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Biomedical subjects

T M Davis

Publications and source records attributed to T M Davis.

At least 73 records · Page 4Linked to original sources
PubMed1997

Glucose metabolism in severe malaria: minimal model analysis of the intravenous glucose tolerance test incorporating a stable glucose label.

Basal plasma glucose is usually increased in uncomplicated malaria, implying insulin resistance. If the infection progresses, the risk of hypoglycemia will increase as host glucose production becomes insufficient for host/parasite demand. To assess the relative contribution of insulin-mediated and non-insulin-mediated glucose disposal to plasma glucose levels in severe malaria, we studied six healthy controls (two males and four females; mean age, 38 years) and eight patients with complicated falciparum malaria (five males and three females; mean age, 31 years) who had a frequently sampled intravenous glucose tolerance test (FSIVGTT) in which 10% of the dextrose bolus was 6,6-D2-glucose. The minimal model was applied to native and labeled plasma glucose and serum insulin profiles over 4 hours postinjection. Basal plasma glucose concentrations in the patients were significantly greater than in the controls (median [range], 6.1 [2.1 to 8.5] v 4.3 [3.9 to 4.7] mmol/L, P = .03). Malaria-associated insulin resistance was confirmed by a lower insulin sensitivity index (SI) in patients (5.6 [2.4 to 17.4] v 16.0 [2.5 to 22.3] x 10(-4).min-1 per microU/mL in controls, P = .026). Glucose effectiveness ([SG] the ability of glucose to reduce its own plasma concentration) was higher in the patients (0.015 [0.006 to 0.024] v 0.008 [0.007 to 0.010] min-1 in controls, p = .019). Glucose disappearance at basal concentration was increased by a median of 42% in severe malaria patients, with the insulin-independent component comprising 81%, versus 67% in controls. Indices of beta-cell function were normal in malaria patients. These data demonstrate that basal plasma glucose utilization is increased approximately 50% in severe malaria, consistent with previously published isotope-turnover studies. Altered SG plays a major role. Prevention and treatment of early hypoglycemia should be based on adequate glucose replacement. Strategies that reduce insulin secretion or effects appear to be of minor importance.

Adolescent↗
PubMed1997

Clearance of young parasite forms following treatment of falciparum malaria in humans: comparison of three simple mathematical models.

To characterize post-treatment clearance of young forms of Plasmodium falciparum from the blood, three differential equation models, a linear decline, a linear then logarithmic decline, and the Michaelis-Menten (MM) kinetic equation, were fitted to log-transformed serial parasite counts from 30 semi-immune patients with synchronous parasitaemias allocated one of six antimalarial drug regimens. The first two equations were solved analytically. The MM equation was solved numerically using a fifth-order Runge-Kutta method. For each equation, parasite clearance was assumed stochastic and log-transformed parasite counts were assumed to be normally distributed at each time-point. Comparisons between models were by Minimum Akaike Information Criterion Estimate. A constrained MM equation fitted the data at least as well as the other two models in 5 of 6 drug groups and also when pooled data were analysed, providing a single index which could be used in drug efficacy studies in similar situations or as part of more complex models that encompass asynchronous, complicated infections.

Adolescent↗
PubMed1997

Factors affecting the pharmacokinetics of parenteral chloramphenicol in enteric fever.

Chloramphenicol pharmacokinetics were studied in 29 Nepalese adults diagnosed with uncomplicated enteric fever and randomized to receive succinate ester 30 mg/kg i.v. or i.m. Serial plasma concentrations of chloramphenicol, and iothalamate (to estimate glomerular filtration rate), antipyrine (hepatocellular function) and Indocyanine Green (liver blood flow) were measured by HPLC and kinetic parameters estimated by non-compartmental analysis. In culture-positive patients (n = 16), mean residence times (MRTs) and steady-state volumes of distribution (V(d)ss) for i.v. chloramphenicol (mean +/- S.D.; 4.9 +/- 0.9 h and 1.9 +/- 0.8 L/kg; n = 7) were less than after i.m. chloramphenicol (12.3 +/- 7.3 h and 3.7 +/- 2.5 L/kg; n = 9; P < 0.05), with a higher peak plasma concentration after i.v. (16.2 +/- 9.1 versus 7.8 +/- 3.6 mg/L; P < 0.05); plasma clearance (Cl(p)) was similar in the two groups (368 +/- 172 and 310 +/- 224 mL/kg/min after i.v. and i.m. respectively). In 17 patients examined during convalescence, MRT and Vdss were less than in acute illness regardless of route chloramphenicol administration. There were similar changes in chloramphenicol kinetic parameters in culture-negative patients. Antipyrine Cl(p) and liver blood flow correlated weakly with chloramphenicol Cl(p) in culture-positive patients (P < 0.1) and were higher in convalescence; no such associations were seen for iothalamate Cl(p). These data indicate that i.v. chloramphenicol produces peak plasma concentrations which are on average twice those after i.m. injection of the same dose, due principally to a smaller V(d)ss. Cl(p) is uninfluenced by route of administration and is determined more by hepatic metabolism than renal excretion. Intramuscular treatment may result in sub-therapeutic chloramphenicol concentrations initially, but continued regular i.v. dosing is more likely to produce levels at which bone marrow toxicity occurs.

