imbalance in energy intake and expenditure. Despite the greater focus on management of obesity, weight loss remains a difficult goal to achieve. Obesity is a chronic medical condition that may require long term treatment, therefore the risks and benefits of all pharmacological agents must be carefully considered. Noradrenergic appetite suppressants (ie. phenyl-propanolamine, phentermine) result in weight loss but stimulatory effects limit their use. The serotonergic agents (fenfluramine, dexfenfluramine) were effective weight loss drugs, but were voluntarily withdrawn from the US market last year because of cardiovascular and pulmonary complications. The combination noradrenergic/serotonergic agent sibutramine is indicated for the management of obesity, particularly in the presence of other cardiovascular risk factors. Modest weight loss is achieved with sibutramine, although weight gain is significant after discontinuation. In addition, long term safety data are not yet available. The thermogenic combination of ephedrine plus caffeine is minimally effective, and adverse effects are usually transient. Other thermogenic agents, such as beta3-agonists, are still under investigation. Agents may alter digestion through lipase inhibition (orlistat) or fat substitution (olestra). Orlistat decreases systemic absorption of dietary fat, decreasing body weight and cholesterol. Olestra is a fat substitute that has been incorporated into snack foods. Olestra substitution for dietary fat has not been studied as a weight loss strategy, although olestra has no caloric value and may be beneficial. The use of orlistat and olestra may be limited by gastrointestinal adverse effects. Finally, the manipulation of leptin and neuropeptide Y are under investigation for the treatment of obesity. Pharmacological agents should be used as an aid to a structured diet and exercise regimen in the treatment of obesity. Weight loss agents may result in initial weight loss, but sustained weight loss is not always achieved even with continuation of treatment. The effect of weight loss obtained while using pharmacotherapeutic agents on morbidity and mortality has not been established. Therefore, diet and exercise should be the focus of any weight loss programme. There is a continued need for safe and effective pharmacotherapeutic agents for the treatment of obesity.

Pharmacologically directed strategies in academic anticancer drug discovery based on the European NCI compounds initiative.

PubMed

Hendriks, Hans R; Govaerts, Anne-Sophie; Fichtner, Iduna; Burtles, Sally; Westwell, Andrew D; Peters, Godefridus J

2017-07-11

The European NCI compounds programme, a joint initiative of the EORTC Research Branch, Cancer Research Campaign and the US National Cancer Institute, was initiated in 1993. The objective was to help the NCI in reducing the backlog of in vivo testing of potential anticancer compounds, synthesised in Europe that emerged from the NCI in vitro 60-cell screen. Over a period of more than twenty years the EORTC-Cancer Research Campaign panel reviewed ∼2000 compounds of which 95 were selected for further evaluation. Selected compounds were stepwise developed with clear go/no go decision points using a pharmacologically directed programme. This approach eliminated quickly compounds with unsuitable pharmacological properties. A few compounds went into Phase I clinical evaluation. The lessons learned and many of the principles outlined in the paper can easily be applied to current and future drug discovery and development programmes. Changes in the review panel, restrictions regarding numbers and types of compounds tested in the NCI in vitro screen and the appearance of targeted agents led to the discontinuation of the European NCI programme in 2017 and its transformation into an academic platform of excellence for anticancer drug discovery and development within the EORTC-PAMM group. This group remains open for advice and collaboration with interested parties in the field of cancer pharmacology.

Organotypic Slice Cultures for Studies of Postnatal Neurogenesis

PubMed Central

Mosa, Adam J.; Wang, Sabrina; Tan, Yao Fang; Wojtowicz, J. Martin

2015-01-01

Here we describe a technique for studying hippocampal postnatal neurogenesis in the rodent brain using the organotypic slice culture technique. This method maintains the characteristic topographical morphology of the hippocampus while allowing direct application of pharmacological agents to the developing hippocampal dentate gyrus. Additionally, slice cultures can be maintained for up to 4 weeks and thus, allow one to study the maturation process of newborn granule neurons. Slice cultures allow for efficient pharmacological manipulation of hippocampal slices while excluding complex variables such as uncertainties related to the deep anatomic location of the hippocampus as well as the blood brain barrier. For these reasons, we sought to optimize organotypic slice cultures specifically for postnatal neurogenesis research. PMID:25867138

Bone as an effect compartment : models for uptake and release of drugs.

PubMed

Stepensky, David; Kleinberg, Lilach; Hoffman, Amnon

2003-01-01

"Bone-seeking agents" are drugs characterised by high affinity for bone, and are disposed in bone for prolonged periods of time while maintaining remarkably low systemic concentrations. As a consequence, the bone becomes a reservoir for bone-seeking agents, and a site of both desirable and adverse effects, depending on the pharmacological activities of the specific agent. For some agents, significant systemic effects may also be produced following their prolonged release from bone, a process that is governed mostly by the rate of bone remodelling. This review covers the pharmacokinetic and pharmacodynamic features of bone-seeking agents with different pharmacological properties, including drugs (bisphosphonates, drug-bisphosphonate conjugates, radiopharmaceuticals and fluoride), bone markers (tetracycline, bone imaging agents) and toxins (lead, chromium, aluminium). In addition, drugs that do not possess bone-seeking properties but are used for therapy of bone diseases (such as antibacterials for treatment of osteomyelitis) are discussed, along with targeting of these drugs to the bone by conjugation to bone-seeking agents, local delivery systems, and other approaches. The pharmacokinetic and pharmacodynamic behaviour of bone-seeking agents is extremely complex due to heterogeneity in bone morphology and physiology. This complexity, accompanied by difficulties in human bone research caused by ethical and other limitations, gave rise to modelling approaches to study bone drug disposition. This review describes the pharmacokinetic models that have been proposed to describe the pharmacokinetic behaviour of bone-seeking agents and predict bone concentrations of these agents for different doses and patient populations. Models of different types (compartmental and physiologically based) and of different complexity have been applied, but their relevance to drug effects in the bone tissue is limited since they describe the behaviour of the "average" drug molecule. Understanding of the cellular and molecular processes responsible for the heterogeneity of bone tissue will provide better comprehension of the influence of microenvironment on drug bone disposition and the resulting pharmacological response.

Mind your salts: when the inactive constituent isn't.

PubMed

Neubig, Richard R

2010-10-01

Many pharmacological agents include "inactive" constituents that are used to alter the solubility, stability, or pharmaceutical properties of a drug. These "salts" are often ignored, and the "active ingredient" gets all of the attention. Pamoic acid (4-[(3-carboxy-2-hydroxynaphthalen-1-yl)methyl]-3-hydroxynaphthalene-2-carboxylic acid) has been used in formulations of several drugs as pamoate salts. This Perspective highlights an Accelerated Communication in this issue (p. 560) that identifies pamoic acid as a potent activator of the orphan G protein-coupled receptor GPR35. This effect may contribute to the pharmacological actions of some agents that are prepared as pamoate salts. Thus, pharmacologists, regulators, and clinicians should "mind their salts" in considering differences among supposedly equivalent agents.

Current concepts regarding pharmacologic treatment of rheumatoid and osteoarthritis.

PubMed

Wildy, K S; Wasko, M C

2001-05-01

Treating patients with osteoarthritis (OA) and rheumatoid arthritis (RA) remains challenging; however, new agents offer the chance for an improved quality of life. As an alternative to traditional nonsteroidal anti-inflammatories, cyclooxygenase-2 inhibitors provide pain relief for OA and RA patients with possible fewer side effects. Otherwise, OA patients may opt for topical agents, injections, or supplements. Rheumatoid arthritis research has led to an improved understanding of the inflammatory cascade and an appreciation of the early tissue destruction. A new treatment philosophy has thus emerged along with the development of new biologic agents; the latter, along with combination therapy and a new disease modifying antirheumatic drug, leflunomide, have greatly expanded the chances for disease control in RA patients.

Drugs in the Pipeline for the Obesity Market

PubMed Central

Klonoff, David C.; Greenway, Frank

2008-01-01

Obesity is a major public health problem. For many obese patients, diet and exercise are an inadequate treatment and bariatric surgery may be too extreme of a treatment. As with many other chronic diseases, pharmacologic treatment may be an attractive option for selected obese patients. Antiobesity drugs may potentially work through one of three mechanisms: (1) appetite suppression, (2) interference with absorption of nutrients, and (3) increased metabolism of nutrients. The three most widely prescribed drugs approved to treat obesity are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2–5 kg in addition to placebo. For pharmacologic therapy in obesity to be widely utilized, greater effectiveness and safety will be needed. Four types of single-agent drugs are in late stage development, including (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs. Four combination agent compounds in late stage development include (1) Contrave, which combines long-acting versions of naltrexone and bupropion; (2) Empatic, which combines long-acting bupropion and long-acting zonisamide; (3) Qnexa, which combines phentermine with controlled release topiramate; and (4) an injectable combination of leptin and pramlintide. Peptide YY and melanin-concentrating hormone receptor-1 antagonists are centrally acting agents in early stage development. It is expected that several new drug products for obesity will become available over the next few years. Their role in managing this disease remains to be determined. PMID:19885278

Drugs in the pipeline for the obesity market.

PubMed

Klonoff, David C; Greenway, Frank

2008-09-01

Obesity is a major public health problem. For many obese patients, diet and exercise are an inadequate treatment and bariatric surgery may be too extreme of a treatment. As with many other chronic diseases, pharmacologic treatment may be an attractive option for selected obese patients. Antiobesity drugs may potentially work through one of three mechanisms: (1) appetite suppression, (2) interference with absorption of nutrients, and (3) increased metabolism of nutrients. The three most widely prescribed drugs approved to treat obesity are phentermine, sibutramine, and orlistat. Drugs approved for treating obesity usually result in an additional weight loss of approximately 2-5 kg in addition to placebo. For pharmacologic therapy in obesity to be widely utilized, greater effectiveness and safety will be needed. Four types of single-agent drugs are in late stage development, including (1) selective central cannabinoid-1 receptor blockers, (2) selective central 5-hydroxytryptamine 2C serotonin receptor agonists, (3) an intestinal lipase blocker, and (4) central-acting incretin mimetic drugs. Four combination agent compounds in late stage development include (1) Contrave, which combines long-acting versions of naltrexone and bupropion; (2) Empatic, which combines long-acting bupropion and long-acting zonisamide; (3) Qnexa, which combines phentermine with controlled release topiramate; and (4) an injectable combination of leptin and pramlintide. Peptide YY and melanin-concentrating hormone receptor-1 antagonists are centrally acting agents in early stage development. It is expected that several new drug products for obesity will become available over the next few years. Their role in managing this disease remains to be determined.

Cell Culture System for Analysis of Genetic Heterogeneity Within Hepatocellular Carcinomas and Response to Pharmacologic Agents.

PubMed

Gao, Qiang; Wang, Zhi-Chao; Duan, Meng; Lin, Yi-Hui; Zhou, Xue-Ya; Worthley, Daniel L; Wang, Xiao-Ying; Niu, Gang; Xia, Yuchao; Deng, Minghua; Liu, Long-Zi; Shi, Jie-Yi; Yang, Liu-Xiao; Zhang, Shu; Ding, Zhen-Bin; Zhou, Jian; Liang, Chun-Min; Cao, Ya; Xiong, Lei; Xi, Ruibin; Shi, Yong-Yong; Fan, Jia

2017-01-01

No targeted therapies have been found to be effective against hepatocellular carcinoma (HCC), possibly due to the large degree of intratumor heterogeneity. We performed genetic analyses of different regions of HCCs to evaluate levels of intratumor heterogeneity and associate alterations with responses to different pharmacologic agents. We obtained samples of HCCs (associated with hepatitis B virus infection) from 10 patients undergoing curative resection, before adjuvant therapy, at hospitals in China. We collected 4-9 spatially distinct samples from each tumor (55 regions total), performed histologic analyses, isolated cancer cells, and carried them low-passage culture. We performed whole-exome sequencing, copy-number analysis, and high-throughput screening of the cultured primary cancer cells. We tested responses of an additional 105 liver cancer cell lines to a fibroblast growth factor receptor (FGFR) 4 inhibitor. We identified a total of 3670 non-silent mutations (3192 missense, 94 splice-site variants, and 222 insertions or deletions) in the tumor samples. We observed considerable intratumor heterogeneity and branched evolution in all 10 tumors; the mean percentage of heterogeneous mutations in each tumor was 39.7% (range, 12.9%-68.5%). We found significant mutation shifts toward C>T and C>G substitutions in branches of phylogenetic trees among samples from each tumor (P < .0001). Of note, 14 of the 26 oncogenic alterations (53.8%) varied among subclones that mapped to different branches. Genetic alterations that can be targeted by existing pharmacologic agents (such as those in FGF19, DDR2, PDGFRA, and TOP1) were identified in intratumor subregions from 4 HCCs and were associated with sensitivity to these agents. However, cells from the remaining subregions, which did not have these alterations, were not sensitive to these drugs. High-throughput screening identified pharmacologic agents to which these cells were sensitive, however. Overexpression of FGF19 correlated with sensitivity of cells to an inhibitor of FGFR 4; this observation was validated in 105 liver cancer cell lines (P = .0024). By analyzing genetic alterations in different tumor regions of 10 HCCs, we observed extensive intratumor heterogeneity. Our patient-derived cell line-based model, integrating genetic and pharmacologic data from multiregional cancer samples, provides a platform to elucidate how intratumor heterogeneity affects sensitivity to different therapeutic agents. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Pharmacological approaches to the treatment of complicated grief: rationale and a brief review of the literature

PubMed Central

Bui, Eric; Nadal-Vicens, Mireya; M. Simon, Naomi

2012-01-01

Complicated grief (CG) is a common and often under-acknowledged cause of profound impairment experienced after the loss of a loved one. Although both clinical and basic research suggests that pharmacological agents might be of use in the treatment of CG, research on pharmacological approaches to this condition is still scarce. Three open-label trials and one randomized trial on bereavement-related depression suggest that tricyclic antidepressants may be effective, although they may be more efficacious for depressive symptoms than for grief-specific symptoms. Four open-label trials (total number of participants, 50) of selective serotonin reuptake inhibitors (SSRIs) have yielded results, providing very preliminary support that they might be effective in the treatment of CG, both as a standalone treatment and in conjunction with psychotherapeutic interventions. These more recent studies have shown an effect on both depression and grief-specific scales. Furthermore, therapeutic interventions for CG may be more effective in conjunction with SSRI administration. Given the small number of pharmacological studies to date, there is a need for randomized trials to test the potential efficacy of pharmacological agents in the treatment of CG. PMID:22754287

Pharmacological enhancement of fear reduction: preclinical models

PubMed Central

Graham, Bronwyn M; Langton, Julia M; Richardson, Rick

2011-01-01

Anxiety disorders have a high prevalence, and despite the substantial advances in the psychological treatment of anxiety, relapse is still a common problem. One approach to improving existing psychological treatments for anxiety has been to develop pharmacological agents that can be used to enhance the processes underlying exposure therapy, which is the most commonly used and empirically validated psychological treatment for anxiety during which individuals are taught to appropriately inhibit fear. Animal models of exposure therapy, particularly fear extinction, have proved to be a very useful way of examining the neural and molecular correlates of fear inhibition, which has in turn led to the identification of numerous drugs that enhance these processes in rats. Several of these drugs have subsequently been tested as novel pharmacological adjuncts to exposure therapy in humans with a range of anxiety disorders. The purpose of this review is to outline the key animal models of exposure therapy and to describe how these have been used to develop potential pharmacological adjuncts for anxiety disorders. Drugs that are currently in clinical use, as well as those currently in the preclinical stages of investigation, are described. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21175588

Thrombopoietic agents.

PubMed

Stasi, Roberto; Bosworth, Jenny; Rhodes, Elizabeth; Shannon, Muriel S; Willis, Fenella; Gordon-Smith, Edward C

2010-01-01

Thrombopoietin (TPO) is the key cytokine involved in thrombopoiesis, and is the endogenous ligand for the thrombopoietin receptor that is expressed on the surface of platelets, megakaryocytes, and megakaryocytic precursors. First-generation thrombopoietic agents were recombinant forms of human TPO, and their development was discontinued after prolonged thrombocytopenia due to neutralizing auto-antibodies cross-reacting with endogenous TPO was observed. Second-generation thrombopoiesis-stimulating molecules are now available, which have unique pharmacological properties and no sequence homology to endogenous TPO. Two of these new agents, romiplostim and eltrombopag, have already completed phase III trials in primary immune thrombocytopenia and have been granted marketing authorization for use in this disease. Phase II and III trials with these novel drugs are ongoing in other conditions characterized by thrombocytopenia, such as chemotherapy, chronic liver disease, and the myelodysplastic syndromes. Most of the other second-generation thrombopoietic growth factors are in early phase clinical development. Copyright 2010 Elsevier Ltd. All rights reserved.

Use of atypical antipsychotics for treatment-resistant major depressive disorder.

PubMed

Papakostas, George I; Shelton, Richard C

2008-12-01

Despite the progressive increase in the number of pharmacologic agents with potential antidepressant activity, many patients suffering from major depressive disorder (MDD) continue to be symptomatic. Clearly, an urgent need exists to develop safer, better tolerated, and more effective treatments for MDD. Use of atypical antipsychotic agents as adjunctive treatment for treatment-resistant MDD (TRD) represents one such effort toward novel pharmacotherapy development. Atypical antipsychotic agents have been hypothesized to be beneficial in treating mood disorders, including TRD, as a result of their complex mechanisms of action. After an initial series of positive case reports, series, and small clinical trials, subsequent larger-scale projects have yielded conflicting results. However, more recently, larger-scale clinical trials have supported the effectiveness of at least some of these medications. This review summarizes the existing data regarding the effectiveness of these medications in treating TRD, including biochemical rationale and clinical data.

Current and Future Trials of Targeted Therapies in Cutaneous Melanoma

PubMed Central

Madhunapantula, SubbaRao V.; Robertson, Gavin P.; Drabick, Joseph J.

2013-01-01

In order to effectively treat melanoma, targeted inhibition of key mechanistic events regulating melanoma development such as cell proliferation, survival, angiogenesis and invasion or metastasis needs to be accomplished. The Mitogen Activated Protein Kinase (MAPK) pathway has been identified as a key player in melanoma development making this cascade an important therapeutic target. However, identification of the ideal pathway member to therapeutically target for maximal clinical benefit remains a challenge. In normal cells, the MAPK pathway relays extracellular signals from the cell membrane to the nucleus via a cascade of phosphorylation events, which promote cancer development. Dysregulation of the MAPK pathway occurs frequently in many human cancers including melanoma. Mutations in the B-RAF and RAS genes, genetic or epigenetic modifications are the key aberrations observed in this signaling cascade. Constitutive activation of this pathway causes oncogenic transformation of cells by promoting cell proliferation, invasion, metastasis, migration, survival and angiogenesis. This review provides an overview of (a) key members of MAPK signaling regulating melanoma development; (b) key proteins which can serve as biomarkers to assess disease progression; (c) the clinical efficacy of various pharmacological agents targeting MAPK pathway; (d) current clinical trials evaluating downstream targets of the MAPK pathway; (e) issues associated with pharmacological agents such as drug resistance, induction of cancers; and finally (e) various strategies overcoming drug resistance. PMID:23288642

Sunscreening Agents

PubMed Central

Martis, Jacintha; Shobha, V; Sham Shinde, Rutuja; Bangera, Sudhakar; Krishnankutty, Binny; Bellary, Shantala; Varughese, Sunoj; Rao, Prabhakar; Naveen Kumar, B.R.

2013-01-01

The increasing incidence of skin cancers and photodamaging effects caused by ultraviolet radiation has increased the use of sunscreening agents, which have shown beneficial effects in reducing the symptoms and reoccurrence of these problems. Many sunscreen compounds are in use, but their safety and efficacy are still in question. Efficacy is measured through indices, such as sun protection factor, persistent pigment darkening protection factor, and COLIPA guidelines. The United States Food and Drug Administration and European Union have incorporated changes in their guidelines to help consumers select products based on their sun protection factor and protection against ultraviolet radiation, whereas the Indian regulatory agency has not yet issued any special guidance on sunscreening agents, as they are classified under cosmetics. In this article, the authors discuss the pharmacological actions of sunscreening agents as well as the available formulations, their benefits, possible health hazards, safety, challenges, and proper application technique. New technologies and scope for the development of sunscreening agents are also discussed as well as the role of the physician in patient education about the use of these agents. PMID:23320122

Discovery, development, and clinical application of sugammadex sodium, a selective relaxant binding agent

PubMed Central

Welliver, Mark; McDonough, John; Kalynych, Nicholas; Redfern, Robert

2008-01-01

Neuromuscular blockade, induced by neuromuscular blocking agents, has allowed prescribed immobility, improved surgical exposure, optimal airway management conditions, and facilitated mechanical ventilation. However, termination of the effects of neuromuscular blocking agents has, until now, remained limited. A novel cyclodextrin encapsulation process offers improved termination of the paralytic effects of aminosteroidal non-depolarizing neuromuscular blocking agents. Sugammadex sodium is the first in a new class of drug called selective relaxant binding agents. Currently, in clinical trials, sugammadex, a modified gamma cyclodextrin, has shown consistent and rapid termination of neuromuscular blockade with few side effects. The pharmacology of cyclodextrins in general and sugammadex in particular, together with the results of current clinical research are reviewed. The ability of sugammadex to terminate the action of neuromuscular blocking agents by direct encapsulation is compared to the indirect competitive antagonism of their effects by cholinesterase inhibitors. Also discussed are the clinical implications that extend beyond fast, effective reversal, including numerous potential perioperative benefits. PMID:19920893

Comparison of TAK-438 (Vonoprazan) to Lansoprazole in the Treatment of Gastric Ulcer Participants With or Without Helicobacter Pylori Infection

ClinicalTrials.gov

2017-05-24

Gastric Ulcer; Peptic Ulcer; Gastrointestinal Diseases; Digestive System Diseases; Lansoprazole; Anti-Ulcer Agents; Gastrointestinal Agents; Proton Pump Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action

Pharmacological management of acute radiation morbidity.

PubMed

Zimmermann, J S; Kimmig, B

1998-11-01

The acute radiation morbidity may be a serious problem for the patient and may be decreased by pharmacological approaches. A database research (Medline, Cancerlit, DIMDI, etc.) was performed in order to obtain pharmacological approaches to decrease the acute radiation morbidity. The evaluation was focused on therapeutic principles but not on special drugs. Different approaches may be chosen to protect healthy tissues from the effects of ionizing radiation: 1. administration of cyto- or radioprotective agents prior to irradiation, 2. administration of agents to avoid additional secondary toxicity by inflammation or superinfection during the treatment cycle (supportive care) and 3. administration of rescue agents, such as bone marrow CSFs or hyperbaric oxygen (HBO), after therapy. For radioprotection, there are reports on cellular protection by vitamine E, vitamine C, beta carotene, ribose-cysteine, glutamine, Mgcl2/adenosine triphosphate and WR-2721 (amifostine). In general, preclinical studies show that the combination of pretreatment with amifostine, irradiation, and G-CSF after radiation enhances hematologic recovery. Assessment of these combined effects, including local supportive therapies, merits further clinical investigation. There are data from prospective studies as well as from empirical clinical experience, that radioprotection and clinical supportive care may reduce the treatment related morbidity by 10 to 30% either. A further improvement of the therapeutic ratio is to be expected by systemically combined application of radioprotectors, supportive care and rescue agents.

The Alkylating-HDAC Inhibition Fusion Principle: Taking Chemotherapy to the Next Level with the First in Class Molecule EDO-S101.

PubMed

Mehrling, Thomas; Chen, Yi

2016-01-01

Chemotherapy may still be an essential component to treat cancer in combination with new targeted therapies. But chemotherapy needs to get smarter in order to make those combination regimens more effective and also more tolerable, particularly for an aging population. We describe the first time the synthesis and pharmacological testing of a fusion molecule comprising of the alkylator bendamustine and the HDAC-inhibitor vorinostat. The drug was designed to allow for the exploitation of both mechanisms of action simultaneously with the goal to provide a molecule with superior efficacy over the single agents. The pharmacological testing confirms the full functional capacity of both moieties and encouraging pharmacological data raises the hope that the drug may turn out to be a great addition to the armentarium of anticancer agents.

JPRS Report, Science & Technology, Japan.

DTIC Science & Technology

1988-06-25

search for antibacterial substances, antitumor agents or biologically active substances such as toxins and other pharmacologically active substances from...total cost of ¥1.35 billion. Delivery is scheduled for March 1988. This helicopter will be used for various purposes, such as rescue activities , etc...long standing, has suddenly changed. Now, it is concentrating very effectively on development activities so as to be one of the pioneers in

Cannabis Pharmacology: The Usual Suspects and a Few Promising Leads.

PubMed

Russo, Ethan B; Marcu, Jahan

2017-01-01

The golden age of cannabis pharmacology began in the 1960s as Raphael Mechoulam and his colleagues in Israel isolated and synthesized cannabidiol, tetrahydrocannabinol, and other phytocannabinoids. Initially, THC garnered most research interest with sporadic attention to cannabidiol, which has only rekindled in the last 15 years through a demonstration of its remarkably versatile pharmacology and synergy with THC. Gradually a cognizance of the potential of other phytocannabinoids has developed. Contemporaneous assessment of cannabis pharmacology must be even far more inclusive. Medical and recreational consumers alike have long believed in unique attributes of certain cannabis chemovars despite their similarity in cannabinoid profiles. This has focused additional research on the pharmacological contributions of mono- and sesquiterpenoids to the effects of cannabis flower preparations. Investigation reveals these aromatic compounds to contribute modulatory and therapeutic roles in the cannabis entourage far beyond expectations considering their modest concentrations in the plant. Synergistic relationships of the terpenoids to cannabinoids will be highlighted and include many complementary roles to boost therapeutic efficacy in treatment of pain, psychiatric disorders, cancer, and numerous other areas. Additional parts of the cannabis plant provide a wide and distinct variety of other compounds of pharmacological interest, including the triterpenoid friedelin from the roots, canniprene from the fan leaves, cannabisin from seed coats, and cannflavin A from seed sprouts. This chapter will explore the unique attributes of these agents and demonstrate how cannabis may yet fulfil its potential as Mechoulam's professed "pharmacological treasure trove." © 2017 Elsevier Inc. All rights reserved.

Interleukin-10: biology, role in inflammation and autoimmunity.

PubMed

Lalani, I; Bhol, K; Ahmed, A R

1997-12-01

Reading this article will increase the readers' knowledge of the biology of interleukin-10 (IL-10) an important cytokine. The survival of an organism and its host defense mechanisms require, among other processes, a complex but target-oriented interaction and an interdependence between the immune and inflammatory pathways. The biologic role of interleukin-10 in these processes is presented as well as the possible involvement of IL-10 in the pathogenesis of various diseases. The influence of pharmacologic agents on IL-10 production and the possible pharmacologic role of IL-10 itself are discussed. A detailed literature search was conducted. Studies considered relevant and important involving both humans and animals, in all languages were used. Material was taken only from peer reviewed journals. IL-10 is produced by CD4+, Tho, Th1, B lymphocytes, mast cells, eosinophils, monocytes, macrophages and keratinocytes. IL-10 has a diverse array of actions, which differ depending on cell type, nature of stimulus and the cellular microenvironment. Interleukin-10 has an important role in the inflammatory and immune systems. In addition, present studies suggest that IL-10 may well play a pivotal role in the pathogenesis of several diseases. It has the potential for therapeutic use. Most of the data on IL-10 have been obtained from in vitro studies or animal experiments. Studies on humans are few, but rapidly increasing. Interleukin-10 is an important molecule with a central role in maintaining health and in the pathogenesis of disease. Known pharmacologic agents and some under investigation can modify IL-10 production in vivo. Development of agents that can selectively affect a very specific biologic action of IL-10 may provide significant benefit in treating autoimmune and inflammatory diseases.

Prescribing pattern of psychotropic medications in child psychiatric practice in a mental referral hospital in Botswana

PubMed Central

Olashore, Anthony; Ayugi, James; Opondo, Philip

2017-01-01

Introduction There is a growing preference for psycho-pharmacological therapy over non-pharmacological care. The prescription pattern and the choice of psychotropic medications vary in different settings. Whilst newer agents and rational prescribing are favored in the more specialized settings, the pattern remains unclear in less specialized units, largely due to lack of data. The aims were to conduct a treatment audit in the only mental referral hospital in Botswana, which is a non-specialized child and adolescent care setting and see how it conforms to best practice. Methods A retrospective audit which involved the extraction of socio-demographic and clinical information from the records of patients who were ≤ 17 years and seen from January 1, 2012-July 31, 2016. Results A total of 238 files were used for this report. Mean age (SD) was 12.41 (4.1) years. Of the 120 (50.4%) patients who had pharmacological intervention, only 85(70.8%) had monotherapy. The most commonly prescribed psychotropic agents were antipsychotics (40%). Off-label use of antipsychotics and polypharmacy were 31.2% and 29.2% respectively. Conclusion The level of conformity to standard practice in terms of psychotropic prescribing in our setting is consistent with the reports from developed countries where more specialized care ostensibly exists. Further studies will be necessary to determine the scope of psychotropic use. PMID:28491214

Assessing the effects of pharmacological agents on respiratory dynamics using time-series modeling.

PubMed

Wong, Kin Foon Kevin; Gong, Jen J; Cotten, Joseph F; Solt, Ken; Brown, Emery N

2013-04-01

Developing quantitative descriptions of how stimulant and depressant drugs affect the respiratory system is an important focus in medical research. Respiratory variables-respiratory rate, tidal volume, and end tidal carbon dioxide-have prominent temporal dynamics that make it inappropriate to use standard hypothesis-testing methods that assume independent observations to assess the effects of these pharmacological agents. We present a polynomial signal plus autoregressive noise model for analysis of continuously recorded respiratory variables. We use a cyclic descent algorithm to maximize the conditional log likelihood of the parameters and the corrected Akaike's information criterion to choose simultaneously the orders of the polynomial and the autoregressive models. In an analysis of respiratory rates recorded from anesthetized rats before and after administration of the respiratory stimulant methylphenidate, we use the model to construct within-animal z-tests of the drug effect that take account of the time-varying nature of the mean respiratory rate and the serial dependence in rate measurements. We correct for the effect of model lack-of-fit on our inferences by also computing bootstrap confidence intervals for the average difference in respiratory rate pre- and postmethylphenidate treatment. Our time-series modeling quantifies within each animal the substantial increase in mean respiratory rate and respiratory dynamics following methylphenidate administration. This paradigm can be readily adapted to analyze the dynamics of other respiratory variables before and after pharmacologic treatments.

Isoprenoids and related pharmacological interventions: potential application in Alzheimer's disease.

PubMed

Li, Ling; Zhang, Wei; Cheng, Shaowu; Cao, Dongfeng; Parent, Marc

2012-08-01

Two major isoprenoids, farnesyl pyrophosphate and geranylgeranyl pyrophosphate, serve as lipid donors for the posttranslational modification (known as prenylation) of proteins that possess a characteristic C-terminal motif. The prenylation reaction is catalyzed by prenyltransferases. The lipid prenyl group facilitates to anchor the proteins in cell membranes and mediates protein-protein interactions. A variety of important intracellular proteins undergo prenylation, including almost all members of small GTPase superfamilies as well as heterotrimeric G protein subunits and nuclear lamins. These prenylated proteins are involved in regulating a wide range of cellular processes and functions, such as cell growth, differentiation, cytoskeletal organization, and vesicle trafficking. Prenylated proteins are also implicated in the pathogenesis of different types of diseases. Consequently, isoprenoids and/or prenyltransferases have emerged as attractive therapeutic targets for combating various disorders. This review attempts to summarize the pharmacological agents currently available or under development that control isoprenoid availability and/or the process of prenylation, mainly focusing on statins, bisphosphonates, and prenyltransferase inhibitors. Whereas statins and bisphosphonates deplete the production of isoprenoids by inhibiting the activity of upstream enzymes, prenyltransferase inhibitors directly block the prenylation of proteins. As the importance of isoprenoids and prenylated proteins in health and disease continues to emerge, the therapeutic potential of these pharmacological agents has expanded across multiple disciplines. This review mainly discusses their potential application in Alzheimer's disease.

Sustained/Continuous Operations Subgroup of the Department of Defense Human Factors Engineering Technical Group: Program Summary and Substracts from the Semiannual Meeting (9th) Held in Pensacola, Florida on 11-12 July 1989.

DTIC Science & Technology

1990-03-01

User’s Guide will include the guidelines on the use of pharmacological agents in the context of sleep management . The nature of short sleep (napping) is...are used to evaluate effects and the mechanisms of action of pharmacological agents. Results and Future Obiectives Benzodiazepines and tryptophan...Arlington, ViA 22202.4302. arid to the Offi(e of Management and Budget. Paperwork RedLction Project (0704.0188), Washington, DC 20503. 1. AGENCY USE

Cellular mechanisms against ischemia reperfusion injury induced by the use of anesthetic pharmacological agents.

PubMed

Álvarez, P; Tapia, L; Mardones, L A; Pedemonte, J C; Farías, J G; Castillo, R L

2014-07-25

Ischemia-reperfusion (IR) cycle in the myocardium is associated with activation of an injurious cascade, thus leading to new myocardial challenges, which account for up to 50% of infarct size. Some evidence implicates reactive oxygen species (ROS) as a probable cause of myocardial injury in prooxidant clinical settings. Damage occurs during both ischemia and post-ischemic reperfusion in animal and human models. The mechanisms that contribute to this damage include the increase in cellular calcium (Ca(2+)) concentration and induction of ROS sources during reperfusion. Pharmacological preconditioning, which includes pharmacological strategies that counteract the ROS burst and Ca(2+) overload followed to IR cycle in the myocardium, could be effective in limiting injury. Currently widespread evidence supports the use of anesthetics agents as an important cardioprotective strategy that act at various levels such as metabotropic receptors, ion channels or mitochondrial level. Their administration before a prolonged ischemic episode is known as anesthetic preconditioning, whereas when given at the very onset of reperfusion, is termed anesthetic postconditioning. Both types of anesthetic conditioning reduce, albeit not to the same degree, the extent of myocardial injury. This review focuses on cellular and pathophysiological concepts on the myocardial damage induced by IR and how anesthetic pharmacological agents commonly used could attenuate the functional and structural effects induced by oxidative stress in cardiac tissue. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

A Systematic Review of Topical Vasodilators for the Treatment of Intraoperative Vasospasm in Reconstructive Microsurgery.

PubMed

Vargas, Christina R; Iorio, Matthew L; Lee, Bernard T

2015-08-01

Intraoperative vasospasm during reconstructive microsurgery is common, often unpredictable, and potentially devastating with regard to flap survival. Current methods of pharmacologic management vary, and may be shifting as a result of changes in the availability of individual medications. This review aims to provide a concise examination of the published literature regarding use, efficacy, and adverse effects of the agents described for local management of vascular spasm during microsurgery. A systematic review of the literature was performed to identify articles relevant to pharmacologic treatment of intraoperative vasospasm in vivo. An additional review of the literature was performed with regard to each agent identified in order to provide clinical background information. Systematic review identified 20 articles, in which 14 vasodilator agents were evaluated. Drugs were classified into five pharmacologic categories: phosphodiesterase inhibitors (papaverine, pentoxifylline, and amrinone), local anesthetics (lidocaine), calcium channel blockers (nicardipine, verapamil, nifedipine, and magnesium sulfate), direct vasodilators (sodium nitroprusside, prostaglandin E1, nitroglycerin, and hydralazine), and alpha antagonists (phentolamine and chlorpromazine). Despite a variety of methods, these studies indicate some degree of experimental evidence of efficacy for each of these agents. Available literature regarding use of topical vasodilating agents for intraoperative management of vasospasm during microsurgery is limited and largely based on animal models, which may not reliably generalize to the reconstructive patient population. Well-controlled translational study in clinically applicable and reproducible models is needed to guide evidence-based clinical management of this important phenomenon.

[Evaluation of anti-inflammatory activity of extracts from Siberian plants].

PubMed

Nesterova, Iu V; Povet'eva, T N; Aksinenko, S G; Suslov, N I; Gaĭdamovich, N N; Nagorniak, Iu G; Popova, E V; Kravtsova, S S; Andreeva, T I

2009-01-01

Experimental investigations have shown that water-alcohol extracts from plants containing alkaloids (Aconitum baikalense, Aconitum septentrionale, Delphinium elatum L., Conium maculatum) and salicylic acid (Filipendula ulmaria, Salix viminalis, Fragaria vesca, Rubus idaeus) inhibited the development of main symptoms of inflammation, viz. exudation, pain, fever, to the same extent as non-steroidal anti-inflammatory agents. The substances studied in this work may be used to develop new efficient pharmacological preparations for the treatment of different inflammatory conditions associated with severe pain syndrome.

Antiretroviral therapy: current drugs.

PubMed

Pau, Alice K; George, Jomy M

2014-09-01

The rapid advances in drug discovery and the development of antiretroviral therapy is unprecedented in the history of modern medicine. The administration of chronic combination antiretroviral therapy targeting different stages of the human immunodeficiency virus' replicative life cycle allows for durable and maximal suppression of plasma viremia. This suppression has resulted in dramatic improvement of patient survival. This article reviews the history of antiretroviral drug development and discusses the clinical pharmacology, efficacy, and toxicities of the antiretroviral agents most commonly used in clinical practice to date. Published by Elsevier Inc.

Current status and future directions of pharmacological therapy for acromegaly.

PubMed

Mercado, Moisés; Espinosa, Etual; Ramírez, Claudia

2016-09-01

Acromegaly is a chronic systemic disorder caused in the vast majority of cases by a GH-secreting pituitary adenoma and resulting in significant morbidity and mortality if left untreated. The treatment of choice is the trans-sphenoidal resection of the adenoma, and although 80% of patients with microadenomas or confined macroadenomas achieve biochemical remission, the surgical success rate for patients harboring tumors with extrasellar extension is below 50%. Thus, a considerable proportion of patients will require some form of adjuvant treatment. Acromegaly can be approached pharmacologically by inhibiting GH secretion by the tumor (somatostatin analogues, dopamine agonists) or by antagonizing GH actions at its target tissues (GH receptor antagonists). The primary pharmacological treatment of acromegaly is increasingly gaining acceptance by both physicians and patients. The decision to use primary pharmacological treatment has to take into account the clinical characteristics of the patient (presence of comorbidities that significantly increase the surgical risk) and the biological nature of the adenoma (tumor size and location), as well as other aspects such as the availability of a pituitary surgeon and the cost of medications. This review provides a critical summary and update of the pharmacological treatment of acromegaly focusing both, on well-established agents and strategies as well as on novel compounds that are currently being developed.

Pattern Recognition Applications in Chemistry and Pharmacology: A ’Pharmacophore Acetylcholinoreceptor’ Subunit Environment Model,

DTIC Science & Technology

1980-06-01

development and refinement of our model took place in three phases: 1. (a) The 3-dimensional structures of the rigid neuro- muscular blocking agents that...Table 1) is an anticholinesterase agent . Bullock (40) has reported that Soman can attack not only AChE irreversibly, but at high concentrations may... VIol AIiilioh’ 101 H At,% -. H~*\\U,,IN,%ttN *ILLIIILI.IIIA.LLIIAIL A I II LLL’L NlMII’LLL lt N AIIL 1AIIN .11I ’IRM INIIIN 911 ANAL I ILLIALIINIIN tMtINHNIN. 14%1AI4 A IAI11N 119

Single cell imaging of Bruton's Tyrosine Kinase using an irreversible inhibitor

NASA Astrophysics Data System (ADS)

Turetsky, Anna; Kim, Eunha; Kohler, Rainer H.; Miller, Miles A.; Weissleder, Ralph

2014-04-01

A number of Bruton's tyrosine kinase (BTK) inhibitors are currently in development, yet it has been difficult to visualize BTK expression and pharmacological inhibition in vivo in real time. We synthesized a fluorescent, irreversible BTK binder based on the drug Ibrutinib and characterized its behavior in cells and in vivo. We show a 200 nM affinity of the imaging agent, high selectivity, and irreversible binding to its target following initial washout, resulting in surprisingly high target-to-background ratios. In vivo, the imaging agent rapidly distributed to BTK expressing tumor cells, but also to BTK-positive tumor-associated host cells.

Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease.

PubMed

Duty, Susan; Jenner, Peter

2011-10-01

Animal models of Parkinson's disease (PD) have proved highly effective in the discovery of novel treatments for motor symptoms of PD and in the search for clues to the underlying cause of the illness. Models based on specific pathogenic mechanisms may subsequently lead to the development of neuroprotective agents for PD that stop or slow disease progression. The array of available rodent models is large and ranges from acute pharmacological models, such as the reserpine- or haloperidol-treated rats that display one or more parkinsonian signs, to models exhibiting destruction of the dopaminergic nigro-striatal pathway, such as the classical 6-hydroxydopamine (6-OHDA) rat and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse models. All of these have provided test beds in which new molecules for treating the motor symptoms of PD can be assessed. In addition, the emergence of abnormal involuntary movements (AIMs) with repeated treatment of 6-OHDA-lesioned rats with L-DOPA has allowed for examination of the mechanisms responsible for treatment-related dyskinesia in PD, and the detection of molecules able to prevent or reverse their appearance. Other toxin-based models of nigro-striatal tract degeneration include the systemic administration of the pesticides rotenone and paraquat, but whilst providing clues to disease pathogenesis, these are not so commonly used for drug development. The MPTP-treated primate model of PD, which closely mimics the clinical features of PD and in which all currently used anti-parkinsonian medications have been shown to be effective, is undoubtedly the most clinically-relevant of all available models. The MPTP-treated primate develops clear dyskinesia when repeatedly exposed to L-DOPA, and these parkinsonian animals have shown responses to novel dopaminergic agents that are highly predictive of their effect in man. Whether non-dopaminergic drugs show the same degree of predictability of response is a matter of debate. As our understanding of the pathogenesis of PD has improved, so new rodent models produced by agents mimicking these mechanisms, including proteasome inhibitors such as PSI, lactacystin and epoximycin or inflammogens like lipopolysaccharide (LPS) have been developed. A further generation of models aimed at mimicking the genetic causes of PD has also sprung up. Whilst these newer models have provided further clues to the disease pathology, they have so far been less commonly used for drug development. There is little doubt that the availability of experimental animal models of PD has dramatically altered dopaminergic drug treatment of the illness and the prevention and reversal of drug-related side effects that emerge with disease progression and chronic medication. However, so far, we have made little progress in moving into other pharmacological areas for the treatment of PD, and we have not developed models that reflect the progressive nature of the illness and its complexity in terms of the extent of pathology and biochemical change. Only when this occurs are we likely to make progress in developing agents to stop or slow the disease progression. The overarching question that draws all of these models together in the quest for better drug treatments for PD is how well do they recapitulate the human condition and how predictive are they of successful translation of drugs into the clinic? This article aims to clarify the current position and highlight the strengths and weaknesses of available models. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

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

Walker, E.M. Jr.; Gale, G.R.

Cisplatin, an agent widely used in the chemotherapy of a variety of human malignancies, is often dose-limited owing to its nephrotoxicity. Some of the approaches under consideration, regarding the reduction of cisplatin nephrotoxicity, include the use of hydration and osmotic diuresis, pharmacological diuretics, chelating agents or agents which otherwise react with cisplatin or reverse cisplatin-induced deoxyribonucleic acid cross-links, and antioxidants to destroy free radicals, especially superoxide radicals, produced by cisplatin. The effects of each of these and other interventions on cisplatin-induced nephrotoxicity are delineated, along with their proposed mechanisms and effects on therapeutic efficacy. The current status of development ofmore » organoplatinum analogs yielding congeners with less nephrotoxicity and greater efficacy is discussed briefly. Finally, a possible role of endogenous and/or exogenous prostaglandins in protecting against or reversing heavy metal nephrotoxicity is suggested.« less

Review of pharmacological therapy for tinnitus.

PubMed

Patterson, Matthew B; Balough, Ben J

2006-01-01

This article provides a review of studies investigating the pharmacological treatment of tinnitus. Tinnitus continues to be a significant and costly health problem without a uniformly accepted treatment. A wide variety of studies exploring prescription, supplement, and vitamin therapies are assessed for efficacy of treatment and for establishing consistencies in symptom definition, assessment, and outcome measures. This review reveals no compelling evidence suggesting the efficacy of any pharmacological agent in the treatment of tinnitus. Analysis of prior investigations provides insight to appropriate methods for future work, which are outlined.

Aripiprazole.

PubMed

Prommer, Eric

2017-03-01

Delirium is a palliative care emergency where patients experience changes in perception, awareness, and behavior. Common features include changes in the sleep-wake cycle, emotional lability, delusional thinking, and language and thought disorders. Delirium results from neurotransmitter imbalances involving several neurotransmitters such as dopamine, glutamate, norepinephrine, acetylcholine, gamma-aminobutyric acid, and serotonin. Untreated delirium causes significant morbidity and mortality. Nonpharmacologic and pharmacologic approaches treat delirium. Current pharmacologic management of delirium involves using agents such as haloperidol or second-generation antipsychotics. Third-generation atypical antipsychotic drugs have emerged as a potential choice for delirium management. Aripiprazole is a third-generation antipsychotic with a dopamine receptor-binding profile distinct from other second-generation antipsychotics. Aripiprazole acts as partial agonist at dopamine D 2 and 5-hydroxytryptamine (5-HT) 1A receptors, stabilizing the dopamine receptor leading to improvement in symptoms. The article reviews the pharmacology, pharmacodynamics, metabolism, and evidence of clinical efficacy for this new antipsychotic agent. This article explores possible roles in palliative care.

Atypical Dopamine Uptake Inhibitors that Provide Clues About Cocaine's Mechanism at the Dopamine Transporter

NASA Astrophysics Data System (ADS)

Hauck Newman, Amy; Katz, Jonathan L.

The dopamine transporter (DAT) has been a primary target for cocaine abuse/addiction medication discovery. However predicted addiction liability and limited clinical evaluation has provided a formidable challenge for development of these agents for human use. The unique and atypical pharmacological profile of the benztropine (BZT) class of dopamine uptake inhibitors, in preclinical models of cocaine effects and abuse, has encouraged further development of these agents. Moreover, in vivo studies have challenged the original DAT hypothesis and demonstrated that DAT occupancy and subsequent increases in dopamine produced by BZT analogues are significantly delayed and long lasting, as compared to cocaine. These important and distinctive elements are critical to the lack of abuse liability among BZT analogues, and improve their potential for development as treatments for cocaine abuse and possibly other neuropsychiatric disorders.

Pattern Recognition of Cardiovascular and Psychomotor Variability in Response to Pharmacological Agent.

DTIC Science & Technology

1985-06-10

research. 7. A. Sleep research, chronobiology , and performance research have developed as three separate areas, but there is (and should be) growing...and Oxygen Uptake Response to performance of Xarate Kata, Journal ot Sports Medicine, Vol. 22, 1982. (6] D.A. Sideris, J.N. Nanas, S.Thomakos, and...DOWNGRADING SCHEDULE Approved for public release; distribution unlimited 4. PERFORMING ORGANIZATION REPORT NUMBER(S) S. MONITORING ORGANIZATION REPORT NUMBER

Averrhoa bilimbi Linn.: A review of its ethnomedicinal uses, phytochemistry, and pharmacology

PubMed Central

Alhassan, Alhassan Muhammad; Ahmed, Qamar Uddin

2016-01-01

Averrhoa bilimbi Linn. is principally cultivated for medicinal purposes in many tropical and subtropical countries of the world. Literature survey about this plant shows that A. bilimbi is mainly used as a folk medicine in the treatment of diabetes mellitus, hypertension, and as an antimicrobial agent. The prime objective of this review is to accumulate and organize literature based on traditional claims and correlate those with current findings on the use of A. bilimbi in the management of different ailments. Through interpreting already published scientific manuscripts (1995 through 2015) retrieved from the different scientific search engines, namely Medline, PubMed, EMBASE, and Science Direct databases, published articles and reports covering traditional and scientific literature related to A. bilimbi's potential role against various ailments have been thoroughly evaluated, interpreted, and discussed. Several pharmacological studies have demonstrated the ability of this plant to act as antidiabetic, antihypertensive, thrombolytic, antimicrobial, antioxidant, hepatoprotective, and hypolipidemic agent. A. bilimbi holds great value in the complementary and alternative medicine as evidenced by the substantial amount of research on it. Therefore, we aimed to compile an up-to-date and comprehensive review of A. bilimbi that covers its traditional and folk medicine uses, phytochemistry, and pharmacology. Hence, this paper presents an up-to-date and comprehensive review of the ethnomedicinal uses, different chemical constituents, and pharmacological activities of A. bilimbi. So far, the biologically active agents have not been isolated from this plant and this can be a good scientific study for the future antidiabetic, antihypertensive, and antimicrobial implications. Hence, this review targets at emphasizing the diverse traditional claims and pharmacological activities of A. bilimbi with respect to carrying out more scientific studies to isolate active principles through advanced technology. PMID:28216948

Averrhoa bilimbi Linn.: A review of its ethnomedicinal uses, phytochemistry, and pharmacology.

PubMed

Alhassan, Alhassan Muhammad; Ahmed, Qamar Uddin

2016-01-01

Averrhoa bilimbi Linn. is principally cultivated for medicinal purposes in many tropical and subtropical countries of the world. Literature survey about this plant shows that A. bilimbi is mainly used as a folk medicine in the treatment of diabetes mellitus, hypertension, and as an antimicrobial agent. The prime objective of this review is to accumulate and organize literature based on traditional claims and correlate those with current findings on the use of A. bilimbi in the management of different ailments. Through interpreting already published scientific manuscripts (1995 through 2015) retrieved from the different scientific search engines, namely Medline, PubMed, EMBASE, and Science Direct databases, published articles and reports covering traditional and scientific literature related to A. bilimbi 's potential role against various ailments have been thoroughly evaluated, interpreted, and discussed. Several pharmacological studies have demonstrated the ability of this plant to act as antidiabetic, antihypertensive, thrombolytic, antimicrobial, antioxidant, hepatoprotective, and hypolipidemic agent. A. bilimbi holds great value in the complementary and alternative medicine as evidenced by the substantial amount of research on it. Therefore, we aimed to compile an up-to-date and comprehensive review of A. bilimbi that covers its traditional and folk medicine uses, phytochemistry, and pharmacology. Hence, this paper presents an up-to-date and comprehensive review of the ethnomedicinal uses, different chemical constituents, and pharmacological activities of A. bilimbi . So far, the biologically active agents have not been isolated from this plant and this can be a good scientific study for the future antidiabetic, antihypertensive, and antimicrobial implications. Hence, this review targets at emphasizing the diverse traditional claims and pharmacological activities of A. bilimbi with respect to carrying out more scientific studies to isolate active principles through advanced technology.

Presynaptic transmitters and depolarizing influences regulate development of the substantia nigra in culture.

PubMed

Friedman, W J; Dreyfus, C F; McEwen, B; Black, I B

1988-10-01

Recent evidence suggests that extracellular signals regulate neurotransmitter traits in brain catecholaminergic (CA) neurons as in the periphery. Development of the dopaminergic phenotype in the mouse substantia nigra (SN) was studied by monitoring tyrosine hydroxylase (TH), the rate-limiting enzyme in CA biosynthesis in vivo and in culture. Explants of SN were dissected from embryonic day 15 embryos and grown in culture for a week. To define the influence of depolarizing signals on central dopaminergic neurons, cultures were grown with the pharmacologic depolarizing agent veratridine. This treatment elicited a significant increase in TH enzyme activity, accompanied by elevated levels of enzyme protein. The increase in activity was prevented by TTX, suggesting that transmembrane Na+ influx was necessary for the rise in TH. A physiologic presynaptic agonist, substance P, also evoked a significant increase in TH activity; however, the coproduced tachykinin peptide, substance K (SK, neurokinin A) elicited a more dramatic rise. The SK effect was blocked by TTX, suggesting that the physiologic agonist was acting through the same mechanism as the pharmacologic agent veratridine. Immunoblot analysis revealed that SK elicited a parallel increase in TH enzyme protein. Our observations suggest that the novel peptide, SK, serves a physiological role in the regulation of TH in the striatonigral pathway.

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.

Radioprotective Agents: Strategies and Translational Advances.

PubMed

Kamran, Mohammad Zahid; Ranjan, Atul; Kaur, Navrinder; Sur, Souvik; Tandon, Vibha

2016-05-01

Radioprotectors are agents required to protect biological system exposed to radiation, either naturally or through radiation leakage, and they protect normal cells from radiation injury in cancer patients undergoing radiotherapy. It is imperative to study radioprotectors and their mechanism of action comprehensively, looking at their potential therapeutic applications. This review intimately chronicles the rich intellectual, pharmacological story of natural and synthetic radioprotectors. A continuous effort is going on by researchers to develop clinically promising radioprotective agents. In this article, for the first time we have discussed the impact of radioprotectors on different signaling pathways in cells, which will create a basis for scientific community working in this area to develop novel molecules with better therapeutic efficacy. The bright future of exceptionally noncytotoxic derivatives of bisbenzimidazoles is also described as radiomodulators. Amifostine, an effective radioprotectant, has been approved by the FDA for limited clinical use. However, due to its adverse side effects, it is not routinely used clinically. Recently, CBLB502 and several analog of a peptide are under clinical trial and showed high success against radiotherapy in cancer. This article reviews the different types of radioprotective agents with emphasis on the strategies for the development of novel radioprotectors for drug development. In addition, direction for future strategies relevant to the development of radioprotectors is also addressed. © 2016 Wiley Periodicals, Inc.

