Comparative clinical trial of castor oil and diclofenac sodium in patients with osteoarthritis.

A randomized, double-blind, comparative clinical study was conducted to compare the safety and efficacy of castor oil with diclofenac sodium in patients with knee osteoarthritis. Subjects with symptoms of knee osteoarthritis were given a castor oil capsule 0.9 mL (n = 50) thrice daily for 4 weeks or a capsule of diclofenac sodium (n = 50), 50 mg thrice daily for 4 weeks. The subjects completed an overall evaluation of symptom relief at 2 weeks and 4 weeks of completed treatment. The subjects were evaluated by clinical, routine laboratory and radiographic investigations for improvement of disease conditions and also for adverse drug reaction. On completion of 4 weeks treatment it was observed that both drugs were significantly effective in the treatment of knee osteoarthritis (p < 0.001) and adverse drug reactions were high with diclofenac sodium, whereas with castor oil there were no adverse effects reported. The present study indicates that castor oil can be used as an effective therapy in primary knee osteoarthritis.

Human genome project: pharmacogenomics and drug development.

Now that all 30,000 or so genes that make up the human genome have been deciphered, pharmaceutical industries are emerging to capitalize the custom based drug treatment. Understanding human genetic variation promises to have a great impact on our ability to uncover the cause of individual variation in response to therapeutics. The study of association between genetics and drug response is called pharmacogenomics. The potential implication of genomics and pharmacogenomics in clinical research and clinical medicine is that disease could be treated according to the interindividual differences in drug disposition and effects, thereby enhancing the drug discovery and providing a stronger scientific basis of each patient's genetic constitution. Sequence information derived from the genomes of many individuals is leading to the rapid discovery of single nucleotide polymorphisms or SNPs. Detection of these human polymorphisms will fuel the discipline of pharmacogenomics by developing more personalized drug therapies. A greater understanding of the way in which individuals with a particular genotype respond to a drug allows manufacturers to identify population subgroups that will benefit most from a particular drug. The increasing emphasis on pharmacogenomics is likely to raise ethical and legal questions regarding, among other things, the design of research studies, the construction of clinical trials and the pricing of drugs.

Role of nutrition in toxic injury.

The importance of nutrition in protecting the living organism against the potentially lethal effects of reactive oxygen species and toxic environmental chemicals has recently been realized. This new perspective has prompted re-evaluation of the food constituents of human diet from the point of view of their nutritional adequacy, deficiency and toxicity. The biological antioxidant defense system is an integrated array of enzymes, antioxidants and free radical scavengers. These include glutathione reductase, glutathione-s-transferase, glutathione peroxidase, phospholipid hydroperoxide glutathione peroxidase, superoxide dismutase (SOD) and catalase, together with the antioxidant vitamins C, E and A. The individual components of this system get utilized in various physiological process and for chemoprotection and therefore require replenishment from the diet. Other components of the diet like carbohydrates, proteins and lipids are important for maintaining the levels of various enzymes required in body's defense system providing protection against carcinogens. However, the emerging newer concepts focus on the role of trace elements and other dietary components in antioxidant defense and detoxification mechanisms. Trace elements like Iron, zinc magnesium, selenium, copper, and manganese are some of the elements involved in antioxidant defense mechanisms. Inadequate intake of these nutrients has been associated with ischemic heart disease, arthritis, stroke and cancer, where pathogenic role of free radicals is suggested. Further the importance of diet in the prevention of chemical induced toxicity can not be undetermined. Recent reports on the role of bioflavonoids as antioxidents and their potential use to reduce the risks of coronary heart disease and cancer in human beings have opened a new arena for future research. Induction of the cytochrome P450 isoenzymes by food pyrolysis, mutagens, alcohol and fasting, on the other hand is reported to contribute to chemical toxicity and carcinogenecity. Certain chemicals moieties in the food are mutagenic and carcinogenic.

Effect of flavone in a canine model of myocardial stunning.

