Ram Pratap

Gugulipid, an extract of Commiphora whighitii with lipid-lowering properties, has protective effects against streptozotocin-induced memory deficits in mice

Gugulipid, an ethyl acetate extract of the resin of plant Commiphora whighitii is an established hypolipidemic agent in clinical practice. The major constituent of gugulipid is guggulsterone [4, 17 (20)-pregnadiene-3, 16-dione]. It has been observed recently that patients receiving lipid-lowering drugs like statins have a reduced risk of dementia. Therefore, the present study was planned to explore the potential of gugulipid as cognitive enhancer. Gugulipid (12.5, 25 and 50 mg/kg, p.o.) showed dose dependent improvement in scopolamine-induced deficits in passive avoidance test. The maximal effective dose of gugulipid i.e. 50 mg/kg, p.o. was used for further studies on streptozotocin (STZ) model of dementia in mice. Gugulipid was investigated for its effect on learning and memory, parameters of oxidative stress (GSH and MDA) and acetylcholinesterase (AChE) activity in the STZ (ic)-treated mice. Intracerebral (ic) injections of STZ (0.5 mg/kg) on 1st and 3rd day caused significant deficit in memory in passive avoidance and Morris water maze test after the 14th day of first dose. In passive avoidance, transfer latency time (TLT) was not increased on retention trials in STZ (ic) group while gugulipid treatment resulted in significant increase in TLT on retention trials in STZ (ic)-treated mice. In Morris water maze test the latency time to reach platform in STZ (ic)-treated mice was significantly higher than control and vehicle (artificial CSF). Pre-treatment of gugulipid (50 mg/kg, p.o.) daily for 14 days started with the first dose of STZ (ic), significantly prevented STZ (ic)-induced memory deficit. Post-treatment i.e. after 14 days of first dose of STZ (ic) of gugulipid (50 mg/kg, p.o.) significantly decreased the latency time indicating anti-dementia activity. Effect of gugulipid and STZ in visible platform test was similar to those seen with hidden platform. Gugulipid and STZ-treated mice did not cause significant change in locomotor activity. Furthermore, STZ (ic) resulted into increase in AChE activity, low level of GSH and high concentration of MDA in brain on 21st day as compared to control. Gugulipid treatment caused significant decrease in AChE activity, low level of MDA and high concentration of GSH in brain following STZ (ic) as compared to vehicle administration in STZ (ic)-treated mice. The study demonstrated that gugulipid has significant protective affect against streptozotocin-induced memory deficits model of dementia that can be attributed to anti-oxidant and anti-AChE activity of gugulipid. These observations suggest gugulipid as a potential anti-dementia drug (CDRI, Lucknow has obtained US patent No. 6896901 for use of gugulipid as cognitive enhancer).

Cardioprotective activity of synthetic guggulsterone (E and Z-isomers) in isoproterenol induced myocardial ischemia in rats: A comparative study.

Guggulsterone, a mixture of cis (E) and trans (Z) isomers (7∶3 w/w) was synthesized from 16-DPA. The isomers were separated by column chromatography and evaluated for cardioprotective and antioxidant activities. Myocardial necrosis induced by isoproterenol in rats caused marked increase in serum creatine phosphokinase and glutamate pyruvate transaminase. Simultaneously in ischemic heart, phospholipase, xanthine oxidase and lipid peroxides were enhanced following depletion of glycogen, phospholipids and cholesterol. Treatment with guggulsterone and its both isomers at the dose of 50 mg/kg po., significantly protected cardiac damage as assessed by the reversal of blood and heart biochemical parameters in ischemic rats. The cardioprotective activity of guggulsterone and of both the isomers were compared with that of gemfibrozil at the same doses. Guggulsterone and both the isomers at tested concentrations (5–20mM) inhibited oxidative degradation of lipids in human low-density lipoprotein and rat liver microsomes induced by metal ionsin vitro. The drug counteracted against the generation of superoxide anions (O2) and hydroxyl radicals (OH−) in non-enzymic test systems. It is suggested that cardioprotective and antioxidant activities of synthetic guggulsterone and guggulsterone obtained from gum resinCommiphora mukul that contains isomers E & Z in the ratio of 46∶54w/w are the same.

Flavone-Based Novel Antidiabetic and Antidyslipidemic Agents

The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations.

Synthesis and antidyslipidemic activity of chalcone fibrates

A series of chalcone based PPAR-α agonists were synthesized and evaluated for their antidyslipidemic activity in high fructose high fat fed dyslipidemic Syrian golden hamsters. Most of the compounds exhibited antidyslipidemic activity. The compounds 4c and 4f have been identified as most potent antidyslipidemics. A definite structure-activity relationship was observed while varying the nature as well as the position of the substituent.

