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Biomedical subjects

T C Smith

Publications and source records attributed to T C Smith.

At least 19 recordsLinked to original sources
PubMed1992

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate following single intravenous infusions of each compound in health volunteers.

The tolerability, pharmacokinetics and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed following intravenous infusions of 5, 10, 15, and 20 mg adinazolam mesylate, 10, 20, 30 and 40 mg NDMAD mesylate, and placebo. Six subjects per dose level received treatments in a double-blind crossover design. No clinically significant changes were seen in blood pressure, pulse, respiration, or clinical laboratory parameters. Untoward effects typical of benzodiazepines were observed almost exclusively after NDMAD administration. Adinazolam and NDMAD pharmacokinetics were dose-independent. NDMAD clearance was 50% of the value for adinazolam. Adinazolam and NDMAD administrations increased uric acid clearance and decreased plasma uric acid. Adinazolam administration had no significant effect on psychomotor performance. NDMAD administration produced dose related decreases in performance; 286 ng/ml NDMAD produced a 50% decrease in DSST. These results confirm that adinazolam and NDMAD both produce uricosuria and definitively show that adinazolam is devoid of benzodiazepine-like effects at therapeutic concentrations; NDMAD mediates these effects. Uricosuric activity is present for both compounds, but the relative potencies are still unknown.

Adolescent↗
PubMed1992

Hypoxia in sleeping children: overnight studies can be reduced to 4 hours without loss of clinical significance.

Twelve recordings of overnight pulse oximetry representing a range of severity of obstructive sleep disturbance were evaluated by 7 experienced clinicians. Each recording was then scored by counting the number of minutes in each hour affected at any time by a fall in saturation to below 90%. Comparison of the clinical evaluation and the overall scores gave a clear level of 5 minutes per hour at and above which all the assessors agreed that the charts had clinically important desaturation. Overnight pulse oximetry was then performed on 25 children aged between 12 months and 10 years about to undergo adenotonsillectomy. The charts were scored by the method above with a score of 5 or more indicating a positive result for hypoxic episodes. The scores for shortened analysis periods of 1, 2, 3 and 4 hours duration were compared with the overall score and no cases which were negative, up to and including 4 hours, became positive in the overall result. Thus recording pulse oximetry for 4 hours provides sufficiently accurate information for clinical purposes.

Child↗
PubMed1991

N-desmethyladinazolam pharmacokinetics and behavioral effects following administration of 10-50 mg oral doses in healthy volunteers.

Results of previous studies suggest that N-desmethyladinazolam, the major metabolite of adinazolam in man, contributes substantially to psychomotor effects and sedation observed following adinazolam administration. Therefore, the pharmacokinetics and pharmacodynamics of N-desmethyladinazolam were explored following administration of single oral doses of placebo and solutions containing 10, 30, and 50 mg N-desmethyladinazolam mesylate in a double-blind, randomized, four-way crossover design to 15 healthy male volunteers. Plasma concentrations of N-desmethyladinazolam were determined by HPLC. Psychomotor performance tests (digit symbol substitution and card sorting by fours and suits), memory tests and sedation scoring were also performed following drug administration. N-Desmethyladinazolam pharmacokinetics were dose independent over this range. Dose-related performance effects were observed at 1, 2, and 6 h after dosing. Memory was likewise affected at 2 h. Psychomotor performance decrements correlated with log N-desmethyladinazolam plasma concentrations. Analysis of the relationship between percentage decrements in digit-symbol substitution and plasma N-desmethyladinazolam using the Hill equation revealed a EC50 of 325 ng/ml. These results establish the relationship between N-desmethyladinazolam plasma concentrations and performance effects; these data will be helpful in assessing the contribution of N-desmethyladinazolam to clinical effects observed after adinazolam administration.

Adult↗
PubMed1991

Squamous cell carcinoma in chronic ulcers in leprosy: a review of 38 consecutive cases.

