Inhibition of allergen-induced pulmonary responses by the selective tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-phenoxy]-pen tane (AMG-126737)

Emerging evidence suggests that mast cell tryptase is a therapeutic target for the treatment of asthma. The effects of this serine protease are associated with both pathophysiologic pulmonary responses and pathologic changes of the asthmatic airway. In this study, the tryptase inhibitor 1,5-bis-[4-[(3-carbamimidoyl-benzenesulfonylamino)-methyl]-p henoxy]-pentane (AMG-126737) was evaluated for its pharmacologic effects against allergen-induced airway responses. AMG-126737 is a potent inhibitor of human lung mast cell tryptase (Ki = 90 nM), with greater than 10- to 200-fold selectivity versus other serine proteases. Intratracheal administration of AMG-126737 inhibited the development of airway hyperresponsiveness in allergen-challenged guinea pigs with an ED50 of 0.015 mg/kg. In addition, the compound exhibited oral activity in the guinea pig model. The in vivo activity of AMG-126737 was confirmed in a sheep model of allergen-induced airway responses, where the compound inhibited early and late phase bronchoconstriction responses and the development of airway hyperresponsiveness. These results support the proposed role of tryptase in the pathology of asthma and suggest that AMG-126737 has potential therapeutic utility in this pulmonary disorder.     

Chemoreflexes: an experimental study

HYPOTHESIS: Transmyocardial laser revascularization (TMLR) will not denervate the heart, because it does not destroy all of the afferents. This study was designed to determine if stimulation of cardiac sympathetic and vagal afferents from an area of the left ventricle treated with TMLR could evoke reflex effects, and thus whether TMLR would denervate the heart. METHODS: The effect of TMLR on reflexes evoked by chemically stimulating cardiac afferents was examined in 9 dogs. Bradykinin and capsaicin were applied topically or injected into the left anterior descending coronary artery before and after TMLR and after bilateral vagotomy and sympathectomy. Aortic (AoP) and left ventricular pressures (LVP) and electrocardiography were monitored. The first derivatives of LVP (dP/dt) were calculated. RESULTS: Topical bradykinin elicited variable hemodynamic responses. Topical capsaicin evoked pressor responses, increasing mean (+/- SEM) AoP (105+/-9 to 115+/-9 mm Hg; P<.001) and positive dP/dt (+dP/dt) (1032+/-81 to 1159+/-10 mm Hg/s; P<.01) before TMLR. Intracoronary capsaicin evoked a depressor response before TMLR. Pressor responses remained intact after TMLR with increases in mean AoP and +dP/dt (115+/-6 to 128+/-5 mm Hg and 1039+/-98 to 1136+/-100 mm Hg/s, respectively; P<.01). Depressor responses also remained intact after TMLR (91+/-10 vs 101+/-11 mm Hg [P<.02], and 865+/-104 vs 931+/-104 mm Hg/s [P<.05], respectively). Hemodynamic responses were diminished after bilateral vagotomy and abolished after bilateral sympathectomy. CONCLUSION: Since activation of cardiac afferent nerves and reflex responses remained intact after TMLR, but changed after vagotomy or sympathectomy, TMLR does not denervate the heart sufficiently to be the cause of improved angina after TMLR.     

Cardiac tamponade masquerading as headache: A diagnostic conundrum

Cardiac tamponade and its protean presentations are well documented. Tamponade presenting after recent cardiac surgery in a patient on anticoagulation is not unknown. However, severe headache as a presenting feature of tamponade is not documented. We describe how one can be misled into investigating causes of headache while the real cause, tamponade, lies hidden.     

Protein Energy Wasting in a Cohort of Maintenance Hemodialysis Patients in Dhaka,Bangladesh

Malnutrition is associated with high rates of mortality among patients with end stage kidney disease (ESKD). There is a paucity of data from Bangladesh, where around 35,000–40,000 people reach ESKD annually. We assessed protein-energy wasting (PEW) amongst 133 patients at a single hemodialysis setting in Dhaka. Patients were 49% male, age 50 ± 13 years, 62% were on twice-weekly hemodialysis. Anthropometric, biochemical, and laboratory evaluations revealed: BMI 24.1 ± 5.2 kg/m², mid-arm muscle circumference (MAMC) 21.6 ± 3.6 cm, and serum albumin 3.7 ± 0.6 g/dL. Based on published criteria, 18% patients had PEW and for these patients, BMI (19.8 ± 2.4 vs. 25.2 ± 5.2 kg/m²), MAMC (19.4 ± 2.4 vs. 22.2 ± 3.8 cm), serum albumin (3.5 ± 0.7 vs. 3.8 ± 0.5 g/dL), and total cholesterol (135 ± 34 vs. 159 ± 40 mg/dL), were significantly lower as compared to non-PEW patients, while hand grip strength was similar (19.5 ± 7.6 vs. 19.7 ± 7.3 kg). Inflammatory C-reactive protein levels tended to be higher in the PEW group (20.0 ± 34.8 vs. 10.0 ± 13.9 p = 0.065). Lipoprotein analyses revealed PEW patients had significantly lower low density lipoprotein cholesterol (71 ± 29 vs. 88 ± 31 mg/dL, p < 0.05) and plasma triglyceride (132 ± 51 vs. 189 ± 103 mg/dL, p < 0.05), while high density lipoprotein cholesterol was similar. Nutritional assessments using a single 24 h recall were possible from 115 of the patients, but only 66 of these were acceptable reporters. Amongst these, while no major differences were noted between PEW and non-PEW patients, the majority of patients did not meet dietary recommendations for energy, protein, fiber, and several micronutrients (in some cases intakes were 60–90% below recommendations). Malnutrition Inflammation Scores were significantly higher in PEW patients (7.6 ± 3.1 vs. 5.3 ± 2.7 p < 0.004). No discernible differences were apparent in measured parameters between patients on twice- vs. thrice-weekly dialysis. Data from a larger cohort are needed prior to establishing patient-management guidelines for PEW in this population.     

