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Biomedical subjects

R K Sharma

Publications and source records attributed to R K Sharma.

At least 37 records · Page 2Linked to original sources
PubMed2005

Structural conservation of residues in BH1 and BH2 domains of Bcl-2 family proteins.

The sequence of Bcl-2 homology domains, BH1 and BH2, is known to be conserved among anti- and pro-apoptotic members of Bcl-2 family proteins. But structural conservation of these domains with respect to functionally active residues playing role in heterodimerization-mediated regulation of apoptosis has never been elucidated. Here, we have suggested the formation of an active site by structurally conserved residues in BH1 (glycine, arginine) and BH2 (tryptophan) domains of Bcl-2 family members, which also accounts for the functional effect of known mutations in BH1 (G145A, G145E) and BH2 (W188A) domains of Bcl-2.

Amino Acid Sequence↗
PubMed2005

Does mycophenolate mofetil decrease the recurrent acute rejection in renal transplant recipients.

PURPOSE: Mycophenolate mofetil (MMF) has emerged as a valuable immunosuppression in renal transplant patients. However, it is expensive and cannot be used routinely in our population. MATERIAL AND METHODS: In a retrospective study, 60 renal transplant patients on MMF based triple immunosuppression were analysed. The indication for MMF was as rescue therapy after treatment of acute vascular rejection (Banff type-4, grade IIA, IIB and III) in all patients. However, 20 such patients also had associated chronic liver diseases. The patients were given 1.5-2.0 g MMF in two divided doses at least for 6 months, depending upon the tolerability, adverse effects and affordability, and followed-up at least for 1 year. The control group consisted of 60 cases of acute vascular rejection (Banff type-4, grade IIA, IIB and III) who were placed on cyclosporine, azathioprine and steroid based maintenance immunosuppressive regimen in same time frame. RESULTS: The incidence recurrent acute rejections in MMF group was 18% and 42% in control group (P < 0.005). The serum transaminases in all patients of the liver diseases became normal in 3-6 months. The incidence of opportunistic infections in MMF and control group were 22% and 11% respectively (P < 0.05). The MMF based regimen was two times more expensive. The 1 year patient and graft survivals between two groups were not statistically significantly different. CONCLUSION: The MMF based regimen significantly decreases the recurrent acute rejections. However, it is expensive and cannot be used routinely in all patients in Indian scenario.

Adult↗
PubMed2005

Percutaneous penetration of diethanolamine through human skin in vitro: application from cosmetic vehicles.

Concern has been raised over the safety of diethanolamine (DEA) which may be present as a minor component of alkanolamide ingredients of cosmetic formulations. Skin penetration data were therefore generated for a range of typical formulations under in-use conditions. Seven rinse-off formulations (A-E, G and H), a leave-on emulsion (F), representing prototype cosmetic formulations and containing representative levels of DEA were prepared. Target levels of DEA were attained by inclusion of DEA as either (14)C-DEA or a combination of (14)C-DEA and unlabeled DEA. Skin permeation and distribution were evaluated using human skin in vitro, static diffusion cells and phosphate buffered saline (pH 7.4) as the receptor phase. At least 12 replicate epidermal membranes were prepared from a minimum of four donors for each test group. Receptor phase samples were taken at appropriate time intervals. At the end of the test period, radioactivity remaining on the skin surface and on the diffusion cell donor cap was determined before the skin samples were tape-stripped. The remaining tissue was solubilized and radioactivity determined. Permeation was very low from all vehicles applied under in-use conditions (range 1-48 ng/cm(2) over 24 h). Comparison was also made between permeation and distribution of DEA from an infinite dose of a simple aqueous solution and the leave-on formulation (F) through paired samples of fresh and frozen full thickness skin from the same donors. When applied as an infinite dose in aqueous solution DEA permeation at 24 h was greater through frozen than through fresh skin. From the leave-on formulation, permeation was similar and very low for both fresh and frozen skin. Recovery of DEA after application of the aqueous solution to fresh human skin and subsequent aqueous and organic extraction of the epidermal and dermal tissue indicated that the majority (>98%) of DEA was in the aqueous extract, suggesting that DEA was in the free state and not associated with the lipid fraction. These data provide a basis for the estimation of the potential systemic exposure and safety margins for DEA in representative cosmetic formulations.

