Pharmacokinetic and pharmacodynamic comparison between Glucophage? and a generic metformin in a rat model

In the present study, we aimed to compare the pharmacokinetics and pharmacodynamics between Glucophage^® and a generic metformin formulation in a diabetic rat model in order to assess the bioequivalence of the generic formulation.Adult male Zucker diabetes fatty rats received Glucophage^® or the generic metformin through gastric gavage at a dose of 180 mg/kg (n = 6 per condition). Both pharmacokinetic parameters (AUC_0–t, AUC_0–∞, C_max) of metformin and plasma glucose levels were compared between the two groups. For pharmacodynamics, rats received Glucophage^® or the generic metformin at doses of 180 and 300 mg·kg^–1·d^–1 for 6 weeks. The measurements included body weight, fasting plasma glucose, glycosylated serum protein (GSP) and serum insulin. Data were analyzed with SPSS 22.0 and Prism 7. The level of statistical significance was set at P<0.05.In single dosing experiments, pharmacokinetic parameters (t_1/2, AUC_0–t and C_max) did not differ between Glucophage^® and the generic metformin (P>0.05). However, plasma glucose was significantly higher in the generic metformin group at 2 h (P = 0.03) and 4 h (P = 0.04) after drug treatment. In repeated dosing experiments, fasting glucose, HOMA-IR and body weight in rats receiving high-dose Glucophage^® were significantly lower at the end of the 6-week treatment period than those in rats receiving high-dose generic metformin (P<0.05 for all). GSP and serum insulin did not differ significantly between the two groups. In rats receiving low-dose metformin, fasting glucose was lower in the Glucophage^® group. HOMA-IR and body weight did not differ between the two groups. Moreover, blood lipids did not differ significantly between the two groups. The generic metformin used in the current study did not differ significantly in pharmacokinetic characteristics with Glucophage^®. However, Glucophage^® was superior in terms of glucose control, body weight loss and insulin sensitivity in repeated administration.     

Trance and shamanism: what's in a name?

This article considers the implications of the definitions and typologies of trance and shamanism for the development and testing of cross-cultural hypotheses through a review of definitions, typologies, and use of key terms and related concepts in anthropology. Authors vary widely in their definitions and applications of terms: some uses are based on reasoned criteria, others on traditional practice; some establish typologies, others prefer continua. Classifications range from narrow and highly specific to broad and inclusive coverage. Some restrict the usage to traditional societies, while others seek applications to Western phenomena, whether faith healers and mediums, or poets, such as Walt Whitman. The concept of control, with a variety of meanings assigned to it, emerges as a significant variable in the comparative study of "trance" and "shamanism" as these terms are used by different authors in widely different manners.     

Impact and Other Factors: What's in a Number?

The journal impact factor is an index used to evaluate the relativequality and importance of a journal and is often used to comparejournals in the same field. It is recognized as a measuringstick by which all journals are evaluated. For many scientists,it is an important consideration when determining where     

Toxicity of ingredients in artificial tears and ophthalmic drugs in a cell attachment and spreading test†

Abstract

During re-epithelialization of corneal erosions, the epithelial cells are attached and migrate on a fibronectin-containing substratum. In earlier studies we found that topical application of the plasmin inhibitor aprotinin promoted healing of corneal epithelial defects, presumably inhibiting proteolytic degradation of fibronectin and related adhesive proteins. The present study investigated, using an in vitro cell culture test, the action of various ophthalmic preparations on cell attachment and spreading on a fibronectin-coated substratum. The cell culture test was designed to simulate the situation in the wounded corneal epithelium in vivo. Analysis of 16 different ophthalmic preparations indicated that the toxicity of some of them in the test could be assigned to specific ingredients (benzalkonium chloride, thimerosal sodium, Tween 80) used as additives. In contrast, chlorobutanol, used widely as a preservative, was nontoxic in the test, in concentrations used in ophthalmic preparations. It should be noted that the wounded and inflamed cornea may be more vulnerable to the toxicity of topical mediations than an intact corneal epithelium. hoper tests of the vehicle are therefore recommended before clinical trials are undertaken.     

