Biomedical subjects
Publications and source records attributed to R Rajagopalan.
Radiation-induced alterations in the levels of p53 and lactate dehydrogenase activities were studied in fibrosarcoma, following exposure to different doses of gamma-irradiation (2-10 Gy). The levels of p53 were elevated in the cytoplasm, while the lactate dehydrogenase activity in tumor tissue was considerably decreased.
Lattice Monte Carlo simulations of two-dimensional amphiphile solutions are used to examine the accuracy of the mixing properties predicted by lattice theories such as the Flory-Huggins theory, random-solution approximation, and quasichemical approximation. The internal energy, Helmholtz free energy, and entropy of mixing have been calculated from the configurational energy data obtained from the simulations, and the effect of nonrandom mixing on these properties has been determined. The quasichemical approximation predicts the entropy and Helmholtz free energy of mixing accurately for the amphiphile solution, but fails to predict the energy of mixing, due to the presence of microphase (self-aggregation) separation, which is beyond the reach of the quasichemical approximation, a mean-field theory. Helmholtz free energy of mixing is predicted accurately, and the shielding of the solvophobic segments in the microphase leads to small energies of mixing compared to the entropy of mixing. Copyright 2000 Academic Press.
The euglycemic and hypolipidemic activities of PAT5A, a novel pyridine analog of thiazolidinedione, have been evaluated in different animal models. Administration of PAT5A to db/db mice resulted in dose-dependent decreases in plasma glucose, triglyceride, and insulin levels, and an improved glucose tolerance. The glucose-lowering activity of PAT5A was better than that of troglitazone and comparable to that of rosiglitazone. In addition, PAT5A showed better lipid-lowering activity than troglitazone or rosiglitazone. A similar profile was seen in ob/ob mice. In high-fat-fed Sprague Dawley rats, PAT5A treatment reduced plasma triglyceride and total cholesterol levels. An in vitro peroxisome proliferator activated receptor gamma (PPARgamma) transactivation assay in HEK-293 cells showed poor transactivation for PAT5A compared with rosiglitazone. PAT5A did not show any PPARalpha- or PPARdelta-activating properties. Ex vivo study in db/db mice treated with PAT5A showed decreased activity of liver glucose 6-phosphatase, a key enzyme in gluconeogenesis. A 28-day probe toxicity study in Wistar rats did not show any treatment-related alterations in hematologic and biochemical parameters, nor any macroscopic and microscopic changes in the vital organs, whereas rosiglitazone treatment increased liver and heart weights. Our results indicate that PAT5A is a potent insulin sensitizer and hypolipidemic compound with a weak PPARgamma activation potential. Both in vivo and in vitro results suggest that PAT5A improves glucose kinetics and lipid levels through mechanisms not related to PPAR activation.
RATIONALE AND OBJECTIVES: To evaluate the efficacy of a novel tumor receptor-specific small-peptide-near-infrared dye conjugate for tumor detection by optical imaging. METHODS: A novel, near-infrared dye-peptide conjugate was synthesized and evaluated for tumor-targeting efficacy in a well-characterized rat tumor model (CA20948) known to express receptors for the chosen peptide. A simple continuous-wave optical imaging system, consisting of a near-infrared laser diode, a cooled CCD camera, and an interference filter, was used in this study. RESULTS: Tumor retention of two non-tumor-specific dyes, indocyanine green and its derivatized analogue, bis-propanoic acid cyanine dye (cypate), was negligible. In contrast, the receptor-specific peptide-cypate conjugate (cytate) was retained in the CA20948 tumor, with an excellent tumor-tonormal-tissue ratio in the six rats examined. CONCLUSIONS: Optical detection of tumors with a receptor-targeted fluorescent contrast agent has been demonstrated. This result represents a new direction in cancer diagnosis and patient management.
Indocyanine green is a medically useful dye that absorbs and fluoresces in the near infrared and has been sporadically employed clinically as an optical tracer agent for liver function evaluation and cardiac output measurements. The poor stability of this dye in aqueous solution, especially at the high concentrations needed for bolus injection, has been a hindrance in clinical application. However, by using carefully chosen macromolecular additives, the stability of these aqueous dye solutions may be enhanced significantly. Such noncovalent binding between dye and carrier molecules was found to preserve substantially the dye in aqueous solutions for several weeks with no apparent changes in the measured in vivo biological properties.
