No abstract

Chronic, nonproductive cough may result from enhanced sensitivity of the cough reflex. Often, this debilitating symptom is refractory to standard antitussive therapy. Baclofen, an agonist of γ-aminobutyric acid (GABA), has been shown, in animals, to have antitussive activity via a central mechanism. Recently, in normal subjects, we have demonstrated the ability of baclofen to inhibit capsaicin-induced cough, as well as cough due to angiotensin-converting enzyme (ACE) inhibitors. Herein, we describe two patients with chronic, refractory cough who obtained symptomatic improvement after a 14-day course of low-dose, oral baclofen, administered in a double-blind, placebo-controlled manner. In addition, both subjects demonstrated significant increases in cough threshold to inhaled capsaicin after treatment with baclofen.

Nausea and vomiting are the most distressing and common side effects of cancer chemotherapy which often result in patient noncompliance. In the present study, standardized methanolic and n-butanolic fractions of Bacopa monnieri were evaluated against cisplatin-induced emesis in the pigeon in relation to their activity on central and intestinal neurotransmitters levels. Cisplatin (7.0 mg/kg, i. v.) induced reproducible emesis without lethality in healthy pigeons. The methanolic (10-40 mg/kg) and the bacoside-rich n-butanolic fractions of B. monnieri (5-20 mg/kg), as well as the antioxidant N-(2-mercaptopropionyl) glycine (10 mg/kg), attenuated cisplatin-induced emesis by 66.3% (p < 0.05), 71.6% (p < 0.001), and 76.5% (p < 0.001), respectively, where the standard antiemetic metoclopramide (30 mg/kg) produced a 48.9% reduction (p < 0.01). The methanolic and n-butanolic fractions of B. monnieri at all of the doses tested significantly reduced the serotonin concentration (p < 0.001) in the brain stem and intestine 3 h after cisplatin administration, while at the 18th h, B. monnieri treatments attenuated not only the dopamine upsurge in the area postrema and brain stem (p < 0.05-0.001), but also the intestinal 5-HT concentration (p < 0.01-0.001). B. monnieri treatments alone did not alter the basal neurotransmitters or their metabolites in the brain areas and intestine. The prolonged suppressive effect of B. monnieri treatments on the behavioral signs of cisplatin-induced emesis, the subsequent supportive neural evidence, and the safety and tolerability profile suggest that B. monnieri methanolic and bacoside-rich n-butanolic fractions might be a valuable adjunct in the treatment of emetogenic chemotherapy, and this warrants further study in other models of emesis.

No abstract

Gamma-aminobutyric acid (GABA) is a central inhibitory neurotransmitter that also exists in the lungs. The GABA-agonist baclofen has been shown to have antitussive activity via a central mechanism in animals. Recently it was demonstrated that a 14-day course of baclofen given three times daily significantly inhibits the cough reflex in healthy volunteers. Because of the prolonged antitussive effect of baclofen that has been previously observed, the present study was conducted to evaluate the antitussive effect of low-dose, oral baclofen given once daily. Forty-one healthy volunteers were randomly assigned in a double-blind manner to receive a 28-day course of baclofen, either 10 mg or 20 mg once daily, or placebo. Subjects underwent cough challenge testing with inhaled capsaicin to establish baseline cough reflex sensitivity, and subsequently after 14 and 28 days of therapy. Subjects receiving baclofen 20 mg daily demonstrated significant inhibition of cough sensitivity after 14 days and after 28 days of therapy compared with baseline. Neither placebo nor baclofen 10 mg daily had a significant effect on cough sensitivity. No serious side effects were experienced by any study participant. These results confirm the recent observation that baclofen has significant antitussive activity in humans. Further, once-daily administration of a relatively low dose of baclofen is sufficient to achieve significant cough inhibition, although at least 14 to 28 days of therapy may be required to attain maximal antitussive effect. These results support further investigation of baclofen or other GABA-agonists as potential therapeutic agents for chronic, nonproductive cough.