Glycyrrhizic Acid in the Treatment of Liver Diseases: Literature Review

PubMed Central

Li, Jian-yuan; Cao, Hong-yan; Cheng, Gen-hong; Sun, Ming-yu

2014-01-01

Glycyrrhizic acid (GA) is a triterpene glycoside found in the roots of licorice plants (Glycyrrhiza glabra). GA is the most important active ingredient in the licorice root, and possesses a wide range of pharmacological and biological activities. GA coupled with glycyrrhetinic acid and 18-beta-glycyrrhetic acid was developed in China or Japan as an anti-inflammatory, antiviral, and antiallergic drug for liver disease. This review summarizes the current biological activities of GA and its medical applications in liver diseases. The pharmacological actions of GA include inhibition of hepatic apoptosis and necrosis; anti-inflammatory and immune regulatory actions; antiviral effects; and antitumor effects. This paper will be a useful reference for physicians and biologists researching GA and will open the door to novel agents in drug discovery and development from Chinese herbs. With additional research, GA may be more widely used in the treatment of liver diseases or other conditions. PMID:24963489

The limits of evidence in drug approval and availability: a case study of cilostazol and naftidrofuryl for the treatment of intermittent claudication.

PubMed

Hong, Haeyeon; Mackey, William C

2014-08-01

Despite numerous efforts to develop effective medications for the treatment of intermittent claudication (IC) over the past 4 decades, a gold standard medical management option has yet to be defined. Although not life-threatening, IC interferes with mobility and activities of daily living, significantly impairing quality of life and potentially causing depression. Cilostazol, the leading pharmacologic agent for IC in the United States, was approved by the US Food and Drug Administration (FDA) in 1999 based on controversial data. Meanwhile, naftidrofuryl, the first-line pharmacologic agent for IC in the United Kingdom and Europe, has never been approved by the FDA and therefore is not available in the United States. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect impossible. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted, because the manufacturers of these agents have much to lose and little to gain from such a study. This article provides an overview of the pharmacology of cilostazol and naftidrofuryl, and the clinical studies leading to their approval and clinical acceptance. It further explores the possible sources of bias in analyzing these clinical trials, some of which have been brought to light by the National Institute for Health and Clinical Excellence (NICE) of the United Kingdom in its technology appraisal guidance. It also speculates the ways in which economic incentives may affect drug-marketing decisions. A literature review of pharmacology and clinical trials for cilostazol and naftidrofuryl was performed in PubMed. The majority of included clinical trials were initially identified through the most recent Cochrane review articles as well as the FDA's approval packet for cilostazol. The technology appraisal guidance of the National Institute for Health and Care Excellence of the United Kingdom and the manufacturer's response to this guidance document were located via an online search engine. The clinical data for cilostazol and naftidrofuryl are plagued by flaws related to lack of protocol standardization, objective endpoints, and strict eligibility criteria in study subjects, making identification of a true treatment effect difficult. Furthermore, no prospective randomized trial comparing the efficacy of cilostazol and naftidrofuryl has been conducted. The history of the evaluation, approval, and marketing of these drugs illustrates the limitations of data in the regulatory approval and marketing of agents whose benefit is subjective and difficult to quantify. Implementation of a standardized protocol with strict eligibility criteria, objective quantifiable measurement of drug effect, and validated endpoints will eventually allow development of an ideal pharmacotherapy for IC. Copyright © 2014 Elsevier HS Journals, Inc. All rights reserved.

Clinical Development of VEGF Signaling Pathway Inhibitors in Childhood Solid Tumors

PubMed Central

Yamashiro, Darrell J.; Fox, Elizabeth

2011-01-01

Angiogenesis is a target shared by both adult epithelial cancers and the mesenchymal or embryonal tumors of childhood. Development of antiangiogenic agents for the pediatric population has been complicated by largely theoretical concern for toxicities specific to the growing child and prioritization among the many antiangiogenic agents being developed for adults. This review summarizes the mechanism of action and preclinical data relevant to childhood cancers and early-phase clinical trials in childhood solid tumors. Single-agent adverse event profiles in adults and children are reviewed with emphasis on cardiovascular, bone health, and endocrine side effects. In addition, pharmacological factors that may be relevant for prioritizing clinical trials of these agents in children are reviewed. Considerations for further clinical evaluation should include preclinical data, relative potency, efficacy in adults, and the current U.S. Food and Drug Administration approval status. Toxicity profiles of vascular endothelial growth factor (VEGF) signaling pathway inhibitors may be age dependent and ultimately, their utility in the treatment of childhood cancer will require combination with standard cytotoxic drugs or other molecularly targeted agents. In combination studies, toxicity profiles, potential drug interactions, and late effects must be considered. Studies to assess the long-term impact of VEGF signaling pathway inhibitors on cardiovascular, endocrine, and bone health in children with cancer are imperative if these agents are to be administered to growing children and adolescents with newly diagnosed cancers. PMID:22042784

Antiviral agents and HIV prevention: controversies, conflicts, and consensus

PubMed Central

Cohen, Myron S.; Muessig, Kathryn E.; Smith, M. Kumi; Powers, Kimberly A.; Kashuba, Angela D.M.

2013-01-01

Antiviral agents can be used to prevent HIV transmission before exposure as preexpo-sure prophylaxis (PrEP), after exposure as postexposure prophylaxis, and as treatment of infected people for secondary prevention. Considerable research has shed new light on antiviral agents for PrEP and for prevention of secondary HIV transmission. While promising results have emerged from several PrEP trials, the challenges of poor adherence among HIV-negative clients and possible increase in sexual risk behaviors remain a concern. In addition, a broader pipeline of antiviral agents for PrEP that focuses on genital tract pharmacology and safety and resistance issues must be developed. Antiretroviral drugs have also been used to prevent HIV transmission from HIV-infected patients to their HIV-discordant sexual partners. The HIV Prevention Trials Network 052 trial demonstrated nearly complete prevention of HIV transmission by early treatment of infection, but the generalizability of the results to other risk groups – including intravenous drug users and MSM – has not been determined. Most importantly, the best strategy for use of antiretroviral agents to reduce the spread of HIV at either the individual level or the population level has not been developed, and remains the ultimate goal of this area of investigation. PMID:22507927

Vascular endothelium summary statement III: Cancer prevention and control.

PubMed

Reed, Eddie; Seffrin, John; Giavazzi, Raffaella; van Hinsbergh, Victor; Madeddu, Paolo

2007-05-01

The biology of vascular endothelium can be modulated through the use of pharmacologic agents. Whereas this has been explored to reasonable extent in cardiovascular disease, it is clear that the ability to modulate vascular endothelium for the purpose of cancer prevention is in its early stages. Among the unanswered questions, we do not understand under what circumstances such pharmacologic interventions might best be started; nor, how long such interventions might be used for a given individual. We present concepts for further exploration in the use of endothelial-active agents for cancer prevention and control; and, strategies for public health practice and research in this area.

New pharmacologic approaches to the prevention of space/motion sickness

NASA Technical Reports Server (NTRS)

Kohl, Randall L.; Macdonald, Scott

1991-01-01

Three fundamental approaches used in the selection of new agents for the evaluation in the prevention of space-motion sickness (SMS) are reviewed, with emphasis on drugs under investigation at the Johnson Space Center. These approaches are: (1) the selection of agents from drug classes that possess pharmacologic properties of established antimotion sickness agents, (2) the selection of drugs that are used to prevent emesis caused by means other than the exposure to motion, and (3) basic research that characterizes individual differences in susceptibility to SMS. In the latter type of studies, it was found that subjects who were more resistant to SMS had higher plasma AVP after severe nausea than subjects with lower resistance. The review details the experimental data collected on AVP and adrenocorticotropin. It is noted that data support interrelated roles for AVP and opioid peptides in SMS.

Pharmacology Curriculum Model--A Report of the ADCO Council on Academic Affairs.

ERIC Educational Resources Information Center

Journal of Optometric Education, 1979

1979-01-01

A curriculum model for various schools and colleges to use in assessing the scope of their individual pharmacology programs is presented. The Council on Academic Affairs of the Association of Schools and Colleges of Optometry prepared this model because of modifications in state laws to allow the use of pharmaceutical agents in the practice of…

Central nervous system side effects associated with zolpidem treatment.

PubMed

Toner, L C; Tsambiras, B M; Catalano, G; Catalano, M C; Cooper, D S

2000-01-01

Zolpidem is one of the newer medications developed for the treatment of insomnia. It is an imidazopyridine agent that is an alternative to the typical sedative-hypnotic agents. Zolpidem use is gaining favor because of its efficacy and its side effect profile, which is milder and less problematic than that of the benzodiazepines and barbiturates used to treat insomnia. Still, side effects are not uncommon with zolpidem use. We report a series of cases in which the patients developed delirium, nightmares and hallucinations during treatment with zolpidem. We will review its pharmacology, discuss previous reports of central nervous system side effects, examine the impact of drug interactions with concurrent use of antidepressants, examine gender differences in susceptibility to side effects, and explore the significance of protein binding in producing side effects.

Neurogenic bowel management after spinal cord injury: A systematic review of the evidence

PubMed Central

Krassioukov, Andrei; Eng, Janice J.; Claxton, Geri; Sakakibara, Brodie M.; Shum, Serena

2011-01-01

OBJECTIVE To systematically review evidence for the management of neurogenic bowel in individuals with spinal cord injuries (SCI). DATA SOURCES Literature searches were conducted for relevant articles, as well as practice guidelines, using numerous electronic databases. Manual searches of retrieved articles from 1950 to July 2009 were also conducted to identify literature. STUDY SELECTION Randomized controlled trials, prospective cohort, case-control, and pre-post studies, and case reports that assessed pharmacological and non-pharmacological intervention for the management of the neurogenic bowel in SCI were included. DATA EXTRACTION Two independent reviewers evaluated each study’s quality, using the PEDro scale for RCTs and the Downs & Black scale for all other studies. Results were tabulated and levels of evidence assigned. DATA SYNTHESIS 2956 studies were found as a result of the literature search. Upon review of the titles and abstracts, 52 studies met the inclusion criteria. Multi-faceted programs are the first approach to neurogenic bowel and are supported by lower levels of evidence. Of the non-pharmacological (conservative and non-surgical) interventions, transanal irrigation is a promising treatment to reduce constipation and fecal incontinence. When conservative management is not effective, pharmacological interventions (e.g., prokinetic agents) are supported by strong evidence for the treatment of chronic constipation. When conservative and pharmacological treatments are not effective, surgical interventions may be considered and are supported by lower levels of evidence in reducing complications. CONCLUSIONS Often, more than one procedure is necessary to develop an effective bowel routine. Evidence is low for non-pharmacological approaches and high for pharmacological interventions. PMID:20212501

A renaissance in marine pharmacology: from preclinical curiosity to clinical reality.

PubMed

Glaser, Keith B; Mayer, Alejandro M S

2009-09-01

Marine pharmacology, the pharmacology of marine natural products, has been for some time more associated with marine natural products chemistry rather than mainstay pharmacology. However, in recent years a renaissance has occurred in this area of research, and has seen the US Food & Drug Administration (FDA) approval in 2004 of Prialt (ziconotide, omega-conotoxin MVIIA) the synthetic equivalent of a conopeptide found in marine snails, used for the management of severe chronic pain. Furthermore Yondelis) (trabectedin, ET-743) an antitumor agent scovered in a marine colonial tunicate, and now produced synthetically, receiving Orphan Drug designation from the European Commission (EC) and FDA for soft tissue sarcomas and ovarian cancer and its registration in 2007 in the EU for the treatment of soft tissue sarcoma. The approval/marketing of so few marine natural products has come after many years of research primarily by the academic community and the sporadic involvement of major pharmaceutical companies. This commentary, through the opinions provided by several leaders in the marine natural products field, will examine the potential reasons and perceptions from both the academic and pharmaceutical communities regarding the development of marine natural products as viable therapeutic entities.

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.

Critical thoughts on current rodent models for evaluating potential treatments of alcohol addiction and withdrawal

PubMed Central

Ripley, Tamzin L; Stephens, David N

2011-01-01

Despite years of neurobiological research that have helped to identify potential therapeutic targets, we do not have a reliable pharmacological treatment for alcoholism. There are a range of possible explanations for this failure, including arguments that alcoholism is a spectrum disorder and that different population subtypes may respond to different treatments. This view is supported by categorisations such as early- and late-onset alcoholism, whilst multifactorial genetic factors may also alter responsivity to pharmacological agents. Furthermore, experience of alcohol withdrawal may play a role in future drinking in a way that may distinguish alcoholism from other forms of addiction. Additionally, our neurobiological models, based largely upon results from rodent studies, may not mimic specific aspects of the human condition and may reflect different underlying phenomena and biological processes from the clinical pattern. As a result, potential treatments may be targeting inappropriate aspects of alcohol-related behaviours. Instead, we suggest a more profitable approach is (a) to identify well-defined intermediate behavioural phenotypes in human experimental models that reflect defined aspects of the human clinical disorder and (b) to develop animal models that are homologous with those phenotypes in terms of psychological processes and underlying neurobiological mechanisms. This review describes an array of animal models currently used in the addiction field and what they tell us about alcoholism. We will then examine how established pharmacological agents have been developed using only a limited number of these models, before describing some alternative novel approaches to achieving homology between animal and human experimental measures. LINKED ARTICLES This article is part of a themed issue on Translational Neuropharmacology. To view the other articles in this issue visit http://dx.doi.org/10.1111/bph.2011.164.issue-4 PMID:21470204

Pharmacological interventions for prevention or treatment of postoperative pain in people undergoing laparoscopic cholecystectomy.

PubMed

Gurusamy, Kurinchi Selvan; Vaughan, Jessica; Toon, Clare D; Davidson, Brian R

2014-03-28

While laparoscopic cholecystectomy is generally considered less painful than open surgery, pain is one of the important reasons for delayed discharge after day-surgery and overnight stay following laparoscopic cholecystectomy. The safety and effectiveness of different pharmacological interventions such as non-steroidal anti-inflammatory drugs, opioids, and anticonvulsant analgesics in people undergoing laparoscopic cholecystectomy is unknown. To assess the benefits and harms of different analgesics in people undergoing laparoscopic cholecystectomy. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, Science Citation Index Expanded, and the World Health Organization International Clinical Trials Registry Platform portal (WHO ICTRP) to March 2013 to identify randomised clinical trials of relevance to this review. We considered only randomised clinical trials (irrespective of language, blinding, or publication status) comparing different pharmacological interventions with no intervention or inactive controls for outcomes related to benefit in this review. We considered comparative non-randomised studies with regards to treatment-related harms. We also considered trials that compared one class of drug with another class of drug for this review. Two review authors collected the data independently. We analysed the data with both fixed-effect and random-effects models using Review Manager 5 analysis. For each outcome, we calculated the risk ratio (RR) or mean difference (MD) with 95% confidence intervals (CI). We included 25 trials with 2505 participants randomised to the different pharmacological agents and inactive controls. All the trials were at unclear risk of bias. Most trials included only low anaesthetic risk people undergoing elective laparoscopic cholecystectomy. Participants were allowed to take additional analgesics as required in 24 of the trials. The pharmacological interventions in all the included trials were aimed at preventing pain after laparoscopic cholecystectomy. There were considerable differences in the pharmacological agents used and the methods of administration. The estimated effects of the intervention on the proportion of participants who were discharged as day-surgery, the length of hospital stay, or the time taken to return to work were imprecise in all the comparisons in which these outcomes were reported (very low quality evidence). There was no mortality in any of the groups in the two trials that reported mortality (183 participants, very low quality evidence). Differences in serious morbidity outcomes between the groups were imprecise across all the comparisons (very low quality evidence). None of the trials reported patient quality of life or time taken to return to normal activity. The pain at 4 to 8 hours was generally reduced by about 1 to 2 cm on the visual analogue scale of 1 to 10 cm in the comparisons involving the different pharmacological agents and inactive controls (low or very low quality evidence). The pain at 9 to 24 hours was generally reduced by about 0.5 cm (a modest reduction) on the visual analogue scale of 1 to 10 cm in the comparisons involving the different pharmacological agents and inactive controls (low or very low quality evidence). There is evidence of very low quality that different pharmacological agents including non-steroidal anti-inflammatory drugs, opioid analgesics, and anticonvulsant analgesics reduce pain scores in people at low anaesthetic risk undergoing elective laparoscopic cholecystectomy. However, the decision to use these drugs has to weigh the clinically small reduction in pain against uncertain evidence of serious adverse events associated with many of these agents. Further randomised clinical trials of low risk of systematic and random errors are necessary. Such trials should include important clinical outcomes such as quality of life and time to return to work in their assessment.

Consequences of cardiovascular adaptation to spaceflight: implications for the use of pharmacological countermeasures

NASA Technical Reports Server (NTRS)

Convertino, Victor A.

2005-01-01

There is little evidence obtained from space flight to support the notion that occurrence of cardiac dysrhythmias, impaired cardiac and vascular function, and manifestation of asymptomatic cardiovascular disease represent serious risks during space flight. Therefore, the development of orthostatic hypotension and instability immediately after return from spaceflight probably reflect the most significant operational risks associated with the cardiovascular system of astronauts. Significant reductions in stroke volume and lower reserve for increasing peripheral vascular resistance contribute to ineffective maintenance of systemic arterial blood pressure during standing after spaceflight despite compensatory elevations in heart rate. The primary mechanism underlying reduced stroke volume appears to be a reduction in preload associated with less circulating blood volume while inadequate peripheral vasoconstriction may be caused partly by hyporeactivity of receptors that control arterial smooth muscle function. A focus for development of future countermeasures for hemodynamic responses to central hypovolemia includes the potential application of pharmacological agents that specifically target and restore blood volume (e.g., fludrocortisone, electrolyte-containing beverages) and reserve for vasoconstriction (e.g., midodrine, vasopressin). Based on systematic evaluations, acute physical exercise designed to elicit maximal effort or inspiratory resistance have shown promise as successful countermeasures that provide protection against development of orthostatic hypotension and intolerance without potential risks and side effects associated with specific pharmacological interventions.

Current and potential pharmacological and psychosocial interventions for anxiety symptoms and disorders in patients with schizophrenia: structured review.

PubMed

Howells, Fleur M; Kingdon, David G; Baldwin, David S

2017-09-01

Between 30% and 62% of patients with schizophrenia present with co-morbid anxiety disorders that are associated with increased overall burden. Our aim was to summarize current and potential interventions for anxiety in schizophrenia. Structured review, summarizing pharmacological and psychosocial interventions used to reduce anxiety in schizophrenia and psychosis. Antipsychotics have been shown to reduce anxiety, increase anxiety, or have no effect. These may be augmented with another antipsychotic, anxiolytic, or antidepressant. Novel agents, such as L-theanine, pregabalin, and cycloserine, show promise in attenuating anxiety in schizophrenia. Psychosocial therapies have been developed to reduce the distress of schizophrenia. Cognitive behavioural therapy (CBT) has shown that benefit and refinements in the therapy have been successful, for example, for managing worry in schizophrenia. CBT usually involves more than 16 sessions, as short courses of CBT do not attenuate the presentation of anxiety in schizophrenia. To address time and cost, the development of manualized CBT to address anxiety in schizophrenia is being developed. The presence of coexisting anxiety symptoms and co-morbid anxiety disorders should be ascertained when assessing patients with schizophrenia or other psychoses as a range of pharmacological and psychosocial treatments are available. Copyright © 2017 John Wiley & Sons, Ltd.

Cannabinoid-based medicines for neurological disorders--clinical evidence.

PubMed

Wright, Stephen

2007-08-01

Whereas the cannabis plant has a long history of medicinal use, it is only in recent years that a sufficient understanding of the pharmacology of the main plant constituents has allowed for a better understanding of the most rational therapeutic targets. The distribution of cannabinoid receptors, both within the nervous system and without, and the development of pharmacological tools to investigate their function has lead to a substantial increase in efforts to develop cannabinoids as therapeutic agents. Concomitant with these efforts, the understanding of the pharmacology of plant cannabinoids at receptor and other systems distinct from the cannabinoid receptors suggests that the therapeutic applications of plant-derived cannabinoids (and presumably their synthetic derivatives also) may be diverse. This review aims to discuss the clinical evidence investigating the use of medicines derived, directly or indirectly, from plant cannabinoids with special reference to neurological disorders. Published studies suggest that the oral administration of cannabinoids may not be the preferred route of administration and that plant extracts show greater evidence of efficacy than synthetic compounds. One of these, Sativex (GW Pharmaceuticals), was approved as a prescription medicine in Canada in 2005 and is currently under regulatory review in the EU.

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.

Therapeutic interventions in sepsis: current and anticipated pharmacological agents

PubMed Central

Shukla, Prashant; Rao, G Madhava; Pandey, Gitu; Sharma, Shweta; Mittapelly, Naresh; Shegokar, Ranjita; Mishra, Prabhat Ranjan

2014-01-01

Sepsis is a clinical syndrome characterized by a multisystem response to a pathogenic assault due to underlying infection that involves a combination of interconnected biochemical, cellular and organ–organ interactive networks. After the withdrawal of recombinant human-activated protein C (rAPC), researchers and physicians have continued to search for new therapeutic approaches and targets against sepsis, effective in both hypo- and hyperinflammatory states. Currently, statins are being evaluated as a viable option in clinical trials. Many agents that have shown favourable results in experimental sepsis are not clinically effective or have not been clinically evaluated. Apart from developing new therapeutic molecules, there is great scope for for developing a variety of drug delivery strategies, such as nanoparticulate carriers and phospholipid-based systems. These nanoparticulate carriers neutralize intracorporeal LPS as well as deliver therapeutic agents to targeted tissues and subcellular locations. Here, we review and critically discuss the present status and new experimental and clinical approaches for therapeutic intervention in sepsis. PMID:24977655

A multichannel scala tympani electrode array incorporating a drug delivery system for chronic intracochlear infusion.

PubMed

Shepherd, Robert K; Xu, Jin

2002-10-01

We have developed a novel scala tympani electrode array suitable for use in experimental animals. A unique feature of this array is its ability to chronically deliver pharmacological agents to the scala tympani. The design of the electrode array is described in detail. Experimental studies performed in guinea pigs confirm that this array can successfully deliver various drugs to the cochlea while chronically stimulating the auditory nerve.

Targeting Estrogen-Induced COX-2 Activity in Lymphangioleiomyomatosis (LAM)

DTIC Science & Technology

2014-12-01

production was also increased in TSC2-deficient cells. In preclinical models, both Celecoxib and aspirin reduced tumor development. LAM patients had...increased by aspirin treatment, indicative of functional COX-2 expression in the LAM airway. In vitro, 15-epi-lipoxin-A4 reduced the proliferation of...inhibit COX-2 pharmacologically, we treated TSC2-deficient cells with aspirin or NS398, and found that both agents reduced COX-2 protein levels and

Synthesis and serotonin transporter activity of sulphur-substituted alpha-alkyl phenethylamines as a new class of anticancer agents.

PubMed

Cloonan, Suzanne M; Keating, John J; Butler, Stephen G; Knox, Andrew J S; Jørgensen, Anne M; Peters, Günther H; Rai, Dilip; Corrigan, Desmond; Lloyd, David G; Williams, D Clive; Meegan, Mary J

2009-12-01

The discovery that some serotonin reuptake transporter (SERT) ligands have the potential to act as pro-apoptotic agents in the treatment of cancer adds greatly to their diverse pharmacological application. 4-Methylthioamphetamine (MTA) is a selective ligand for SERT over other monoamine transporters. In this study, a novel library of structurally diverse 4-MTA analogues were synthesised with or without N-alkyl and/or C-alpha methyl or ethyl groups so that their potential SERT-dependent antiproliferative activity could be assessed. Many of the compounds displayed SERT-binding activity as well as cytotoxic activity. While there was no direct correlation between these two effects, a number of derivatives displayed anti-tumour effects in lymphoma, leukaemia and breast cancer cell lines, showing further potential to be developed as possible chemotherapeutic agents.

Anticancer agents derived from natural cinnamic acids.

PubMed

Su, Ping; Shi, Yaling; Wang, Jinfeng; Shen, Xiuxiu; Zhang, Jie

2015-01-01

Cancer is the most dangerous disease that causes deaths all over the world. Natural products have afforded a rich source of drugs in a number of therapeutic fields including anticancer agents. Many significant drugs have been derived from natural sources by structural optimization of natural products. Cinnamic acid has gained great interest due to its antiproliferative, antioxidant, antiangiogenic and antitumorigenic potency. Currently it has been observed that cinnamic acid and its analogs such as caffeic acid, sinapic acid, ferulic acid, and isoferulic acid display various pharmacological activities, such as immunomodulation, anti-inflammation, anticancer and antioxidant. They have served to be the major sources of potential leading anticancer compounds. In this review, we focus on the anticancer potency of cinnamic acid derivatives and novel strategies to design these derivatives. We hope this review will be useful for researchers who are interested in developing anticancer agents.

Pharmacological and Chemical Effects of Cigarette Additives

PubMed Central

Rabinoff, Michael; Caskey, Nicholas; Rissling, Anthony; Park, Candice

2007-01-01

We investigated tobacco industry documents and other sources for evidence of possible pharmacological and chemical effects of tobacco additives. Our findings indicated that more than 100 of 599 documented cigarette additives have pharmacological actions that camouflage the odor of environmental tobacco smoke emitted from cigarettes, enhance or maintain nicotine delivery, could increase the addictiveness of cigarettes, and mask symptoms and illnesses associated with smoking behaviors. Whether such uses were specifically intended for these agents is unknown. Our results provide a clear rationale for regulatory control of tobacco additives. PMID:17666709

Therapeutic potential of cannabinoids in counteracting chemotherapy-induced adverse effects: an exploratory review.

PubMed

Ostadhadi, Sattar; Rahmatollahi, Mahdieh; Dehpour, Ahmad-Reza; Rahimian, Reza

2015-03-01

Cannabinoids (the active constituents of Cannabis sativa) and their derivatives have got intense attention during recent years because of their extensive pharmacological properties. Cannabinoids first developed as successful agents for alleviating chemotherapy associated nausea and vomiting. Recent investigations revealed that cannabinoids have a wide range of therapeutic effects such as appetite stimulation, inhibition of nausea and emesis, suppression of chemotherapy or radiotherapy-associated bone loss, chemotherapy-induced nephrotoxicity and cardiotoxicity, pain relief, mood amelioration, and last but not the least relief from insomnia. In this exploratory review, we scrutinize the potential of cannabinoids to counteract chemotherapy-induced side effects. Moreover, some novel and yet important pharmacological aspects of cannabinoids such as antitumoral effects will be discussed. Copyright © 2014 John Wiley & Sons, Ltd.

Management of exaggerated gag reflex in dental patients using intravenous sedation with dexmedetomidine.

PubMed

Reshetnikov, Aleksei P; Kasatkin, Anton A; Urakov, Aleksandr L; Baimurzin, Dmitrii Y

2017-01-01

Pharmacological sedation is one of the effective ways of prevention of gag reflex development in patients experiencing anxiety and fright before dental treatment. We are reporting a case where we could successfully eliminate exaggerated gag reflex (intravenous [IV] Gagging Severity Index) in a dental patient using IV sedation with dexmedetomidine. IV administration of dexmedetomidine provided elimination of gag reflex at a depth of sedation for the patient with the Richmond Agitation-Sedation Scale score of -2 and -1. The patient received dexmedetomidine 1.0 μg/kg for 10 min and then a continuous infusion of dexmedetomidine 0.4 μg/kg/h. The use of dexmedetomidine for sedation may be an alternative to other pharmacological agents in patients with dental anxiety accompanied by exaggerated gag reflex.

Viral infection and antiviral therapy in the neonatal intensive care unit.

PubMed

Barford, Galina; Rentz, Alison C; Faix, Roger G

2004-01-01

Viral diseases are leading causes of mortality and morbidity among infants requiring care in the neonatal intensive care unit (NICU), with ongoing discoveries of new viral pathology likely to add to the burdens posed. Many viral diseases in NICU infants are undiagnosed or appreciated only late in the course because of subtle or asymptomatic presentation, confusion with bacterial disease, and failure to consider viral disease. We present an overview of viral disease in NICU infants, with emphasis on pharmacologic agents currently employed for prophylaxis and treatment of such diseases. Advances in molecular biology and popular demand to develop antiviral agents for viral diseases (eg, human immunodeficiency virus) offer great promise for the future.

Preservation of human performance capacity under prolonged space flight conditions

NASA Technical Reports Server (NTRS)

Yeremin, A. V.; Bogdashevskiy, R. M.; Baburin, Y. F.

1975-01-01

Prophylactic measures directed toward preservation of health and maintenance of the performance ability of a man during prolonged space flight stress center on the selection of optimum work and rest cycles, physical exercises, the use of pharmacological agents, conditioning of the cardiovascular apparatus, etc. A specially selected set of hormone and pharmacological preparations is recommended to stimulate hemopoiesis.

Raphanus sativus (Radish): Their Chemistry and Biology

PubMed Central

Gutiérrez, Rosa Martha Pérez; Perez, Rosalinda Lule

2004-01-01

Leaves and roots of Raphanus sativus have been used in various parts of the world to treat cancer and as antimicrobial and antiviral agents. The phytochemistry and pharmacology of this radish is reviewed. The structures of the compounds isolated and identified are listed and aspects of their chemistry and pharmacology are discussed. The compounds are grouped according to structural classes. PMID:15452648

Advances in pharmacologic strategies for cancer cachexia.

PubMed

Madeddu, Clelia; Mantovani, Giovanni; Gramignano, Giulia; Macciò, Antonio

2015-01-01

Cancer cachexia is a severe inflammatory metabolic syndrome accounting for fatigue, an impairment of normal activities and, eventually, death. The loss of muscle mass associated with body weight loss is the main feature of this syndrome. The present review aims to describe the advances in the pharmacological approaches for cancer cachexia, highlighting the impact on weight loss, muscle wasting and related outcomes. Among the pharmacological agents, attention should yet be given to the currently most widely studied drugs, such as progestogens and NSAIDs. Emerging drugs, such as ghrelin and selective androgen receptor modulators, have obtained promising results in recent randomized clinical trials. Larger sample sizes and more robust data on the effectiveness of anti-cytokine agents are needed. Any pharmacological approach to counteract cancer cachexia should always be associated with an adequate caloric intake, obtained by diet or through enteral or parenteral supplementation, if indicated. Finally, we can currently state that a combined approach that simultaneously targets the fundamental pathways involved in the pathogenesis of cancer cachexia is likely to be the most effective in terms of improvements in body weight as well as muscle wasting, function, physical performance and quality of life.

Are pharmacological interventions between conception and birth effective in improving reproductive outcomes in North American swine?

PubMed

Wessels, J M; Khalaj, K; Kridli, R T; Edwards, A K; Bidarimath, M; Tayade, C

2014-08-01

The objective of this review is to evaluate the effectiveness of using pharmacological compounds on reproductive outcomes, particularly litter size, in North American swine. While the opportunity to improve reproduction in North American pigs exists, numerous hurdles need to be overcome in order to achieve measureable results. In the swine industry, the majority of piglet losses are incurred during pregnancy and around farrowing. Over the last 20 years, a reduction in losses has been achieved through genetic selection and nutritional management; however, these topics are the focus of other reviews. This review will evaluate attempts to improve litter size by reducing losses at various stages of the reproductive process, from the time of conception to the time of farrowing, using pharmacological compounds. Generally, these compounds are used to either alter physiological processes related to fertilization, embryonic attachment or uterine capacity, etc., or to facilitate management aspects of the breeding females such as inducing parturition. Although some of the pharmacological agents reviewed here show some positive effects on improving reproductive parameters, the inconsistent results and associated risks usually outweigh the benefits gained. Thus, at the present time, the use of pharmacological agents to enhance reproduction in North American swine may only be recommended for herds with low fertility and presents an avenue of research that could be further explored. © 2014 Blackwell Verlag GmbH.

Potential New Pharmacological Agents Derived From Medicinal Plants for the Treatment of Pancreatic Cancer.

PubMed

Azimi, Haniye; Khakshur, Ali Asghar; Abdollahi, Mohammad; Rahimi, Roja

2015-01-01

In the present article, we reviewed plants and phytochemical compounds demonstrating beneficial effects in pancreatic cancer to find new sources of pharmaceutical agents. For this purpose, Scopus, PubMed, Web of Science, and Google scholar were searched for plants or herbal components with beneficial effects in the treatment of pancreatic cancer. Data were collected up to January 2013. The search terms were "plant," "herb," "herbal therapy," or "phytotherapy" and "pancreatic cancer" or "pancreas." All of the human in vivo and in vitro studies were included. According to studies, among diverse plants and phytochemicals, 12 compounds including apigenin, genistein, quercetin, resveratrol, epigallocatechin gallate, benzyl isothiocyanate, sulforaphane, curcumin, thymoquinone, dihydroartemisinin, cucurbitacin B, and perillyl alcohol have beneficial action against pancreatic cancer cells through 4 or more mechanisms. Applying their plausible synergistic effects can be an imperative approach for finding new efficient pharmacological agents in the treatment of pancreatic cancer.

Treatment-resistant Schizophrenia: Evidence-based Strategies

PubMed Central

Englisch, Susanne; Zink, Mathias

2012-01-01

Treatment-resistant symptoms complicate the clinical course of schizophrenia, and a large proportion of patients do not reach functional recovery. In consequence, polypharmacy is frequently used in treatment-refractory cases, addressing psychotic positive, negative and cognitive symptoms, treatment-emergent side effects caused by antipsychotics and comorbid depressive or obsessive-compulsive symptoms. To a large extent, such strategies are not covered by pharmacological guidelines which strongly suggest antipsychotic monotherapy. Add-on strategies comprise combinations of several antipsychotic agents and augmentations with mood stabilizers; moreover, antidepressants and experimental substances are applied. Based on the accumulated evidence of clinical trials and meta-analyses, combinations of clozapine with certain second-generation antipsychotic agents and the augmentation of antipsychotics with antidepressants seem recommendable, while the augmentation with mood stabilizers cannot be considered superior to placebo. Forthcoming investigations will have to focus on innovative pharmacological agents, the clinical spectrum of cognitive deficits and the implementation of cognitive behavioral therapy. PMID:22654380

Novel therapeutics for type 2 diabetes: insulin resistance.

PubMed

Altaf, Q-A; Barnett, A H; Tahrani, A A

2015-04-01

Insulin resistance (IR) plays an important role in the pathogenesis of type 2 diabetes (T2D) and cardiovascular disease. Hence improving IR is a major target of treatment in patients with T2D. Obesity and lack of exercise are major causes of IR. However, recent evidence implicates sleep disorders and disorders of the circadian rhythm in the pathogenesis of IR. Weight loss and lifestyle changes are the cornerstone and most effective treatments of IR, but adherence and patient's acceptability are poor. Bariatric surgery results in significant and sustainable long-term weight loss associated with beneficial impact on IR and glucose metabolism, making this an attractive treatment option for patients with T2D. Currently available pharmacological options targeting IR (such as metformin and thiazolidinediones) do not maintain glycaemic measures within targets long term and can be associated with significant side effects. Over the last two decades, many pharmacological agents targeting different aspects of the insulin signalling pathway were developed to improve IR, but only a minority reached clinical trials. Such treatments need to be specific and reversible as many of the components of the insulin signalling pathway are involved in other cellular functions such as apoptosis. Recent evidence highlighted the role of circadian rhythm and sleep-related disorders in the pathogenesis of IR. In this article, we review the latest developments in the pharmacological and non-pharmacological interventions targeting IR including bariatric surgery. We will also review the role of circadian rhythm and sleep-related disorders in the development and treatment of IR. © 2014 John Wiley & Sons Ltd.

Social Communication is an Emerging Target for Pharmacotherapy in Autism Spectrum Disorder - A Review of the Literature on Potential Agents.

PubMed

Baribeau, Danielle A; Anagnostou, Evdokia

2014-02-01

To review the published literature and registered clinical trials on pharmacologic interventions targeting social communication impairment in Autism Spectrum Disorder (ASD). A comprehensive search of several databases (PubMed, MEDLINE, PsycINFO, Clinical trials.gov) was conducted to identify pharmacologic agents that have been, or will be, tested as treatments for social communication impairment in individuals with ASD. Evidence from basic science research supporting rational drug discovery is surveyed. Data from animal models and early clinical trials suggest that novel and existing compounds, including N-methyl-D-aspartate (NMDA) modulators, γ-aminobutyric acid (GABA) agonists, metabotropic glutamate receptor (mGluR) antagonists and neuropeptides, may enhance social communication/function in ASD. Results from numerous Phase 2 and Phase 3 clinical trials are expected in the near future. Recent evidence suggests that social communication may be an appropriate target for pharmacologic manipulation. It is hoped that, in combination with behavioural interventions, novel therapeutics may soon be clinically available to help improve social outcomes.

Macrolides: a promising pharmacologic therapy for chronic obstructive pulmonary disease

PubMed Central

Qiu, Shilin; Zhong, Xiaoning

2016-01-01

Chronic inflammation plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, there are no effective anti-inflammatory pharmacologic therapies available for COPD so far. Recent evidence suggests that an immunologic mechanism has a role in the pathogenesis of COPD. Macrolides possess anti-inflammatory and immune-modulating effects may be helpful in the treatment of COPD. Several clinical studies have shown that long-term use of macrolides reduces the frequency of COPD exacerbations. However, the subgroups that most effectively respond to long-term treatment of macrolides still need to be determined. The potential adverse events to individuals and the microbial resistance in community populations raises great concern on the long-term use of macrolides. Thus, novel macrolides have anti-inflammatory and immuno-modulating effects, but without antibiotic effects, and are promising as an anti-inflammatory agent for the treatment of COPD. In addition, the combination of macrolides and other anti-inflammatory pharmacologic agents may be a new strategy for the treatment of COPD. PMID:28030992

Pharmacotherapy of eating disorders.

PubMed

Davis, Haley; Attia, Evelyn

2017-11-01

Medications are commonly prescribed in the treatment of eating disorders. In this review, we discuss relevant medications used for the treatment of bulimia nervosa, binge eating disorder (BED), and anorexia nervosa. We focus on recent research developments, where applicable, in addition to discussing important findings from older studies to provide a complete synopsis of the current evidence base for eating disorder treatment using pharmacologic agents. Medications are generally useful for patients with bulimia nervosa and BED. For bulimia nervosa, antidepressant medications are the primary pharmacologic treatment and limited new research has been completed. For BED, lisdexamfetamine is reported to be generally well tolerated and effective, and is the first medication to be indicated by the US Food and Drug Administration for treatment of BED. For anorexia nervosa, there is limited evidence supporting benefits of medications. Second-generation antipsychotics, particularly olanzapine, appear to demonstrate some benefit for weight gain in anorexia nervosa, although are not advised as a stand-alone treatment. Transdermal administration of hormonal agents is also being explored for improving bone health in anorexia nervosa. Although pharmacotherapy has established utility in bulimia nervosa and BED, further research on medications for the treatment of eating disorders, particularly anorexia nervosa, is necessary.

Pharmacology and toxicology of Cannabis derivatives and endocannabinoid agonists.

PubMed

Gerra, Gilberto; Zaimovic, Amir; Gerra, Maria L; Ciccocioppo, Roberto; Cippitelli, Andrea; Serpelloni, Giovanni; Somaini, Lorenzo

2010-01-01

For centuries Cannabis sativa and cannabis extracts have been used in natural medicine. Delta(9)-tetrahydrocannabinol (THC) is the main active ingredient of Cannabis. THC seems to be responsible for most of the pharmacological and therapeutic actions of cannabis. In a few countries THC extracts (i.e. Sativex) or THC derivatives such as nabilone, and dronabinol are used in the clinic for the treatment of several pathological conditions like chemotherapy-induced nausea and vomiting, multiple sclerosis and glaucoma. On the other hand the severe side effects and the high abuse liability of these agents represent a serious limitation in their medical use. In addition, diversion in the use of these active ingredients for recreational purpose is a concern. Over recent years, alternative approaches using synthetic cannabinoid receptor agonists or agents acting as activators of the endocannabinoid systems are under scrutiny with the hope to develop more effective and safer clinical applications. Likely, in the near future few of these new molecules will be available for clinical use. The present article review recent study and patents with focus on the cannabinoid system as a target for the treatment of central nervous system disorders with emphasis on agonists.

Cyclodextrins: improving the therapeutic response of analgesic drugs: a patent review.

PubMed

de Oliveira, Makson G B; Guimarães, Adriana G; Araújo, Adriano A S; Quintans, Jullyana S S; Santos, Márcio R V; Quintans-Júnior, Lucindo J

2015-01-01

Cyclodextrins (CDs) are cyclic oligosaccharides that have recently been recognized as useful tools for optimizing the delivery of such problematic drugs. CDs can be found in at least 35 pharmaceutical products, such as anticancer agents, analgesic and anti-inflammatory drugs. Besides, several studies have demonstrated that CD-complexed drugs could provide benefits in solubility, stability and also improve pharmacological response when compared with the drug alone. The patent search was conducted in the databases WIPO, Espacenet, USPTO, Derwent and INPI, using the keywords cyclodextrin, pain and its related terms (analgesia, hyperalgesia, hypernociception, nociception, antinociception, antinociceptive). We found 442 patents. Criteria such as the complexation of analgesic agents and evidence of improvement of the therapeutic effect were indispensable for the inclusion of the patent. So, 18 patents were selected. We noticed that some patents are related to the complexation of opioids, NSAIDs, as well as natural products, in different types of CDs. The use of CDs creates the prospect of developing new therapeutic options for the most effective treatment of painful conditions, allowing a reduction of dosage of analgesic drugs and the occurrence of side effects. Thus, CDs can be an important tool to improve the efficacy and pharmacological profile of analgesic drugs.

Andrographolide, a potential cancer therapeutic agent isolated from Andrographis paniculata.

PubMed

Rajagopal, Sriram; Kumar, R Ajaya; Deevi, Dhanvanthri S; Satyanarayana, Chitkala; Rajagopalan, R

2003-01-01

Andrographis paniculata plant extract is known to possess a variety of pharmacological activities. Andrographolide, the major constituent of the extract is implicated towards its pharmacological activity. We studied the cellular processes and targets modulated by andrographolide treatment in human cancer and immune cells. Andrographolide treatment inhibited the in vitro proliferation of different tumor cell lines, representing various types of cancers. The compound exerts direct anticancer activity on cancer cells by cell-cycle arrest at G0/G1 phase through induction of cell-cycle inhibitory protein p27 and decreased expression of cyclin-dependent kinase 4 (CDK4). Immunostimulatory activity of andrographolide is evidenced by increased proliferation of lymphocytes and production of interleukin-2. Andrographolide also enhanced the tumor necrosis factor-alpha production and CD marker expression, resulting in increased cytotoxic activity of lymphocytes against cancer cells, which may contribute for its indirect anticancer activity. The in vivo anticancer activity of the compound is further substantiated against B16F0 melanoma syngenic and HT-29 xenograft models. These results suggest that andrographolide is an interesting pharmacophore with anticancer and immunomodulatory activities and hence has the potential for being developed as a cancer therapeutic agent.

Cannabidiol and Sodium Nitroprusside: Two Novel Neuromodulatory Pharmacological Interventions to Treat and Prevent Psychosis.

PubMed

Crippa, José Alexandre; Hallak, Jaime Eduardo Cecílio; Abílio, Vanessa Costhek; de Lacerda, Acioly Luiz Tavares; Zuardi, Antonio Waldo

2015-01-01

Since most patients with schizophrenia do not respond properly to treatment, scientific effort has been driven to the development of new compounds acting on pharmacological targets beyond the dopaminergic system. Therefore, the aim is to review basic and clinical research findings from studies evaluating the effects of cannabidiol (CBD), an inhibitor of the reuptake and metabolism of anandamide and several other effects on nervous system, and sodium nitroprusside, a nitric oxide donor, on the prevention and treatment of psychosis. Animal and human research supports that CBD and sodium nitroprusside might be effective in the prevention and treatment of psychosis in general and especially in schizophrenia. The evidence available to date shows that CBD and sodium nitroprusside act in pathways associated with psychotic symptoms and that they may be important agents in the management of prodromal psychotic states and psychosis. This underscores the relevance of further research on the effects of these agents and others that mediate the activity of the cannabinoid system and of nitric oxide, as well as comparative studies of their antipsychotic effects and those of other antipsychotic drugs currently used to treat schizophrenia.

Sexual dysfunction with antihypertensive and antipsychotic agents.

PubMed

Smith, P J; Talbert, R L

1986-05-01

The physiology of the normal sexual response, epidemiology of sexual dysfunction, and the pharmacologic mechanisms involved in antihypertensive- and antipsychotic-induced problems with sexual function are discussed, with recommendations for patient management. The physiologic mechanisms involved in the normal sexual response include neurogenic, psychogenic, vascular, and hormonal factors that are coordinated by centers in the hypothalamus, limbic system, and cerebral cortex. Sexual dysfunction is frequently attributed to antihypertensive and antipsychotic agents and is a cause of noncompliance. Drug-induced effects include diminished libido, delayed orgasm, ejaculatory disturbances, gynecomastia, impotence, and priapism. The pharmacologic mechanisms proposed to account for these adverse effects include adrenergic inhibition, adrenergic-receptor blockade, anticholinergic properties, and endocrine and sedative effects. The most frequently reported adverse effect on sexual function with the antihypertensive agents is impotence. It is seen most often with methyldopa, guanethidine, clonidine, and propranolol. In contrast, the most common adverse effect on sexual function with the antipsychotic agents involves ejaculatory disturbances. Thioridazine, with its potent anticholinergic and alpha-blocking properties, is cited most often. Drug-induced sexual dysfunction may be alleviated by switching to agents with dissimilar mechanisms to alter the observed adverse effect while maintaining adequate control of the patient's disease state.

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

Pharmacologic Hemostatic Agents in Total Joint Arthroplasty-A Cost-Effectiveness Analysis.

PubMed

Ramkumar, Dipak B; Ramkumar, Niveditta; Tapp, Stephanie J; Moschetti, Wayne E

2018-03-03

Total knee and hip arthroplasties can be associated with substantial blood loss, affecting morbidity and even mortality. Two pharmacological antifibrinolytics, ε-aminocaproic acid (EACA) and tranexamic acid (TXA) have been used to minimize perioperative blood loss, but both have associated morbidity. Given the added cost of these medications and the risks associated with then, a cost-effectiveness analysis was undertaken to ascertain the best strategy. A cost-effectiveness model was constructed using the payoffs of cost (in United States dollars) and effectiveness (quality-adjusted life expectancy, in days). The medical literature was used to ascertain various complications, their probabilities, utility values, and direct medical costs associated with various health states. A time horizon of 10 years and a willingness to pay threshold of $100,000 was used. The total cost and effectiveness (quality-adjusted life expectancy, in days) was $459.77, $951.22, and $1174.87 and 3411.19, 3248.02, and 3342.69 for TXA, no pharmacologic hemostatic agent, and EACA, respectively. Because TXA is less expensive and more effective than the competing alternatives, it was the favored strategy. One-way sensitivity analyses for probability of transfusion and myocardial infarction for all 3 strategies revealed that TXA remains the dominant strategy across all clinically plausible values. TXA, when compared with no pharmacologic hemostatic agent and with EACA, is the most cost-effective strategy to minimize intraoperative blood loss in hip and knee total joint arthroplasties. These findings are robust to sensitivity analyses using clinically plausible probabilities. Copyright © 2018 Elsevier Inc. All rights reserved.

Pharmacological treatment of diabetic neuropathic pain.

PubMed

Smith, Howard S; Argoff, Charles E

2011-03-26

Neuropathic pain continues to be a difficult and challenging clinical issue to deal with effectively. Painful diabetic polyneuropathy is a complex pain condition that occurs with reasonable frequency in the population and it may be extremely difficult for clinicians to provide patients with effective analgesia. Chronic neuropathic pain may occur in approximately one of every four diabetic patients. The pain may be described as burning or a deep-seated ache with sporadic paroxysms of lancinating painful exacerbations. The pain is often constant, moderate to severe in intensity, usually primarily involves the feet and generally tends to worsen at night. Treatment may be multimodal but largely involves pharmacological approaches. Pharmacological therapeutic options include antidepressants (tricyclic antidepressants, serotonin-norepinephrine reuptake inhibitors), α2δ ligands and topical (5%) lidocaine patch. Other agents may be different antiepileptic drugs (carbamazepine, lamotrigine, topiramate), topical capsaicin, tramadol and other opioids. Progress continues with respect to understanding various mechanisms that may contribute to painful diabetic neuropathy. Agents that may hold some promise include neurotrophic factors, growth factors, immunomodulators, gene therapy and poly (adenosine diphosphate-ribose) polymerase inhibitors. It is hoped that in the future clinicians will be able to assess patient pathophysiology, which may help them to match optimal therapeutic agents to target individual patient aberrant mechanisms.

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 therapeutic potential of Cordyceps with special reference to Cordycepin.

PubMed

Tuli, Hardeep S; Sandhu, Sardul S; Sharma, A K

2014-02-01

An entomopathogenic fungus, Cordyceps sp. has been known to have numerous pharmacological and therapeutic implications, especially, in terms of human health making it a suitable candidate for ethno-pharmacological use. Main constituent of the extract derived from this fungus comprises a novel bio-metabolite called as Cordycepin (3'deoxyadenosine) which has a very potent anti-cancer, anti-oxidant and anti-inflammatory activities. The current review discusses about the broad spectrum potential of Cordycepin including biological and pharmacological actions in immunological, hepatic, renal, cardiovascular systems as well as an anti-cancer agent. The article also reviews the current efforts to delineate the mechanism of action of Cordycepin in various bio-molecular processes. The study will certainly draw the attention of scientific community to improve the bioactivity and production of Cordycepin for its commercial use in pharmacological and medical fields.

Pharmacologic development of male hormonal contraceptive agents.

PubMed

Roth, M Y; Amory, J K

2011-01-01

The world population continues to increase dramatically despite the existence of contraceptive technology. The use of male hormonal contraception may help in preventing un intended pregnancies and managing future population growth. Male hormonal contraception relies on the administration of exogenous hormones to suppress spermatogenesis. Clinical trials have tested several regimens using testosterone, alone or in combination with a progestin. These regimens were shown to be >90% effective in preventing conception and were not associated with serious adverse events.

Pharmacological effects of biotin.

PubMed

Fernandez-Mejia, Cristina

2005-07-01

In the last few decades, more vitamin-mediated effects have been discovered at the level of gene expression. Increasing knowledge on the molecular mechanisms of these vitamins has opened new perspectives that form a connection between nutritional signals and the development of new therapeutic agents. Besides its role as a carboxylase prosthetic group, biotin regulates gene expression and has a wide repertoire of effects on systemic processes. The vitamin regulates genes that are critical in the regulation of intermediary metabolism: Biotin has stimulatory effects on genes whose action favors hypoglycemia (insulin, insulin receptor, pancreatic and hepatic glucokinase); on the contrary, biotin decreases the expression of hepatic phosphoenolpyruvate carboxykinase, a key gluconeogenic enzyme that stimulates glucose production by the liver. The findings that biotin regulates the expression of genes that are critical in the regulation of intermediary metabolism are in agreement with several observations that indicate that biotin supply is involved in glucose and lipid homeostasis. Biotin deficiency has been linked to impaired glucose tolerance and decreased utilization of glucose. On the other hand, the diabetic state appears to be ameliorated by pharmacological doses of biotin. Likewise, pharmacological doses of biotin appear to decrease plasma lipid concentrations and modify lipid metabolism. The effects of biotin on carbohydrate metabolism and the lack of toxic effects of the vitamin at pharmacological doses suggest that biotin could be used in the development of new therapeutics in the treatment of hyperglycemia and hyperlipidemia, an area that we are actively investigating.

Differentiating low-molecular-weight heparins based on chemical, biological, and pharmacologic properties: implications for the development of generic versions of low-molecular-weight heparins.

PubMed

Jeske, Walter P; Walenga, Jeanine M; Hoppensteadt, Debra A; Vandenberg, Curtis; Brubaker, Aleah; Adiguzel, Cafer; Bakhos, Mamdouh; Fareed, Jawed

2008-02-01

Low-molecular-weight heparins (LMWHs) are polypharmacologic drugs used to treat thrombotic and cardiovascular disorders. These drugs are manufactured using different chemical and enzymatic methods, resulting in products with distinct chemical and pharmacologic profiles. Generic LMWHs have been introduced in Asia and South America, and several generic suppliers are seeking regulatory approval in the United States and the European Union. For simple small-molecule drugs, generic drugs have the same chemical structure, potency, and bioavailability as the innovator drug. Applying this definition to complex biological products such as the LMWHs has proved difficult. One major issue is defining appropriate criteria to demonstrate bioequivalence; pharmacopoeial specifications alone appear to be inadequate. Whereas available generic versions of LMWHs exhibit similar molecular and pharmacopoeial profiles, marked differences in their biological and pharmacologic behavior have been noted. Preliminary studies have demonstrated differences in terms of anti-Xa activity and tissue factor pathway inhibitor release after subcutaneous administration, as well as antiplatelet and profibrinolytic effects. The current data emphasize the need to consider multiple functional parameters when defining bioequivalence of biologic drugs with complex structures and activities and also underscore the importance of further pharmacologic studies involving animal models and human clinical trials. The U.S. Food and Drug Administration and the European Medicine Evaluation Agency are currently developing guidelines for the acceptance of biosimilar agents including LMWHs. Until such guidelines are complete, generic interchange may not be feasible.