Administration, Cutaneous↗
PubMed2005

Intranasal mucoadhesive microemulsions of zolmitriptan: preliminary studies on brain-targeting.

The aim of this investigation was to prepare microemulsions containing zolmitriptan (ZT) for rapid drug delivery to the brain to treat acute attacks of migraine and to characterize microemulsions and evaluate biodistribution in rats. Zolmitriptan microemulsions (ZME) were prepared using the titration method and were characterized for globule size distribution and zeta potential. ZT was radiolabeled using (99m)Tc (technetium) and radiolabeled-drug formulations of ZT were used to carry out biodistribution of drug in the brain of Swiss albino rats after intranasal and intravenous administration. The pharmacokinetic parameters, drug targeting efficiency (%DTE) and direct nose-to-brain drug transport (%DTP) were calculated. Brain scintigraphy imaging in rats were also performed to ascertain the uptake of drug into the brain. ZME were transparent and stable with mean globule size of 35 +/- 25 nm and zeta potential of - 38- - 52 mV. (99m)Tc-labeled-drug formulations of ZT were found to be stable and suitable to perform in vivo studies. Following intranasal administrations of zolmitriptan mucoadhesive microemulsion (ZMME), ZME, Zolmitriptan solution (ZS) and intravenous administration of ZS, brain/blood uptake ratios at 0.50 h were found to be 0.70, 0.56, 0.27 and 0.13, respectively, indicating effective brain-targeting following intranasal administration of ZMME. Comparing intranasal administration of ZMME with intravenous administration of ZME, the %DTE and %DTP were found higher indicating effective drug transport following intranasal administration and highest brain-targeting following ZMME administration. Rat brain scintigrams showed substantial uptake of drug into the brain after intranasal administration of ZMME. Studies of this investigation conclusively demonstrated rapid and larger extent of transport into the rat brain following intranasal administration of ZMME and can play a promising role in the treatment of acute attacks of migraine.

Administration, Intranasal↗
PubMed2005

Stem cell fate specification: role of master regulatory switch transcription factor PU.1 in differential hematopoiesis.

PU.1 is a versatile hematopoietic cell-specific ETS-family transcriptional regulator required for the development of both the inborn and the adaptive immunity, owing to its potential ability to regulate the expression of multiple genes specific for different lineages during normal hematopoiesis. It functions in a cell-autonomous manner to control the proliferation and differentiation, predominantly of lymphomyeloid progenitors, by binding to the promoters of many myeloid genes including the macrophage colony-stimulating factor (M-CSF) receptor, granulocyte-macrophage (GM)-CSF receptor alpha, and CD11b. In B cells, it regulates the immunoglobulin lambda 2-4 and kappa 3' enhancers, and J chain promoters. Besides lineage development, PU.1 also directs homing and long-term engraftment of hematopoietic progenitors to the bone marrow. PU.1 gene disruption causes a cell-intrinsic defect in hematopoietic progenitor cells, recognized by an aberrant myeloid and B lymphoid development. It also immortalizes erythroblasts when overexpressed in many cell lines. Although a number of reviews have been published on its functional significance, in the following review we attempted to consolidate information about the differential participation and role of transcription factor PU.1 at various stages of hematopoietic development beginning from stem cell proliferation, lineage commitment and terminal differentiation into distinct blood cell types, and leukemogenesis.

Animals↗
PubMed2005

Post-transplant lymphoproliferative disorders after live donor renal transplantation.

