B. Dinesh Kumar

In vitro drug release studies on guar gum-based colon targeted oral drug delivery systems of 5-fluorouracil.

Intravenous administration of 5-fluorouracil for colon cancer therapy produces severe systemic side-effects due to its cytotoxic effect on normal cells. The broad objective of the present study was to develop novel tablet formulations for site-specific delivery of 5-fluorouracil to the colon without the drug being released in the stomach or small intestine using guar gum as a carrier. Fast-disintegrating 5-fluorouracil core tablets were compression coated with 60% (FHV-60), 70% (FHV-70) and 80% (FHV-80) of guar gum, and were subjected to in vitro drug release studies. The amount of 5-fluorouracil released from the compression-coated tablets in the dissolution medium at different time intervals was estimated by a HPLC method. Guar gum compression-coated tablets released only 2.5-4% of the 5-fluorouracil in simulated GI fluids. When the dissolution study was continued in simulated colonic fluids (4% w/v rat caecal content medium) the compression-coated FHV-60, FHV-70 and FHV-80 tablets released another 70, 55 and 41% of the 5-fluorouracil respectively. The results of the study show that compression-coated tablets containing 80% (FHV-80) of guar gum are most likely to provide targeting of 5-fluorouracil for local action in the colon, since they released only 2.38% of the drug in the physiological environment of the stomach and small intestine. The FHV-80 formulation showed no change either in physical appearance, drug content or dissolution pattern after storage at 40 degrees C/RH 75% for 6 months. The differential scanning calorimetric study showed that 5-fluorouracil did not interact with the formulation excipients used in the study.

Development of colon targeted drug delivery systems for mebendazole.

The objective of the present study is to develop colon targeted drug delivery systems for mebendazole using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for drug content uniformity, and were subjected to in vitro drug release studies. The amount of mebendazole released from the matrix tablets at different time intervals was estimated by a high-performance liquid chromatography method. Guar gum matrix tablets released 8-15% of the mebendazole in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids the matrix tablets containing 20% of guar gum released another 83% of mebendazole after degradation into 2-3 pieces. The matrix tablets containing 30% of guar gum also released about 50% of mebendazole in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that matrix tablets containing either 20% or 30% of guar gum are most likely to provide targeting of mebendazole for local action in the colon. The mebendazole matrix tablets containing either 20% or 30% of guar gum showed no change either in physical appearance, drug content or dissolution pattern after storage at 45 degrees C/75% relative humidity for 3 months. Differential scanning calorimetry indicated no possibility of interaction between mebendazole and guar gum.

In vivo pharmacokinetics in human volunteers: oral administered guar gum-based colon-targeted 5-fluorouracil tablets

The objective of the present study is to compare the guar gum-based colon-targeted tablets of 5-fluorouracil against an immediate release tablet by in vitro dissolution and in vivo pharmacokinetic studies in human volunteers. Twelve healthy volunteers participated in the study. 5-Fluorouracil was administered at a dose of 50 mg both in immediate release tablet and colon-targeted tablet. On oral administration of colon-targeted tablets, 5-fluorouracil started appearing in the plasma at 6 h, and reached the peak concentration (C(max) of 216+/-15 ng/ml) at 7.6+/-0.1 h (T(max)), whereas the immediate release tablets produced peak plasma concentration (C(max) of 278+/-21 ng/ml) at 0.6+/-0.01 h (T(max)). The AUC(0- infinity ) for 5-fluorouracil from colon-targeted tablet and immediate release tablet were found to be 617+/-39 and 205+/-21 ng/ml/h, respectively. Colon-targeted tablets showed delayed t(max), delayed absorption time (t(a)), decreased C(max) and decreased absorption rate constant when compared to the immediate release tablets. The results of the study indicated that the guar gum-based colon-targeted formulation did not release the drug in stomach and small intestine, but delivered it to the colon resulting in a slow absorption of the drug and making it available for local action in colon.

