S.K. Gupta

Piperine in food: Interference in the pharmacokinetics of phenytoin

SummaryThis study was carried out to explore the effect of piperine-containing food in altering the pharmacokinetics of phenytoin, an antiepileptic drug with a narrow therapeutic index. A preliminary pharmacokinetic study was carried out in mice by administering phenytoin (10 mg) orally, with or without piperine (0.6 mg). Subsequently, oral pharmacokinetics of phenytoin was carried out in six healthy volunteers in a crossover design. Phenytoin tablet (300 mg) was given 30 minutes after ingestion of a soup (melahu rasam) with or without black pepper. A further study of intavenous pharmacokinetics of phenytoin (1 mg) in rats with or without oral pretreatment with piperine (10 mg) was also conducted. The phenytoin concentration in the serum was analyzed by HPLC. The study showed a significant increase in the kinetic estimates of Ka, AUC(0−10) and AUC(0−∞) in the piperine-fed mice. Similarly, in human volunteers piperine increased Ka, AUC(0−48), AUC(0−∞), and delayed elimination of phenytoin. Intravenous phenytoin in the oral piperine-treated rat group showed a significant alteration in the elimination phase indicating its metabolic blockade. The significance of this finding in epileptic patients maintained on phenytoin therapy requires further investigation. This study may also have implications in the case of other drugs having a low therapeutic index.

Comparison of Analgesic and Anti-Inflammatory Activity of Meloxicam Gel with Diclofenac and Piroxicam Gels in Animal Models: Pharmacokinetic Parameters after Topical Application

Meloxicam, a non-steroidal anti-inflammatory drug, is a preferential inhibitor of cyclooxygenase-2 and has demonstrated potent analgesic and anti-inflammatory activity after oral administration. The present work was carried out to elucidate the anti-inflammatory and analgesic activity of a newer topical gel formulation of meloxicam (1% w/w gel) and compare it with 0.5% w/w piroxicam and 1% w/w diclofenac gels in experimental animal models. The study was also extended to determine the pharmacokinetic profile of a newer formulation of meloxicam gel after topical application on depilated skin of rats. The anti-inflammatory activities of meloxicam, piroxicam and diclofenac gels were compared using carrageenan-induced acute paw oedema and complete Freund’s adjuvant-induced chronic paw oedema in rats. Meloxicam gel showed increased protection against inflammation as compared to piroxicam and diclofenac gels. Acetic acid-induced writhing and formalin-induced phase I and phase II pain models were used to compare their analgesic activity. Meloxicam gel showed significant protection in formalin-induced phase II pain whereas its analgesic activity was less as compared to diclofenac and piroxicam gels in writhing test and formalin-induced phase I pain. The pharmacokinetic studies showed peak plasma drug concentration (Cmax) of 48.48 ± 6.57 µg/ml at 2 h (Tmax) after topical application of 500 mg of meloxicam gel formulation. The area under the curve as calculated from 0 to 6 h was found to be 114.18 ± 4.23 and 194.13 ± 3.78 µg·h/ml for 0 to ∝. The results indicate that topical preparation of meloxicam could be an effective alternative to diclofenac and piroxicam gels in inflammatory conditions and its associated pain with the possibility of less systemic side-effects.

Analgesic efficacy and pharmacokinetics of topical nimesulide gel in healthy human volunteers: double-blind comparison with piroxicam, diclofenac and placebo

AbstractObjective: The present study was conducted to compare the analgesic efficacy of a new topical gel formulation of nimesulide (10 mg of pure drug) with that of placebo, diclofenac and piroxicam gels (10 mg of pure drug) in three parallel groups in a double-blinded, randomized fashion with vehicle placebo. The analgesic activity of nimesulide was subsequently correlated with its pharmacokinetic profile. Methods: The drugs were applied on a fixed marked area on the skin of the right forearm. Pain stimulus was administered using a modification of the Hollander method, before and at 15, 30, 60, 120 min and 240 min post-treatment. The pain experienced by the subjects was ranked separately on the visual analogue scale (VAS) and the ten-point category scale. Antinociception induced by the treatments was evaluated through the placebo-related ratings (PRR) and total pain relief (TOTPAR) analysis. The plasma concentration of nimesulide was estimated using high-performance liquid chromatography (HPLC). Results: Nimesulide exhibited better efficacy than diclofenac, piroxicam and placebo. It demonstrated faster onset of action in concordance with earlier studies. Peak analgesic effect was observed at 120 min post-treatment, which correlated with the pharmacokinetic profile of the drug in gel formulation. In this study, diclofenac was found to be superior to piroxicam though both drugs exhibited peak analgesic effect at 60 min post-treatment. In the modified Hollander method, a good correlation was found between the ten point category scale and the VAS, indicating that it may serve as a sensitive and reliable method for the screening of analgesic drugs. Conclusion: The superior analgesic activity of nimesulide (as gel formulation), correlating with its pharmacokinetic profile, indicates that the topical route of administration may be a safe and effective alternative to the presently used oral and rectal routes.

