AIDS in the world of work: when information is not enough.

PIP: As AIDS continues to decimate the workforce on most continents, and especially in Africa, governments, unions and employers are taking various steps to fight the disease. As part of the continuing series of reports by the International Labor Office, this paper examines the health condition of workers in Uganda. It is shown that Uganda was the first African country to openly acknowledge the gravity of the AIDS epidemic and develop a strategy to fight it. In the country, AIDS is no longer perceived as a public health problem, but as a broader social issue. The impact of this problem falls mainly on workers especially the poor. Labor unions efforts still remain at the stage of providing information due to lack of resources. Although, knowledge of AIDS risk is already well known, many still do not know any method of protection and its application. Unions in Uganda are not considered direct major players in the fight against AIDS, however, they can help improve the working conditions and the lives of the workers. The paper highlights the need for a multifaceted action to improve the worker's lives, care for persons infected with HIV, and ease the socioeconomic effects of AIDS.^ieng

High-performance liquid chromatographic monitoring of intravenously administered diacetylmorphine and morphine and their metabolites in human plasma.

A rapid and selective reversed-phase high-performance liquid chromatographic assay with gradient elution and diode-array detection for diacetylmorphine, morphine, codeine, and their free and glucuronidated metabolites in plasma, was developed. After addition of ethylmorphine as internal standard the plasma samples were extracted using C18 ODS-2 solid-phase columns with a recovery better than 80%. The limit of quantitation using an injection volume of 2 microl was 25 ng/ml for each compound. The intra- and inter-day precision was better than 5%. The described method cannot only be used for pharmacokinetic studies but also for intoxication cases to monitor a wide range of opiates.

Dexmedetomidine decreases thiopental dose requirement and alters distribution pharmacokinetics.

BACKGROUND: alpha 2-Adrenergic agonists such as dexmedetomidine can be used to reduce the dose requirement of intravenous and volatile anesthetics. Whereas dexmedetomidine and volatile anesthetics interact pharmacodynamically (reduction of MAC), the mechanism of interaction between dexmedetomidine and intravenous anesthetics is not known. METHODS: Fourteen male ASA physical status 1 patients were randomly assigned to serve as control subjects (n = 7) or to be treated with dexmedetomidine (n = 7; 100, 30, and 6 ng.kg-1.min-1 for 10 min, 15 min, and thereafter, respectively). After 35 min, in all patients, thiopental (100 mg/min) was infused until burst suppression appeared in the raw tracing of the electroencephalogram. By using concentrations of thiopental in plasma and the electroencephalogram as a continuous pharmacologic effect measure, the apparent effect site concentrations for thiopental were estimated in both groups. Three-compartment pharmacokinetics were calculated for thiopental. RESULTS: Dexmedetomidine reduced the thiopental dose requirement for electroencephalographic burst suppression by 30%. There was no difference in estimated thiopental effect site concentrations between dexmedetomidine and control patients, suggesting the absence of a major pharmacodynamic interaction. Dexmedetomidine significantly decreased distribution volumes (V2, V3, and Vdss) and distribution clearances (Cl12 and Cl13) of thiopental. CONCLUSIONS: The thiopental dose-sparing effect of dexmedetomidine on the electroencephalogram is not the result of a pharmacodynamic interaction but rather can be explained by a dexmedetomidine-induced decrease in thiopental distribution volume and distribution clearances. Dexmedetomidine reduces thiopental distribution, most probably by decreasing cardiac output and regional blood flow.

Automated determination of midazolam in human plasma by high-performance liquid chromatography using column switching.

An automated gradient high-performance liquid chromatographic method using a column-switching technique was developed in order to determine and quantify midazolam (separated from the metabolite alpha-hydroximidazolam) in human plasma. After dilution with an internal standard (flurazepam) solution, containing 20% acetonitrile, 400 microliters of the plasma samples were injected onto a precolumn (17 x 4.6 mm I.D., C18 Corasil 37-53 microns) and retained. Proteins and polar plasma components were washed out using a 0.1 M sodium hydroxide solution, followed by an equilibration with a phosphate buffer of pH 8.0. After column-switching midazolam and flurazepam were eluted and transferred to the analytical column (RP-select B) in the backflush mode, separated by gradient elution and detected at 230 nm by ultraviolet detection. Precision of replicate analyses on the same day was 1.5% for midazolam and 0.7% for flurazepam. Recovery of midazolam was in the range 80-89% and the detection limit was 2 ng/ml plasma.