Adolescent↗
PubMed1997

The hypothalamic-pituitary-adrenocortical axis in severe falciparum malaria: effects of cytokines.

Patients with malaria can have features of adrenal insufficiency. Because of the pathophysiological and clinical implications of an Addisonian state, the hypothalamic-pituitary-adrenocortical axis was assessed in nine Vietnamese adults with complicated malaria. A CRH test was performed on admission (in convalescence in five cases) and in six healthy controls. Basal plasma ACTH concentrations in the patients and controls were similar [median (range): 2.9 (0.2-9.7) vs. 3.5 (1.9-13.4) pmol/L, respectively; P > 0.1]. Serum cortisol levels were greater in the patients [882 (294-1682) vs. 190 (110-676) nmol/L; P < 0.01], but three (33%) had values within the control range. Basal serum corticosteroid-binding globulin concentrations were similar in patients and controls (P = 0.23). The post-CRH rise in plasma ACTH was attenuated in the patients [peak: 6.1 (0.9-23.2) vs. 14.5 (6.2-21.5) pmol/L in controls; P < 0.05]; basal and peak plasma ACTH correlated with plasma interleukin-6 in this group (rs > or = 0.60; P < or = 0.04). Serum cortisol responses to CRH were depressed in acute illness [peak 990 (394-1, 805) nmol/L or 10 (0-50%) above baseline vs. 500 (429-703) nmol/L or 160 (10-380%) in controls; P < 0.05]. The median estimated serum cortisol t1/2 was 4.6 h in the patients and 1.6 h in the controls. These data suggest that, relative to a normal stress response, primary and secondary adrenal insufficiency can occur in severe malaria but may be attenuated by increased circulating interleukin-6 concentrations and impaired cortisol metabolism. The benefits of stress-dose corticosteroid replacement are unknown but could be considered in hypoglycemic patients or those with a serum cortisol within or below the reference range.

Adrenocorticotropic Hormone↗
PubMed1997

U.K. Prospective Diabetes Study 22. Effect of age at diagnosis on diabetic tissue damage during the first 6 years of NIDDM.

OBJECTIVE: To assess the effect of age at diagnosis on the initial prevalence and subsequent risk of the progression of diabetic tissue damage in patients with NIDDM. RESEARCH DESIGN AND METHODS: The prevalence of Q-wave myocardial infarction, absent dorsalis pedis pulses, retinopathy, absent ankle jerks, hypertension, and microalbuminuria were determined at baseline and at 3 and 6 years of follow-up in five consecutive 6-year age-cohorts of 3,027 newly diagnosed white patients aged between 36 and 65 years recruited to the U.K. Prospective Diabetes Study. The effect of age at diagnosis on the initial prevalence and the risk of progression of these complications and associated conditions was analyzed using logistic regression and proportional odds methods, respectively. RESULTS: Q-wave myocardial infarction and hypertension were more prevalent in older patients at presentation, but age at diagnosis did not have a significant effect on the increased risk of either after 6 years of NIDDM. Absent dorsalis pedis pulses and ankle jerks were also more prevalent in the older age-groups at presentation, but age at diagnosis was a significant predictor of the increasing prevalence of both during follow-up. The baseline prevalence of retinopathy and microalbuminuria was not related to age. The subsequent risk of retinopathy, but not microalbuminuria, increased significantly with age at diagnosis. CONCLUSIONS: Age at diagnosis has a variable impact on different types of diabetic tissue damage and may thus be an important variable in epidemiological and intervention studies in NIDDM. Regular ophthalmologic surveillance and examination of the feet increase in importance with increasing age since the diagnosis of NIDDM.