Ketamine: An Update on Cellular and Subcellular Mechanisms with Implications for Clinical Practice.

PubMed

Iacobucci, Gary J; Visnjevac, Ognjen; Pourafkari, Leili; Nader, Nader Djalal

2017-02-01

Ketamine is one of the oldest hypnotic agents used to provide an anesthetic agent with analgesic properties and minimal suppressive effects on respiration. The ability of ketamine in modulating glutamatergic (N-methyl D-aspartate) pain receptors has made this anesthetic drug a new option for the management of patients with chronic pain syndromes. Further preclinical and clinical findings suggest ketamine may have wide ranging effects on both cognition and development. Recent advances have revealed an unprecedented role for ketamine in the acute management of depression. The purpose of this review is to integrate a number of basic science, preclinical, and clinical studies with the goal of providing insight into the possible signaling events underlying ketamine's biological effects in pain management, depression, cognition and memory, and neurodevelopment. Narrative literature review. Health science library. A comprehensive literature search was performed for the following medical subject headings and keywords (ketamine, anesthesia, pain, analgesia, depression, NMDA receptors) on PubMed, Google Scholar, and Medline from 1966 to the present time. The search was then limited to those in the English language. The full text of the relevant articles were printed and reviewed by all authors. We provided a comprehensive review of the literature that explored the pharmacologic aspects of ketamine from its conception as an anesthetic to its evolution as a drug used for treatment of depression and pain. To address the patient response variability observed in clinical studies, we have provided possible patient-specific factors that could contribute to outcome variability. Like any review, this study was limited by publication bias and missing information on negative studies which were denied publication. Ketamine, an old anesthetic agent with analgesic properties, is currently being considered for treating patients with chronic pain and depression. The complex pharmacological characteristics of ketamine make this medication a multifaceted therapeutic option in these cases. Key Words: Ketamine, anesthetics, pain, depression, pharmacology.

A Histological Assessment of Lung Injury in Rats Exposed to Inhaled Sulfur Mustard across Dose and Time

DTIC Science & Technology

2015-06-01

J (2008) Health effects of exposure to vesicant agents. In: Chemical Warfare Agents – Chemistry , Pharmacology, Toxicology, and Therapeutics. Eds...sulfphide and the protective effect of flavonoids . Toxicology 69: 35-42. Wada S, Nishimoto Y, Miyanishi M, Kambe S, Miller R W(1968) Mustard gas as

Modifying the risk of atypical antipsychotics in the treatment of juvenile-onset schizophrenia.

PubMed

Townsend, Lisa; Findling, Robert L

2010-02-01

This review summarizes the evidence for use of typical and atypical antipsychotic medications for the treatment of juvenile-onset schizophrenia. We highlight the risks and benefits of antipsychotic agents for youth with this disorder, paying special attention to weight gain and metabolic effects, an area of specific concern within child and adolescent psychiatry. We describe the seriousness of juvenile-onset schizophrenia and its impact on long-term functioning, noting that pharmacological treatment remains the standard of care for this disorder. We focus on weight gain and metabolic effects associated with atypical agents and review strategies to modify risks associated with these agents. We summarize strategies for attenuating the risk of weight gain for youth on atypical antipsychotics, including what is known about nutritional counseling and exercise programs as well as pharmacotherapy with adjunctive weight loss agents. Given the negative consequences associated with untreated schizophrenia, it appears that the most effective way to improve the risk:benefit ratio in the treatment of adolescents with schizophrenia is to reduce the risks associated with pharmacological treatment.

Pharmacotherapy in Generalized Anxiety Disorder: Novel Experimental Medicine Models and Emerging Drug Targets.

PubMed

Baldwin, David S; Hou, Ruihua; Gordon, Robert; Huneke, Nathan T M; Garner, Matthew

2017-04-01

Many pharmacological and psychological approaches have been found efficacious in patients with generalized anxiety disorder (GAD), but many treatment-seeking patients will not respond and others will relapse despite continuing with interventions that initially had beneficial effects. Other patients will respond but then stop treatment early because of untoward effects such as sexual dysfunction, drowsiness, and weight gain. There is much scope for the development of novel approaches that could have greater overall effectiveness or acceptability than currently available interventions or that have particular effectiveness in specific clinical subgroups. 'Experimental medicine' studies in healthy volunteers model disease states and represent a proof-of-concept approach for the development of novel therapeutic interventions: they determine whether to proceed to pivotal efficacy studies and so can reduce delays in translating innovations into clinical practice. Investigations in healthy volunteers challenged with the inhalation of air 'enriched' with 7.5% carbon dioxide (CO 2 ) indicate this technique provides a validated and robust experimental medicine model, mirroring the subjective, autonomic, and cognitive features of GAD. The anxiety response during CO 2 challenge probably involves both central noradrenergic neurotransmission and effects on acid-base sensitive receptors and so may stimulate development of novel agents targeted at central chemosensors. Increasing awareness of the potential role of altered cytokine balance in anxiety and the interplay of cytokines with monoaminergic mechanisms may also encourage the investigation of novel agents with modulating effects on immunological profiles. Although seemingly disparate, these two approaches to treatment development may pivot on a shared mechanism in exerting anxiolytic-like effects through pharmacological effects on acid-sensing ion channels.

Animal models of sepsis.

PubMed

Fink, Mitchell P

2014-01-01

Sepsis remains a common, serious, and heterogeneous clinical entity that is difficult to define adequately. Despite its importance as a public health problem, efforts to develop and gain regulatory approval for a specific therapeutic agent for the adjuvant treatment of sepsis have been remarkably unsuccessful. One step in the critical pathway for the development of a new agent for adjuvant treatment of sepsis is evaluation in an appropriate animal model of the human condition. Unfortunately, the animal models that have been used for this purpose have often yielded misleading findings. It is likely that there are multiple reasons for the discrepancies between the results obtained in tests of pharmacological agents in animal models of sepsis and the outcomes of human clinical trials. One of important reason may be that the changes in gene expression, which are triggered by trauma or infection, are different in mice, a commonly used species for preclinical testing, and humans. Additionally, many species, including mice and baboons, are remarkably resistant to the toxic effects of bacterial lipopolysaccharide, whereas humans are exquisitely sensitive. New approaches toward the use of animals for sepsis research are being investigated. But, at present, results from preclinical studies of new therapeutic agents for sepsis must be viewed with a degree of skepticism.

Bioactivity and pharmacological properties of α-mangostin from the mangosteen fruit: a review.

PubMed

Chen, Guoqing; Li, Yong; Wang, Wei; Deng, Liping

2018-05-01

α-Mangostin (α-MG) is the most representative xanthone isolated from the pericarp of mangosteen, possessing extensive biological activities and pharmacological properties, considered as an antineoplastic agent, antioxidant, anti-proliferation and induces apoptosis. Areas covered: The bioactivity and pharmacological properties of α-MG are being actively investigated by various industrial and academic institutions. The bioactivities of α-MG have been summarized in several previous reviews, which were worthy of high compliment. However, recently, many new literatures about the bioactivities of α-MG have been further reported from 2016 to 2017. Herein, the activities of α-MG are supplemented and summarized in this text. Expert opinion: As previously said, α-MG possesses good bioactivities pharmacological properties. More recently, it found that α-MG has the effect of maintaining cardiovascular system and gastrointestinal health and controlling free radical oxidation. Furthermore, α-MG has more applications in cosmetics, with the effects of anti-aging, anti-wrinkle, acne treatment, maintenance of skin lubrication. The application of α-MG in treating rheumatoid arthritis has been disclosed and the MG-loaded self-micro emulsion (MG-SME) was designed to improve its pharmacokinetic deficiencies. As mentioned above, α-MG can be a promising drug, also worthy of developing, and further research is crucial for the future application of α-MG.

Synthesis of 14-Alkoxymorphinan Derivatives and Their Pharmacological Actions

NASA Astrophysics Data System (ADS)

Schmidhammer, Helmut; Spetea, Mariana

Among opioids, morphinans play an important role as therapeutically valuable drugs. They include pain relieving agents such as naturally occurring alkaloids (e.g. morphine, codeine), semisynthetic derivatives (e.g. oxycodone, oxymorphone, buprenorphine), and synthetic analogs (e.g. levorphanol). Currently used opioid analgesics also share a number of severe side effects, limiting their clinical usefulness. The antagonist morphinans, naloxone and naltrexone are used to treat opioid overdose, opioid dependence, and alcoholism. All these opioid drugs produce their biological actions through three receptor types, µ, δ, and κ, belonging to the G-protein-coupled receptor family. Considerable effort has been put forward to understand the appropriate use of opioid analgesics, while medicinal chemistry and opioid pharmacology have been continuously engaged in the search for safer, more efficacious and nonaddicting opioid compounds, with the final goal to reduce complications and to improve patient compliance. Toward this goal, recent advances in chemistry, ligand-based structure activity relationships and pharmacology of 14-alkoxymorphinans are reviewed in this chapter. Current developments of different structural patterns of 14-alkoxymorphinans as research tools and their potential therapeutic opportunities are also summarized.

Pharmacological Tools to Study the Role of Astrocytes in Neural Network Functions.

PubMed

Peña-Ortega, Fernando; Rivera-Angulo, Ana Julia; Lorea-Hernández, Jonathan Julio

2016-01-01

Despite that astrocytes and microglia do not communicate by electrical impulses, they can efficiently communicate among them, with each other and with neurons, to participate in complex neural functions requiring broad cell-communication and long-lasting regulation of brain function. Glial cells express many receptors in common with neurons; secrete gliotransmitters as well as neurotrophic and neuroinflammatory factors, which allow them to modulate synaptic transmission and neural excitability. All these properties allow glial cells to influence the activity of neuronal networks. Thus, the incorporation of glial cell function into the understanding of nervous system dynamics will provide a more accurate view of brain function. Our current knowledge of glial cell biology is providing us with experimental tools to explore their participation in neural network modulation. In this chapter, we review some of the classical, as well as some recent, pharmacological tools developed for the study of astrocyte's influence in neural function. We also provide some examples of the use of these pharmacological agents to understand the role of astrocytes in neural network function and dysfunction.

Cynaropicrin: A Comprehensive Research Review and Therapeutic Potential As an Anti-Hepatitis C Virus Agent

PubMed Central

Elsebai, Mahmoud F.; Mocan, Andrei; Atanasov, Atanas G.

2016-01-01

The different pharmacologic properties of plants-containing cynaropicrin, especially artichokes, have been known for many centuries. More recently, cynaropicrin exhibited a potential activity against all genotypes of hepatitis C virus (HCV). Cynaropicrin has also shown a wide range of other pharmacologic properties such as anti-hyperlipidemic, anti-trypanosomal, anti-malarial, antifeedant, antispasmodic, anti-photoaging, and anti-tumor action, as well as activation of bitter sensory receptors, and anti-inflammatory properties (e.g., associated with the suppression of the key pro-inflammatory NF-κB pathway). These pharmacological effects are very supportive factors to its outstanding activity against HCV. Structurally, cynaropicrin might be considered as a potential drug candidate, since it has no violations for the rule of five and its water-solubility could allow formulation as therapeutic injections. Moreover, cynaropicrin is a small molecule that can be easily synthesized and as the major constituent of the edible plant artichoke, which has a history of safe dietary use. In summary, cynaropicrin is a promising bioactive natural product that, with minor hit-to-lead optimization, might be developed as a drug for HCV. PMID:28008316

A Gas Chromotographic-Mass Spectrometric Approach to Examining Stereoselective Interaction of Human Plasma Proteins with Soman

DTIC Science & Technology

2008-02-01

ABSTRACT See reprint. 15. SUBJECT TERMS Human plasma proteins, soman, nerve agent , bioscavenger, gas chromatography, mass spectrometry 16. SECURITY...usually referred to as nerve agents ) are tabun (ethyl dimethylamidocyanophosphate, or GA ), sarin (iso- propyl methylfluorophosphonate, or GB), soman...Pharmacology and toxicology of chemical warfare agents Ann. Acad. Med. Singapore 2&: 104-107 (1997). 11. C Macilwain. Study proves Iraq used nerve gas . Nature 3

Engineering of Paraoxonases for Pre- and Post-treatment of Intoxication by a Broad Spectrum of Nerve Agents and Pesticides

DTIC Science & Technology

2014-08-01

chemical warfare nerve agents (CWNA). Enzymes identified in these screens should be capable of catalytically neutralizing the target agent under...soluble form. 4. Large-scale production of selected enzyme candidates, and their kinetic, structural and pharmacological evaluation 6...employed, with an enzyme protein concentration of 0.5-2 mM in the assay cuvette, the activity measured was indistinguishable from the rate of

Update on Management of Cancer-Related Cachexia.

PubMed

Anderson, Lindsey J; Albrecht, Eliette D; Garcia, Jose M

2017-01-01

Cachexia is a metabolic syndrome driven by inflammation and characterized by loss of muscle with or without loss of fat mass. In cancer cachexia, the tumor burden and host response induce increased inflammation, decreased anabolic tone, and suppressed appetite leading to the clinical presentation of reduced body weight and quality of life (QOL). There is no approved treatment for cancer cachexia, and commonly used nutritional and anti-inflammatory strategies alone have proven ineffective for management of symptoms. Several other pharmacological agents are currently in development and have shown promise as a clinical strategy in early-phase trials. Recently, it has been proposed that multimodal strategies, with an anabolic focus, initiated early in the disease/treatment progression may provide the most therapeutic potential for symptom management. Here we review the data from recent clinical trials in cancer cachexia including pharmacological, exercise, and nutritional interventions.

Improving the Clinical Pharmacologic Assessment of Abuse Potential: Part 1: Regulatory Context and Risk Management.

PubMed

Sellers, Edward M

2018-02-01

This article brings to the attention of drug developers the Food and Drug Administration's (FDA's) recent final Guidance to Industry on Assessment of Abuse Potential and provides practical suggestions about compliance with the Guidance. The Guidance areas are reviewed, analyzed, and placed in the context of current scientific knowledge and best practices to mitigate regulatory risk. The Guidance provides substantial new detail on what needs to be done at all stages of drug development for central nervous system-active drugs. However, because many psychopharmacologic agents have unique preclinical and clinical features, the plan for each agent needs to be not only carefully prepared but also reviewed and approved by the FDA. Examples are provided where assumptions about interpretation of the Guidance can delay development. If the expertise and experience needed for assessing abuse potential during drug development do not exist within a company, external preclinical and clinical expert should be involved. Consultation with the FDA is encouraged and important because the specific requirements for each drug will vary.

Intracellular studies of the nucleoside reverse transcriptase inhibitor active metabolites: a review.

PubMed

Rodriguez Orengo, J F; Santana, J; Febo, I; Diaz, C; Rodriguez, J L; Garcia, R; Font, E; Rosario, O

2000-03-01

Nucleoside reverse transcriptase inhibitors (NRTIs) plasma concentrations do not correlate with clinical efficacy or toxicity. These agents need to be phosphorylated to become active against HIV-infection. Thus, the characterization of the NRTIs intracellular metabolite pharmacological parameters will provide a better understanding that could lead to the development of more rational dose regimens in the HIV-infected population. Furthermore, intracellular measurements of NRTIs may provide a better marker with respect to clinical efficacy and toxicity than plasma concentrations. Thus, in this article we review the latest information regarding the intracellular pharmacological parameters of zidovudine (ZDV) and lamivudine (3TC) active metabolites in HIV-infected patients including the results from our recent clinical studies. We will start the discussion with ZDV and 3TC clinical efficacy, followed by systemic pharmacokinetics studies. We will then discuss the in vitro and in vivo intracellular studies with particular emphasis in the method development to measure these metabolites and we will conclude with the most current data from our clinical trials.

Discovery of a Novel Series of Inhibitors of Lymphoid Tyrosine Phosphatase with Activity in Human T Cells†

PubMed Central

Stanford, Stephanie M.; Krishnamurthy, Divya; Falk, Matthew D.; Messina, Rossella; Debnath, Bikash; Li, Sheng; Liu, Tong; Kazemi, Roza; Dahl, Russell; He, Yantao; Yu, Xiao; Chan, Andrew C.; Zhang, Zhong-Yin; Barrios, Amy M.; Woods, Virgil L.; Neamati, Nouri; Bottini, Nunzio

2011-01-01

The lymphoid tyrosine phosphatase LYP, encoded by the PTPN22 gene, is a critical regulator of signaling in T cells and recently emerged as a candidate target for therapy of autoimmune diseases. Here, by library screening, we identified a series of noncompetitive inhibitors of LYP that showed activity in primary T cells. Kinetic analysis confirmed that binding of the compounds to the phosphatase is nonmutually exclusive with respect to a known bidentate competitive inhibitor. The mechanism of action of the lead inhibitor compound 4e was studied by a combination of hydrogen/deuterium-exchange mass spectrometry and molecular modeling. The results suggest that the inhibitor interacts critically with a hydrophobic patch located outside the active site of the phosphatase. Targeting of secondary allosteric sites is viewed as a promising yet unexplored approach to develop pharmacological inhibitors of protein tyrosine phosphatases. Our novel scaffold could be a starting point to attempt development of “nonactive site” anti-LYP pharmacological agents. PMID:21341673

Enabling personalized cancer medicine decisions: The challenging pharmacological approach of PBPK models for nanomedicine and pharmacogenomics (Review).

PubMed

Vizirianakis, Ioannis S; Mystridis, George A; Avgoustakis, Konstantinos; Fatouros, Dimitrios G; Spanakis, Marios

2016-04-01

The existing tumor heterogeneity and the complexity of cancer cell biology critically demand powerful translational tools with which to support interdisciplinary efforts aiming to advance personalized cancer medicine decisions in drug development and clinical practice. The development of physiologically based pharmacokinetic (PBPK) models to predict the effects of drugs in the body facilitates the clinical translation of genomic knowledge and the implementation of in vivo pharmacology experience with pharmacogenomics. Such a direction unequivocally empowers our capacity to also make personalized drug dosage scheme decisions for drugs, including molecularly targeted agents and innovative nanoformulations, i.e. in establishing pharmacotyping in prescription. In this way, the applicability of PBPK models to guide individualized cancer therapeutic decisions of broad clinical utility in nanomedicine in real-time and in a cost-affordable manner will be discussed. The latter will be presented by emphasizing the need for combined efforts within the scientific borderlines of genomics with nanotechnology to ensure major benefits and productivity for nanomedicine and personalized medicine interventions.

Method for photo-altering a biological system to improve biological effect

DOEpatents

Hill, Richard A.; Doiron, Daniel R.; Crean, David H.

2000-08-01

Photodynamic therapy is a new adjunctive therapy for filtration surgery that does not use chemotherapy agents or radiation, but uses pharmacologically-active sensitizing compounds to produce a titratable, localized, transient, post operative avascular conjunctiva. A photosensitizing agent in a biological system is selectively activated by delivering the photosensitive agent to the biological system and laser activating only a spatially selected portion of the delivered photosensitive agent. The activated portion of the photosensitive agent reacts with the biological system to obtain a predetermined biological effect. As a result, an improved spatial disposition and effectuation of the biological effect by the photosensitive agent in the biological system is achieved.

Protective effect of Clerodendron glandulosum extract against experimentally induced metabolic syndrome in rats.

PubMed

Jadeja, Ravirajsinh N; Thounaojam, Menaka C; Ansarullah; Patel, Vaibhav B; Devkar, Ranjitsinh V; Ramachandran, A V

2010-12-01

Metabolic syndrome (MetS) has become one of the major health burdens worldwide. To date, no single pharmacological agent has been developed to correct metabolic abnormalities associated with MetS. Use of indigenous medicinal plants as alternative medicines against MetS could be beneficial due to multiple therapeutic usage, easy availability, and relatively few side effects. To investigate the protective effect of Clerodendron glandulosum Coleb. (Verbenaceae) aqueous leaf extract (CgE) against experimentally induced MetS in rats. Changes in body weight, food and fluid intake, plasma glucose, insulin, fasting insulin resistance index (FIRI), plasma total lipid profile, free fatty acids (FFA), oral glucose tolerance test (OGTT), blood pressure and vascular reactivity have been investigated in various experimental groups. Fructose+CgE groups recorded significant decrement (P <0.05) in plasma glucose, insulin, FIRI, total cholesterol, triglycerides, LDL, VLDL and FFA, whereas plasma HDL level was significantly increased (P <0.05) along with an efficient clearance of glucose during OGTT and lowered area under curve values. FRU+CgE groups also showed significantly decreased (P <0.05) mean arterial blood pressure along with decreased vasoconstriction and increased vasorelaxation in response to administration of various pharmacological agents. These results were comparable with metformin treated rats. C. glandulosum leaf extract ameliorates experimentally induced MetS by improving dyslipidemia and insulin resistance. This study provides the first pharmacological evidence for the protective role of C. glandulosum leaves against experimentally induced MetS. Thus, therapeutic use of C. glandulosum in controlling MetS is indicated.

Use of antipsychotic medications for the management of delirium: an audit of current practice in the acute care setting.

PubMed

Tropea, J; Slee, J; Holmes, A C N; Gorelik, A; Brand, C A

2009-02-01

Despite delirium being common in older hospitalized people, little is known about its management. The aims of this study are (1) to describe the pharmacological management of delirium in an acute care setting as a baseline measure prior to the implementation of newly developed Australian guidelines; and (2) to determine what areas of delirium pharmacological management need to be targeted for future practical guideline implementation and quality improvement activities. A medical record audit was conducted using a structured audit form. All patients aged 65 years and over who were admitted to a general medical or orthopaedic unit of the Royal Melbourne Hospital between 1 March 2006 and 28 February 2007 and coded with delirium were included. Data on the use of antipsychotic medications for the management of delirium in relation to best practice recommendations were assessed. Overall 174 episodes of care were included in the analysis. Antipsychotic medications were used for the management of most patients with severe behavioral and or emotional disturbance associated with delirium. There was variation in the prescribing patterns of antipsychotic agents and the documentation of medication management plans. Less than a quarter of patients prescribed antipsychotic medication were started on a low dose and very few were reviewed on a regular basis. A wide range of practice is seen in the use of antipsychotic agents to manage older patients with severe symptoms associated with delirium. The findings highlight the need to implement evidence-based guideline recommendations with a focus on improving the consistency in the pharmacological management and documentation processes.

Chem Ed Compacts

ERIC Educational Resources Information Center

Wolf, Walter A., Ed.

1977-01-01

Discusses the determination of eutectic composition, the mathematics of chemical equilibrium, the wave functions of one-electron orbitals, and the use of pharmacological agents in introductory chemistry courses. (SL)

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.

Pharmacologic management of sexual dysfunction: benefits and limitations.

PubMed

Segraves, Robert Taylor

2003-03-01

What is the current knowledge concerning the pharmacologic treatment of human sexual dysfunction? A number of interventions, including oral phophodiesterase inhibitors and intracorporeal agents with vasodilatory effects, are available to treat male erectile disorder. Serotonergic drugs have been shown to be effective in the treatment of rapid ejaculation. Various lines of research suggest that high dosages of androgenic agents may eventually have a role in the treatment of decreased libido in females. There may be a role for phophodiesterase inhibitors in the treatment of a subgroup of women with arousal disorders. Normal sexual function involves successful integration of biological, psychological, and interpersonal influences. Clinical psychiatry with its biopsychosocial model should incorporate the treatment of human sexual dysfunction within its purview.

Mapping Proteome-Wide Interactions of Reactive Chemicals Using Chemoproteomic Platforms

PubMed Central

Counihan, Jessica L.; Ford, Breanna; Nomura, Daniel K.

2015-01-01

A large number of pharmaceuticals, endogenous metabolites, and environmental chemicals act through covalent mechanisms with protein targets. Yet, their specific interactions with the proteome still remain poorly defined for most of these reactive chemicals. Deciphering direct protein targets of reactive small-molecules is critical in understanding their biological action, off-target effects, potential toxicological liabilities, and development of safer and more selective agents. Chemoproteomic technologies have arisen as a powerful strategy that enable the assessment of proteome-wide interactions of these irreversible agents directly in complex biological systems. We review here several chemoproteomic strategies that have facilitated our understanding of specific protein interactions of irreversibly-acting pharmaceuticals, endogenous metabolites, and environmental electrophiles to reveal novel pharmacological, biological, and toxicological mechanisms. PMID:26647369

Dual/multitargeted xanthone derivatives for Alzheimer's disease: where do we stand?

PubMed

Cruz, Maria I; Cidade, Honorina; Pinto, Madalena

2017-09-01

To date, the current therapy for Alzheimer's disease (AD) based on acetylcholinesterase inhibitors is only symptomatic, being its efficacy limited. Hence, the recent research has been focused in the development of different pharmacological approaches. Here we discuss the potential of xanthone derivatives as new anti-Alzheimer agents. The interference of xanthone derivatives with acetylcholinesterase and other molecular targets and cellular mechanisms associated with AD have been recently systematically reported. Therefore, we report xanthones with anticholinesterase, monoamine oxidase and amyloid β aggregation inhibitory activities as well as antioxidant properties, emphasizing xanthone derivatives with dual/multitarget activity as potential agents to treat AD. We also propose the structural features for these activities that may guide the design of new, more effective xanthone derivatives. [Formula: see text].

Effects of Chemical Agents on the Cholinergic Neurotransmitter System: Mechanisms of Adaptation.

DTIC Science & Technology

1984-06-20

DFP; 19h cholinergic agonist, oxotremorine ; oxotremorine analogs, A ~ mustards BM 123 and BM 130; pharmacological, (see reverse i - = V u M pan...anticholinesterase, DFP; a cholinergic agonist, oxotremorine ; and two oxotremorine mustards, BM 123 and BM 130. The studies were of four major kinds...findings. The general pharmacological investigations were directed primarily toward the mustard analogs of oxotremorine and used in vitro and in vivo

New antiepileptic drug development.

PubMed

Dreifuss, F E

1994-01-01

The development of new antiepileptic drugs is poised on the cusp between empiricism and the rational scientific development of medicaments designed to perform specific neurophysiologic functions in keeping with modern ideas of epilepsy generation and spread. It takes into account the difference between seizures and their underlying disorder known as epilepsies and the fact that, although seizures can be effectively treated with pharmacologic agents, the development of epilepsy requires both a predisposition (which may be innate or preventable) and precipitating factors that determine the timing of the individual seizures. The local membrane phenomena or cellular substrates of epilepsy can be described, as can the process of epileptogenesis. New antiepileptic development can be viewed in the light of these concepts.

Themed section: Advances in nutritional pharmacology. Editorial.

PubMed

Wainwright, C L; McGrath, J C

2009-09-01

A themed section in this issue of Br J Pharmacol, on 'Advances in Nutritional Pharmacology', provides a valuable and timely update on progress in this area. The value of dietary components to improvement in health and, particularly, to prevention of cardiovascular disease and cancer, is frequently reported in the media and therefore often captures the attention of the wider public. Understanding the pharmacological mechanisms by which nutritional elements confer their health benefits enables us to keep the public informed, but also aids in the identification of new targets for drug development. In recent years there has been significant progress in this field. Four rapidly developing areas are reviewed. Vosper (2009) covers the identification of a receptor for niacin and the subsequent development of selective agonists as lipid lowering agents. Wu-Wong (2009) describes the development of new Vitamin D analogues for the treatment of cardiovascular disease. de Roos et al. (2009) provide detailed insight into how omega-3 fatty acids, also known as longchain n-3 polyunsaturated fatty acids (PUFAs) protect against cardiovascular disease. Zhou et al. (2009) cover the mechanisms underlying the beneficial effects of resveretrol in protection against cancer. These reviews are complimented by three key original articles focusing on endogenous mechanisms of weight control involving endocannabinoids (Izzo et al., 2009), a circulating protein, the soluble leptin receptor (Zhang & Scarpace, 2009) and a treatment, zinc plus cyclo-(His-Pro) (CHP), known to increase insulin metabolism (Song et al., 2009).

Development and Testing of an In Vitro Assay for Screening of Potential Therapeutic Agents against Na Channel Neurotoxins

DTIC Science & Technology

1987-02-03

or by synthesis , the search almost certainly would have failed (3). Fortunately, the accumulated knowledge of sodium channel pharmacology allows the...distinct sodium channel domains. These studies were made possible by the synthesis of a tritiated analog of BTX, batrachotoxinin-A benzoate (BTX-B), of...elaborated upon. Creveling et al. (11) found that the local anesthetic lidocaine ethiodide was 10 times more potent at displacing specifically bound [3H]BTX-B

Effects of NO-modulating agents on the development of acute painful reaction in rats.

PubMed

Dyuizen, I V; Lamash, N E

2008-08-01

Painful reaction of rats to intraperitoneal injections of L-arginine, Nw-nitro-L-arginine, and agmatine was studied on the model of formalin-induced inflammation. All drugs exhibited a dubious effect on the patterns of nociceptive behavior depending on the phase of painful reaction. The dynamics of nitrate/nitrite content in animal blood and serum indicated the presence of NO-dependent and NO-independent components in the mechanisms of pharmacological effects of these drugs.

A Systematic Review of NMDA Receptor Antagonists for Treatment of Neuropathic Pain in Clinical Practice.

PubMed

Aiyer, Rohit; Mehta, Neel; Gungor, Semih; Gulati, Amitabh

2018-05-01

To investigate the efficacy of N-methyl-D-aspartate receptor (NMDAR) antagonists for neuropathic pain (NeuP) and review literature to determine if specific pharmacologic agents provide adequate NeuP relief. Literature was reviewed on PubMed using a variety of key words for 8 NMDAR antagonists. These key words include: "Ketamine and Neuropathy," "Ketamine and Neuropathic Pain," "Methadone and Neuropathy," "Methadone and Neuropathic Pain," "Memantine and Neuropathic pain," "Memantine and Neuropathy," "Amantadine and Neuropathic Pain," "Amantadine and Neuropathy," "Dextromethorphan and Neuropathic Pain," "Dextromethorphan and Neuropathy," "Carbamazepine and Neuropathic Pain," "Carbamazepine and Neuropathy," "Valproic Acid and Neuropathy," "Valproic Acid and Neuropathic Pain," "Phenytoin and Neuropathy," and "Phenytoin and Neuropathic Pain." With the results, the papers were reviewed using the PRISMA (Preferred Reporting in Systematic and Meta-Analyses) guideline. A total of 58 randomized controlled trials were reviewed among 8 pharmacologic agents, which are organized by date and alphabetical order. Of the trials for ketamine, 15 showed some benefit for analgesia. Methadone had 3 positive trials, while amantadine and memantine each only had 2 trials showing NeuP analgesic properties. Dextromethorphan and valproic acid both had 4 randomized controlled trials that showed some NeuP treatment benefit while carbamazepine had over 8 trials showing efficacy. Finally, phenytoin only had 1 trial that showed clinical response in treatment. There are a variety of NMDAR antagonist agents that should be considered for treatment of NeuP. Nevertheless, continued and further investigation of the 8 pharmacologic agents is needed to continue to evaluate their efficacy for treatment of NeuP.

Cancer-associated thrombosis: prevention and treatment

PubMed Central

Brose, K.M.J.; Lee, A.Y.Y.

2008-01-01

Patients with cancer are at high risk to develop venous thromboembolism, and they are also more likely to develop complications from anticoagulant treatment. Because little research has focused on the oncology population to date, the optimal methods of prophylaxis and treatment remain uncertain in some clinical situations. Currently, low molecular weight heparin and warfarin are the most frequently used pharmacologic agents; however, they have their limitations. Other therapeutic options, such as inferior caval filters, are poorly studied and remain controversial. A summary of the most recent evidence on the prevention and treatment of venous thromboembolism in cancer patients is presented here. PMID:18231650

Antimicrobial Peptides: An Emerging Category of Therapeutic Agents.

PubMed

Mahlapuu, Margit; Håkansson, Joakim; Ringstad, Lovisa; Björn, Camilla

2016-01-01

Antimicrobial peptides (AMPs), also known as host defense peptides, are short and generally positively charged peptides found in a wide variety of life forms from microorganisms to humans. Most AMPs have the ability to kill microbial pathogens directly, whereas others act indirectly by modulating the host defense systems. Against a background of rapidly increasing resistance development to conventional antibiotics all over the world, efforts to bring AMPs into clinical use are accelerating. Several AMPs are currently being evaluated in clinical trials as novel anti-infectives, but also as new pharmacological agents to modulate the immune response, promote wound healing, and prevent post-surgical adhesions. In this review, we provide an overview of the biological role, classification, and mode of action of AMPs, discuss the opportunities and challenges to develop these peptides for clinical applications, and review the innovative formulation strategies for application of AMPs.

The current state of GPCR-based drug discovery to treat metabolic disease.

PubMed

Sloop, Kyle W; Emmerson, Paul J; Statnick, Michael A; Willard, Francis S

2018-02-02

One approach of modern drug discovery is to identify agents that enhance or diminish signal transduction cascades in various cell types and tissues by modulating the activity of GPCRs. This strategy has resulted in the development of new medicines to treat many conditions, including cardiovascular disease, psychiatric disorders, HIV/AIDS, certain forms of cancer and Type 2 diabetes mellitus (T2DM). These successes justify further pursuit of GPCRs as disease targets and provide key learning that should help guide identifying future therapeutic agents. This report reviews the current landscape of GPCR drug discovery with emphasis on efforts aimed at developing new molecules for treating T2DM and obesity. We analyse historical efforts to generate GPCR-based drugs to treat metabolic disease in terms of causal factors leading to success and failure in this endeavour. © 2018 The British Pharmacological Society.

Chemopreventive Agents and Inhibitors of Cancer Hallmarks: May Citrus Offer New Perspectives?

PubMed Central

Cirmi, Santa; Ferlazzo, Nadia; Lombardo, Giovanni E.; Maugeri, Alessandro; Calapai, Gioacchino; Gangemi, Sebastiano; Navarra, Michele

2016-01-01

Fruits and vegetables have long been recognized as potentially important in the prevention of cancer risk. Thus, scientific interest in nutrition and cancer has grown over time, as shown by increasing number of experimental studies about the relationship between diet and cancer development. This review attempts to provide an insight into the anti-cancer effects of Citrus fruits, with a focus on their bioactive compounds, elucidating the main cellular and molecular mechanisms through which they may protect against cancer. Scientific literature was selected for this review with the aim of collecting the relevant experimental evidence for the anti-cancer effects of Citrus fruits and their flavonoids. The findings discussed in this review strongly support their potential as anti-cancer agents, and may represent a scientific basis to develop nutraceuticals, food supplements, or complementary and alternative drugs in a context of a multi-target pharmacological strategy in the oncology. PMID:27827912

AKI Associated with Cardiac Surgery

PubMed Central

Thiele, Robert H.; Isbell, James M.

2015-01-01

Approximately 18% of patients undergoing cardiac surgery experience AKI (on the basis of modern standardized definitions of AKI), and approximately 2%–6% will require hemodialysis. The development of AKI after cardiac surgery portends poor short- and long-term prognoses, with those developing RIFLE failure or AKI Network stage III having an almost 2-fold increase in the risk of death. AKI is caused by a variety of factors, including nephrotoxins, hypoxia, mechanical trauma, inflammation, cardiopulmonary bypass, and hemodynamic instability, and it may be affected by the clinician’s choice of fluids and vasoactive agents as well as the transfusion strategy used. The risk of AKI may be ameliorated by avoidance of nephrotoxins, achievement of adequate glucose control preoperatively, and use of goal-directed therapy hemodynamic strategies. Remote ischemic preconditioning is an exciting future strategy, but more work is needed before widespread implementation. Unfortunately, there are no pharmacologic agents known to reduce the risk of AKI or treat established AKI. PMID:25376763

Special Issue: "Molecules against Alzheimer".

PubMed

Decker, Michael; Muñoz-Torrero, Diego

2016-12-16

This Special Issue, entitled "Molecules against Alzheimer", gathers a number of original articles, short communications, and review articles on recent research efforts toward the development of novel drug candidates, diagnostic agents and therapeutic approaches for Alzheimer's disease (AD), the most prevalent neurodegenerative disorder and a leading cause of death worldwide. This Special Issue contains many interesting examples describing the design, synthesis, and pharmacological profiling of novel compounds that hit one or several key biological targets, such as cholinesterases, β-amyloid formation or aggregation, monoamine oxidase B, oxidative stress, biometal dyshomeostasis, mitochondrial dysfunction, serotonin and/or melatonin systems, the Wnt/β-catenin pathway, sigma receptors, nicotinamide phosphoribosyltransferase, or nuclear erythroid 2-related factor. The development of novel AD diagnostic agents based on tau protein imaging and the use of lithium or intranasal insulin for the prevention or the symptomatic treatment of AD is also covered in some articles of the Special Issue.

Methamphetamine-induced hyperthermia and dopaminergic neurotoxicity in mice: pharmacological profile of protective and nonprotective agents.

PubMed

Albers, D S; Sonsalla, P K

1995-12-01

Neurotoxic doses of methamphetamine (METH) can cause hyperthermia in experimental animals. Damage sustained to dopaminergic nerve terminals by this stimulant can be reduced by environmental cooling or by pharmacological manipulation which attenuates the hyperthermia. Many pharmacological agents with very diverse actions protect against METH-induced neuropathology. Several of these compounds, as well as drugs which do not protect, were investigated to determine if there was a relationship between protection and METH-induced hyperthermia. Mice received METH with or without concurrent administration of other drugs and core (i.e., colonic) temperature was monitored during treatment. The animals were sacrificed > or = 5 days later and neostriatal tyrosine hydroxylase activity and dopamine were measured. Core temperature was significantly elevated (> or = 2 degrees C) in mice treated with doses of METH which produced > or = 90% losses in striatal dopamine but not in mice less severally affected (only 50% loss of dopamine). Concurrent treatment of mice with METH and pharmacological agents which protected partially or completely from METH-induced toxicity also prevented the hyperthermic response (i.e., dopamine receptor antagonists, fenfluramine, dizocilpine, alpha-methyl-p-tyrosine, phenytoin, aminooxyacetic acid and propranol). These findings are consistent with the hypothesis that the hyperthermia produced by METH contributes to its neuropathology. However, studies with reserpine, a compound which dramatically lowers core temperature, demonstrated that hyperthermia per se is not a requirement for METH-induced neurotoxicity. Although core temperature was elevated in reserpinized mice treated with METH as compared with reserpinized control mice, their temperatures remained significantly lower than in nonreserpinized control mice. However, the hypothermic state produced in the reserpinized mice did not provide protection from METH-induced toxicity. These data demonstrate that hyperthermia per se contributes to but is not solely responsible for the METH-induced neuropathology.

Current Pharmacological Management of Gastroesophageal Reflux Disease

PubMed Central

Wang, Yao-Kuang; Hsu, Wen-Hung; Wang, Sophie S. W.; Lu, Chien-Yu; Kuo, Fu-Chen; Su, Yu-Chung; Yang, Sheau-Fang; Chen, Chiao-Yun; Wu, Deng-Chyang

2013-01-01

Gastroesophageal reflux disease (GERD), a common disorder with troublesome symptoms caused by reflux of gastric contents into the esophagus, has adverse impact on quality of life. A variety of medications have been used in GERD treatment, and acid suppression therapy is the mainstay of treatment for GERD. Although proton pump inhibitor is the most potent acid suppressant and provides good efficacy in esophagitis healing and symptom relief, about one-third of patients with GERD still have persistent symptoms with poor response to standard dose PPI. Antacids, alginate, histamine type-2 receptor antagonists, and prokinetic agents are usually used as add-on therapy to PPI in clinical practice. Development of novel therapeutic agents has focused on the underlying mechanisms of GERD, such as transient lower esophageal sphincter relaxation, motility disorder, mucosal protection, and esophageal hypersensitivity. Newer formulations of PPI with faster and longer duration of action and potassium-competitive acid blocker, a newer acid suppressant, have also been investigated in clinical trials. In this review, we summarize the current and developing therapeutic agents for GERD treatment. PMID:23878534

The 2014 Philip S. Portoghese Medicinal Chemistry Lectureship: The "Phenylalkylaminome" with a Focus on Selected Drugs of Abuse.

PubMed

Glennon, Richard A

2017-04-13

The phenylalkylamine, particularly the phenylethylamine, moiety is a common structural feature found embedded in many clinically approved agents. Greater still is its occurrence in drugs of abuse. The simplest phenylethylamine, 2-phenylethylamine itself, is without significant central action when administered at moderate doses, but fairly simple structural modifications profoundly impact its pharmacology and result in large numbers of useful pharmacological tools, agents with therapeutic potential, and in drugs of abuse (e.g., hallucinogens, central stimulants, empathogens), the latter of which are the primary focus here. In vivo drug discrimination techniques and in vitro receptor/transporter methods have been applied to understand the actions of these phenylalkylamines and their mechanisms of action. Thus far, depending upon pendent substituents, certain receptors (e.g., serotonin receptors) and monoamine transporters (i.e., serotonin, dopamine, and norepinephrine transporters) have been implicated as playing major roles in the actions of these abused agents in a complex and, at times, interwoven manner.

[Six-month follow-up study of drug treatment for cannabis addiction: comparison study of four drugs].

PubMed

Shoenfeld, Netta; Bodnik, Dana; Rosenberg, Oded; Kotler, Moshe; Dannon, Pinhas

2011-12-01

Marijuana addiction is one of the most common forms of addiction worldwide. A variety of reasons for use exist, however, there are only a few tested treatments with frequent relapses. In this study, we examined the efficacy of four pharmacotherapy agents for the treatment of marijuana addiction: naltrexone, bupropion, escitalopram and bromazepam. A total of 59 patients were randomly assigned into four groups. Each group received one of the pharmacological agents for 120 days. Four types of questionnaires were employed: The Hamilton Rating Scale for Depression--21 items, the Hamilton Rating Scale for Anxiety, the Global Assessment of Functioning and a Visual Analogue Scale for perceived need of the drug. In addition, random urine tests were performed to detect tetrahydrocannabinol [THC). Naltrexone proved to be the most efficacious of the four agents, with only four dropouts. Other agents proved less efficacious with six, seven and eights dropouts for bupropion, bromazepam and escitalopram, respectively. In addition, naltrexone was most efficacious in reducing anxiety and depression rates, and increasing functioning and perceived need for drug use. Out of four pharmacological agents, naltrexone proved to be most efficacious in treating marijuana addiction and related disorders. Further studies are needed to confirm our results.

Advancements in anti-inflammatory therapy for dry eye syndrome.

PubMed

McCabe, Erin; Narayanan, Srihari

2009-10-01

The goal of this literature review is to discuss recent discoveries in the pathophysiology of dry eye and the subsequent evolution of diagnostic and management techniques. The mechanisms of various anti-inflammatory treatments are reviewed, and the efficacy of common pharmacologic agents is assessed. Anti-inflammatory therapy is evaluated in terms of its primary indications, target population, and utility within a clinical setting. The Medline PubMed database and the World Wide Web were searched for current information regarding dry eye prevalence, pathogenesis, diagnosis, and management. After an analysis of the literature, major concepts were integrated to generate an updated portrayal of the status of dry eye syndrome. Inflammation appears to play a key role in perpetuating and sustaining dry eye. Discoveries of inflammatory markers found within the corneal and conjunctival epithelium of dry eye patients have triggered recent advancements in therapy. Pharmacologic anti-inflammatory therapy for dry eye includes 2 major categories: corticosteroids and immunomodulatory agents. Fatty acid and androgen supplementation and oral antibiotics have also shown promise in dry eye therapy because of their anti-inflammatory effects. Anti-inflammatory pharmacologic agents have shown great success in patients with moderate to severe dry eye when compared with alternative treatment modalities. A deeper understanding of the link between inflammation and dry eye validates the utilization of anti-inflammatory therapy in everyday optometric practice.

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

Bench-to-bedside review: Molecular pharmacology and clinical use of inert gases in anesthesia and neuroprotection

PubMed Central

2010-01-01

In the past decade there has been a resurgence of interest in the clinical use of inert gases. In the present paper we review the use of inert gases as anesthetics and neuroprotectants, with particular attention to the clinical use of xenon. We discuss recent advances in understanding the molecular pharmacology of xenon and we highlight specific pharmacological targets that may mediate its actions as an anesthetic and neuroprotectant. We summarize recent in vitro and in vivo studies on the actions of helium and the other inert gases, and discuss their potential to be used as neuroprotective agents. PMID:20836899

The incorporation of hydrophobic protein receptors and artificial lipid membranes.

PubMed

Reader, T A; Fiszer de Plazas, S; Salas, P J; de Robertis, E

1976-01-01

The mechanism of chemical synaptic transmission implies: 1) the existence of a specific protein receptor at the postsynaptic membrane, and 2) the interaction between the transmitter released and the receptor, thus producing a change in ionic permeability. Previous studies from our laboratory have shown that special hydrophobic proteins extracted from postsynpatic membranes of different tissues showed a high affinity binding for the different pharmacological agents. The present paper describes experiments in which different hydrophobic protein binding acetylcholine, noradrenaline, gamma-aminobutyric acid, and glutamate were incorporated into artificial lipid membranes, similar to those first described by Mueller et al. (19). The effect of the different pharmacological agents was tested under experimental conditions of voltage clamp and the d.c. current changes measured. The results were then compared for the different lipid-protein membranes employed during the steady state and during transient conductance changes. The specificity of the responses indicate that artificial lipid membranes containing these hydrophobic proteins from electroplax, myocardium, spleen capsule and shrimp muscle can be used as a model to study pharmacologic receptors.

Pharmacologic therapy for acute pancreatitis

PubMed Central

Kambhampati, Swetha; Park, Walter; Habtezion, Aida

2014-01-01

While conservative management such as fluid, bowel rest, and antibiotics is the mainstay of current acute pancreatitis management, there is a lot of promise in pharmacologic therapies that target various aspects of the pathogenesis of pancreatitis. Extensive review of preclinical studies, which include assessment of therapies such as anti-secretory agents, protease inhibitors, anti-inflammatory agents, and anti-oxidants are discussed. Many of these studies have shown therapeutic benefit and improved survival in experimental models. Based on available preclinical studies, we discuss potential novel targeted pharmacologic approaches that may offer promise in the treatment of acute pancreatitis. To date a variety of clinical studies have assessed the translational potential of animal model effective experimental therapies and have shown either failure or mixed results in human studies. Despite these discouraging clinical studies, there is a great clinical need and there exist several preclinical effective therapies that await investigation in patients. Better understanding of acute pancreatitis pathophysiology and lessons learned from past clinical studies are likely to offer a great foundation upon which to expand future therapies in acute pancreatitis. PMID:25493000

A new pharmacological agent (AKB-4924) stabilizes hypoxia inducible factor-1 (HIF-1) and increases skin innate defenses against bacterial infection.

PubMed

Okumura, Cheryl Y M; Hollands, Andrew; Tran, Dan N; Olson, Joshua; Dahesh, Samira; von Köckritz-Blickwede, Maren; Thienphrapa, Wdee; Corle, Courtney; Jeung, Seung Nam; Kotsakis, Anna; Shalwitz, Robert A; Johnson, Randall S; Nizet, Victor

2012-09-01

Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 increases HIF-1 levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and methicillin-resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinetobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections.

A New Pharmacological Agent (AKB-4924) Stabilizes Hypoxia Inducible Factor (HIF) and Increases Skin Innate Defenses Against Bacterial Infection

PubMed Central

Okumura, Cheryl Y.M.; Hollands, Andrew; Tran, Dan N.; Olson, Joshua; Dahesh, Samira; von Köckritz-Blickwede, Maren; Thienphrapa, Wdee; Corle, Courtney; Jeung, Seung Nam; Kotsakis, Anna; Shalwitz, Robert A.; Johnson, Randall S.; Nizet, Victor

2013-01-01

Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is a major regulator of energy homeostasis and cellular adaptation to low oxygen stress. HIF-1 is also activated in response to bacterial pathogens and supports the innate immune response of both phagocytes and keratinocytes. In this work, we show that a new pharmacological compound AKB-4924 (Akebia Therapeutics) increases HIF-1α levels and enhances the antibacterial activity of phagocytes and keratinocytes against both methicillin-sensitive and -resistant strains of Staphylococcus aureus in vitro. AKB-4924 is also effective in stimulating the killing capacity of keratinocytes against the important opportunistic skin pathogens Pseudomonas aeruginosa and Acinitobacter baumanii. The effect of AKB-4924 is mediated through the activity of host cells, as the compound exerts no direct antimicrobial activity. Administered locally as a single agent, AKB-4924 limits S. aureus proliferation and lesion formation in a mouse skin abscess model. This approach to pharmacologically boost the innate immune response via HIF-1 stabilization may serve as a useful adjunctive treatment for antibiotic-resistant bacterial infections. PMID:22371073

THE PHARMACOLOGY OF RADIOPROTECTANT CHEMICALS. GENERAL PHARMACOLOGY OF / cap beta/-MERCAPTOETHYLAMINE

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

Mundy, R.L.; Heiffer, M.H.

1960-09-01

When 100 mg of beta -mercaptoethylamine is administered intravenously to the dog over a period of 5 min a characteristic set of reactions is produced. The most notable of these in the nonanesthetized dog are violent emesis, agitation frequently leading to tonic-clonic convulsions, ataxia and a characteristic swaying movement of the front portion of the body, generalized depression, loss of pain sense, severe hypotension, relative bradycardia, blood- tinged diarrhea, and a mixed stimulation and depression of respiration. Anesthesia prevents the emetic and convulsive components of the reaction but does not affect the cardiovascular changes. The agent produces a delayed, severe,more » prolonged hypotension. The possibility is discussed that the physiological changes produced by this agent may contribute to its radioprotective potential. 27 references. (auth)« less

Antidiabetic drugs of plant origin used in China: compositions, pharmacology, and hypoglycemic mechanisms.

PubMed

Jia, Wei; Gao, Wen-yuan; Xiao, Pei-gen

2003-02-01

The paper reviewed compositions and pharmacological effects of eight antidiabetic herbal drugs that have been approved by health regulatory agency for commercial use in China. Investigators attributed the hypoglycemic effect of these products to their ability to restore the functions of pancreatic tissues and cause an increase in insulin output, to inhibit the intestinal absorption of glucose, or to the facilitation of metabolites in insulin-dependent processes. Treatment with herbal drugs has an effect on protecting beta cells and smoothing out fluctuations in glucose levels. The use of these naturally derived agents in conjunction with conventional drug treatments such as an chemical agent or insulin permits the use of lower doses of the drug and/or decreased frequency of administration which decreases the side effects most commonly observed.

Transdermal drug delivery: feasibility for treatment of superficial bone stress fractures.

PubMed

Aghazadeh-Habashi, Ali; Yang, Yang; Tang, Kathy; Lőbenberg, Raimar; Doschak, Michael R

2015-12-01

Transdermal drug delivery offers the promise of effective drug therapy at selective sites of pathology whilst reducing systemic exposure to the pharmaceutical agents in off-target organs and tissues. However, that strategy is often limited to cells comprising superficial tissues of the body (rarely to deeper bony structures) and mostly indicated with small hydrophobic pharmacological agents, such as steroid hormones and anti-inflammatory gels to skin, muscle, and joints. Nonetheless, advances in transdermal liposomal formulation have rendered the ability to readily incorporate pharmacologically active hydrophilic drug molecules and small peptide biologics into transdermal dosage forms to impart the effective delivery of those bioactive agents across the skin barrier to underlying superficial tissue structures including bone, often enhanced by some form of electrical, chemical, and mechanical facilitation. In the following review, we evaluate transdermal drug delivery systems, with a particular focus on delivering therapeutic agents to treat superficial bone pain, notably stress fractures. We further introduce and discuss several small peptide hormones active in bone (such as calcitonins and parathyroid hormone) that have shown potential for transdermal delivery, often under the added augmentation of transdermal drug delivery systems that employ lipo/hydrophilicity, electric charge, and/or microprojection facilitation across the skin barrier.

Clinical Pharmacokinetics and Pharmacodynamics of Safinamide.

PubMed

Müller, Thomas; Foley, Paul

2017-03-01

The symptoms of Parkinson's disease (PD) reflect disruptions of a number of brain neurotransmitter systems of varying type and degree. Pharmacological agents with multiple neurochemical mechanisms of action are therefore promising candidates for countering these problems and providing comprehensive symptomatic relief for patients. The pharmacological profile of safinamide includes reversible monoamine oxidase B inhibition, blockage of voltage-dependent Na + channels, modulation of Ca 2+ channels, and inhibition of glutamate release. Safinamide is administered once daily at oral doses of 50-100 mg; it is well-tolerated and safe. Clinical trials have found that it ameliorates motor symptoms when added to established levodopa or single dopamine receptor agonist therapy. The future role of safinamide in PD may be that it enables a reduction in the dosage of dopamine replacement therapies, thereby reducing the adverse effects associated with these treatments. The clinical convenience (once-daily administration), safety, and tolerability of safinamide are better than those of dopamine receptor agonists. The introduction of safinamide reflects a change of approach to drug development for anti-parkinsonian agents in that its broad spectrum of action corresponds to the multiple heterogeneous alterations of brain neurochemistry in PD, rather than being targeted at a single receptor type or neurochemical process. Safinamide is a promising new instrument for the effective symptomatic therapy of PD.