Complementary anti-inflammatory effects of a β-blocker and a corticosteroid in an asthma model

Glucocorticosteroids are the mainstay treatment for chronic asthma; however, adverse effects can limit their usefulness. We previously determined in experimental asthma that chronic administration of β₂-adrenoceptor inverse agonists reduced airway hyperresponsiveness and indexes of inflammation. However, the effect of co-administration of glucocorticosteroids with β₂-adrenoceptor inverse agonists is unknown. Therefore, we evaluated the anti-inflammatory effect of co-administration of dexamethasone, a glucocorticosteroid, and nadolol, a β₂-inverse agonist, in a murine asthma model. We measured eosinophils and cytokines in bronchoalveolar lavage fluid and mucin content in epithelial cells after exposure to different concentrations of dexamethasone and nadolol. Dexamethasone was administered for 3 days and nadolol for 24 days prior to ovalbumin challenge. Both drugs were continued during five daily intranasal challenges with ovalbumin. Independent administration of dexamethasone (0.4 mg/kg/day) or nadolol (25 ppm) reduced bronchoalveolar lavage eosinophils by 58% and 36%, respectively (P < 0.05). Co-administration of both drugs yielded an additive reduction in eosinophils (81%, P < 0.05). Co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) also yielded a greater reduction in mucin volume density (83%) than either drug alone (18% for dexamethasone and 62% for nadolol) and greater than high-dose dexamethasone (71%) alone (P < 0.05). Similarly, co-administration of both drugs (dexamethasone 0.4 mg/kg/day and nadolol 25 ppm) yielded an additive effect on the reduction of type 2 cytokines in bronchoalveolar lavage fluid equivalent to the administration of a 10-fold higher dose of dexamethasone. In Summary, the simultaneous administration of a glucocorticosteroid and a β₂-adrenoceptor inverse agonist was more effective at reducing indexes of airway inflammation than either drug given alone; suggesting nadolol may possess “glucocorticoid-sparing” properties.     

Lindane and cancer in humans: a false alarm?

In up to 21 years of follow-up in a study to periodically screen pharmaceuticals for possible carcinogenic effects, 1146 persons who received lindane, an established carcinogen in animal experiments, showed for the first time a statistically significant increase in incidence of cancer (43 cases observed, 30.2 expected, standardized morbidity ratio 1.42, 95% confidence interval 1.03-1.92). The computer-stored data on drug dispensing and cancer occurrence also showed some evidence of a dose-response relationship. Review of the complete medical records suggested that at least part of the association was due to confounding by indication. Four of the cancer patients had Kaposi's sarcoma due to AIDS and the acquisition of pediculosis pubis or scabies, commonly treated with lindane, is associated with behaviour that also predisposes to AIDS. Four other patients also had strong risk factors that could readily be blamed for their cancer and one had not used the drug. Also, the location of the skin lesions or infestations treated with lindane seemed to bear no relation to the cancer sites. It is concluded that this study provides no convincing evidence of carcinogenicity of lindane; nor does it rule it out. In pharmacoepidemiology, it is advisable to supplement analyses of routinely collected data on drugs and clinical events with review of medical records when interesting associations are noted.     

Conducting community clinical trials in a developing country-problems and pitfalls

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Harmine, a β-carboline alkaloid, inhibits osteoclast differentiation and bone resorption in vitro and in vivo

