Navin Sheth

Sitagliptin protects renal ischemia reperfusion induced renal damage in diabetes

This study was designed to investigate the possible effect of sitagliptin on renal damage induced by renal ischemia reperfusion (I/R) in diabetic rats. T2DM in rats was induced by the administration of nicotinamide (230 mg/kg, i.p.), 15 min prior to a single dose of streptozotocin (65 mg/kg, i.v.). In vivo renal I/R was performed in both T2DM and normal rats. Each protocol comprised ischemia for 30 min followed by reperfusion for 24h and a treatment period of 14 days before induction of ischemia. Sitagliptin treated diabetic rats that underwent renal I/R demonstrated significant decrease in the serum concentrations of aspartate aminotransferase (p < 0.01), urea nitrogen (p < 0.01) and creatinine (p < 0.001) compared to renal I/R in diabetic rats. Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in renal tissue were significantly (p < 0.05, p < 0.001, p < 0.01, p < 0.05 respectively) decreased after renal I/R in sitagliptin treated rats compared to diabetic rats. Antioxidant enzymes like glutathione (p < 0.05), glutathione peroxidase (p < 0.001), superoxide dismutase (p < 0.05) and catalase (p < 0.001) were significantly increased after renal I/R in sitagliptin treated diabetic rats compared to non treated diabetic rats. The typical DNA laddering was observed when renal I/R performed in diabetic rats, which indicates cell apoptosis. Sitagliptin treated rats demonstrated a decrease in DNA fragmentation and apoptosis. Furthermore, renal histopathology preserved in sitagliptin treated rats verified protection against renal I/R in diabetes. The results of present investigation established sitagliptin treatment attenuated renal damage induced by renal I/R in diabetic rats.

Formulation and development of a self-nanoemulsifying drug delivery system of irbesartan.

Irbesartan (IRB) is an angiotensin II receptor blocker antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water-soluble IRB. The solubility of IRB in various oils was determined to identify the oil phase of SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. The optimized SNEDDS formulation contained IRB (75 mg), Cremophor® EL (43.33%), Carbitol® (21.67%) and Capryol® 90 (32%). SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size and zeta potential. The optimized formulation of IRB-loaded SNEDDS exhibited complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug solution by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of IRB from SNEDDS compared with the pure drug solution. These results suggest the potential use of SNEDDS to improve dissolution and oral bioavailability of poorly water-soluble IRB.

Phytochemical and pharmacological review of Lagenaria sicereria.

Lagenaria siceraria (Molina) standley (LS) (Family: Cucurbitaceae) is an annual herbaceous climbing plant with a long history of traditional medicinal uses in many countries, especially in tropical and subtropical regions. Since ancient times the climber has been known for its curative properties, and has been utilized for treatment of various ailments, including jaundice, diabetes, ulcer, piles, colitis, insanity, hypertension, congestive cardiac failure (CCF), and skin diseases. Its fruit pulp is used both as an emetic and purgative, and for its cooling, diuretic, antibilious, and pectoral properties. Boiled in oil this pulp is used to treat rheumatism and insomnia. A wide range of chemical compounds including sterols, terpenoids, flavonoids, and saponins have been isolated from the species. Its extracts have been found to possess various pharmacological activities. Below, we give a comprehensive review of its ethnomedical uses, chemical constituents, and pharmacological profile as a medicinal plant. Particular attention is given to its analgesic, anti-inflammatory, antihyperlipidemic, diuretic, hepatoprotective, anthelmintic, and antibacterial effects so that its potential uses in pharmaceutics can be better evaluated.

