Biomedical subjects
C Reid
Publications and source records attributed to C Reid.
The synthesis of symmetrical and unsymmetrical P1/P1' cyclic ureas as HIV protease inhibitors.
Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.
A review of relationships between active living and determinants of health.
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Multiskilling and multicredentialing of the health professional: role of the cardiac sonographer. Sonographer Council of the American Society of Echocardiography.
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Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors.
BACKGROUND: Recent clinical trials have demonstrated that HIV protease inhibitors are useful in the treatment of AIDS. It is necessary, however, to use HIV protease inhibitors in combination with other antiviral agents to inhibit the development of resistance. The daunting ability of the virus to rapidly generate resistant mutants suggests that there is an ongoing need for new HIV protease inhibitors with superior pharmacokinetic and efficacy profiles. In our attempts to design and select improved cyclic urea HIV protease inhibitors, we have simultaneously optimized potency, resistance profile, protein binding and oral bioavailability. RESULTS: We have discovered that nonsymmetrical cyclic ureas containing a 3-aminoindazole P2 group are potent inhibitors of HIV protease with excellent oral bioavailability. Furthermore, the 3-aminoindazole group forms four hydrogen bonds with the enzyme and imparts a good resistance profile. The nonsymmetrical 3-aminoindazoles DMP 850 and DMP 851 were selected as our next generation of cyclic urea HIV protease inhibitors because they achieve 8 h trough blood levels in dog, with a 10 mg/kg dose, at or above the protein-binding-adjusted IC90 value for the worst single mutant--that containing the Ile84-->Val mutation. CONCLUSIONS: In selecting our next generation of cyclic urea HIV protease inhibitors, we established a rigorous set of criteria designed to maximize chances for a sustained antiviral effect in HIV-infected individuals. As DMP 850 and DMP 851 provide plasma levels of free drug that are sufficient to inhibit wild-type HIV and several mutant forms of HIV, they could show improved ability to decrease viral load for clinically significant time periods. The ultimate success of DMP 850 and DMP 851 in clinical trials might depend on achieving or exceeding the oral bioavailability seen in dog.
Design and selection of DMP 850 and DMP 851: the next generation of cyclic urea HIV protease inhibitors
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Covert manipulation of energy density of high carbohydrate diets in 'pseudo free-living' humans.
OBJECTIVE: This study examined the effects of varying the energy density (ED) of high carbohydrate (HC) diets on food and energy intake (EI), subjective hunger and body weight in humans. DESIGN: Randomised cross-over design. Subjects were each studied twice during 14 d, throughout which they had ad libitum access to one of two covertly-manipulated diets. SUBJECTS AND METHODS: Six healthy men (mean age (s.d.)=32.17 y s.d. (5.26 y), mean weight=69.74 kg s.d. (2.75 kg), mean height=1.76 m s.d. (0.05 m), body mass index (BMI)=22.57 (2.2) kg/m2) were studied. The fat, carbohydrate (CHO) and protein content (as % energy) and ED of each diet were 21:66:13% and 357 kJ/100 g, (low-energy density (LED)) or 22:66:12% and 629 kJ/100 g (high-energy density (HED)). A medium fat diet was provided at maintenance (1.6 x BMR, MF for 2 d) before each ad libitum period. Subjects could alter the amount, but not the composition of foods eaten. RESULTS: Mean EI was 8.67 and 14.82 MJ/d on the LED and HED diets, respectively. Subjects felt significantly more hungry on the LED diet, than on the HED diet (F(1,160)38.28; P < 0.001) and found the diets to be similarly pleasant (72.72 mm vs 71.54 mm (F(1,392)0.31; P = 0.579)). Mean body weight decreased on the LED diet at a rate of 0.1 kg/d and increased at 0.06 kg/d on the HED diet (F(1,131)86.60; P < 0.001), giving total weight changes of -1.41 kg and +0.84 kg, respectively, both of which were significantly different from zero (P < 0.01). CONCLUSION: Excess EI is possible on HC, HED diets, at least under conditions where diet selection is precluded. Comparison of these results with previous studies, which altered ED using fat, suggests that CHO may be a better cue for hunger than fat.
The effect of covertly manipulating the energy density of mixed diets on ad libitum food intake in 'pseudo free-living' humans.