Adult↗
PubMed1997

Longevity of antibody responses to a Salmonella typhi-specific outer membrane protein: interpretation of a dot enzyme immunosorbent assay in an area of high typhoid fever endemicity.

The objective of this study was to investigate the longevity of positive dot enzyme immunosorbent assay (dot EIA) results for IgM and IgG to a Salmonella typhi outer membrane protein in Malaysian children with enteric fever. The patients were children one month to 12 years of age with clinical evidence of typhoid fever, positive blood or stool cultures for S. typhi, and/or a positive Widal test result who were admitted over a two-year period to General Hospital (Kota Bharu, Malaysia). These patients received standard inpatient treatment for enteric fever including chloramphenicol therapy for 14 days. Dot EIA tests were performed as part of clinical and laboratory assessments on admission, at two weeks, and then at 3, 6, 9, 12, 15, 18, and 21 months postdischarge. Assessment of the longevity of positive dot EIA IgM and IgG titers was done by Kaplan-Meier analysis. In 94 evaluable patients, 28% were dot EIA IgM positive but IgG negative on admission, 50% were both IgM and IgG positive, and 22% were IgM negative and IgG positive. Mean persistence of IgM dot EIA positivity was 2.6 months (95% confidence interval = 2.0-3.1 months) and that of IgG was 5.4 months (4.5-6.3 months). There were no significant differences between the three subgroups. Thus, positive IgM and IgG results determined by dot EIA within four and seven months, respectively, following documented or suspected enteric fever in a child from an endemic area should be interpreted with caution. In other clinical situations, the dot EIA remains a rapid and reliable aid to diagnosis.

Anti-Bacterial Agents↗
PubMed1996

Selective high-performance liquid chromatographic determination of artesunate and alpha- and beta-dihydroartemisinin in patients with falciparum malaria.

A novel solid-phase extraction and a robust high-performance liquid chromatographic (HPLC) separation procedure for artesunate and alpha- and beta-dihydroartemisinin, using post-column alkali decomposition and UV detection is described. Extraction was performed with Bond-Elut Phenyl solid-phase extraction cartridges and analysis by HPLC was carried out using a Waters Symmetry C8 5-microns 150 x 3.9 mm I.D. column. The mobile phase was 50% acetonitrile in 0.1 M acetate buffer (pH 4.8) delivered at a flow-rate of 0.7 ml/min. The column eluate was mixed with 1.2 M potassium hydroxide in 90% methanol delivered at 0.3 ml/min, in a 1-ml reaction coil at 69 degrees C, to form UV-absorbing chromophores which were detected at 290 nm. The recovery of all analytes was greater than 80%. There was no significant difference in the peak-area ratio of alpha- and beta-dihydroartemisinin in plasma. Preliminary pharmacokinetic data from six adult Vietnamese patients who received 120 mg of artesunate by intravenous injection for the treatment of acute falciparum malaria are presented. Despite limited data, the mean half-life of artesunate was approximately 3.5 min while that for dihydroartemisinin was 34 min. These data confirm the relatively rapid clearance of both artesunate and its principle active metabolite, dihydroartemisinin.

Antimalarials↗
PubMed1996

In vitro stage-specific sensitivity of Plasmodium falciparum to quinine and artemisinin drugs.