Bone homeostasis is controlled by the balance between osteoblastic bone formation and osteoclastic bone resorption. Excessive bone resorption is involved in the pathogenesis of bone-related disorders such as osteoporosis, arthritis and periodontitis. To obtain new antiresorptive agents, we searched for natural compounds that can inhibit osteoclast differentiation and function. We found that harmine, a β-carboline alkaloid, inhibited multinucleated osteoclast formation induced by receptor activator of nuclear factor-κB ligand (RANKL) in RAW264.7 cells. Similar results were obtained in cultures of bone marrow macrophages supplemented with macrophage colony-stimulating factor and RANKL, as well as in cocultures of bone marrow cells and osteoblastic UAMS-32 cells in the presence of vitamin D(3) and prostaglandin E(2). Furthermore, harmine prevented RANKL-induced bone resorption in both cell and bone tissue cultures. Treatment with harmine (10 mg/kg/day) also prevented bone loss in ovariectomized osteoporosis model mice. Structure-activity relationship studies showed that the C3-C4 double bond and 7-methoxy group of harmine are important for its inhibitory activity on osteoclast differentiation. In mechanistic studies, we found that harmine inhibited the RANKL-induced expression of c-Fos and subsequent expression of nuclear factor of activated T cells (NFAT) c1, which is a master regulator of osteoclastogenesis. However, harmine did not affect early signaling molecules such as ERK, p38 MAPK and IκBα. These results indicate that harmine inhibits osteoclast formation via downregulation of c-Fos and NFATc1 induced by RANKL and represses bone resorption. These novel findings may be useful for the treatment of bone-destructive diseases.     

Novel aβ isoforms in Alzheimer's disease - their role in diagnosis and treatment

The last decades have witnessed an explosion in studies of the role of amyloid-β (Aβ) in the progress of the neurodegenerative disorder Alzheimer's disease (AD) and it is now widely accepted that Aβ is related to the pathogenesis of AD. For example, studies have shown that Aβ is neurotoxic and that the neurotoxicity of Aβ is related to its aggregation state. The concentration of the 42 amino acid form of Aβ (Aβ1-42) is reduced in the cerebrospinal fluid (CSF) from AD patients, which is believed to reflect the AD pathology with plaques in the brain acting as sinks. Less well investigated, however, is the ability of other Aβ isoforms to distinguish AD patients from controls and to identify treatment effects in clinical trials. Recently, novel C-truncated forms of Aβ (Aβ1-14, Aβ1-15, and Aβ1-16) were identified in human CSF. The presence of these small peptides is consistent with a catabolic amyloid precursor protein cleavage pathway by β- followed by α-secretase. It has been shown that Aβ1-14, Aβ1-15, and Aβ1-16 increase dose-dependently in response to γ-secretase inhibitor treatment while Aβ1-42 levels are unchanged. Here, we review the many aspects of Aβ and its isoforms with special focus on their potential role as diagnostic and theragnostic markers.     

Modeling asthma and COPD in animals: a pointless exercise?

Animal modeling has been essential to the development of every drug used to treat asthma and chronic obstructive pulmonary disease (COPD). Determining the safety and efficacy of new therapeutics will also depend upon animal experimentation, and future targets for therapeutic intervention will probably be identified during careful experimentation using animals. Animal modeling of chronic diseases is made possible by the fact that the processes associated with the regulation of breathing, gas exchange, airway smooth-muscle contraction and relaxation, blood flow through the pulmonary and bronchial vasculature, inflammatory cell recruitment, mucus secretion, mucociliary clearance and airway surface liquid composition are highly conserved in mammals. This conservation is apparent at the whole-organ level and also at the level of the cell and the genome. The subtleties of how the airways and lungs are regulated and experimentally measured in different species make the more complex processes associated with asthma and COPD difficult to faithfully model or duplicate in mammals, particularly in mammals such as rodents that are only distantly related to humans.     

Uncertainty and variability in human exposure limits – a chemical-specific approach for ciprofloxacin and methotrexate

