Biomedical subjects
Publications and source records attributed to E McDonald.
As the Joint Commission on Accreditation of Healthcare Organizations (Joint Commission) has shifted the focus of its survey process to the organization as a whole, new techniques are needed to prepare for surveys. Staten Island University Hospital used teams based on the eleven important functions to achieve a successful survey.
Coadministration with the human immunodeficiency virus (HIV) protease inhibitor ritonavir was investigated as a method for enhancing the levels of other peptidomimetic HIV protease inhibitors in plasma. In rat and human liver microsomes, ritonavir potently inhibited the cytochrome P450 (CYP)-mediated metabolism of saquinavir, indinavir, nelfinavir, and VX-478. The structural features of ritonavir responsible for CYP binding and inhibition were examined. Coadministration of other protease inhibitors with ritonavir in rats and dogs produced elevated and sustained plasma drug levels 8 to 12 h after a single dose. Drug exposure in rats was elevated by 8- to 46-fold. A > 50-fold enhancement of the concentrations of saquinavir in plasma was observed in humans following a single codose of ritonavir (600 mg) and saquinavir (200 mg). These results indicate that ritonavir can favorably alter the pharmacokinetic profiles of other protease inhibitors. Combination regimens of ritonavir and other protease inhibitors may thus play a role in the treatment of HIV infection. Because of potentially substantial drug level increases, however, such combinations require further investigation to establish safe regimens for clinical use.
The purpose of this study was to assess the suitability of different radiation dosimetry methods and record radiation exposures during paediatric catheterization. Three methods of dosimetry were employed: thermoluminescent dosimetry (TLD), dose-area product and calculation of entrance surface dose from calibrated exposure factors. Examinations included bi-plane fluoroscopy, and cineangiography for diagnosis and treatment of congenital heart disease. The most suitable method of radiation dosimetry for cardiac catheterization is the use of calculated entrance dose or a dose-area product meter. Children were exposed to high levels of radiation during cardiac catheterization but there was a wide variation in radiation dosage. Careful consideration should be given to the suitability of radiation dosimetry for cardiac catheterization.
A series of novel, azacyclic ureas which are highly potent inhibitors of the HIV-1 protease (IC50 = 4.1 to < 0.5 nM) were synthesized. Aqueous solubilities of this series of compounds were improved by incorporating polar functional groups at the P1' P2 and P2' positions. These compounds also possess good anti-viral activity by inhibition of the cytopathic effect of HIV-13B in MT-4 cells in vitro.
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The design, synthesis, and molecular modeling studies of a novel series of azacyclic ureas, which are inhibitors of human immunodeficiency virus type 1 (HIV-1) protease that incorporate different ligands for the S1', S2, and S2' substrate-binding sites of HIV-1 protease are described. The synthesis of this series is highly flexible in the sense that the P1', P2, and P2' residues of the inhibitors can be changed independently. Molecular modeling studies on the phenyl ring of the P2 and P2' ligand suggested incorporation of hydrogen-bonding donor/acceptor groups at the 3' and 4-positions of the phenyl ring should increase binding potency. This led to the discovery of compound 7f (A-98881), which possesses high potency in the HIV-1 protease inhibition assay and the in vitro MT-4 cell culture assay (Ki = approximately 5 pM and EC50 = 0.002 microM). This compares well with the symmetrical cyclic urea 1 pioneered at DuPont Merck.
A series of novel pseudo-symmetrical and unsymmetrical inhibitors based on the backbone modification of a peptidomimetic were synthesized and found to be highly potent inhibitors of the HIV-1 protease (IC50 = 2.9 to < 0.5 nM). These compounds also possess good antiviral activity in vitro as measured by inhibition of the cytopathic effect of HIV-1(3B) in MT-4 lymphocytes. Importantly, some of these compounds also have good oral bioavailabilities in rats (F = 30.6% to 100%). One of these compounds 4C, also has good oral bioavailability in beagle dogs and cynomolgus monkeys.