The development of post-transplant lymphoproliferative disorders (PTLD) is a well-recognized complication of solid organ transplantation in patients receiving immunosuppressive therapy. The literature on PTLD in live renal allograft recipients is scarce and most of the data pertains to PTLD in cadaveric transplants. As live donor grafts form the mainstay of transplantation programme in India, this study was carried out to define the profile of PTLD in live donor renal allograft recipients. On retrospective evaluation, nine cases of PTLD amongst 1700 live donor allograft recipients from January 1989 to August 2004, were detected at a tertiary care hospital in north India. The clinicopathological features of these cases were evaluated. Mean age at diagnosis of PTLD was 38 yr with median post-transplant latency period of 7 yr. All cases were from extra-renal sites, five being in ileum/jejunum, three in retroperitoneal lymph nodes and one in epididymus. All cases received cyclosporin, azathioprine and prednisolone in varying combinations as immunosuppressive therapy. One case was treated for rejection by anti-thymocyte globulin. Seven patients were seronegative for Epstein-Barr virus at the time of diagnosis. All were B-cell monomorphic PTLD, classifiable as B-cell diffuse large cell lymphomas, with five extranodal and three nodal lymphomas. Management included reduction in immunosuppression, acyclovir therapy, surgical excision and chemotherapy. On follow-up, four patients died, two presented with recurrence, two were in remission and one was lost to follow-up. This study comprising of live related/unrelated renal allograft recipients observed late onset high grade monomorphic PTLD with paucity of early onset polymorphic lesions. Long post-transplant latency period, aggressive behaviour and poor response to treatment necessitate long-term cancer surveillance to facilitate early detection and newer therapeutic strategies to improve the outcome in these patients.

Adult↗
PubMed2005

Neonatal hypothyroidism-induced changes in rat testis size, dependence on temperature.

OBJECTIVE: Effects of transient neonatal hypothyroidism (HPOT) on adult testis size and serum hormone profiles were evaluated in the Charles foster strain of rats, maintained under the temperature of 21 degrees C (HPOTL) or of 34 degrees C (HPOTH). METHODS: Hypothyroidism was induced in suckling pups in preweanling period (1-21 days), by administering 0.1% 6-propyl-2-thiouracil in drinking water to mothers. Body mass and testis characteristics, the steroidogenic potential [measured by histochemical localization of 3alpha-, 3beta- and 17beta-hydroxysteroid dehydrogenases (HSDHs)] and serum concentrations of thyroid-stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), luteinizing hormone (LH), testosterone (T) and corticosterone (Cort) were evaluated on the 35th, 45th, 60th and 90th day of age. RESULTS: The HPOTH rats showed lower testis masses, while the HPOTL rats showed higher testis masses and lower body masses after 90 days. Histologically, the testes of the HPOTH rats demonstrated increased germ cell degeneration after 35 and 45 days and reduced tubular size, germ cell numbers and sperm density after 90 days. In contrast, the testes of the HPOTL rats showed reduced tubular diameters after 35 and 45 days, and increased tubular diameters, germ cell numbers and sperm density after 90 days. Serum TSH, T3, T4, LH and T concentrations and 3beta- and 17beta-HSDH activities were reduced in both groups of the HPOT rats after 35 and 45 days. Intratubular steroidogenesis and a prominent triangle up5 pathway were also found in the HPOT animals. CONCLUSION: The temperature has a definite influence on the thyroid hormone action, postnatal growth and function of rat testes.

Age Factors↗
PubMed2004

Labeling efficiency and biodistribution of Technetium-99m labeled nanoparticles: interference by colloidal tin oxide particles.