The histories of 38 consecutive cases of squamous cell carcinoma (SCC) arising in chronic ulcers of leprosy patients treated between 1981 and 1990 at the McKean Rehabilitation Centre, Northern Thailand were analysed retrospectively. The study included 37 individual patients; 29 males and 8 females. The average age was 60 years, the average duration of leprosy was 34 years and the average duration of ulcers was 12 years. Most patients (76%) came from leprosy settlements. Patients with borderline-tuberculoid (BT) leprosy were most commonly affected (63%), followed by lepromatous (LL) leprosy (21%) and borderline-lepromatous (BL) leprosy (16%). Four patients (11%) had histories of SCC on other extremities. Metastatic spread was observed in 2 cases (5%), both instances leading to death. The commonest site of involvement of SCC was the foot, but it was seen on the knee in 1 patient and on the hand in 2 others. The incidence rate of SCC in the group at risk (leprosy patients with disability grading 1 and 2) is calculated as being 0.79:1000 per year. SCC was seen in 1.8% of all cases admitted for ulcer care at the Centre. Treatment is by radical amputation. SCC in chronic ulcers in leprosy patients cannot be considered rare and emphasizes the need for an active policy of disability prevention in leprosy programmes.

Adult↗
PubMed1990

Clinical pharmacology of adinazolam and N-desmethyladinazolam mesylate after single oral doses of each compound in healthy volunteers.

The tolerance, pharmacokinetics, and pharmacodynamics of adinazolam and N-desmethyladinazolam (NDMAD) were assessed after single oral doses of 10, 30, and 50 mg adinazolam mesylate, NDMAD mesylate, and placebo. Within doses, six healthy male volunteers received these treatments in a double-blind crossover design. No clinically significant changes were observed in blood pressure, pulse, respiration, or clinical laboratory test results. Untoward effects were typical of benzodiazepines. Adinazolam and NDMAD kinetics were dose independent. Greater than 95% of the adinazolam dose was metabolized to NDMAD. Adinazolam and NDMAD mesylate produced dose-related increases in uric acid clearance and decreases in plasma uric acid. Both adinazolam and NDMAD mesylate administration resulted in dose-related sedation and decrements in psychomotor performance. Within doses, decrements produced by adinazolam and NDMAD were quantitatively similar. These results suggest that both adinazolam and NDMAD possess uricosuric activity and support the hypothesis that NDMAD primarily mediates benzodiazepine-like effects of adinazolam mesylate.

Administration, Oral↗
PubMed1990

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers.

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population.

Adult↗
PubMed1990

Studies of human leprosy lesions in situ using suction-induced blisters. 2. Cell changes and soluble interleukin 2 receptor (Tac peptide) in reversal reactions.

To examine the pathogenesis of type 1 (reversal) reactions in leprosy, we studied cellular and soluble immunologic components of skin lesions in 10 patients with reactions, 24 active patients without reactions, and 33 control patients whose leprosy had been treated and cured. Cells and Tac-peptide levels were obtained from fluid aspirated from blisters induced by suction directly over representative skin lesions. During reversal reactions: a) the lesions contained an increased number and percentage of CD4+ (T-helper) cells; b) Tac-peptide levels were elevated in half of the lesions; c) the increases in Tac peptide and CD4+ cells were directly correlated; and d) systemic administration of corticosteroids appeared to cause a reduction in the intralesional CD4+ cell population. These findings were localized to the skin, and do not represent simple filtration of these components from the peripheral blood. We conclude that spontaneous lymphocyte activation in situ, primarily of CD4+ cells, is an important feature of reversal reactions, and may be an intermittent or cyclic phenomenon during the reaction. Findings in active patients without reactions are consistent with the hypothesis that differing states of immunologic equilibrium have been established in different portions of the leprosy spectrum. In reversal reactions we may, therefore, be examining immunologic processes set in motion when a pre-existing equilibrium has been upset by spontaneous, natural events. The mechanism of such spontaneous changes in immunity in leprosy is of considerable interest, not only to understand the reaction, but also to examine the underlying determinants of delayed-type hypersensitivity and cell-mediated immunity in leprosy and the potential for artificially manipulating these responses, as proposed with vaccines or immunotherapy.

Adult↗
PubMed1989

Validation of the use of the lipophilic thiocyanate anion for the determination of membrane potential in Ehrlich ascites tumor cells.