Utility of misoprostol for labor induction in severe pre-eclampsia and eclampsia

OBJECTIVES: To determine the effectiveness and safety of misoprostol in severe pre-eclampsia and eclampsia patients with unripe cervix. METHODS: A prospective observational study was carried out in 135 severe pre-eclampsia and eclampsia patients who required termination of pregnancy at the Department of Obstetrics and Gynecology, Khulna Medical College Hospital, Khulna, Bangladesh during January 2002 to October 2003. Fifty micrograms of misoprostol was used every 4 h in cases of unripe cervix (Bishop score < or = 6) in severe pre-eclampsia and eclampsia patients. Maternal and perinatal outcome as well as any complications were recorded. RESULTS: In severe pre-eclampsia and eclampsia patients vaginal delivery occurred in 79.3 and 80.5% of cases, and cesarean section was performed in 20.6 and 19.4% of cases, respectively. The maximum required responsive dose was 50-150 microg. Oxytocin augmentation was required in 29.3 and 35% of cases, respectively. Induction to delivery time was median 8 h, interquartile ranges 4.2-8.2 h in the severe pre-eclampsia group, and median 9 h, interquartile ranges 6.8-12.5 h in the eclampsia group, and average hospital stay was 3.4 +/- 1.8 and 3.7 +/- 1.7 days, respectively. The only maternal complications were hyperstimulation which occurred in 6.8 and 5.1% of cases, respectively. Neonatal death occurred in five (11.3%) and eight cases (12.1%), respectively. CONCLUSION: Intravaginal misoprostol is well tolerated and very effective for the induction of labor in severe pre-eclampsia and eclampsia patients with unripe cervix.     

Optimization of 2-phenylaminoimidazo[4,5-h]isoquinolin-9-ones: orally active inhibitors of lck kinase

The tyrosine kinase p56lck (lck) is essential for T cell activation; thus, inhibitors of lck have potential utility as autoimmune agents. Our initial disclosure of a new class of lck inhibitors based on the phenylaminoimidazoisoquinolin-9-one showed reasonable cellular activity but did not work in vivo upon oral administration. Our current work highlights the further use of rational drug design and molecular modeling to produce a series of lck inhibitors that demonstrate cellular activity below 100 nM and are as efficacious as cyclosporin A in an in vivo mouse model of anti-CD3-induced IL-2 production.     

Polymorphism of glutathione S-transferases as genetic risk factors for the development of complications in type 2 diabetes mellitus

Background

Diabetes is characterized by chronic hyperglycemia that produces dysregulation of cellular metabolism and result in excess free radical production and oxidative stress. Glutathione S-transferases (GSTs) are a family of multifunctional enzymes that work as antioxidants. Therefore, diminished expression of GSTs may result in a reduced body defense against oxidative stress, followed by development of diabetic complications.

Objectives

To investigate the possible association between GSTM1 and GSTT1 polymorphism and the occurrence of complications in type 2 DM and to study the other risk factors for complications in DM.

Methods

Twenty noncomplicated type 2 diabetic patients and 40 complicated type 2 diabetic patients were enrolled in the study. The GSTM1 and GSTT1 genotypes were identified by polymerase chain reaction of peripheral blood DNA samples. Analysis of data was done by using SPSS (SPSS, Chicago, Ill).

Results

The frequencies of null GSTM1 and GSTT1 genotypes were 55% (11/20) and 40% (8/20), respectively, in noncomplicated DM group. The frequencies of null GSTM1 and GSTT1 genotype in complicated DM group were 57.5% (23/40) and 60% (24/40), respectively. The null GSTT1 genotype was more prevalent in the group of complicated DM with odds ratio (odds ratio, 2.3; 95% confidence interval, 0.75-6.7) when compared with noncomplicated DM.

Conclusion

Our data provide evidence that diabetics with null GSTT1 genotypes are substantially at higher risk for developing complications.