Encapsulation in Cationic Liposomes Enhances Antitumour Efficacy and Reduces the Toxicity of Etoposide, a Topo-Isomerase II Inhibitor

Etoposide exerts its antineoplastic effect by forming a ternary complex with topo-isomerase II and DNA, leading to DNA breaks and cell death. However, it causes myelosuppression and its lipophilicity poses a major limitation during administration. Liposomes have been reported to increase the efficacy and reduce the toxicity of antineoplastic agents. Recent evidence suggests that cationic liposomes bind efficiently to tumours. The present study was thus designed to encapsulate etoposide in cationic liposomes and to evaluate its antitumour efficacy and systemic toxicity in comparison with a conventional parenteral formulation. Etoposide encapsulated in liposomes was synthesised by thin film hydration followed by an extrusion method. Fibrosarcoma was induced in mice by subcutaneous administration of 20-methylcholanthrene. Chemotherapy was started when the tumour reached 200 mm3 in volume. Liposomal etoposide (10 mg/m2/day for 5 days) significantly delayed tumour growth as compared to non-liposomal etoposide. The median time of death was calculated to be 19.5, 26.25 and 56 days in vehicle-treated controls, non-liposomal-etoposide- and liposomal-etoposide-treated groups, respectively. A transient reduction in body weight was seen in both the liposomal- and non-liposomal-etoposide-treated groups. The maximum tolerated dose was however significantly higher in the group treated with liposomal etoposide, which also exhibited a lesser degree of myelosuppression than the animals treated with non-liposomal etoposide. The present findings suggest that cationic liposomes could be considered as potential for delivery of etoposide to tumours.

Comparative Analgesic Activity of Nimesulide and Diclofenac by Intramuscular Route: Correlation with Pharmacokinetic Profile of Nimesulide

Nimesulide, a selective cyclooxygenase-2-inhibiting nonsteroidal anti-inflammatory drug, has been found to be a potent anti-inflammatory and analgesic drug, when administered orally, rectally or topically. The aim of the present study was to evaluate the comparative efficacy of intramuscularly injected nimesulide with that of diclofenac and to elucidate the pharmacokinetic profile of this formulation. Swiss albino mice were used in the experiment. Analgesic activity was tested using the acetic acid writhing test and the tail-flick latency test. Plasma levels of nimesulide and its active metabolite, hydroxynimesulide, were determined by a HPLC method. A peak analgesic effect was observed between 60 and 120 min, while Cmax (10.6 ± 3.8 µg/ml) of nimesulide was reached at 60 min (Tmax). Analgesia was induced within 15 min of administration of nimesulide and was significantly higher than that of diclofenac at 90 and 120 min posttreatment in the writhing reflex and at 60 and 90 min in the tail-flick latency test. The results indicate that intramuscularly injected nimesulide may be an alternative mode of administration in uncooperative patients or when immediate analgesic effects are warranted.

Comparative Analgesic Efficacy of Nimesulide and Diclofenac Gels after Topical Application on the Skin

Nimesulide is a newer non-steroidal anti-inflammatory drug (NSAID) with selective cyclo-oxygenase (COX)-2 blocking property and has demonstrated a potent analgesic and anti-inflammatory activity on oral and rectal administration. However, the Cmax through both these routes is reached only after 3 h of administration. Dose-dependent gastrointestinal side effects also limit the concentration of drug that can be achieved at the site of inflammation when administered through these routes. The present study was conducted to evaluate the antinociception induced by a new gel formulation of nimesulide when applied on the skin. Efficacy of topical nimesulide gel 1% (w/w) was studied on mice in the acetic-acid-induced writhing, tail flick latency (TFL) test and formalin-induced pain models. The antinociceptive effect of nimesulide was compared to diclofenac gel (1% w/w). Both the drugs induced dose-dependent analgesia with peak effect seen between 90 and 120 min after treatment. Greater antinociceptive effect (expressed as percent maximum possible effect) was seen in the writhing test than in the TFL test, indicating the peripheral action of both drugs. Nimesulide evidenced significant protection in the first phase of formalin-induced pain indicating modulation of peripheral nociceptors unlike other conventional NSAIDs. This suggests that COX-2 may be a primary contributor to afferent evoked increase in prostanoid-mediated changes in pain processing. Antinociception seen following drug application on the skin was lower than that seen on intraperitoneal administration, indicating localised action following topical application. The findings of the present study suggest that the transgel formulation of nimesulide provides significant analgesic activity when applied topically.

