Cultural coping as a risk for depression and hypertension: the SABPA prospective study.

OBJECTIVE: In past studies, a lack of social support has been associated with cardiovascular disease (CVD) risk, particularly in black Africans. However, whether or not coping strategies have beneficial effects on blood pressure (BP) and emotional well-being is not clear. We therefore assessed the relationship between BP levels, depression and coping strategies. METHODS: A prospective bi-ethnic cohort followed 359 black and white South African school teachers (aged 20-65 years) over a three-year period. Data on ambulatory 24-hour blood pressure, depression, coping strategies (defensiveness, social support, avoidance) and culture-specific coping scores (cognitive/emotional debriefing, spiritual-, collectivistic and ritualcentred) were obtained. RESULTS: Over three years, chronic depression (38 vs 19%) and hypertension (68 vs 35%) were apparent in blacks ( d-values > 0.3) as opposed to whites. In both groups, depression was accompanied by more avoidance (loss-of-control) coping. Consistent spiritual and increasing collectivistic coping were apparent in whites. Over time, increasing defensiveness (OR 1.08, p ≤ 0.05) and ritual coping (OR 1.27, p ≤ 0.01; d-values > 0.5), predicted chronic depression in blacks. The change in their symptoms of depression predicted 24-hour hypertension (OR 1.11, p = 0.04). No similar associations existed in whites. CONCLUSIONS: Blacks showed increasing defensiveness and ritual- and spiritual-centred coping in an attempt to combat chronic depression, which may be costly, as reflected by their chronic hypertensive status. Whites showed consistent spiritual- centred coping while utilising avoidance or loss-of-control coping, with a trend of seeking less social support or isolation as a coping mechanism. During counselling of depressed patients with hypertension, the beneficial effects of social support and spiritual coping may be of great importance.

Cardiometabolic markers to identify cardiovascular disease risk in HIV-infected black South Africans.

BACKGROUND: The prevalence of HIV is the highest in sub-Saharan Africa; South Africa (SA) is one of the most affected countries with the highest number of adults living with HIV infection in the world. Besides the traditional risk factors for cardiovascular disease (CVD) in the general population, in people living with HIV there are specific factors - chronic inflammation, metabolic changes associated with the infection, therapy, and lipodystrophy - that potentially increase the risk for developing CVD. OBJECTIVE: This study proposes a screening discriminant model to identify the most important risk factors for the development of CVD in a cohort of 140 HIV-infected black Africans from the North West Province, SA. METHODS: Anthropometric measures, systolic blood pressure, diastolic blood pressure and the carotid-dorsalis pedis pulse wave velocity were determined. Blood was analysed to determine the levels of total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, triglycerides (TGs) and glucose. Partial least squares discriminant analysis was performed as a supervised pattern recognition method. Independent Student's t-tests were further employed to compare the means of risk factors on interval scales; for comparison of categorical risk factors between groups, chi2 tests were used. RESULTS: A TG:HDL-C ratio > or = 1.49, TC:HDL-C ratio > or = 5.4 and an HDL-C level < or = 0.76 mmol/l indicated CVD risk in this cohort of patients living with HIV. CONCLUSION: The results have important health implications for black Africans living with HIV as these lipid levels may be a useful indicator of the risk for CVD.

Attenuated NOx responses and myocardial ischemia, a possible risk for structural vascular disease in African men: the SABPA study.

Chronically elevated blood pressure has been associated with impaired NO-mediated vasodilation and structural vascular disease risk. This study aimed to determine whether significant associations exist regarding NO metabolite (NOx) responses, cardiovascular function and structural vascular disease in a cohort of African and Caucasian men. The study included 81 African and 94 Caucasian male teachers stratified via median splits into low and high NOx ethnic groups. Ambulatory blood pressure, electrocardiogram monitoring and ultrasound carotid intima-media thickness (CIMT) images were obtained. Cardiovascular measurements and fasting blood for NOx responses were measured during rest and on challenging the cardiovascular system with the Stroop colour-word conflict test. African men displayed significantly higher resting NOx as well as higher number of 24 h silent ischemic events than their Caucasian counterparts. Low NOx African men displayed enhanced α-adrenergic and ECG ST segment depression acute mental stress responses as well as 24 h silent ischemic events associated with CIMT (adjusted R(2) = 0.47; ß = 0.25; confidence interval (CI) = 0.13, 0.41). African men demonstrated a vulnerable cardiovascular profile. Novel findings revealed α-adrenergic-driven blood pressure responses and less NO bioavailability during acute stress. The association between myocardial ischemia and CIMT in this group emphasized their risk for future coronary artery disease and cerebrovascular events.