Pharmacology for sleep disturbance in PTSD.

PubMed

Lipinska, Gosia; Baldwin, David S; Thomas, Kevin G F

2016-03-01

Symptoms of sleep disturbance, particularly nightmares and insomnia, are a central feature of post-traumatic stress disorder (PTSD). Emerging evidence suggests that specific treatment of PTSD-related sleep disturbance improves other symptoms of the disorder, which in turn suggests that such disturbance may be fundamental to development and maintenance of the disorder. This mini-review focuses on pharmacological treatment of sleep disturbance in adult PTSD (specifically, studies testing the efficacy of antidepressants, adrenergic inhibiting agents, antipsychotics and benzodiazepine and non-benzodiazepine hypnotics). We conclude that only prazosin, an adrenergic inhibiting agent, has had its efficacy established by multiple randomised controlled trials. There is also high-level evidence supporting use of eszopiclone, as well as risperidone and olanzapine as adjunct therapy. Antidepressants such as sertraline, venlafaxine and mirtazapine, benzodiazepines such as alprazolam and clonazepam and non-benzodiazepine hypnotics such as zolpidem appear ineffective in treating PTSD-related sleep disturbance. Most studies that report reduced frequency of nightmares and insomnia also report decreases in overall symptom severity. Such findings suggest that (i) sleep disruption is central to PTSD; (ii) treating sleep disruption may be an effective way to address other symptoms of the disorder and (iii) PTSD symptoms tend to cluster together in predictable ways. Copyright © 2016 John Wiley & Sons, Ltd.

The World Federation of Societies of Biological Psychiatry (WFSBP) guidelines for the treatment of adolescent sexual offenders with paraphilic disorders

PubMed Central

Thibaut, Florence; Bradford, John M. W.; Briken, Peer; De La Barra, Flora; Häßler, Frank; Cosyns, Paul

2016-01-01

Abstract The primary aim of these guidelines was to evaluate the role of pharmacological agents in the treatment of adolescents with paraphilic disorders who are also sexual offenders or at-risk of sexual offending. Psychotherapeutic and psychosocial treatments were also reviewed. Adolescents with paraphilic disorders specifically present a different therapeutic challenge as compared to adults. In part, the challenge relates to adolescents being in various stages of puberty and development, which may limit the use of certain pharmacological agents due to their potential side effects. In addition, most of the published treatment programmes have used cognitive behavioural interventions, family therapies and psychoeducational interventions. Psychological treatment is predicated in adolescents on the notion that sexually deviant behaviour can be controlled by the offender, and that more adaptive behaviours can be learned. The main purposes of these guidelines are to improve the quality of care and to aid physicians in their clinical decisions. These guidelines brought together different expert views and involved an extensive literature research. Each treatment recommendation was evaluated and discussed with respect to the strength of evidence for efficacy, safety, tolerability and feasibility. An algorithm is proposed for the treatment of paraphilic disorders in adolescent sexual offenders or those who are at risk. PMID:26595752

Discovery of novel immunostimulants by dendritic-cell–based functional screening

PubMed Central

Mizumoto, Norikatsu; Gao, Jimin; Matsushima, Hironori; Ogawa, Yasushi; Tanaka, Hiroaki; Takashima, Akira

2005-01-01

Immunostimulants represent an emerging class of drugs for the treatment of infectious disorders and cancer. CpG oligonucleotides and imiquimod, prototypic drugs in this category, are now known to activate dendritic cells (DCs). Here we report the development of a highly sensitive, unbiased functional screen to detect DC-stimulatory signals. Because interleukin-1β (IL-1β) mRNA expression is closely associated with DC activation, we engineered DCs to stably express a fluorescent marker gene under the control of IL-1β promoter. By screening about 3000 compounds with the resulting DC biosensor clone, we identified DC-stimulatory potentials of topoisomerase I inhibitors (camptothecin derivatives) and microtubule depolymerizing drugs (colchicine and podophyllotoxin). In response to treatment with each agent, bone marrow–derived DC preparations exhibited characteristic phenotypic and/or functional changes associated with DC activation. All of these agents also triggered nuclear factor–κB (NFκB) activation in DCs, suggesting a common pharmacologic mechanism of action. Furthermore, locally administered colchicine induced in situ maturation and migration of DCs and augmented both humoral and cellular immune responses. These results support the practical utility of the DC-based biosensor system to discover novel DC-targeted immunostimulants and unveil previously unrecognized (and totally unexpected) pharmacologic activities of several drugs that are commonly used for the treatment of various disorders. PMID:16002424

Plant-Derived Urease Inhibitors as Alternative Chemotherapeutic Agents.

PubMed

Hassan, Sherif T S; Žemlička, Milan

2016-07-01

Inhibition of the metalloenzyme urease has important pharmacologic applications in the field of antiulcer and antigastric cancer agents. Urease is involved in many serious infections caused by Helicobacter pylori in the gastric tract as well as by Proteus and related species in the urinary tract. Although numerous studies have described several novel urease inhibitors (UIs) used for the treatment of gastric and urinary infections, all these compounds have exhibited severe side effects, toxicity, and instability. Therefore, to overcome such problems, it is necessary to search for new sources of UIs, such as natural products, that provide reduced side effects, low toxicity, greater stability, and bioavailability. As limited studies have been conducted on plant-derived UIs, this paper aims to highlight and summarize the most promising compounds isolated and identified from plants, such as terpenoids, phenolic compounds, alkaloids, and other substances with inhibitory activities against plant and bacterial ureases; these are in vitro and in vivo studies with an emphasis on structure-activity relationship studies and types of inhibition that show high and promising levels of anti-urease activity. This will aid medicinal chemists in the design and synthesis of novel and pharmacologically potent UIs useful for the development of antiulcer drugs. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Uses and misuses of statistics: the case of strontium ranelate and the number needed to treat.

PubMed

Pedrazzoni, M; Giusti, A; Pioli, G

2011-09-01

In the last 15 years, several pharmacological agents for the prevention of fractures have been developed and commercialized. Most of them showed to be effective in reducing fracture risk. The enhanced availability of drugs to prevent fractures has generated a fierce competition among pharmaceutical companies to conquer a share of the potential market, often with claims of superiority of a drug over another without direct comparisons. The definitive way to compare different treatments would require randomized head to head trials. These trials are expensive, need large samples and are unlikely to be ever performed. Therefore, it has become a common practice to compare pharmacological agents through observational studies on administrative databases or by the indirect comparison of the results of individual randomised-controlled trials (RCT) and their meta-analyses. These studies may produce evidence of clinical value, complementary to that given by RCT. However, without a proper and complete analysis, they may result in a biased picture of effectiveness and be completely misleading. In this article, we critically disclose how such competition may produce biased and misleading picture of evidence, by reviewing the significance of the number needed to treat, absolute risk reduction and relative risk reduction in relation to vertebral fractures prevention with available drugs.

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review.

PubMed

Soeiro, M N C; Werbovetz, K; Boykin, D W; Wilson, W D; Wang, M Z; Hemphill, A

2013-07-01

Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates.

Arzanol, a Potent mPGES-1 Inhibitor: Novel Anti-Inflammatory Agent

PubMed Central

Kothavade, Pankaj S.; Nagmoti, Dnyaneshwar M.; Bulani, Vipin D.; Juvekar, Archana R.

2013-01-01

Arzanol is a novel phloroglucinol α-pyrone, isolated from a Mediterranean plant Helichrysum italicum (Roth) Don ssp. microphyllum which belongs to the family Asteraceae. Arzanol has been reported to possess a variety of pharmacological activities. However, anti-inflammatory, anti-HIV, and antioxidant activities have been studied in some detail. Arzanol has been reported to inhibit inflammatory transcription factor NFκB activation, HIV replication in T cells, releases of IL-1β, IL-6, IL-8, and TNF-α, and biosynthesis of PGE2 by potentially inhibiting mPGES-1 enzyme. Diversity of mechanisms of actions of arzanol may be useful in treatment of disease involving these inflammatory mediators such as autoimmune diseases and cancer. This review presents comprehensive information on the chemistry, structure-activity relationship, and pharmacological activities of arzanol. In addition this review discusses recent developments and the scope for future research in these aspects. PMID:24198734

[Drug therapy of female urinary incontinence].

PubMed

Hampel, C; Gillitzer, R; Pahernik, S; Melchior, S W; Thüroff, J W

2005-03-01

Drug treatment for female urinary incontinence requires a thorough knowledge of the differential diagnosis and pathophysiology of incontinence as well as of the pharmacological agents employed. Pharmacotherapy has to be tailored to suit the incontinence subtype and should be carefully balanced according to efficacy and side effects of the drug. Women with urge incontinence require treatment that relaxes or desensitizes the bladder (antimuscarinics, estrogens, alpha-blockers, beta-mimetics, botulinum toxin A, resiniferatoxin, vinpocetine), whereas patients with stress incontinence need stimulation and strengthening of the pelvic floor and external sphincter (alpha-mimetics, estrogens, duloxetine). Females with overflow incontinence need reduction of outflow resistance (baclofen, alpha-blockers, intrasphincteric botulinum toxin A) and/or improvement of bladder contractility (parasympathomimetics). If nocturia or nocturnal incontinence are the major complaints, control of diuresis is obtained by administration of the ADH analogue desmopressin. Future developments will help to further optimize the pharmacological therapy for female urinary incontinence.

The power and promise of "rewiring" the mitogen-activated protein kinase network in prostate cancer therapeutics.

PubMed

Papatsoris, Athanasios G; Karamouzis, Michalis V; Papavassiliou, Athanasios G

2007-03-01

Prostate cancer is the most frequently diagnosed cancer among men and the second leading cause of male cancer deaths. Initially, tumor growth is androgen dependent and thus responsive to pharmacologic androgen deprivation, but there is a high rate of treatment failure because the disease evolves in an androgen-independent state. Growing evidence suggests that the Ras/mitogen-activated protein kinase (MAPK) signaling cascade represents a pivotal molecular circuitry participating directly or indirectly in prostate cancer evolution. The crucial role of the protein elements comprising this complex signal transduction network makes them potential targets for pharmacologic interference. Here, we will delineate the current knowledge regarding the involvement of the Ras/MAPK pathway in prostate carcinogenesis, spotlight ongoing research concerning the development of novel targeted agents such as the Ras/MAPK inhibitors in prostate cancer, and discuss the future perspectives of their therapeutic efficacy.

MRP4/ABCC4 as a new therapeutic target: meta-analysis to determine cAMP binding sites as a tool for drug design.

PubMed

Yaneff, Agustín; Sahores, Ana; Gomez, Natalia; Carozzo, Alejandro; Shayo, Carina; Davio, Carlos

2017-12-29

MRP4 transports multiple endogenous and exogenous substances and is critical not only for detoxification but also in the homeostasis of several signaling molecules. Its dysregulation has been reported in numerous pathological disorders, thus MRP4 appears as an attractive therapeutic target. However, the efficacy of MRP4 inhibitors is still controversial. The design of specific pharmacological agents with the ability to selectively modulate the activity of this transporter or modify its affinity to certain substrates represents a challenge in current medicine and chemical biology. The first step in the long process of drug rational design is to identify the therapeutic target and characterize the mechanism by which it affects the given pathology. In order to develop a pharmacological agent with high specific activity, the second step is to systematically study the structure of the target and identify all the possible binding sites. Using available homology models and mutagenesis assays, in this review we recapitulate the up-to-date knowledge about MRP structure and aligned amino acid sequences to identify the candidate MRP4 residues where cyclic nucleotides bind. We have also listed the most relevant MRP inhibitors studied to date, considering drug safety and specificity for MRP4 in particular. This metaanalysis platform may serve as a basis for the future development of inhibitors of MRP4 cAMP specific transport. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Dextroamphetamine: a pharmacologic countermeasure for space motion sickness and orthostatic dysfunction

NASA Technical Reports Server (NTRS)

Snow, L. Dale

1996-01-01

Dextroamphetamine has potential as a pharmacologic agent for the alleviation of two common health effects associated with microgravity. As an adjuvant to Space Motion Sickness (SMS) medication, dextroamphetamine can enhance treatment efficacy by reducing undesirable Central Nervous System (CNS) side effects of SMS medications. Secondly, dextroamphetamine may be useful for the prevention of symptoms of post-mission orthostatic intolerance caused by cardiovascular deconditioning during spaceflight. There is interest in developing an intranasal delivery form of dextroamphetanmine for use as a countermeasure in microgravity conditions. Development of this dosage form will require an analytical detection method with sensitivity in the low ng range (1 to 100 ng/mL). During the 1995 Summer Faculty Fellowship Program, two analytical methods were developed and evaluated for their suitability as quantitative procedures for dextroamphetamine in studies of product stability, bioavailability assessment, and pharmacokinetic evaluation. In developing some of the analytical methods, beta-phenylethylamine, a primary amine structurally similar to dextroamphetamine, was used. The first analytical procedure to be evaluated involved hexane extraction and subsequent fluorescamine labeling of beta-phenylethylamine. The second analytical procedure to be evaluated involved quantitation of dextroamphetamine by an Enzyme-Linked ImmunoSorbent Assay (ELISA).

New drugs for the treatment of rheumatoid arthritis.

PubMed

Schuna, A A; Megeff, C

2000-02-01

New pharmacologic treatment options for rheumatoid arthritis (RA) are described. Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely prescribed for RA but are limited by the risk of adverse effects, especially gastrointestinal and renal toxicity. The therapeutic effects of these agents are mediated primarily through inhibition of cyclooxygenase (COX) and prevention of subsequent formation of prostaglandins and related inflammatory mediators. Nonspecific COX inhibition appears to be responsible for much of the toxicity of NSAIDs. Agents have been developed that can selectively inhibit the COX-2 isoform, while sparing COX-1. Celecoxib and other COX-2 inhibitors appear to be no more efficacious than conventional NSAIDs, but offer superior safety. COX-2 inhibitors should be considered for patients who are candidates for NSAID therapy but at risk for GI bleeding. Unlike disease-modifying antirheumatic drugs (DMARDs), these agents do not alter underlying disease progression. Leflunomide is a newer DMARD that reduces pyrimidine synthesis, thus decreasing rheumatoid inflammation. Leflunomide appears to be as effective as methotrexate but, unlike that drug, does not necessitate monitoring for bone marrow toxicity. Etanercept, the first biological agent with FDA-approved labeling for use in RA, has shown efficacy and minimal toxicity, except for injection-site reactions. Other biologicals that have been investigated for use in RA include infliximab and interleukin-1-receptor antagonist. COX-2 inhibitors, leflunomide, and etanercept are promising new drugs available for treating RA. Other agents are under development.

Evaluation of Pharmacologic Agents to Suppress Intraocular Cellular Proliferation Following Trauma. Revision.

DTIC Science & Technology

1986-07-01

following enucleation e.q . . .. - .° -15- TABLE 3 METHYLTREXATE 2 m& 2 day post pharm. Clinical Tractional Detacnent* animal op uveiti agent- # (1-4) or...op uveiti agent - - # (1-4) or control 1 wk 2 wk 4 wk 6 wk 12 wk Grogs "aam** __. editta njection of’ drug Orange 31 3 C Reflex / S 2 C R IF 1 C E D...1.0 mg *2 day pobt pharm. Clinical Tractional Detachment* animal op uveitis agent Si (1-4) or control 1 wk 2 wk 4 wk 6 wk 12 wk Groud Exum** Imeie

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.

Histaminergic and serotonergic receptor blocking substances from the medicinal plant Garcinia mangostana.

PubMed

Chairungsrilerd, N; Furukawa, K; Ohta, T; Nozoe, S; Ohizumi, Y

1996-10-01

A crude methanolic extract of the fruit hull of Mangosteen, Garcinia mangostana L. inhibited the contractions of isolated thoracic rabbit aorta induced by histamine and serotonin. The extract of the fruit hull has been fractionated by silica gel chromatography, monitoring the pharmacological activity to give alpha- and gamma-mangostin. On the basis of pharmacological data, it is suggested that alpha-mangostin and gamma-mangostin are a histaminergic and a serotonergic receptor blocking agent, respectively.

Neuroprotection for the new millennium. Matchmaking pharmacology and technology

NASA Technical Reports Server (NTRS)

Andrews, R. J.

2001-01-01

A major theme of the 1990s in the pathophysiology of nervous system injury has been the multifactorial etiology of irreversible injury. Multiple causes imply multiple opportunities for therapeutic intervention--hence the abandonment of the "magic bullet" single pharmacologic agent for neuroprotection in favor of pharmacologic "cocktails". A second theme of the 1990s has been the progress in technology for neuroprotection, minimally- or non-invasive monitoring as well as treatment. Cardiac stenting has eliminated the need, in many cases, for open heart surgery; deep brain stimulation for Parkinson's disease has offered significant improvement in quality of life for many who had exhausted cocktail drug treatment for their disease. Deep brain stimulation of the subthalamic nucleus offers a novel treatment for Parkinson's disease where a technological advance may actually be an intervention with effects that are normally expected from pharmacologic agents. Rather than merely "jamming" the nervous system circuits involved in Parkinson's disease, deep brain stimulation of the subthalamic nucleus appears to improve the neurotransmitter imbalance that lies at the heart of Parkinson's disease. It may also slow the progression of the disease. Given the example of deep brain stimulation of the subthalamic nucleus for Parkinson's disease, in future one may expect other technological or "hardware" interventions to influence the programming or "software" of the nervous system's physiologic response in certain disease states.

Anti-CD22 and anti-CD79b antibody-drug conjugates preferentially target proliferating B cells.

PubMed

Fuh, Franklin K; Looney, Caroline; Li, Dongwei; Poon, Kirsten A; Dere, Randall C; Danilenko, Dimitry M; McBride, Jacqueline; Reed, Chae; Chung, Shan; Zheng, Bing; Mathews, William Rodney; Polson, Andrew; Prabhu, Saileta; Williams, Marna

2017-04-01

CD22 and CD79b are cell-surface receptors expressed on B-cell-derived malignancies such as non-Hodgkin's lymphoma (NHL). An anti-mitotic agent, monomethyl auristatin E, was conjugated to anti-CD22 and anti-CD79b antibodies to develop target-specific therapies for NHL. The mechanism of action (MOA) and pharmacological and pharmacokinetic (PK) profiles of these antibody-drug conjugates (ADCs) were investigated in cynomolgus monkeys. Animals were administered anti-CD22 or anti-CD79b ADCs, respective unconjugated antibodies or vehicle. Pharmacodynamic effects on total and proliferating B cells and serum PK were then assessed. Antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) of the ADCs were evaluated in vitro. Depletion of B cells was observed after administration of either ADC or the respective unconjugated antibodies. An extended duration of depletion was observed in animals administered ADCs. Similarly, preferential depletion of proliferating B cells in blood and germinal centre B cells in spleen were only observed in animals administered ADCs. Serum PK profiles of ADCs and respective unconjugated antibodies were comparable. In vitro, anti-human CD22 and anti-human CD79b antibodies showed no or only moderate ADCC activity, respectively; neither antibody had CDC activity. The findings support the proposed MOA: initial depletion of total B cells by antibody-mediated opsonization, followed by preferential, sustained depletion of proliferating B cells by the auristatin conjugate due to its anti-mitotic action. Delivering potent anti-mitotic agents to B cells via the specificity of monoclonal antibodies provides a means to eliminate pathogenic B cells in NHL with improved risk-benefit profiles over traditional chemotherapeutics. © 2016 Genentech. British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.

Local pharmacological effects of tungstate on the color-pattern determination of butterfly wings: a possible relationship between the eyespot and parafocal element.

PubMed

Dhungel, Bidur; Otaki, Joji M

2009-11-01

Butterfly wing color patterns can be changed by the application of a temperature shock or pharmacological agents such as tungstate, producing a distinctive type of elemental modification called the TS (temperature shock) type. Heterochronic uncoupling between the signaling and reception steps during the color-pattern determination process has been proposed as a mechanism for TS-type changes. As an extension of this hypothesis, both the parafocal element (PFE) and the eyespot in the same wing compartment are considered to be determined by morphogenic signal(s) emitted from the same eyespot focus. However, these models need to be examined with additional experimental data. Furthermore, there is controversy as to whether the action of tungstate on wing color patterns is direct or Indirect. Using a species of nymphalid butterfly (Junonia orithya), we have devised a simple method for the local application of pharmacological agents directly on developing wings of pupae. Local tungstate application resulted in reduced eyespots and circular dislocated PFEs in the eyespot-less compartments only on the treated wing, demonstrating that tungstate directly induces color-pattern changes on wings. We further examined the eyespot-PFE relationship in normal and cold-shocked Individuals, showing that an eyespot can be superimposed on a PFE and vice versa, probably depending on the timing of their fate determination. Taken together, we propose a two-morphogen model for the normal color-pattern determination, in which the morphogenic signals for the eyespot and PFE are different from each other despite their Identical origin. This two-morphogen model is compatible with the heterochronic uncoupling model for TS-type changes.

The endocannabinoid system as a target for the treatment of cannabis dependence.

PubMed

Clapper, Jason R; Mangieri, Regina A; Piomelli, Daniele

2009-01-01

The endocannabinoid system modulates neurotransmission at inhibitory and excitatory synapses in brain regions relevant to the regulation of pain, emotion, motivation, and cognition. This signaling system is engaged by the active component of cannabis, Delta9-tetrahydrocannabinol (Delta9-THC), which exerts its pharmacological effects by activation of G protein-coupled type-1 (CB1) and type-2 (CB2) cannabinoid receptors. During frequent cannabis use a series of poorly understood neuroplastic changes occur, which lead to the development of dependence. Abstinence in cannabinoid-dependent individuals elicits withdrawal symptoms that promote relapse into drug use, suggesting that pharmacological strategies aimed at alleviating cannabis withdrawal might prevent relapse and reduce dependence. Cannabinoid replacement therapy and CB1 receptor antagonism are two potential treatments for cannabis dependence that are currently under investigation. However, abuse liability and adverse side-effects may limit the scope of each of these approaches. A potential alternative stems from the recognition that (i) frequent cannabis use may cause an adaptive down-regulation of brain endocannabinoid signaling, and (ii) that genetic traits that favor hyperactivity of the endocannabinoid system in humans may decrease susceptibility to cannabis dependence. These findings suggest in turn that pharmacological agents that elevate brain levels of the endocannabinoid neurotransmitters, anandamide and 2-arachidonoylglycerol (2-AG), might alleviate cannabis withdrawal and dependence. One such agent, the fatty-acid amide hydrolase (FAAH) inhibitor URB597, selectively increases anandamide levels in the brain of rodents and primates. Preclinical studies show that URB597 produces analgesic, anxiolytic-like and antidepressant-like effects in rodents, which are not accompanied by overt signs of abuse liability. In this article, we review evidence suggesting that (i) cannabis influences brain endocannabinoid signaling and (ii) FAAH inhibitors such as URB597 might offer a possible therapeutic avenue for the treatment of cannabis withdrawal.

Nitrates and Nitrites in the Treatment of Ischemic Cardiac Disease

PubMed Central

Nossaman, Vaughn E.; Nossaman, Bobby D.; Kadowitz, Philip J.

2010-01-01

The organic nitrite, amyl of nitrite, was initially used as a therapeutic agent in the treatment of angina pectoris in 1867, but was replaced over a decade later by the organic nitrate, nitroglycerin (NTG), due to the ease of administration and longer duration of action. The administration of organic nitrate esters, such as NTG, continues to be used in the treatment of angina pectoris and heart failure during the birth of modern pharmacology. The clinical effectiveness is due to vasodilator activity in large veins and arteries through an as yet unidentified method of delivering nitric oxide (NO), or a NO-like compound to vascular smooth muscle cells. The major drawback with NTG administration is the rapid development of tolerance; and with amyl of nitrite, the duration and route of administration. Although amyl of nitrite are no longer used in the treatments of hypertension or ischemic heart disease, the nitrite anion has recently been discovered to possess novel pharmacologic actions such as modulating hypoxic vasodilation and providing cytoprotection in ischemia-reperfusion injury. Although the actions of these two similar chemical classes (nitrites and organic nitrates) have often been considered to be alike, we still do not understand their mechanism of action. However, the recent discovery that the nitrite anion, derived from either sodium nitrite or an intermediate NTG form, may act as a storage form for NO and provides support for investigating the use of these agents in the treatment of ischemic cardiovascular states. We review what is presently known about the use of nitrites and nitrates, the potential uses of these agents, and their mechanisms of action. PMID:20539102

Treatment options for moderate-to-very severe chronic obstructive pulmonary disease.

PubMed

Cazzola, Mario; Rogliani, Paola; Ora, Josuel; Matera, Maria Gabriella

2016-01-01

The appropriate drug management of COPD is still based on the use of bronchodilators, possibly associated with an anti-inflammatory agent. However, there are still fundamental questions that require clarification to optimise their use and major unmet clinical needs that must be addressed. The advances obtained with the pharmacological options currently consolidated and the different approaches that are often used in an attempt to respond to unmet therapeutic needs are reviewed Expert opinion: In view of the unsatisfactory status of current treatments for COPD, there is an urgent need for alternative and more effective therapeutic approaches that will help to relieve patient symptoms and affect the natural course of COPD, inhibiting chronic inflammation and reversing the disease process or preventing its progression. However, new pharmacologic options have proved difficult to develop. Therefore, it is mandatory to optimize the use of the treatment options at our disposal. However, there are still fundamental questions regarding their use, including the step-up and step-down pharmacological approach, that require clarification to optimise the use of these drugs. It is likely that phenotyping COPD patients would help in identifying the right treatment for each COPD patient and improve the effectiveness of therapies.

Forging a modern generation of polyphenol-based therapeutics.

PubMed

Wright, Bernice

2013-06-01

The long-standing debate that polyphenol secondary metabolites from dietary plants are important nutritional components continues due to compelling evidence for their abilities to ameliorate degenerative conditions including, cancer, neurological disorders and cardiovascular disease. The clinical use of polyphenols is not, however, mainstream as issues regarding poor selectivity, dosage, toxicity and delivery methods are unresolved. The paper by Rieder et al. suggests that the lack of selectivity, at least for the stilbene, resveratrol, may not be a major limiting factor. The present commentary is a critique of this significant finding that is focused on deciding how the use of resveratrol as clinical medicine could be advanced, and how this new information integrates with current knowledge of polyphenol physiological effects. This commentary suggests that the multi-target nature of polyphenols may be translated into reliable therapy using the current systems/network pharmacology approach concerned with developing viable therapeutic agents that achieve specific effects through interactions with a wide array of targets. This article is a commentary on Rieder et al., pp. 1244-1258 of BJP 167:6. To view this paper visit http://dx.doi.org/10.1111/j.1476-5381.2012.02063.x. © 2013 The Author. British Journal of Pharmacology © 2013 The British Pharmacological Society.

Pharmacological approaches to intervention in hypomyelinating and demyelinating white matter pathology

PubMed Central

Chew, Li-Jin; DeBoy, Cynthia A

2015-01-01

White matter disease afflicts both developing and mature central nervous systems. Both cell intrinsic and extrinsic dysregulation result in profound changes in cell survival, axonal metabolism and functional performance. Experimental models of developmental white matter (WM) injury and demyelination have not only delineated mechanisms of signaling and inflammation, but have also paved the way for the discovery of pharmacological approaches to intervention. These reagents have been shown to enhance protection of the mature oligodendrocyte cell, accelerate progenitor cell recruitment and/or differentiation, or attenuate pathological stimuli arising from the inflammatory response to injury. Here we highlight reports of studies in the CNS in which compounds, namely peptides, hormones, and small molecule agonists/antagonists, have been used in experimental animal models of demyelination and neonatal brain injury that affect aspects of excitotoxicity, oligodendrocyte development and survival, and progenitor cell function, and which have been demonstrated to attenuate damage and improve WM protection in experimental models of injury. The molecular targets of these agents include growth factor and neurotransmitter receptors, morphogens and their signaling components, nuclear receptors, as well as the processes of iron transport and actin binding. By surveying the current evidence in non-immune targets of both the immature and mature WM, we aim to better understand pharmacological approaches modulating endogenous oligodendroglia that show potential for success in the contexts of developmental and adult WM pathology. PMID:26116759

State-dependent compound inhibition of Nav1.2 sodium channels using the FLIPR Vm dye: on-target and off-target effects of diverse pharmacological agents.

PubMed

Benjamin, Elfrida R; Pruthi, Farhana; Olanrewaju, Shakira; Ilyin, Victor I; Crumley, Gregg; Kutlina, Elena; Valenzano, Kenneth J; Woodward, Richard M

2006-02-01

Voltage-gated sodium channels (NaChs) are relevant targets for pain, epilepsy, and a variety of neurological and cardiac disorders. Traditionally, it has been difficult to develop structure-activity relationships for NaCh inhibitors due to rapid channel kinetics and state-dependent compound interactions. Membrane potential (Vm) dyes in conjunction with a high-throughput fluorescence imaging plate reader (FLIPR) offer a satisfactory 1st-tier solution. Thus, the authors have developed a FLIPR Vm assay of rat Nav1.2 NaCh. Channels were opened by addition of veratridine, and Vm dye responses were measured. The IC50 values from various structural classes of compounds were compared to the resting state binding constant (Kr)and inactivated state binding constant (Ki)obtained using patch-clamp electrophysiology (EP). The FLIPR values correlated with Ki but not Kr. FLIPRIC50 values fell within 0.1-to 1.5-fold of EP Ki values, indicating that the assay generally reports use-dependent inhibition rather than resting state block. The Library of Pharmacologically Active Compounds (LOPAC, Sigma) was screened. Confirmed hits arose from diverse classes such as dopamine receptor antagonists, serotonin transport inhibitors, and kinase inhibitors. These data suggest that NaCh inhibition is inherent in a diverse set of biologically active molecules and may warrant counterscreening NaChs to avoid unwanted secondary pharmacology.

Pharmacologic Treatments for Binge-Eating Disorder.

PubMed

McElroy, Susan L

2017-01-01

Binge-eating disorder (BED) is the most common eating disorder and is associated with poor physical and mental health outcomes. Psychological and behavioral interventions have been a mainstay of treatment for BED, but as understanding of this disorder has grown, pharmacologic agents have become promising treatment options for some patients. At this time, only one drug-the stimulant prodrug lisdexamfetamine-is approved for the treatment of BED. Numerous classes of medications including antidepressants, anticonvulsants, and antiobesity drugs have been explored as off-label treatments for BED with variable success. Although not all patients with BED may be suitable candidates for pharmacotherapy, all patients should be considered for and educated about pharmacologic treatment options. © Copyright 2017 Physicians Postgraduate Press, Inc.

Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery.

PubMed

Brunner, Nathan; de Jesus Perez, Vinicio A; Richter, Alice; Haddad, François; Denault, André; Rojas, Vanessa; Yuan, Ke; Orcholski, Mark; Liao, Xiaobo

2014-03-01

Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population.

Perioperative pharmacological management of pulmonary hypertensive crisis during congenital heart surgery

PubMed Central

2014-01-01

Abstract Pulmonary hypertensive crisis is an important cause of morbidity and mortality in patients with pulmonary arterial hypertension secondary to congenital heart disease (PAH-CHD) who require cardiac surgery. At present, prevention and management of perioperative pulmonary hypertensive crisis is aimed at optimizing cardiopulmonary interactions by targeting prostacyclin, endothelin, and nitric oxide signaling pathways within the pulmonary circulation with various pharmacological agents. This review is aimed at familiarizing the practitioner with the current pharmacological treatment for dealing with perioperative pulmonary hypertensive crisis in PAH-CHD patients. Given the life-threatening complications associated with pulmonary hypertensive crisis, proper perioperative planning can help anticipate cardiopulmonary complications and optimize surgical outcomes in this patient population. PMID:25006417

The combined use of aspirin, a statin, and blood pressure-lowering agents (polypill components) in clinical practice in patients with vascular diseases or type 2 diabetes mellitus.

PubMed

Lafeber, Melvin; Grobbee, Diederick E; Spiering, Wilko; van der Graaf, Yolanda; Bots, Michiel L; Visseren, Frank L J

2013-10-01

Based on guidelines, patients with established cardiovascular disease are likely to already receive a combination of aspirin, a statin, and blood pressure (BP)-lowering agents. Combining these pharmacological agents into a cardiovascular polypill could be considered in these patients to reduce prescription gaps and non-adherence. We aimed to assess the prevalence of the combined use of aspirin, statin, and BP-lowering agents in patients with established cardiovascular diseases or type 2 diabetes mellitus (DM2) in the period 1996-2009. In total, 5702 patients with coronary artery disease (CAD), cerebrovascular disease (CVD), peripheral arterial occlusive disease (PAOD), abdominal aortic aneurysm (AAA) or, DM2 were included in the period 1996-2009. The overall use of combination therapy with aspirin, statin, and ≥ 1 BP-lowering agent increased substantially from 9% in 1996 to 66% in 2009 and ≥ 2 BP-lowering agents increased from 1% to 47%. In 2009, combination therapy with ≥ 1 BP-lowering agent was used by 83% of those with CAD, 48% of those with CVD, 43% of those with PAOD, 36% of the patients with AAA, and 19% of the patients with DM2. In most patient groups, obesity, metabolic syndrome, hypertension concomitant CAD, CVD, or DM2 were related to the use of combination therapy in models adjusted for age and gender. A high proportion of patients with established cardiovascular diseases already uses a combination of pharmacological agents. Introduction of a polypill in high-risk patients might be feasible to reduce prescription gaps and increase adherence to indicated therapy.

Management of dry eye disease.

PubMed

Lemp, Michael A

2008-04-01

The management of dry eye disease (DED) encompasses both pharmacologic and nonpharmacologic approaches, including avoidance of exacerbating factors, eyelid hygiene, tear supplementation, tear retention, tear stimulation, and anti-inflammatory agents. Artificial tears are the mainstay of DED therapy but, although they improve symptoms and objective findings, there is no evidence that they can resolve the underlying inflammation in DED. Topical corticosteroids are effective anti-inflammatory agents, but are not recommended for long-term use because of their adverse-effect profiles. Topical cyclosporine--currently the only pharmacologic treatment approved by the US Food and Drug Administration specifically for DED--is safe for long-term use and is disease-modifying rather than merely palliative. Treatment selection is guided primarily by DED severity. Recently published guidelines propose a severity classification based on clinical signs and symptoms, with treatment recommendations according to severity level.

Inkjet Printing of Amphotericin B onto Biodegradable Microneedles Using Piezoelectric Inkjet Printing

NASA Astrophysics Data System (ADS)

Boehm, Ryan D.; Miller, Philip R.; Schell, Wiley A.; Perfect, John R.; Narayan, Roger J.

2013-04-01

The delivery of amphotericin B, a pharmacologic agent with activity against a broad spectrum of fungi as well as against parasitic protozoa, has been complicated by the fact that amphotericin B exhibits poor solubility in aqueous solutions at physiologic pH levels. In this study, piezoelectric inkjet printing was used to modify the surfaces of Gantrez 169 BF microneedles (Ashland, Covington, KY). These amphotericin B-loaded microneedles demonstrated activity against Candida parapsilosis in a radial diffusion assay. The results of this study suggest that a combination of visible light dynamic mask microstereolithography, micromolding, and piezoelectric inkjet printing may be used to prepare amphotericin B-loaded microneedles with antifungal properties. It is envisioned that microneedles containing amphotericin B may be used for transdermal delivery of pharmacologic agents for the treatment of cutaneous fungal infections as well as cutaneous leishmaniasis.

Safranal: From an Aromatic Natural Product to a Rewarding Pharmacological Agent

PubMed Central

Rezaee, Ramin; Hosseinzadeh, Hossein

2013-01-01

Safranal, the main component of Crocus sativus essential oil, is thought to be the main cause of saffron unique odor. It is now about eighty years that this compound has been discovered and since then different scientific experiments have been done investigating its biological-pharmacological activities. Safranal effects in CNS have been more attractive to scientists and an escalating number of papers have been published regarding its neuropsychological effects. These promising properties of safranal propose its presence as a therapeutic agent in future, although there is a great need for further clinical trials and toxicological studies. In this review article, according to Scopus ®, Thomson Reuters Web of Knowledge®, Scientific Information Database (SID) ® and Pubmed ® all papers published until July 2012 were thoroughly discussed and a brief note of each study was prepared. PMID:23638289

[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.

Insights into the key roles of proteoglycans in breast cancer biology and translational medicine

PubMed Central

Theocharis, Achilleas D.; Skandalis, Spyros S.; Neill, Thomas; Multhaupt, Hinke A. B.; Hubo, Mario; Frey, Helena; Gopal, Sandeep; Gomes, Angélica; Afratis, Nikos; Lim, Hooi Ching; Couchman, John R.; Filmus, Jorge; Sanderson, Ralph D.; Schaefer, Liliana; Iozzo, Renato V.; Karamanos, Nikos K.

2015-01-01

Proteoglycans control numerous normal and pathological processes, among which are morphogenesis, tissue repair, inflammation, vascularization and cancer metastasis. During tumor development and growth, proteoglycan expression is markedly modified in the tumor microenvironment. Altered expression of proteoglycans on tumor and stromal cell membranes affects cancer cell signaling, growth and survival, cell adhesion, migration and angiogenesis. Despite the high complexity and heterogeneity of breast cancer, the rapid evolution in our knowledge that proteoglycans are among the key players in the breast tumor microenvironment suggests their potential as pharmacological targets in this type of cancer. It has been recently suggested that pharmacological treatment may target proteoglycan metabolism, their utilization as targets for immunotherapy or their direct use as therapeutic agents. The diversity inherent in the proteoglycans that will be presented herein provides the potential for multiple layers of regulation of breast tumor behavior. This review summarizes recent developments concerning the biology of selected proteoglycans in breast cancer, and presents potential targeted therapeutic approaches based on their novel key roles in breast cancer. PMID:25829250

A model of axonal transport drug delivery

NASA Astrophysics Data System (ADS)

Kuznetsov, Andrey V.

2012-04-01

In this paper a model of targeted drug delivery by means of active (motor-driven) axonal transport is developed. The model is motivated by recent experimental research by Filler et al. (A.G. Filler, G.T. Whiteside, M. Bacon, M. Frederickson, F.A. Howe, M.D. Rabinowitz, A.J. Sokoloff, T.W. Deacon, C. Abell, R. Munglani, J.R. Griffiths, B.A. Bell, A.M.L. Lever, Tri-partite complex for axonal transport drug delivery achieves pharmacological effect, Bmc Neuroscience 11 (2010) 8) that reported synthesis and pharmacological efficiency tests of a tri-partite complex designed for axonal transport drug delivery. The developed model accounts for two populations of pharmaceutical agent complexes (PACs): PACs that are transported retrogradely by dynein motors and PACs that are accumulated in the axon at the Nodes of Ranvier. The transitions between these two populations of PACs are described by first-order reactions. An analytical solution of the coupled system of transient equations describing conservations of these two populations of PACs is obtained by using Laplace transform. Numerical results for various combinations of parameter values are presented and their physical significance is discussed.

Pharmacologic inhibition of squalene synthase and other downstream enzymes of the cholesterol synthesis pathway: a new therapeutic approach to treatment of hypercholesterolemia.

PubMed

Seiki, Stephanie; Frishman, William H

2009-01-01

Hypercholesterolemia is a major risk factor for the development of atherosclerotic vascular diseases. The most popular agents for cholesterol reduction are the statin drugs, which are competitive inhibitors of hydroxymethylglutaryl-coenzyme A (HMG-CoA) reductase, the primary rate-limiting enzyme in the hepatic biosynthesis of cholesterol. Although relatively safe and effective, the available statins can cause elevations in liver enzymes and myopathy. Squalene synthase is another enzyme that is downstream to HMG-CoA reductase in the cholesterol synthesis pathway and modulates the first committed step of hepatic cholesterol biosynthesis at the final branch point of the cholesterol biosynthetic pathway. Squalene epoxidase and oxidosqualene cyclase are other enzymes that act distally to squalene synthase. Pharmacologic inhibitors of these downstream enzymes have been developed, which may reduce low-density lipoprotein cholesterol and reduce the myopathy side effect seen with upstream inhibition of HMG-CoA. At this juncture, one squalene synthase inhibitor, lapaquistat (TAK-475) is in active clinical trials as a monotherapy, but there have been suggestions of increased hepatotoxicity with the drug.

Drugs in development for Parkinson's disease: an update.

PubMed

Johnston, Tom H; Brotchie, Jonathan M

2006-01-01

The current development of emerging pharmacological treatments for Parkinson's disease (PD), front preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The alpha2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal' synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and alpha-synuclein oligomerization inhibitors, remain in development.

Pharmacological Treatment of Neonatal Opiate Withdrawal: Between the Devil and the Deep Blue Sea

PubMed Central

Liu, Anthony; Björkman, Tracey; Stewart, Caroline; Nanan, Ralph

2011-01-01

Illicit drug use with opiates in pregnancy is a major global health issue with neonatal withdrawal being a common complication. Morphine is the main pharmacological agent administered for the treatment of neonatal withdrawal. In the past, morphine has been considered by and large inert in terms of its long-term effects on the central nervous system. However, recent animal and clinical studies have demonstrated that opiates exhibit significant effects on the growing brain. This includes direct dose-dependent effects on reduction in brain size and weight, protein, DNA, RNA, and neurotransmitters—possibly as a direct consequence of a number of opiate-mediated systems that influence neural cell differentiation, proliferation, and apoptosis. At this stage, we are stuck between the devil and the deep blue sea. There are no real alternatives to pharmacological treatment with opiates and other drugs for neonatal opiate withdrawal and opiate addiction in pregnant women. However, pending further rigorous studies examining the potential harmful effects of opiate exposure in utero and the perinatal period, prolonged use of these agents in the neonatal period should be used judiciously, with caution, and avoided where possible. PMID:21760818

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

PubMed

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

2015-05-01

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

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.

Emerging links between type 2 diabetes and Alzheimer’s disease

PubMed Central

Sridhar, Gumpeny R; Lakshmi, Gumpeny; Nagamani, Gumpeny

2015-01-01

Type 2 diabetes mellitus and Alzheimer’s disease are both associated with increasing age, and each increases the risk of development of the other. Epidemiological, clinical, biochemical and imaging studies have shown that elevated glucose levels and diabetes are associated with cognitive dysfunction, the most prevalent cause of which is Alzheimer’s disease. Cross sectional studies have clearly shown such an association, whereas longitudinal studies are equivocal, reflecting the many complex ways in which the two interact. Despite the dichotomy, common risk and etiological factors (obesity, dyslipidemia, insulin resistance, and sedentary habits) are recognized; correction of these by lifestyle changes and pharmacological agents can be expected to prevent or retard the progression of both diseases. Common pathogenic factors in both conditions span a broad sweep including chronic hyperglycemia per se, hyperinsulinemia, insulin resistance, acute hypoglycemic episodes, especially in the elderly, microvascular disease, fibrillar deposits (in brain in Alzheimer’s disease and in pancreas in type 2 diabetes), altered insulin processing, inflammation, obesity, dyslipidemia, altered levels of insulin like growth factor and occurrence of variant forms of the protein butyrylcholinesterase. Of interest not only do lifestyle measures have a protective effect against the development of cognitive impairment due to Alzheimer’s disease, but so do some of the pharmacological agents used in the treatment of diabetes such as insulin (especially when delivered intranasally), metformin, peroxisome proliferator-activated receptors γ agonists, glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. Diabetes must be recognized as a risk for development of Alzheimer’s disease; clinicians must ensure preventive care be given to control and postpone both conditions, and to identify cognitive impairment early to manage it appropriately. PMID:26069723

Epigenetics in non-small cell lung cancer: from basics to therapeutics.

PubMed

Ansari, Junaid; Shackelford, Rodney E; El-Osta, Hazem

2016-04-01

Lung cancer remains the number one cause of cancer-related deaths worldwide with 221,200 estimated new cases and 158,040 estimated deaths in 2015. Approximately 80% of cases are non-small cell lung cancer (NSCLC). The diagnosis is usually made at an advanced stage where the prognosis is poor and therapeutic options are limited. The evolution of lung cancer is a multistep process involving genetic, epigenetic, and environmental factor interactions that result in the dysregulation of key oncogenes and tumor suppressor genes, culminating in activation of cancer-related signaling pathways. The past decade has witnessed the discovery of multiple molecular aberrations that drive lung cancer growth, among which are epidermal growth factor receptor (EGFR) mutations and translocations involving the anaplastic lymphoma kinase (ALK) gene. This has translated into therapeutic agent developments that target these molecular alterations. The absence of targetable mutations in 50% of NSCLC cases and targeted therapy resistance development underscores the importance for developing alternative therapeutic strategies for treating lung cancer. Among these strategies, pharmacologic modulation of the epigenome has been used to treat lung cancer. Epigenetics approaches may circumvent the problem of tumor heterogeneity by affecting the expression of multiple tumor suppression genes (TSGs), halting tumor growth and survival. Moreover, it may be effective for tumors that are not driven by currently recognized druggable mutations. This review summarizes the molecular pathology of lung cancer epigenetic aberrations and discusses current efforts to target the epigenome with different pharmacological approaches. Our main focus will be on hypomethylating agents, histone deacetylase (HDAC) inhibitors, microRNA modulations, and the role of novel epigenetic biomarkers. Last, we will address the challenges that face this old-new strategy in treating lung cancer.

Quest for Efficacious Next-Generation Taxoid Anticancer Agents and Their Tumor-Targeted Delivery

PubMed Central

2018-01-01

Paclitaxel and docetaxel are among the most widely used chemotherapeutic drugs against various types of cancer. However, these drugs cause undesirable side effects as well as drug resistance. Therefore, it is essential to develop next-generation taxoid anticancer agents with better pharmacological properties and improved activity especially against drug-resistant and metastatic cancers. The SAR studies by the authors have led to the development of numerous highly potent novel second- and third-generation taxoids with systematic modifications at the C-2, C-10, and C-3′ positions. The third-generation taxoids showed virtually no difference in potency against drug-resistant and drug-sensitive cell lines. Some of the next-generation taxoids also exhibited excellent potency against cancer stem cells. This account summarizes concisely investigations into taxoids over 25 years based on a strong quest for the discovery and development of efficacious next-generation taxoids. Discussed herein are SAR studies on different types of taxoids, a common pharmacophore proposal for microtubule-stabilizing anticancer agents and its interesting history, the identification of the paclitaxel binding site and its bioactive conformation, characteristics of the next-generation taxoids in cancer cell biology, including new aspects of their mechanism of action, and the highly efficacious tumor-targeted drug delivery of potent next-generation taxoids. PMID:29468872

Long-term bioavailability of redox nanoparticles effectively reduces organ dysfunctions and death in whole-body irradiated mice.

PubMed

Feliciano, Chitho P; Tsuboi, Koji; Suzuki, Kenshi; Kimura, Hiroyuki; Nagasaki, Yukio

2017-06-01

Radioprotective agents have been developed to protect patients against the damaging and lethal effects of ionizing radiation. However, in addition to the intrinsic ability to target reactive oxygen species (ROS), the ability to retain a significant level of bioavailability is desirable in radioprotective agents because that would increase and prolong their radioprotective efficacy and improve its safety. Here, we report the development of a novel nanoparticle-based radioprotective agent with improved bioavailability, which suppressed the adverse effects typically associated with low-molecular-weight (LMW) antioxidants. We developed biocompatible and colloidally stable nanoparticles in which nitroxide radicals that were covalently conjugated (redox nanoparticles, RNP N ) effectively scavenged radiation-induced ROS with a characteristically prolonged bioavailability and tissue-residence time compared with that of conventional LMW antioxidants. The confinement of the nitroxide radicals in the RNP N core prevented its rapid metabolism and excretion out of the body. The nano-sized formulation prevented internalization of RNP N in healthy cells, thereby preserving the normal function of the redox reactions in the cell. This improved pharmacological performance dramatically reduced the radiation-induced organ dysfunctions and increased the survival time of the lethally irradiated mice when the nanoparticles were administered 3-24 h before whole-body irradiation. Copyright © 2017 Elsevier Ltd. All rights reserved.

Oral amiodarone: historical overview and development.

PubMed

Pollak, P T

1998-01-01

To review the historical development of amiodarone and the changing perceptions of the drug, and discuss its electrophysiologic, pharmacologic, and pharmacokinetic properties. Review of relevant literature. In the 1970s and 1980s a plethora of new antiarrhythmic agents, including amiodarone, was introduced. Amiodarone is predominately a class III antiarrhythmic, but also possesses class I, II, and IV effects. By 1977 it was described as the ideal antiarrhythmic agent. However, clinicians underestimated potential difficulties caused by misunderstanding its variable absorption, slow initial response at nonloading dosages, and extended half-life. Elevated dosages also produced frequent adverse effects. Thus, early enthusiasm for the drug's efficacy was gradually replaced by a focus on its toxicity. The 1990s witnessed reacceptance of the agent as more logical initial regimens and lower maintenance dosages decreased adverse effects, and amiodarone emerged as one of the few drugs effective in suppressing and preventing arrhythmias that does not increase mortality. Remaining challenges include delineation of an optimal oral regimen, identification of markers useful in clinical monitoring, and elucidation of the relationship between dose-tissue concentration and response and dose-toxicity associations. Amiodarone is an increasingly valuable component of today's antiarrhythmic therapy.

Pharmacological therapy of spondyloarthritis.

PubMed

Palazzi, Carlo; D'Angelo, Salvatore; Gilio, Michele; Leccese, Pietro; Padula, Angela; Olivieri, Ignazio

2015-01-01

The current pharmacological therapy of spondyloarthritis (SpA) includes several drugs: Non-steroidal anti-inflammatory drugs, corticosteroids, traditional disease-modifying antirheumatic drugs and biologic drugs. A systematic literature search was completed using the largest electronic databases (Medline, Embase and Cochrane), starting from 1995, with the aim to review data on traditional and biologic agents commercialised for SpA treatment. Randomised controlled trials and large observational studies were considered. In addition, studies performed in SpA patients treated with other, still unapproved, drugs (rituximab, anti-IL6 agents, apremilast, IL17 inhibitors and anakinra) were also taken into account. Biologic agents, especially anti-TNF drugs, have resulted in significant progress in improving clinical symptoms and signs, reducing inflammatory features in laboratory tests and imaging findings, and recovering all functional indexes. Anti-TNF drugs have radically changed the evolution of radiographic progression in peripheral joints; the first disappointing data concerning their efficacy on new bone formation of axial SpA has been recently challenged by studies enrolling patients who have been earlier diagnosed and treated. The opportunity to extend the interval of administration or to reduce the doses of anti-TNF agents can favourably influence the costs. Ustekinumab, the first non-anti-TNF biologic drug commercialised for psoriatic arthritis, offers new chances to patients that are unresponsive to anti-TNF.

Bradycardia in a Pediatric Heart Transplant Recipient: Is It the Sugammadex?

PubMed

King, Adele; Naguib, Aymen; Tobias, Joseph D

2017-01-01

Sugammadex is a novel pharmacologic agent that is used to selectively reverse the effects of the neuromuscular blocking agents rocuronium and vecuronium. Various advantages have been reported when comparing its reversal of neuromuscular blockade to that achieved with acetylcholinesterase inhibitors (neostigmine). In heart transplant recipients, bradycardia may occur following the administration of acetylcholinesterase inhibitors, due to the denervation of the heart. Theoretically, the combination of rocuronium and sugammadex could be advantageous in this clinical scenario to avoid the potential bradycardia resulting from neostigmine administration. We present a 10-year-old male who developed profound bradycardia immediately following the administration of intravenous sugammadex. The options for reversal of neuromuscular blockade in heart transplant recipients is discussed, previous reports of bradycardia following sugammadex are presented, and the role of sugammadex in the bradycardia in our patient is reviewed.

Opioid-Induced Bowel Dysfunction

PubMed Central

Cheng, Vivian; Lembo, Anthony

2013-01-01

Opioid-induced bowel dysfunction (OIBD) is a potentially debilitating side effect of chronic opioid use. It refers to a collection of primarily gastrointestinal motility disorders induced by opioids, of which opioid-induced constipation (OIC) is the most common. Management of OIBD is difficult, and affected patients will often limit their opioid intake at the expense of experiencing more pain, to reduce the negative impact of OIBD on their quality of life. Effective pharmacologic therapy for OIC is considered an unmet need and several agents have recently been given priority review and approval for OIC. Furthermore, multiple agents currently in development show promise in treating OIC without significant impact on analgesia or precipitation of withdrawal symptoms. The approval and availability of such medications would represent a significant improvement in the management of OIC and OIBD in patients with chronic pain. PMID:23900996

Tobacco Harms, Nicotine Pharmacology, and Pharmacologic Tobacco Cessation Interventions for Women.