The inhibitory effects of quinine, chloroquine and 4 qinghaosu drugs, artemisinin, artemether, artesunate and dihydroartemisinin, on 4 culture-adapted isolates and 2 standard clones of Plasmodium falciparum were determined in vitro. All isolates were sensitive to the widely used antimalarial drugs quinine (EC50 range 3 x 10(-8)-1 x 10(-7) mol/L) and chloroquine (EC50 range 1 x 10(-9)-7 x 10(-9) mol/L), irrespective of the geographical origin or treatment history of the patients from which they were taken. In general, the qinghaosu drugs were more potent than the conventional antimalarials, having EC50 values of 3 x 10(-11)-3 x 10(-8) mol/L. Stage-specific data indicated that quinine has a primary mode of action on mature parasite forms, achieving 80-100% growth inhibition within 2-4 h of drug exposure. The stage-specific activity of the 3 qinghaosu drugs artemisinin, artemether and dihydroartemisinin differed from that of quinine, and each derivative displayed a unique stage-specific profile. Artemisinin was rapidly effective against both rings and schizonts, achieving 100% growth inhibition within 6-8 h. The inhibitory effects of artemether were less rapid, requiring 10 h to achieve 70-80% ring stage growth inhibition. Dihydroartemisinin was highly effective against all parasite stages in most cases achieving 100% growth inhibition within 2-4 h of exposure. The results confirm that the qinghaosu drugs are potent antimalarials, and suggest different stage-specific profiles compared to conventional antimalarial drugs.

Adult↗
PubMed1996

Effect of aging on the spatial learning deficit produced by diazepam in rats.

1. After pretraining in an undrugged state, young (6 months) and aged (18-24 months) rats were trained on a spatial learning-set task after receiving one of four doses of diazepam (1, 2, 3 or 5 mg/kg) or the drug vehicle. The effects of 5 mg/kg of diazepam were also assessed on the spatial learning-set task one full hour after injection (delay condition) as well as on the visible platform task. 2. During pretraining (undrugged), aged rats demonstrated a transient impairment on the visible platform task but subsequently did not differ significantly from young rats on the submerged platform task. On the spatial learning-set task, aged rats performed as well as young rats under control conditions and diazepam produced a comparable dose-dependent impairment of spatial learning. However, when the 1 hr delay was interposed between diazepam administration and maze testing, only aged rats exhibited a spatial learning impairment. Diazepam did not impair performance on the visible platform task in either young or aged rats. 3. These results indicate that although the amnesic effect of diazepam is not initially greater in aged rats, it persists for longer periods.

Aging↗
PubMed1996

Neurological, cardiovascular and metabolic effects of mefloquine in healthy volunteers: a double-blind, placebo-controlled trial.

1. To assess neurological, cardiovascular, metabolic and other side-effects of mefloquine given in conventional prophylactic dose to healthy volunteers, a double-blind, randomized, placebo-controlled trial was conducted. In addition, the identity of the active drug was concealed until the end of the trial. 2. A total of 106 healthy adults were recruited, of whom 95 (mean age 24 years; 45% males) completed the full study protocol. 3. Subjects had a baseline assessment, received placebo as first dose, were randomized to mefloquine 250 mg or placebo weekly for 4 weeks starting a week later, and were reassessed after the 2nd and 4th active/placebo doses. Subjects kept a daily symptom diary from 2 weeks before until 2 weeks after the dosing period. 4. Plasma mefloquine assay suggested compliance in all 46 subjects allocated active treatment (week 5 mean +/- s.d.; 2.35 +/- 0.94 mumol l-1. Mefloquine did not alter calcium homoeostasis but produced a mean 0.5 mmol l-1 fall in serum glucose over the study period (P < 0.001) and relative hyperinsulinaemia. Symbol digit modalities, and digit forwards and backwards test scores, were similar in active and placebo groups across the three assessments, as were lying/standing blood pressure and high-tone hearing loss. Electrocardiographic QTc interval prolongation and diarrhoea were mild but transient side-effects of mefloquine (P < 0.01). Neurological symptoms were comparable in the two groups throughout the study. There was no evidence of drug toxicity in 11 subjects who withdrew. 5. Mefloquine prophylaxis does not appear to produce low-grade but debilitating neurological symptoms or to alter the results of sensitive tests of cerebral function. However, there may be situations in which mefloquine might contribute to hypoglycaemia and cardiac dysrhythmias.

Adult↗
PubMed1996

A prospective clinical and bacteriologic study of inguinal buboes in Thai men.