A drug survey - precepts and practices

SummaryAn attempt has been made to quantitate drug consumption in a conurbation. The prescribing habits of physicians, self medication rate and therapeutic classes of drugs purchased have been evaluated. The study indicates that some of the prevailing practices in the area are unhealthy. The high self medication rate, faulty prescribing habits of physicians and liberal dispensing methods of pharmacist need to be viewed with concern. The wide gap between the precepts and practices prevailing among practitioners, the use of potent medicines without proper medical advice and the uninhibited sale of scheduled drugs over the pharmacy counter require careful consideration. If such unhealthy trends persist iatrogenic problems may surface in the near future. The physician, pharmacist and the public need to cooperate to create the proper pattern of drug usage.

Studies on the development of colon-targeted delivery systems for celecoxib in the prevention of colorectal cancer.

The nonsteroidal anti-inflammatory drugs (NSAIDs) are found to be potential chemopreventive agents of colorectal cancer. Celecoxib, an NSAID with selective cyclooxygenase-2 inhibition, was proved to be effective for the prevention of colon cancer in patients with familial adenomatous polyposis (FAP) and sporadic polyps. In the light of this information, the present study was carried out to develop oral colon-targeting drug delivery systems for celecoxib using guar gum as a carrier. Matrix tablets containing various proportions of guar gum were prepared by wet granulation technique using starch paste as a binder. The tablets were evaluated for hardness, drug content and were subjected to in vitro drug release studies. The amount of celecoxib released from the matrix tablets at different time intervals was estimated by a HPLC method. Guar gum matrix tablets released only 2-4% of celecoxib in the physiological environment of stomach and small intestine depending on the proportion of guar gum used in the formulation. When the dissolution study was continued in simulated colonic fluids (rat caecal content medium), the matrix tablets containing 20% of guar gum released another 37% of celecoxib after degradation by the colonic bacterial action. The matrix tablets containing 30% of guar gum released about 24% of celecoxib in simulated colonic fluids indicating the susceptibility of the guar gum formulations to the rat caecal contents. The results of the study show that the matrix tablets containing either 20 or 30% of guar gum are most likely to target celecoxib for local action in the colon. The guar gum matrix tablets of celecoxib showed no change either in physical appearance, drug content or in dissolution pattern after storage at 40°C/RH 75% for 6 months. Differential scanning calorimetry (DSC) studies indicated no possibility of interaction between celecoxib and guar gum/other formulation excipients.

Detection of Occupational Lead Nephropathy Using Early Renal Markers

Automotive use of leaded gasoline continues to be an important source of occupational exposure to lead in India and other countries. The present study assessed the renal function and markers of early renal damage of 22 mechanics at three automobile garages. Urinary N-acetyl-3-D-glucosaminidase activity and beta-2-microglobulin levels were significantly increased in auto garage mechanics with blood leads of 30-69 micrograms/dL. A significant correlation was observed between blood lead levels and urinary N-acetyl-3-D-glucosaminidase activity but not with urine beta-2-microglobulin levels. A marginal impairment in creatinine clearance was not statistically significant. Urinary N-acetyl-3-D-glucosaminidase activity offers a sensitive monitor of blood lead and renal tubular injury.

In vivo evaluation of guargum-based colon-targeted oral drug delivery systems of celecoxib in human volunteers

SummaryThe present study involved the in vivo evaluation of orally administered guar gum-based colon-targeted tablet formulations of celecoxib (colon-targeted tablet-20 or colon-targeted tablet-30) as compared with an immediate release capsule in 15 human volunteers. Blood samples were obtained at different time intervals and the plasma concentration of celecoxib was estimated by reversed phase HPLC. The immediate release capsules of celecoxib might have disintegrated very fast in GI tract and absorbed quickly from stomach and small intestine thereby producing peak plasma concentration (Cmax of 478±57 ng/ml) within 3.8±0.1 h (Tmax). Though celecoxib could be seen in plasma after oral administration of colon-targeted tablet-20 or colon-targeted tablet-30 between 1 and 2 h, low levels of drug were observed upto 8h resulting in peak concentration (Cmax) of 78±6ng/ml or 88±15ng/ml at 10.5±1.9 h or 13.5±1.4 h (Tmax) respectively, whereas the immediate release capsules produced peak plasma concentration (Cmax) of 478±57 ng/ml at 3.8±0.1h (Tmax). Colon-targeted tablets showed decreased AUC0–∞, Cmax and absorption rate constant, prolonged absorption time (ta), and increased t1/2 in comparison with the immediate release capsules. The results of the study indicated that the guar gum-based colon-targeted tablets of celecoxib did not release the drug significantly in stomach and small intestine, but delivered to the colon resulting in a slow absorption of the drug and making it available for local action in the colon.

