Studies In Healthy Individuals Research Articles

Acetaminophen: Acute and chronic effects on renal function

Acetaminophen (APAP) is normally metabolized in the liver and kidney by P450 enzymes. No toxicity is observed with therapeutic doses of APAP. However, after ingestion of large quantities of APAP (>2,000 mg/kg), highly reactive quinones, metabolites of APAP, are generated; these react with glutathione and sulfhydryl groups on critical proteins, resulting in cellular dysfunction and hepatic and renal toxicity. The P450 metabolizing enzymes differ somewhat in character between the liver and kidney. Factors that enhance renal toxicity include chronic liver disease, possibly gender, concurrent renal insults, and conditions that alter the activity of P450-metabolizing enzyme systems. Acute renal toxicity is characterized by cellular injury primarily confined to the proximal tubule and significant reductions in glomerular filtration rate. However, there is little evidence that chronic administration of APAP contributes to chronic renal disease and analgesic nephropathy. The only report on this subject suggests that combination therapy with aspirin is required for medullary damage in rats. No evidence exists for the development of chronic analgesic nephropathy with APAP alone. Epidemiologic studies in healthy individuals have failed to demonstrate a significant correlation between APAP use and chronic renal disease and classic analgesic nephropathy. Therefore, large doses of APAP can produce both renal and hepatic failure, but little evidence exists for production of classic analgesic nephropathy with the use of APAP alone.

Clinical pharmacokinetics of molsidomine.

Molsidomine is a prodrug for the formation of nitric oxide (NO). Its pharmacokinetics are characterised by rapid absorption and hydrolysis, taking a short time to achieve maximal systemic concentrations of both the parent compound and its active metabolite, SIN-1. The time to peak plasma drug concentration (tmax) is 1 to 2 hours. The bioavailability of the parent compound after oral administration in tablet form is 44 to 59%, but further metabolism to release NO and form polar metabolites is rapid; the half-life (t-1/2) of SIN-1 is 1 to 2 hours. Urinary excretion accounts for more than 90% of the part of the administered dose of molsidomine which is not excreted unchanged. Protein binding of the parent compound is very low (3 to 11%) and its volume of distribution (Vd) corresponds to the range of bodyweight. Single-dose studies (1, 2 and 4 mg) have revealed linear pharmacokinetics, and multiple dose studies in healthy individuals (2 mg 3 times daily for 7 days) and coronary artery disease (CAD) patients (4 mg 4 times daily for 4 weeks) do not show any accumulation of the drug. A study in young and elderly individuals indicated that the first-pass effect is decreased and t-1/2 prolonged with age, resulting in an increased area under the concentration-time curve (AUC) of molsidomine and SIN-1. In patients with liver disease and congestive heart failure similar changes were observed, but much less so in patients with CAD. Clearance was also impaired in patients with liver disease, but the pharmacokinetics of molsidomine were not markedly altered by impaired renal function. In general, due to a large therapeutic dose range, dosage adjustments are not required on the basis of clinical experience. In certain patients a lower starting dose may be recommended, such as in those with impaired liver or kidney function, in congestive heart failure or in the presence of concomitant treatment with other vasoactive compounds. A linear dose-effect relationship is observed with counterclockwise hysteresis, i.e. a greater effect associated with the decrease of plasma concentrations than during their increase, which may be at least partly due to the metabolic delay in the formation of NO from SIN-1. Accordingly, the duration of action of molsidomine is longer than would be expected on the basis of the elimination half-life. The pharmacokinetics of molsidomine support the recommended dosages for use in angina pectoris.

Review article : Exercise training variables influencing the enhancement of voluntary muscle strength

That muscle strength is important to the performance of functional activities and can be increased by exercise training is well accepted. The extent to which training is able to enhance muscle strength, however, is dependent on a number of training variables. Among these variables are training intensity, frequency and duration. The importance of these variables is the subject of this review. Although the review is based primarily on studies of healthy individuals, it has implications for clinicians working with rehabilitation patients.

The role of the left and right thalamus in language asymmetry: Dichotic listening in Parkinson patients undergoing stereotactic thalamotomy

Fourteen patients with Parkinson's disease (rigidity and unilateral tremor as main symptoms) were treated with stereotactic thalamotomy. The operation was performed in either the left or right ventrolateral thalamus, depending on which hand (or foot) was most affected with tremor. Nine patients were operated on the left side and four on the right side. All patients were tested for asymmetry of language functioning with dichotic presentations of consonant-vowel (CV) syllables. The patients had to indicate which of the two syllables he/she heard on each trial. Dichotic listening was performed before and after the operation, as well as during electrical stimulation of the VL nucleus just before the lesion was carried out. The results revealed essentially three things: an overall reduced right ear advantage (REA) in the patient group compared to what is known from studies of healthy individuals; an increase in REA during left-sided stimulations; and a marked reduction in REA after left-sided lesions. It is concluded that the present data support the notion put forward by Ojemann (e.g., 1975) of a lateralized activating gating mechanism in the left VL nucleus that gates access for language information to the appropriate cortical areas. The gating mechanism seems to be activated by stimulation, and deactivated after lesions. Dichotic listening may thus be a heuristic instrument in assessment of language functions in Parkinson patients.