Human exposure limits (HELs) for chemicals with a toxicological threshold are traditionally derived using default assessment factors that account for variations in exposure duration, species sensitivity and individual sensitivity. The present paper elaborates a probabilistic approach for human hazard characterization and the derivation of HELs. It extends the framework for evaluating and expressing uncertainty in hazard characterization recently proposed by WHO-IPCS, i.e. by the incorporation of chemical-specific data on human variability in toxicokinetics. The incorporation of human variability in toxicodynamics was based on the variation between adverse outcome pathways (AOPs). Furthermore, sources of interindividual variability and uncertainty are propagated separately throughout the derivation process. The outcome is a two-dimensional human dose distribution that quantifies the population fraction exceeding a pre-selected critical effect level with an estimate of the associated uncertainty. This enables policy makers to set separate standards for the fraction of the population to be protected and the confidence level of the assessment. The main sources of uncertainty in the human dose distribution can be identified in order to plan new research for reducing uncertainty. Additionally, the approach enables quantification of the relative risk for specific subpopulations. The approach is demonstrated for two pharmaceuticals, i.e. the antibiotic ciprofloxacin and the antineoplastic methotrexate. For both substances, the probabilistic HEL is mainly influenced by uncertainty originating from: (1) the point of departure (PoD), (2) extrapolation from sub-acute to chronic toxicity and (3) interspecies extrapolation. However, when assessing the tails of the two-dimensional human dose distributions, i.e. the section relevant for the derivation of human exposure limits, interindividual variability in toxicodynamics also becomes important.     

Clinical practice and recent recommendations in hypertension management – reporting a gap in a global survey of 1259 primary care physicians in 17 countries

ABSTRACT

Objective: High blood pressure (BP) is a leading risk factor for cardiovascular morbidity and mortality. Effective antihypertensive pharmacotherapy is available but recognition and proper management of hypertension and BP goal achievement is still poor. Therefore, it was hypothesized that physicians’ attitude towards high BP, as well as patients’ perception and knowledge, may influence actual management of hypertension.

Research design and methods: Telephone interviews were carried out with a random sample of 1259 primary care physicians in 17 countries worldwide from 12 December 2005 to 13 January 2006 using a central computer assisted telephone interview methodology (CATI).

Results: (1) Physicians believed that 62 ± 21% of their patients had their BP controlled. (2) They were mostly in line with guideline recommended BP goals and 96% were aware of the elevated cardiovascular risk of hypertension, but 41% aimed to reduce BP to acceptable levels only. (3) Physicians indicated that in 41% of patients monotherapy controls BP and 71% would escalate to combination therapy after monotherapy failure. (4) 54% regard hyper­tension management as difficult. (5) Physicians estimated that between 60 and 70% of patients know their BP goal but thought that there was still room for improvement of hypertension management on the patient side.

Conclusion: Although many effective treatment options for arterial hypertension exist, BP goal achievement worldwide is suboptimal, leaving patients at an un­necessary cardiovascular risk. An increase in patients’ awareness and compliance together with an increased adherence of physicians to current guidelines should help in reducing the long term cardiovascular consequences of hypertension.     

Patients’ perspectives on participation in clinical trials and subsequent ethical challenges in a hospital setting in Jordan

International Journal of Clinical Pharmacy - Background The number of global clinical trials is increasing. Recruitment rate in clinical trials is a challenging task that affects sample size, power...     

Organochlorine compounds in liver and concentrations of vitellogenin and 17β-estradiol in plasma of sea bass fed with a commercial or with a natural diet

Results from previous experiments directed to determine the effect of different nutritional factors or the effect of xenobiotics on hormonal control of reproduction, lead to the hypothesis that hormonal perturbations repeatedly observed in sea bass (Dicentrarchus labrax) broodstock feeding commercial diets could have been caused by the presence of aryl hydrocarbon receptor (AhR) ligands, such as dioxins, furans and polychlorinated biphenyls (PCBs) in the diet. To evaluate this hypothesis, dioxins and related compounds were analysed in liver of female sea bass fed with a commercial or with a natural diet consisting of trash fish (bogue, Boops boops), and concentrations of vitellogenin (VTG) and 17β-estradiol (E2) were determined in plasma obtained previously in monthly samplings of these animals. As observed in other experiments, females fed with a commercial diet exhibited lower VTG and higher E2 plasma levels than females fed with the natural diet. In liver, sea bass fed with the commercial diet exhibited a profile clearly dominated by high-chlorinated dioxins while in fish fed with the natural diet this profile was dominated by low chlorinated furans. However, typical AhR ligands, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin showed no differences between groups or, as is the case of planar PCBs, showed higher concentrations in the liver of fish fed with the natural diet. These results do not permit to explain the observed hormonal alterations by a possible antiestrogenic effect caused by dioxins and related compounds.     