Examination of the structural basis for antiviral activity, oral pharmacokinetics, and hepatic metabolism among a series of symmetry-based inhibitors of the human immunodeficiency virus (HIV) protease led to the discovery of ABT-538, a promising experimental drug for the therapeutic intervention in acquired immunodeficiency syndrome (AIDS). ABT-538 exhibited potent in vitro activity against laboratory and clinical strains of HIV-1 [50% effective concentration (EC50) = 0.022-0.13 microM] and HIV-2 (EC50 = 0.16 microM). Following a single 10-mg/kg oral dose, plasma concentrations in rat, dog, and monkey exceeded the in vitro antiviral EC50 for > 12 h. In human trials, a single 400-mg dose of ABT-538 displayed a prolonged absorption profile and achieved a peak plasma concentration in excess of 5 micrograms/ml. These findings demonstrate that high oral bioavailability can be achieved in humans with peptidomimetic inhibitors of HIV protease.
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Rhabdomyolysis should be considered in the differential diagnosis of acute muscle weakness or pain in patients who have recently increased their level of exercise, no matter what their previous level of physical fitness. Measurement of an elevated creatine kinase level confirms the diagnosis. Management of rhabdomyolysis is aimed at avoiding acute renal failure through aggressive fluid replacement to maintain a high urine output.
The usual aids to diagnosis--such as symptoms and antinuclear antibodies--do not reliably distinguish this important entity from idiopathic SLE. Age, sex, and antibody type are often clues, but in some cases, only time and clinical course will tell.
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From 686 patients attending primary care physicians, 77 were identified by a screening procedure as having chronic fatigue. Of these, 65 were given a comprehensive psychological, social and physical evaluation. Seventeen cases (26%) met criteria for the chronic fatigue syndrome. Forty-seven (72%) received an ICD-9 diagnosis of whom 23 had neurotic depression, with a further 5 meeting criteria for neurasthenia. Forty-nine were 'cases' as defined by the revised Clinical Interview Schedule (CIS-R), and 42 if the fatigue item was excluded. Psychiatric morbidity was more related to levels of social stresses than was severity of fatigue. The main difference between these subjects and those examined in hospital settings is that the former are less liable to attribute their symptoms to wholly physical causes, including viruses, as opposed to social or psychological factors. Identification and management of persistent fatigue in primary care may prevent the secondary disabilities seen in patients with chronic fatigue syndromes.
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Subjective impairment of memory and concentration is a frequent complaint in sufferers from chronic fatigue. To study this, 65 general practice attenders identified as having chronic fatigue were administered a structured psychiatric interview and a brief screening battery of cognitive tests. Subjective cognitive impairment was strongly related to psychiatric disorder, especially depressed mood, but not fatigue, anxiety, or objective performance. Simple tests of attention and concentration showed some impairment but this was influenced by both fatigue and depression. Subjects with high levels of fatigue performed less well on a memory task requiring cognitive effort, even in the absence of depression. There was no evidence for mental fatiguability. The relationship between depression, fatigue, and cognitive function requires further research.
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Forty-six homosexual men and women who were twins took part in a study of their sexuality and that of their co-twin. Discordance for sexual orientation in the monozygotic pairs confirmed that genetic factors are insufficient explanation of the development of sexual orientation. There was a high level of shared knowledge of sexual orientation between members of twin pairs, and a relatively high likelihood of sexual relations occurring with same sex co-twins at some time, particularly in monozygotic pairs. The implications of these results for the study of the origins of sexual orientation and for twin research are discussed.
Multiple sclerosis, the commonest neurological disease of young Australians, has a wide range of symptoms and may lead to varying degrees of physical and cognitive disability. Characteristically, the disease runs an episodic course, but it may be progressive from the outset. To date, treatments aimed at modifying the disease process have been disappointing, but recognition and management of the symptoms have improved, leading to an improved quality of life for people with multiple sclerosis.