The interference of colloidal tin oxides on the biodistribution of (99m)Technetium radiolabeled chitosan nanoparticles has been overcome by using sodium borohydride instead of commonly used stannous salts as reducing agent for the reduction of (99m)Tc (VII) to lower valency states. Biodistribution of radiolabeled chitosan nanoparticles prepared by using stannous chloride method revealed localization of the radioactivity mainly in the liver and spleen while that of radiolabeled chitosan nanoparticles prepared by using sodium borohydride method manifested the presence of radioactivity in blood up to an extent of 10% even after 2 h. Interestingly, the reduction of radioactivity in the latter case with the progress of time was not manifested through an increase in activity in the liver. Rather, a time dependent increased accumulation of radioactive materials was observed in the stomach. From the results it has been concluded that the biodistribution is strongly influenced by the presence of colloidal particles of tin oxides and (99m)Tc labeled chitosan nanoparticles are RES evading and long circulating in blood when Tc (VII) is reduced by sodium borohydride and not by stannous chloride during radiolabeling process.

Animals↗
PubMed2004

Amyloidosis complicating rhinophyma.

Rhinophyma is the advanced stage of acne rosacea and a source of embarrassment for the patient. Secondary localized cutaneous amyloidosis complicating rhinophyma is not reported in the literature. A patient with rhinophyma was treated by excision and primary closure. The histologic examination showed amyloidosis.

Adult↗
PubMed2004

Comparison of peritoneal equilibration test with 99mTc-DTPA excretion in the assessment of peritoneal permeability.

Assessment of peritoneal permeability is necessary for successful management of end-stage renal disease (ESRD) patients by continuous ambulatory peritoneal dialysis (CAPD). The objective of this study was to develop an alternative method of assessing the peritoneal permeability and to compare this method with the conventional method, the peritoneal equilibrium test, first described by Twardowski in 1987. Twenty patients undergoing regular CAPD were included in this study. Before starting the peritoneal dialysis, 370 MBq (10 mCi) technetium-99m diethylene triamine penta-acetic acid ((99m)Tc-DTPA) was injected intravenously. A standard dose of the same quantity was kept and used later for calculations. At the end of 4 h, a dialysate fluid sample (1 ml) was collected and the total dialysis effluent fluid volume was measured. Excretion of (99m)Tc-DTPA into the dialysate fluid as a percentage of the injected dose was calculated. Simultaneously, standard peritoneal equilibrium test values were recorded for comparison. Peritoneal excretion of (99m)Tc-DTPA ranged from 8% to 25% of the injected dose, depending on the peritoneal membrane permeability. When the results were compared with the conventional method, a good correlation (r=0.79) was found. This innovative radionuclide technique is a simple and convenient method to assess the peritoneal membrane permeability and can be used as an alternative to the peritoneal equilibrium test, which is very cumbersome and associated with many limitations.

Adult↗
PubMed2004

Preparation, characterization, and biodistribution study of technetium-99m -labeled leuprolide acetate-loaded liposomes in Ehrlich ascites tumor-bearing mice.

The purpose of this study was to prepare conventional and sterically stabilized liposomes containing leuprolide acetate in an attempt to prolong the biological half life of the drug, to reduce the uptake by reticuloendothelial system (RES), and to reduce the injection frequency of intravenously administered peptide drugs. The conventional and sterically stabilized liposomes containing leuprolide acetate were prepared by reverse phase evaporation method and characterized for entrapment efficiency and particle size. Radiolabeling of leuprolide acetate and its liposomes was performed by direct labeling with reduced technetium-99m. Its biodistribution and imaging characteristics were studied in ehrlich ascites tumor (EAT)-bearing mice after labeling with technetium-99m. The systemic pharmacokinetic studies were performed in rabbits. A high uptake by tumor was observed by sterically stabilized liposome containing leuprolide acetate compared with free drug and conventional liposomes. The liver/tumor uptake ratio of free drug, conventional (LL), and sterically stabilized liposomes (SLL5000 and SLL2000) was found to be 20, 7.99, 1.63, and 1.23, respectively, which showed the increased accumulation of sterically stabilized liposomes in tumor compared with the free drug and conventional liposomes at 24 hours postinjection. Liver uptake of sterically stabilized liposomes was still 7-fold less than the conventional liposomes. The marked accumulation of liposomes in the tumor-bearing mice was also documented by gamma scintigraphic studies. The findings demonstrate the distribution of these liposomes within solid tumor and prove that the sterically stabilized liposomes experience increased tumor uptake and prolonged circulation half life. Hence these findings will be relevant for the optimal design of long circulating liposomes for the peptide drugs and for targeting of liposomes toward tumor.