OBJECTIVE: This study examined the effects of covert alterations in the energy density (ED) of mixed, medium fat (MF) diets on ad libitum food and energy intake (EI), subjective hunger and body weight in humans. DESIGN: Randomised cross-over design. Subjects were each studied three times (factorial design), during 14d, throughout which they had ad libitum access to one of three covertly-manipulated MF diets. SUBJECTS: Six healthy men, mean age (s.e.m.) = 30.0 y (12.76 y), mean weight = 71.67 kg (19.80 kg); mean height = 1.79 m (0.22 m), body mass index (BMI) = 22.36 (2.60) kg/m2, were studied. The fat, carbohydrate (CHO) and protein in each diet (as a proportion of the total energy) and energy density (ED) were, low-ED (LED), 38:49:13%; 373 kJ/100 g; medium-ED (MED), 40:47:13%; 549 kJ/100 g; high-ED (HED), 39:48:13%; 737 kJ/100 g. Subjects could alter the amount but not the composition of foods eaten. They were resident in (but not confined to) a metabolic suite throughout the study. RESULTS: Solid food intake decreased as ED increased, giving mean values of 2.84, 2.51 and 2.31 kg/d, respectively. This was insufficient to defend energy balance, since energy intake increased with increasing ED (F(2,10) 16.08; P < 0.001) giving mean intakes of 10.12, 12.80 and 16.17 MJ/d, respectively. Rated pleasantness of food (measured on visual analogue scales) was not significantly different between diets nor was subjective hunger different between the LED, MED and HED diets, respectively. Diet significantly affected body weight (F(2,10) = 4.62; P = 0.038), producing changes of -1.20, 0.02 and 0.95 kg, respectively, by day 14. CONCLUSION: Dietary ED can influence EI and body weight, since changes in amount eaten alone are insufficient to defend energy balance, when subjects feed on unfamiliar diets and diet selection is precluded. Comparison with our previous studies suggest that there was compensation in solid food intake when ED was altered using mixed diets (as in this study) compared to previous studies which primarily used fat or CHO to alter dietary ED.
Incremental increases in Breslow thickness of thick melanoma have a linear effect on mortality.
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The prevalence of isolated systolic hypertension in patients 60 years of age and over attending Australian general practitioners.
AIMS: To determine the prevalence of isolated systolic hypertension (ISH) in patients 60 years of age and over attending general practitioners, and the proportion of patients in whom blood pressure (BP) remains within the ISH range when measured on three successive occasions and when using home BP monitoring. METHODS: BP was measured in 38 832 patients. Patients categorized as having ISH were reviewed after one week. Patients who had BPs in the ISH range at the second visit were provided with a home BP monitor and attended again in one week's time for further clinic blood pressure measurements. RESULTS: 8.6% of all patients were classified as having ISH and 31.4% as having borderline ISH at the first clinic visit. ISH was twice as prevalent in patients receiving antihypertensive therapy (12.4%) than in those not on antihypertensive therapy (6.2%). Of the patients initially categorized as having ISH, and who attended all three clinic visits and completed the home BP monitoring, 52.3% were confirmed as having ISH, 34.0% fell into the borderline ISH range and only 7.0% had a normal BP reading at the third clinic visit. The use of home BP monitoring produced similar results. CONCLUSION: ISH is present on first screening in approximately 8% of elderly Australian patients. This prevalence falls by about 50% when BP is measured on two further occasions, with most patients subsequently falling into the borderline ISH range. Home BP monitoring does not reduce the percentage of patients classified as having ISH on the basis of three clinic measurements.
Continuing medical education one year on--how was it for me?
Over the period of a year I have systematically recorded any episodes of continuing medical education (CME) that I have attended, and reflect on the effectiveness of this system in terms of whether it has achieved its objective, that is, has my behaviour changed, and whether the existence of the need to record CME has influenced this effect. I consider which aspects of CME have been most beneficial. I conclude that the proposed level of CME is readily achievable, useful, but costly. The way in which I learn most or best is in preparing presentations or teaching sessions. There has been some debate on the usefulness of keeping a record of CME to which I would like to add my opinion. I also recommend the form of record keeping I have used as an impetus to reflection and research on the topic of education received, as this reinforces and enhances the educational experience.
Cystic fibrosis and mucins.
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Hypoechoic plaque at US of the carotid artery: an independent risk factor for incident stroke in adults aged 65 years or older. Cardiovascular Health Study.
PURPOSE: To investigate the association between incident (first) stroke and the echogenicity of internal carotid arterial plaque at ultrasonography (US). MATERIALS AND METHODS: A cohort of 4, 886 individuals who, at baseline, were 65 years of age or older and without symptoms of cerebrovascular disease was followed up for an average of 3.3 years. Baseline clinical findings were from color Doppler and duplex US studies of the carotid arteries and a record of traditional risk factors: age, sex, presence of diabetes mellitus, pack-years of cigarette smoking, presence of hypertension, elevated systolic and diastolic blood pressure, elevated low-density lipoprotein cholesterol level. RESULTS: Incident strokes, excluding hemorrhagic strokes and strokes of cardiac origin, were seen in 104 individuals (2.1%) at risk. Age- and sex-adjusted odds ratios for incident stroke were significant for hypoechoic plaque (odds ratio, 2.53; 95% CI, 1,42,4.53). After controlling for risk factors in a Cox proportional hazards model, the relative risk (RR) of incident stroke was 1.72 (p = .015) for hypoechoic plaque and 2.32 (P = .004) for internal carotid arterial narrowing of at least 50%. In addition, hypoechoic plaque (RR, 2.78; CI, 1.36,5.69) and 50%-100% stenosis (RR, 3.08; CI, 1.28, 7.41) were associated with ipsilateral, nonfatal stroke. CONCLUSION: In asymptomatic adults aged 65 years or older, that risk of incident stroke was associated with two US features: hypoechoic internal carotid arterial plaque and an estimated internal carotid arterial stenosis of 50%-100%.