Several thiazolidinediones having chroman moieties were synthesized and evaluated for their euglycemic and hypolipidemic activities. Some of the analogues having an aminoalkyl group as a linker between the chroman ring and 4-[5-(2,4-dioxo-1, 3-thiazolidinyl)methyl]phenoxy moiety seem to be better than troglitazone. In vitro transactivation assays of PPARgamma have been carried out with these glitazones to understand their molecular mechanism. For the first time we have found that some of the unsaturated thiazolidinediones are superior to their saturated counterpart in the in vivo assay. A more potent thiazolidinedione analogue than troglitazone is reported. Pharmacokinetic studies have shown that protection of the OH group in the chroman moiety leads to a decrease in metabolism, thereby resulting in a superior pharmacological profile.
A series of substituted pyridyl- and quinolinyl-containing 2, 4-thiazolidinediones having interesting cyclic amine as a linker have been synthesized. Both unsaturated thiazolidinediones 5 and saturated thiazolidinediones 6 and their various salts were evaluated in db/db mice for euglycemic and hypolipidemic effects and compared with BRL compound 11 and BRL-49653, respectively. Some of the potent compounds were converted to various salts in order to obtain improved activities. Among all the salts evaluated, the maleate salt of unsaturated TZD 5a was found to be a very potent euglycemic and hypolipidemic compound. Some of the more interesting compounds have also been evaluated in ob/ob mice and compared with rosiglitazone (maleate salt of BRL-49653). Oral glucose tolerance tests were performed in both db/db and ob/ob mice. Pharmacokinetic studies of 5a maleate are also reported. Receptor binding studies of PPARgamma by 5a/5a maleate did not show any significant transactivation of PPARalpha or PPARgamma.
Several thiazolidinedione derivatives having 5-hydroxy-2,3-dihydro-2, 2,4,6,7-pentamethylbenzofuran moieties and their 5-benzyloxy derivatives and 5-hydroxy-2,4,6,7-tetramethylbenzofuran moieties were synthesized and evaluated in db/db mice. Insertion of an N-Me group into the linker between thiazolidinedione and substituted benzofuran pharmacophores showed considerable improvement in their euglycemic activity. Further improvement has been observed when a pyrrolidine moiety is introduced in the structure to give 5-[4-[N-[3(R/S)-5-benzyloxy-2,3-dihydro-2,2,4,6, 7-pentamethylbenzofuran-3-ylmethyl]-(2S)-pyrrolidin-2- ylmethoxy]pheny lene]thiazolidine-2,4-dione (21a). At a 100 mg/kg/day dose of the maleate salt, compound 21a reduced the plasma glucose and triglyceride to the level of lean littermate, i.e. 8 +/- 1 mM, and is the most potent and efficacious compound reported in this series.
Euglycemic and hypolipidemic activities of a novel indole analogue of thiazolidinedione, DRF 2189 (CAS 172647-53-9), have been evaluated in different animal models. Compared to troglitazone (CAS 97322-87-7), DRF 2189 exhibited interesting plasma glucose and triglyceride lowering activity in genetically diabetic and obese db/db mice. It also produced a significant reduction in plasma glucose, triglyceride, total cholesterol levels and improvement in oral glucose tolerance in another genetic mouse model, the ob/ob mice. In high-fat diet fed Sprague-Dawley rats, DRF 2189 treatment showed improvement in plasma lipid parameters. Like other thiazolidinediones, this compound also possesses peroxisome proliferator activated receptor gamma (PPAR gamma) transactivation potential. In anaesthetized rat experiment, DRF 2189 produced a transient fall in blood pressure without any change in the ECG pattern. It showed non-specific smooth muscle relaxant activity against acetylcholine, histamine and potassium chloride induced contractions in isolated guinea pig ileum. A twenty-eight-day toxicity study in Wistar rats did not show any signs of treatment related adverse effects. The overall antidiabetic and hypolipidemic activities of DRF 2189 are comparable with rosiglitazone (CAS 155141-29-0) and superior to troglitazone. In conclusion, results from these preclinical studies indicate that DRF 2189, a novel thiazolidinedione, has a marked potential for the management of type-2 diabetes.