PubMed

Baraona, L Kim; Lovelace, Dawn; Daniels, Julie L; McDaniel, Linda

2017-05-01

Firsthand and secondhand tobacco use is linked to a multitude of harmful illnesses, adverse perinatal outcomes, and death. Cessation attempts among women may be hampered by their unique biologic response to nicotine. Current research has revealed epigenetic changes from intrauterine nicotine exposure that have intergenerational consequences. Multiple studies have demonstrated the efficacy of various pharmacologic tobacco cessation interventions in conjunction with behavioral counseling. Based on this evidence, the US Preventative Services Task Force (USPSTF) 2015 guideline recommends pharmacologic therapy for all nonpregnant persons who smoke in addition to behavioral counseling. The effectiveness of pharmacologic treatments among pregnant women is less clear, with far fewer studies evaluating potential benefits and harms. While exposure to pharmacologic therapies raises concerns for fetal safety, these potential risks must be weighed against those of continued tobacco use, which guarantees fetal exposure to nicotine. First-line tobacco cessation medications include nicotine replacement therapy (NRT), bupropion, and varenicline. Second-line medications include nortriptyline and clonidine. Pharmacokinetics, effectiveness, regimens, and safety profiles for nonpregnant, pregnant, and lactating women are reviewed. Alternative tobacco cessation options and potential new pharmacologic tobacco cessation agents are discussed. Initiating brief interventions, using the 5A's and 5R's model is described. © 2017 by the American College of Nurse-Midwives.

Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer☆

PubMed Central

Moser, Justin C.; Rawal, Malvika; Wagner, Brett A.; Du, Juan; Cullen, Joseph J.; Buettner, Garry R.

2013-01-01

Labile iron, i.e. iron that is weakly bound and is relatively unrestricted in its redox activity, has been implicated in both the pathogenesis as well as treatment of cancer. Two cancer treatments where labile iron may contribute to their mechanism of action are pharmacological ascorbate and ionizing radiation (IR). Pharmacological ascorbate has been shown to have tumor-specific toxic effects due to the formation of hydrogen peroxide. By catalyzing the oxidation of ascorbate, labile iron can enhance the rate of formation of hydrogen peroxide; labile iron can also react with hydrogen peroxide. Here we have investigated the magnitude of the labile iron pool in tumor and normal tissue. We also examined the ability of pharmacological ascorbate and IR to change the size of the labile iron pool. Although a significant amount of labile iron was seen in tumors (MIA PaCa-2 cells in athymic nude mice), higher levels were seen in murine tissues that were not susceptible to pharmacological ascorbate. Pharmacological ascorbate and irradiation were shown to increase the labile iron in tumor homogenates from this murine model of pancreatic cancer. As both IR and pharmacological ascorbate may rely on labile iron for their effects on tumor tissues, our data suggest that pharmacological ascorbate could be used as a radio-sensitizing agent for some radio-resistant tumors. PMID:24396727

Strategic incorporation of fluorine in the drug discovery of new-generation antitubercular agents targeting bacterial cell division protein FtsZ⋆

PubMed Central

Ojima, Iwao; Awasthi, Divya; Wei, Longfei; Haranahalli, Krupanandan

2016-01-01

This article presents an account of our research on the discovery and development of new-generation fluorine-containing antibacterial agents against drug-resistant tuberculosis, targeting FtsZ. FtsZ is an essential protein for bacterial cell division and a highly promising therapeutic target for antibacterial drug discovery. Through design, synthesis and semi-HTP screening of libraries of novel benzimidazoles, followed by SAR studies, we identified highly potent lead compounds. However, these lead compounds were found to lack sufficient metabolic and plasma stabilities. Accordingly, we have performed extensive study on the strategic incorporation of fluorine into lead compounds to improve pharmacological properties. This study has led to the development of highly efficacious fluorine-containing benzimidazoles as potential drug candidates. We have also performed computational docking analysis of these novel FtsZ inhibitors to identify their putative binding site. Based on the structural data and docking analysis, a plausible mode-of-action for this novel class of FtsZ inhibitors is proposed. PMID:28555087

Antihypertensive drugs.

PubMed

Laurent, Stéphane

2017-10-01

Successful treatment of hypertension is possible with limited side effects given the availability of multiple antihypertensive drug classes. This review describes the various pharmacological classes of antihypertensive drugs, under two major aspects: their mechanisms of action and side effects. The mechanism of action is analysed through a pharmacological approach, i.e. the molecular receptor targets, the various sites along the arterial system, and the extra-arterial sites of action, in order to better understand in which type of hypertension a given pharmacological class of antihypertensive drug is most indicated. In addition, side effects are described and explained through their pharmacological mechanisms, in order to better understand their mechanism of occurrence and in which patients drugs are contra-indicated. This review does not address the effectiveness of monotherapies in large randomized clinical trials and combination therapies, since these are the matters of other articles of the present issue. Five major pharmacological classes of antihypertensive drugs are detailed here: beta-blockers, diuretics, angiotensin converting enzyme inhibitors, angiotensin II receptor antagonists, and calcium channel blockers. Four additional pharmacological classes are described in a shorter manner: renin inhibitors, alpha-adrenergic receptor blockers, centrally acting agents, and direct acting vasodilators. Copyright © 2017. Published by Elsevier Ltd.

Pharmacological Management of Cardiorenal Syndromes

PubMed Central

House, Andrew A.; Haapio, Mikko; Lassus, Johan; Bellomo, Rinaldo; Ronco, Claudio

2011-01-01

Cardiorenal syndromes are disorders of the heart and kidneys whereby acute or chronic dysfunction in one organ may induce acute or chronic dysfunction of the other. The pharmacological management of Cardiorenal syndromes may be complicated by unanticipated or unintended effects of agents targeting one organ on the other. Hence, a thorough understanding of the pathophysiology of these disorders is paramount. The treatment of cardiovascular diseases and risk factors may affect renal function and modify the progression of renal injury. Likewise, management of renal disease and associated complications can influence heart function or influence cardiovascular risk. In this paper, an overview of pharmacological management of acute and chronic Cardiorenal Syndromes is presented, and the need for high-quality future studies in this field is highlighted. PMID:21660311

Maximizing value in opioid utilization: Is oxycodone immediate release a good option for pain management?

PubMed

Pergolizzi, Joseph V; Köknel Talu, Gül; Zmponga, Gianpetrio; Erdine, Serdar; Taylor, Robert; Ayan, Burak; Raffa, Robert B

2015-01-01

The modern approach to the management of pain involves optimizing all aspects of the process. This includes utilization of pharmacologic and non-pharmacologic modalities, consideration of patient characteristics, proper matching of the physiology of the pain with the analgesic's mechanism of action (pharmacodynamics, PD), and the onset and duration of action (pharmacokinetics, PK). No single agent or formulation satisfies all of the requirements for all patients. Aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) are effective options for inflammatory pain and, as is acetaminophen, for mild pain. Specialized agents are helpful for particular pains, such as for migraine headache. Opioids remain the standard option for severe pain. Although they are generally a safe and effective option, opioids can produce dose-limiting adverse effects and have abuse potential. The goal of pain therapy is thus to achieve the maximum pain relief with the least amount of opioid exposure. Against this background of measured approach to the use of analgesics, an immediate release (IR) oral formulation of the established opioid oxycodone has been developed to provide rapid onset of action and rate of titration, both of which could maximize temporal matching of dose with pain level and reduce total exposure to drug. This article considers the option of an immediate release (IR) oral formulation for the management of pain.

Dimethyl sulfoxide (DMSO) exacerbates cisplatin-induced sensory hair cell death in zebrafish (Danio rerio).

PubMed

Uribe, Phillip M; Mueller, Melissa A; Gleichman, Julia S; Kramer, Matthew D; Wang, Qi; Sibrian-Vazquez, Martha; Strongin, Robert M; Steyger, Peter S; Cotanche, Douglas A; Matsui, Jonathan I

2013-01-01

Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under the control of the Brn3c promoter/enhancer. Recently, several small molecule screens have been conducted using zebrafish to identify potential pharmacological agents that could be used to protect sensory hair cells in the presence of ototoxic drugs. Dimethyl sulfoxide (DMSO) is typically used as a solvent for many pharmacological agents in sensory hair cell cytotoxicity assays. Serendipitously, we found that DMSO potentiated the effects of cisplatin and killed more sensory hair cells than treatment with cisplatin alone. Yet, DMSO alone did not kill hair cells. We did not observe the synergistic effects of DMSO with the ototoxic aminoglycoside antibiotic neomycin. Cisplatin treatment with other commonly used organic solvents (i.e. ethanol, methanol, and polyethylene glycol 400) also did not result in increased cell death compared to cisplatin treatment alone. Thus, caution should be exercised when interpreting data generated from small molecule screens since many compounds are dissolved in DMSO.

Dimethyl Sulfoxide (DMSO) Exacerbates Cisplatin-induced Sensory Hair Cell Death in Zebrafish (Danio rerio)

PubMed Central

Gleichman, Julia S.; Kramer, Matthew D.; Wang, Qi; Sibrian-Vazquez, Martha; Strongin, Robert M.; Steyger, Peter S.; Cotanche, Douglas A.; Matsui, Jonathan I.

2013-01-01

Inner ear sensory hair cells die following exposure to aminoglycoside antibiotics or chemotherapeutics like cisplatin, leading to permanent auditory and/or balance deficits in humans. Zebrafish (Danio rerio) are used to study drug-induced sensory hair cell death since their hair cells are similar in structure and function to those found in humans. We developed a cisplatin dose-response curve using a transgenic line of zebrafish that expresses membrane-targeted green fluorescent protein under the control of the Brn3c promoter/enhancer. Recently, several small molecule screens have been conducted using zebrafish to identify potential pharmacological agents that could be used to protect sensory hair cells in the presence of ototoxic drugs. Dimethyl sulfoxide (DMSO) is typically used as a solvent for many pharmacological agents in sensory hair cell cytotoxicity assays. Serendipitously, we found that DMSO potentiated the effects of cisplatin and killed more sensory hair cells than treatment with cisplatin alone. Yet, DMSO alone did not kill hair cells. We did not observe the synergistic effects of DMSO with the ototoxic aminoglycoside antibiotic neomycin. Cisplatin treatment with other commonly used organic solvents (i.e. ethanol, methanol, and polyethylene glycol 400) also did not result in increased cell death compared to cisplatin treatment alone. Thus, caution should be exercised when interpreting data generated from small molecule screens since many compounds are dissolved in DMSO. PMID:23383324

Simultaneous Characterization of Intravenous and Oral Pharmacokinetics of Lychnopholide in Rats by Transit Compartment Model.

PubMed

Lachi-Silva, Larissa; Sy, Sherwin K B; Voelkner, Alexander; de Sousa, João Paulo Barreto; Lopes, João Luis C; Silva, Denise B; Lopes, Norberto P; Kimura, Elza; Derendorf, Hartmut; Diniz, Andrea

2015-08-01

The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99 % as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68 %. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent. Georg Thieme Verlag KG Stuttgart · New York.

Novel amidines and analogues as promising agents against intracellular parasites: a systematic review

PubMed Central

Soeiro, M. N. C.; Werbovetz, K.; Boykin, D.W.; Wilson, W. D.; Wang, M. Z.; Hemphill, A.

2013-01-01

SUMMARY Parasitic protozoa comprise diverse aetiological agents responsible for important diseases in humans and animals including sleeping sickness, Chagas disease, leishmaniasis, malaria, toxoplasmosis and others. They are major causes of mortality and morbidity in tropical and subtropical countries, and are also responsible for important economic losses. However, up to now, for most of these parasitic diseases, effective vaccines are lacking and the approved chemotherapeutic compounds present high toxicity, increasing resistance, limited efficacy and require long periods of treatment. Many of these parasitic illnesses predominantly affect low-income populations of developing countries for which new pharmaceutical alternatives are urgently needed. Thus, very low research funding is available. Amidine-containing compounds such as pentamidine are DNA minor groove binders with a broad spectrum of activities against human and veterinary pathogens. Due to their promising microbicidal activity but their rather poor bioavailability and high toxicity, many analogues and derivatives, including pro-drugs, have been synthesized and screened in vitro and in vivo in order to improve their selectivity and pharmacological properties. This review summarizes the knowledge on amidines and analogues with respect to their synthesis, pharmacological profile, mechanistic and biological effects upon a range of intracellular protozoan parasites. The bulk of these data may contribute to the future design and structure optimization of new aromatic dicationic compounds as novel antiparasitic drug candidates. PMID:23561006

A review on the ethnomedicinal uses, phytochemistry and pharmacology of Alpinia officinarum Hance.

PubMed

Abubakar, Ibrahim Babangida; Malami, Ibrahim; Yahaya, Yakubu; Sule, Sahabi Manga

2018-05-25

Alpinia officinarum Hance is a perennial plant that has been traditionally used for many decades to treat several ailments including inflammation, pain, stomach-ache, cold, amongst others. Pharmacological studies over the years have demonstrated remarkable bioactivities that could be further explored for development of new therapeutic agents against various ailments. The paper critically reviewed the ethno-medicinal uses, pharmacology, and phytochemistry of A. officinarum. Keywords including A. officinarum and its synonyms were searched using electronic databases including ISI web of knowledge, Science direct, Scopus, PubMed, Google scholar and relevant database for Masters and Doctoral theses. A. officinarum is prepared in Asia, Turkey, Morocco and Iran as a decoction, infusion or juice as a single preparation or in combination with other herbs, food or drinks for the treatment of general health problems including cold, inflammation, digestive disorders, etc. Pharmacological studies revealed the potent in vitro and in vivo bioactivities of various parts of A. officinarum that include anti-inflammatory, cytotoxicity, homeostasis, lipid regulation, antioxidant, antiviral, antimicrobial, antiosteoporosis, etc. Over 90 phytochemical constituents have been identified and isolated from A. officinarum comprising vastly of phenolic compounds especially diarylheptanoids isolated from the rhizome and considered the most active bioactive components. In vitro and in vivo studies have confirmed the potency of A. officinarum. However, further studies are required to establish the mechanisms mediating its bioactivities in relation to the medicinal uses as well as investigating any potential toxicity for future clinical studies. Copyright © 2018 Elsevier B.V. All rights reserved.

Assessing the anticancer effects associated with food products and/or nutraceuticals using in vitro and in vivo preclinical development-related pharmacological tests.

PubMed

Lefranc, Florence; Tabanca, Nurhayat; Kiss, Robert

2017-10-01

This review is part of a special issue entitled "Role of dietary pattern, foods, nutrients and nutraceuticals in supporting cancer prevention and treatment" and describes a pharmacological strategy to determine the potential contribution of food-related components as anticancer agents against established cancer. Therefore, this review does not relate to chemoprevention, which is analysed in several other reviews in the current special issue, but rather focuses on the following: i) the biological events that currently represent barriers against the treatment of certain types of cancers, primarily metastatic cancers; ii) the in vitro and in vivo pharmacological pre-clinical tests that can be used to analyse the potential anticancer effects of food-related components; and iii) several examples of food-related components with anticancer effects. This review does not represent a catalogue-based listing of food-related components with more or less anticancer activity. By contrast, this review proposes an original pharmacological strategy that researchers can use to analyse the potential anticancer activity of any food-related component-e.g., by considering the crucial characteristics of cancer biological aggressiveness. This review also highlights that cancer patients undergoing chemotherapy should restrict the use of "food complements" without supervision by a medical nutritionist. By contrast, an equilibrated diet that includes the food-related components listed herein would be beneficial for cancer patients who are not undergoing chemotherapy. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

Network pharmacology-based virtual screening of natural products from Clerodendrum species for identification of novel anti-cancer therapeutics.

PubMed

Gogoi, Barbi; Gogoi, Dhrubajyoti; Silla, Yumnam; Kakoti, Bibhuti Bhushan; Bhau, Brijmohan Singh

2017-01-31

Plant-derived natural products (NPs) play a vital role in the discovery of new drug molecules and these are used for development of novel therapeutic drugs for a specific disease target. Literature review suggests that natural products possess strong inhibitory efficacy against various types of cancer cells. Clerodendrum indicum and Clerodendrum serratum are reported to have anticancer activity; therefore a study was carried out to identify selective anticancer agents from these plants species. In this report, we employed a docking weighted network pharmacological approach to understand the multi-therapeutics potentiality of C. indicum and C. serratum against various types of cancer. A library of 53 natural products derived from these plants was compiled from the literature and three dimensional space analyses were performed in order to establish the drug-likeness of the NPs library. Further, an NPs-cancer network was built based on docking. We predicted five compounds, namely apigenin 7-glucoside, hispidulin, scutellarein-7-O-beta-d-glucuronate, acteoside and verbascoside, to be potential binding therapeutics for cancer target proteins. Apigenin 7-glucoside and hispidulin were found to have maximum binding interactions (relationship) with 17 cancer drug targets in terms of docking weighted network pharmacological analysis. Hence, we used an integrative approach obtained from network pharmacology for identifying combinatorial drug actions against the cancer targets. We believe that our present study may provide important clues for finding novel drug inhibitors for cancer.

Alkaloids from piper: a review of its phytochemistry and pharmacology.

PubMed

Gutierrez, Rosa Martha Perez; Gonzalez, Adriana Maria Neira; Hoyo-Vadillo, Carlos

2013-02-01

Piper has been used for long timelike condiment and food, but also in traditional medicine around of the world. This work resumes the available and up to date work done on members of the Piperaceae family and their uses for therapeutic purposes. Information on Piper genus was gathered via internet using scientific databases such as Scirus, Google Scholar, CAB-abstracts, MedlinePlus, Pubmed, SciFinder, Scopus and Web of Science. The largeleafed perennial plant Piper is used for its spicy aromatic scent and flavor. It has an important presence in the cuisine of different cultures. Another quality of these plants is their known medicinal properties. It has been used as emollient, antirheumatic, diuretic, stimulant, abortifacient, anti-inflammatory, antibacterial, antifungal and antidermatophytic. A survey of the literature shows that the genus Piper is mainly known for its alkaloids with cytotoxic, chemopreventive, antimetastatic and antitumor properties in several types of cancer. Studies of its alkaloids highlight the existence of various potential leads to develop new anti-cancer agents. Modern pharmacology studies have demonstrated that its crude extracts and active compounds possess wide pharmacological activities, especially asantioxidant, anti-depressive, hepatoprotective, antimicrobial, anti-obesity, neuropharmacological, to treat cognitive disorders, anti-hyperlipidemic, anti-feedant, cardioactive, immuno-enhancing, and anti-inflamatory. All this evidence supporting its traditional uses. This review summarizes the up-to-date and comprehensive information concerning the botany, traditional use, phytochemistry and pharmacology of Piper together with its toxicology, and discusses the possible trend and scope for further research on Piper in the future.

Glutamatergic Deficits in Schizophrenia - Biomarkers and Pharmacological Interventions within the Ketamine Model.

PubMed

Haaf, Moritz; Leicht, Gregor; Curic, Stjepan; Mulert, Christoph

2018-06-19

The basic mechanism of pharmacotherapy in schizophrenia has barely changed in the last 60 years. Currently used medications allow the effective treatment of positive symptoms via antagonistic effects at dopamine receptors whereas the effect on negative and cognitive symptoms is most often negligible. The observation that N-methyl-D-aspartate glutamate receptor (NMDAR) antagonists such as ketamine transiently induce schizophrenia-like positive, negative and cognitive symptoms has led to a paradigm shift from dopaminergic to glutamatergic dysfunction in pharmacological models of schizophrenia. The NMDAR hypofunction can explain not only the whole range of schizophrenia symptoms but also the dopaminergic dysfunction itself, and it emphasizes the need for pharmacologicallytargeted glutamatergic neurotransmission. Moreover, ketamine-induced psychopathological changes in healthy participants were accompanied by altered electro-(EEG), magnetoencephalographic (MEG) (e.g. Mismatch Negativity (MMN), N100), and functional magnetic resonance imaging (fMRI) signals, reminiscent of findings observed in patients with schizophrenia. Hence, the ketamine model offers the possibility to assess the effect of novel pharmacological agents on schizophrenia-like symptoms and neurophysiology, thereby potentially facilitating drug research and development by providing a way to ascertain functional target engagement and the ability to prioritize candidate drugs. Therefore, this review summarizes the recent evidence from EEG, MEG and fMRI studies on potential biomarkers found in healthy subjects treated with ketamine and pharmacological interventions within the ketamine model. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA)

PubMed Central

Docherty, J R

2008-01-01

This review examines the pharmacology of stimulants prohibited by the World Anti-Doping Agency (WADA). Stimulants that increase alertness/reduce fatigue or activate the cardiovascular system can include drugs like ephedrine available in many over-the-counter medicines. Others such as amphetamines, cocaine and hallucinogenic drugs, available on prescription or illegally, can modify mood. A total of 62 stimulants (61 chemical entities) are listed in the WADA List, prohibited in competition. Athletes may have stimulants in their body for one of three main reasons: inadvertent consumption in a propriety medicine; deliberate consumption for misuse as a recreational drug and deliberate consumption to enhance performance. The majority of stimulants on the list act on the monoaminergic systems: adrenergic (sympathetic, transmitter noradrenaline), dopaminergic (transmitter dopamine) and serotonergic (transmitter serotonin, 5-HT). Sympathomimetic describes agents, which mimic sympathetic responses, and dopaminomimetic and serotoninomimetic can be used to describe actions on the dopamine and serotonin systems. However, many agents act to mimic more than one of these monoamines, so that a collective term of monoaminomimetic may be useful. Monoaminomimietic actions of stimulants can include blockade of re-uptake of neurotransmitter, indirect release of neurotransmitter, direct activation of monoaminergic receptors. Many of the stimulants are amphetamines or amphetamine derivatives, including agents with abuse potential as recreational drugs. A number of agents are metabolized to amphetamine or metamphetamine. In addition to the monoaminomimetic agents, a small number of agents with different modes of action are on the list. A number of commonly used stimulants are not considered as Prohibited Substances. PMID:18500382

Testing for a "sobering pill"

DOT National Transportation Integrated Search

1974-12-01

The concept of blocking or neutralizing the effect of alcohol on the brain was investigated in a series of human tests. It was found that pharmacological agents which stimulate the dopaminergic system tend to neutralize the alcohol reduced performanc...

Novel Pharmacotherapeutic Approaches In Treatment Of Alcohol Addiction.

PubMed

Mohamad, Rashidi Mohamed Pakri; Kumar, Jaya; Ahmad, Shihab Udin; Mohamed, Isa Naina

2018-05-22

In the past two decades, the search for novel pharmacotherapies to treat alcohol addiction been a global endeavour. This has resulted in several drugs that have been approved and successfully marketed for public use while some are still in the testing phase. These pharmacological agents, though effective for the treatment of alcoholism, are not without shortcomings; such as abuse potential, serious mental and physical adverse effects, interaction with alcohol and also poor metabolism and excretion. As more is being understood about the neurobiology of alcohol addiction as well as the unique pharmacological action of these drugs, new agents are evaluated for potential benefits when used as a adjunct in combination therapy. This review article summarizes the novel pharmacotherapeutic approaches in treatment of alcohol addiction by focusing on the drugs, which includes neramexane, gabapentin, baclofen, aripiprazole, nalmafene, and quetiapine. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Atomic layer deposition of TIO{sub 2} thin films on nanoporous alumina templates : medical applications.

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

Narayan, R. J.; Monteiro-Riviere, N. A.; Brigmon, R. L.

2009-06-01

Nanostructured materials may play a significant role in controlled release of pharmacologic agents for treatment of cancer. Many nanoporous polymer materials are inadequate for use in drug delivery. Nanoporous alumina provides several advantages over other materials for use in controlled drug delivery and other medical applications. Atomic layer deposition was used to coat all the surfaces of a nanoporous alumina membrane in order to reduce the pore size in a controlled manner. Neither the 20 nm nor the 100 nm TiO{sub 2}-coated nanoporous alumina membranes exhibited statistically lower viability compared to the uncoated nanoporous alumina membrane control materials. Nanostructured materialsmore » prepared using atomic layer deposition may be useful for delivering a pharmacologic agent at a precise rate to a specific location in the body. These materials may serve as the basis for 'smart' drug delivery devices, orthopedic implants, or self-sterilizing medical devices.« less

Aristoforin, a novel stable derivative of hyperforin, is a potent anticancer agent.

PubMed

Gartner, Michael; Müller, Thomas; Simon, Jan C; Giannis, Athanassios; Sleeman, Jonathan P

2005-01-01

Hyperforin, a natural product of St. John's wort (Hypericum perforatum L.), has a number of pharmacological activities, including antidepressive and antibacterial properties. Furthermore, hyperforin has pronounced antitumor properties against different tumor cell lines, both in vitro and in vivo. Despite being a promising novel anticancer agent, the poor solubility and stability of hyperforin in aqueous solution limits its potential clinical application. In this study, we present the synthesis of hyperforin derivatives with improved pharmacological activity. The synthesized compounds were tested for their solubility and stability properties. They were also investigated for their antitumor properties, both in vitro and in vivo. One of these hyperforin derivatives, Aristoforin, is more soluble in aqueous solution than hyperforin and is additionally highly stable. Importantly, it retains the antitumor properties of the parental compound without inducing toxicity in experimental animals. These data strongly suggest that Aristoforin has potential as an anticancer drug.

Therapeutic Symptomatic Strategies in the Parasomnias.

PubMed

Manni, Raffaele; Toscano, Gianpaolo; Terzaghi, Michele

2018-06-05

The purpose of this review was to discuss the currently available pharmacologic and non-pharmacologic treatment options for parasomnias. Recent pathophysiological findings about sleep structure in parasomnias helped understanding several drug mechanisms of action. Serotoninergic theory accounts for the effect of serotoninergic drugs. Study about spectral analysis of sleep showed the effect of clonazepam on spectral bands. Cannabinoids proved to be effective in some of parasomnias, as in many other neurological disorders. A series of therapeutic strategies were analyzed and compared. Benzodiazepines, antidepressant drugs, and L-5-hydroxytryptophan may be beneficial in DOA. SSRI and topiramate are effective in SRED. RBD responds to clonazepam, melatonin, and to a lesser extent to dopaminergic and anticholinergic agents. Prazosin and cannabinoids are effective in nightmare disorder. Sleep paralysis may respond to antidepressant agents. Tricyclic antidepressant may be effective in sleep-related hallucinations and exploding head syndrome. Sleep enuresis may be successfully treated with desmopressin, anticholinergic drugs, and imipramine.

Immunology proves a great success for treating systemic autoimmune diseases - a perspective on immunopharmacology: IUPHAR Review 23.

PubMed

Ishii, Masaru

2017-07-01

Recent advances in the bioengineering of monoclonal antibodies (mAbs) have revolutionized the treatment of several immunological and rheumatic diseases. mAbs exhibit high specificity and affinity, and are very effective targeting agents, associated with minimal off-target adverse effects. Of several relevant immunological diseases, rheumatoid arthritis was the condition initially treated with mAbs, with great success. Currently, many immunological disorders are targeted and successfully treated using such novel approaches; these include inflammatory bowel diseases, multiple sclerosis, lupus and psoriasis. Today, the efforts of researchers in basic immunology (with a long history) have borne fruit; bioengineered mAbs are employed in clinical practice. In this brief review, I will describe the current and emerging therapeutic mAbs and molecular targeted agents, and discuss the future of the field, especially from the viewpoint of pharmacology. © 2017 The British Pharmacological Society.

Pharmacological therapy for amblyopia

PubMed Central

Singh, Anupam; Nagpal, Ritu; Mittal, Sanjeev Kumar; Bahuguna, Chirag; Kumar, Prashant

2017-01-01

Amblyopia is the most common cause of preventable blindness in children and young adults. Most of the amblyopic visual loss is reversible if detected and treated at appropriate time. It affects 1.0 to 5.0% of the general population. Various treatment modalities have been tried like refractive correction, patching (both full time and part time), penalization and pharmacological therapy. Refractive correction alone improves visual acuity in one third of patients with anisometropic amblyopia. Various drugs have also been tried of which carbidopa & levodopa have been popular. Most of these agents are still in experimental stage, though levodopa-carbidopa combination therapy has been widely studied in human amblyopes with good outcomes. Levodopa therapy may be considered in cases with residual amblyopia, although occlusion therapy remains the initial treatment choice. Regression of effect after stoppage of therapy remains a concern. Further studies are therefore needed to evaluate the full efficacy and side effect profile of these agents. PMID:29018759

Advancing the management of childhood epilepsies.

PubMed

Cross, J Helen; Kluger, Gerhard; Lagae, Lieven

2013-07-01

Childhood epilepsies comprise a heterogeneous group of disorders and syndromes that vary in terms of severity, prognosis and treatment requirements. Effective management requires early, accurate recognition and diagnosis, and a holistic approach that addresses each individual's medical and psychosocial needs within the context of their overall health status and quality of life. With increasing understanding of underlying aetiologies, new approaches to management and treatment are emerging. For example, genetic testing is beginning to provide a tool to aid differential diagnosis and a means of predicting predisposition to particular types of epilepsy. Despite the availability of an increasing number of antiepileptic drugs (AEDs)--due not only to the development of new AEDs, but also to changes in regulatory requirements that have facilitated clinical development--seizure control and tolerability continue to be suboptimal in many patients, and there is therefore a continuing need for new treatment strategies. Surgery and other non-pharmacological treatments (e.g. vagus nerve stimulation, ketogenic diet) are already relatively well established in paediatric epilepsy. New pharmacological treatments include generational advances on existing AEDs and AEDs with novel modes of action, and non-AED pharmacological interventions, such as immunomodulation. Emerging technologies include novel approaches allowing the delivery of medicinal agents to specific areas of the brain, and 'closed-loop' experimental devices employing algorithms that allow treatment (e.g., electrical stimulation) to be targeted both spatially and temporally. Although in early stages of development, cell-based approaches (e.g., focal targeting of adenosine augmentation) and gene therapy may also provide new treatment choices in the future. Copyright © 2013 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Development of radiotracers for oncology – the interface with pharmacology

PubMed Central

Sharma, Rohini; Aboagye, Eric

2011-01-01

There is an increasing role for positron emission tomography (PET) in oncology, particularly as a component of early phase clinical trials. As a non-invasive functional imaging modality, PET can be used to assess both pharmacokinetics and pharmacodynamics of novel therapeutics by utilizing radiolabelled compounds. These studies can provide crucial information early in the drug development process that may influence the further development of novel therapeutics. PET imaging probes can also be used as early biomarkers of clinical response and to predict clinical outcome prior to the administration of therapeutic agents. We discuss the role of PET imaging particularly as applied to phase 0 studies and discuss the regulations involved in the development and synthesis of novel radioligands. The review also discusses currently available tracers and their role in the assessment of pharmacokinetics and pharmacodynamics as applied to oncology. LINKED ARTICLES This article is part of a themed section on Imaging. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2011.163.issue-8BJP has previously published an Imaging in Pharmacology themed section, edited by A Davenport and C Daly. To view this section visit http://dx.doi.org/10.1111/bph.2010.159.issue-4 PMID:21175573

New Therapeutic Approaches in Diabetic Retinopathy

PubMed Central

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

2015-01-01

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

VMAT2 inhibitors for the treatment of tardive dyskinesia.

PubMed

Scorr, Laura M; Factor, Stewart A

2018-06-15

Tardive dyskinesia (TD) is an often disabling hyperkinetic movement disorder caused by exposure to dopamine receptor blocking agents. Although initially thought to most commonly occur with typical antipsychotics, the incidence is likely similar with atypical antipsychotics and antiemetics such as metoclopramide. Increased prescribing of these agents as well as low rates of remission have contributed to a rising prevalence of TD. Although this condition was described nearly 60 years ago, it is only within the past year that two novel therapeutic agents were FDA approved. Characterization of the VMAT2 inhibitor tetrabenazine, which was identified as a therapeutic agent for TD in older clinical trials, has yielded two distinct pharmacologic strategies to optimize response. The first strategy, used to create deutetrabenazine, employed deuterization of tetrabenazine to stabilize the pharmacokinetics and eliminate high peak plasma levels. The second strategy was the creation of a prodrug, valbenazine, for the two most active isoforms of tetrabenazine that also resulted in more stable pharmacokinetics and eliminated peak plasma levels. Both agents have been demonstrated to be effective and safe for the treatment of TD in multicenter, controlled trials and their development has led to a resurgence of interest in the characterization and treatment of this movement disorder. Copyright © 2018 Elsevier B.V. All rights reserved.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors from Natural Products: Discovery of Next-Generation Antihyperglycemic Agents.

PubMed

Choi, Chang-Ik

2016-08-27

Diabetes mellitus is a chronic condition associated with the metabolic impairment of insulin actions, leading to the development of life-threatening complications. Although many kinds of oral antihyperglycemic agents with different therapeutic mechanisms have been marketed, their undesirable adverse effects, such as hypoglycemia, weight gain, and hepato-renal toxicity, have increased demand for the discovery of novel, safer antidiabetic drugs. Since the important roles of the sodium-glucose cotransporter 2 (SGLT2) for glucose homeostasis in the kidney were recently elucidated, pharmacological inhibition of SGLT2 has been considered a promising therapeutic target for the treatment of type 2 diabetes. Since the discovery of the first natural SGLT2 inhibitor, phlorizin, several synthetic glucoside analogs have been developed and introduced into the market. Furthermore, many efforts to find new active constituents with SGLT2 inhibition from natural products are still ongoing. This review introduces the history of research on the development of early-generation SGLT2 inhibitors, and recent progress on the discovery of novel candidates for SGLT2 inhibitor from several natural products that are widely used in traditional herbal medicine.

Pharmacological validation of Trypanosoma brucei phosphodiesterases B1 and B2 as druggable targets for African sleeping sickness.

PubMed

Bland, Nicholas D; Wang, Cuihua; Tallman, Craig; Gustafson, Alden E; Wang, Zhouxi; Ashton, Trent D; Ochiana, Stefan O; McAllister, Gregory; Cotter, Kristina; Fang, Anna P; Gechijian, Lara; Garceau, Norman; Gangurde, Rajiv; Ortenberg, Ron; Ondrechen, Mary Jo; Campbell, Robert K; Pollastri, Michael P

2011-12-08

Neglected tropical disease drug discovery requires application of pragmatic and efficient methods for development of new therapeutic agents. In this report, we describe our target repurposing efforts for the essential phosphodiesterase (PDE) enzymes TbrPDEB1 and TbrPDEB2 of Trypanosoma brucei , the causative agent for human African trypanosomiasis (HAT). We describe protein expression and purification, assay development, and benchmark screening of a collection of 20 established human PDE inhibitors. We disclose that the human PDE4 inhibitor piclamilast, and some of its analogues, show modest inhibition of TbrPDEB1 and B2 and quickly kill the bloodstream form of the subspecies T. brucei brucei . We also report the development of a homology model of TbrPDEB1 that is useful for understanding the compound-enzyme interactions and for comparing the parasitic and human enzymes. Our profiling and early medicinal chemistry results strongly suggest that human PDE4 chemotypes represent a better starting point for optimization of TbrPDEB inhibitors than those that target any other human PDEs.

Drug-induced apnea.

PubMed

Boutroy, M J

1994-01-01

Drugs have been in the past and will in the future still be liable to induce apnea in neonates, infants and older children. At these different stages of development, the child may be abnormally vulnerable to respiratory disorders and apnea, and doses of drugs, without any abnormal side effects in adult patients, can be harmful in younger subjects. Drugs responsible for apnea during development are numerous, but more than half of the problems are induced by sedatives and hypnotics, among which phenothiazines, barbiturates, benzodiazepines (included transplacentally acquired) and general anesthetics are a few. Other pharmacological families are apnea inducers in the neonatal period and childhood: analgesics and opioid narcotics, agents acting at the levels of neuromuscular function and autonomic ganglia, and cardiovascular agents. The pathogenesis of these apneas depends on the disturbance of any mechanism responsible for the respiratory activity: medullary centers and brain stem structures, afferent influx to CNS, sleep stages, upper airways, lungs and respiratory muscles. At key stages such as birth and infancy, drugs may emphasize the particular sensitivity of the mechanisms responsible for inducing apnea. This might explain unexpected respiratory disorders during development.

Xanthones from Mangosteen Extracts as Natural Chemopreventive Agents: Potential Anticancer Drugs

PubMed Central

Shan, T.; Ma, Q.; Guo, K.; Liu, J.; Li, W.; Wang, F.; Wu, E.

2011-01-01

Despite decades of research, the treatment and management of malignant tumors still remain a formidable challenge for public health. New strategies for cancer treatment are being developed, and one of the most promising treatment strategies involves the application of chemopreventive agents. The search for novel and effective cancer chemopreventive agents has led to the identification of various naturally occurring compounds. Xanthones, from the pericarp, whole fruit, heartwood, and leaf of mangosteen (Garcinia mangostana Linn., GML), are known to possess a wide spectrum of pharmacologic properties, including anti-oxidant, anti-tumor, anti-allergic, anti-inflammatory, anti-bacterial, anti-fungal, and anti-viral activities. The potential chemopreventive and chemotherapeutic activities of xanthones have been demonstrated in different stages of carcinogenesis (initiation, promotion, and progression) and are known to control cell division and growth, apoptosis, inflammation, and metastasis. Multiple lines of evidence from numerous in vitro and in vivo studies have confirmed that xanthones inhibit proliferation of a wide range of human tumor cell types by modulating various targets and signaling transduction pathways. Here we provide a concise and comprehensive review of preclinical data and assess the observed anticancer effects of xanthones, supporting its remarkable potential as an anticancer agent. PMID:21902651

Fraxinus: A Plant with Versatile Pharmacological and Biological Activities.

PubMed

Sarfraz, Iqra; Rasul, Azhar; Jabeen, Farhat; Younis, Tahira; Zahoor, Muhammad Kashif; Arshad, Muhammad; Ali, Muhammad

2017-01-01

Fraxinus , a member of the Oleaceae family, commonly known as ash tree is found in northeast Asia, north America, east and western France, China, northern areas of Pakistan, India, and Afghanistan. Chemical constituents of Fraxinus plant include various secoiridoids, phenylethanoids, flavonoids, coumarins, and lignans; therefore, it is considered as a plant with versatile biological and pharmacological activities. Its tremendous range of pharmacotherapeutic properties has been well documented including anticancer, anti-inflammatory, antioxidant, antimicrobial, and neuroprotective. In addition, its bioactive phytochemicals and secondary metabolites can be effectively used in cosmetic industry and as a competent antiaging agent. Fraxinus presents pharmacological effectiveness by targeting the novel targets in several pathological conditions, which provide a spacious therapeutic time window. Our aim is to update the scientific research community with recent endeavors with specifically highlighting the mechanism of action in different diseases. This potentially efficacious pharmacological drug candidate should be used for new drug discovery in future. This review suggests that this plant has extremely important medicinal utilization but further supporting studies and scientific experimentations are mandatory to determine its specific intracellular targets and site of action to completely figure out its pharmacological applications.

Agent-Based Modeling in Systems Pharmacology.

PubMed

Cosgrove, J; Butler, J; Alden, K; Read, M; Kumar, V; Cucurull-Sanchez, L; Timmis, J; Coles, M

2015-11-01

Modeling and simulation (M&S) techniques provide a platform for knowledge integration and hypothesis testing to gain insights into biological systems that would not be possible a priori. Agent-based modeling (ABM) is an M&S technique that focuses on describing individual components rather than homogenous populations. This tutorial introduces ABM to systems pharmacologists, using relevant case studies to highlight how ABM-specific strengths have yielded success in the area of preclinical mechanistic modeling.

Breast Cancer Resistance to Cyclophosphamide and Other Oxazaphosphorines

DTIC Science & Technology

1996-10-01

therapeutic potential of gossypol as a male contraceptive agent and in gynaecological disease. Drugs, 38:333-341, 1989. Wu, Y.-W., Chik, C. L. and Knazek, R. A...Olgiati and Toscano, 1983; Olgiati et al., 1984). Initially, gossypol was of investigative interest mainly because of its male contraceptive properties...clinical pharmacology and therapeutic potential of gossypol as a male contraceptive agent and in gynaecological disease. Drugs 38 (1989) 333-341. Wu, D.-F

New Prescriptions for Migraine in the Emergency Department

PubMed Central

Lane, Peter L.

1992-01-01

Migraine headache is a common affliction and presenting symptom in the emergency department. Its diagnosis is entirely clinical, and the treating physician should ensure precise diagnosis before commencing therapy. General non-pharmacological measures and oral medications are usually effective in relieving the symptoms. Occasionally, patients with fixed migraines require parenteral therapy. Some medications used for migraine are antiemetic agents, ergot preparations, narcotic agents, phenothiazines (particularly chlorpromazine), and newer selective serotonin agonists. PMID:21221402

Factors Influencing Renal Vasculature during Anesthesia, Trauma, and Oliguric Renal Failure States in Man

DTIC Science & Technology

1980-03-01

striking influence of prior sodium intake on the pathogenesis of acute renal failure, raising the possibility that the renin - angiotensin system was...the product of the renin - angiotensin system , is the most powerful renal vasoconstrictor agent yet identified. These observations, viewed in the light of... angiotensin and, when they became available, to a detailed study of agents suitable for pharmacologic interruption of the renin - angiotensin system . We showed

Managing bleeding and emergency reversal of newer oral anticoagulants: a review for primary care providers.

PubMed

Peacock, W Frank

2014-10-01

The therapeutic landscape for anticoagulation management is undergoing a shift from the use of traditional anticlotting agents such as heparins and warfarin as the only options to the growing adoption of newer target-specific oral anticoagulants (TSOACs) with novel mechanisms of action. Dabigatran, the first TSOAC approved for use in the United States, is a direct competitive inhibitor of thrombin. It has predictable kinetics, with an elimination half-life of 12 to 17 hours in healthy volunteers. Apixaban and rivaroxaban are selective inhibitors of factor Xa, and also display first-order kinetics. In younger healthy individuals, apixaban has an apparent half-life of approximately 12 hours, whereas rivaroxaban has an elimination half-life of 5 to 9 hours. Understanding the pharmacologic properties of these newer drugs can lead to better insights regarding their respective safety and efficacy profiles and their application in clinical practice. Laboratory assessments have been developed to measure the anticoagulant efficacy of these newer agents. However, the results of these tests can be highly variable, and are therefore not always useful for monitoring the anticoagulation effects of these agents. In addition, several strategies have been documented for the potential reversal of the anticoagulant effects of these drugs, from the temporary discontinuation of an agent before elective surgery to suggested emergency procedures in the case of major bleeding events. New, specific reversal agents for dabigatran, apixaban, and rivaroxaban are currently being developed, and dabigatran has received fast-track designation from the US Food and Drug Administration. Until comprehensive clinical guidelines are developed, institutions involved in emergency care should establish their own procedures for the management of patients undergoing anticoagulation who require emergency treatment. These protocols should include appropriate laboratory testing to assess anticoagulant activity as part of the inpatient workup if time allows, and the potential use of hemodialysis, prohemostatic agents, and reversal agents when available.

Oral bioavailability of curcumin: problems and advancements.

PubMed

Liu, Weidong; Zhai, Yingjie; Heng, Xueyuan; Che, Feng Yuan; Chen, Wenjun; Sun, Dezhong; Zhai, Guangxi

2016-09-01

Curcumin is a natural compound of Curcuma longa L. and has shown many pharmacological activities such as anti-inflammatory, anti-oxidant in both preclinical and clinical studies. Moreover, curcumin has hepatoprotective, neuroprotective activities and protects against myocardial infarction. Particularly, curcumin has also demonstrated favorite anticancer efficacy. But limiting factors such as its extremely low oral bioavailability hampers its application as therapeutic agent. Therefore, many technologies have been developed and applied to overcome this limitation. This review described the main physicochemical properties of curcumin and summarized the recent studies in the design and development of oral delivery systems for curcumin to enhance the solubility and oral bioavailability, including liposomes, nanoparticles and polymeric micelles, phospholipid complexes, and microemulsions.

Targeting iron metabolism in drug discovery and delivery

PubMed Central

Crielaard, Bart J.; Lammers, Twan; Rivella, Stefano

2017-01-01

Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available. PMID:28154410

Modern industrial and pharmacological applications of indigo dye and its derivatives--a review.

PubMed

Stasiak, Natalia; Kukuła-Koch, Wirginia; Głowniak, Kazimierz

2014-01-01

Plant sources, chemical properties, bioactivities, as well as the synthesis of indigo dye and its derivatives, are reviewed in this paper. These compounds were chosen because of their significant benefits and scope of application as both coloring agents in the textile industry and as pharmacologically active natural products. Their use in traditional chinese medicine (TCM) has directed the attention of European researchers and medical doctors alike. The preparation of indigoferous plants--Indigo naturalis is currently about to be introduced into the European Pharmacopoeia.

Pharmacologic study of calcium influx pathways in rabbit aortic smooth muscle

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

Lukeman, D.S.

1987-01-01

Functional characteristics and pharmacologic domains of receptor-operated and potential-sensitive calcium (Ca/sup 2 +/) channels (ROCs and PSCs, respectively) were derived via measurements of /sup 45/Ca/sup 2 +/ influx (M/sup Ca/) during activation by the neurotransmitters norepinephrine (NE), histamine (HS), and serotonin (5-HT) and by elevated extracellular potassium (K/sup +/) in the individual or combined presence of organic Ca/sup 2 +/ channel antagonists (CAts), calmodulin antagonists (Calm-ants), lanthanum (La/sup 3 +/), and agents that increase intracellular levels of cyclic AMP.

[At the origin of the development of russian angiology (dedicated to the 150 birthday of academician N.P. Kravkov)].

PubMed

Uzbekova, D G

2015-01-01

The article describes scientific activity of outstanding pharmacologist, Academician N.P. Kravkov (1865-1924) on studying dynamics of the vascular system in experiment: Using the method of isolated animal organs of animals, N.P. Kravkov discovered self-maintained periodic contractions of vessels independent of the central nervous system and not associated with cardiac contractions. On isolated animal organs (heart, kidneys, spleen, womb, pancreas and others) specialists of the laboratory of N.P. Kravkov studied vascular reactions and sensitivity of vascular zones to administration of pharmacological agents in normal conditions and on various experimental ''pathological" models. For studying physiology and pharmacology of coronary vessels irrespective of cardiac contractions masking change in their lumen N.P. Kravkov suggested his original method of cardiac arrest by means of administration of strophanthin followed by passing through vessels of the unfunctioning heart solutions of various pharmacological substances. N.P. Kravkov and !{is followers studied alterations in vascular tonicity on isolated organs of cadavers of people who had died of various diseases: tuberculosis, typhoid fever and epidemic typhus, scarlet fever, measles, diphtheria, pneumonia et cet. The scientist believed that studying the functional state of vessels on post-mortem material would make it possible to more precisely and accurately solve the problem of intravital alterations thereof N.P. Kravkov's works on physiology and pathology of'the vascular system served as the basis for the developing clinical discipline, i.e. angiology.

Constipation-predominant irritable bowel syndrome: A review of current and emerging drug therapies

PubMed Central

Jadallah, Khaled A; Kullab, Susan M; Sanders, David S

2014-01-01

Irritable bowel syndrome (IBS) is a highly prevalent medical condition that adversely affects patient quality of life and constitutes a significant economic burden on healthcare resources. A large proportion of patients suffer from the constipation subtype of IBS (IBS-C), most commonly afflicting older individuals and those with a lower socioeconomic status. Conventional pharmacologic and nonpharmacologic treatment options have limited efficacies and/or significant adverse events, which lead to increased long-term health care expenditures. Failure to effectively treat IBS-C patients over the past decades has largely been due to a poor understanding of disease pathophysiology, lack of a global view of the patient, and an inappropriate selection of patients and treatment endpoints in clinical trials. In recent years, however, more effective and safer drugs have been developed for the treatment of IBS-C. The advancement in the area of pharmacologic treatment is based on new knowledge of the pathophysiologic basis of IBS-C and the development of drugs with increased selectivity within pharmacologic classes with recognized efficacies. This narrative review covers the spectrum of available drugs and their mechanisms of action, as well as the efficacy and safety profiles of each as determined in relevant clinical trials that have investigated treatment options for IBS-C and chronic constipation. A brief summary of laxative-based treatment options is presented, followed by up-to-date assessments for three classes of drugs: prokinetics, prosecretory agents, and bile acid modulators. PMID:25083062

Does Pharmacological Therapy Still Play a Role in Preventing Sudden Death in Surgically Treated Tetralogy of Fallot?

PubMed

Gabriele, Bronzetti; Maurizio, Brighenti; Marco, Bonvicini

2018-01-01

Tetralogy of Fallot (TOF) is the most common cyanotic congenital heart disease, with a familial recurrence risk of 3%. Despite performing an optimal surgical repair, TOF patients may feature a poor medium and long-term survival rate: atrial re-entrant tachycardia will develop in more than 30% of patients and high-grade ventricular arrhythmias will be seen in about 10% of patients. These life-threatening arrhythmias and consequent sudden death continue to represent serious complications following TOF repair. Radiofrequency ablation and implantable cardioverter defibrillator are today the most effective therapeutic tools in these subjects, while the administration of antiarrhythmic drugs (Ib agents, beta blockers, and amiodarone), widely prescribed in the past, is now limited to few conditions. However pharmacological therapy still plays a role in the management of those patients who are resistant to the above stated invasive electrophysiological treatments. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

The Multifunctional Effects of Nobiletin and Its Metabolites In Vivo and In Vitro

PubMed Central

Li, Linfu; Shi, Weimei; Liu, Hai; Yang, Jianqiong

2016-01-01

Nobiletin (NOB) chemically known as 5,6,7,8,3′,4′-hexamethoxyflavone is a dietary polymethoxylated flavonoid found in Citrus fruits. Recent evidences show that NOB is a multifunctional pharmaceutical agent. The various pharmacological activities of NOB include neuroprotection, cardiovascular protection, antimetabolic disorder, anticancer, anti-inflammation, and antioxidation. These events may be underpinned by modulation of signaling cascades, including PKA/ERK/MEK/CREB, NF-κB, MAPK, Ca2+/CaMKII, PI3K/Akt1/2, HIF-1α, and TGFβ signaling pathways. The metabolites may exhibit stronger beneficial effects than NOB on diseases pathogenesis. The biological activities of NOB have been clarified on many systems. This review aims to discuss the pharmacological effects of NOB with specific mechanisms of actions. NOB may become a promising candidate for potential drug development. However, further investigations of NOB on specific intracellular targets and clinical trials are still needed, especially for in vivo medical applications. PMID:27761146

NEONATAL ABSTINENCE SYNDROME: PHARMACOLOGIC STRATEGIES FOR THE MOTHER AND INFANT

PubMed Central

Kraft, Walter K.; Stover, Megan W.; Davis, Jonathan M.

2015-01-01

Opioid use in pregnancy has increased dramatically over the past decade. Since prenatal opioid use is associated with numerous obstetrical and neonatal complications, this now has become a major public health problem. In particular, in utero opioid exposure can result in neonatal abstinence syndrome (NAS) which is a serious condition characterized by central nervous system hyperirritability and autonomic nervous system dysfunction. The present review seeks to define current practices regarding the approach to the pregnant mother and neonate with prenatal opiate exposure. Although the cornerstone of prenatal management of opioid dependence is opioid maintenance therapy, the ideal agent has yet to be definitively established. Pharmacologic management of NAS is also highly variable and may include an opioid, barbiturate, and/or α-agonist. Genetic factors appear to be associated with the incidence and severity of NAS. Establishing pharmacogenetic risk factors for the development of NAS has the potential for creating opportunities for “personalized genomic medicine” and novel, individualized therapeutic interventions. PMID:26791055

Antiviral Activity of Natural Products Extracted from Marine Organisms

PubMed Central

Uzair, Bushra; Mahmood, Zahra; Tabassum, Sobia

2011-01-01

Many epidemics have broken out over the centuries. Hundreds and thousands of humans have died over a disease. Available treatments for infectious diseases have always been limited. Some infections are more deadly than the others, especially viral pathogens. These pathogens have continuously resisted all kinds of medical treatment, due to a need for new treatments to be developed. Drugs are present in nature and are also synthesized in vitro and they help in combating diseases and restoring health. Synthesizing drugs is a hard and time consuming task, which requires a lot of man power and financial aid. However, the natural compounds are just lying around on the earth, may it be land or water. Over a thousand novel compounds isolated from marine organisms are used as antiviral agents. Others are being pharmacologically tested. Today, over forty antiviral compounds are present in the pharmacological market. Some of these compounds are undergoing clinical and preclinical stages. Marine compounds are paving the way for a new trend in modern medicine. PMID:23678429

Pharmacological treatment of anxiety disorders in children and adolescents: a review for practitioners

PubMed Central

Feucht, Cynthia; Brown, Kelly; Ramsay, Jessica

2018-01-01

Anxiety disorders are common in children and adolescents with reported prevalence rates between 10% and 30%. A combined approach to treatment has been found to be the most effective for optimal outcomes and is typically comprised of psychotherapy (especially exposure-based cognitive behavior therapy), family and patient education, and use of medication if indicated. In children and adolescents who might benefit from use of medications, selective serotonin reuptake inhibitors (SSRIs) are the drugs of choice. The safety and efficacy of medications other than SSRIs in the treatment of children and adolescents with anxiety disorders are not fully established. Most children and adolescents respond well to treatment with long lasting resolution of symptoms, although, recurrence of the same, or development of a different type of anxiety disorder, is not uncommon. In most children and adolescents, anxiety disorders tend to persist into adulthood requiring long-term treatment planning. This paper reviews the pharmacological agents used in the treatment of anxiety disorders in children and adolescents. PMID:29441280

New therapies for vascular anomalies of the gastrointestinal tract.