Anaesthetic management of the morbidly obese patient.
Morbidly obese patients are prone to many clinical conditions that can effect anaesthesia. Of major concern to the anaesthetist are difficulties with airway management and abnormalities of cardiorespiratory function. Safe anaesthesia requires an appreciation of potential problems and a thorough understanding of the pathophysiological changes that accompany morbid obesity.
Improved P1/P1' substituents for cyclic urea based HIV-1 protease inhibitors: synthesis, structure-activity relationship, and X-ray crystal structure analysis.
We present several novel P1/P1' substituents that can replace the characteristic benzyl P1/P1' moiety of the cyclic urea based HIV protease inhibitor series. These substituents typically provide 5-10-fold improvements in binding affinity compared to the unsubstituted benzyl analogs. The best substituent was the 3,4-(ethylenedioxy)benzyl group. Proper balancing of the molecule's lipophilicity facilitated the transfer of this improved binding affinity into a superior cellular antiviral activity profile. Several analogs were evaluated further for protein binding and resistance liabilities. Compound 18 (IC90 = 8.7 nM) was chosen for oral bioavailability studies based on its log P and solubility profile. A 10 mg/kg dose in dogs provided modest bioavailability with Cmax = 0.22 microg/mL. X-ray crystallographic analysis of two analogs revealed several interesting features responsible for the 3,4-(ethylenedioxy)benzyl-substituted analog's potency: (1) Comparing the two complexes revealed two distinct binding modes for each P1/P1' substituent; (2) The ethylenedioxy moieties are within 3.6 A of Pro 81 providing additional van der Waals contacts missing from the parent structure; (3) The enzyme's Arg 8 side chain moves away from the P1 substituent to accommodate the increased steric volume while maintaining a favorable hydrogen bond distance between the para oxygen substituent and the guanidine NH.
Probing protein hydration and conformational states in solution.
The addition of polyethylene glycol (PEG), of various molecular weights, to solutions bathing yeast hexokinase increases the affinity of the enzyme for its substrate glucose. The results can be interpreted on the basis that PEG acts directly on the protein or indirectly through water activity. The nature of the effects suggests to us that PEG's action is indirect. Interpretation of the results as an osmotic effect yields a decrease in the number of water molecules, delta Nw, associated with the glucose binding reaction. delta Nw is the difference in the number of PEG-inaccessible water molecules between the glucose-bound and glucose-free conformations of hexokinase. At low PEG concentrations, delta Nw increases from 50 to 326 with increasing MW of the PEG from 300 to 1000, and then remains constant for MW-PEG up to 10,000. This suggests that up to MW 1000, solutes of increasing size are excluded from ever larger aqueous compartments around the protein. Three hundred and twenty-six waters is larger than is estimated from modeling solvent volumes around the crystal structures of the two hexokinase conformations. For PEGs of MW > 1000, delta Nw falls from 326 to about 25 waters with increasing PEG concentration, i.e., PEG alone appears to "dehydrate" the unbound conformation of hexokinase in solution. Remarkably, the osmotic work of this dehydration would be on the order of only one k T per hexokinase molecule. We conclude that under thermal fluctuations, hexokinase in solution has a conformational flexibility that explores a wide range of hydration states not seen in the crystal structure.
A self-administered questionnaire for detection of unrecognised coronary heart disease.
On an individual and a population basis, an increased incidence of coronary heart disease is associated with classical cardiovascular risk factors, but many cases occur in people not identified as at high risk. Conversely, many people at high statistical risk do not develop coronary disease. We used a questionnaire to identify unrecognised coronary heart disease in people attending large-scale health survey centres. Participants were required to report the presence and characteristics of any chest pain. Those returning responses consistent with myocardial ischaemia were offered treadmill exercise ECG tests. Over 18 months, 4070 questionnaires were returned. Of 475 respondents offered testing, 229 (198 male, 131 female) accepted. Thirty-two subjects (15 male, 17 female: a detection rate of 13.9 per cent of those assessed as likely on questionnaire, or 0.8 per cent of all respondents) had results consistent with significant coronary heart disease. Follow-up was available in 30 cases. There was no difference in classical risk-factor distribution (including multivariate risk percentiles: 42.4 (male) and 46.7 (female)) between those newly diagnosed with coronary heart disease and their community counterparts. More women than men were identified as suffering from unrecognised coronary heart disease, with a preponderance of younger women. Cost per case identified was A$1220. Screening by self-administered questionnaire is a useful and relatively cost-effective means of identifying unrecognised coronary heart disease.
Neonatal presentation of Caroli's disease.
A neonatal presentation of Caroli's disease with severe cardiac and progressive renal pathology is described. The availability of small paediatric endoscopes ensured early diagnosis. Despite aggressive medical management, the baby died with severe bleeding complications before potentially life saving multiple organ transplantation could take place.