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BACKGROUND: Cyclic nucleotide Phosphodiesterases (PDEs) are ubiquitously distributed in mammalian tissues and play a major role in cell signaling by hydrolyzing cyclic Adenosine Monophosphate (cAMP) and cyclic Guanosine Monophosphate (cGMP). Impairments in signal transduction have been implicated as possible mechanism of reduced plasticity and neuronal survival in major depressive disorders. PDE inhibitors possess a potentially powerful means to manipulate secondary messengers involved in learning, memory and mood. Cilostazol is an antiplatelet agent indicated for the treatment of intermittent claudication with peripheral artery occlusion and for the prevention of ischemic stroke worldwide. Various animal studies have reported neuroprotective, anti apoptotic, cognition and cerebral blood flow improvement properties of cilostazol. MATERIALS AND METHODS: In this study, the antidepressant and anxiolytic effects of cilostazol were evaluated in mice using behavioral tests sensitive to clinically effective antidepressant compound. RESULTS: Cilostazol, administered intraperitoneally (20 mg/kg), decreased immobility time of mice when subjected to forced swim test and tail suspension test as compared to standard fluoxetine (20 mg/kg). Cilostazol also produced significant decrease in the number of marbles buried as compared to fluoxetine in marble burying model. CONCLUSION: The present study suggests that cilostazol possesses potential antidepressant and anxiolytic activity, which could be of therapeutic interest for use in patients with depressive disorders.

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OBJECTIVE: To determine the association between altered thyroid hormones and insulin resistance (IR). MATERIALS AND METHODS: Eight euthyroid (EU), eight hypothyroid (HO), and eight hyperthyroid (HR) patients with no past medical history were studied in this cross-sectional study at the Care Institute of Medical Sciences, Ahmedabad, India, The fasting blood sample were analyzed for thyroid stimulating hormone (TSH), lipid profile, insulin, and glucose. Homeostatic model assessment (HOMA) was calculated for assessing IR. RESULTS: HOMA values were significantly higher in HR and HO groups as compared to the EU group (P < 0.05). Insulin levels were also found to be significantly increased in HR and HO groups as compared to the EU group (P < 0.05). Cholesterol, triglycerides (TG), and low density lipoprotein (LDL) were significantly raised in HO as compared to EU and HR groups (P < 0.05) whereas high density lipoprotein levels (HDL) were lower. HOMA and insulin were found to be positively correlated with TSH in HO and negatively in HR. CONCLUSION: Thyroid disorder, including both hypo- and hyper have been associated with IR due to various mechanisms such as altered insulin secretion and lipid levels. IR was comparable in patients with both HO and HR. Although HO and HR constitute an IR state, more studies need to be done in order to clarify the underlying pathogenic mechanism. Thus, an altered thyroid state can lead to IR leading to glucose-related disorder such as diabetes dyslipidemia.

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A rapid, specific and sensitive liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for the determination of penciclovir in human plasma. The method involved simple, one-step SPE procedure coupled with a C(18) , 75 × 4.mm, 3 µm column with a flow-rate of 0.5 mL/min, and acyclovir was used as the internal standard. The Quattro Micro mass spectrometry was operated under the multiple reaction-monitoring mode using the electrospray ionization technique. Using 250 µL plasma, the methods were validated over the concentration range 52.555-6626.181 ng/mL, with a lower limit of quantification of 52.55 ng/mL. The intra- and inter-day precision and accuracy values were found to be within the assay variability limits as per the FDA guidelines. The developed assay method was applied to a clinical pharmacokinetic study in human volunteers.