Novel compounds having a dual pharmacophore were synthesised and evaluated for their insulin sensitiser and anti-inflammatory properties in different animal models.
A series of [[(heterocyclyl)ethoxy]benzyl]-2,4-thiazolidinediones have been synthesized by the condensation of corresponding aldehyde 1 and 2,4-thiazolidinedione followed by hydrogenation. Both unsaturated thiazolidinedione 2 and its saturated counterpart 3 have shown antihyperglycemic activity. Many of these compounds have shown superior euglycemic and hypolipidemic activity compared to troglitazone (CS 045). The indole analogue DRF-2189 (3g) was found to be a very potent insulin sensitizer, comparable to BRL-49653 in genetically obese C57BL/6J-ob/ob and 57BL/KsJ-db/db mice. Pharmacokinetic and tissue distribution studies conducted on BRL-49653 and DRF-2189 (3g) indicate that these drugs are well-distributed in target tissues. On the basis of euglycemic activity as well as enhanced selectivity against reduction of triglycerides in plasma, DRF-2189 (3g) has been selected for further evaluation.
Several thiazolidinediones having antioxidant moities in their structural motif have been synthesised and evaluated for their euglycemic and hypolipidemic activities. A few of them have been found to be superior to troglitazone.
Using appropriate protection and deprotection sequence novel hydroxyacyl chains of the type CO(CH2)nOH are synthesized and are utilized to develop new analogues of forskolin. Several compounds showed good positive inotropic activity. Compound 12 is almost 10 times more active than forskolin (EC50 = 0.002 microgram/ml).].
Using the novel lead from hydroxy acetyl substituted forskolin analogues, such as 7 beta-hydroxyacetyl-7 beta-deacetyl forskolin or 6 beta-hydroxyacetyl forskolin, a number of water soluble omega-amino acyl derivatives were synthesized. Two such compounds 6 and 18 showed better in vitro activity but failed to show in vivo activity.
The Dermatology-specific Quality of Life (DSQL) instrument is a new tool which has been developed to address the effects of skin disease and its treatment on physical and social functioning and self-perceptions. Previous reports have demonstrated its cross-sectional validity. The current study examines the DSQL's responsiveness to 12 weeks of acne treatment in a placebo-controlled randomized clinical trial. The DSQL change scores were moderately correlated (r = 0.18 to 0.37) with treatment efficacy parameters including: dermatologist's rating of improvement of acne and a skin irritation score, and highly correlated with patient's global rating of acne severity. Within treatment groups, the DSQL discriminated clinically meaningful changes associated with small and moderate effect sizes. The DSQL total score showed statistically significant differences on nearly all comparisons with placebo. The DSQL dimension scores were sensitive to the most effective therapy compared to placebo. Responsiveness benchmarks are provided for small and moderatesized treatment effects. As a comprehensive instrument, the DSQL is a practical and psychometrically sound tool for use in clinical trials in dermatology.
A 4-week, double-blind, randomized clinical trial, comparing the efficacy and safety of clobetasol propionate emollient cream 0.05% and its vehicle, was conducted at four private dermatology clinics in 81 non-hospitalized patients (> or = 12 years old) with moderate-to-severe atopic dermatitis covering 2% or more of their body surface. All patients had at least one lesion 2 cm or more in diameter. Three signs/symptoms of target lesions (erythema, pruritus, and induration/papulation) were scored by investigators on a scale of 0-3 (in 0.5-point increments; 0 = absent, 1 = mild, 2 = moderate, and 3 = severe); the total of the three scores had to be > or = 6 for patients to qualify for study entry. Patients were excluded if they were immunocompromised, pregnant, or nursing; had skin atrophy, telangiectasia or striae in skin areas to be treated; or had received topical treatments for atopic dermatitis within 1 week prestudy, intramuscular triamcinolone within 6 weeks prestudy, or long-term systemic corticosteroid usage within 6 months prestudy. Patients were randomized in a 1:1 ratio to receive either clobetasol propionate emollient 0.05% twice daily (n = 41), or the emollient vehicle twice daily (n = 40), for 4 weeks. A fingertip unit, equaling approximately 0.5 g in males and 0.43 g in females (enough to cover approximately 2% of the body), was used to measure and apply a thin film of study drug to the affected areas. The efficacy was evaluated by investigators and patients on days 4, 8, 15, and 29 after initiation of therapy, and 2 weeks after the end of treatment (day 43). Investigators performed a physician's gross assessment based on the percentage improvement of the target lesion. They also rated changes from baseline in mean severity scores for six individual signs/symptoms (erythema, pruritus, induration/papulation, lichenification, erosion/oozing/crusting, and scaling/dryness) and for total signs/symptoms according to the severity scoring system described above. Patients rated their response to treatment as excellent, good, fair, poor, or worse. Laboratory assessments were made on days 15, 29, and (if necessary) day 43.
