Effect of combination treatment of S-amlodipine with peroxisome proliferator-activated receptor agonists on metabolic and cardiovascular parameters in Zucker fa/fa rats.

Background: Type 2 diabetes is a complex metabolic disorder characterized by hyperglycemia, impaired glucose tolerance and insulin resistance associated with dyslipidemia and hypertension. The available drugs are not sufficiently efficacious in reducing cardiovascular risk and restoring normal glucose metabolism associated with type 2 diabetes as a mono- or a combination therapy. The present study examined the combined effects of an antihypertensive (S-Amlodipine) and an insulin-sensitizing agent, peroxisome proliferator-activated receptor (PPAR) agonists (Pioglitazone and Ragaglitazar), on cardiovascular risk factors in aged diabetic and insulin-resistant Zucker fa/fa rats.

Discovery of tetrahydropyrido[4,3-d]pyrimidine derivatives for the treatment of neuropathic pain.

A series of tetrahydropyridopyrimidine derivatives were synthesized and evaluated for neurotoxicity and peripheral analgesic activity followed by assessment of antiallodynic and antihyperalgesic potential in two peripheral neuropathic pain models, the chronic constriction injury (CCI) and partial sciatic nerve ligation (PSNL). Compounds (4b and 4d) exhibiting promising efficacies in four behavioral assays of allodynia and hyperalgesia (spontaneous pain, tactile allodynia, cold allodynia and mechanical hyperalgesia) were quantified for their ED50 values (15.12-65.

Discovery of novel tetrahydro-pyrazolo [4,3-c] pyridines for the treatment of neuropathic pain: synthesis and neuropharmacology.

We disclose the discovery of a novel series of tetrahydropyrido-pyrazoles that are potent inhibitors of tumour necrosis factor-alpha (TNF-α), nitric oxide and cannabinoid receptor subtype 1 (CB₁). We report herein the synthesis and neuropharmacological screening results of the titled compounds in two acute pain and two neuropathic pain models in rodents. Particularly the analogue N-(4-bromophenyl)-3-tert-butyl-5-ethyl-4,5,6,7-tetrahydro-1H-pyrazolo[4,3-c]pyridine-1-carboxamide (8a) exhibited pronounced acute antinociceptive efficacy, also being effective in chronic constriction injury (ED₅₀ = 23.

Discovery of Fused Triazolo-thiadiazoles as Inhibitors of TNF-alpha: Pharmacophore Hybridization for Treatment of Neuropathic Pain.

Introduction: Neuropathic pain is a complex, chronic pain state that is usually accompanied by tissue injury. With neuropathic pain, the nerve fibers themselves may be damaged, dysfunctional, or injured.

Methods: A series of pharmacophoric hybrids of substituted aryl semicarbazides incorporated into a fused triazolo-thiadiazole nucleus were synthesized and evaluated for neuropathic pain activity.

Discovery of novel 1,2,4-triazol-5-ones as tumor necrosis factor-alpha inhibitors for the treatment of neuropathic pain.

In this work, synthetic integration of substituted semicarbazides and various aliphatic, aryl and heteroaryl acids into 1,2,4-triazol-5-ones was accomplished. Following the assessment of neurotoxicity and peripheral analgesic activity, the compounds were evaluated in two peripheral models of neuropathic pain, the chronic constriction injury and partial sciatic nerve ligation to assess their antihyperalgesic and antiallodynic potential. ED(50) studies undertaken for selected compounds exhibiting promising efficacies (1c, 3c and 4a) revealed values ranging from 13.

Discovery of molecules for the treatment of neuropathic pain: synthesis, antiallodynic and antihyperalgesic activities of 5-(4-nitrophenyl)furoic-2-acid hydrazones.

Neuropathic pain is a chronic pain condition that occurs and persists in a heterogeneous group of etiologically different diseases characterized by a primary lesion or dysfunction of the peripheral or central nervous system. Current treatment options do not provide adequate relief for many patients and a significant number of the agents used have dose limiting side effects. During the course of our work on the synthesis and screening of new drugs for the treatment of neuropathic pain, we have identified 5-(4-nitrophenyl)furoic-2-acid hydrazones which showed significant antiallodynic and antihyperalgesic activities in a chronic constriction injury (CCI) model of neuropathic pain in rat.

Current approaches with the glutamatergic system as targets in the treatment of neuropathic pain.

Glutamate is the most widely distributed and a major excitatory neurotransmitter in the CNS. It has been found to play a critical role in various physiological functions in which increased glutamate or its subsequent stimulation is thought to have a role in pathophysiological mechanism of various CNS diseases like epilepsy, stroke, depression and pain. Early attempts to develop glutamatergic antagonists failed in clinical studies due to nonselective or competitive antagonism and have a lot of safety issues like loss of cognitive functions, psychomimetic effect and sedation.

Therapeutic potential of inhaled p38 mitogen-activated protein kinase inhibitors for inflammatory pulmonary diseases.

Background: Over the past two decades, p38 MAPK (mitogen-activated protein kinase) has been the subject of intense multidisciplinary research. p38 MAPK inhibitors have been shown to be efficacious in several disease models, including rheumatoid arthritis, psoriasis, Crohn's disease, and stroke. Recent studies support a role for p38 MAPK in the development, maintenance, and/or exacerbation of a number of pulmonary diseases, such as asthma, cystic fibrosis, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD).

Protective effect of coenzyme Q10 in simvastatin and gemfibrozil induced rhabdomyolysis in rats.

Administration of simvastatin (80 mg/kg, po. evening dose) and gemfibrozil (600 mg/kg, po twice) for 30 days produced significant decrease in the level of reduced glutathione, superoxide dismutase, catalase and increase in the level of lipid peroxidation and various serum parameters (creatine phosphokinase, lactate dehydrogenase, serum glutamate oxaloacetate transaminase, creatinine, urea and blood urea nitrogen). This suggested involvement of oxidative stress in rhabdomyolysis.