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OBJECTIVE: Punarnavashtak kwath (PNK) is a classical Ayurvedic formulation, mentioned in Ayurvedic literature Bhaishajya Ratnavali, for hepatic disorders and asthma. This study investigated the hepatoprotective activity of PNK to validate the traditional use of this formulation. MATERIALS AND METHODS: PNK was prepared in the laboratory according to the method given in Ayurvedic literature. Phytochemical screening was performed to determine the presence of phytoconstituents. Hepatoprotective activity was evaluated against CCl(4)-induced hepatotoxicity in rats and by its effect on the HepG2 cell line. RESULTS: Preliminary phytochemical screening revealed the presence of alkaloids, tannins, flavonoids, saponins, and a bitter principle in PNK. Administration of PNK produced significant hepatoprotective effect as demonstrated by decreased levels of serum liver marker enzymes such as aspartate transaminase, serum alanine transaminase, serum alkaline phosphatase, and serum bilirubin and an increase in protein level. Thiopentone-induced sleeping time was also decreased in the PNK-treated animals compared with the CCl(4)-treated group. It also showed antioxidant activity by increase in activity of glutathione, superoxide dismutase, and catalase and by a decrease in thiobarbituric acid reactive substance level compared with the CCl(4)-treated group. Results of a histopathological study also support the hepatoprotective activity of PNK. Investigation carried out on the HepG2 cell line depicted significant increase in viability of cells exposed to PNK as compared with CCl(4)-treated cells. DISCUSSION AND CONCLUSION: It can be concluded that PNK protects hepatocytes from CCl(4)-induced liver damages due to its antioxidant effect on hepatocytes. An in vitro study on HepG2 cell lines also supports its protective effect.

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A rapid, sensitive and rugged solid-phase extraction ultraperformance liquid chromatography tandem mass spectrometry (LC-MS/MS) method was developed for determination of oseltamivir phosphate (OP) and oseltamivir carboxylate (OC) in human plasma. The procedure for sample preparation includes a simple SPE extraction procedure coupled with a Chromatopack C(18) column (50 × 3.0 mm, i.d., 3.0 µm) with isocratic elution at a flow-rate of 0.600 mL /min and acyclovir was used as the internal standard. The analysis was performed on a triple-quadrupole tandem mass spectrometer by multiple reaction monitoring mode via electrospray ionization. Using 500 µL plasma, the methods were validated over the concentration ranges 0.92-745.98 and 5.22-497.49 ng/mL for OP and OC, with a lower limit of quantification of 0.92 and 5.22 ng/mL. The intra- and inter-day precision and accuracy of the quality control samples were within 10.1%. The recovery was 68.72, 70.66 and 71.59% for OP, OC and IS, respectively. Total run time was only 1.0 min. The method was highly reproducible with excellent chromatography properties.

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The present investigation was undertaken to study the comparative effectiveness of beta-adrenergic antagonist propranolol and calcium channel blocker verapamil on L-thyroxine-induced alteration on glycemic control and histamine sensitivity on rats and guinea pigs, respectively. Injection of L-thyroxine sodium every alternate day for 3 weeks in guinea pigs (75 microg/kg, i.p.) and rats (75 mg/kg, s.c.) produced a condition similar to thyrotoxicosis. Verapamil and propranolol administered daily in the third week along with L-thyroxine to two separate groups of hyperthyroid animals reversed thyroxine-induced loss in body weight, reduction in serum TSH levels, and rise in body temperature. Effect on glucose metabolism and insulin sensitivity was studied on rats. Compared to normal rats, L-thyroxine-treated animals showed a state of hyperglycemia, hyperinsulinemia, impaired glucose tolerance, and insulin resistance. Propranolol (10 mg/kg, i.p.) treatment significantly decreased fasting serum glucose levels without affecting serum insulin levels, AUC glucose, and K(ITT) values. Treatment with verapamil (5 mg/kg, i.p.) significantly reduced fasting serum glucose and insulin levels, AUC glucose, and significantly increased K(ITT) values. Effect of propranolol (15 mg/kg, orally) and verapamil (20 mg/kg, orally) treatment on histamine sensitivity was studied on L-thyroxine-treated guinea pigs. Compared to normal guinea pigs, L-thyroxine-treated guinea pigs showed an increased sensitivity to histamine-induced asphyxia. Verapamil treatment reversed this increased histamine sensitivity while propranolol aggravated it. In conclusion, compared to propranolol, verapamil has advantageous effects on glucose metabolism, insulin and histamine sensitivity and could therefore be a valuable addition as an adjunctive therapy option currently available for thyrotoxicosis associated with diabetes and/or anaphylaxis.

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