Colocasia esculenta: A potent indigenous plant

Colocasia esculenta (CE) Linn. (Family: Araceae) is an annual herbaceous plant with a long history of usage in traditional medicine in several countries across the world, especially in the tropical and subtropical regions. The herb has been known since ancient times for its curative properties and has been utilized for treatment of various ailments such as asthma, arthritis, diarrhea, internal hemorrhage, neurological disorders, and skin disorders. The juice of CE corm is widely used for treatment of body ache and baldness. A wide range of chemical compounds including flavonoids, β-sitosterol, and steroids have been isolated from this species. Extracts from this plant have been found to possess various pharmacological activities. This contribution provides a comprehensive review of its ethnomedical uses, chemical constituents, and the pharmacological profile as a medicinal plant. Particular attention has been given to analgesic, anti-inflammatory, anti-cancer, and hypolipidemic effects presented in this review in order to evaluate the potential use of this plant in pharmaceuticals.

Exaggerated Liver Injury Induced by Renal Ischemia Reperfusion in Diabetes: Effect of Exenatide

Background/Aim: This study was designed to investigate the possible effect of exenatide (Glucagon like Peptide-1 receptor agonist) on liver injury (distant organ) induced by renal ischemia reperfusion (IR) in diabetic rats. Materials and Methods: In vivo renal IR was performed in both type 2 diabetic and normal rats. Each protocol comprised ischemia for 30 minutes followed by reperfusion for 24 hours and a treatment period of 14 days before induction of ischemia. Results: Lipid peroxidation, xanthine oxidase activity, myeloperoxidase activity and nitric oxide level in liver tissue were significantly increased (P < 0.01, P < 0.001, P < 0.001, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Antioxidant enzymes like glutathione, superoxide dismutase, catalase and glutathione peroxidase were significantly reduced (P < 0.05, P < 0.05, P < 0.01, P < 0.05, respectively), after IR in diabetic rats compared to normal rats. Exenatide treatment significantly normalized (P < 0.01), these biochemical parameters in treated rats compared to diabetic IR rats. Serum creatinine phosphokinase activity and liver function enzymes were also significantly normalized (P < 0.001, P < 0.001, respectively), after administration of exenatide. Conclusion: Exenatide exerted protective effect on exaggerated remote organ (liver) injury induced by renal IR in diabetes.

Neuroprotective activity of Matricaria recutita against fluoride-induced stress in rats

Context: Oxidative stress plays a key role in pathophysiology of many neurodegenerative disorders such as Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and so on. Although Matricaria recutita L. (Asteraceae), German chamomile, is traditionally used for central nervous system (CNS)-related diseases, its antistress properties have received little attention. Objective: The present study evaluated the neuroprotective effect of German chamomile against aluminium fluoride (AlF4−)-induced oxidative stress in rats. Materials and methods: The Sprague-Dawley rats of either sex (200–250 g) were selected and grouped as: group I received normal saline; group II received AlF4− (negative control); groups III, IV, and V received 100, 200, and 300 mg/kg, orally, German chamomile methanol extract (GCME) along with AlF4−; and group VI received quercetin (25 mg/kg, i.p.) + AlF4−, respectively. After 10 days treatment with GCME, oxidative stress was induced by administering AlF4− through drinking water for 7 days. Then, the protective antioxidant enzyme levels were measured and the histopathological studies were carried out. Results: The GCME showed dose-dependent neuroprotective activity by significant decrease in lipid peroxidation (LPO) and increase in the superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and total thiol levels in extract-treated animals as compared with negative control group (P < 0.001). The histopathological studies also revealed the potent neuroprotective action of German chamomile against oxidative brain damage. Conclusion: The present study for the first time shows potent neuroprotective activity of the methanol extract of German chamomile against AlF4−-induced oxidative stress in rats.

Anticonvulsant activity of solasodine isolated from Solanum sisymbriifolium fruits in rodents.