Thiopental pharmacodynamics. I. Defining the pseudo-steady-state serum concentration-EEG effect relationship.

To assess depth of anesthesia for intravenous anesthetics using clinical stimuli and observed responses, it is necessary to achieve constant serum concentrations of drug that result in constant biophase or central nervous system concentrations. The goal of this investigation was to use a computer-controlled infusion pump (CCIP) to obtain constant serum thiopental concentrations and use the electroencephalogram (EEG) as a measure of thiopental's central nervous system drug effect. The number of waves per second obtained from aperiodic waveform analysis was used as the EEG measure. A CCIP was used in six male volunteers to attain rapidly and then maintain for 6-min time periods the following pseudo-steady-state constant serum thiopental target concentrations: 10, 20, 30, and 40 micrograms/ml. The median performance error (bias) of the CCIP using 149 measurements of thiopental serum concentrations in six subjects was +5%, and the median absolute performance error (accuracy) was 16%. Following the step change in serum thiopental concentration, the EEG number of waves per second stabilized within 2-3 min and the remained constant until the target serum thiopental concentration was changed. When the constant serum thiopental concentration was plotted against the number of waves per second for each subject, a biphasic serum concentration versus EEG effect relationship was seen. This biphasic concentration:response relationship was characterized with a nonparametric pharmacodynamic model. The awake, baseline EEG was 10.6 waves/s; at peak activation the EEG was 19.1 waves/s and occurred at a serum thiopental concentration of 13.3 micrograms/ml. At a serum thiopental concentration of 31.2 micrograms/ml the EEG had slowed to 10.6 waves/s (back to baseline) and at 41.2 micrograms/ml was 50% below the baseline, awake value. Zero waves per second occurred at serum thiopental concentrations greater than 50 micrograms/ml. Using a CCIP it is possible to establish constant serum thiopental concentration rapidly and characterize the concentration versus EEG drug effect relationship.

A three-step approach combining Bayesian regression and NONMEM population analysis: application to midazolam.

NONMEM, the only available supported program for population pharmacokinetic analysis, does not provide the analyst with individual subject parameter estimates. As a result, the relationship between pharmacokinetic parameters and demographic factors such as age, gender, and body weight cannot be sought by plotting demographic factors vs. kinetic parameters. To overcome this problem, we devised a three-step approach. In step 1, an initial NONMEM analysis provides the population pharmacokinetic parameters without taking into account the demographic factors. Step 2 consists of individual bayesian regressions using the measured drug concentrations for each subject and the population pharmacokinetic parameters obtained in step 1. The bayesian parameter estimates of the individual subject can be plotted against the demographic factors of interest. From the scatter plots, it can be seen which are the demographic factors that appear to affect the pharmacokinetic parameters. In step 3, the NONMEM analysis is resumed, and the demographic factors found in step 2 are entered into the NONMEM regression model in a stepwise manner. This method was used to analyze the pharmacokinetics of midazolam in 64 subjects from 714 plasma concentrations and 11 demographic factors. CL (elimination clearance) and V1 were found to be a function of body weight. Age and liver disease were found to decrease CL. Of the 11 demographic factors recorded for each patient, none was found to influence VSS or intercompartmental clearance.

Prednisolone concentrations in cerebrospinal fluid after different prednisolone prodrugs.

The concentration-time curves of prednisolone in cerebrospinal fluid (CSF) and plasma were measured following an equimolar i.v. bolus dose of prednisolone phosphate (five patients) and prednisolone phthalate (four patients). Independent of the prodrug administered, the value of the AUC (0.360 min) in CSF was more than three times lower than the corresponding value in plasma. The AUCs of unbound prednisolone in plasma were higher after prednisolone phosphate, than after prednisolone phthalate (68.1 +/- 15.7 vs 19.0 +/- 5.2 micrograms ml-1 min, P less than 0.001). Similarly, the AUCs of prednisolone were higher in the CSF after prednisolone phosphate, than after prednisolone phthalate (17.6 +/- 2.8 vs 3.3 +/- 1.0 micrograms ml-1 min, P less than 0.0001). The results indicate that the concentrations of prednisolone in CSF are much lower than the unbound concentrations in plasma and that therapeutic inequivalence should be expected when the two prodrugs are given in equimolar doses.

Electroencephalographic effects of benzodiazepines. I. Choosing an electroencephalographic parameter to measure the effect of midazolam on the central nervous system.

