Syntheses of new tetrasubstituted thiophenes as novel anti-inflammatory agents

A series of new tetrasubstituted thiophenes (4a-4i, 5a-5i and 6a-6f) have been synthesized as novel anti-inflammatory agents and were evaluated for their anti-inflammatory activity in carrageenin-induced rat hind paw oedema model at the doses of 10, 20 and 40mg/kg body weight. Among ester series, the best compound 4c showed 71% protection at 10mg/kg, 72% at 20mg/kg, and 76% at 40mg/kg to inflamed paw; while in acid series 5a showed 79% protection at 10mg/kg, 80% at 20mg/kg, and 70% at 40mg/kg, and 5c showed 72% protection at 10mg/kg, 75% at 20mg/kg, and 69% at 40mg/kg, to inflamed paw. In case of oxime series 6a-6f, the anti-inflammatory activities of the candidates were found to be poor as compared to acid and ester series. It was found on the basis of SAR studies of target compounds, that the presence of OCH(3) at R(2) position and H, OCH(3) at R(1) are one of the requirements for eliciting comparable anti-inflammatory activity in both tetrasubstituted thiophenes' ester and acid series. Compounds 4a-4i, 5a-5i were investigated for their analgesic activity in acetic acid induced writhing response model at 10mg/kg dose. Among the ester series compound 4e showed maximum protection of 60%, while 4a, 4b, and 4i exhibited 55%, 45%, and 43% protection, respectively. The result showed that presence of H, Cl at R(1) and OCH(3), CH(3) at R(2) in tetrasubstituted thiophene ester series enhances their analgesic activity. The candidates of acid series 5a-5i showed poor analgesic activity as compared to the standard drug ibuprofen. Compounds 4a-4i, 5a-5i were evaluated for their in vitro antioxidant nitric oxide radical scavenging assay. Among the ester series 4a showed maximum in vitro nitric oxide radical scavenging activity having IC(50) value 30.08microg/ml while in acid series 5a has IC(50) value 25.20microg/ml. The results showed that the presence of R(1)=H, R(2)=OCH(3) and R(1)=R(2)=OCH(3) enhances nitric oxide radical scavenging property in tetrasubstituted thiophenes' acid series.     

Strain analysis of flexing blood pump diaphragms.

Blood pumps usually use elastomer diaphragms that undergo repeated small-strain flexing (deformation). The stresses and strains that develop in the mechanically actuated diaphragms dictate the useful life and fluid-solid interactions of the diaphragm. A knowledge of these stresses and strains is essential for proper design of the pump's elastomer diaphragm. A nonlinear axisymmetric finite-element stress-strain analysis has been carried out on a Hexsyn rubber diaphragm used in a blood pump to illustrate a finite-element modeling technique. A situation involving the application of an axial deformation load on the diaphragm has been considered. In particular, the strains developed in a blood pump diaphragm during pumping have been quantified to illustrate the analysis technique.     

Antagonism of P2Y₁₂ reduces physiological thromboxane levels

Antiplatelet therapy for the management of patients with cardiovascular risks often includes a combination therapy of aspirin and clopidogrel, acting through inhibition of thromboxane generation and blockade of G(i)-coupled P2Y?? receptor, respectively. We hypothesized that ADP acting through P2Y?? regulates physiological thromboxane levels. The serum thromboxane levels in mice (n?=?3) dosed with clopidogrel and prasugrel were decreased by 83.1?±?5.3% and 94.26?±?1.75% respectively compared to untreated mice. Pre-treatment of human blood (n?=?3) ex vivo with active metabolites of clopidogrel or prasugrel led to a reduction in thromboxane levels to 16.3?±?3.2% and 4.9?±?0.8% respectively, compared to untreated human serum. We also evaluated serum thromboxane levels in P2Y receptor null mice (n?=?4). Whereas serum thromboxane levels in P2Y? null mice were similar to those in wild type littermates, those in the P2Y?? null mice were inhibited by 83.15?±?3.8%. Finally, in a pilot study, serum thromboxane levels were reduced by 76.05?±?8.41% in healthy human volunteers (n?=?6) upon dosing with clopidogrel, compared to the levels before dosing. In conclusion, P2Y?? antagonism alone can decrease physiological thromboxane levels. Thus, this study could pave way the for newer/modified treatment regimens for the management of patients with thrombotic complications who are allergic or non-responsive to aspirin.     

Baclofen in the management of inhalant withdrawal: a case series

Introduction: Abuse of inhalants and solvents is a significant public health problem. There is no specific treatment for inhalant withdrawal.Objective: To study the effect of baclofen in treating craving and withdrawal symptoms in patients with inhalant dependence.Case Reports: Case studies of 3 young male patients with DSM-IV diagnoses of inhalant dependence treated in an inpatient setting with baclofen are presented. All patients had nonspecific withdrawal symptoms in the form of irritability, insomnia, and craving. Baclofen was given in doses up to 50 mg/day and was continued throughout the period of hospitalization.Discussion: All patients reported significant reduction in withdrawal symptoms within 48 hours of treatment and were free of symptoms for the duration of their hospital stay. One patient continued the medication as an outpatient and has remained abstinent to date. Baclofen was well tolerated by all patients. Our results suggest that baclofen may be an effective treatment modality in this patient population. These effects are possibly due to the agonistic action of baclofen at gamma-aminobutyric acid B receptors in the ventral tegmental area.