PubMed

Fox, Victor L

2018-06-01

Vascular anomalies are a morphologically and biologically diverse group of vascular channel abnormalities that are often congenital but may evolve or change over time in the developing child. Classification is based on a combination of physical and biological properties and clinical behavior that differentiate primarily between tumors and malformations and includes a few provisionally unclassified lesions. Anomalies of the gastrointestinal (GI) tract may present clinically with GI bleeding, abdominal pain, high-output cardiac failure, and malabsorption. This review focuses on new therapies for the treatment of GI bleeding. Important new pharmacological therapies include treatment of hemangioma with non-selective and selective beta-antagonist agents, propranolol and atenolol, and treatment of blue rubber bleb nevus syndrome and cutaneo-visceral angiomatosis with thrombocytopenia (also known as multifocal lymphangioendotheliomatosis with thrombocytopenia) with sirolimus, an inhibitor of the mammalian target of rapamycin. Therapeutic endoscopy may offer an effective alternative to bowel resection for colonic varices and other focal vascular anomalies of the GI tract that fail to respond to pharmacological therapy.

21 CFR 514.1 - Applications.

Code of Federal Regulations, 2011 CFR

2011-04-01

... post office address of, and must be countersigned by, an authorized attorney, agent, or official... pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific... quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii...

21 CFR 514.1 - Applications.

Code of Federal Regulations, 2010 CFR

2010-04-01

... post office address of, and must be countersigned by, an authorized attorney, agent, or official... pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific... quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii...

21 CFR 514.1 - Applications.

Code of Federal Regulations, 2012 CFR

2012-04-01

... post office address of, and must be countersigned by, an authorized attorney, agent, or official... pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific... quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii...

21 CFR 514.1 - Applications.

Code of Federal Regulations, 2014 CFR

2014-04-01

... post office address of, and must be countersigned by, an authorized attorney, agent, or official... pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific... quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii...

21 CFR 514.1 - Applications.

Code of Federal Regulations, 2013 CFR

2013-04-01

... post office address of, and must be countersigned by, an authorized attorney, agent, or official... pharmacologically related drugs. (c) Description of dosage form and quantitative composition. (ii) Scientific... quantitative statement of composition. Reasonable alternatives for any listed component may be specified. (ii...

Foeniculum vulgare Mill: A Review of Its Botany, Phytochemistry, Pharmacology, Contemporary Application, and Toxicology

PubMed Central

Patel, Vainav V.; Bandivdekar, Atmaram H.

2014-01-01

Foeniculum vulgare Mill commonly called fennel has been used in traditional medicine for a wide range of ailments related to digestive, endocrine, reproductive, and respiratory systems. Additionally, it is also used as a galactagogue agent for lactating mothers. The review aims to gather the fragmented information available in the literature regarding morphology, ethnomedicinal applications, phytochemistry, pharmacology, and toxicology of Foeniculum vulgare. It also compiles available scientific evidence for the ethnobotanical claims and to identify gaps required to be filled by future research. Findings based on their traditional uses and scientific evaluation indicates that Foeniculum vulgare remains to be the most widely used herbal plant. It has been used for more than forty types of disorders. Phytochemical studies have shown the presence of numerous valuable compounds, such as volatile compounds, flavonoids, phenolic compounds, fatty acids, and amino acids. Compiled data indicate their efficacy in several in vitro and in vivo pharmacological properties such as antimicrobial, antiviral, anti-inflammatory, antimutagenic, antinociceptive, antipyretic, antispasmodic, antithrombotic, apoptotic, cardiovascular, chemomodulatory, antitumor, hepatoprotective, hypoglycemic, hypolipidemic, and memory enhancing property. Foeniculum vulgare has emerged as a good source of traditional medicine and it provides a noteworthy basis in pharmaceutical biology for the development/formulation of new drugs and future clinical uses. PMID:25162032

Ginseng Compounds: An Update on Their Molecular Mechanisms and Medical Applications

PubMed Central

Lü, Jian-Ming; Yao, Qizhi; Chen, Changyi

2010-01-01

Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginsenosides, the major pharmacologically active ingredients of ginseng, appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anti-cancer. Approximately 40 ginsenoside compounds have been identified. Researchers are now focused on using purified individual ginsenoside to reveal the specific mechanism of functions of ginseng instead of using whole ginseng root extracts. Each ginsenoside may have different effects in pharmacology and mechanisms due to their different chemical structures. Among them the most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, Rd and Rh1. The molecular mechanisms and medical applications of ginsenosides have attracted much attention and hundreds of papers have been published in the last few years. The general purpose of this update is to provide current information on recently described effects of ginsenosides on antioxidation, vascular system, signal transduction pathways and interaction with receptors. Their therapeutic applications in animal models and humans as well as the pharmacokinetics and toxicity of ginsenosides are also discussed in this review. This review concludes with some thoughts for future directions in the further development of ginseng compounds as effective therapeutic agents. PMID:19601854

Adult Status Epilepticus: A Review of the Prehospital and Emergency Department Management

PubMed Central

Billington, Michael; Kandalaft, Osama R.; Aisiku, Imoigele P.

2016-01-01

Seizures are a common presentation in the prehospital and emergency department setting and status epilepticus represents an emergency neurologic condition. The classification and various types of seizures are numerous. The objectives of this narrative literature review focuses on adult patients with a presentation of status epilepticus in the prehospital and emergency department setting. In summary, benzodiazepines remain the primary first line therapeutic agent in the management of status epilepticus, however, there are new agents that may be appropriate for the management of status epilepticus as second- and third-line pharmacological agents. PMID:27563928

Traditional uses, phytochemistry and pharmacology of wild banana (Musa acuminata Colla): A review.

PubMed

Mathew, Nimisha Sarah; Negi, Pradeep Singh

2017-01-20

Musa acuminata, the wild species of banana is a plant of the tropical and subtropical regions. Over the past few decades, the health benefits of M. acuminata have received much attention. All parts of the plant including fruits, peel, pseudostem, corm, flowers, leaves, sap and roots have found their use in the treatment of many diseases in traditional medicine. Literature review have indicated use of M. acuminata in the treatment of various diseases such as fever, cough, bronchitis, dysentery, allergic infections, sexually transmitted infections, and some of the non-communicable diseases. The reported pharmacological activities of M. acuminata include antioxidant, antidiabetic, immunomodulatory, hypolipidemic, anticancer, and antimicrobial especially anti-HIV activity. This review presents information on the phytochemicals and pharmacological studies to validate the traditional use of different parts of M. acuminata in various diseases and ailments. A comprehensive assessment of the biological activities of M. acuminata extracts is included and possible mechanisms and phytochemicals involved have also been correlated to provide effective intervention strategies for preventing or managing diseases. A literature search was performed on M. acuminata using ethnobotanical textbooks, published articles in peer-reviewed journals, local magazines, unpublished materials, and scientific databases such as Pubmed, Scopus, Web of Science, ScienceDirect, and Google Scholar. The Plant List, Promusa, Musalit, the Integrated Taxonomic Information System (ITIS) databases were used to validate the scientific names and also provide information on the subspecies and cultivars of M. acuminata. The edible part of M. acuminata provides energy, vitamins and minerals. All other parts of the plant have been used in the treatment of many diseases in traditional medicine. The rich diversity of phytochemicals present in them probably contributes to their beneficial effects, and validates the role of M. acuminata plant parts used by various tribes and ethnic groups across the geographical areas of the world. This review presents information on phytochemicals and pharmacological activities of M. acuminata plant parts. Pharmacological studies support the traditional uses of the plant, and probably validate the uses of M. acuminata by the indigenous people to treat and heal many infections and diseases. Some studies on animal models have been carried out, which also provide evidence of efficacy of the M. acuminata plant as a therapeutic agent. These observations suggest that M. acuminata plant parts possesses pluripharmacological properties, and can be used in designing potent therapeutic agents. However, individual bioactive constituent(s) from different parts of this plant need further investigations to confirm various pharmacological claims, and to explore the potential of M. acuminata in the development of drugs and use in functional foods. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Principles of antidote pharmacology: an update on prophylaxis, post-exposure treatment recommendations and research initiatives for biological agents

PubMed Central

Ramasamy, S; Liu, CQ; Tran, H; Gubala, A; Gauci, P; McAllister, J; Vo, T

2010-01-01

The use of biological agents has generally been confined to military-led conflicts. However, there has been an increase in non-state-based terrorism, including the use of asymmetric warfare, such as biological agents in the past few decades. Thus, it is becoming increasingly important to consider strategies for preventing and preparing for attacks by insurgents, such as the development of pre- and post-exposure medical countermeasures. There are a wide range of prophylactics and treatments being investigated to combat the effects of biological agents. These include antibiotics (for both conventional and unconventional use), antibodies, anti-virals, immunomodulators, nucleic acids (analogues, antisense, ribozymes and DNAzymes), bacteriophage therapy and micro-encapsulation. While vaccines are commercially available for the prevention of anthrax, cholera, plague, Q fever and smallpox, there are no licensed vaccines available for use in the case of botulinum toxins, viral encephalitis, melioidosis or ricin. Antibiotics are still recommended as the mainstay treatment following exposure to anthrax, plague, Q fever and melioidosis. Anti-toxin therapy and anti-virals may be used in the case of botulinum toxins or smallpox respectively. However, supportive care is the only, or mainstay, post-exposure treatment for cholera, viral encephalitis and ricin – a recommendation that has not changed in decades. Indeed, with the difficulty that antibiotic resistance poses, the development and further evaluation of techniques and atypical pharmaceuticals are fundamental to the development of prophylaxis and post-exposure treatment options. The aim of this review is to present an update on prophylaxis and post-exposure treatment recommendations and research initiatives for biological agents in the open literature from 2007 to 2009. PMID:20860656

Botany, phytochemistry, pharmacology, and potential application of Polygonum cuspidatum Sieb.et Zucc.: a review.

PubMed

Peng, Wei; Qin, Rongxin; Li, Xiaoli; Zhou, Hong

2013-07-30

Polygonum cuspidatum Sieb. et Zucc. (Polygonum cuspidatum), also known as Reynoutria japonica Houtt and Huzhang in China, is a traditional and popular Chinese medicinal herb. Polygonum cuspidatum with a wide spectrum of pharmacological effects has been used for treatment of inflammation, favus, jaundice, scald, and hyperlipemia, etc. The present paper reviews the traditional applications as well as advances in botany, phytochemistry, pharmacodynamics, pharmacokinetics and toxicology of this plant. Finally, the tendency and perspective for future investigation of this plant are discussed, too. A systematic review of literature about Polygonum cuspidatum is carried out using resources including classic books about Chinese herbal medicine, and scientific databases including Pubmed, SciFinder, Scopus, the Web of Science and others. Polygonum cuspidatum is widely distributed in the world and has been used as a traditional medicine for a long history in China. Over 67 compounds including quinones, stilbenes, flavonoids, counmarins and ligans have been isolated and identified from this plant. The root of this plant is used as the effective agent in pre-clinical and clinical practice for regulating lipids, anti-endotoxic shock, anti-infection and anti-inflammation, anti-cancer and other diseases in China and Japan. As an important traditional Chinese medicine, Polygonum cuspidatum has been used for treatment of hyperlipemia, inflammation, infection and cancer, etc. Because there is no enough systemic data about the chemical constituents and their pharmacological effects or toxicities, it is important to investigate the pharmacological effects and molecular mechanisms of this plant based on modern realization of diseases' pathophysiology. Drug target-guided and bioactivity-guided isolation and purification of the chemical constituents from this plant and subsequent evaluation of their pharmacologic effects will promote the development of new drug and make sure which chemical constituent or multiple ingredients contributes its pharmacological effects. Additionally, chemicals and their pharmacological effects of the other parts such as the aerial part of this plant should be exploited in order to avoid resource waste and find new chemical constituents. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence.

PubMed

Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

2015-01-01

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents.

Efficacy and mechanism of action of the tyrosine kinase inhibitors gefitinib, lapatinib and neratinib in the treatment of HER2-positive breast cancer: preclinical and clinical evidence

PubMed Central

Segovia-Mendoza, Mariana; González-González, María E; Barrera, David; Díaz, Lorenza; García-Becerra, Rocío

2015-01-01

An increasing number of tumors, including breast cancer, overexpress proteins of the epidermal growth factor receptor (EGFR) family. The interaction between family members activates signaling pathways that promote tumor progression and resistance to treatment. Human epidermal growth factor receptor type II (HER2) positive breast cancer represents a clinical challenge for current therapy. It has motivated the development of novel and more effective therapeutic EGFR family target drugs, such as tyrosine kinase inhibitors (TKIs). This review focuses on the effects of three TKIs mostly studied in HER2- positive breast cancer, lapatinib, gefitinib and neratinib. Herein, we discuss the mechanism of action, therapeutic advantages and clinical applications of these TKIs. To date, TKIs seem to be promising therapeutic agents for the treatment of HER2-overexpressing breast tumors, either as monotherapy or combined with other pharmacological agents. PMID:26609467

Pharmacologic treatment of acute pediatric methamphetamine toxicity.

PubMed

Ruha, Anne-Michelle; Yarema, Mark C

2006-12-01

To report our experience with the use of benzodiazepines and haloperidol for sedation of pediatric patients with acute methamphetamine poisoning. We performed a retrospective chart review of 18 pediatric patients who were admitted to an intensive care unit for methamphetamine toxicity from January 1997 to October 2004 and treated with benzodiazepines or haloperidol. Clinical features, dose of drug received, and laboratory test results were noted. Adverse effects from the use of haloperidol such as prolonged QTc, dystonic reactions, and torsades de pointes were recorded. Eighteen patients received a benzodiazepine, the dose of which varied depending on the agent used. Twelve patients also received parenteral haloperidol. No complications developed from the use of either haloperidol or benzodiazepines. In this case series of pediatric patients poisoned with methamphetamine, parenteral benzodiazepines and haloperidol were used to control agitation. No serious adverse effects were observed from the use of these agents.

New Evidence against Chromium as an Essential Trace Element.

PubMed

Vincent, John B

2017-12-01

Nearly 60 y ago, chromium, as the trivalent ion, was proposed to be an essential element, but the results of new studies indicate that chromium currently can only be considered pharmacologically active and not an essential element. Regardless, articles still continue to appear in the literature claiming chromium is an essential element. Chromium has been marketed as an agent to reduce body mass and develop muscle; however, such marketing claims are no longer allowed in the United States because these claims, similar to claims of essential status, are not supported by experiments. Trivalent chromium has also been proposed as a therapeutic agent to increase insulin sensitivity and affect lipid metabolism. Although effective in certain rodent models, beneficial effects in humans have not been unequivocally established. Molecular mechanisms have been proposed for the beneficial effects but have not been definitively shown to occur in animals. © 2017 American Society for Nutrition.

Clinical pharmacokinetics and pharmacodynamics of repaglinide.

PubMed

Hatorp, Vibeke

2002-01-01

Repaglinide is a novel, fast-acting prandial oral hypoglycaemic agent developed for the treatment of patients with type 2 diabetes whose disease cannot be controlled by diet and exercise alone. Although repaglinide binds to the sulphonylurea binding sites on pancreatic beta-cells and has a similar mechanism of action, repaglinide exhibits distinct pharmacological properties compared with these agents. Following administration, repaglinide is absorbed rapidly and has a fast onset of dose-dependent blood-glucose lowering effect. The drug is eliminated rapidly via the biliary route, without accumulation in the plasma after multiple doses. Repaglinide is well tolerated in patients with type 2 diabetes, including elderly patients and patients with hepatic or renal impairment. The pharmacokinetic profile of repaglinide and the improvements in post-prandial hyperglycaemia and overall glycaemic control make repaglinide suitable for administration preprandially, with the opportunity for flexible meal arrangements, including skipped meals, without the risk of hypoglycaemia.

Angiogenesis inhibitors: current strategies and future prospects.

PubMed

Cook, Kristina M; Figg, William D

2010-01-01

Angiogenesis has become an attractive target for drug therapy because of its key role in tumor growth. An extensive array of compounds is currently in preclinical development, with many now entering the clinic and/or achieving approval from the US Food and Drug Administration. Several regulatory and signaling molecules governing angiogenesis are of interest, including growth factors (eg, vascular endothelial growth factor, platelet-derived growth factor, fibroblast growth factor, and epidermal growth factor), receptor tyrosine kinases, and transcription factors such as hypoxia inducible factor, as well as molecules involved in mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase (PI3K) signaling. Pharmacologic agents have been identified that target these pathways, yet for some agents (notably thalidomide), an understanding of the specific mechanisms of antitumor action has proved elusive. The following review describes key molecular mechanisms and novel therapies that are on the horizon for antiangiogenic tumor therapy. (c) 2010 American Cancer Society, Inc.

Prospects for pharmacologic inhibition of hepatic glucose production.

PubMed

Kurukulasuriya, R; Link, J T; Madar, D J; Pei, Z; Rohde, J J; Richards, S J; Souers, A J; Szczepankiewicz, B G

2003-01-01

Type 2 diabetes is a widespread disease where effective pharmacologic therapies can have a profound beneficial public health impact. Increased hepatic glucose production (HGP) is observed in diabetics and its moderation by currently available agents provides therapeutic benefits. This review describes the challenges associated with the discovery of small molecules that inhibit HGP. Gluconeogenesis, glycogenolysis, liver architecture, and hepatocyte composition are described to provide background information on hepatic function. Current methods of target validation for drug discovery, HGP measurement, diabetes animal models, as well as current drug therapies are covered. In the accompanying review article the new drug targets being probed to produce the next generation of therapies are described. Significant pharmaceutical and academic efforts to pharmacologically inhibit HGP has the opportunity to provide new therapeutics for type 2 diabetics.

OPTIMIZING DIAGNOSIS AND MANANGEMENT IN MILD-TO-MODERATE ALZHEIMER’S DISEASE

PubMed Central

Galvin, James E.

2012-01-01

Alzheimer’s disease (AD) is characterized by progressive declines in cognitive function and ability to carry out activities of daily living; and the emergence and worsening of behavioral/neuropsychiatric symptoms. While there is no cure for AD, non-pharmacologic interventions and medications that modulate neurotransmission can slow symptomatic progression. Medical foods may also be useful as adjuncts to pharmacologic agents in AD. Medium chain triglycerides aimed at improving cerebral metabolism significantly improve Alzheimer’s Disease Assessment Scale-Cognitive scores when added to ongoing pharmacotherapy in patients with mild-to-moderate AD. Combination of interventions, such as non-pharmacologic treatments, pharmacotherapy, and medical foods, with complementary mechanisms of action may provide a rational approach that may result in maximum preservation of cognitive function in patients with AD. PMID:22973426

Foundations of Pharmacotherapy for Heart Failure With Reduced Ejection Fraction: Evidence Meets Practice, Part I.

PubMed

Paul, Sara; Page, Robert L

2016-01-01

Pharmacologic treatment for systolic heart failure, otherwise known as heart failure with reduced ejection fraction, has been established through clinical trials and is formulated into guidelines to standardize the diagnosis and treatment. The premise of pharmacologic therapy in heart failure with reduced ejection fraction is aimed primarily at interrupting the neurohormonal cascade that is responsible for altering left ventricular shape and function. This is the first in a series of articles to describe the pharmacologic agents in the guidelines that impact the morbidity and mortality associated with heart failure. Angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and vasodilators will be presented in the context of the mechanism of action in heart failure, investigational trials that showed beneficial effects, and the practical application for clinical use.

An audit of the pharmacological management of ischaemic stroke patients in a metropolitan Australian hospital.

PubMed

Khalil, Viviane; Li, Matthew; Hua, Qiantong Amanda

2015-02-01

According to the Australian Bureau of Statistics, stroke is the second leading cause of death in Australia. The clinical Guidelines for stroke management published by the National Stroke Foundation provide a series of evidence based recommendations to assist clinicians in the management of stroke patients. Appropriate management of patients admitted to stroke units reduces death and disability by 20 %. Moreover, a multidisciplinary team approach also improves patient outcomes. To retrospectively review the pharmacological management of ischaemic stroke patients in a metropolitan Australian hospital, and to compare adherence with the guidelines for stroke management with the national stroke foundation data with and without pharmacist intervention. A retrospective audit of medical records was undertaken of all patients admitted to a large teaching hospital with the diagnosis of stroke or cerebral infarction from January 2013 to May 2013. A total of 124 patients were included in the study. Most patients were discharged on appropriate pharmacological intervention for the prevention of secondary stroke: antihypertensive agents (71 %), lipid lowering agents (67 %) and antithrombotic (85 %) medications. The majority of the cohort was discharged on the appropriate evidence based medications for the management of secondary stroke. Further improvement may be achieved by pharmacist intervening as part of a multidisciplinary team.

Targeting memory processes with drugs to prevent or cure PTSD

PubMed Central

Cain, Christopher K.; Maynard, George D.; Kehne, John H.

2015-01-01

Introduction Post-traumatic stress disorder (PTSD) is a chronic debilitating psychiatric disorder resulting from exposure to a severe traumatic stressor and an area of great unmet medical need. Advances in pharmacological treatments beyond the currently approved SSRIs are needed. Areas covered Background on PTSD, as well as the neurobiology of stress responding and fear conditioning, is provided. Clinical and preclinical data for investigational agents with diverse pharmacological mechanisms are summarized. Expert opinion Advances in the understanding of stress biology and mechanisms of fear conditioning plasticity provide a rationale for treatment approaches that may reduce hyperarousal and dysfunctional aversive memories in PTSD. One challenge is to determine if these components are independent or reflect a common underlying neurobiological alteration. Numerous agents reviewed have potential for reducing PTSD core symptoms or targeted symptoms in chronic PTSD. Promising early data support drug approaches that seek to disrupt dysfunctional aversive memories by interfering with consolidation soon after trauma exposure, or in chronic PTSD, by blocking reconsolidation and/or enhancing extinction. Challenges remain for achieving selectivity when attempting to alter aversive memories. Targeting the underlying traumatic memory with a combination of pharmacological therapies applied with appropriate chronicity, and in combination with psychotherapy, is expected to substantially improve PTSD treatment. PMID:22834476

Pharmacologic Agents for Chronic Diarrhea

PubMed Central

2015-01-01

Chronic diarrhea is usually associated with a number of non-infectious causes. When definitive treatment is unavailable, symptomatic drug therapy is indicated. Pharmacologic agents for chronic diarrhea include loperamide, 5-hydroxytryptamine type 3 (5-HT3) receptor antagonists, diosmectite, cholestyramine, probiotics, antispasmodics, rifaximin, and anti-inflammatory agents. Loperamide, a synthetic opiate agonist, decreases peristaltic activity and inhibits secretion, resulting in the reduction of fluid and electrolyte loss and an increase in stool consistency. Cholestyramine is a bile acid sequestrant that is generally considered as the first-line treatment for bile acid diarrhea. 5-HT3 receptor antagonists have significant benefits in patients with irritable bowel syndrome (IBS) with diarrhea. Ramosetron improves stool consistency as well as global IBS symptoms. Probiotics may have a role in the prevention of antibiotic-associated diarrhea. However, data on the role of probiotics in the treatment of chronic diarrhea are lacking. Diosmectite, an absorbent, can be used for the treatment of chronic functional diarrhea, radiation-induced diarrhea, and chemotherapy-induced diarrhea. Antispasmodics including alverine citrate, mebeverine, otilonium bromide, and pinaverium bromide are used for relieving diarrheal symptoms and abdominal pain. Rifaximin can be effective for chronic diarrhea associated with IBS and small intestinal bacterial overgrowth. Budesonide is effective in both lymphocytic colitis and collagenous colitis. The efficacy of mesalazine in microscopic colitis is weak or remains uncertain. Considering their mechanisms of action, these agents should be prescribed properly. PMID:26576135

Targeting the NFκB signaling pathways for breast cancer prevention and therapy.

PubMed

Wang, Wei; Nag, Subhasree A; Zhang, Ruiwen

2015-01-01

The activation of nuclear factor-kappaB (NFκB), a proinflammatory transcription factor, is a commonly observed phenomenon in breast cancer. It facilitates the development of a hormone-independent, invasive, high-grade, and late-stage tumor phenotype. Moreover, the commonly used cancer chemotherapy and radiotherapy approaches activate NFκB, leading to the development of invasive breast cancers that show resistance to chemotherapy, radiotherapy, and endocrine therapy. Inhibition of NFκB results in an increase in the sensitivity of cancer cells to the apoptotic effects of chemotherapeutic agents and radiation and restoring hormone sensitivity, which is correlated with increased disease-free survival in patients with breast cancer. In this review article, we focus on the role of the NFκB signaling pathways in the development and progression of breast cancer and the validity of NFκB as a potential target for breast cancer prevention and therapy. We also discuss the recent findings that NFκB may have tumor suppressing activity in certain cancer types. Finally, this review also covers the state-of-the-art development of NFκB inhibitors for cancer therapy and prevention, the challenges in targeting validation, and pharmacology and toxicology evaluations of these agents from the bench to the bedside.

Molecular targets of organophosphorus compounds and antidotal agents on nicotinic, glutamatergic and gabaergic synapses. Appendix 1. Final report

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

Albuquerque, E.X.

1994-03-16

There are several major motivators behind this work. We need to understand OP intoxication sufficiently to provide insight and direction for development of improved antidotal therapy. The persistent environmental use of chemical insecticides, which some feel is necessary for optimal agricultural production but others challenge vehemently, requires that we understand the toxicological consequences of such use. Also, OPs have such a powerful effect or, vital functions, it could be immensely beneficial to understand in great detail the physiological mechanisms that are targeted by OPs. Such information could benefit medical treatments of diseases and pathologies other than those directly caused bymore » OPs. Finally, we hope to present the material in a manner that will be instructive to a broad spectrum of professionals in pharmacology and toxicology. Where it is appropriate, we may draw heavily from other topical reviews. In all cases, we will provide citations to original work and/or well-referenced RA I, Lab Animals, Rats, Frogs, Compounds, Nerve Agents, Organophosphorous, BD, CD Agents, XCSM, Neurotransmitters, Receptors, Ion Channel, Oximes.« less

Applications of Venom Proteins as Potential Anticancer agents.

PubMed

Ejaz, Samina; Hashmi, Fatima Bashir; Malik, Waqas Nazir; Ashraf, Muhammad; Nasim, Faiz Ul-Hassan; Iqbal, Muhammad

2018-06-13

Venoms, the secretions of venomous animals, are conventionally thought to be the source of toxic substances though the views about venoms in the recent era have been changed. Venoms are the proven source of many biologically and pharmacologically important useful molecules. Bioactive components present in different venoms are mainly proteins and peptides either enzymatic or non-enzymatic which have tremendous therapeutic potential and are being used for the treatment of variety of diseases including cancer. Many venoms proteins and peptides have been reported as potential anticancer agents. Venom proteins kill cancer cells through a variety of mechanisms which induce apoptosis and ultimately lead to cell death. Therefore, the understanding regarding sources and classification of venoms, biological role of venomous proteins, their anticancer potential and mechanisms to suppress/kill cancer cells needs to be addressed. The present review is an attempt to highlight the reported work and develop strategies to answer the key questions regarding the use of venomous proteins as therapeutic agents. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Novel thrombin and factor Xa inhibitors: challenges to reversal of their anticoagulation effects.

PubMed

Yates, Sean; Sarode, Ravi

2013-11-01

Warfarin has been the sole oral anticoagulant used in the management of thromboembolic disorders for over 60 years. Target-specific oral anticoagulants (TSOAs) have recently emerged as alternatives to warfarin, because they do not require laboratory monitoring. Nevertheless, with the rising use of TSOAs, there is growing concern among clinicians regarding management of bleeding in patients taking them. Unlike warfarin, there is no antidote or reversal agent for TSOAs. This review summarizes recent developments and attempts to provide a systematic approach to patients on TSOAs presenting with bleeding complications. Currently, data involving clinical management of TSOAs are limited and primarily based on ex-vivo or animal models using hemostatic agents with uncertain implications in bleeding patients. There is a pressing need for randomized clinical trials evaluating the safety and efficacy of hemostatic agents. Without evidence-based guidelines for TSOA management, appropriate patient care requires an understanding of TSOA pharmacology, their effect on coagulation tests and, hence, a correct interpretation of test results, as well as a systematic approach to bleeding complications.

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.

Teaching the pharmacology of antiarrhythmic drugs.

PubMed

Zdanowicz, Martin M; Lynch, Launa M J

2011-09-10

To provide doctor of pharmacy (PharmD) students with highly integrated, comprehensive and up-to-date instruction related to the pharmacology of antiarrhythmic drugs. Students were taught the medicinal chemistry, pharmacology, and therapeutics of antiarrhythmic agents in the cardiology module presented in quarter 7 of the PharmD curriculum. Important foundational information for this topic was presented to students in prerequisite physiology courses and pathophysiology courses offered earlier in the curriculum. Emphasis was placed on student critical thinking and active involvement. Weekly recitation sessions afforded students the opportunity to apply the information they learned regarding arrhythmia pharmacotherapy to comprehensive patient cases. Student comprehension was measured using class exercises, short quizzes, case write-ups, comprehensive examinations, group exercises, and classroom discussion. Students were afforded the opportunity to evaluate the course, and the instructors as well as rate the degree to which the course achieved its educational outcomes. Students learned about cardiac arrhythmias through a high-quality, interdisciplinary series of classes presented by faculty members with extensive experience related to the pharmacology and pharmacotherapy of cardiac arrhythmias.

International Union of Basic and Clinical Pharmacology. XC. multisite pharmacology: recommendations for the nomenclature of receptor allosterism and allosteric ligands.

PubMed

Christopoulos, Arthur; Changeux, Jean-Pierre; Catterall, William A; Fabbro, Doriano; Burris, Thomas P; Cidlowski, John A; Olsen, Richard W; Peters, John A; Neubig, Richard R; Pin, Jean-Philippe; Sexton, Patrick M; Kenakin, Terry P; Ehlert, Frederick J; Spedding, Michael; Langmead, Christopher J

2014-10-01

Allosteric interactions play vital roles in metabolic processes and signal transduction and, more recently, have become the focus of numerous pharmacological studies because of the potential for discovering more target-selective chemical probes and therapeutic agents. In addition to classic early studies on enzymes, there are now examples of small molecule allosteric modulators for all superfamilies of receptors encoded by the genome, including ligand- and voltage-gated ion channels, G protein-coupled receptors, nuclear hormone receptors, and receptor tyrosine kinases. As a consequence, a vast array of pharmacologic behaviors has been ascribed to allosteric ligands that can vary in a target-, ligand-, and cell-/tissue-dependent manner. The current article presents an overview of allostery as applied to receptor families and approaches for detecting and validating allosteric interactions and gives recommendations for the nomenclature of allosteric ligands and their properties. U.S. Government work not protected by U.S. copyright.

Cholinesterases, a target of pharmacology and toxicology.

PubMed

Pohanka, Miroslav

2011-09-01

Cholinesterases are a group of serine hydrolases that split the neurotransmitter acetylcholine (ACh) and terminate its action. Of the two types, butyrylcholinesterase and acetylcholinesterase (AChE), AChE plays the key role in ending cholinergic neurotransmission. Cholinesterase inhibitors are substances, either natural or man-made that interfere with the break-down of ACh and prolong its action. Hence their relevance to toxicology and pharmacology. The present review summarizes current knowledge of the cholinesterases and their inhibition. Particular attention is paid to the toxicology and pharmacology of cholinesterase-related inhibitors such as nerve agents (e.g. sarin, soman, tabun, VX), pesticides (e.g. paraoxon, parathion, malathion, malaoxon, carbofuran), selected plants and fungal secondary metabolites (e.g. aflatoxins), drugs for Alzheimer's disease (e.g. huperzine, metrifonate, tacrine, donepezil) and Myasthenia gravis (e.g. pyridostigmine) treatment and other compounds (propidium, ethidium, decamethonium). The crucial role of the cholinesterases in neural transmission makes them a primary target of a large number of cholinesterase-inhibiting drugs and toxins. In pharmacology, this has relevance to the treatment of neurodegenerative disorders.

Comparative drug dose and drug combinations in patients that present to hospital due to self-poisoning.

PubMed

Armstrong, Thomas M; Davies, Matthew S; Kitching, Gary; Waring, W Stephen

2012-11-01

Self-poisoning is a common reason for acute presentation to hospital. Commonly involved drugs have been reported, but few data exist concerning the different combinations of agents or comparative doses ingested. The present study sought to better characterise the typical patterns of drug overdose that may present via the emergency department. Consecutive adults ≥16 years of age that presented to York Hospital owing to self-poisoning were studied for 2010-2011 inclusive. The primary outcome measure was reported dose, expressed as a multiple of the defined daily dose (DDD) to allow comparison between different agents. There were 1024 patients, including 622 women (60.7%), and median age was 32 years (range, 16 to 92 years). Overdose in men was associated with a higher overall quantity of drugs: arithmetic mean of 20 DDD multiples (95% CI, 15-26) versus 13 (11-15), p = 0.001. Overdose involved a single agent only in 538 patients (52.5%). The mean paracetamol dose was 4.0 (95% CI, 3.7-4.3) DDD multiples; the doses of antidepressants (19.4, 17.0-21.7, p < 0.0001) and benzodiazepines (18.0, 12.8-23.2, p < 0.0001) were comparatively higher. The types of agents involved in self-poisoning and common combinations of agents are characterised. Psychotropic medications were ingested in comparatively larger quantities than analgesic agents and had worse clinical outcome. Further work is required to understand the factors that determine the quantity of drug ingested in patients at risk of drug overdose so as to minimise the risk of significant toxicity. © 2012 The Authors Basic & Clinical Pharmacology & Toxicology © 2012 Nordic Pharmacological Society.

Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention

PubMed Central

Glennon, Richard A.

2015-01-01

The term “synthetic cathinones” is fairly new; but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back >100 years. One structural element cathinone analogs have in common is an α-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, >40 synthetic cathinones have been identified on the clandestine market and many have multiple “street names”. Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (MDMA; Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the “and/or” term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure-activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more “basic science” research. At this time, treatment is mostly palliative. PMID:24484988

A Review of Pharmacologic Treatment for Compulsive Buying Disorder.

PubMed

Soares, Célia; Fernandes, Natália; Morgado, Pedro

2016-04-01

At present, no treatment recommendations can be made for compulsive buying disorder. Recent studies have found evidence for the efficacy of psychotherapeutic options, but less is known regarding the best pharmacologic treatment. The purpose of this review is to present and analyze the available published evidence on the pharmacological treatment of compulsive buying disorder. To achieve this, we conducted a review of studies focusing on the pharmacological treatment of compulsive buying by searching the PubMed/MEDLINE database. Selection criteria were applied, and 21 studies were identified. Pharmacological classes reported included antidepressants, mood stabilizers, opioid antagonists, second-generation antipsychotics, and N-methyl-D-aspartate receptor antagonists. We found only placebo-controlled trials for fluvoxamine; none showed effectiveness against placebo. Three open-label trials reported clinical improvement with citalopram; one was followed by a double-blind discontinuation. Escitalopram was effective in an open-label trial but did not show efficacy in the double-blind phase. Memantine was identified as effective in a pilot open-label study. Fluoxetine, bupropion, nortriptyline, clomipramine, topiramate and naltrexone were only reported to be effective in clinical cases. According to the available literature, there is no evidence to propose a specific pharmacologic agent for compulsive buying disorder. Future research is required for a better understanding of both pathogenesis and treatment of this disorder.

Fluoroscopy-guided hydrostatic reduction of intussusception in infancy: role of pharmacological premedication.

PubMed

Esposito, Francesco; Ambrosio, Concetta; De Fronzo, Simona; Panico, Maria Rita; D'Aprano, Marilena; Giugliano, Anna Marcella; Noviello, Domenico; Oresta, Patrizia

2015-06-01

Intussusception is one of the most common causes of paediatric emergency. Fluoroscopy-guided hydrostatic reduction is a common nonoperative management strategy for the treatment of intussusception. The role of pharmacological premedication in increasing the success rate of hydrostatic reduction is still controversial. The purpose of this study was to verify the presence of a possible correlation between pharmacological premedication and the percentage of hydrostatic reduction of intussusception in paediatric patients. This study considered children with a diagnosis of idiopathic intussusception treated at our hospital between January 2007 and June 2013. One group of patients underwent hydrostatic reduction by barium enema without any preliminary therapy. A second group of patients received pharmacological premedication with both a sedative and an anti-oedematous agent before the procedure. A total of 398 patients were treated with barium enema for therapeutic purposes. In the group of patients who received no premedication (n = 254), 165 (65 %) children achieved hydrostatic reduction of the intussusception. Among the patients who received pharmacological premedication prior to barium enema (n = 144), 122 (85 %) children achieved resolution of the intussusception. Our study shows that the use of pharmacological premedication is effective for the reduction of the intussusception, as its limit patient stress, fluoroscopic time and radiation dose.

Pharmacological treatment of sexual offenders in German outpatient treatment centers.

PubMed

Turner, Daniel; Gregório Hertz, Priscilla; Sauter, Julia; Briken, Peer; Rettenberger, Martin

2018-05-04

In Germany, depending on a sexual offender's culpability and the severity of the offence, he/she can be placed either in the forensic-psychiatric or the correctional system. Numbers related to the pharmacological treatment of sexual offenders for the correctional system are missing so far. In sexual offenders, the pharmacological treatment of paraphilic disorders is of special importance. The present study aimed at assessing the prevalence of pharmacological sexual offender treatment in German outpatient treatment centers supervising mainly clients from the correctional sector. An online questionnaire was sent to 112 outpatient treatment centers and 21 provided data relevant for the present study. The included institutions reported about a total of 813 sexual offenders, of whom 200 (24.6%) were treated with pharmacological agents, most frequently antipsychotics (14.8%) and selective-serotonin-reuptake-inhibitors (7.1%). Of the total sample, 26.7% of sexual offenders were diagnosed with a paraphilic - mainly with a pedophilic - disorder. Only 2% were treated with androgen-deprivation therapy. Compared with forensic-psychiatric institutions, only a minority of sexual offenders are treated with medication specifically addressing paraphilic symptomatology. However, the prevalence of paraphilic disorders found in the present study suggests that pharmacological treatment of paraphilic fantasies and behaviors could be of great importance in the correctional sector as well.

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.

Controlled-release, pegylation, liposomal formulations: new mechanisms in the delivery of injectable drugs.

PubMed

Reddy, K R

2000-01-01

To review recent developments in novel injectable drug delivery mechanisms and outline the advantages and disadvantages of each. A MEDLINE (1995-January 2000) search using the terms polyethylene glycol, liposomes, polymers, polylactic acid, and controlled release was conducted. Additional references were identified by scanning bibliographies. All articles were considered for inclusion. Abstracts were included only if they were judged to add critical information not otherwise available in the medical literature. A number of systems that alter the delivery of injectable drugs have been developed in attempts to improve pharmacodynamic and pharmacokinetic properties of therapeutic agents. New drug delivery systems can be produced either through a change in formulation (e.g., continuous-release products, liposomes) or an addition to the drug molecule (e.g., pegylation). Potential advantages of new delivery mechanisms include an increased or prolonged duration of pharmacologic activity, a decrease in adverse effects, and increased patient compliance and quality of life. Injectable continuous-release systems deliver drugs in a controlled, predetermined fashion and are particularly appropriate when it is important to avoid large fluctuations in plasma drug concentrations. Encapsulating a drug within a liposome can produce a prolonged half-life and a shift of distribution toward tissues with increased capillary permeability (e.g., tumors, infected tissue). Pegylation provides a method for modification of therapeutic proteins to minimize many of the limitations (e.g., poor stability, short half-life, immunogenicity) associated with these agents. Pegylation of therapeutic proteins is an established process with new applications. However, not all pegylated proteins are alike, and each requires optimization on a protein-by-protein basis to derive maximum clinical benefit. The language required to describe each pegylated therapeutic protein must be more precise to accurately distinguish each protein's differential pharmacologic properties.

PDTCM: a systems pharmacology platform of traditional Chinese medicine for psoriasis.

PubMed

Wang, Dongmei; Gu, Jiangyong; Zhu, Wei; Luo, Fang; Chen, Lirong; Xu, Xiaojie; Lu, Chuanjian

2017-12-01

Psoriasis is a refractory skin disorder, and usually requires a lifetime control. Traditional Chinese medicine (TCM) is effective and safe for this disease. However, the cellular and molecular mechanisms of TCM remedies for psoriasis are still not fully understood. TCM contains numerous natural products. Natural products have historically been invaluable as a resource of therapeutic agents. Yet, there is no integrated information about active compounds of TCM for psoriasis. We use systems pharmacology methods to develop the Psoriasis Database of Traditional Chinese Medicine (PDTCM). The database covered a number of psoriasis-related information (formulas, TCM, compounds, target proteins, diseases and biomarkers). With these data information, an online platform was constructed Results: PDTCM comprises 38 empirical therapeutic formulas, 34373 compounds from 1424 medicinal plants, 44 psoriasis-related proteins and 76 biomarkers from 111 related diseases. On this platform, users can screen active compounds for a psoriasis-related target and explore molecular mechanisms of TCM. Accordingly, users can also download the retrieved structures and data information with a defined value set. In addition, it helps to get a better understanding of Chinese prescriptions in disease treatment. With the systems pharmacology-based data, PDTCM would become a valuable resource for TCM in psoriasis-related research. Key messages PDTCM platform comprises a great deal of data on TCM and psoriasis. On this platform, users can retrieve and get needed information with systems pharmacology methods, such as active compounds screening, target prediction and molecular mechanisms exploration. It is a tool for psoriasis-related research on natural drugs systematically.

Cough Suppressant and Pharmacologic Protussive Therapy

PubMed Central

Bolser, Donald C.

2011-01-01

Background Cough-suppressant therapy, previously termed nonspecific antitussive therapy, incorporates the use of pharmacologic agents with mucolytic effects and/or inhibitory effects on the cough reflex itself. The intent of this type of therapy is to reduce the frequency and/or intensity of coughing on a short-term basis. Methods Data for this review were obtained from several National Library of Medicine (PubMed) searches (from 1960 to 2004), which were performed between May and September 2004, of the literature published in the English language, limited to human studies, using combinations of the search terms “cough,” “double-blind placebo-controlled,” “antitussive,” “mucolytic,” “cough clearance,” “common cold,” “protussive,” “guaifenesin,” “glycerol,” and “zinc.” Results Mucolytic agents are not consistently effective in ameliorating cough in patients with bronchitis, although they may be of benefit to this population in other ways. Peripheral and central antitussive agents can be useful in patients with chronic bronchitis, but can have little efficacy in patients with cough due to upper respiratory infection. Some protussive agents are effective in increasing cough clearance, but their long-term effectiveness has not been established. DNase is not effective as a protussive agent in patients with cystic fibrosis. Inhaled mannitol is acutely effective in this patient population, but its therapeutic potential must be investigated further. Conclusions These findings suggest that suppressant therapy is most effective when used for the short-term reduction of coughing. Relatively few drugs are effective as cough suppressants. PMID:16428717

Dextromethorphan/quinidine sulfate (Zenvia) for Pseudobulbar Affect

PubMed Central

Rosen, Howard

2010-01-01

SUMMARY A new agent containing a combination of Dextromethorphan and Quinidine is currently under development for the treatment of pseudobulbar affect (PBA). PBA is a disorder of emotional regulation, characterized by uncontrollable outbursts of laughing and/or crying that are disproportionate to the emotions being experienced. The pathophysiology of PBA is currently unknown, although the disorder is thought to occur exclusively in the setting of neurological disease. The most influential theory on PBA posits that emotional outbursts are being generated in the brainstem autonomously due to loss of regulatory control by the frontal lobes. Although rarely life-threatening, PBA can have significant impact on patients’ quality of life and thus merits treatment. There are currently no approved treatments for PBA. Several agents have been found to be effective in small placebo-controlled trials and case series, with the most commonly used agents being tricyclic antidepressants and selective serotonin reuptake inhibitors. Both these treatments are inexpensive and relatively low-risk, although the quality and quantity of the available data on their efficacy are not optimal. DM has several pharmacological mechanisms of action relevant to the brain. It is an NMDA-receptor antagonist, which prompted investigators to study its potential for slowing progression in ALS, where glutamate toxicity is thought to be a factor. The combination agent DM/Q was developed to slow the metabolism of DM by P450 2D6 enzymes in the liver. DM/Q was not effective in slowing ALS progression, but patients noted that it helped to control their emotional outbursts, suggesting it might be useful as a treatment for PBA. DM is also a sigma1 receptor agonist. These receptors are widely distributed in the brain, but probably most heavily in the limbic system, suggesting that DM may exert its emotion-controlling effects via these receptors. The endogenous ligands for sigma1 receptors are not altogether known, although they appear to include gonadal steroids. DM/Q was recently shown to be effective in reducing the severity of PBA in two large studies of Amyotrophic Lateral Sclerosis (ALS) and Multiple Sclerosis (MS), which are probably the most common neurological settings. These are the largest treatment studies of PBA ever done. The agent was safe and relatively well tolerated. Further studies are being conducted to see if efficacy can be maintained with lower doses of quinidine. If DM/Q is approved by the FDA for treatment of PBA, this would be the first agent approved for this purpose. Currently, the antidepressants are probably the most attractive pharmacologic options for treatment of PBA. The choice of whether to use DM/Q in this setting will likely depend on individual patient factors, as well as cost. PMID:19137121

Regulation of the nitric oxide oxidase activity of myeloperoxidase by pharmacological agents.

PubMed

Maiocchi, Sophie L; Morris, Jonathan C; Rees, Martin D; Thomas, Shane R

2017-07-01

The leukocyte-derived heme enzyme myeloperoxidase (MPO) is released extracellularly during inflammation and impairs nitric oxide (NO) bioavailability by directly oxidizing NO or producing NO-consuming substrate radicals. Here, structurally diverse pharmacological agents with activities as MPO substrates/inhibitors or antioxidants were screened for their effects on MPO NO oxidase activity in human plasma and physiological model systems containing endogenous MPO substrates/antioxidants (tyrosine, urate, ascorbate). Hydrazide-based irreversible/reversible MPO inhibitors (4-ABAH, isoniazid) or the sickle cell anaemia drug, hydroxyurea, all promoted MPO NO oxidase activity. This involved the capacity of NO to antagonize MPO inhibition by hydrazide-derived radicals and/or the ability of drug-derived radicals to stimulate MPO turnover thereby increasing NO consumption by MPO redox intermediates or NO-consuming radicals. In contrast, the mechanism-based irreversible MPO inhibitor 2-thioxanthine, potently inhibited MPO turnover and NO consumption. Although the phenolics acetaminophen and resveratrol initially increased MPO turnover and NO consumption, they limited the overall extent of NO loss by rapidly depleting H 2 O 2 and promoting the formation of ascorbyl radicals, which inefficiently consume NO. The vitamin E analogue trolox inhibited MPO NO oxidase activity in ascorbate-depleted fluids by scavenging NO-consuming tyrosyl and urate radicals. Tempol and related nitroxides decreased NO consumption in ascorbate-replete fluids by scavenging MPO-derived ascorbyl radicals. Indoles or apocynin yielded marginal effects. Kinetic analyses rationalized differences in drug activities and identified criteria for the improved inhibition of MPO NO oxidase activity. This study reveals that widely used agents have important implications for MPO NO oxidase activity under physiological conditions, highlighting new pharmacological strategies for preserving NO bioavailability during inflammation. Copyright © 2017 Elsevier Inc. All rights reserved.

Pharmacologic properties of brewery dust extracts in vitro.

PubMed

Schachter, E N; Zuskin, E; Rienzi, N; Goswami, S; Castranova, V; Whitmer, M; Siegel, P

2001-06-01

To study the effects of extracts of brewery dust on isolated guinea pig tracheal smooth muscle in vitro. Parallel pharmacologic intervention on guinea pig tracheal rings that were obtained from the same animal. Mount Sinai School of Medicine, Department of Pulmonary Medicine. The isolated guinea pig tracheal tissue of 18 guinea pigs. Pretreatment of guinea pig rings by mediator-modifying agents before challenge with the brewery dust extracts. The effect of brewery dust extracts on isolated guinea pig tracheal smooth muscle was studied using water-soluble extracts of dust obtained from brewery materials, including hops, barley, and brewery yeast. Dust extracts were prepared as a 1:10 (wt/vol) aqueous solution. Dose-related contractions of nonsensitized guinea pig tracheas were demonstrated using these extracts. The dust extracts contained significant quantities of bacterial components (eg, endotoxin and n-formyl-methionyl-leucyl-phenylalanine), but these agents were not thought to contribute directly to the constrictor effect of the dusts. Pharmacologic studies were performed by pretreating guinea pig tracheal tissue with the following drugs known to modulate smooth muscle contraction: atropine; indomethacin; pyrilamine; LY171883; nordihydroguaiaretic acid; captopril; thiorphan; verapamil; and TMB8. The constrictor effects of the dust extracts were inhibited by a wide variety of agents, the patterns of which depended on the dust extract. Atropine consistently and strikingly reduced the contractile effects of these extracts. These observations may suggest an interaction of the extracts with parasympathetic nerves or, more directly, with muscarinic receptors. The inhibition of contraction by the blocking of other mediators was less effective and varied with the dust extract. We suggest that brewery dust extracts cause a dose-related airway smooth muscle constriction by nonimmunologic mechanisms involving a variety of airway mediators and, possibly, cholinergic receptors. This effect is not dependent on presensitization of the guinea pigs.

The Rise, Fall and Subsequent Triumph of Thalidomide: Lessons Learned in Drug Development

PubMed Central

Rehman, Waqas; Arfons, Lisa M.; Lazarus, Hillard M.

2011-01-01

Perhaps no other drug in modern medicine rivals the dramatic revitalization of thalidomide. Originally marketed as a sedative, thalidomide gained immense popularity worldwide among pregnant women because of its effective anti-emetic properties in morning sickness. Mounting evidence of human teratogenicity marked a dramatic fall from grace and led to widespread social, legal and economic ramifications. Despite its tragic past thalidomide emerged several decades later as a novel and highly effective agent in the treatment of various inflammatory and malignant diseases. In 2006 thalidomide completed its remarkable renaissance becoming the first new agent in over a decade to gain approval for the treatment of plasma cell myeloma. The catastrophic collapse yet subsequent revival of thalidomide provides important lessons in drug development. Never entirely abandoned by the medical community, thalidomide resurfaced as an important drug once the mechanisms of action were further studied and better understood. Ongoing research and development of related drugs such as lenalidomide now represent a class of irreplaceable drugs in hematological malignancies. Further, the tragedies associated with this agent stimulated the legislation which revamped the FDA regulatory process, expanded patient informed consent procedures and mandated more transparency from drug manufacturers. Finally, we review recent clinical trials summarizing selected medical indications for thalidomide with an emphasis on hematologic malignancies. Herein, we provide a historic perspective regarding the up-and-down development of thalidomide. Using PubMed databases we conducted searches using thalidomide and associated keywords highlighting pharmacology, mechanisms of action, and clinical uses. PMID:23556097

Pharmacologic Vitreolysis

PubMed Central

Nazari, Hossein; Modarres-Zadeh, Mehdi; Maleki, Arash

2010-01-01

The vitreoretinal interface is involved in a wide range of vitreoretinal disorders and separation of the posterior vitreous face from the retinal surface is an essential part of vitrectomy surgeries. A diverse range of enzymatic and non-enzymatic agents are being studied as an adjunct before or during vitrectomy to facilitate the induction of posterior vitreous detachment. There is a significant body of knowledge in the literature about different vitreolytic agents under investigation for a variety of pathologies involving the vitreoretinal interface which will be summarized in this review. PMID:22737326

Synthesis of Pharmacological Heterocyclic Derivatives Based Surfactants.

PubMed

El-Sayed, Refat; Fadda, Ahmed A

2016-01-01

Synthesis of chromenopyrimidine derivatives and the related fused system carried out by the reaction of chromene derivative 1 with various reagents under suitable reaction conditions. Condensation of stearoyl chloride with these heterocycles, then, propoxylated the products using propylene oxide to produce surface active agents having a twofold capacity as surface and antimicrobial dynamic specialists which may be served in the production of medications, pesticides, beautifying agents or may be utilized as an antimicrobial. Some of the surface properties and antimicrobial activity were resolved.

Design, synthesis, and preliminary pharmacological evaluation of 1, 4-diazabicyclo[4.3.0]nonan-9-ones as a new class of highly potent nootropic agents.

PubMed

Manetti, D; Ghelardini, C; Bartolini, A; Bellucci, C; Dei, S; Galeotti, N; Gualtieri, F; Romanelli, M N; Scapecchi, S; Teodori, E

2000-05-18

Several 4-substituted 1,4-diazabicyclo[4.3.0]nonan-9-ones have been synthesized and tested in vivo on mouse passive avoidance test, to evaluate their nootropic activity. The results show that they represent a new class of nootropic drugs with a pharmacological profile very similar to that of piracetam, showing much higher potency with respect to the reference. Among the compounds studied, 7 (DM 232) shows outstanding potency, being active at the dose of 0. 001 mg kg(-1) sc.

