The in vitro pharmacological profile of KR31080, a nonpeptide AT1 receptor antagonist

Summary— KR31080 (2-butyl-5-methyl-6-(1-oxopyridin-2-yl)-3-[[2'-(1H-tetrazol-5-yl) biphenyl-4-yl]methyl]-3H-imidazo[4,5-b] pyridine) is a potent inhibitor of angiotensin type 1 (AT₁) receptors in rabbit aorta and human recombinant AT₁ receptors. In the isolated rabbit thoracic aorta, KR31080 caused a nonparallel shift to the right of the concentration-response curves to angiotensin II (All) with decreased maximal response (pD'₂ = 10.1 ± 0.1), but had no effect on the contractile response induced by norepinephrine. KR31080 inhibited specific [¹²⁵I]AII binding to rabbit aortic membranes (AT, receptors) and [¹²⁵I][Sar¹, Ile⁸]AII binding to human recombinant AT₁ receptors in a concentration-dependent manner with IC₅₀ values of 0.84 ± 0.08 nM and 1.92 ± 0.15 nM, respectively, but did not inhibit specific [¹²⁵I)AII binding to bovine cerebellum membranes (ÀT₂ receptors). In the Scatchard analysis, KR31080 interacted with rabbit aortic AT₁ receptors in a competitive manner, similar to losartan. These results demonstrate that KR31080 is a potent and AT₁ selective angiotensin receptor antagonist which exerts a competitive antagonism in the [¹²⁵I]AII binding assay and insurmountable AT₁ receptor antagonism in the functional study.     

Respiratory symptoms and bronchial reactivity: identification of a syndrome and its relation to asthma

Two postal questionnaire surveys were carried out among the adult population of Southampton aimed at clarifying the diagnostic criteria for asthma (study 1) and at testing the validity of symptoms so identified as diagnostic of bronchial hyper-reactivity (study 2). The questionnaires asked about respiratory symptoms and included three questions thought likely to disclose increased bronchial reactivity. Laboratory measurements on subsamples of respondents included spirometry and bronchial challenge with increasing doses of histamine till a concentration was reached provoking a fall of more than 20% (PC greater than 20) in forced expiratory volume in one second. In the first study no normal subject (that is, one who did not report shortness of breath or wheezing on the questionnaire) had a PC greater than 20 below 0.5 g/l. Of 51 subjects who reported shortness of breath or wheezing, or both, nine had a cluster of abnormalities consisting of one or more symptoms of bronchial irritability, nocturnal dyspnoea, and prolonged morning tightness together with PC greater than 20 values of 0.5 g/l or less. These symptoms in conjunction with a low PC greater than 20 were termed the bronchial irritability syndrome. In the second study bronchial challenge confirmed the close association of these symptoms with bronchial hyper-reactivity, all other subjects being less reactive to histamine. Only 27% of subjects with symptoms of the bronchial irritability syndrome had been diagnosed as asthmatic by their general practitioners. The bronchial irritability syndrome is a definable entity for epidemiological study and patient care.     

Corpus callosum: interactive effects of infantile handling and testosterone in the rat

Previous research found that the corpus callosum of male rats is larger than that of females; handling rats in infancy enhances this sex difference; and female rat pups, when handled in infancy and given 1 injection of testosterone propionate (TP) on Day 4 of life, will have callosa as large as those of males. In 2 experiments, male pups were castrated on Day 1 or received sham surgery; female pups were injected with TP on Day 4 or received an oil injection. Litters were handled or nonhandled. The previous finding that females, when handled and given TP in infancy, have a larger callosum was confirmed; however, a TP effect when administered to nonhandled females was not found. Because handling is known to cause a corticosterone release, these findings were interpreted as evidence of a developmental interaction between adrenal and gonadal hormones at the cortical level.     

Enhanced cis-platinum ototoxicity in children with brain tumours who have received simultaneous or prior cranial irradiation

We report on four children who received cis-platinum simultaneously with, or in one case 10 months after, cranial irradiation and experienced exaggerated ototoxicity affecting all audible frequencies. The hearing loss was severe, affecting the critical areas for speech perception, and necessitated the provision of bilateral hearing aids. The audiograms of these patients are shown and compared to those of four children who had received cis-platinum as part of their treatment for neuroblastoma but without cranial irradiation. The precipitation of the exaggerated hearing loss with the administration of cis-platinum in one patient 10 months after finishing cranial irradiation suggests that care should be taken in the timing of cis-platinum administration in relation to concurrent or previous cranial irradiation.     