The utility of the lipophilic anion thiocyanate (SCN-) as a probe for the indirect estimation of the cell membrane potential (Vm) in Ehrlich ascites tumor cells has been evaluated by comparison to direct electrophysiological measurements. SCN accumulation is consistent with first-order uptake into a single, kinetically-identifiable cellular compartment, achieving steady-state distribution in 20-30 min at 22 degrees C. The steady state distribution ratio ([SCN-]e/[SCN-]e) in physiological saline is 0.44 +/- 0.02. Treatment of the cells with propranolol (0.13 mM), an activator of Ca2+ dependent K+ channels, reduces the steady-state distribution ratio to 0.19 +/- 0.02. Conversely, treatment with BaCl2 (10 mM), an antagonist of the pathway, increases the SCN- distribution ratio to 0.62 +/- 0.01. The equilibrium potentials (VSCN) calculated under these conditions are virtually identical to direct electrophysiological measurements of the Vm made under the same conditions. The effect of varying extracellular [K+] ([K+]e) in the presence of constant [Na+]e = 100 mM has also been tested. In control cells, elevation of [K+]e from 6 to 60 mM reduces VSCN from -20.6 +/- 1.0 to -13.2 +/- 1.2 mV. Again, microelectrode measurements give excellent quantitative agreement. Propranolol increases the sensitivity of the cells to varying [K+]e, so that a 10-fold elevation reduces VSCN by approximately 31 mV. BaCl2 greatly reduces this response: a 10-fold elevation in [K+]e yielding only a 4-mV reduction in VSCN. It is concluded that the membrane potential of Ehrlich cells can be estimated accurately from SCN- distribution measurements.

Animals↗
PubMed1989

Experimental data acquisition and manipulation by microcomputer.

To improve experiment management, we developed a microcomputer system which automatically displays, collects, manipulates and stores data in real-time. Upon completion of all experiments, it automatically performs statistical analysis, prints graphs and stores the results. The components required to accomplish these tasks include: (1) a microprocessor and visual monitor; (2) transducers, each with preamplifier, filter and amplifier; (3) couplers from each amplifier to the computer; (4) software to direct display, manipulation, statistical analysis and storage of data; and (5) hardware to allow real-time graphic and hard copy display. The resulting system allows sampling rates up to 300 Hz and accuracy of 0.20% full scale, 0-200 mm Hg. It provides great flexibility, efficiency and reliability in data management, and thereby facilitates the organization and completion of research protocols. It simplicity of design and operation makes it easy to use, and it is extremely cost effective. We present a method of laboratory microcomputerization as a practical alternative for management of physiological experimentation.

Analog-Digital Conversion↗
PubMed1989

Multiple-dose pharmacokinetics and pharmacodynamics of adinazolam in elderly subjects.

The pharmacokinetics and pharmacodynamics of adinazolam (AD) were evaluated in 21 elderly subjects (mean age, 69 +/- 4 years) at four dose levels during a placebo-controlled, double-blind, dose escalation regimen in which the oral dose was varied from 10 to 60 mg daily, in divided doses. Fifteen subjects received adinazolam mesylate; six received placebo. Plasma samples collected during a single dosing interval in each dosing period (3 days) were assayed for adinazolam and monodesmethyl adinazolam (NDMAD) by high-performance liquid chromatography (HPLC). Urine samples were collected during a single interval during the 20- and 40-mg daily dose periods and assayed for NDMAD by HPLC. Pharmacologic effects of adinazolam were assessed using psychomotor performance tests and sedation ratings. Adinazolam pharmacokinetics were linear over the dosage range studied. Daily dose had no significant effect on dose-normalized AUC and Cmax for AD. Dose-normalized NDMAD AUC values as well as beta values were not significantly affected by the daily dose of adinazolam. The ratio NDMAD/AD was not substantially affected by the dose. Renal clearance of NDMAD for the 20- and 40-mg daily doses were 5.6 +/- 2.1 and 5.5 +/- 2.2 liters/hr, respectively, and did not correlate with creatinine clearance. Adinazolam and NDMAD did not substantially accumulate in elderly subjects, even upon multiple dosing at 8-hr intervals. The dosing regimens in this experiment appeared to be well tolerated in the elderly, as performance tests and sedation scores indicated no substantial dose-related effects of adinazolam on psychomotor performance.

Aged↗