Recurrent angioedema associated with pharmacological inhibition of dipeptidyl peptidase IV.

PubMed

Hermanrud, Thorbjørn; Bygum, Anette; Rasmussen, Eva Rye

2017-01-10

Angioedema (AE) of the upper airways is a severe and potentially life-threatening condition. The incidence has been increasing in the past two decades, primarily due to increased use of medications inhibiting the degradation of vasoactive peptides. Acquired angioedema related to angiotensin-converting enzyme inhibitors (ACEI-AAE) is well known, but other pharmaceutical agents also affect the degradation of bradykinin and substance P. We present a middle-aged man with recurrent episodes of severe AE of the oral cavity, hypopharynx and larynx due to pharmacological inhibition of dipeptidyl peptidase IV. 2017 BMJ Publishing Group Ltd.

Pharmacologic Therapy in Men's Health: Hypogonadism, Erectile Dysfunction, and Benign Prostatic Hyperplasia.

PubMed

Berkseth, Kathryn E; Thirumalai, Arthi; Amory, John K

2016-07-01

This article reviews current pharmacologic treatment options for 3 common men's health concerns: hypogonadism, erectile dysfunction (ED), and benign prostatic hyperplasia (BPH). Specific topics addressed include: management of male hypogonadism using testosterone replacement therapy, use of oral phosphodiesterase inhibitors as first-line therapy for men with ED and the utility of intraurethral and intrapenile alprostadil injections for patients who do not respond to oral medications, and the role of alpha1-adrenergic antagonists, 5-alpha-reductase inhibitors, anticholinergic agents, and herbal therapies in the management of BPH. Copyright © 2016 Elsevier Inc. All rights reserved.

Marine Pharmacology in 2000: Marine Compounds with Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiplatelet, Antituberculosis, and Antiviral Activities; Affecting the Cardiovascular, Immune, and Nervous Systems and Other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M. S.; Hamann, Mark T.

2016-01-01

During 2000 research on the pharmacology of marine chemicals involved investigators from Australia, Brazil, Canada, Egypt, France, Germany, India, Indonesia, Israel, Italy, Japan, the Netherlands, New Zealand, Phillipines, Singapore, Slovenia, South Korea, Spain, Sweden, Switzerland, United Kingdom, and the United States. This current review, a sequel to the authors’ 1998 and 1999 reviews, classifies 68 peer-reviewed articles on the basis of the reported preclinical pharmacologic properties of marine chemicals derived from a diverse group of marine animals, algae, fungi, and bacteria. Antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antituberculosis, or antiviral activity was reported for 35 marine chemicals. An additional 20 marine compounds were shown to have significant effects on the cardiovascular and nervous system, and to possess anti-inflammatory or immunosuppressant properties. Finally, 23 marine compounds were reported to act on a variety of molecular targets and thus could potentially contribute to several pharmacologic classes. Thus, as in 1998 and 1999, during 2000 pharmacologic research with marine chemicals continued to contribute potentially novel chemical leads to the ongoing global search for therapeutic agents in the treatment of multiple disease categories. PMID:14583811

Marine pharmacology in 2003-4: marine compounds with anthelmintic antibacterial, anticoagulant, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems, and other miscellaneous mechanisms of action.

PubMed

Mayer, Alejandro M S; Rodríguez, Abimael D; Berlinck, Roberto G S; Hamann, Mark T

2007-05-01

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998-2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003-2004, research on the pharmacology of marine natural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea, Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for novel therapeutic agents with broad spectrum activity.

Marine pharmacology in 2003-4: Marine Compounds with Anthelminthic, Antibacterial, Anticoagulant, Antifungal, Anti-inflammatory, Antimalarial, Antiplatelet, Antiprotozoal, Antituberculosis, and Antiviral Activities; affecting the Cardiovascular, Immune and Nervous Systems, and other Miscellaneous Mechanisms of Action

PubMed Central

Mayer, Alejandro M.S.; Rodriguez, Abimael D.; Berlinck, Roberto G.S.; Hamann, Mark T.

2007-01-01

The current marine pharmacology review that covers the peer-reviewed literature during 2003 and 2004 is a sequel to the authors' 1998-2002 reviews, and highlights the preclinical pharmacology of 166 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria. Anthelminthic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 67 marine chemicals. Additionally 45 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as possessing anti-inflammatory effects. Finally, 54 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2003-2004, research on the pharmacology of marine natural products which involved investigators from Argentina, Australia, Brazil, Belgium, Canada, China, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Morocco, the Netherlands, New Zealand, Norway, Panama, the Philippines, Portugal, Russia, Slovenia, South Korea, Spain, Thailand, Turkey, United Kingdom, and the United States, contributed numerous chemical leads for the continued global search for novel therapeutic agents with broad spectrum activity. PMID:17392033

Medicinal Plants from Mexico, Central America, and the Caribbean Used as Immunostimulants

PubMed Central

Juárez-Vázquez, María del Carmen; Campos-Xolalpa, Nimsi

2016-01-01

A literature review was undertaken by analyzing distinguished books, undergraduate and postgraduate theses, and peer-reviewed scientific articles and by consulting worldwide accepted scientific databases, such as SCOPUS, Web of Science, SCIELO, Medline, and Google Scholar. Medicinal plants used as immunostimulants were classified into two categories: (1) plants with pharmacological studies and (2) plants without pharmacological research. Medicinal plants with pharmacological studies of their immunostimulatory properties were subclassified into four groups as follows: (a) plant extracts evaluated for in vitro effects, (b) plant extracts with documented in vivo effects, (c) active compounds tested on in vitro studies, and (d) active compounds assayed in animal models. Pharmacological studies have been conducted on 29 of the plants, including extracts and compounds, whereas 75 plants lack pharmacological studies regarding their immunostimulatory activity. Medicinal plants were experimentally studied in vitro (19 plants) and in vivo (8 plants). A total of 12 compounds isolated from medicinal plants used as immunostimulants have been tested using in vitro (11 compounds) and in vivo (2 compounds) assays. This review clearly indicates the need to perform scientific studies with medicinal flora from Mexico, Central America, and the Caribbean, to obtain new immunostimulatory agents. PMID:27042188

Medicinal Plants from Mexico, Central America, and the Caribbean Used as Immunostimulants.

PubMed

Alonso-Castro, Angel Josabad; Juárez-Vázquez, María Del Carmen; Campos-Xolalpa, Nimsi

2016-01-01

A literature review was undertaken by analyzing distinguished books, undergraduate and postgraduate theses, and peer-reviewed scientific articles and by consulting worldwide accepted scientific databases, such as SCOPUS, Web of Science, SCIELO, Medline, and Google Scholar. Medicinal plants used as immunostimulants were classified into two categories: (1) plants with pharmacological studies and (2) plants without pharmacological research. Medicinal plants with pharmacological studies of their immunostimulatory properties were subclassified into four groups as follows: (a) plant extracts evaluated for in vitro effects, (b) plant extracts with documented in vivo effects, (c) active compounds tested on in vitro studies, and (d) active compounds assayed in animal models. Pharmacological studies have been conducted on 29 of the plants, including extracts and compounds, whereas 75 plants lack pharmacological studies regarding their immunostimulatory activity. Medicinal plants were experimentally studied in vitro (19 plants) and in vivo (8 plants). A total of 12 compounds isolated from medicinal plants used as immunostimulants have been tested using in vitro (11 compounds) and in vivo (2 compounds) assays. This review clearly indicates the need to perform scientific studies with medicinal flora from Mexico, Central America, and the Caribbean, to obtain new immunostimulatory agents.

Fraxinus: A Plant with Versatile Pharmacological and Biological Activities

PubMed Central

Sarfraz, Iqra; Jabeen, Farhat; Younis, Tahira; Arshad, Muhammad; Ali, Muhammad

2017-01-01

Fraxinus, a member of the Oleaceae family, commonly known as ash tree is found in northeast Asia, north America, east and western France, China, northern areas of Pakistan, India, and Afghanistan. Chemical constituents of Fraxinus plant include various secoiridoids, phenylethanoids, flavonoids, coumarins, and lignans; therefore, it is considered as a plant with versatile biological and pharmacological activities. Its tremendous range of pharmacotherapeutic properties has been well documented including anticancer, anti-inflammatory, antioxidant, antimicrobial, and neuroprotective. In addition, its bioactive phytochemicals and secondary metabolites can be effectively used in cosmetic industry and as a competent antiaging agent. Fraxinus presents pharmacological effectiveness by targeting the novel targets in several pathological conditions, which provide a spacious therapeutic time window. Our aim is to update the scientific research community with recent endeavors with specifically highlighting the mechanism of action in different diseases. This potentially efficacious pharmacological drug candidate should be used for new drug discovery in future. This review suggests that this plant has extremely important medicinal utilization but further supporting studies and scientific experimentations are mandatory to determine its specific intracellular targets and site of action to completely figure out its pharmacological applications. PMID:29279716

A standalone perfusion platform for drug testing and target validation in micro-vessel networks

PubMed Central

Zhang, Boyang; Peticone, Carlotta; Murthy, Shashi K.; Radisic, Milica

2013-01-01

Studying the effects of pharmacological agents on human endothelium includes the routine use of cell monolayers cultivated in multi-well plates. This configuration fails to recapitulate the complex architecture of vascular networks in vivo and does not capture the relationship between shear stress (i.e. flow) experienced by the cells and dose of the applied pharmacological agents. Microfluidic platforms have been applied extensively to create vascular systems in vitro; however, they rely on bulky external hardware to operate, which hinders the wide application of microfluidic chips by non-microfluidic experts. Here, we have developed a standalone perfusion platform where multiple devices were perfused at a time with a single miniaturized peristaltic pump. Using the platform, multiple micro-vessel networks, that contained three levels of branching structures, were created by culturing endothelial cells within circular micro-channel networks mimicking the geometrical configuration of natural blood vessels. To demonstrate the feasibility of our platform for drug testing and validation assays, a drug induced nitric oxide assay was performed on the engineered micro-vessel network using a panel of vaso-active drugs (acetylcholine, phenylephrine, atorvastatin, and sildenafil), showing both flow and drug dose dependent responses. The interactive effects between flow and drug dose for sildenafil could not be captured by a simple straight rectangular channel coated with endothelial cells, but it was captured in a more physiological branching circular network. A monocyte adhesion assay was also demonstrated with and without stimulation by an inflammatory cytokine, tumor necrosis factor-α. PMID:24404058

New Antiresorptive Therapies for Postmenopausal Osteoporosis

PubMed Central

2015-01-01

Osteoporosis is a systemic skeletal disease whose risk increases with age and it is common among postmenopausal women. Currently, almost all pharmacological agents for osteoporosis target the bone resorption component of bone remodeling activity. Current antiresorptive agents are effective, but the effectiveness of some agents is limited by real or perceived intolerance, longterm adverse events (AEs), coexisting comorbidities, and inadequate long-term adherence. New antiresorptive therapies that may expand options for the prevention and treatment of osteoporosis include denosumab, combination of conjugated estrogen/bazedoxifene and cathepsin K inhibitors. However, the long-term efficacy and AEs of these antiresorptive therapies need to be confirmed in studies with a longer follow-up period. PMID:26046031

Vasopressin antagonists as aquaretic agents for the treatment of hyponatremia.

PubMed

Palm, Catrin; Pistrosch, Frank; Herbrig, Kay; Gross, Peter

2006-07-01

Hyponatremia is the most frequent electrolyte disorder encountered in hospitalized patients. It is a state of relative water excess due to stimulated arginine vasopressin (AVP) and fluid intake greater than obligatory losses. This kind of hyponatremia occurs in the syndrome of inappropriate antidiuretic hormone secretion, congestive heart failure, and liver cirrhosis. Fluid restriction is the presently recommended treatment for hyponatremia. However, fluid restriction may be very difficult for patients to achieve, is slow to work, and does not allow a graded therapeutic approach. More efficient and specific treatments of hyponatremia are needed. In this respect, pharmacologic research has yielded a number of compounds exhibiting antagonistic qualities at the vasopressin V2 receptor. Among these agents, peptidic derivatives of AVP turned out to have intrinsic antidiuretic properties in vivo when given over days or weeks. The development of such agents for use in patients has not been pursued. However, several promising nonpeptide, vasopressin receptor antagonists have been described; these agents are VPA-985 (lixivaptan), YM-087 (conivaptan), OPC-41061 (tolvaptan), and SR-121463. Prospective, randomized, placebo-controlled trials performed with these agents found that they corrected hyponatremia efficiently and safely. Most of the studies were conducted over a 4- to 28-day period. Long-term studies will be needed in the future to address such issues as the eventual benefit to patients and the effects of vasopressin antagonists on morbidity and mortality of patients with hyponatremia.

[Strategy for the development of dipeptide drugs].

PubMed

Gudasheva, T A

2011-01-01

The author describes an original approach to the development of dipeptide drugs based on the concept of the leading role of the beta-bend in the interaction of biologically active endogenous peptides with their receptors. The approach called "peptide-based drug design" includes both developments from the structure of a known psychotropic agent toward its topological peptide analog and developments from the active dipeptide site of a neuropeptide toward its mimetic. This strategy has been worked out at the V.V. Zakusov Research Institute of Pharmacology for 25 years. Results of investigations that discovered endogenous peptide prototypes of the known non-peptidic drugs (piracetam and sulpiride) are presented. They provided a basis for the creation of highly active non-toxic oral dipeptide preparations, such as nootrop Noopept, potential anti psychotic Dilept, and potential selective anxiolytic GB-115.

Pharmacotherapy of Acute Lung Injury and Acute Respiratory Distress Syndrome

PubMed Central

Raghavendran, Krishnan; Pryhuber, Gloria S.; Chess, Patricia R.; Davidson, Bruce A.; Knight, Paul R.; Notter, Robert H.

2009-01-01

Acute lung injury (ALI) and the acute respiratory distress syndrome (ARDS) are characterized by rapid-onset respiratory failure following a variety of direct and indirect insults to the parenchyma or vasculature of the lungs. Mortality from ALI/ARDS is substantial, and current therapy primarily emphasizes mechanical ventilation and judicial fluid management plus standard treatment of the initiating insult and any known underlying disease. Current pharmacotherapy for ALI/ARDS is not optimal, and there is a significant need for more effective medicinal chemical agents for use in these severe and lethal lung injury syndromes. To facilitate future chemical-based drug discovery research on new agent development, this paper reviews present pharmacotherapy for ALI/ARDS in the context of biological and biochemical drug activities. The complex lung injury pathophysiology of ALI/ARDS offers an array of possible targets for drug therapy, including inflammation, cell and tissue injury, vascular dysfunction, surfactant dysfunction, and oxidant injury. Added targets for pharmacotherapy outside the lungs may also be present, since multiorgan or systemic pathology is common in ALI/ARDS. The biological and physiological complexity of ALI/ARDS requires the consideration of combined-agent treatments in addition to single-agent therapies. A number of pharmacologic agents have been studied individually in ALI/ARDS, with limited or minimal success in improving survival. However, many of these agents have complementary biological/biochemical activities with the potential for synergy or additivity in combination therapy as discussed in this article. PMID:18691048

Pharmacological modulations of cardiac ultra-rapid and slowly activating delayed rectifier currents: potential antiarrhythmic approaches.

PubMed

Islam, Mohammed A

2010-01-01

Despite the emerging new insights into our understandings of the cellular mechanisms underlying cardiac arrhythmia, medical therapy for this disease remains unsatisfactory. Atrial fibrillation (AF), the most prevalent arrhythmia, is responsible for significant morbidity and mortality. On the other hand, ventricular fibrillation results in sudden cardiac deaths in many instances. Prolongation of cardiac action potential (AP) is a proven principle of antiarrhythmic therapy. Class III antiarrhythmic agents prolong AP and QT interval by blocking rapidly activating delayed rectifier current (I(Kr)). However, I(Kr) blocking drugs carry the risk of life-threatening proarrhythmia. Recently, modulation of atrial-selective ultra-rapid delayed rectifier current (I(Kur)), has emerged as a novel therapeutic approach to treat AF. A number of I(Kur) blockers are being evaluated for the treatment of AF. The inhibition of slowly activating delayed rectifier current (I(Ks)) has also been proposed as an effective and safer antiarrhythmic approach because of its distinguishing characteristics that differ in remarkable ways from other selective class III agents. Selective I(Ks) block may prolong AP duration (APD) at rapid rates without leading to proarrhythmia. This article reviews the pathophysiological roles of I(Kur) and I(Ks) in cardiac repolarization and the implications of newly developed I(Kur) and I(Ks) blocking agents as promising antiarrhythmic approaches. Several recent patents pertinent to antiarrhythmic drug development have been discussed. Further research will be required to evaluate the efficacy and safety of these agents in the clinical setting.

Medications for Sleep Schedule Adjustments in Athletes.

PubMed

Baird, Matthew B; Asif, Irfan M

Sleep schedule adjustments are common requirements of modern-day athletes. Many nonpharmacologic and pharmacologic strategies exist to facilitate circadian rhythm shifts to maximize alertness and performance during competition. This review summarizes the evidence for commonly used pharmacologic agents and presents recommendations for the sports medicine provider. MEDLINE searches were performed using the following keywords: sleep aids, circadian rhythm adjustment, athletes and sleep, caffeine and sports, melatonin and athletes, and sleep aids and sports. Pertinent articles were extracted and discussed. Clinical review. Level 2. There are very few available studies investigating pharmacologic sleep aids in athletes. Data from studies involving shift workers and airline personnel are more abundant and were used to formulate recommendations and conclusions. Melatonin, caffeine, and nonbenzodiazepine sleep aids have a role in facilitating sleep schedule changes in athletes and maximizing sports performance through sleep enhancement.

[Non-pharmacological diabetes therapy].

PubMed

Martin, Stephan; Kolb, Hubert

2008-02-01

Diabetes mellitus type 2 is a life-style disease that is triggered by obesity and lack of physical activity. The pathophysiological basis of the disease is a reduction of insulin sensitivity, that is caused by the trigger factors. Glucose metabolic disorders appear if overproduction of insulin can not compensate the insulin resistance. In early phases postprandial blood glucose is increased, in late phases elevation of fasting blood glucose is noted. In the general awareness manifestation of type 2 diabetes is associated with an initiation of a pharmacological therapy. This is not the case, as described in detail in this review. Next to epidemiological studies, which indicate trigger factors, intervention trials will be discussed that led to a shift in paradigm in the diabetology. Non-pharmacological interventions are a therapeutical alternative in a lot of patients or are able to reduce the amount of antidiabetic agents significantly.

Approach to managing patients with sulfa allergy

PubMed Central

Ponka, David

2006-01-01

OBJECTIVE To present an approach to use of sulfonamide-based (sulfa) medications for patients with sulfa allergy and to explore whether sulfa medications are contraindicated for patients who require them but are allergic to them. SOURCES OF INFORMATION A search of current pharmacology textbooks and of MEDLINE from 1966 to the present using the MeSH key words “sulfonamide” and “drug sensitivity” revealed review articles, case reports, one observational study (level II evidence), and reports of consensus opinion (level III evidence). MAIN MESSAGE Cross-reactivity between sulfa antibiotics and nonantibiotics is rare, but on occasion it can affect the pharmacologic and clinical management of patients with sulfa allergy. CONCLUSION How a physician approaches using sulfa medications for patients with sulfa allergy depends on the certainty and severity of the initial allergy, on whether alternatives are available, and on whether the contemplated agent belongs to the same category of sulfa medications (ie, antibiotic or nonantibiotic) as the initial offending agent. PMID:17279201

Is rivastigmine safe as pretreatment against nerve agents poisoning? A pharmacological, physiological and cognitive assessment in healthy young adult volunteers.

PubMed

Lavon, Ophir; Eisenkraft, Arik; Blanca, Merav; Raveh, Lily; Ramaty, Erez; Krivoy, Amir; Atsmon, Jacob; Grauer, Ettie; Brandeis, Rachel

2015-07-01

Rivastigmine, a reversible cholinesterase inhibitor, approved as a remedy in Alzheimer's disease, was suggested as pretreatment against nerve agents poisoning. We evaluated the pharmacokinetic, pharmacodynamic, physiologic, cognitive and emotional effects of repeated rivastigmine in young healthy male adults, in a double blind, placebo controlled crossover trial. Three groups completed 3 treatment periods: 0, 1.5 and 3mg twice a day, for a total of 5 intakes. Parameters monitored were: vital signs, ECG, laboratory tests, sialometry, visual accommodation, inspiratory peak flow, and cognitive function tests. Adverse reactions were mild. Peak blood levels and peak cholinesterase inhibition increased with repeated intakes, and high variability and non-linear pharmacokinetics were demonstrated. In addition, two cognitive functions were affected (perceptual speed and dynamic tracking). The complicated pharmacological profile and the high inter-personal variability limit the potential use of rivastigmine as pretreatment for war fighters and first responders. Copyright © 2015 Elsevier Inc. All rights reserved.

Reproducible insulin secretion from isolated rat pancreas preparations using an organ bath.

PubMed

Morita, Asuka; Ouchi, Motoshi; Terada, Misao; Kon, Hiroe; Kishimoto, Satoko; Satoh, Keitaro; Otani, Naoyuki; Hayashi, Keitaro; Fujita, Tomoe; Inoue, Ken-Ichi; Anzai, Naohiko

2018-02-09

Diabetes mellitus is a lifestyle-related disease that is characterized by inappropriate or diminished insulin secretion. Ex vivo pharmacological studies of hypoglycemic agents are often conducted using perfused pancreatic preparations. Pancreas preparations for organ bath experiments do not require cannulation and are therefore less complex than isolated perfused pancreas preparations. However, previous research has generated almost no data on insulin secretion from pancreas preparations using organ bath preparations. The purpose of this study was to investigate the applicability of isolated rat pancreas preparations using the organ bath technique in the quantitative analysis of insulin secretion from β-cells. We found that insulin secretion significantly declined during incubation in the organ bath, whereas it was maintained in the presence of 1 µM GLP-1. Conversely, amylase secretion exhibited a modest increase during incubation and was not altered in the presence of GLP-1. These results demonstrate that the pancreatic organ bath preparation is a sensitive and reproducible method for the ex vivo assessment of the pharmacological properties of hypoglycemic agents.

Treatment options for the management of exercise-induced asthma and bronchoconstriction.

PubMed

Millward, David T; Tanner, Lindsay G; Brown, Mark A

2010-12-01

Treatment for exercise-induced bronchospasm and exercise-induced asthma includes both pharmacologic and nonpharmacologic options. Pharmacologic agents that have been proven to be effective for treating these conditions include short- and long-acting β2-adrenoceptor agonists, mast cell-stabilizing agents, anticholinergics, leukotriene receptor antagonists, and inhaled corticosteroids (ICS). When selecting the most appropriate medication, factors to consider include the effectiveness of each, the duration of action, frequency of administration, potential side effects, and tolerance level. Long-acting β2-adrenoceptor agonists should not be used without ICS. Nonpharmacologic treatments include physical conditioning, incorporating a warm-up before and a cool-down period after exercise, performing nasal breathing, avoiding cold weather or environmental allergens, using a face mask or other aid to warm and humidify inhaled air, and modifying dietary intake. The data to support nonpharmacologic treatments are limited; however, they are routinely recommended because of the low risk associated with their use. This article highlights the advantages and limitations of each treatment option.

Microwave-assisted extraction, HPLC analysis, and inhibitory effects on carbonic anhydrase I, II, VA, and VII isoforms of 14 blueberry Italian cultivars.

PubMed

Mollica, Adriano; Locatelli, Marcello; Macedonio, Giorgia; Carradori, Simone; Sobolev, Anatoly P; De Salvador, Roberto F; Monti, Simona M; Buonanno, Martina; Zengin, Gokhan; Angeli, Andrea; Supuran, Claudiu T

2016-01-01

The multi-component fingerprint and the biological evaluation of plant-derived material are indispensable for the pharmaceutical field, in food quality control procedures, and in all plant-based products. We investigated the quantitative content of biologically active compounds (anthocyanins and chlorogenic acid) of microwave-assisted blueberry extracts from 14 different Italian cultivars, using validated high-performance liquid chromatography-photodiode array detector (HPLC-PDA) method and routinely instrument configuration. The carbonic anhydrase (CA, EC 4.2.1.1) inhibition profiles against several pharmacologically relevant CA isoforms of blueberry extracts and some bioactive compounds were also investigated. The various cultivars showed a highly variable content in anthocyanins and chlorogenic acid, and their CA inhibitory effects were also highly variable. Overall these data prove that antioxidant natural products found in blueberries may be useful for designing pharmacological agents in which various CAs are involved, e.g., antiobesity, antitumor, or anticonvulsants agents.

Triglycerides: A reappraisal.

PubMed

Wiesner, Philipp; Watson, Karol E

2017-08-01

Elevated cholesterol levels are clearly independently associated with adverse cardiovascular events. Another class of lipid particles, triglycerides, is also abundant in the human body and has been found in atherosclerotic plaques. Recent observational studies have demonstrated an association between elevated triglyceride levels and increased risk for future cardiovascular events. With this knowledge and the discovery of effective agents to lower triglyceride levels, the management of triglycerides is currently undergoing a renaissance. Unfortunately, no randomized, controlled clinical trials have been completed to date, proving that lowering triglycerides will reduce cardiovascular events. In this review we highlight some of the evidence that led to this stage and discuss the current data on pharmacologic intervention of triglyceride levels and the effect on clinical outcomes. Lastly, we want to give the reader insight on what the most recent lipid guidelines state about clinical triglyceride management, mention new pharmacological agents, and highlight the clinical evidence for safe and effective lowering of triglycerides levels with life style modification. Copyright © 2017. Published by Elsevier Inc.

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

VMAT2 Inhibitors for Tardive Dyskinesia-Practice Implications.

PubMed

Peckham, Alyssa M; Nicewonder, Jessica A

2018-01-01

Tardive dyskinesia is a potentially irreversible, debilitating, hyperkinetic movement disorder that can result from dopamine receptor antagonists. Prompt recognition and resolution of symptoms are instrumental in preventing disease irreversibility, though current treatment options have fallen short of robust, effective, and long-term symptom control. In April 2017, the Food and Drug Administration (FDA) approved 2 new vesicular monoamine transporter 2 (VMAT2) inhibitors, deutetrabenazine and valbenazine, for chorea related to Huntington's disease and tardive dyskinesia, respectively. These agents were pharmacologically modified from tetrabenazine, a VMAT2 inhibitor used off-label in the treatment of tardive dyskinesia. Despite FDA-labeled indications of deutetrabenazine and valbenazine, each agent was explored as a treatment option for those with tardive dyskinesia. In this study, the pharmacologic modifications of the 2 new VMAT2 inhibitors are described, with detailed explanation as to how these may impact clinical practice. The associated case series, observational studies, and clinical trials exploring their use in the treatment of tardive dyskinesia are reported with expert opinion on practice implication.

Fibromyalgia Pathogenesis and Treatment Options Update.

PubMed

Chinn, Steven; Caldwell, William; Gritsenko, Karina

2016-04-01

This review article presents and summarizes up-to-date literature on the clinical manifestations, diagnosis, pathophysiological mechanisms, and treatment options for fibromyalgia patients. First, the most recent diagnostic criteria for fibromyalgia, as put forth by the American College of Rheumatology will be summarized. Clinical features, including chronic widespread pain, hyperalgesia, mood disorders, anxiety, and disturbed sleep patterns will be explored in-depth. The pathogenesis and pathophysiology of fibromyalgia involves alterations in multiple ascending and descending central nervous system pathways, as well as peripheral pathways, leading to heightened pain sensitivity. Risk factors have been studied extensively, and the most recent research focuses on various genetic influences and the contributions of stress and poor sleep. Lastly, the discussion in this article focuses on treatment options for fibromyalgia; some have been mainstay options for many years. Pharmacological agents include tricyclic antidepressants, anti-epileptic drugs, selective serotonin reuptake inhibitors, norepinephrine/serotonin reuptake inhibitors, as well as some investigational agents. The evidence behind non-pharmacologic treatments, including massage therapy, exercise, and acupuncture, are discussed.

Levodopa-induced dyskinesias in Parkinson’s disease: emerging treatments

PubMed Central

Bargiotas, Panagiotis; Konitsiotis, Spyridon

2013-01-01

Parkinson’s disease therapy is still focused on the use of L-3,4-dihydroxyphenylalanine (levodopa or L-dopa) for the symptomatic treatment of the main clinical features of the disease, despite intensive pharmacological research in the last few decades. However, regardless of its effectiveness, the long-term use of levodopa causes, in combination with disease progression, the development of motor complications termed levodopa-induced dyskinesias (LIDs). LIDs are the result of profound modifications in the functional organization of the basal ganglia circuitry, possibly related to the chronic and pulsatile stimulation of striatal dopaminergic receptors by levodopa. Hence, for decades the key feature of a potentially effective agent against LIDs has been its ability to ensure more continuous dopaminergic stimulation in the brain. The growing knowledge regarding the pathophysiology of LIDs and the increasing evidence on involvement of nondopaminergic systems raises the possibility of more promising therapeutic approaches in the future. In the current review, we focus on novel therapies for LIDs in Parkinson’s disease, based mainly on agents that interfere with glutamatergic, serotonergic, adenosine, adrenergic, and cholinergic neurotransmission that are currently in testing or clinical development. PMID:24174877

Multiple Ligands Targeting Cholinesterases and β-Amyloid: Synthesis, Biological Evaluation of Heterodimeric Compounds with Benzylamine Pharmacophore.

PubMed

Szałaj, Natalia; Bajda, Marek; Dudek, Katarzyna; Brus, Boris; Gobec, Stanislav; Malawska, Barbara

2015-08-01

Alzheimer's disease (AD) is a fatal and complex neurodegenerative disorder for which effective treatment remains the unmet challenge. Using donepezil as a starting point, we aimed to develop novel potential anti-AD agents with a multidirectional biological profile. We designed the target compounds as dual binding site acetylcholinesterase inhibitors, where the N-benzylamine pharmacophore is responsible for interactions with the catalytic anionic site of the enzyme. The heteroaromatic fragment responsible for interactions with the peripheral anionic site was modified and three different heterocycles were introduced: isoindoline, isoindolin-1-one, and saccharine. Based on the results of the pharmacological evaluation, we identified compound 8b with a saccharine moiety as the most potent and selective human acetylcholinesterase inhibitor (IC50  = 33 nM) and beta amyloid aggregation inhibitor. It acts as a non-competitive acetylcholinesterase inhibitor and is able to cross the blood-brain barrier in vitro. We believe that compound 8b represents an important lead compound for further development as potential anti-AD agent. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Plant-derived anticancer agents - curcumin in cancer prevention and treatment.

PubMed

Creţu, Elena; Trifan, Adriana; Vasincu, Al; Miron, Anca

2012-01-01

Nowadays cancer is still a major public health issue. Despite all the progresses made in cancer prevention, diagnosis and treatment, mortality by cancer is on the second place after the one caused by cardiovascular diseases. The high mortality and the increasing incidence of certain cancers (lung, prostate, colorectal) justify a growing interest for the identification of new pharmacological agents efficient in cancer prevention and treatment. In the last fifty years many plant-derived agents (vinblastine, vincristine, vindesine, paclitaxel, docetaxel, topotecan, irinotecan, elliptinium) played a major role in cancer treatment. Other very promising plant-derived anticancer agents (combrestatins, betulinic acid, roscovitine, purvalanols, indirubins) are in clinical or preclinical trials. Curcumin, a liposoluble polyphenolic pigment isolated from the rhizomes of Curcuma longa L. (Zingiberaceae), is another potential candidate for new anticancer drug development. Curcumin has been reported to influence many cell-signaling pathways involved in tumor initiation and proliferation. Curcumin inhibits COX-2 activity, cyclin D1 and MMPs overexpresion, NF-kB, STAT and TNF-alpha signaling pathways and regulates the expression of p53 tumor suppressing gene. Curcumin is well-tolerated but has a reduced systemic bioavailability. Polycurcumins (PCurc 8) and curcumin encapsulated in biodegradable polymeric nanoparticles (NanoCurc) showed higher bioavailability than curcumin together with a significant tumor growth inhibition in both in vitro and in vivo studies. BILITY.

Pharmacological and therapeutic directions in ADHD: Specificity in the PFC.

PubMed

Levy, Florence

2008-02-28

Recent directions in the treatment of ADHD have involved both a broadening of pharmacological perspectives to include nor-adrenergic as well as dopaminergic agents. A review of animal and human studies of pharmacological and therapeutic directions in ADHD suggests that the D1 receptor is a specific site for dopaminergic regulation of the PFC, but optimal levels of dopamine (DA) are required for beneficial effects on working memory. Animal and human studies indicate that the alpha-2A receptor is also important for prefrontal regulation, leaving open the question of the relative importance of these receptor sites. The therapeutic effects of ADHD medications in the prefrontal cortex have focused attention on the development of working memory capacity in ADHD. The actions of dopaminergic vs noradrenergic agents, currently available for the treatment of ADHD have overlapping, but different actions in the prefrontal cortex (PFC) and subcortical centers. While stimulants act on D1 receptors in the dorsolateral prefrontal cortex, they also have effects on D2 receptors in the corpus striatum and may also have serotonergic effects at orbitofrontal areas. At therapeutic levels, dopamine (DA) stimulation (through DAT transporter inhibition) decreases noise level acting on subcortical D2 receptors, while NE stimulation (through alpha-2A agonists) increases signal by acting preferentially in the PFC possibly on DAD1 receptors. On the other hand, alpha-2A noradrenergic transmission is more limited to the prefrontal cortex (PFC), and thus less likely to have motor or stereotypic side effects, while alpha-2B and alpha-2C agonists may have wider cortical effects. The data suggest a possible hierarchy of specificity in the current medications used in the treatment of ADHD, with guanfacine likely to be most specific for the treatment of prefrontal attentional and working memory deficits. Stimulants may have broader effects on both vigilance and motor impulsivity, depending on dose levels, while atomoxetine may have effects on attention, anxiety, social affect, and sedation via noradrenergic transmission. At a theoretical level, the advent of possible specific alpha-2A noradrenergic therapies has posed the question of the role of working memory in ADHD. Head to head comparisons of stimulant and noradrenergic alpha-2A, alpha-2B and alpha-2C agonists, utilizing vigilance and affective measures should help to clarify pharmacological and therapeutic differences.

Arginase Inhibitor in the Pharmacological Correction of Endothelial Dysfunction

PubMed Central

Pokrovskiy, Mihail V.; Korokin, Mihail V.; Tsepeleva, Svetlana A.; Pokrovskaya, Tatyana G.; Gureev, Vladimir V.; Konovalova, Elena A.; Gudyrev, Oleg S.; Kochkarov, Vladimir I.; Korokina, Liliya V.; Dudina, Eleonora N.; Babko, Anna V.; Terehova, Elena G.

2011-01-01

This paper is about a way of correction of endothelial dysfunction with the inhibitor of arginase: L-norvaline. There is an imbalance between vasoconstriction and vasodilatation factors of endothelium on the basis of endothelial dysfunction. Among vasodilatation agents, nitrogen oxide plays the basic role. Amino acid L-arginine serves as a source of molecules of nitrogen oxide in an organism. Because of the high activity of arginase enzyme which catalyzes the hydrolysis of L-arginine into ornithine and urea, the bioavailability of nitrogen oxide decreases. The inhibitors of arginase suppress the activity of the given enzyme, raising and production of nitrogen oxide, preventing the development of endothelial dysfunction. PMID:21747978

Diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams

PubMed Central

2015-01-01

Summary The conjugate addition reaction has been a useful tool in the formation of carbon–carbon bonds. The utility of this reaction has been demonstrated in the synthesis of many natural products, materials, and pharmacological agents. In the last three decades, there has been a significant increase in the development of asymmetric variants of this reaction. Unfortunately, conjugate addition reactions using α,β-unsaturated amides and lactams remain underdeveloped due to their inherently low reactivity. This review highlights the work that has been done on both diastereoselective and enantioselective conjugate addition reactions utilizing α,β-unsaturated amides and lactams. PMID:25977728

Indole alkaloid marine natural products: An established source of cancer drug leads with considerable promise for the control of parasitic, neurological and other diseases

PubMed Central

Gul, Waseem; Hamann, Mark T.

2016-01-01

The marine environment produces natural products from a variety of structural classes exhibiting activity against numerous disease targets. Historically marine natural products have largely been explored as anticancer agents. The indole alkaloids are a class of marine natural products that show unique promise in the development of new drug leads. This report reviews the literature on indole alkaloids of marine origin and also highlights our own research. Specific biological activities of indole alkaloids presented here include: cytotoxicity, antiviral, antiparasitic, anti-inflammatory, serotonin antagonism, Ca-releasing, calmodulin antagonism, and other pharmacological activities. PMID:16236327

Screening of effective pharmacological treatments for MELAS syndrome using yeasts, fibroblasts and cybrid models of the disease.

PubMed

Garrido-Maraver, Juan; Cordero, Mario D; Moñino, Irene Domínguez; Pereira-Arenas, Sheila; Lechuga-Vieco, Ana V; Cotán, David; De la Mata, Mario; Oropesa-Ávila, Manuel; De Miguel, Manuel; Bautista Lorite, Juan; Rivas Infante, Eloy; Alvarez-Dolado, Manuel; Navas, Plácido; Jackson, Sandra; Francisci, Silvia; Sánchez-Alcázar, José A

2012-11-01

MELAS (mitochondrial encephalomyopathy, lactic acidosis and stroke-like episodes) is a mitochondrial disease most usually caused by point mutations in tRNA genes encoded by mitochondrial DNA (mtDNA). Approximately 80% of cases of MELAS syndrome are associated with a m.3243A > G mutation in the MT-TL1 gene, which encodes the mitochondrial tRNALeu (UUR). Currently, no effective treatments are available for this chronic progressive disorder. Treatment strategies in MELAS and other mitochondrial diseases consist of several drugs that diminish the deleterious effects of the abnormal respiratory chain function, reduce the presence of toxic agents or correct deficiencies in essential cofactors. We evaluated the effectiveness of some common pharmacological agents that have been utilized in the treatment of MELAS, in yeast, fibroblast and cybrid models of the disease. The yeast model harbouring the A14G mutation in the mitochondrial tRNALeu(UUR) gene, which is equivalent to the A3243G mutation in humans, was used in the initial screening. Next, the most effective drugs that were able to rescue the respiratory deficiency in MELAS yeast mutants were tested in fibroblasts and cybrid models of MELAS disease. According to our results, supplementation with riboflavin or coenzyme Q(10) effectively reversed the respiratory defect in MELAS yeast and improved the pathologic alterations in MELAS fibroblast and cybrid cell models. Our results indicate that cell models have great potential for screening and validating the effects of novel drug candidates for MELAS treatment and presumably also for other diseases with mitochondrial impairment. © 2012 The Authors. British Journal of Pharmacology © 2012 The British Pharmacological Society.

Alcohol use disorders and current pharmacological therapies: the role of GABAA receptors

PubMed Central

Liang, Jing; Olsen, Richard W

2014-01-01

Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents. PMID:25066321

Pharmacology and Clinical Drug Candidates in Redox Medicine

PubMed Central

Casas, Ana I.; Maghzal, Ghassan J.; Seredenina, Tamara; Kaludercic, Nina; Robledinos-Anton, Natalia; Di Lisa, Fabio; Stocker, Roland; Ghezzi, Pietro; Jaquet, Vincent; Cuadrado, Antonio

2015-01-01

Abstract Significance: Oxidative stress is suggested to be a disease mechanism common to a wide range of disorders affecting human health. However, so far, the pharmacotherapeutic exploitation of this, for example, based on chemical scavenging of pro-oxidant molecules, has been unsuccessful. Recent Advances: An alternative emerging approach is to target the enzymatic sources of disease-relevant oxidative stress. Several such enzymes and isoforms have been identified and linked to different pathologies. For some targets, the respective pharmacology is quite advanced, that is, up to late-stage clinical development or even on the market; for others, drugs are already in clinical use, although not for indications based on oxidative stress, and repurposing seems to be a viable option. Critical Issues: For all other targets, reliable preclinical validation and drug ability are key factors for any translation into the clinic. In this study, specific pharmacological agents with optimal pharmacokinetic profiles are still lacking. Moreover, these enzymes also serve largely unknown physiological functions and their inhibition may lead to unwanted side effects. Future Directions: The current promising data based on new targets, drugs, and drug repurposing are mainly a result of academic efforts. With the availability of optimized compounds and coordinated efforts from academia and industry scientists, unambiguous validation and translation into proof-of-principle studies seem achievable in the very near future, possibly leading towards a new era of redox medicine. Antioxid. Redox Signal. 23, 1113–1129. PMID:26415051

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years.

PubMed

Dos Santos, Rafael G; Osório, Flávia L; Crippa, José Alexandre S; Riba, Jordi; Zuardi, Antônio W; Hallak, Jaime E C

2016-06-01

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking.

PubMed

Nair, Sunila G; Adams-Deutsch, Tristan; Epstein, David H; Shaham, Yavin

2009-09-01

Relapse to old, unhealthy eating habits is a major problem in human dietary treatments. The mechanisms underlying this relapse are unknown. Surprisingly, until recently this clinical problem has not been systematically studied in animal models. Here, we review results from recent studies in which a reinstatement model (commonly used to study relapse to abused drugs) was employed to characterize the effect of pharmacological agents on relapse to food seeking induced by either food priming (non-contingent exposure to small amounts of food), cues previously associated with food, or injections of the pharmacological stressor yohimbine. We also address methodological issues related to the use of the reinstatement model to study relapse to food seeking, similarities and differences in mechanisms underlying reinstatement of food seeking versus drug seeking, and the degree to which the reinstatement procedure provides a suitable model for studying relapse in humans. We conclude by discussing implications for medication development and future research. We offer three tentative conclusions: (1)The neuronal mechanisms of food-priming- and cue-induced reinstatement are likely different from those of reinstatement induced by the pharmacological stressor yohimbine. (2)The neuronal mechanisms of reinstatement of food seeking are possibly different from those of ongoing food-reinforced operant responding. (3)The neuronal mechanisms underlying reinstatement of food seeking overlap to some degree with those of reinstatement of drug seeking.

Pharmacology of modality-specific transient receptor potential vanilloid-1 antagonists that do not alter body temperature.

PubMed

Reilly, Regina M; McDonald, Heath A; Puttfarcken, Pamela S; Joshi, Shailen K; Lewis, LaGeisha; Pai, Madhavi; Franklin, Pamela H; Segreti, Jason A; Neelands, Torben R; Han, Ping; Chen, Jun; Mantyh, Patrick W; Ghilardi, Joseph R; Turner, Teresa M; Voight, Eric A; Daanen, Jerome F; Schmidt, Robert G; Gomtsyan, Arthur; Kort, Michael E; Faltynek, Connie R; Kym, Philip R

2012-08-01

The transient receptor potential vanilloid-1 (TRPV1) channel is involved in the development and maintenance of pain and participates in the regulation of temperature. The channel is activated by diverse agents, including capsaicin, noxious heat (≥ 43°C), acidic pH (< 6), and endogenous lipids including N-arachidonoyl dopamine (NADA). Antagonists that block all modes of TRPV1 activation elicit hyperthermia. To identify efficacious TRPV1 antagonists that do not affect temperature antagonists representing multiple TRPV1 pharmacophores were evaluated at recombinant rat and human TRPV1 channels with Ca(2+) flux assays, and two classes of antagonists were identified based on their differential ability to inhibit acid activation. Although both classes of antagonists completely blocked capsaicin- and NADA-induced activation of TRPV1, select compounds only partially inhibited activation of the channel by protons. Electrophysiology and calcitonin gene-related peptide release studies confirmed the differential pharmacology of these antagonists at native TRPV1 channels in the rat. Comparison of the in vitro pharmacological properties of these TRPV1 antagonists with their in vivo effects on core body temperature confirms and expands earlier observations that acid-sparing TRPV1 antagonists do not significantly increase core body temperature. Although both classes of compounds elicit equivalent analgesia in a rat model of knee joint pain, the acid-sparing antagonist tested is not effective in a mouse model of bone cancer pain.

Molecular pathways involved in the early and late damage induced by testis ischemia: evidence for a rational pharmacological modulation.

PubMed

Altavilla, D; Romeo, C; Squadrito, F; Marini, H; Morgia, G; Antonuccio, P; Minutoli, L

2012-01-01

Testicular torsion or torsion of the spermatic cord is a surgical emergency in which misdiagnosis and inappropriate treatment can lead to male infertility. Events occurring during testicular torsion and detorsion are representative of an ischemia-reperfusion injury observed in other organs. The two most important factors determining testicular damage are the degree of twisting and the early onset of a surgical treatment to counter-rotate both testis and spermatic cord for inducing reperfusion. The damage from reperfusion is more severe than that induced by ischemia and several mechanisms are implicated in the development of testicular damage following torsion and detorsion. However, these mechanisms have not yet been fully clarified and, as a consequence, there is still a strong need to identify specific pharmacological treatment to limit the damage triggered by the reperfusion procedures. Ischemia and reperfusion of testis result in elevated production of reactive oxygen species (ROS), activate mitogen activated protein kinases (MAPKs) and PPARβ/δ receptor, induce transcription factors and growth factors including NF-κB and VEGF, trigger apoptotic machinery and induce several inflammatory cytokines, including TNF-α and IL-1β . This pathological cascade is responsible for the testicular atrophy, decreased blood flow and impaired spermatogenesis. Several pharmacological approaches have been characterized as promising therapeutic agents for the management of testicular torsion and may be useful to ameliorate the sequel of this disease.

Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years

PubMed Central

dos Santos, Rafael G.; Osório, Flávia L.; Crippa, José Alexandre S.; Riba, Jordi; Zuardi, Antônio W.; Hallak, Jaime E. C.

2016-01-01

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings. PMID:27354908

Chinese Herbal Medicines Attenuate Acute Pancreatitis: Pharmacological Activities and Mechanisms

PubMed Central

Xiang, Hong; Zhang, Qingkai; Qi, Bing; Tao, Xufeng; Xia, Shilin; Song, Huiyi; Qu, Jialin; Shang, Dong

2017-01-01

Acute pancreatitis (AP) is a commonly occurring gastrointestinal disorder. An increase in the annual incidence of AP has been observed, and it causes acute hospitalization and high mortality. The diagnosis and treatment guidelines for AP recommend conservative medical treatments focused on reducing pancreatic secretion and secondary injury, as a primary therapeutic approach. Unfortunately, the existing treatment options have limited impact on the incidence and severity of AP due to the complex and multifaceted pathological process of this disease. In recent decades, Chinese herbal medicines (CHMs) have been used as efficient therapeutic agents to attenuate AP in Asian countries. Despite early cell culture, animal models, and clinical trials, CHMs are capable of interacting with numerous molecular targets participating in the pathogenesis of AP; however, comprehensive, up-to-date communication in this field is not yet available. This review focuses on the pharmacological activities of CHMs against AP in vitro and in vivo and the underlying mechanisms. A computational prediction of few selected and promising plant-derived molecules (emodin, baicalin, resveratrol, curcumin, ligustrazine, and honokiol) to target numerous proteins or networks involved in AP was initially established based on a network pharmacology simulation. Moreover, we also summarized some potential toxic natural products for pancreas in order to more safe and reasonable medication. These breakthrough findings may have important implications for innovative drug research and the future development of treatments for AP. PMID:28487653

Beyond the Condom: Frontiers in Male Contraception

PubMed Central

Roth, Mara Y.; Amory, John K.

2016-01-01

Nearly half of all pregnancies worldwide are unplanned, despite numerous contraceptive options available. No new contraceptive method has been developed for men since the invention of condom. Nevertheless, more than 25% of contraception worldwide relies on male methods. Therefore, novel effective methods of male contraception are of interest. Herein we review the physiologic basis for both male hormonal and nonhormonal methods of contraception. We review the history of male hormonal contraception development, current hormonal agents in development, as well as the potential risks and benefits of male hormonal contraception options for men. Nonhormonal methods reviewed will include both pharmacological and mechanical approaches in development, with specific focus on methods which inhibit the testicular retinoic acid synthesis and action. Multiple hormonal and nonhormonal methods of male contraception are in the drug development pathway, with the hope that a reversible, reliable, safe method of male contraception will be available to couples in the not too distant future. PMID:26947703

Antimicrobial Drugs

PubMed Central

Becker, Daniel E.

2013-01-01

Antibiotics play a vital role in dental practice for managing orofacial infections. They are used to manage existing infection and they are also used as prophylaxis for certain medical conditions and surgical procedures. This article will review pharmacological and therapeutic considerations for the proper use of these agents for dental infections. PMID:24010989

Suicidality in Bipolar I Disorder

ERIC Educational Resources Information Center

Johnson, Sheri L.; McMurrich, Stephanie L.; Yates, Marisa

2005-01-01

People with bipolar disorder are at high suicide risk. The literature suggests that suicidality is predicted by higher symptom severity and less use of pharmacological agents, but few studies have examined the joint contributions of these variables. The present study examines the conjoint contribution of symptom severity and pharmacological…

Effects of Atmospheric Contaminants under Hyperbaric Conditions with Particular Reference to Vision

DTIC Science & Technology

1986-08-13

effects on consciousness. Proceedings of international symposium on submarine and space medicine. New York: MacMillan, pp. 3-18. Phil , R.O., Parkes...evaluation of pharmacological agents in hyperbaric air and helium-oxygen. In C.W. Shilling and W.M. Beckett , Underwater Physiology

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.

Post-traumatic stress disorder in children and adolescents: epidemiology, diagnosis and treatment options.

PubMed

Donnelly, Craig L; Amaya-Jackson, Lisa

2002-01-01

Post-traumatic stress disorder (PTSD) is a common psychiatric condition in childhood and adolescence. Rates vary widely depending upon the type of trauma exposure. Interpersonal traumas, such as rape or physical abuse, are more likely to result in PTSD than exposure to natural or technological disaster. Clinical presentations are exceedingly complex and children with PTSD are at increased risk of having comorbid psychiatric diagnoses. Because of its complexity and frequent occurrence with other disorders, assessment of PTSD necessitates a broad-based evaluation utilizing multiple informations and structured instruments specific to the symptoms of PTSD in youth. Cognitive-behavioral therapy (CBT) is the treatment of first choice. Pharmacological agents for PTSD treatment have received little empirical investigation in childhood. Pharmacological treatment is used to target disabling symptoms of the disorder, which limit psychotherapy or life functioning, by helping children to tolerate working through distressful material in therapy and life. Pharmacological treatment should be based on a stepwise approach utilizing broad spectrum medications such as the selective serotonin reuptake inhibitors as first-line agents. Comorbid conditions should be identified and treated with appropriate medication or psychosocial interventions. Treatment algorithms are provided to guide rational medication strategies for children and adolescents with PTSD, subsyndromal PTSD, and in PTSD that is comorbid with other psychiatric conditions of childhood. Reduction in even one debilitating symptom of PTSD can improve a child's overall functioning across multiple domains.

N-Acetyl Cysteine and Vitamin D Supplementation in Treatment Resistant Obsessive- compulsive Disorder Patients: a General Review.

PubMed

di Michele, Flavia; Siracusano, Alberto; Talamo, Alessandra; Niolu, Cinzia

2018-04-17

Obsessive-compulsive disorder (OCD) is a disabling mental illness for which pharmacological and psychosocial interventions are all too often inadequate. This demonstrates the need for more targeted therapeutics. Recent preclinical and clinical studies have implicated dysfunction of glutamatergic neurotransmission in the pathophysiology of OCD. Moreover there are studies suggesting that neuroimmune abnormalities may play an important role in the pathogenesis of OCD. N-acetyl cysteine (NAC) is a safe and readily available agent that would modify the synaptic release of glutamate in subcortical brain regions via modulation of the cysteine-glutamate antiporter. The modulation of inflammatory pathways may also play a role in the benefits seen following NAC treatment. Therefore NAC can be considered a neuroprotective agent. This paper explores the role of NAC in the treatment of OCD conditions refractory to first-line pharmacological interventions, reviewing the clinical studies published in the last decade. The possible benefit mechanisms of NAC for this disorder will be discussed, as well as the role of vitamin D supplementation, given its specific property of stimulating the formation of glutathione in the brain. Nutraceutical supplementation in treatment resistance OCD may be important not only for improving obsessive-compulsive symptomatology, but also from a psychological perspective, given its better acceptance by the patients compared to pharmacological treatment. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Marine pharmacology in 2001–2002: Marine compounds with anthelmintic, antibacterial, anticoagulant, antidiabetic, antifungal, anti-inflammatory, antimalarial, antiplatelet, antiprotozoal, antituberculosis, and antiviral activities; affecting the cardiovascular, immune and nervous systems and other miscellaneous mechanisms of action

PubMed Central

Mayer, Alejandro M.S.; Hamann, Mark T.