Structural vascular disease in Africans: Performance of ethnic-specific waist circumference cut points using logistic regression and neural network analyses: The SABPA study.

A recently proposed model for waist circumference cut points (RPWC), driven by increased blood pressure, was demonstrated in an African population. We therefore aimed to validate the RPWC by comparing the RPWC and the Joint Statement Consensus (JSC) models via Logistic Regression (LR) and Neural Networks (NN) analyses. Urban African gender groups (N=171) were stratified according to the JSC and RPWC cut point models. Ultrasound carotid intima media thickness (CIMT), blood pressure (BP) and fasting bloods (glucose, high density lipoprotein (HDL) and triglycerides) were obtained in a well-controlled setting. The RPWC male model (LR ROC AUC: 0.71, NN ROC AUC: 0.71) was practically equal to the JSC model (LR ROC AUC: 0.71, NN ROC AUC: 0.69) to predict structural vascular -disease. Similarly, the female RPWC model (LR ROC AUC: 0.84, NN ROC AUC: 0.82) and JSC model (LR ROC AUC: 0.82, NN ROC AUC: 0.81) equally predicted CIMT as surrogate marker for structural vascular disease. Odds ratios supported validity where prediction of CIMT revealed -clinical -significance, well over 1, for both the JSC and RPWC models in African males and females (OR 3.75-13.98). In conclusion, the proposed RPWC model was substantially validated utilizing linear and non-linear analyses. We therefore propose ethnic-specific WC cut points (African males, ≥90 cm; -females, ≥98 cm) to predict a surrogate marker for structural vascular disease.

Defensive active coping facilitates chronic hyperglycaemia and endothelial dysfunction in African men: the SABPA study.

BACKGROUND: Dissociation between behavioural defensive active coping (AC) control albeit physiological "loss of control" responses was associated with silent ischaemia and structural wall abnormalities in African men. Whether it applies to structural alterations and endothelial dysfunction is uncertain. We therefore aimed to determine AC ethnic-gender specific receiver operating characteristic (ROC) carotid intima media far wall (CIMTf) cut points best associated with 24-h BP, -silent ischaemia and glycated haemoglobin (HbA1c). METHODS: Participants included African and Caucasians (N=317) without pre-existing stroke or atrial fibrillation, aged 45 ± 9 years. The Coping Strategy Indicator was used to measure AC. Ultrasound CIMTf, ambulatory BP, silent ischaemia and fasting blood samples were obtained. RESULTS: Between 69 and 77% of AC African men showed above normal diastolic BP and HbA1c levels compared to 44-48% of AC Caucasian men. In AC African women, 41-60% showed above normal BP, silent ischaemia and HbA1c levels compared to 17-44% of their Caucasian counterparts. ROC curve analyses, detecting optimal CIMTf cut points, ranged between 0.57 and 0.65 mm (BP) and 0.71 and 0.74 mm (silent ischaemia) in AC ethnic-gender groups. Only HbA1C (>5.7%), with a sensitivity/specificity 47%/74%, after controlling for confounders, predicted structural alterations at an optimal cut point of 0.69 mm in AC African men (OR 4.5; 95% CI 2.93-18.73). CONCLUSION: Novel findings of behavioural resilience were apparent in the AC African female despite a high prevalence of risk markers. In AC males, chronic hyperglycaemia facilitated endothelial dysfunction, i.e. a physiological "loss of control" and susceptibility to stroke risk.

Change over three years in adolescents' physical activity levels and patterns after a physical activity intervention: play study.