Animals↗
PubMed2004

Selective use of mycophenolate mofetil in renal transplant patients in Indian scenario.

PURPOSE: Although mycophenolate mofetil (MMF) has emerged as a valuable immunosuppressive in renal transplantation, its high cost demands that it be used selectively. MATERIALS AND METHODS: This retrospectively study included 55 renal transplant patients on MMF for rescue therapy after treatment of acute vascular rejection (n = 45), acute/chronic liver disease with elevated transaminases (n = 4), early chronic rejection (n = 2), cyclosporine toxicity (n = 3), and cyclosporine-induced hemolytic-uremic syndrome (n = 1). The patients were given 1.5 to 2 g MMF in divided doses for at least 6 months, depending upon the tolerability, adverse effects, and finances, and followed for 1 year. The patients on MMF following treatment of acute rejections were compared with controls who received azathioprine-based triple immunosuppression after treatment of an acute rejection episode. RESULTS: The incidence of recurrent acute rejection in the first year was 18% in the MMF group compared to 42% in the control group (P < .005). The serum transaminases in the acute/chronic liver disease group reached normal levels at 3 to 6 months. The serum creatinine remained stable for a mean duration of 8 months in the early chronic rejection patients. The patients with cyclosporine toxicity showed stable graft function on low-dose cyclosporine. The patient with hemolytic-uremic syndrome showed stable graft function for 4 years. The MMF-based triple regimen is two times more expensive than an azathioprine-based regimen. CONCLUSION: MMF significantly decreases the recurrence of acute rejection. It is a good alternative agent in special situations like acute/chronic liver diseases with elevated transaminases, early chronic rejection, cyclosporine toxicity, and cyclosporine-induced hemolytic-uremic syndrome. Because of the high cost it should be used selectively in our population.

Acute Disease↗
PubMed2004

Fungal peritonitis in patients on continuous ambulatory peritoneal dialysis: a single centre Indian experience.

BACKGROUND: Fungal peritonitis (FP) is a serious complication in patients on continuous ambulatory peritoneal dialysis (CAPD). We reviewed our FP cases to analyse the causative agents and possible risk factors in relation to FP and its outcome and mortality. METHODS: Records of all FP cases were reviewed. FP was diagnosed based on effluent cell count and positive fungal culture in suitable media. RESULTS: Between October 1993 and November 2001, 261 patients underwent CAPD. FP was detected in 28 patients, one episode in each patient (14.3% of the total peritonitis episodes). Candida species and dematiaceous fungi+/-Candida species were responsible for 89.3 and 10.7% of episodes, respectively. Patients with preceding bacterial peritonitis (BP) developed FP more frequently (25.6%) than de novo cases (2.9%) (P<0.0001) and lower proportion of them continued CAPD (8.6% vs. 60%; P=0.007). Mortality in patients having abdominal pain with and without fever, and catheter in situ was significantly higher than in those patients who did not have these risk factors (9/11 vs. 6/17, P=0.01; 13/17 vs. 2/11, P=0.003; 6/6, vs. 9/22, P=0.01, respectively). CONCLUSIONS: Higher proportion of our patients had FP; preceding BP was a significant risk factor for development of FP and technique failure. Abdominal pain+/-fever in patients and catheter in situ were identified as risk factors associated with mortality.

Female↗
PubMed2004

Celecoxib incorporated chitosan microspheres: in vitro and in vivo evaluation.