Putative cardioprotective action of flavone (10, 20 and 30 mg/kg) was investigated in a canine model of regional ischemia (20 min) followed by 60 min of reperfusion. In animals pretreated with vehicle, myocardial stunning was evidenced by significant changes in hemodynamic parameters (depressed mean arterial pressure, LV peak (+) dP/dt, LV peak (-) dP/dt and elevated LV end-diastolic pressure) and biochemical parameters (decreased myocardial ATP and rise in plasma malondialdehyde or MDA; a marker of free radical-induced injury). A reduction in plasma MDA was noted with 20 and 30 mg/kg flavone, although attenuation of myocardial dysfunction was evident with all the three doses. The results suggest that besides a significant dose-dependent antioxidant effect, flavone may also have some cardioprotective actions per se, which needs to be further investigated.

Role of Lipistat in protection against isoproterenol induced myocardial necrosis in rats: a biochemical and histopathological study.

A test drug (Lipistat) comprising of equal-proportions of extracts of Terminalia arjuna, Inula racemosa Hook, latex of Commiphora mukul, in three different doses (225 mg/kg; 350 mg/kg; 450 mg/kg) were administered orally daily for 6 days a week for 60 days in rats. Thereafter, the rats were subjected to isoproterenol (ISO) induced (85 mg/kg, s.c. for 2 days) myocardial necrosis. Gross and microscopic examinations (histopathology) were done along with estimations of myocardial tissue high energy phosphates (HEP) stores and lactate content. Gross examination showed significant (P < 0.05) cardioprotection in Lipistat treated animals. On microscopic examination no statistically significant reduction in myocardial damage by 350 and 450 mg/kg of Lipistat were observed although loss of myocardial HEP stores and accumulation of lactate were significantly prevented. The results of the present study suggest the potential usefulness of Lipistat in the prevention of ischemic heart disease.

Effects of supplementation with iloprost on the cardioprotection by BW755C (a dual inhibitor of cyclooxygenase and lipoxygenase enzymes) in myocardial reperfusion injury.

The effect of BW755C (a dual inhibitor of cyclo- and lipoxygenase enzymes) alone and in combination with iloprost (a PGI2 analogue) on myocardial reperfusion injury was investigated in anaesthetised open-chest dogs. The left anterior descending coronary artery was occluded for a period of 40 min followed by reperfusion for 3 h. Dogs were administered either saline, BW755C (10 mg kg-1 slow bolus) or BW755C plus iloprost (100 ng kg-1 min-1 for 75 min) just prior to reperfusion. The haemodynamic data showed significant reduction in MAP and both LV peak-positive and peak-negative dP/dt following reperfusion in the saline-treated group, along with a delayed recovery of LVEDP. These changes were accompanied by significant depletion of myocardial ATP and glycogen stores. Administration of BW755C prevented the haemodynamic changes and replenished the HEP stores. Although coadministration of iloprost with BW755C afforded early normalisation of LVEDP and LV peak positive dP/dt, but MAP and LV peak negative dP/dt remained significantly depressed. Therefore, it might be concluded from this study that supplementation of BW755C with iloprost may have deleterious haemodynamic effects on the reperfused myocardium, particularly in the doses used.

Effect of short and long-term exposure to diesel exhaust on sensitivity of guinea pig tracheal preparation to histamine.

Single exposure, to diesel exhaust (1 part exhaust diluted by 5 parts of clean air) reduced EC50 of histamine indicating hyperresponsiveness of the receptors in trachea of exposed guinea pigs. In contrast, following repeated exposure for 7, 14 or 21 days (15 min/day), EC50 was progressively increased indicating the possibility of down-regulated histamine receptors. Further, simultaneous significant increase in histamine levels (bioassayed on guinea pig ileum) in bronchial airway lavage fluid supports the aforementioned hypothesis. The change in lung/body weight ratio and suspended particulate matter deposited on filters followed the same temporal pattern as EC50. The findings are suggestive of differential effects of diesel exhaust on airway depending upon the duration of exposure.

