Synthesis and alpha 1-adrenoceptor antagonistic activity of some 4-amino-5,7-dimethyl-2-(substituted) aminopyrido (2,3-d) pyrimidines

A series of new 4-amino-5,7-dimethyl-2- (substituted)aminopyrido(2,3-d)pyrimidines (5) have been synthesized and tested for selective alpha 1-adrenoreceptor antagonistic activity. Some of the compounds were found to antagonize alpha 1-adrenoreceptor in a competitive and reversible manner. When screened on rat anococcygeus muscle some of the compounds exhibited significant alpha 1-adrenoreceptor antagonistic activity (pA2 values in the range of 5.2-7.8). The most potent compound (5j) was evaluated by an in vivo method and was found to reduce the systolic and diastolic blood pressure of spontaneously hypertensive rats. The percentage reduction in blood pressure by test compound 5j was found to be higher than that of the standard drug prazosin (CAS 19216-56-9) at the same dose level (1 mg/kg p.o.). Chemically, prazosin is a 4-aminoquinazolin derivative. Pyridopyrimidine is a known bioisostere of quinazoline. The study revealed that isosteric replacement of the benzene ring of prazosin by a pyridine ring increases the potency.     

A case report of fatal dapsone-induced agranulocytosis in an Indian mid-borderline leprosy patient

Fatal agranulocytosis in an Indian male receiving 100mg of dapsone daily, hospitalized for mid-borderline leprosy in type I reaction with triple nerve paralysis is reported. Various case reports concerning dapsone-induced agranulocytosis are reviewed.     

Effects of tezosentan, a dual endothelin receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxic shock

Background/Purpose: Endothelin is a potent mediator of the cardiovascular and renal systems. Studies have found that endothelin has an important role in regulating cardiac function and renal perfusion in neonates who are suffering from endotoxic shock. The authors believe that blockade of the endothelin response during endotoxemia will have a beneficial effect on neonatal cardiac and renal functions. In this study the authors have examined the effects of tezosentan, a dual endothelin-receptor antagonist, on the cardiovascular and renal systems of neonatal piglets during endotoxemia. Methods: Thirteen piglets were subjected to endotoxic shock and divided into a fluid-therapy group that received 0.9% normal saline and a group that received tezosentan (1 mg/kg/h). Mean arterial pressure (MAP), heart rate (HR), and glomerular filtration rate (GFR) were plotted at baseline, 1, 2, and 3 hours. Cardiac index (CI), renal blood flow (RBF), systemic vascular resistance (SVR), and renal vascular resistance (RVR) were obtained at baseline, 1, and 3 hours after baseline. Results: (P [lt ] .05 for 3 hours versus baseline and tezosentan versus fluid). Although fluid therapy in endotoxemia had no significant effect on MAP and RVR, it significantly increased HR (139 [plusmn] 17 to 246 [plusmn] 17 beats/min) and SVR (0.08 [plusmn] 0.05 to 0.33 [plusmn] 0.09 mm Hg/mL/min) and decreased CI (407 [plusmn] 208 to 98 [plusmn] 13 mL/min/kg), RBF (1.84 [plusmn] 0.38 to 0.97 [plusmn] 0.34 mL/min/kg kidney), and GFR (0.20 [plusmn] 0.05 to 0.11 [plusmn] 0.04 mL/min/kg) at 3 hours. The use of tezosentan also significantly increased HR (130 [plusmn] 14 to 220 [plusmn] 31 beats/min), but unlike in the fluid therapy group, there was a significant fall in MAP (77 [plusmn] 10 to 54 [plusmn] 9 mm Hg) and RVR (1.92 [plusmn] 0.44 to 1.77 [plusmn] 0.64 mm Hg/mL/min) and a less severe decrease in CI (482 [plusmn] 188 to 176 [plusmn] 67 mL/min/kg) at 3 hours. SVR, RBF, and GFR were maintained. Conclusions: Endotoxic shock affected cardiac and renal functions in both treatment groups. Fluid therapy alone could not prevent a statistically significant fall in CI, RBF, and GFR or prevent the increase in HR and SVR. Endothelin antagonism with tezosentan resulted in a statistically significant fall in MAP and RVR from baseline, not seen in the fluid-therapy group. CI and RBF were significantly higher, and MAP, SVR, and RVR were significantly lower when compared with the fluid-therapy group at 3 hours. GFR also was maintained at baseline with tezosentan. During endotoxemia, endothelin antagonism maintained renal and cardiac functions better than with fluid therapy alone.     