One-hundred thirteen men (mean age, 23 years) who presented with inguinal buboes to a government-operated hospital for sexually transmitted diseases (STDs) in Bangkok were studied between February 1987 and February 1989. The median duration of preceding symptoms was 7 days (range, 1-62 days). The majority of patients (74; 65%) had received treatment previously; 31 (27%) were febrile, 13 (12%) had extrainguinal lymphadenopathy, and 31 (27%) had concurrent active genital ulcers. There was no history of genital ulceration in 66 (58%) of the patients. Pus was obtained from 51 of the 110 buboes aspirated for culture; 21 (41%) of these cultures yielded Haemophilus ducreyi, and 2 (3.9%) were positive for Chlamydia trachomatis on immunofluorescence microscopy. Saline (1 mL) was injected and reaspirated from the buboes of 35 of the other 59 patients; 3 buboes yielded H. ducreyi and 9 were positive for C. trachomatis. All cultures for other aerobic and anaerobic bacteria and viruses in intact buboes were negative. Syphilis serology was positive in only one case. Patients attending STD clinics in this region who have large, fluctuant, edematous inguinal buboes containing pus should receive presumptive treatment for chancroid. If there is no pus, then the bubo is more likely to be caused by lymphogranuloma venereum.

Adolescent↗
PubMed1996

Serum lipid profiles in Malay mothers and neonates: a cross-sectional study.

OBJECTIVE: Preliminary epidemiological data suggest that dyslipidaemia contributes significantly to rising mortality due to atherosclerosis in Peninsular Malays. The aim of this study was to determine whether abnormal serum lipid profiles are present at birth in this population. METHODOLOGY: The patients were 487 non-diabetic Malay women who had an uncomplicated antenatal course and delivered healthy singleton babies at term. Cord blood and maternal post-partum venous blood samples were taken for assay of serum cholesterol and triglyceride concentrations using standard enzymatic methods. RESULTS: Maternal total serum cholesterol concentrations (mean +/- SD; 7.5 +/- 2.5 mmol/L) were higher than in other reported series (range of published means 5.2-6.5 mmol/L) with a correspondingly low high-density lipoprotein (HDL): total cholesterol ratio. The mean cord blood total serum cholesterol (1.7 +/- 1.0 mmol/L) was consistent with previously reported population means (1.5-1.9 mmol/L) but there was a relatively high low-density lipoprotein (LDL)-cholesterol and depressed HDL: cholesterol ratio. Significant correlations between maternal and neonatal serum total (P = 0.038) and especially HDL-cholesterol (P < 0.001) were observed. Maternal and cord blood serum triglyceride levels were comparable to those in other series. CONCLUSIONS: These cross-sectional data provide evidence that abnormal serum cholesterol profiles are found in pregnant Malay women and their neonates which may have implications for the prevalence of macrovascular disease in the Malay population.

Adult↗
PubMed1995

Glucose tolerance in rural diabetic Thais, first-degree relatives and non-diabetic controls.

To determine whether non-insulin-dependent diabetes mellitus (NIDDM) in a rural Thai population is characterised by insulin resistance and hyperinsulinaemia, 17 unselected diabetic outpatients from a regional hospital, five first-degree relatives and 10 healthy controls were studied. Subjects in these groups were matched as closely as possible for age and sex, and mean body mass indices were similar (mean +/- S.D.; 21.8 +/- 5.5, 20.6 +/- 1.4 and 21.8 +/- 2.3 kg/m2, respectively, P > 0.5). Beta-cell function (%B) and insulin sensitivity (%S), expressed relative to values for non-diabetic Caucasians, were assessed mathematically using the 'CIGMA' model and plasma glucose and insulin achieved after a standard 1-h glucose infusion. The diabetic patients had higher fasting plasma glucose concentrations than the controls (8.6 +/- 4.0 vs. 4.6 +/- 0.4 mmol/l, P < 0.01) but plasma insulin levels were comparable (geometric mean [-S.D.-+S.D.]; 4.0 [1.7-9.4] vs. 4.0 [1.7-9.2] mU/l, P > 0.1). %B in the diabetic group (21% [10-41]) was lower than in the controls (128% [88-187], P < 0.001) while %S tended to be higher (185% [86-400] vs. 111% [49-251], 0.1 > P > 0.05). Relatives had intermediate values of both variables. %S and %B correlated poorly in the diabetic group (P > 0.1) but together accounted for 90% of the variation in basal plasma glucose (multiple r = 0.95, n = 17, P < 0.0001). Beta-cell dysfunction appears the primary defect in diabetic patients from a Thai subsistence farming population. Insulin resistance may not always characterise NIDDM in geographical areas where a 'thrifty genotype' would be expected; other factors associated with diabetes in developing countries (such increased susceptibility to serious infections) may also influence diabetes prevalence.

Adult↗