Context: Solanum sisymbriifolium Lam. (Solanaceae), commonly known as sticky nightshade, is traditionally used for central nervous system (CNS) disorders. Although solasodine has been isolated from this plant, little is known about its anticonvulsant and CNS depressant actions. Objective: We investigated anticonvulsant and CNS depressant effects of solasodine isolated from S. sisymbriifolium using several experimental models. Materials and methods: Swiss albino mice (n = 6) were employed for pentylenetetrazole (PTZ) and picrotoxin (PCT)-induced convulsions and thiopental-induced sleep time. Different groups of Wistar albino rats (n = 6) were subjected to maximal electroshock (MES) test. Solasodine, a steroidal glycoalkaloid, was isolated from dried fruits of S. sisymbriifolium and identified by GC-MS. Results: The results showed that intraperitoneal (i.p.) injection of solasodine (25 mg/kg) significantly delayed (p < 0.01) latency of hind limb tonic extensor (HLTE) phase in the PCT-induced convulsions. In the MES model, solasodine significantly reduced (p < 0.001) duration of HLTE at 25, 50, and 100 mg/kg, i.p. in a dose-dependent manner. Interestingly, solasodine did not produce any significant reduction in PTZ-induced convulsions. Prior treatment of solasodine (25, 50, and 100 mg/kg, i.p.) significantly potentiated thiopental-provoked sleep in a dose-dependent manner (p < 0.001). Discussion and conclusion: Our study, for the first time, shows potent anticonvulsant and CNS depressant activities of solasodine. It is likely that solasodine, in part, is responsible for the anticonvulsant and sedative properties of S. sisymbriifolium. The future study should focus on the exact mechanism of action of solasodine.

Design and development of a self-nanoemulsifying drug delivery system for telmisartan for oral drug delivery

Background and Aim: Telmisartan (TEL) is an angiotensin II receptor blocker (ARB) antihypertensive agent. The aim of the present investigation was to develop a self-nanoemulsifying drug delivery system (SNEDDS) to enhance the oral bioavailability of poorly water soluble TEL. Materials and Methods: The solubility of TEL in various oils was determined to identify the oil phase of a SNEDDS. Various surfactants and co-surfactants were screened for their ability to emulsify the selected oil. Pseudoternary phase diagrams were constructed to identify the efficient self-emulsifying region. A SNEDDS was further evaluated for its percentage transmittance, emulsification time, drug content, phase separation, dilution, droplet size, zeta potential, pH, refractive index, and viscosity. Results: The developed SNEDDS formulation contained TEL (20 mg), Tween® 20 (43.33%w/w), Carbitol® (21.67%w/w), and Acrysol® EL 135 (32%w/w). The optimized formulation of the TEL-loaded SNEDDS exhibited a complete in vitro drug release in 15 min as compared with the plain drug, which had a limited dissolution rate. It was also compared with the pure drug suspension by oral administration in male Wister rats. The in vivo study exhibited a 7.5-fold increase in the oral bioavailability of TEL from the SNEDDS compared with the pure drug suspension. Conclusions: These results suggest the potential use of the SNEDDS to improve the dissolution and oral bioavailability of poorly water soluble TEL.

Studies in Dissolution Enhancement of Ezetimibe by Solid Dispersions in Combination with a Surface Adsorbent