Dose escalation pharmacokinetics and lipid lowering activity of a novel farnesoid X receptor modulator: 16-Dehydropregnenolone

Objectives: To study the dose escalation pharmacokinetics and lipid lowering activity of a novel FXR modulator, 16-Dehydropregnenolone (DHP). Materials and Methods: The disposition of DHP following oral (36, 72, 100 and 150 mg/kg) and intravenous (1, 5 and 10 mg/kg) administration and its dose-response relationship were carried out in Sprague–Dawley rats. DHP and its metabolite 5-pregnene-3β-ol-16, 17-epoxy-20-one (M1) were analyzed by a validated LC-MS/MS method in plasma after intravenous and oral administration. Dose escalation lipid lowering activities were carried out by triton-induced hyperlipidemic model. Results: Oral administration resulted in higher amount of M1 formation as compared to intravenous administration. Dose escalation intravenous administration (1, 5 and 10 mg/kg) resulted in nonlinear increase in AUC of DHP. This was due to saturation of metabolism. On the contrary, systemic AUC and Cmax after oral administration show non-linear pharmacokinetics where saturated systemic DHP and M1 pharmacokinetics was observed above 72 mg/kg, indicating saturated oral absorption. Lipid lowering activity by its oral route of administration was in accordance with its pharmacokinetic profile and reached saturation above 72 mg/kg. Conclusion: DHP exhibits route and dose-dependent pharmacokinetics. Pharmacokinetic and lipid lowering activity by oral route indicate saturation of oral absorption at higher doses. The study contributes to the understanding of the plasma disposition pharmacokinetics of DHP and its metabolite in rats by oral and intravenous route of administration.

Antithrombotic effect of thiopurinol

Antithrombotic activity of ten pyrazolo pyrimidine derivatives was tested in mouse pulmonary thromboembolism model. Out of these compounds, Thiopurinol (C5H4N4S) showed dose-dependent protection in mice from death/paralysis induced by collagen + adrenaline. It also caused dose-dependent inhibition of thrombus formation in the cat. Thiopurinol inhibited aggregation of platelets induced by ADP and arachidonic acid but did not inhibit superoxide generation. It had no antiinflammatory activity nor any effect on cardiovascular system. The results indicate that the antithrombotic activity of the compound is mediated via inhibition of platelet aggregation.

A Simple Method for Synthesis of Spongosine, Azaspongosine, and Their Antiplatelet Effects

Abstract Reaction of 2-ethylthioadenine (1) with protected ribose (2) in the presence of stannic chloride gave 2-ethylthioadenosine (4). Oxidation of 5 with potassium permanganate yielded the corresponding sulfone (6) which furnished spongosine (7) after treatment with sodium methoxide. Similarly, reactions of 7-amino-5-ethylthio-1,2,3-triazolo[4,5-d]pyrimidine (8) with the ribose (2) gave 8-azaspongosine (13). The compounds (4) and 7 demonstrated potent antiaggregatory effects both in human platelet-rich plasma and whole blood, whereas, the aza analog (13) showed no inhibitory activity on platelet aggregation. Both (4) and (7) inhibit platelet aggregation in the presence of adenosine deaminase, whereas, adenosine is non-inhibitory, suggesting that analogs (4) and (7) are poor substrates for adenosine deaminase.

Acyclic Pyrazolo[3,4-d]Pyrimidine Nucleoside as Potential Leishmaniostatic Agent

A new synthesis of 6-amino-1-hydroxyethoxymethyl-4 (5H)-oxopyrazolo[3, 4]pyrimidine (4) has been mentioned. Compound 4 exhibited inhibition of amastigotes of Leishmania donovani to the extent of 89% at 30 μg/mL, whereas iso-guanine analogue 5 had the inhibition only to the extent of 52.8% at 100 μg/mL in vitro. In hamster model the maximum inhibitory response for compound 4 against amastigotes multiplication was observed to be 94% at 50 mg/kg single dose for 5 consecutive days. *CDRI Communication no. 6522.

Liquid chromatographic-tandem mass spectrometry assay for quantitation of a novel antidiabetic S002-853 in rat plasma and its application to pharmacokinetic study.

A sensitive and selective LC-MS/MS method has been developed and validated for the estimation of novel antidiabetic synthetic flavonoid S002-853 in rat plasma using centchroman as an internal standard. The method involves a simple two-step liquid-liquid extraction with diethyl ether. The analyte was chromatographed on a Pierce Spheri-5, guard cyano column (30 x 4.6 mm i.d., 5 microm) with isocratic mobile phase consisting of methanol-ammonium acetate buffer (pH 4.6, 10 mm; 90 : 10, v/v) at a flow rate of 0.75 mL/min. The API 4000 triple-quadrupole LC-MS/MS system was operated under multiple reaction-monitoring mode. The ionization was performed by electrospray ionization technique in positive ion mode. The chromatographic run time was 6 min and the weighted (1/x(2)) calibration curves were linear over the range 0.78-400 ng/mL. The limit of detection and lower limit of quantification were 0.195 and 0.78 ng/mL, respectively. The intra- and inter-batch accuracy (%bias) and precision (%RSD) were found to be less than 8.47 and 11.6% respectively. The average absolute recoveries of S002-853 and internal standard from spiked plasma samples were >90%. S002-853 was stable for 8 h at ambient temperature, 4 weeks at -60 degrees C and after three freeze-thaw cycles. The assay was successfully applied to determine the pharmacokinetic parameters in male Sprague-Dawley rats after an oral dose administration at 25 mg/kg.

Synthesis and Antiviral Activity of 3-(β-D-Ribofuranosyl)-1,2,4-oxadiazole-5-carboxamide

Abstract 3-(β-D-Ribofuranosyl)-1,2,4-oxadiazole-5-carboxamide (5) was prepared by condensation reaction of amidoxime 6 with monoethyl oxaloyl chloride followed by reaction with ammonia. The compound 5, however, did not exhibit any significant activity against herpes simplex virus type-I (HSV-I) and semliki forest virus (SFV).