AIM: This study aimed to determine over a three-year period what the PA levels and patterns of adolescents will be after participating in a physical activity (PA) intervention. METHODS: African adolescents (158 boys, 211 girls, N.=309) from a disadvantaged environment in South Africa with a mean age of 14.9±1.4, boys and 14.3±1.4 girls) participated in the study as a PA intervention group (N.=282) and a control group (N.=87). Multi-level modelling (repeated measures analysis of covariance (ANCOVA) adjusted for attendance percentage and gender to compare the intervention and control groups and repeated measures analysis of variance (ANOVA) over time, with a Bonferroni post hoc test were used to determine how the variables differ across the various testing opportunities. Week and weekend PA levels and patterns were analysed separately. RESULTS: Similar mean PA levels were found among the boys during week and weekend baseline measurements, with a significantly higher mean PA-level after three years in the intervention group. Baseline measurements for girls indicated statistically significant mean differences during the week and the weekend, although these mean differences were not significant during the end measurements. Boys and girls (excluding the intervention group of boys), showed a tendency of declining mean PA over the three years. The PA intervention showed a stabilising effect on PA levels and contributed to more active choices among the intervention group of boys, especially during weekends. CONCLUSION: Participation in similar PA interventions is recommended for adolescent boys, with adaptation to the content for girls.

Determining the waist circumference cut off which best predicts the metabolic syndrome components in urban Africans: the SABPA study.

Various studies have shown that the relationship between waist circumference (WC) and abdominal obesity is age, gender as well as ethnicity-dependent. WC criteria for Sub Saharan Africans have not been defined by the International Diabetes Federation (IDF). The aim was to determine which WC cut off best predicted Metabolic Syndrome (MetS) in a group of urban African teachers (80 males and 93 females). We determined sphygmomanometer blood pressure, WC, glucose, high density lipoprotein cholesterol (HdL) and triglyceride (TRIG) values. The males' MetS profile was less favourable as their glucose, TRIG and blood pressure levels were higher than the proposed cut off for MetS. The females could be classified as obese, based on their mean BMI (32.78±6.36) and WC (93.48±15.68). Receiver operating characteristic (ROC) WC cut offs of 90, 91, 94 and 96 cm for the respective MetS components in males (blood pressure, HdL, glucose and TRIG) were suggested. In the females, cut offs of 92, 98, 94 and 94 cm for TRIG, blood pressure, HdL and glucose respectively, were put forward. Odds ratios revealed that increased blood pressure best predicted ROC WC in both males (OR 9.59; 95% CI 3.14-29.32) and females (OR 3.11; 95% CI 1.30-7.42) irrespective of age. We suggest that the optimal cut off point for the males be set at 90 cm, as opposed to the current 94 cm; whilst the female cut off be set at 98 cm as opposed to the existing cut off of 80 cm. Larger sample groups are recommended to justify our data.

Estimating an Effect Size in One-Way Multivariate Analysis of Variance (MANOVA).

When two or more univariate population means are compared, the proportion of variation in the dependent variable accounted for by population group membership is eta-squared. This effect size can be generalized by using multivariate measures of association, based on the multivariate analysis of variance (MANOVA) statistics, to establish whether population mean vectors are practically significant different. In the case of random samples from populations, approximate and asymptotically unbiased estimators of these effect sizes as well as confidence intervals are suggested under the assumptions of equal covariance matrices and normality. Statistical properties of these estimators are studied by Monte Carlo simulations. The accuracy and spread of the proposed effect sizes are also compared with those of other multivariate measures of association in Monte Carlo simulations. The proposed effect sizes are also illustrated by applying them in an empirical example using college admission test data obtained from StatSoft (2007) .

Cardiovascular reactivity in Black South-African males of different age groups: the influence of urbanization.

OBJECTIVE: Blacks in an urban environment seem to be more vulnerable to excessive increases in blood pressure during daily life events. This greater cardiovascular reactivity during acute stress situations in urban Blacks may lead to the development of hypertension in their later lives. Because Blacks in South Africa are involved in a massive process of urbanization, which may lead to chronic diseases of lifestyle like hypertension and diabetes, this study was undertaken to compare the cardiovascular reactivity patterns of urbanized and rural Black males in the North-West province of South Africa. DESIGN: Two hundred twenty-three Black males of different age groups, Group 1: younger than 25 years of age; Group 2: between 25 and 44 years of age; and Group 3: 45 years of age and older. Participants were randomly selected from rural and urbanized settlements. METHODS: After resting blood pressure was recorded with a Finapres apparatus, and cardiac output, stroke volume, heart rate, and total peripheral vascular resistance had been obtained, an acute laboratory stressor (hand dynamometer exercise) was applied and the above measurements repeated. RESULTS: The SBP, DBP, and MAP increased 28% and 42% in both the rural and the urbanized groups. There was a shift from a central reactivity pattern (increased cardiac output) in the young rural group (< 25 years) to a peripheral reactivity pattern (increased total peripheral resistance) in the > or = 45 years old urbanized males after applying the stressor. CONCLUSIONS: Cardiovascular reactivity differs between Black males from a rural area compared to urbanized Black males. The urbanized males > or = 45 years of age were at a higher risk of developing cardiovascular disease because their total peripheral resistance reactivity increased the most during application of the stressor.