Antiemetic efficacy of ginger (Zingiber officinale) against cisplatin-induced emesis in dogs.

Effect of ginger (Zingiber officinale Roscoe, Zingiberaceae) extracts (acetone, 50% ethanolic and aqueous) were investigated for antiemetic activity against emesis induced by 3 mg/kg cisplatin (the 100% emetic dose i.v.) in-healthy mongrel dogs. The acetone and 50% ethanolic extract at the doses of 25, 50, 100 and 200 mg/kg p.o. exhibited significant protection while aqueous extract at these doses was ineffective against cisplatin emesis. The acetone extract was more effective than ethanolic extract. However, both were less effective when compared to 5-HT3 receptors antagonist-granisetron. Neither of the ginger extract was effective against apomorphine-induced emesis. The findings suggest that ginger could be an effective and cheap antiemetic adjunct to cancer chemotherapy.

Lack of any additional benefit in combining aspirin with iloprost in a canine model of myocardial reperfusion injury.

The effects of iloprost infusion (100 ng/kg/min for 75 min) alone and in combination with aspirin (3 mg/kg IV bolus) were compared in a canine model of myocardial reperfusion injury. Regional ischemia of 40 min was produced by temporary occlusion of the left anterior descending coronary artery, after which the myocardium was reperfused for a period of 3 hours. Mean arterial pressure (MAP), heart rate (HR), left ventricular end diastolic pressure (LVEDP), positive (+) LVdP/dtmax and negative (-) LVdP/dtmax were monitored. Rate pressure product and (-) dP/dt/Pmax were also derived from the above. Myocardial tissue levels of adenosine triphosphate (ATP), creatine phosphate (CP), glycogen and lactate were estimated. Following reperfusion in the saline treated group, there was a significant fall in (i) MAP, (ii) (+) LVdP/dtmax and (iii) (-) LVdP/dtmax. LVEDP was corrected about 2 hours after reperfusion. Despite correction of lactate accumulation, ATP and glycogen were not restored although the CP store was replenished. The hemodynamic profiles in both iloprost and in combination treated groups were similar; (i) depressed MAP (particularly during iloprost infusion) without any significant change in HR (ii) no significant depression in (+) LVdP/dtmax (iii) depression in (-) LVdP/dtmax but not when corrected for lower Pmax and (iv) a significant reduction in the incidence of reperfusion arrhythmias. Similarly, in both the drug/s treated groups, ATP, CP and lactate were normalised although glycogen store was not restored. The results of this study indicate (i) cardioprotective effect of iloprost even when administered prior to reperfusion and (ii) no additional protective effect of combining iloprost and aspirin.

Involvement of renin-angiotensin system in hypertensive effect of cadmium in rats.

Role of renin-angiotensin system in hypertension induced by cadmium chloride (CdCl2) in rats has been investigated. Intravenous administration of CdCl (1 mg/kg) produced a biphasic response i.e. a transient fall followed by a marked and consistent rise in blood pressure. The peak hypertensive effect was accompanied by raised PRA levels. Pretreatment with captopril (1 mg/kg, i.v.) losartan (1 mg/kg, i.v.) or captopril + losartan attenuated the pressor response to Cd by 62%, 42% and 100% respectively in separate groups. Central administration of Cd (10 micrograms/rat, i.c.v.) showed a biphasic response similar to that observed after i.v. route. However, it was not accompanied by raised PRA levels. Prior treatment with losartan (10 micrograms/rat, i.c.v.) completely abolished the pressor response to Cd (i.c.v.) whereas it was not affected significantly by captopril (10 micrograms/rat, i.c.v.). On the other hand, centrally administered losartan only partially reduced the pressor response to i.v. Cd. The results are discussed in light of a differential involvement of central vs peripheral renin-angiotensin system in the hypertensive effect of Cd.

Cadmium induced nephrotoxicity in rats.