Abstract. Controlled-release (CR) tablet formulation of olanzapine was developed using a binary mixture of Methocel® K100 LV-CR and Ethocel® standard 7FP premium by the dry granulation slugging method. Drug release kinetics of CR tablet formulations F1, F2, and F3, each one suitably compressed for 9-, 12-, and 15-kg hardness, were determined in a dissolution media of 0.1 N HCl (pH 1.5) and phosphate buffer (pH 6.8) using type II dissolution apparatus with paddles run at 50 rpm. Ethocel® was found to be distinctly controlling drug release, whereas the hardness of tablets and pH of the dissolution media did not significantly affect release kinetics. The CR test tablets containing 30% Methocel® and 60% Ethocel® (F3) with 12-kg hardness exhibited pH-independent zero-order release kinetics for 24 h. In vivo performance of the CR test tablet and conventional reference tablet were determined in rabbit serum using high-performance liquid chromatography coupled with electrochemical detector. Bioavailability parameters including C max , T max , and AUC 0-48 h of both tablets were compared. The CR test tablets produced optimized C max and extended T max (P<0.05). A good correlation of drug absorption in vivo and drug release in vitro (R 2 =0.9082) was observed. Relative bioavailability of the test tablet was calculated as 94%. The manufacturing process employed was reproducible and the CR test tablets were stable for 6 months at 40±2°C/75±5% relative humidity. It was concluded that the CR test tablet formulation successfully developed may improve tolerability and patient adherence by reducing adverse effects.

Background: Fear, stress, and anxiety-like behaviors originate from traumatic events in life. Stress response is managed by endocannabinoids in the body by limiting the uncontrolled retrieval of aversive memories. Pharmacotherapy-modulating endocannabinoids, especially anandamide, presents a promising tool for treating anxiety disorders. Here, we investigated the effect of kaempferol, a flavonoid, in the extinction of fear related memories and associated anxiety-like behavior. Methods: The ability of kaempferol to inhibit fatty-acid amide hydrolase (FAAH, the enzyme that catabolizes anandamide) was assessed in vitro using an enzyme-linked immunosorbent assay (ELISA) kit. For animal studies (in vivo), the extinction learning was evaluated using contextual fear conditioning (CFC, a behavioral paradigm based on ability to learn and remember aversive stimuli). Furthermore, an elevated plus-maze (EPM) model was used for measuring anxiety-like behavior, while serum corticosterone served as a biochemical indicator of anxiety. Lastly, the interaction of kaempferol with FAAH enzyme was also assessed in silico (computational study). Results: Our data showed that kaempferol inhibited the FAAH enzyme with an IC50 value of 1 µM. In CFC, it reduced freezing behavior in rats. EPM data demonstrated anxiolytic activity as exhibited by enhanced number of entries and time spent in the open arm. No change in blood corticosterone levels was noted. Our computational study showed that Kaempferol interacted with the catalytic amino acids (SER241, PHE192, PHE381, and THR377) of FAAH enzyme Conclusion: Our study demonstrate that kaempferol facilitated the extinction of aversive memories along with a reduction of anxiety. The effect is mediated through the augmentation of endocannabinoids via the inhibition of FAAH enzyme.

Ethnopharmacological relevance: Anthocleista vogelii Planch is a medicinal plant traditionally used in West Africa for the management and treatment of diabetes mellitus. Aim of the study: To determine the antidiabetic activities of chloroform fraction (CF) of Anthocleista vogelii Planch root bark in rats with diet-and alloxan-induced obesity-diabetes. Materials and Methods: Inhibitory activities of CF against α-amylase and α-glucosidase activities were determined in vitro. Three weeks old rats were fed with high-fat diet for 9 weeks to induce obesity prior to further induction of diabetes using alloxan (150 mg/kg body weight, i.p.). Blood glucose levels and body weight were measured every 7 days throughout the experiment. Glucose tolerance was assessed in normal and CF-treated rats on day 21. Terminal blood samples were collected from sacrificed animals for the measurement of serum insulin levels. Pancreases were excised from treated and untreated animals for histopathological examination. Results: LCMS/MS chromatographic profile of CF via positive and negative modes revealed 13 and 23 compounds respectively. Further analysis revealed quebrachitol (QCT), loganin, sweroside, oleoside 11-methyl ester and ferulic acid, which have been previously reported for their antidiabetic activities, as constituents of CF. CF inhibited activities of α-amylase (IC 50 = 51.60 ± 0.92 µg/ml) and α-glucosidase (IC 50 = 5.86 ± 0.97 µg/ml) in a dose-dependent manner. Treatment of animals with obesity-diabetes with 100 and 200 mg/kg CF significantly improved glucose tolerance (P<0.001) and enhanced serum insulin levels (P<0.05) compared to diabetic control rats. Conclusions: Antidiabetic activities of CF might be mediated via inhibition of α-amylase and αglucosidase activities, and enhancement of insulin and leptin sensitivity in obesity-diabetes rats. This study further substantiates the traditional use of A. vogelii in the management and treatment of diabetes in Africa and encourages further studies to investigate its mechanism of action.