A combination of statistical methods for the analysis of the relative validation data of the quantitative food frequency questionnaire used in the THUSA study. Transition, Health and Urbanisation in South Africa.

OBJECTIVE: To apply structural equation modelling (SEM) and estimation of variance components to the relative validation data obtained from the quantitative food frequency questionnaire (QFFQ) used in the Transition, Health and Urbanisation in South Africa (THUSA) study. DESIGN: A cross-sectional study. SETTING: A community-based field study in an African population conducted during 1996. SUBJECTS: Residents of the North West Province, South Africa, aged between 15 and 65 years. METHODS: Relative validity of the QFFQ was tested against 7-day weighed food records, 24-hour urinary nitrogen (UN) excretion and estimated basal metabolic rate (BMR). SEM and estimation of variance components were applied to the log-transformed energy, protein, fat, calcium, iron, vitamin A and vitamin C intakes. UN excretion was used as a biomarker in the application of the SEM to protein and estimated BMR to energy intakes. RESULTS: Constant bias (alphaQ) derived by the SEM varied from 0.85 (vitamin C) to 5.8 (energy). There was significant proportional bias for all nutrients except vitamin C. Validation coefficients (ro(Q,T) varied from 0.3 (fat, calcium, iron) to 0.7 (vitamin C). The inclusion of estimated BMR in the SEM for energy increased ro(Q, T) from 0.38 to 0.42. The estimation of variance components gave slightly lower correlations for the relationship between intakes from the QFFQ and the unknown true intake. CONCLUSIONS: Robust statistical methods were successfully applied in a relative validation study for a QFFQ in an African population. Estimated BMR as a biomarker for energy intake produced more meaningful results than UN excretion as a biomarker for protein intake.

Stability and partitioning of closantel and rafoxanide in ruminal fluid of sheep.

The stability and the partitioning of closantel and rafoxanide in ruminal fluid (RF) was examined in vitro. Stability was evaluated in two studies in a ruminal fluid-artificial saliva (RF-AS) mixture containing either drug. Drug concentrations were measured in samples collected sequentially from four batches of RF-AS fortified with either closantel or rafoxanide in one study and in four separately incubated aliquots of a RF-AS mixture of each drug in the second study at the start and at various intervals during a 24 h incubation period. The viability of the in vitro RF-AS incubation model was validated by the presence of digoxin degradation (T1/2 of 39,1 +/- 13 h) and by the absence of significant time related differences (P> 0,5) in volume of gas produced, pH and methylene blue reduction time of the RF-AS drug mixture. Partitioning of closantel and rafoxanide was determined by measuring the relative drug concentration of the fluid and particulate phases in RF fortified with either drug at different concentrations. Closantel and rafoxanide were shown to be stable in a RF-AS mixture and were not subjected to any significant biodegradation. An initial marked reduction in drug concentration measured in the RF-AS mixture during the first 2 h of incubation was attributed to the attachment of both drugs onto particulate matter. This was subsequently confirmed in the partitioning study. More than 80% of closantel and rafoxanide was shown to be associated with the particulate phase of RF

Primary care drug therapy training: the solution for PHC nurses?

The priority of the National Health System in South Africa is primary health care (PHC). The approach involves a health system led by PHC services and includes personal and curative services for acute minor ailments delivered by PHC nurses. The nurses are also responsible for the treatment of these ailments with essential drugs according to protocols as proposed in the Essential Drugs List. A before-after experimental research design was used to evaluate the effect of a competency-based primary care drug therapy (PCDT) training programme for PHC nurses in the treatment of acute minor ailments. An experimental group (n = 35) and control group (n = 31) consisting of registered nurses undergoing training in PHC at Gold Fields Nursing College were randomly selected. The results showed a significant increase in prescribing outcomes and medicine utilisation.