Onset of hypertension and nephropathy after 1,2, and 4 weeks of exposure to cadmium chloride (1 mg/kg, ip) was studied in rats by measuring changes in blood pressure and renal function (urinary output, electrolytes, serum creatinine, inulin clearance and Na+K+ ATPase). Significant decrease in body weight and rise in blood pressure were observed as early as one week of exposure while microalbuminuria was detected in 50% of the animals after 2 weeks. Na+K+ ATPase, a renal tubular enzyme, was depressed after 1 week with maximum lowering occurring after 4 weeks. There were no detectable changes in fluid intake, urine output, electrolytes, inulin clearance and serum creatinine even after 4 weeks. It is concluded that hypertension and tubular lesion set in earlier than glomerulopathy as indicated by microalbuminuria and the latter could be the consequence of rise in blood pressure.

Protective actions of a thromboxane receptor antagonist, SQ 29548 on the ischemic myocardium: morphologic and hemodynamic effects.

The effects of thromboxane A2 (TXA2)/prostaglandin endoperoxide receptor blockade on myocardial infarct size and cardiac dynamics were determined in a canine model of 24 h acute myocardial infarction. Anesthetized open-chest dogs were subjected to left anterior descending (LAD) coronary artery occlusion. Twenty minutes post-occlusion the dogs were given i.v. saline (0.9% NaCl solution) (n = 12) or the TXA2 receptor antagonist SQ 29548 (0.2 mg/kg i.v. loading dose +0.2 mg/kg/h i.v. for 4 h) (n = 10). SQ 29548 treatment resulted in a significant (P < 0.01) reduction in infarct size. Heart rate (HR) and systolic blood pressure (SAP) were not markedly affected by the drug. The sharp rise in the left ventricular end diastolic pressure (LVEDP) in the saline-treated animals was significantly lowered by SQ 29548 treatment and the correction of this variable was maintained till 24 h post-occlusion. The lowered maximal rate of rise of left ventricular pressure (LVdP/dt max) in the saline-treated animals was corrected albeit non-significantly by the drug treatment. Thus, SQ 29548 treatment resulted in a significant salvage of myocardial tissue and marked alterations in left ventricular dynamics. The study suggests a deleterious role for thromboxane A2 in ischemia; indicating that TXA2 blockade may have potential as a mode of therapy for ischemic heart disease.

An experimental study on cardiotoxicity of aluminium phosphide.

Aluminium phosphide(AlP), a grain fumigant pesticide, was studied for its cardiotoxicity in anaesthetised rats. The hemodynamic and cardiac biochemical changes were investigated following intragastric administration of different doses of AlP (10, 20 and 40 mg). With 10 and 20 mg dose of AlP an immediate fall in BP was observed which recovered partially and stabilized for 10 minutes followed by a gradual fall till the animal died. However, with a higher dose (40 mg) there was no recovery in BP, instead the initial fall continued till the death of the animal. An increase in the heart rate was observed with 10 and 20 mg dose of AlP for 15 minutes which was followed by a marked fall till cardiac arrest ensued. On the other hand, 40 mg dose produced only a transient tachycardia followed by a prolonged bradycardia. ECG changes at all dose levels included initial tachycardia and ST segment elevation progressing to QRS broadening. However, marked conduction defects as evidenced by the ventricular ectopics were noticed only with 40 mg. The mean survival time dose dependently decreased with 10 mg(55 +/- 3 min), 20 mg(35 +/- 2 min) and 40 mg(18 +/- 2 min) of AlP. The cardiac glycogen, ATP and CP levels were significantly lowered in animals treated with 10, 20 and 40 mg of AlP. Higher levels of MDA in the cardiac tissue were observed with 10, 20 and 40 mg of AlP. Thus it is suggested that the deleterious effect of AlP on heart is mediated by both declined cellular metabolism of the myocardium as well as by necrosis of the cardiac tissue resulting in the release of reactive oxygen intermediates.