Oral bioavailability of phenobarbital: a comparison of a solution in myvacet 9‐08, a suspension, and a tablet

Purpose: A threeway crossover study with seven healthy male volunteers was conducted to determine the relative bioavailability of phenobarbital after single dose administration of 100 mg of phenobarbital as oral solution in Myvacet 908, and as a suspension, compared with a 100 mg phenobarbital tablet. Materials and methods: At 4week intervals each subject received the solution in Myvacet 908, the suspension and the tablet in randomized order. Blood samples were collected for 48 h after each dose for analysis of phenobarbital. From the individual serum concentrationversustime curves C _maxand T _max were determined and AUC₀₄₈ was calculated. Results: All three oral dosage forms of phenobarbital are bioequivalent. No significant diffences in T _maxwere observed. Conclusion: The oral solution in Myvacet 908, and the suspension of phenobarbital proved to be bioequivalent to a tablet.     

Drug pricing and reimbursement in France. Towards a new model?

The pharmaceutical market in France is characterised by low prices and high sales volumes. Despite these advantageous market conditions, the French pharmaceutical industry has in general been an underperformer in the global context. Acknowledgement of the contributory role made by state regulation of drug expenditures in creating this situation has resulted in a number of attempts to correct problems within the market. At best, these have achieved only temporary improvements. Since 1993, however, a new drug policy, which emphasises voluntary moderation by physicians of their own prescribing activities rather than the use of budgetary means to cut expenditures, has been in operation in France. This 'medicalised strategy' involves 2 main instruments, viz., a list of guidelines for clinical practice (Références Médicales Opposables) and a set of 'industrial conventions' (agreed between each drug company and the government) for determining drug prices. While it is too early at this stage to determine whether these new approaches will be beneficial in the long term, some changes in drug prescribing have already been observed, and it is clear that the new policy has also encouraged more healthy relationships between policymakers, the medical profession, and the pharmaceutical industry in France.     

Theoretical and practical considerations in virtual screening: a beaten field?

In this review, several aspects of virtual screening are presented. Although, docking and scoring have been the most widely employed techniques, ligand-based virtual screening has also gained momentum in recent years. We have classified the docking programs into four categories, based on their underline theories, and accordingly describe the most up-to-date algorithms and newest versions. Similarly, three categories of scoring functions are presented, while their weighting schemes on particular binding terms are discussed. The latter is important, since knowledge of the function can be used to select the ones that could be more appropriate for targets of similar nature. Challenging aspects, such as protein flexibility and practices to select the most appropriate docking/scoring schemes, are also discussed. Finally, a real-life example is presented where a pharmacophore-driven approach combined with a docking exercise were undertaken in an iterative manner to successfully enhance the virtual screening hit rates. In the end, we present our own perspective for best practices in the field based on our experiences.     

Application of a Dynamic Fluid and pH Model to Simulate Intraluminal and Systemic Concentrations of a Weak Base in GastroPlus™

The application of preclinical in vitro and in silico models can help formulation scientists to predict the in vivo performance of a drug in an early stage of oral drug product development. An important aspect is that these models should include equations that represent mechanisms that are biorelevant and are sensitive to changes in parameter values. Human gastrointestinal physiology involves many processes that change as a function of time. In this work, a dynamic fluid and pH model was applied in GastroPlus^? to simulate intraluminal and systemic concentrations of the weak base posaconazole in a biorelevant manner. Simulated results were compared with observed data, extracted from a previously reported human in vivo gastrointestinal aspiration study. Three different formulations were explored (i.e., 1 solution [20 mg dose strength] and 2 suspensions [both 40 mg dose strength]). Simulated results were compared and in line with the observed results for different intraluminal (e.g., precipitated fraction) and systemic parameters (e.g., plasma C_max). The optimization of the advanced compartmental and absorption transit model related to fluid dynamics and dynamic pH in this work creates perspectives to validate this model with other reference data derived from aspiration/magnetic resonance imaging studies.