Haemodynamic changes in the cardiovascular system during the early phases of orthostasis.

In this study, we monitored the changes in arterial blood pressure continuously in two groups of Caucasian men during normal passive orthostasis as well as reversed passive orthostasis. Group A consisted of a group of 23 younger men (16 +/- 0.5 years) and group B consisted of 21 older men (62.9 +/- 2.7 years). The normal passive orthostatic test and the reversed passive orthostatic test were used to induce blood pressure changes. We found that the temporary and initial changes in blood pressure during the normal and reversed orthostatic tests were significantly lower in the older group. Heart rate increases were also lower in the older group. These findings could be explained in terms of a reduced compliance of the thin walled venous blood vessels in the elderly.

Relative bioavailability of rafoxanide following intraruminal and intra-abomasal administration in sheep.

The bioavailability of rafoxanide was compared after intraruminal and intra-abomasal administration in healthy adult sheep (n = 6) in a single dose, 2 parallel group study at 7.5 mg/kg. Rafoxanide concentrations in plasma were measured by means of HPLC analysis. Primary pharmacokinetic parameters for bioavailability and disposition of rafoxanide in plasma for both routes of administration were determined by non-compartmental and non-linear, 1-compartmental pharmacokinetic analysis, respectively. Significantly (P < or = 0.05) higher peak plasma concentrations (c(max)) of rafoxanide and a more rapid rate of absorption (c. 3.5 times) was observed in sheep after intra-abomasal (i-a) administration compared to intraruminal (i.r.) administration. A significantly (P < or = 0.05) longer lag period (t(lag)) before absorption (6.8 +/- 2.9 h) occurred after i.r. than after i-a treatment (1.9 +/- 0.6 h). There was no significant difference (P > 0.05) in AUC, MRT and in the rates of elimination (k10-HL and t(1/2beta)) between the i.r. and i-a routes of administration. The results of the study demonstrated the important influence of the rumino-reticulum on absorption of rafoxanide in sheep.

Intravascular plasma disposition and salivary secretion of closantel and rafoxanide in sheep.

The plasma and salivary disposition of closantel and rafoxanide were examined following intravenous administration in adult sheep. Two studies were conducted with rafoxanide at 7.5 mg/kg and 1 with closantel using 2 doses (5 and 15 mg/kg). The pharmacokinetic profile of both drugs in plasma were best described by a 2-compartmental model with 1st-order rate constants. Plasma disposition of closantel and rafoxanide were characterised by a rapid distribution (t1/2(alpha)) of <30 min), long elimination half-life (t1/2(beta)) of 17.0 +/- 4.0 days for closantel and 7.2 +/- 0.6 days for rafoxanide), small apparent volume of distribution (V(SS) of <0.15 l/kg) and a slow rate of total body clearance (Cl of <0.01 ml/min/kg). The area under the drug plasma concentration curve (AUC) of closantel at 5 mg/kg was nearly twice as large as that of rafoxanide at 7.5 mg/kg resulting from the slower t1/2(beta) observed with closantel compared to rafoxanide. Large individual differences were observed in the rate measurements of distribution (k12, k21 and t1/2(alpha)), whereas the parameters of elimination (k10, t1/2(beta) and Cl), were more consistent between animals. A dose proportional increase in AUC was observed for closantel administered at 5 and 15 mg/kg. A low, constant salivary concentration of closantel (mean of 0.04 +/- 0.05 microg/mL) and rafoxanide (mean of 0.07 +/- 0.04 microg/mL) was observed during the 24-h examination period after dosing.

Identifying and developing rugby talent among 10-year-old boys: a practical model.

The re-entry of South Africa into the international sporting arena and the resultant need for the identification and development of talent, especially among formerly deprived groups of people, provided the incentive for this study. Its aim was to identify the physical, motor and anthropometric variables that will enable coaches to identify 10-year-old boys, based on their abilities, who could become successful rugby players. Altogether, 173 ten-year-old boys with no rugby experience from a cross-section of the population were selected at random and subjected to 14 physical and motor tests and 14 anthropometric measurements. From 22 schools which participated in the Western Transvaal primary schools under-11 rugby league, the three top teams (n = 45 individuals) were selected and also tested. The results from these three teams were used as the criteria for rugby talent among 10-year-old boys. To establish the best predictors of talent, a stepwise discriminant analysis was conducted: this indicated eight variables (four motor and four anthropometric) that discriminated maximally between the talented and the rest of the players of this age. With classification functions based on these eight variables, 93.8% of all the subjects were classified correctly, indicating good validity. A canonical analysis, based on the selected variables, was then conducted on all the under-11 teams that played in the league in the region (n = 330), and they were ranked according to the scores of the first canonical variable from the most to the least talented. By comparing these results with the players who were chosen for the region's primary schools team, a success rate of 88% in prediction of talent was established. We conclude that this is a successful and practical method to aid the teacher and the coach in selecting and developing talent among 10-year-old rugby players in South Africa.