OBJECTIVE: The objective of this observational prospective study was to demonstrate the cost effectiveness of patch testing in patients suspected of allergic contact dermatitis (ACD) and to determine the order in which different severity groups rank in terms of cost effectiveness. DESIGN AND SETTING: This observational study was conducted on 567 patients from 10 investigator sites in the US over a period of 1 year. All patients with a suspicion of contact allergy who exhibited at least moderate disease activity were included in the study and were stratified according to disease severity and whether or not they were patch tested. In each severity category, the cost effectiveness of patch testing was evaluated. Patients who were ruled out for contact allergy (without the use of patch test) by the first 6 months after admission were excluded. A validated dermatology-specific quality of life (DSQL) instrument was administered to all patients at the start of the study, and at 6 and 12 months thereafter. The cost-effectiveness analysis is demonstrated using a decision-analytical model. Costs included office visits and prescription costs without generic substitution. The cost of patch testing was not included due to the large variation in price among commercially available products. MAIN OUTCOME MEASURES AND RESULTS: Patch testing was performed on 22% of patients with mild disease, 41% of patients with moderate disease and 50% of those with severe disease. There was a significant difference between the patch-tested and non-patch-tested groups in terms of the time to obtain a confirmed diagnosis (medians = 8 and 175 days, respectively) and a significant difference in the ratio of patients who had a confirmed diagnosis (88 and 69%, respectively). As a result of changes made in their lifestyle, 66% of patients in the patch-tested group and 51% in the non-patch-tested group reported 75% or more improvement in their disease symptoms after 6 months. Early confirmation of diagnosis helped reduce the prediagnosis cost of treatment which was mostly based on preliminary diagnosis. The greatest quality-of-life (QOL) benefits from patch testing relative to nonpatch testing occurred in patients with recurrent/chronic ACD. CONCLUSIONS: Patch testing is most cost effective and reduces the cost of therapy in patients with severe ACD. Greater improvements in quality of life were seen in patients with recurrent/chronic ACD who were patch tested than patients who were not patch tested within the same group. Results were not sensitive to changes due to the addition of indirect costs or costs using generic substitution.
BACKGROUND: A previous retrospective study indicated that patch testing is cost-effective and well accepted by patients. OBJECTIVE: The objective of this observational prospective study was to show the cost-effectiveness of patch testing in patients suspected of allergic contact dermatitis (ACD) and to determine the order in which different severity groups rank in terms of cost-effectiveness. METHODS: This observational study was conducted in 567 patients from 10 investigator sites over a period of 1 year. All patients with a suspicion of contact allergy who exhibited at least moderate disease activity were included in the study and were stratified according to disease severity and whether or not they were patch tested. In each severity category, the cost-effectiveness of patch testing was evaluated. Patients who were ruled out for contact allergy by the first 6 months after admission were excluded. A validated dermatology-specific quality of life instrument was administered to all the patients at entrance into the study and at 6 and 12 months after that. The cost-effectiveness analysis is shown using a decision analysis model. RESULTS: Patch testing was performed on 22% of patients with mild disease, 41% of patients with moderate disease, and 50% of patients with severe disease. As a result of changes made in their lifestyle, 66% in the patch-tested group and 51% in the non-patch-tested group reported 75% or more improvement in disease symptoms after 6 months. Early confirmation of diagnosis helped reduce the prediagnosis costs of treatment, which was mostly based on preliminary diagnosis. The greatest quality of life benefits from patch testing, relative to no patch testing, occurred in subjects with recurrent or chronic ACD. CONCLUSION: Patch testing is most cost-effective and reduces the cost of therapy in patients with severe ACD.