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.     

Bilateral macular hemorrhage caused by azathioprine-induced aplastic anemia in a corneal graft recipient

PURPOSE: To report the occurrence of bilateral macular hemorrhage following the use of azathioprine for immunosuppression in a corneal transplant recipient. METHODS: The patient underwent therapeutic penetrating keratoplasty for progressive fungal keratitis in his left eye. Although the infection did not recur, the graft failed with vascularization of the cornea in three quadrants. He underwent repeat penetrating keratoplasty 2 years later and was treated with azathioprine (100 mg daily) to enhance graft survival. Four months after instituting azathioprine therapy, he developed aplastic anemia and macular hemorrhage in both eyes. RESULTS: Fluorescein angiography revealed a preretinal location of the macular hemorrhage. After cessation of azathioprine therapy and treatment with blood component replacement, hematological parameters improved and the macular hemorrhage cleared with good visual recovery during the next 2 months. CONCLUSION: This report highlights the serious ocular and systemic complications that can occur following the use of systemic immunosuppressants after ophthalmic surgery.     

Complications of laser-in-situ-keratomileusis

Laser-in-situ-keratomileusis (LASIK) has become a popular technique of refractive surgery because of lower postoperative discomfort, early visual rehabilitation and decreased postoperative haze. Compared to photorefractive keratectomy (PRK), LASIK involves an additional procedure of creating a corneal flap. This may result in complications related to the flap, interface and underlying stromal bed. The common flap-related complications include thin flap, button holing, free caps, flap dislocation and flap striae. The interface complications of diffuse lamellar keratitis, epithelial ingrowth and microbial keratitis are potentially sight threatening. Compared to PRK, there is less inflammation and faster healing after LASIK, but there is a longer period of sensory denervation leading to the complication of dry eyes. The refractive complications include undercorrection, regression, irregular astigmatism, decentration and visual aberrations. Honest and unbiased reporting is important to understand the aetiology and redefine the management.     

Role of Ca2+ channels on the hypothermic response produced by activation of kappa-opioid receptors

The effect of nimodipine (NIM) and lercanidipine (LER) 1,4-dihydropyridine (DHP) calcium channel blockers (CCBs) on the hypothermic response of selective kappa-opioid receptor agonists U50,488H (U50), PD117,302 (PD) and U69,593 (U69) was determined in rats by recording colonic temperature using digital telethermometer. Intraperitoneal (i.p.) injections of U50 (7.5, 15, 22.5 and 40 mg/kg), PD (7.5, 15 and 22.5 mg/kg) and U69 (5 and 20 mg/kg) produced a dose-dependent hypothermic response. However, higher doses of U50 (60 and 80 mg/kg) produced hypothermia, which is less when compared to that produced by 22.5-mg/kg dose of U50. NIM (1 mg/kg i.p.; 15 min prior) and LER (0.3 mg/kg i.p.; 15 min prior) did not produce any change in basal colonic temperature. Treatment of NIM and LER potentiated the U50 (7.5, 15, 22.5 and 40 mg/kg)-induced hypothermic effect. NIM did not potentiate hypothermia produced by U50 (60 mg/kg). On the other hand, PD (7.5, 15 and 22.5 mg/kg)- and U69 (5 and 20 mg/kg)-induced hypothermia was unaffected by the pretreatment of either NIM or LER. This differential modulation of kappa-opioid agonist-induced hypothermia by CCBs suggest that there may be two mechanisms, Ca(2+)-sensitive and Ca(2+)-insensitive, involved in kappa-opioid agonist-induced hypothermic response.     

Prospects for rational development of pharmacological gap junction channel blockers

Connexin-null mice and human genetic gap junction diseases illustrate the important roles that gap junction channels play under normal conditions, and the neuro- and cardioprotective effects of gap junction blocking agents demonstrate that closure of these channels may be beneficial in certain pathological situations. This overview summarizes studies in which gap junction modifying reagents have been characterized, highlighting examples of agents for which selectivity for gap junction subtypes has been demonstrated. In addition, strategies for targeting connexin domains through peptide inhibitors are outlined, which may ultimately provide agents that are not only connexin-selective in their actions, but also affect only a subset of a gap junction channel's gating responses.     

Pharmacological therapies in fibromyalgia

The fibromyalgia syndrome (FMS) is a common, chronic, widespread pain disorder that mainly affects middle-aged women. In addition to pain complaints, fatigue and disturbed sleep are symptoms frequently reported by these patients. Many FMS patients also meet diagnostic criteria for mood disorders (e.g. depression) as well as other so-called 'functional somatic syndromes', including irritable bowel syndrome, temporomandibular joint disorder, and subsets of chronic low-back pain. A wide variety of medications are used to manage the eclectic symptomatology of FMS patients, although relatively few have been rigorously tested. This chapter provides a contemporary update of the state of FMS pharmacotherapy, with an emphasis on compounds that have been tested in double-blind, randomized, controlled trials. Particular attention is paid to the efficacy of these therapies on the associated symptoms and co-morbid syndromes commonly seen in FMS patients.     

Trichotillomania: a review and case report

Although patients with trichotillomania typically present to dermatologists, the diagnosis and treatment lie in the field of psychiatry. We report an unusual case of a 33-year-old woman with severe trichotillomania. We review common clinical and pathologic findings of this often chronic and socially debilitating disorder. In addition, we discuss treatment options for dermatologists and how collaboration with psychiatrists is the most effective management for these difficult-to-treat patients.