Angiotensin converting enzyme inhibition in chronic allograft nephropathy

BACKGROUND: Although angiotensin-converting enzyme inhibition has been shown to slow progression of chronic allograft nephropathy in animal models, no studies have examined its efficacy in humans. METHODS: We retrospectively analyzed 63 patients with biopsy-proven chronic allograft nephropathy who had > or =6 months dialysis-free follow-up at our institution. A total of 32 patients treated for > or =6 consecutive months with angiotensin-converting enzyme inhibition and/or angiotensin-receptor blocker (ARB) therapy (group 1) were compared with 31 patients not on these agents (group 2). RESULTS: Except for a higher incidence of hypertension (100 vs. 78%, P=0.005) in group 1, there were no significant differences in baseline clinical characteristics at time of biopsy. With a mean follow-up time of 27 months in both groups, 6 of 32 (19%) group 1 patients vs. 12 of 31 (39%) group 2 reached the primary endpoint of > or =50% increase in serum creatinine (P=0.10). Mean time to primary endpoint was 46.6 months in group 1 vs. 32.7 months in group 2 (P=0.07). Three of 32 (9%) of group 1 patients vs. 8 of 31 (26%) of group 2 returned to dialysis during this time (P=0.11). Significantly fewer patients in group 1 reached the combined secondary endpoint of allograft failure or death (9.4 vs. 35.5%, P=0.01); in addition, group 1 had a longer mean time to this endpoint (51.2 vs. 37.6 months, P=0.03). On multivariate analysis, the only predictor of progression to primary endpoint was a high baseline serum creatinine (P=0.02). No significant differences in hyperkalemia or anemia were found between the two groups. CONCLUSIONS: Angiotensin-converting enzyme inhibition/angiotensin-receptor blocker therapy is well tolerated in renal allograft recipients with chronic allograft nephropathy. It is associated with a trend of slowing renal insufficiency as well as a significant survival benefit in the combined endpoint of allograft failure or death.     

Resection of liver metastases: state of the art

In this article, we present current surgical perspectives on the management of liver metastases, with a focus on state-of-the-art resection, by drawing on clinical data provided in the medical literature. Metastases from colorectal cancer are the most amenable to resection, when considering long-term benefits. To highlight the evidence-based rationalefor surgical resection, a succinct comparison of all treatment modalities for liver metastasis from colorectal cancer is provided. Special emphasis has been placed on the current status of perioperative patient evaluation, durability of results, prognosticators, technical advances, and alternative treatment strategies. In various areas, we have attempted to delineate any improvements on the horizon. The role of surgical resection in noncolorectal metastases is also discussed.     

Idiopathic hypertrophic cranial pachymeningitis

Idiopathic hypertrophic cranial pachymeningitis is a rare form of fibrosing chronic inflammatory process of unknown etiology, which causes thickening of the intracranial dura mater. We present four patients with hypertrophic cranial pachymeningitis who presented with chronic headache and cranial nerve palsies. The diagnosis of idiopathic hypertrophic cranial pachymeningitis was based on neuroimaging findings of thickened enhancing dura, exclusion of known causes and histopathologic findings compatible with nonspecific inflammation in the meningeal biopsies. Corticosteroid therapy was effective in all cases in inducing a complete or partial remission of the neurologic symptoms and signs. We describe the clinical, radiological and pathological features of idiopathic hypertrophic cranial pachymeningitis and discuss the relationship of this entity with other inflammatory fibrosclerotic disorders to explain the pathogenesis. A high index of suspicion, prompt confirmation of the diagnosis by meningeal biopsy, and early institution and long-term maintenance of steroid therapy may help to prevent irreversible neurologic sequelae, especially blindness.     

Atypical meningioma: a clinicopathological analysis

In this retrospective study, 382 operated cases of meningiomas were reviewed. 32 cases (8.3%) were histopathologically classified as atypical meningioma. The anatomical locations and histological features in all the thirty-two cases were correlated with their recurrence rates and biological behaviour. The overall recurrence rate for atypical meningioma within two years was 28% as compared to 9.3% in benign meningiomas. It is being emphasized that an accurate histopathological interpretation of atypical meningioma is essential for predicting the recurrence, biological behavior as well as post-operative management modalities.     

Supravital staining: It's role in detecting early malignancies

The efficacy of supravital staining in the detection of malignancies in oro and oropharyngeal lesions and its role in the detection of malignant changes in premalignant lesions were studied. This prospective study comprises 90 cases of clinically suspicious lesions and it was done over a period of 3 years. Most of the patients had multiple risk factors for the development of malignancy. All underwent staining with a modified solution of 1% toluidine blue (TB). In our study the overall sensitivity was 97.29% and the specificity was 62.5%.     

Familial infantile myaesthenia

We report a family of two brothers with familial infantile myaesthenia which is an autosomal recessive congenital myaesthenic syndrome. It is a presynaptic neuro muscular junction disorder, responsive to treatment and has got good prognosis.