The application of new bioavailability parameters in the bioequivalence testing of antimicrobial agents.

Two new bioavailability parameters were recently suggested [Koeleman et al. 1991] to define (i) the time that the concentration in the blood stays above a defined minimum effective concentration, te and (ii) the onset of the effect, to. In addition to conventional bioequivalence parameters, the new bioavailabilty parameters (to and te) were calculated in this study and statistically compared for penicillin, chloroquine, oxytetracycline, amoxycillin and flucloxacillin from available bioequivalence data. For oxytetracycline, flucloxacillin and amoxycillin, the conventional bioavailability parameters indicated partial equivalence whereas using the te and to parameters, more realistic indications of the possible extent of the performance of a drug from dosage forms were obtained than with the conventional bioequivalence parameters. The new parameters gave additional information for a better evaluation of the performance of a drug from a dosage form.

The influence of different types of breakfast on the absorption of paracetamol among members of an ethnic group.

It is well known that food influences the absorption and therapeutic efficacy of many drugs. In this study, the influence of three different types of breakfast, on the absorption of paracetamol was studied in a South African ethnic population group (Tswanas). The results indicated that breakfasts with a high fat content delayed the absorption of paracetamol to the largest extent while breakfasts with a high carbohydrate content delayed the absorption of paracetamol to a lesser extent.

New bioavailability parameters to compare the efficacy of antimicrobial drugs in dosage forms.

Pharmacokinetic parameters such as AUC, Cmax and tmax have been used to represent the rate and extent of absorption of drugs from dosage forms in comparative bioequivalence testing. None of these parameters gives a direct indication of how long the drug concentration is maintained above an acceptable level e.g. minimum inhibitory concentration (MIC) or the minimum effective concentration (MEC). This is clinically important in evaluating the onset and duration of a therapeutic effect obtained from a test dosage form in comparison to the reference dosage form. The purpose of this study is to investigate the possibility of a bioavailability parameter which relates the time that the drug concentration in the systemic circulation is maintained above a certain level (te) and the first time that the blood concentration exceeds this level (to). Two methods were used to calculate the time that drug levels are maintained above a certain minimum level. The proposed parameters proved to be valuable when the efficacy of erythromycin was used as an example. Although some problems, such as undefined MIC/MEC may arise, te and to can be used along with the conventional bioequivalence parameters to obtain a better indication of the clinical efficacy.

An approach to select the appropriate statistical method for testing bioequivalence.

Since most bioavailability studies are usually done with only a limited number of volunteers (usually 10-30), the statistical properties of the calculated bioavailability parameters are not well defined. The established statistical methods to test bioequivalence are usually based on either the assumption of normality or a symmetrical distribution. However, the decision of which method to apply, depends primarily on the distributional assumption of the data. In this study, an approach is followed where the small data base of a limited number of volunteers is expanded by adding pseudo-volunteers by "bootstrap" simulations. From such a larger data base it is easier to determine the statistical distributional properties of bioavailability parameters, which in its turn leads to the identification of an appropriate statistical method. With more certainty on which statistical method to apply, the original data can be used more effectively in testing for bioequivalence. In this paper, comparisons are made between the distributions of bioavailability parameters of an actual 60-volunteer study and those of two simulated data sets. Each such data set contained a random sample of 10 volunteers each (from the 60 volunteers), together with 50 pseudo-volunteers. These 50 volunteers were simulated from the random sample of 10 real volunteers. Good correspondences were obtained when comparing these two data sets with the original data, which indicated the validity to use this approach in bioavailability studies where a small number of volunteers had been used. This method proved useful to define the distributional properties for a relative small number of parameter-values available.