ANTI-INFLAMMATORY ACTIVITY OF TOPICAL NIMESULIDE GEL IN VARIOUS EXPERIMENTAL MODELS

Abstract1|Objective and Design The anti-inflammatory activity of topically applied nimesulide gel was compared in different experimental models with that of diclofenac and piroxicam gels.2|Material Wistar albino rats of either sex were used.3|TreatmentIn acute models, 50 mg of nimesulide or diclofenac were applied to right hind paws 1 h (carrageenan) or immediately before (formalin) irritant injection (sub-plantar). In adjuvant arthritis, 50 mg of nimesulide, diclofenac or piroxicam were applied daily to injected paws for 14 days.4|Methods Paw volume was measured by plethysmograph. Statistical significance was tested with Students t-test.5|Results In the carrageenan paw odema, topical nimesulide gel exhibited similar anti-inflammatory activity to diclofenac gel, and was more effective than diclofenac gel in formalin-paw odema. In both acute (18h) and chronic (14d) phases of adjuvant arthritis, nimesulide gel was more effective than diclofenac or piroxicam gels.6|Conclusion Topical nimesulide gel possesses higher anti-inflammatory activity than that of diclofenac or piroxicam gels.

Influence of piperine on nimesulide induced antinociception

Piperine (1‐peperoyl piperidine), an alkaloid extracted from Piper nigrum Linn is an inhibitor of hepatic and other enzymes involved in the biotransformation of drugs. In the present study piperine showed a dose dependent synergistic effect on nimesulide induced antinociception, in the acetic acid induced writhing test in mice. Piperine at a dose of 10 mg/kg significantly (p < 0.001) increased the analgesic activity of nimesulide administered at a submaximal dose of 6.5 mg/kg. In the formalin test, nimesulide alone (10 mg/kg, oral) did not modify phase I or nociceptor mediated pain while a combination of nimesulide (10 mg/kg) with piperine (10 mg/kg) significantly decreased it. In phase II or inflammatory pain, duration of formalin induced behaviour was 80 ± 7 s, 61 ± 7.3 s and 5.33 ± 3.3 s in control, nimesulide treated and piperine plus nimesulide treated groups respectively, indicating a synergistic activity of piperine with nimesulide. The antinociceptive effect correlated well with increased plasma concentration of nimesulide. The plasma concentration after oral administration of nimesulide (10 mg/kg) alone was 8.03 ± 0.99 ug/mL. However, when it was administered with piperine (10 mg/kg), the plasma concentration of nimesulide increased to 11.9 ± 0.23 ug/mL. This indicates that piperine inhibits the biotransformation and metabolism of nimesulide leading to significantly (p < 0.05) higher levels of drug in the systemic circulation. The findings of the present study suggest that piperine could be used as a biological enhancer when coadministered with nimesulide.

Evaluation of the Antitumour Activity of Liposomal Formulations of Etoposide Against Choriocarcinoma Xenografts in Balb/c nu/nu Mice

Conventional delivery of etoposide for anticancer therapy is restricted by its lipophilicity and vehicle-associated adverse effects. Liposomes have been reported to increase the efficacy and reduce the toxicity of antineoplastic agents. This study was conducted to evaluate novel cationic and sterically-stabilized long-circulating pegylated liposomal formulations of etoposide against JEG3 cell-induced choriocarcinoma xenografts in Balb/c nu/nu mice. Small unilamellar liposomes loaded with etoposide were prepared by thin-film hydration followed by an extrusion method. The total encapsulation of etoposide was 3.6 and 2.74 mol % for cationic and pegylated liposomes, respectively. At a dose of 10 mg m−2/day for 5 days, both the formulations significantly delayed tumour growth and increased the lifespan of the host compared with conventional delivery of etoposide. Liposomes could thus be considered as potential useful carriers for the delivery of etoposide.

Cisplatin-induced pica behaviour in rats is prevented by antioxidants with antiemetic activity

Pica, eating of non-nutritive substances such as kaolin in rats has been suggested as an illness response behaviour, analogous to vomiting in species that have developed emetic reflex. We have recently demonstrated that antioxidants-glutathione, N-(2- mercaptopropionyl)glycine (tiopronin), vitamin C and vitamin E-exert antiemetic effect against cisplatin-induced emesis in dogs. In the present study, the effect of these antioxidants was investigated against pica model in rats. Pretreatment with these agents significantly inhibited the cisplatin induced enhanced kaolin intake. However, these agents failed to exert any significant improvement in the decreased food intake by cisplatin. The findings confirm the potential of these antioxidants as antiemetics against cancer chemotherapy induced vomiting, though they may not improve the anorexia. The experiments further support that pica in rats can be used as a good alternative rodent model to dogs and cats particularly for preliminary and rapid screening of antiemetic agents.