2016-01-01

During 2001–2002, research on the pharmacology of marine chemicals continued to be global in nature involving investigators from Argentina, Australia, Brazil, Canada, China, Denmark, France, Germany, India, Indonesia, Israel, Italy, Japan, Mexico, Netherlands, New Zealand, Pakistan, the Philippines, Russia, Singapore, Slovenia, South Africa, South Korea, Spain, Sweden, Switzerland, Thailand, United Kingdom, and the United States. This current article, a sequel to the authors’ 1998, 1999 and 2000 marine pharmacology reviews, classifies 106 marine chemicals derived from a diverse group of marine animals, algae, fungi and bacteria, on the basis of peer-reviewed preclinical pharmacology. Anthelmintic, antibacterial, anticoagulant, antifungal, antimalarial, antiplatelet, antiprotozoal, antituberculosis or antiviral activities were reported for 56 marine chemicals. An additional 19 marine compounds were shown to have significant effects on the cardiovascular, immune and nervous system as well as to possess anti-inflammatory and antidiabetic effects. Finally, 31 marine compounds were reported to act on a variety of molecular targets and thus may potentially contribute to several pharmacological classes. Thus, during 2001–2002 pharmacological research with marine chemicals continued to contribute potentially novel chemical leads for the ongoing global search for therapeutic agents for the treatment of multiple disease categories. PMID:15919242

Hyperglycemia Associated With Targeted Oncologic Treatment: Mechanisms and Management.

PubMed

Goldman, Jonathan W; Mendenhall, Melody A; Rettinger, Sarah R

2016-07-29

: Molecularly targeted cancer therapy has rapidly changed the landscape of oncologic care, often improving patients' prognosis without causing as substantial a quality-of-life decrement as cytotoxic chemotherapy does. Nevertheless, targeted agents can cause side effects that may be less familiar to medical oncologists and that require the attention and expertise of subspecialists. In this review, we focus on hyperglycemia, which can occur with use of new anticancer agents that interact with cell proliferation pathways. Key mediators of these pathways include the tyrosine kinase receptors insulin growth factor receptor 1 (IGF-1R) and epidermal growth factor receptor (EGFR), as well as intracellular signaling molecules phosphatidylinositol 3-kinase (PI3K), AKT, and mammalian target of rapamycin (mTOR). We summarize available information on hyperglycemia associated with agents that inhibit these molecules within the larger context of adverse event profiles. The highest incidence of hyperglycemia is observed with inhibition of IGF-1R or mTOR, and although the incidence is lower with PI3K, AKT, and EGFR inhibitors, hyperglycemia is still a common adverse event. Given the interrelationships between the IGF-1R and cell proliferation pathways, it is important for oncologists to understand the etiology of hyperglycemia caused by anticancer agents that target those pathways. We also discuss monitoring and management approaches for treatment-related hyperglycemia for some of these agents, with a focus on our experience during the clinical development of the EGFR inhibitor rociletinib. Treatment-related hyperglycemia is associated with several anticancer agents. Many cancer patients may also have preexisting or undiagnosed diabetes or glucose intolerance. Screening can identify patients at risk for hyperglycemia before treatment with these agents. Proper monitoring and management of symptoms, including lifestyle changes and pharmacologic intervention, may allow patients to continue benefiting from use of anticancer agents. ©AlphaMed Press.

Safety pharmacology investigations in toxicology studies: an industry survey.

PubMed

Authier, Simon; Vargas, Hugo M; Curtis, Michael J; Holbrook, Mark; Pugsley, Michael K

2013-01-01

The Safety Pharmacology (SP) Society (SPS) conducted an industry survey in 2012 in an attempt to define current industry practices as they relate to inclusion of safety pharmacology (SP) endpoints into Toxicology studies. A total of 361 participants from Asia (9.1%), Europe (19.4%) and North America (71.4%) responded to the survey. The preponderance of respondents were toxicologists (53.2%) followed by safety pharmacologists (27.2%) and scientists involved in the conduct of both disciplines (19.6%). Most participants (58.6%) were from pharmaceutical companies employing more than 500 employees. A majority (68.2%) reported having experience in designing, performing or interpreting the SP component of a study when performed as part of a toxicology study. Some participants (42.0%) had submitted data to a regulatory agency where ICHS7 studies were performed as part of a toxicology study rather than as a standalone study. When comparing species that were used in studies in which SP was added to toxicology studies, canines were the most frequently reported animals used for new chemical entities (NCE) whereas non-human (NH) primates were the most frequent for the assessment of biological agents. The most frequent primary motivator for adding ICHS7 SP endpoints to regulatory toxicology studies was to generate additional data to allow for determination of an integrated risk assessment thereby testing Confidence in Safety (CIS) to better manage and/or mitigate risk. The current ability to add safety pharmacology endpoints into regulatory toxicology studies was used to address a specific concern (by 42.1% of respondents) to allow management of risk more effectively (36.8%) or to generate data that contributes to cessation of the progression of a compound (21.1%). For an NCE, SP measurements in toxicology studies were conducted in addition to standalone SP studies (by 40.6% of respondents) or in addition/instead of standalone safety pharmacology studies (by 39.8% of respondents). For biological agents, a majority (74.3%) indicated SP measurements in toxicology were conducted instead of standalone studies as outlined in the ICHS6 guideline while inclusion of SP endpoints in toxicology studies for biological agents in addition to standalone studies was reported by only 25.7% of the respondents. The survey highlights that obtaining regulatory agreement for the proposed combined SP/Tox study designs may be useful before study conduct in some cases. Respondents suggest that such discussion could occur at the pre-IND meeting before the IND/CTA enabling program. Copyright © 2013 Elsevier Inc. All rights reserved.

Comparative pharmacodynamic analysis of imidazoline compounds using rat model of ocular mydriasis with a test of quantitative structure-activity relationships.

PubMed

Raczak-Gutknecht, Joanna; Nasal, Antoni; Frąckowiak, Teresa; Kornicka, Anita; Sączewski, Franciszek; Wawrzyniak, Renata; Kubik, Łukasz; Kaliszan, Roman

2017-09-10

Imidazol(in)e derivatives, having the chemical structure similar to clonidine, exert diverse pharmacological activities connected with their interactions with alpha2-adrenergic receptors, e.g. hypotension, bradycardia, sedation as well as antinociceptive, anxiolytic, antiarrhythmic, muscle relaxant and mydriatic effects. The mechanism of pupillary dilation observed after systemic administration of imidazol(in)es to rats, mice and cats depends on the stimulation of postsynaptic alpha2-adrenoceptors within the brain. It was proved that the central nervous system (CNS)-localized I1-imidazoline receptors are not engaged in those effects. It appeared interesting to analyze the CNS-mediated pharmacodynamics of imidazole(in)e agents in terms of their chromatographic and calculation chemistry-derived parameters. In the present study a systematic determination and comparative pharmacometric analysis of mydriatic effects in rats were performed on a series of 20 imidazol(in)e agents, composed of the well-known drugs and of the substances used in experimental pharmacology. The eye pupil dilatory activities of the compounds were assessed in anesthetized Wistar rats according to the established Koss method. Among twenty imidazol(in)e derivatives studied, 18 produced diverse dose-dependent mydriatic effects. In the quantitative structure-activity relationships (QSAR) analysis, the pharmacological data (half maximum mydriatic effect - ED 50 in μmol/kg) were considered along with the structural parameters of the agents from molecular modeling. The theoretically calculated lipophilicity parameters, CLOGP, of imidazol(in)es, as well as their lipophilicity parameters from HPLC, logk w , were also considered. The attempts to derive statistically significant QSAR equations for a full series of the agents under study were unsuccessful. However, for a subgroup of eight apparently structurally related imidazol(in)es a significant relationship between log(1/ED 50 ) and logk w values was obtained. The lack of "predictive" QSAR for the whole series of the structurally diverse agents is probably due to a complex mechanism of the ligand-alpha2-adrenergic receptor interactions, which are predominantly of a highly structurally specific polar nature. Such interactions are difficult to quantify with the established chemical structural descriptors, contrary to the less specific, molecular bulkiness-related interactions. Copyright © 2017 Elsevier B.V. All rights reserved.

Nanobiology for the pharmacology of cellular ion channels.

PubMed

Kabanov, Alexander V; Kirpichnikov, Mikhail P; Khokhlov, Alexey R

2009-03-01

Writing this editorial is especially pleasing. First, it provides us an opportunity to introduce new directives to the field of Neuroimmune Pharmacology and to explain why the field of nanomedicine is likely an important part of its future growth and development. Second, it is an opportunity to showcase research in this area currently operative in Russia that may not be readily accessible to the readership. Third, it is a platform to better explain why the Journal Editorial leadership was enthusiastic about the science and its relationship to the Society on NeuroImmune Pharmacology strategic goals. All are brought to bear in this issue of the Journal of Neuroimmune Pharmacology. The issue includes articles presented at a recent joint US-Russian workshop entitled, "Health in the 21st Century: Nanomedicine and Self-Organization of Biological Systems" held at M.V. Lomonosov Moscow State University (MSU), Moscow, Russia, December 10-11, 2007. The conjoint meeting was organized through the Departments of Biology, Chemistry, and Physics, MSU and by the Center for Drug Delivery and Nanomedicine and Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center (Omaha, NE). The speakers included established internationally regarded scientists from these institutions as well as graduate students and faculties at MSU. In addition to selected papers by workshop contributors, we have included several papers closely aligned to the theme of nanomedicine and nanopharmacology of the central nervous system in order to provide a biological anchor for this research. We understand that such works are new to many but hope that its organization and interdisciplinary approaches will appeal to this audience. All together, it is our hope that, by gathering basic and clinical scientists with the common interest of using nanotechnology in the delivery of therapeutic agents with a focus on nanopharmacology and complex supramolecular biological assembly, the papers included will provide a platform for thought, discussion, and future translational research.

Neuropharmacological Manipulation of Restrained and Free-flying Honey Bees, Apis mellifera.

PubMed

Søvik, Eirik; Plath, Jenny A; Devaud, Jean-Marc; Barron, Andrew B

2016-11-26

Honey bees demonstrate astonishing learning abilities and advanced social behavior and communication. In addition, their brain is small, easy to visualize and to study. Therefore, bees have long been a favored model amongst neurobiologists and neuroethologists for studying the neural basis of social and natural behavior. It is important, however, that the experimental techniques used to study bees do not interfere with the behaviors being studied. Because of this, it has been necessary to develop a range of techniques for pharmacological manipulation of honey bees. In this paper we demonstrate methods for treating restrained or free-flying honey bees with a wide range of pharmacological agents. These include both noninvasive methods such as oral and topical treatments, as well as more invasive methods that allow for precise drug delivery in either systemic or localized fashion. Finally, we discuss the advantages and disadvantages of each method and describe common hurdles and how to best overcome them. We conclude with a discussion on the importance of adapting the experimental method to the biological questions rather than the other way around.

The Potential Therapeutic Effects of Artesunate on Stroke and Other Central Nervous System Diseases

PubMed Central

Zuo, Shilun; Li, Qiang; Liu, Xin

2016-01-01

Artesunate is an important agent for cerebral malaria and all kinds of other severe malaria because it is highly efficient, lowly toxic, and well-tolerated. Loads of research pointed out that it had widespread pharmacological activities such as antiparasites, antitumor, anti-inflammation, antimicrobes activities. As we know, the occurrence and development of neurological disorders usually refer to intricate pathophysiologic mechanisms and multiple etiopathogenesis. Recent progress has also demonstrated that drugs with single mechanism and serious side-effects are not likely the candidates for treatment of the neurological disorders. Therefore, the pluripotent action of artesunate may result in it playing an important role in the prevention and treatment of these neurological disorders. This review provides an overview of primary pharmacological mechanism of artesunate and its potential therapeutic effects on neurological disorders. Meanwhile, we also briefly summarize the primary mechanisms of artemisinin and its derivatives. We hope that, with the evidence presented in this review, the effect of artesunate in prevention and curing for neurological disorders can be further explored and studied in the foreseeable future. PMID:28116289

The Effect of the Prosthetic Group on the Pharmacologic Properties of 18F-labeled Rhodamine B, a Potential Myocardial Perfusion Agent for PET

PubMed Central

Bartholomä, Mark D.; Gottumukkala, Vijay; Zhang, Shaohui; Baker, Amanda; Dunning, Patricia; Fahey, Frederic H.; Treves, S. Ted; Packard, Alan B.

2013-01-01

We recently reported the development of the 2-[18F]fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [18F]fluoroethyl prosthetic group, has significant uptake in the myocardium in rats, but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared 18F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of 18F-labeled compounds. They also support the value of continued investigation of 18F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging. PMID:23210516

Effect of the prosthetic group on the pharmacologic properties of 18F-labeled rhodamine B, a potential myocardial perfusion agent for positron emission tomography (PET).

PubMed

Bartholomä, Mark D; Gottumukkala, Vijay; Zhang, Shaohui; Baker, Amanda; Dunning, Patricia; Fahey, Frederic H; Treves, S Ted; Packard, Alan B

2012-12-27

We recently reported the development of the 2-[(18)F]fluoroethyl ester of rhodamine B as a potential positron emission tomography (PET) tracer for myocardial perfusion imaging. This compound, which was prepared using a [(18)F]fluoroethyl prosthetic group, has significant uptake in the myocardium in rats but also demonstrates relatively high liver uptake and is rapidly hydrolyzed in vivo in mice. We have now prepared (18)F-labeled rhodamine B using three additional prosthetic groups (propyl, diethylene glycol, and triethylene glycol) and found that the prosthetic group has a significant effect on the in vitro and in vivo properties of these compounds. Of the esters prepared to date, the diethylene glycol ester is superior in terms of in vitro stability and pharmacokinetics. These observations suggest that the prosthetic group plays a significant role in determining the pharmacological properties of (18)F-labeled compounds. They also support the value of continued investigation of (18)F-labeled rhodamines as PET radiopharmaceuticals for myocardial perfusion imaging.

The male genital tract is not a pharmacological sanctuary from efavirenz.

PubMed

Avery, L B; Bakshi, R P; Cao, Y J; Hendrix, C W

2011-07-01

Many antiretroviral (ARV) drugs have large blood plasma-to-seminal plasma (BP/SP) concentration ratios. Concern exists that these drugs do not adequately penetrate the male genital tract (MGT), resulting in the MGT becoming a "pharmacological sanctuary" from these agents, with ineffective MGT concentrations despite effective blood concentrations. Efavirenz (EFV) is the most highly protein-bound ARV drug, with >99% binding in blood plasma and the largest BP/SP total EFV concentration ratio, reportedly ranging from 11 to 33. To evaluate protein binding as an explanation for the differences between the drug concentrations in blood and semen, we developed a novel ultrafiltration method, corrected for the duration of centrifugation, to measure protein binding in the two matrices. In six subjects, protein-free EFV concentrations were the same in blood and semen; the median (interquartile range (IQR)) protein-free EFV SP/BP ratio was 1.21 (0.99-1.35); EFV protein binding was 99.82% (99.79-99.86) in BP and 95.26% (93.24-96.67) in SP. This shows that the MGT is not a sanctuary from EFV.

Sleep and its disorders in translational medicine.

PubMed

Paterson, Louise M; Nutt, David J; Wilson, Sue J

2011-09-01

The study of sleep is a useful approach to studying the brain in psychiatric disorders and in investigating the effects of psychotropic drugs. Sleep physiology lends itself well to pharmacological and physiological manipulation, as it has the advantage of a functional output, the electroencephalograph, which is common to all mammals, and can be measured in freely moving (or naturally sleeping) animals under controlled laboratory conditions or in a naturalistic home environment. The complexity of sleep architecture varies between species but all share features which are comparable. In addition, sleep architecture is sensitive to changes in brain neurotransmitters such as serotonin, so cross-species sleep measurement can be combined with pharmacological manipulation to investigate the receptor mechanisms controlling sleep-wake regulation and sleep architecture in response to known and novel agents. Translational approaches such as these have improved our understanding of sleep circuitry and facilitated the development of new treatments for sleep disorders, particularly insomnia. This review provides examples of how research findings within the sleep field have been translated between animal models, healthy volunteers and patient populations with particular focus on the serotonergic system.

Integrating psychopharmacology and cognitive remediation to treat cognitive dysfunction in the psychotic disorders.

PubMed

Medalia, Alice; Opler, Lewis A; Saperstein, Alice M

2014-04-01

Cognitive deficits are a prominent and enduring aspect of schizophrenia, which pose a significant barrier to achieving functional goals. The most promising intervention for treating cognitive impairment is cognitive remediation (CR), a behaviorally based therapy associated with medium effect sizes for cognitive and functional outcomes. However, there is a sizeable group of nonresponders whose CR outcomes become limited when the therapeutic approach fails to address individual differences in baseline cognition, motivation variables, and the extent to which CR offers opportunities for generalization. This speaks to a need to develop cognitive interventions that are both personalized and scalable. Emerging data suggest that specific pharmacological agents have the potential to enhance and accelerate behaviorally based CR effects. This article will review the rationale and preliminary evidence to support combining CR and pharmacotherapy. We will review crucial aspects of cognitive interventions that offer the most promise for improving not only cognitive outcomes, but also for enhancing improvement in real-world functioning. Finally, we will address methodological issues to be considered for future research on combined pharmacological and CR interventions.

Pharmacokinetics of drugs in pregnancy.

PubMed

Feghali, Maisa; Venkataramanan, Raman; Caritis, Steve

2015-11-01

Pregnancy is a complex state where changes in maternal physiology have evolved to favor the development and growth of the placenta and the fetus. These adaptations may affect preexisting disease or result in pregnancy-specific disorders. Similarly, variations in physiology may alter the pharmacokinetics or pharmacodynamics that determines drug dosing and effect. It follows that detailed pharmacologic information is required to adjust therapeutic treatment strategies during pregnancy. Understanding both pregnancy physiology and the gestation-specific pharmacology of different agents is necessary to achieve effective treatment and limit maternal and fetal risk. Unfortunately, most drug studies have excluded pregnant women based on often-mistaken concerns regarding fetal risk. Furthermore, over two-thirds of women receive prescription drugs while pregnant, with treatment and dosing strategies based on data from healthy male volunteers and non-pregnant women, and with little adjustment for the complex physiology of pregnancy and its unique disease states. This review will describe basic concepts in pharmacokinetics and their clinical relevance and highlight the variations in pregnancy that may impact the pharmacokinetic properties of medications. Copyright © 2015 Elsevier Inc. All rights reserved.

Evolving therapies for the management of chronic and acute decompensated heart failure.

PubMed

Cook, Jennifer C; Tran, Richard H; Patterson, J Herbert; Rodgers, Jo E

2016-11-01

The pharmacology, clinical efficacy, and safety profiles of evolving therapies for the management of chronic heart failure (HF) and acute decompensated heart failure (ADHF) are described. HF confers a significant financial burden despite the widespread use of traditional guideline-directed medical therapies such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, β-blockers, and aldosterone receptor antagonists, and the rates of HF-related mortality and hospitalization have remained unacceptably high. In response to a demand for novel pharmacologic agents, several therapeutic compounds have recently gained approval or are currently under review by the Food and Drug Administration. Sacubitril-valsartan has demonstrated benefit in reducing cardiovascular mortality and HF-related hospitalizations in clinical trials, while ivabradine and ferric carboxymaltose have proven efficacious in reducing HF-related hospitalizations. Lastly, the role of serelaxin in ADHF is currently under investigation in an ongoing Phase III study. While large, outcome-driven clinical trials are fundamental in informing the clinical application of these therapeutic agents, careful patient selection is imperative to ensuring similar outcomes postmarketing. In addition, optimization of current guideline-directed medical therapy remains essential as new therapies emerge and are incorporated into guideline recommendations. Additional therapeutic agents currently undergoing investigation include bucindolol hydrochloride, cimaglermin alfa, nitroxyl, omecamtiv mecarbil, TRV027, and ularitide. Clinical practitioners should remain abreast of emerging literature so that new therapeutic entities are optimally applied and positive patient outcomes are achieved. Recently introduced agents for the treatment of patients with HF include sacubitril-valsartan, ivabradine, and ferric carboxymaltose. Additional agents worthy of attention include serelaxin and other therapies currently under investigation. Copyright © 2016 by the American Society of Health-System Pharmacists, Inc. All rights reserved.

Development of Nano-Liposomal Formulations of Epidermal Growth Factor Receptor Inhibitors and their Pharmacological Interactions on Drug-Sensitive and Drug-Resistant Cancer Cell Lines

NASA Astrophysics Data System (ADS)

Trummer, Brian J.

A rapidly expanding understanding of molecular derangements in cancer cell function has led to the development of selective, targeted chemotherapeutic agents. Growth factor signal transduction networks are frequently activated in an aberrant fashion, particularly through the activity of receptor tyrosine kinases (RTK). This has spurred an intensive effort to develop receptor tyrosine kinase inhibitors (RTKI) that are targeted to specific receptors, or receptor subfamilies. Chapter 1 reviews the pharmacology, preclinical, and clinical aspects of RTKIs that target the epidermal growth factor receptor (EGFR). EGFR inhibitors demonstrate significant success at inhibiting phosphorylation-based signaling pathways that promote cancer cell proliferation. Additionally RTKIs have physicochemical and structural characteristics that enable them to function as inhibitors of multi-drug resistance transport proteins. Thus EGFR inhibitors and other RTKIs have both on-target and off-target activities that could be beneficial in cancer therapy. However, these agents exert a number of side effects, some of which arise from their hydrophobic nature and large in vivo volume of distribution. Side effects of the EGFR inhibitor gefitinib include skin rash, severe myelotoxicity when combined with certain chemotherapeutic agents, and impairment of the blood brain barrier to xenobiotics. Weighing the preclinical and clinical observations with the EGFR inhibitors, we developed the primary overall hypothesis of this research: that drug-carrier formulations of RTKIs such as the EGFR inhibitors could be developed based on nanoparticulate liposomal carriers. Theoretically, this carrier strategy would ameliorate toxicity and improve the biodistribution and tumor selectivity of these agents. We hypothesized specifically that liposomal formulations could shift the biodistribution of EGFR inhibitors such as gefitinib away from skin, bone marrow, and the blood brain barrier, and toward solid tumors, due to leaky tumor vasculature and the resulting Enhanced Permeability and Retention (EPR) phenomenon. In Chapter 2 we report that both gefitinib and the structurally similar EGFR inhibitor erlotinib display environment-dependent fluorescence properties. Peak excitation was 345 nm, and the emission peak ranged from 365 to 476 nm, depending upon the polarity of the environment and physical state of the drug. The fluorescence was negligible in aqueous solution, but intense in organic solvents or membrane bilayers. The environment-sensitive fluorescence properties of these drugs enabled rapid evaluation of numerous parameters affecting liposomal drug incorporation and performance. Up to 4-6 mol% of gefitinib could be incorporated in the liposome bilayer, based upon hydrophobic interactions with membrane bilayers. In contrast, 40-60 mol% could be loaded into the aqueous core of pre-formed liposomes at high efficiency, using a remote loading procedure. A stable formulation consisting of distearoylphosphatidylcholine: polyethylene glycol-distereoylphosphatidylethanolamine: cholesterol (DSPC:PEGDSPE:Chol, 9:1:5 mol:mol:mol) and containing drug at 50-60 mol% gefitinib (L-GEF) showed minimal leakage in serum-containing medium over 24 h at 37°C, which should be sufficient to improve biodistribution in vivo. Chapter 3 investigated the pharmacological activity of liposome-encapsulated gefitinib, alone and in combination with several prevalent anticancer agents. Experiments with MCF7 breast cancer cell lines demonstrated that liposome encapsulated gefitinib formulation (L-GEF) had a 2-fold higher IC50 (concentration of drug resulting in half-maximal growth inhibition) than free gefitinib. Lower in vitro potency would be consistent with delayed drug release from the carrier. Therapeutic effects were investigated in combination with the cytotoxic agents paclitaxel and doxorubicin. The drug-resistant MCF7R cell line was 23-fold more resistant to paclitaxel than the parental, drug-sensitive MCF7S cell line, and MCF7R was 12-fold more resistant than MCF7S to doxorubicin. A concentration of 3 muM gefitinib, which had no discernible effect upon MCF7R cell proliferation, reduced resistance to paclitaxel to 6-fold, relative to the parental MCF7S cell line, and reduced resistance to doxorubicin to 8-fold, compared to MCF7S. The cytostatic effect of a wider range of gefitinib:paclitaxel ratios was evaluated in order to permit quantitative analysis of the mechanisms of drug interaction, using response surface models. LGEF in combination with paclitaxel was found to be synergistic in MCF7R multidrug-resistant cells, with a psi value of 0.29. Free GEF combined with paclitaxel was also synergistic, with a psi value of 0.40. The confidence intervals for both psi values were below 1, indicating statistical significance for synergy. The fluorescence of gefitinib and doxorubicin permitted visualization of cellular uptake and intracellular distribution of these drugs in multicellular spheroids of rat 9L gliosarcoma cells, which recapitulate some of the barrier functions to drug distribution within tumors. Gefitinib altered the intracellular distribution of doxorubicin, and overcame the nuclear exclusion of doxorubicin in these drug-resistant cells. Chapter 4 discusses the significance of the findings relating both to the formulations produced and to their pharmacology, and concludes that nanoparticulate formulations of gefitinib have the properties necessary to alter drug biodistribution and pharmacokinetics. Such formulations have the potential to provide an effective means to enhance EGFR-inhibitor efficacy in combination chemotherapy.

Pharmacology in space. Part 1. Influence of adaptive changes on pharmacokinetics

NASA Technical Reports Server (NTRS)

Lathers, C. M.; Charles, J. B.; Bungo, M. W.

1989-01-01

The topic of pharmacology in space, i.e. the administration of drugs during space flight and the subsequent pharmacokinetic handling of the pharmaceuticals, is a new field about which little is known. In a two-part series, Claire Lathers and colleagues highlight some of the current questions in this field. In this first article the physiological and biochemical changes associated with weightlessness in space are discussed. These changes induce adaptive alterations which may influence the pharmacokinetic properties of drugs. The cardiovascular system is of particular relevance here. Also discussed are the classes of pharmacological agent that are most likely to be used during space flight for medical problems and thus, by necessity, will become drugs to be examined in space to determine whether their pharmacokinetic and pharmacodynamic properties are altered. Therapy of the most common spaceflight ailment-motion sickness-will be considered next month in Part 2.

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.

Ginsenosides from American ginseng: Chemical and pharmacological diversity

PubMed Central

Qi, Lian-Wen; Wang, Chong-Zhi; Yuan, Chun-Su

2011-01-01

Ginseng occupies a prominent position in the list of best-selling natural products in the world. Compared to the long history of use and widespread research on Asian ginseng, the study of American ginseng is relatively limited. In the past decade, some promising advances have been achieved in understanding the chemistry, pharmacology and structure-function relationship of American ginseng. To date, there is no systematic review of American ginseng. In this review, we present the different structures of the ginsenosides in American ginseng, including naturally occurring compounds and those resulting from steaming or biotransformation. Preclinical and clinical studies published in the past decade will also be discussed. We highlight the chemical and pharmacological diversity and potential structural-activity relationship of ginsenosides. Our hope is that this article is a useful reference to chemists and biologists researching American ginseng, and will open the door to novel agents in drug discovery. PMID:21396670

21 CFR 349.3 - Definitions.

Code of Federal Regulations, 2010 CFR

2010-04-01

... § 200.50, to be applied to the eyelid or instilled in the eye. (b) Astringent. A locally acting pharmacologic agent which, by precipitating protein, helps to clear mucus from the outer surface of the eye. (c..., usually a water-soluble polymer, which is applied topically to the eye to protect and lubricate mucous...

21 CFR 349.3 - Definitions.

Code of Federal Regulations, 2011 CFR

2011-04-01

... § 200.50, to be applied to the eyelid or instilled in the eye. (b) Astringent. A locally acting pharmacologic agent which, by precipitating protein, helps to clear mucus from the outer surface of the eye. (c..., usually a water-soluble polymer, which is applied topically to the eye to protect and lubricate mucous...

Maintenance pharmacological immunosuppressive strategies in renal transplantation.

PubMed Central

Vella, J. P.; Sayegh, M. H.

1997-01-01

Current maintenance immunosuppressive regimens for transplantation are based on three classes of drugs: corticosteroids, immunophilin-binding agents (eg, cyclosporin and tacrolimus), and antimetabolites (eg, azathioprine and mycophenolate). Drugs from the various classes inhibit the immune system at different points and are thus synergistic when used in combination. PMID:9338020

The Use of Adenosine Agonists to Treat Nerve Agent-Induced Seizure and Neuropathology

DTIC Science & Technology

2016-09-01

Status epilepticus may be caused by loss of adenosine anticonvulsant mechanisms. Neuroscience. 58: 245-261. 37. Bueters, T. J., et al. 2002...Pharmacology. 113: 1386-1390. 57. Niquet, J., et al. 2015. Neuroprotective effects of deep hypothermia in refractory status epilepticus . Annals of

Pharmacological Approaches to Performance Enhancement in Animals,

DTIC Science & Technology

found to improve performance disrupted by exposure to hypoxia. These substances included piracetam , nimodipine, and ipsapirone. An additional...their low toxicity , and their lack of negative effects on normal cognitive performance, it is suggested that these drugs could prove to be useful therapeutic agents under conditions of high information processing load.

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology–Friends of Cancer Research HIV Working Group

PubMed Central

Uldrick, Thomas S.; Ison, Gwynn; Rudek, Michelle A.; Noy, Ariela; Schwartz, Karl; Bruinooge, Suanna; Schenkel, Caroline; Miller, Barry; Dunleavy, Kieron; Wang, Judy; Zeldis, Jerome; Little, Richard F.

2018-01-01

Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute–sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute–sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need. PMID:28968173

Modernizing Clinical Trial Eligibility Criteria: Recommendations of the American Society of Clinical Oncology-Friends of Cancer Research HIV Working Group.

PubMed

Uldrick, Thomas S; Ison, Gwynn; Rudek, Michelle A; Noy, Ariela; Schwartz, Karl; Bruinooge, Suanna; Schenkel, Caroline; Miller, Barry; Dunleavy, Kieron; Wang, Judy; Zeldis, Jerome; Little, Richard F

2017-11-20

Purpose People with HIV are living longer as a result of effective antiretroviral therapy. Cancer has become a leading cause of morbidity and mortality in this patient population. However, studies of novel cancer therapeutics have historically excluded patients with HIV. Critical review of eligibility criteria related to HIV is required to accelerate development of and access to effective therapeutics for HIV-infected patients with cancer and make studies more generalizable to this patient population. Methods From January through April 2016, the HIV Working Group conducted a series of teleconferences; a review of 46 New Drug Applications from registration studies of unique agents studied in adults with cancer that led to the initial US Food and Drug Administration approval of that agent from 2011 to 2015; and a review of HIV-related eligibility criteria from National Cancer Institute-sponsored studies. Results were discussed and refined at a multistakeholder workshop held May 12, 2016. The HIV Working Group developed recommendations for eligibility criteria that focus on pharmacologic and immunologic considerations in this patient population and that balance patient safety, access to appropriate investigational agents, and study integrity. Results Exclusion of patients with HIV remains common in most studies of novel cancer agents. Models for HIV-related eligibility criteria in National Cancer Institute-sponsored studies are instructive. HIV infection itself should no longer be an exclusion criterion for most studies. Eligibility criteria related to HIV infection that address concurrent antiretroviral therapy and immune status should be designed in a manner that is appropriate for a given cancer. Conclusion Expanding clinical trial eligibility to be more inclusive of patients with HIV is justified in most cases and may accelerate the development of effective therapies in this area of unmet clinical need.

Prophylactic Measures During Induction for Acute Myeloid Leukemia.

PubMed

McCarthy, Matthew W; Walsh, Thomas J

2017-03-01

Improved management of infectious complications of acute myeloid leukemia (AML) has contributed substantially to the success of care over the past half century. An important approach to reducing infectious complications during the induction period of chemotherapy involves the use of prophylactic antibacterial, antiviral, and antifungal agents targeting likely pathogens. There is not a one-size-fits-all approach to prophylaxis; every patient undergoing induction therapy should be evaluated individually and within the context of local microbiologic epidemiology and host risk factors. Pharmacologic and non-pharmacologic interventions as well as novel diagnostic platforms can help mitigate the risk of life-threatening infection in patients with AML who undergo induction chemotherapy.

Lasers and light sources for rosacea.

PubMed

Goldberg, David J

2005-03-01

Pharmacologic agents remain the mainstay for initial and maintenance treatment of rosacea. However, monochromatic (i.e., laser) and polychromatic light-based therapies are increasingly being used for the treatment of certain signs of rosacea. Despite the increased use of lasers and other light-based therapies, few well-controlled studies have been conducted on their use for the treatment of rosacea. The studies that do exist suggest that these modalities have value in treating erythematotelangiectatic rosacea, including persistent erythema and phymatous rosacea. Light-based therapies should be strongly considered in cases of serious erythema, flushing, and telangiectasia because these signs are not optimally addressed by pharmacologic interventions.

Metastatic melanoma - a review of current and future drugs.

PubMed

Velho, Tiago Rodrigues

2012-11-19

Melanoma is one of the most aggressive cancers, and it is estimated that 76,250 men and women will be diagnosed with melanoma of the skin in the USA in 2012. Over the last few decades many drugs have been developed but only in 2011 have new drugs demonstrated an impact on survival in metastatic melanoma. A systematic search of literature was conducted, and studies providing data on the effectiveness of current and/or future drugs used in the treatment of metastatic melanoma were selected for review. This review discusses the advantages and limitations of these agents, evaluating past, current and future clinical trials designed to overcome such limitations. To date, there are four drugs approved by the Food and Drug Administration for melanoma (dacarbazine, interleukin-2, ipilimumab and vemurafenib). Despite efforts to develop new drugs, few of them have demonstrated any clinical benefits. Approved in 1975, dacarbazine remains the gold standard in chemotherapy, although ipilimumab and vemurafenib have raised many hopes in the last few years. Combining dacarbazine or other chemotherapy agents with new pharmacological agents may be a new way to achieve better clinical responses in patients with metastatic melanoma. Advances in the molecular knowledge of melanoma have led to major improvements in the treatment of patients with metastatic melanoma, providing new targets and insights. However, heterogeneity amongst study populations, different approaches to treatment and the different melanoma types and localisations included in the trials makes their comparison difficult. New studies focusing on drugs developed in recent decades are warranted.

The therapeutic journey of benzimidazoles: a review.

PubMed

Bansal, Yogita; Silakari, Om

2012-11-01

Presence of benzimidazole nucleus in numerous categories of therapeutic agents such as antimicrobials, antivirals, antiparasites, anticancer, anti-inflammatory, antioxidants, proton pump inhibitors, antihypertensives, anticoagulants, immunomodulators, hormone modulators, CNS stimulants as well as depressants, lipid level modulators, antidiabetics, etc. has made it an indispensable anchor for development of new therapeutic agents. Varied substitutents around the benzimidazole nucleus have provided a wide spectrum of biological activities. Importance of this nucleus in some activities like, Angiotensin I (AT(1)) receptor antagonism and proton-pump inhibition is reviewed separately in literature. Even some very short reviews on biological importance of this nucleus are also known in literature. However, owing to fast development of new drugs possessing benzimidazole nucleus many research reports are generated in short span of time. So, there is a need to couple the latest information with the earlier information to understand the current status of benzimidazole nucleus in medicinal chemistry research. In the present review, various derivatives of benzimidazole with different pharmacological activities are described on the basis of substitution pattern around the nucleus with an aim to help medicinal chemists for developing an SAR on benzimidazole derived compounds for each activity. This discussion will further help in the development of novel benzimidazole compounds. Copyright © 2012 Elsevier Ltd. All rights reserved.

Managing Agitation Associated with Schizophrenia and Bipolar Disorder in the Emergency Setting.

PubMed

Zeller, Scott L; Citrome, Leslie

2016-03-01

Patient agitation represents a significant challenge in the emergency department (ED), a setting in which medical staff are working under pressure dealing with a diverse range of medical emergencies. The potential for escalation into aggressive behavior, putting patients, staff, and others at risk, makes it imperative to address agitated behavior rapidly and efficiently. Time constraints and limited access to specialist psychiatric support have in the past led to the strategy of "restrain and sedate," which was believed to represent the optimal approach; however, it is increasingly recognized that more patient-centered approaches result in improved outcomes. The objective of this review is to raise awareness of best practices for the management of agitation in the ED and to consider the role of new pharmacologic interventions in this setting. The Best practices in Evaluation and Treatment of Agitation (BETA) guidelines address the complete management of agitation, including triage, diagnosis, interpersonal calming skills, and medicine choices. Since their publication in 2012, there have been further developments in pharmacologic approaches for dealing with agitation, including both new agents and new modes of delivery, which increase the options available for both patients and physicians. Newer modes of delivery that could be useful in rapidly managing agitation include inhaled, buccal/sublingual and intranasal formulations. To date, the only formulation administered via a non-intramuscular route with a specific indication for agitation associated with bipolar or schizophrenia is inhaled loxapine. Non-invasive formulations, although requiring cooperation from patients, have the potential to improve overall patient experience, thereby improving future cooperation between patients and healthcare providers. Management of agitation in the ED should encompass a patient-centered approach, incorporating non-pharmacologic approaches if feasible. Where pharmacologic intervention is necessary, a cooperative approach using non-invasive medications should be employed where possible.

Enhancing value of clinical pharmacodynamics in oncology drug development: An alliance between quantitative pharmacology and translational science.

PubMed

Venkatakrishnan, K; Ecsedy, J A

2017-01-01

Clinical pharmacodynamic evaluation is a key component of the "pharmacologic audit trail" in oncology drug development. We posit that its value can and should be greatly enhanced via application of a robust quantitative pharmacology framework informed by biologically mechanistic considerations. Herein, we illustrate examples of intersectional blindspots across the disciplines of quantitative pharmacology and translational science and offer a roadmap aimed at enhancing the caliber of clinical pharmacodynamic research in the development of oncology therapeutics. © 2016 American Society for Clinical Pharmacology and Therapeutics.

Matrix metalloproteinase inhibitors as anticancer agents.

PubMed

Konstantinopoulos, Panagiotis A; Karamouzis, Michalis V; Papatsoris, Athanasios G; Papavassiliou, Athanasios G

2008-01-01

The important role of matrix metalloproteinases (MMPs) in the process of carcinogenesis is well established. However, despite very promising activity in a plethora of preclinical models, MMP inhibitors (MMPIs) failed to demonstrate a statistically significant survival advantage in advanced stage clinical trials in most human malignancies. Herein, we review the implication of MMPs in carcinogenesis, outline the pharmacology and current status of various MMPIs as anticancer agents and discuss the etiologies for the discrepancy between their preclinical and clinical evaluation. Finally, strategies for effective incorporation of MMPIs in current anticancer therapies are proposed.

Evaluation of Pharmacologic Agents to Suppress Intraocular Cellular Proliferation Following Trauma

DTIC Science & Technology

1986-07-01

Tracttonal Detachment* aniawl op uVeitis agent-- -- 1 (1-4) or control 1 wk 2 wk 4 wk 6 wk 12 wk Gross Lama* Imadi to Injaetica or drug 61 1 D S L C R F...BIBLIOGRAPHY 1. Mimura Y: The effect of colchicine treatment on ocular lesions in Behcet’s disease. Ophthalmol Jpn 26:902-908, 1985. 2. Brown W O... Treatment of intraocular proliferation with intravitreal injection of triamcinolone acetonide. Am J Ophthalmol 90:810, 1980. 9. Trese MT, Spitznas M

Phytochemicals and the breakthrough of traditional herbs in the management of sexual dysfunctions.

PubMed

Adimoelja, A

2000-01-01

Traditional herbs have been a revolutionary breakthrough in the management of erectile dysfunction and have become known world-wide as an 'instant' treatment. The modern view of the management of erectile dysfunction subscribes to a single etiology, i.e. the mechanism of erection. A large number of pharmacological agents are orally consumed and vasoactive agents inserted intraurethrally or injected intrapenially to regain good erection. Modern phytochemicals have developed from traditional herbs. Phytochemicals focus their mechanism of healing action to the root cause, i.e. the inability to control the proper function of the whole body system. Hence phytochemicals manage erectile dysfunction in the frame of sexual dysfunction as a whole entity. Protodioscin is a phytochemical agent derived from Tribulus terrestris L plant, which has been clinically proven to improve sexual desire and enhance erection via the conversion of protodioscine to DHEA (De-Hydro-Epi-Androsterone). Preliminary observations suggest that Tribulus terrestris L grown on different soils does not consistently produce the active component Protodioscin. Further photochemical studies of many other herbal plants are needed to explain the inconsistent results found with other herbal plants, such as in diversities of Ginseng, Eurycoma longifolia, Pimpinella pruacen, Muara puama, Ginkgo biloba, Yohimbe etc.

Chemotherapy- and radiotherapy-induced oral mucositis: review of preventive strategies and treatment.

PubMed

Saadeh, Claire E

2005-04-01

Oral mucositis is a frequently encountered and potentially severe complication associated with administration of chemotherapy and radiotherapy. Although many pharmacologic interventions have been used for the prevention and treatment of oral mucositis, there is not one universally accepted strategy for its management. Most preventive and treatment strategies are based on limited, often anecdotal, clinical data. Basic oral hygiene and comprehensive patient education are important components of care for any patient with cancer at risk for development of oral mucositis. Nonpharmacologic approaches for the prevention of oral mucositis include oral cryotherapy for patients receiving chemotherapy with bolus 5-fluorouracil, and low-level laser therapy for patients undergoing hematopoietic stem cell transplantation. Chlorhexidine, amifostine, hematologic growth factors, pentoxifylline, glutamine, and several other agents have all been investigated for prevention of oral mucositis. Results have been conflicting, inconclusive, or of limited benefit. Treatment of established mucositis remains a challenge and focuses on a palliative management approach. Topical anesthetics, mixtures (also called cocktails), and mucosal coating agents have been used despite the lack of experimental evidence supporting their efficacy. Investigational agents are targeting the specific mechanisms of mucosal injury; among the most promising of these is recombinant human keratinocyte growth factor.

Automated processing of human bone marrow can result in a population of mononuclear cells capable of achieving engraftment following transplantation.

PubMed

Areman, E M; Cullis, H; Spitzer, T; Sacher, R A

1991-10-01

A concentrate of mononuclear bone marrow cells is often desired for ex vivo treatment with pharmacologic agents, monoclonal antibodies, cytokines, and other agents prior to transplantation. A method has been developed for automated separation of mononuclear cells from large volumes of harvested bone marrow. A programmable instrument originally designed for clinical ex vivo cell separation and the plasma-pheresis of patients and blood donors was adapted to permit rapid preparation, in a closed sterile system, of a bone marrow product enriched with mononuclear cells. A mean (+/- SEM) of 53 +/- 30 percent of the original mononuclear cells was recovered in a volume of 125 +/- 42 mL containing 82 +/- 12 percent mononuclear cells. This technique removed 95 +/- 9 percent of the red cells in the original marrow. No density gradient materials or sedimenting agents were employed in this process. Of 36 marrows processed by this technique, 19 autologous (6 of which were purged with 4-hydroperoxycyclophosphamide) and 7 allogeneic marrows have been transplanted, with all evaluable patients achieving a neutrophil count of 0.5 x 10(9) per L in a mean (+/- SEM) of 21 +/- 6 days.

Monitoring of Nonsteroidal Immunosuppressive Drugs in Patients With Lung Disease and Lung Transplant Recipients

PubMed Central

Meyer, Keith C; Nathanson, Ian; Angel, Luis; Bhorade, Sangeeta M; Chan, Kevin M; Culver, Daniel; Harrod, Christopher G; Hayney, Mary S; Highland, Kristen B; Limper, Andrew H; Patrick, Herbert; Strange, Charlie; Whelan, Timothy

2012-01-01

Objectives: Immunosuppressive pharmacologic agents prescribed to patients with diffuse interstitial and inflammatory lung disease and lung transplant recipients are associated with potential risks for adverse reactions. Strategies for minimizing such risks include administering these drugs according to established, safe protocols; monitoring to detect manifestations of toxicity; and patient education. Hence, an evidence-based guideline for physicians can improve safety and optimize the likelihood of a successful outcome. To maximize the likelihood that these agents will be used safely, the American College of Chest Physicians established a committee to examine the clinical evidence for the administration and monitoring of immunosuppressive drugs (with the exception of corticosteroids) to identify associated toxicities associated with each drug and appropriate protocols for monitoring these agents. Methods: Committee members developed and refined a series of questions about toxicities of immunosuppressives and current approaches to administration and monitoring. A systematic review was carried out by the American College of Chest Physicians. Committee members were supplied with this information and created this evidence-based guideline. Conclusions: It is hoped that these guidelines will improve patient safety when immunosuppressive drugs are given to lung transplant recipients and to patients with diffuse interstitial lung disease. PMID:23131960

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

Synthetic anabolic agents: steroids and nonsteroidal selective androgen receptor modulators.

PubMed

Thevis, Mario; Schänzer, Wilhelm

2010-01-01

The central role of testosterone in the development of male characteristics, as well as its beneficial effects on physical performance and muscle growth, has led to the search for synthetic alternatives with improved pharmacological profiles. Hundreds of steroidal analogs have been prepared with a superior oral bioavailability, which should also possess reduced undesirable effects. However, only a few entered the pharmaceutical market due to severe toxicological incidences that were mainly attributed to the lack of tissue selectivity. Prominent representatives of anabolic-androgenic steroids (AAS) are for instance methyltestosterone, metandienone and stanozolol, which are discussed as model compounds with regard to general pharmacological aspects of synthetic AAS. Recently, nonsteroidal alternatives to AAS have been developed that selectively activate the androgen receptor in either muscle tissue or bones. These so-called selective androgen receptor modulators (SARMs) are currently undergoing late clinical trials (IIb) and will be prohibited by the World Anti-Doping Agency from January 2008. Their entirely synthetic structures are barely related to steroids, but particular functional groups allow for the tissue-selective activation or inhibition of androgen receptors and, thus, the stimulation of muscle growth without the risk of severe undesirable effects commonly observed in steroid replacement therapies. Hence, these compounds possess a high potential for misuse in sports and will be the subject of future doping control assays.

New developments in the epidemiology and genetics of gout.

PubMed

Zaka, Raihana; Williams, Charlene J

2006-06-01

The prevalence of gout appears to be rapidly increasing worldwide and is no longer a disorder suffered primarily by over-fed alcohol consumers. Emerging risk factors include longevity, metabolic syndrome, and new classes of pharmacologic agents. In some ethnic populations, no obvious risk factors can explain the high incidence of hyperuricemia and gout, suggesting a genetic liability. Studies to identify genes associated with gout have included families with defects in purine metabolism, as well as families in whom the occurrence of gout is secondary to renal disorders such as juvenile hyperuricemic nephropathy and medullary cystic kidney disease. Case-control studies of isolated aboriginal cohorts suffering from primary gout have revealed several chromosomal loci that may harbor genes that are important to the development and/or progression of gout.

Opportunities and Challenges for Natural Products as Novel Antituberculosis Agents.

PubMed

Farah, Shrouq I; Abdelrahman, Abd Almonem; North, E Jeffrey; Chauhan, Harsh

2016-01-01

Current tuberculosis (TB) treatment suffers from complexity of the dosage regimens, length of treatment, and toxicity risks. Many natural products have shown activity against drug-susceptible, drug-resistant, and latent/dormant Mycobacterium tuberculosis, the pathogen responsible for TB infections. Natural sources, including plants, fungi, and bacteria, provide a rich source of chemically diverse compounds equipped with unique pharmacological, pharmacokinetic, and pharmacodynamic properties. This review focuses on natural products as starting points for the discovery and development of novel anti-TB chemotherapy and classifies them based on their chemical nature. The classes discussed are divided into alkaloids, chalcones, flavonoids, peptides, polyketides, steroids, and terpenes. This review also highlights the importance of collaboration between phytochemistry, medicinal chemistry, and physical chemistry, which is very important for the development of these natural compounds.

Imaging-related medications: a class overview

PubMed Central

2007-01-01

Imaging-related medications (contrast agents) are commonly utilized to improve visualization of radiographic, computed tomography (CT), and magnetic resonance (MR) images. While traditional medications are used specifically for their pharmacological actions, the ideal imaging agent provides enhanced contrast with little biological interaction. The radiopaque agents, barium sulfate and iodinated contrast agents, confer “contrast” to x-ray films by their physical ability to directly absorb x-rays. Gadolinium-based MR agents enhance visualization of tissues when exposed to a magnetic field. Ferrous-ferric oxide–based paramagnetic agents provide negative contrast for MR liver studies. This article provides an overview of clinically relevant information for the imaging-related medications commonly in use. It reviews the safety improvements in new generations of drugs; risk factors and precautions for the reduction of severe adverse reactions (i.e., extravasation, contrast-induced nephropathy, metformin-induced lactic acidosis, and nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis); and the significance of diligent patient screening before contrast exposure and appropriate monitoring after exposure. PMID:17948119

The current status and trend of clinical pharmacology in developing countries

PubMed Central

2013-01-01

Background Several international forums for promoting clinical pharmacology in developing countries have been held since 1980, and several clinical pharmacology programmes targeting developing countries were instituted such that the status of clinical pharmacology in developing countries is not where it was 50 years ago. Therefore, a survey and an appraisal of the literature on the current status of clinical pharmacology in developing countries were undertaken with a hope that it would enable development of appropriate strategies for further promotion of clinical pharmacology in these countries. Methods First, nine determinants (or enabling factors) for running a successful clinical pharmacology programme were identified, i.e., disease burden, drug situation, economic growth, clinical pharmacology activities, recognition, human capital, government support, international collaboration, and support for traditional/alternative medicines. These factors were then evaluated with regard to their current status in the developing countries that responded to an electronic questionnaire, and their historical perspective, using the literature appraisal. From these, a projected trend was constructed with recommendations on the way forward. Results Clinical pharmacology services, research and teaching in developing countries have improved over the past 50 years with over 90% of countries having the appropriate policies for regulation and rational use of medicines in place. Unfortunately, policy implementation remains a challenge, owing to a worsening disease burden and drug situation, versus fewer clinical pharmacologists and other competing priorities for the national budgets. This has led to a preference for training ‘a physician clinical pharmacologist’ in programmes emphasizing local relevancy and for a shorter time, and the training of other professionals in therapeutics for endemic diseases (task shifting), as the most promising strategies of ensuring rational use of medicines. Conclusion Clinical pharmacology in developing countries is advancing in a different way to that in the developed world and continuing support for these efforts will go a long way in promoting improved health for all. PMID:24074056

Pharmacological management of osteogenesis

PubMed Central

Nardone, Valeria; D'Asta, Federica; Brandi, Maria Luisa

2014-01-01

Osteogenesis and bone remodeling are complex biological processes that are essential for the formation of new bone tissue and its correct functioning. When the balance between bone resorption and formation is disrupted, bone diseases and disorders such as Paget's disease, fibrous dysplasia, osteoporosis and fragility fractures may result. Recent advances in bone cell biology have revealed new specific targets for the treatment of bone loss that are based on the inhibition of bone resorption by osteoclasts or the stimulation of bone formation by osteoblasts. Bisphosphonates, antiresorptive agents that reduce bone resorption, are usually recommended as first-line therapy in women with postmenopausal osteoporosis. Numerous studies have shown that bisphosphonates are able to significantly reduce the risk of femoral and vertebral fractures. Other antiresorptive agents indicated for the treatment of osteoporosis include selective estrogen receptor modulators, such as raloxifene. Denosumab, a human monoclonal antibody, is another antiresorptive agent that has been approved in Europe and the USA. This agent blocks the RANK/RANKL/OPG system, which is responsible for osteoclastic activation, thus reducing bone resorption. Other approved agents include bone anabolic agents, such as teriparatide, a recombinant parathyroid hormone that improves bone microarchitecture and strength, and strontium ranelate, considered to be a dual-action drug that acts by both osteoclastic inhibition and osteoblastic stimulation. Currently, anti-catabolic drugs that act through the Wnt-β catenin signaling pathway, serving as Dickkopf-related protein 1 inhibitors and sclerostin antagonists, are also in development. This concise review provides an overview of the drugs most commonly used for the control of osteogenesis in bone diseases. PMID:24964310

Neprilysin inhibition: a brief review of past pharmacological strategies for heart failure treatment and future directions

PubMed Central

Howell, Erik H.; Cameron, Scott J.

2016-01-01

Heart failure (HF) is a manifestation of aberrant vascular responses and remains a public health concern with a worldwide prevalence of around 23 million and a 5-year mortality numerically equivalent to many cancers. Over the last two decades, mortality from HF reached a plateau with current pharmaceutical agents and mechanical cardiac support. In the last several years, various “novel” pharmaceutical agents have been tested in clinical trials and ultimately met with disappointment, showing only incremental benefit in the treatment of HF. Designing a HF drug with enhanced efficacy over existing agents seemed like a Sisyphean task. Yet again, pharmaceutical chemists have demonstrated their prowess in lateral thinking by developing a vasoactive agent which is a co-crystallized compound of valsartan and sacubitril in a one-to-one molar ratio; the former molecule belongs to a family of agents that are the current standard of care for HF and the latter molecule is a novel agent which inhibits neprilysin — a neutral endopeptidase found in human plasma which alters neurohumoral responses. In July of 2015, a drug which is a combination of valsartan and sacubitril was formally licensed by the United States Food and Drug Administration for the treatment of HF. This review describes the evolution of HF medications focusing on rational drug design with the first HF medication, the beta adrenergic receptor antagonist. We then discuss the biochemical and physiological properties of sacubitril/valsartan which likely lead to its dramatic ability to ameliorate HF mortality. PMID:27665860