Recently, considerable interest has been focussed on the use of biodegradable polymers for specialized applications such as controlled release of drug formulations; meanwhile, microsphere drug delivery systems using various kinds of biodegradable polymers have been studied extensively during the past two decades. In the present investigation, it was aimed to prepare microsphere formulations of celecoxib using a natural polymer, chitosan as a carrier for intra-articular administration to extend the retention of the drug in the knee joint. Microsphere formulations were evaluated in vitro for particle size, entrapment efficiency, surface morphology and in vitro drug release. For in vivo studies, (99m)Technetium- labeled glutathione was used as a radiopharmaceutical to demonstrate arthritic lesions by gamma scintigraphy. Evaluation of arthritic lesions post therapy in rats showed a significant difference (P < 0.005) in the group treated with celecoxib solution compared to the group treated with celecoxib loaded chitosan microspheres.

Animals↗
PubMed2004

Enhanced tumour uptake of doxorubicin loaded poly(butyl cyanoacrylate) nanoparticles in mice bearing Dalton's lymphoma tumour.

The objective of this study is to enhance the delivery of Doxorubicin hydrochloride to Dalton's lymphoma solid tumour through poly(butyl cyanoacrylate) (PBC) nanoparticles. Doxorubicin loaded PBC (DPBC) nanoparticles were prepared by emulsion polymerization and characterized by particle size analysis, zeta potential and scanning electron microscopy. Doxorubicin HCl (Dox) and DPBC nanoparticles were radiolabeled with 99mTc by reduction method using stannous chloride and optimized the labeling parameters to obtain high labeling efficiency. The in vitro stability of 99mTc-labeled complexes was determined by DTPA and cysteine challenge test. The labeled complexes showed very low transchelation and high in vitro and serum stability. 99mTc labeled complexes of Dox and DPBC nanoparticles were administered subcutaneously below the Dalton's lymphoma tumour and biodistribution was studied. The distribution of DPBC nanoparticles to the blood, heart and organs of RES such as liver, lung and spleen was biphasic with a rapid initial distribution, followed by a significant decrease later at 6 h post-injection. The distribution of Dox to tissues was very low initially and increased significantly at 6 h post-injection indicating its accumulation at the injection site for a longer time. The concentration of DPBC nanoparticles was also found high in tissues at 6 h post-injection indicating their accumulation at the subcutaneous site and consequent disposition to tissues with time. A significantly high tumour uptake of DPBC nanoparticles (approximately 13 fold higher at 48 h post-injection) (P <0.001) was found compared to free Dox. The tumour concentrations of both Dox and DPBC nanoparticles increased with time indicating their slow penetration from the injection site into tumour. The concentration of DPBC nanoparticles in the femur bone in the tumour region was also significantly higher (P <0.001) than free Dox and increased with time. The study signifies the advantage of delivering Dox to Dalton's lymphoma through PBC nanoparticles by facilitating enhanced tumour uptake and prolonged tumour retention, which are expected to lead to greater therapeutic effect in the form of tumour regression.

Animals↗
PubMed2004

Cytotoxic and topographical properties of 6-arylidene-2-dimethylaminomethylcyclohexanone hydrochlorides and related compounds.

A number of 2-arylidenecyclohexanones (1a-h) were converted into the corresponding Mannich bases (2a-h) and (3a,f). Evaluation against murine L1210 cells as well as human Molt 4/C8 and CEM T-lymphocytes revealed the marked cytotoxicity of the Mannich bases and also the fact that almost invariably these compounds were more potent than the precursor enones (1a-h). Further evaluation of most of the Mannich bases towards a panel of nearly 60 human tumour cell lines confirmed their utility as potent cytotoxins. In this assay, the compounds showed growth-inhibiting properties greater than the anticancer alkylator melphalan. QSAR studies revealed that in some cell lines compounds possessing small electron-attracting aryl substituents showed the greatest potencies. Molecular modeling and X-ray crystallography demonstrated that various interatomic distances and torsion angles correlated with cytotoxicity. A representative compound (2a) demonstrated weak inhibiting properties towards human N-myristoyltransferase and stimulated a tyrosine protein kinase. A single dose of 100 mg/kg of most of the compounds did not prove to be lethal in mice.

Acyltransferases↗