Lead and trace element levels in placenta, maternal and cord blood: A cross-sectional pilot study

To determine lead (Pb) and trace element (Fe, Zn, Cu, Mg) levels in placenta, maternal and cord blood; further, to assess the interactions between Pb and trace elements, if any.

Hesperidin, a citrus flavonoid, protects against l-methionine-induced hyperhomocysteinemia by abrogation of oxidative stress, endothelial dysfunction and neurotoxicity in Wistar rats

Abstract Context: Hesperidin (HSP), a flavanoglycone found in citrus fruits, has antioxidant, anti-inflammatory and neuroprotective properties. Objective: This study evaluates the protective effect of HSP on l-methionine-induced hyperhomocysteinemia (HHcy) in rats. Materials and methods: Male Wistar rats were randomly divided into seven groups as DMSO, l-methionine, HSP (25, 50 and 100 mg/kg), HSP-per se (100 mg/kg) and donepezil (0.1 mg/kg). HHcy was induced by oral administration of l-methionine (1.7 g/kg) for 32 days. From the 14th day of study HSP (25, 50 and 100 mg/kg) and donepezil was administered orally to l-methionine-treated rats. Cognitive impairment induced by HHcy was determined using the Morris water maze (MWM) and Y-maze on video tracking system (28th–32nd day). Different biomarkers of HHcy in serum and brain and vascular reactivity were evaluated and histopathology (thoracic aorta and brain) was done. Results: HSP (100 mg/kg) treatment in l-methionine-treated rats exhibited significant (p < 0.001) dose-dependent activity and reduced behavioural deficits, brain acetylcholinesterase (25.99 ± 2.36 versus 10.73 ± 1.26 μmoles/mg), brain lipid peroxidation (15.25 ± 1.65 versus 6.18 ± 0.74 nM/mg), serum homocysteine (Hcy) (22.37 ± 0.30 versus 11.01 ± 1.01 μg/mL) and serum cholesterol (182.7 ± 2.15 versus 101.5 ± 2.76 mg/dL) and increased brain antioxidant levels. HSP significantly (p < 0.001) reduced endothelial dysfunction (ED) by abolishing the effect of l-methionine on acetylcholine-induced endothelial-dependent relaxation and increased serum nitrite and vascular nitric oxide bioavailability along with the restoration of histological aberrations. Conclusion: HSP exerts a protective effect on HHcy by abrogating oxidative stress, ED and neurotoxicity.

Thiamine reduces tissue lead levels in rats: mechanism of interaction

Lead (Pb) toxicity has been a serious concern in industrialized societies because of its association with functional deficits in nervous, haematopoietic and renal systems. Several studies have shown beneficial effects of thiamine on Pb toxicity. It is speculated that Pb chelation by thiamine may be a possible mechanism. However, the exact nature of these interactions remained elusive. In the present study we have characterized the interaction of Pb with thiamine using UV–Vis as well as fluorescence spectroscopic methods and studied the effect of thiamine treatment on blood and tissue Pb levels during simultaneous or post-exposure to Pb in rat model. The spectroscopic studies revealed that Pb interacts with the pyrimidine ring of thiamine, leading to its solubilization at physiological pH. Further, thiamine reduced the Pb levels in blood, kidney and bone during both simultaneous and post-exposure Pb treatment. Interestingly, thiamine appears to prevent the accumulation of Pb in bone during simultaneous treatment. Together these results suggest that pyrimidine ring of thiamine mediates its interaction with Pb, leading to the prevention of its accumulation and/or increased clearance from tissues.