Search for nicotinic acetylcholine receptors on human leukocytes: absence of α-bungarotoxin binding in studies of healthy individuals and myasthenia gravis patients

To investigate whether nicotinic acetylcholine receptors might be present on blood mononuclear cells we studied the binding of [ 125I]α-bungarotoxin to mononuclear cells from three normal controls and seven myasthenia gravis patients. The medulloblastoma cell line, TE671, which expresses a functional nicotinic acetylcholine receptor having pharmacological properties similar to that of skeletal muscle receptor, was used as a positive control for α-bungarotoxin binding. None of the mononuclear cell samples studied exhibited specific binding of α-bungarotoxin.

Maximal isokinetic cycle ergometry in patients with coronary artery disease

We assessed the utility of short-term (30 s) maximal isokinetic cycle ergometry as an additional method of investigating the limitations to exercise in 33 carefully selected patients with documented coronary artery disease. The technique proved safe and reproducible in these patients. In relation to normal standards, performance was better in the maximal isokinetic cycle ergometer test (peak power = 819 +/- 116 W; average power = 532 +/- 72 W; total work = 13.1 +/- 2.1 kJ; 95-101% of predicted) than in the progressive incremental exercise test (VO2 = 1.80 +/- 0.37 l.min-1; power output = 919 +/- 165 kpm.min-1; 70-80% of predicted). Beta blockade did not affect maximal performance during either isokinetic or progressive incremental cycling, although maximal heart rate was significantly lower during both tests in patients on beta blockade. Power output in the progressive exercise was not as strongly related to the indices measured during the 30 s isokinetic test (r = 0.59-0.63) as it was in previous studies of healthy individuals (r = 0.89). The ability to detect individual variations in short-term exercise capacity measured with maximal isokinetic cycle ergometry may have significant potential value 1) as an additional method of determining the limitations to exercise and 2) when executing an exercise prescription in patients with coronary artery disease.

Neurobiological approaches in human behavior genetics.

An attempt should be made to base analysis of problems in human behavior genetics on existing knowledge of human biochemical genetics and neurobiology. Examples for this approach are studies showing HY antigen patterns of the opposite sex in transsexuality, slight psychological deviations in heterozygotes of recessive metabolic diseases such as phenylketonuria and lipid storage diseases, and psychological studies in healthy individuals with various genetic variants of the normal human electroencephalogram (EEG). Results of such studies will help gradually to replace emotional controversy by rational assessment of facts.

On the use of statistical models of within-person variation in long-term studies of healthy individuals.

Two statistical models for forecasting from very short time series have been applied to serial data from 162 participants in a health monitoring program. One model assumes stationary (“homeostatic”) variability over time with statistically independent observations: the other model presumes nonstationary (“random walk”) variation with a high degree of autocorrelation between observations. The data consist of results from 14 biochemical and seven hematological tests in blood collected on several successive weeks during each of four or more annual examinations of the subjects. Based on the average week-to-week variation in a given individual during the first three sampling periods, forecast ranges for the mean of every analyte measured during the fourth period in that individual were calculated from the two models. The random-walk model was better at detecting trends (at the 5% level of significance) during the first four sampling periods, with an average sensitivity of 56%, close to that predicted from theory. The stationary model was more adept at detecting a sudden nonrandorn change from the past record. When both models were used together, about 63% of the highest decile of nontrend changes were detected. We present tabulations of the magnitudes of observed trends and of the larger non-trend changes so that the probable clinical usefulness of detecting such changes may be assessed.

Relationship between serum chromium concentrations and glucose utilization in normal and infected subjects.

Studies in healthy individuals demonstrate that serum chromium concentrations fall precipitiously following the intravenous administration of a 30-gm. glucose load. Significant decreases from baseline control fasting serum Cr concentrations were also observed when intravenous glucose was given during sandfly fever. Glucose disappearance rates also decreased significantly to approximately one half of pre-illness control values while serum Cr values declined still further. In addition, serum Cr disappearance rates could be calculated. When individual preexposure and postexposure serum glucose and Cr disappearance rates were compared, significant linear correlation was found (P smaller than 0.05). Acute infection appears to reduce the availability of circulating Cr, which may contribute to the altered glucose metabolism characteristic of acute infections even in the presence of elevated insulin levels and other hormonal changes.