Public knowledge about AIDS increasing

In response to concern over the perceived limited effectiveness of Department of Health and Social Security (UK) advertising campaigns to inform the public of the basic facts of Acquired Immunodeficiency Syndrome (AIDS), a prospective questionnaire study was undertaken in Southampton, England to test the effectiveness of government education prior to a January, 1987 government television/leaflet advertising campaign. 300 questionnaires about AIDS were mailed in December of 1986 to a sample drawn from electoral rolls. The response rate was 61%. Most of the questions were drawn from material covered in the campaign. The results seemed to indicate a small overall increase in knowledge about AIDS. Some changes from a June survey were noted, e.g.: more people were aware that AIDS is a virus for which there is no cure and that it is not readily transmitted by sharing washing, eating or drinking utensils; more people believed that the statement that women are at greater risk for catching AIDS is false. Respondents were generally favorable to the government's continued use of television, even with explicit language, and to its use of the schools, for AIDS education. Many were not aware of the dangers to intravenous drug users or of the symptoms of AIDS. Other surveys have shown an increasing knowledge of AIDS dangers. It is possible that television coverage of the problem will continue to be necessary, in order that less literate populations be reached. Further AIDS health education in general is needed.     

Gunshot wounds to the spine associated with a perforated viscus

The cases of 42 patients with low-velocity gunshot wounds to the spine with an associated perforated viscus were reviewed. All viscus perforations occurred prior to the spinal injury. There were a total of 51 perforations, including 14 of the colon, 15 of the small bowel, 15 of the stomach, five of the esophagus, and two of the pharynx. All patients had significant neurologic deficits, with 23 patients suffering a complete neurologic injury. Average clinical follow-up was 18 months (range: 4-64 months). Only three patients developed documented spinal or paraspinal infections. One case of acute meningitis occurred after an isolated stomach perforation, while two other patients developed psoas abscesses after colon injuries. The roles of initial antibiotic therapy and of early bullet removal were evaluated in regard to infection. An extended course of broad spectrum antibiotics combined with bedrest appeared to significantly reduce the risk of spinal or paraspinal infection as compared with a previous study. Early bullet removal did not appear to be a significant factor in the prevention of infection. Prospective studies are needed to accurately delineate the role of initial antibiotic therapy for the prevention of spinal infection in these injuries.     

Reflex sympathetic dystrophy in cervical spinal cord injury patients

Sixty consecutive patients admitted to the spinal cord injury unit at a Downey, California medical center were evaluated for hand and upper extremity pain. Patients averaged nine months postinjury and had an average age of 37 years. Seven patients (11.7%) complained of diffuse hand pain, swelling, and stiffness. All patients with complaints were evaluated with three-phase radionuclide scintigraphy. Six of those seven patients had scintigrams consistent with reflex sympathetic dystrophy (RSD), an overall incidence of 10%. Three of these six patients were treated with stellate ganglion blocks, which gave relief of symptoms and allowed return to their rehabilitation program. An awareness of RSD as a cause of pain in spinal cord injured patients should lead to earlier recognition and treatment.     

Cognitive enhancing agents: current status in the treatment of Alzheimer's disease

Extensive recent literature on drugs used to enhance cognitive functioning, reflects the growing social problem of dementia. Many clinical trials have been undertaken with variable success. In most cases the disorder studied has been Alzheimer's disease. The pharmacological approach has been designed to rectify the presumed pathophysiological processes characteristic of the condition. Agents tested include cerebral vasodilators, cerebral metabolic enhancers, nootropics, psychostimulants, neuropeptides and neurotransmitters with a special emphasis on drugs used to enhance cholinergic function. Ethical and practical issues concerning clinical drug trials in dementia will be discussed.     

Pharmacologic strategies for managing pain in children.

Erroneous presumptions about children's reactions to pain have misguided professionals' management of this issue. Recent recognition and understanding of the pain experience in children have prompted research and clinical advances in treatment and care. Considerable study is still needed to further comprehend the difference between the perception and reaction to pain in the pediatric population.