The aim of this investigation was to improve the dissolution properties of the water-insoluble drug ezetimibe (EZE) and potentially improve bioavailability. A combination of melt and adsorption techniques was employed for the preparation of solid dispersions. PEG 4000, PEG 6000, and Gelucire 44/14 were used as hydrophilic carriers, and lactose monohydrate was used as an adsorbent. Phase solubility curves are of AL type, indicating a linear relationship between drug solubility and carrier concentration. Dissolution studies reveal an improvement of in vitro drug release. Mathematical modeling indicates that drug release data are best described by the Korsmeyer–Peppas model, with Fickian diffusion as the possible drug-release mechanism. Physicochemical characterization of solid dispersions by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD) suggests a reduction in drug crystallinity following dissolution enhancement. Hence, the present investigation reveals that the dissolution characteristics of EZE could be ameliorated in a solid dispersion. INTRODUCTION Out of several methods employed to enhance the dissolution characteristics of poorly water-soluble drugs, solid dispersion techniques have been widely reported by various researchers with encouraging results for different drugs. However, a solid dispersion system is somewhat limited by poor flow properties and poor stability. The processing variables of solid dispersions can be improved by the addition of adsorbent in the solid dispersion melt, thereby increasing the effective surface area of the drug leading to improved dissolution (1, 2). Various carriers have been used to prepare solid dispersion systems; among those, polyethylene glycols (PEG) and Gelucire 44/14 are employed in the present investigation. PEGs are used because of their low toxicity, high water solubility, low cost, and availability in a wide range of molecular weights. Gelucire 44/14 is a mixture of glycerol and PEG 1500 esters of long-chain fatty acids. The suffixes 44 and 14 refer to its melting point and its hydrophilic/lipophilic balance (HLB), respectively. PEG 4000, PEG 6000, and Gelucire 44/14 have been used successfully to improve the dissolution properties of poorly water-soluble drugs by preparing solid-dispersion systems (3–5). However, the solid dispersions prepared with these carriers are sticky and difficult to handle. Hence, they must be used in amalgamation with an adsorbent to improve their flow properties. Ezetimibe (EZE), 1-(4–fluorophenyl) –3(R)-[3-(4–fluorophenyl) –3(S) hydroxy-propyl]-4(S)-(4-hydroxyphenyl)-2azetidinone, is the first lipid-lowering drug that inhibits the intestinal uptake of cholesterol without affecting the absorption of fat-soluble nutrients. It is indicated as a monotherapy or in combination with statins for the treatment of hypercholesterolemia (6). EZE, being practically insoluble in water, exhibits a low dissolution profile in gastrointestinal fluids with variable bioavailability. Thus, researchers have investigated different approaches to ameliorate the dissolution characteristics of EZE (7–9) and optimize bioavailability with a less variable pharmacokinetic profile. In the present investigation, an attempt was made to improve the dissolution properties of EZE by preparing free-flowing solid dispersions. A combination of solid dispersion and adsorption techniques was employed for the preparation of the solid systems, using lactose monohydrate as adsorbent. The prepared solid dispersions were characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD). MATERIALS AND METHODS Materials EZE was kindly gifted by Mepro Pharmaceuticals Ltd. (Surendranagar, India). Gelucire 44/14 was a generous gift sample from Gattefosse Pvt. Ltd. (Mumbai, India). PEG 4000 and PEG 6000 were purchased from Sisco Research Lab Pvt. Ltd. (Mumbai, India). All reagents were of analytical grade. Double-distilled water was used throughout the work. Methods Phase Solubility Phase solubility studies were carried out as described by Higuchi and Connors (10). A quantity of EZE (about 10 mg) that exceeded its solubility was added to flasks containing 25 mL of solutions of different polymer *Corresponding author. diss-18-03-07.indd 55 8/31/2011 3:26:40 PM dx.doi.org/10.14227/DT180311P55

Solasodine protects rat brain against ischemia/reperfusion injury through its antioxidant activity

Ischemic stroke is the second leading cause of death worldwide. The major limitation of stroke management is the lack of clinically effective therapy. Antioxidants have been demonstrated as potent neuroprotective agents by enhancing the defense mechanism(s), whereas reducing the oxidative stress in the ischemic stroke models. In the present study, we evaluated neuroprotective potential of solasodine, an antioxidant glycoalkaloid of Solanum species, against global model of ischemia in rats. Ischemia/reperfusion (I/R)-injury produced marked elevation in lipid peroxidation (LPO) and nitric oxide (NO), whereas superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) levels were decreased in experimental animals. Prior administration of solasodine (100 and 200mg/kg, p.o.) significantly heightened SOD, CAT, GSH and total thiols, whereas reduced LPO and NO levels in the brain. Interestingly, brain coronal sectioning and histopathology studies revealed a marked reversal of I/R-provoked neuronal damage in the solasodine treatment groups. Taken together, our study, for the first time, demonstrates neuroprotective potential of solasodine against global ischemia-induced cerebral injury in experimental rats. We propose that the neuroprotection offered by solasodine could be attributed, at least in part, to its anti-oxidant property.