The goal of this investigation was to determine a numerical electroencephalographic parameter that best indicated the degree of the effect of midazolam, administered in hypnotic doses, on the central nervous system. This electroencephalographic parameter could then be used to relate midazolam plasma concentrations and electroencephalographic drug effect (pharmacodynamic modeling). Intravenous doses of midazolam (3.75 to 25 mg) were given to five men at an infusion rate of 5 mg/min. A cortical electroencephalogram was continuously recorded. Two waveform analysis approaches were examined: fast Fourier transformation and aperiodic analysis. From fast Fourier transformation and aperiodic analysis a set of parameters were examined as measures of drug effect. We conclude that the voltage per second from aperiodic analysis provided the electroencephalographic parameter that optimally measured the effect of midazolam on the central nervous system.

Electroencephalographic effects of benzodiazepines. II. Pharmacodynamic modeling of the electroencephalographic effects of midazolam and diazepam.

The comparative pharmacodynamics of midazolam and diazepam were examined by use of the electroencephalogram as a measure of drug effect on the central nervous system. Intravenous doses of 7.5, 15, and 25 mg midazolam and 15, 30, and 50 mg diazepam were given on repeated occasions to three volunteers. Arterial plasma concentration and electroencephalogram voltage were related with nonparameteric and parametric pharmacodynamic models. The peak increases in voltage (maximal effect) and the slopes of the plasma concentration versus effect curve were similar for both drugs. The half-time of blood:brain equilibration was significantly longer for midazolam than diazepam (4.8 minutes versus 1.6 minutes). Midazolam was found to have an intrinsic steady-state potency that was approximately five times greater than that of diazepam (152 ng/ml versus 958 ng/ml).

Cortical initiation of phasic electrodermal activity.

In order to investigate the role of the cerebral cortex in elicitation of spontaneous electrodermal responses (EDRs), electrocortical activity (EEG) preceding peripheral fluctuations was investigated. During one 30-min session, subjects imagined arousing situations. EEG and EDR average waveforms were computed with respect to the EDR maxima. In Grand Average EEG waveforms, transient activity preceding EDR onset at about 2.3 seconds, lasting for about 1 s, was observed. The main power of this phasic event was in the alpha frequency band. Digital filtering of EEG waveforms supported the assumption of a visceral control process at cortical level, responsible for triggering peripheral EDRs. Whereas the phenomenon occurred slightly earlier frontally than centrally, it was strongest at the vertex. The possible interpretation of this electrocortical phenomenon, related to the evocation of electrodermal responses, as a final common pathway of different EDR generating systems is discussed.

Estimating the rate of thiopental blood-brain equilibration using pseudo steady state serum concentrations.

The equilibration between drug serum concentration and drug effect under non-steady state concentrations has been classically modeled using an effect compartment where the transfer from the serum to the effect compartment is considered to be a first-order process. The purpose of the present study was to examine whether an effect compartment with first-order transfer was adequate for describing thiopental serum concentration-EEG pharmacodynamics. The study has two facets: (i) Successive pseudo steady state serum concentrations of thiopental having a square wave shape were produced and maintained in six human subjects by means of a computer-driven infusion pump. An aperiodic wave form transformation of the electroencephalogram (EEG) was used as a continuous measure of thiopental EEG drug effect. The time course of the EEG effect following each thiopental serum concentration square wave showed an exponential pattern. The first-order rate constant for equilibration of the effect site concentration with the drug serum concentration (keo) was estimated by fitting a monoexponential model to the effect vs. time data resulting from the pseudo steady state thiopental serum concentration profile. (ii) In a second experiment, data were obtained from a classical design, i.e., a zero-order intravenous infusion of thiopental. The same subjects were studied. The keo was estimated by means of a semiparametric iterative method using convolution (effect compartment, transfer of drug from serum to site of action is assumed to be a first-order process). The mean pseudo steady state value for keo of 0.51 min-1 was not different from the mean value of 0.46 min-1 from the semi parametric approach when data from a linear portion of the drug concentration vs. effect curve were examined. The pseudo steady state technique gave inaccurate estimates of keo in the nonlinear portion of the thiopental concentration vs. response curve, i.e., at the peak of the biphasic concentration-effect relationship.

Treatment of liver disease with malotilate. A pharmacokinetic and pharmacodynamic phase II study in cirrhosis.

Malotilate, a sulphur-containing compound with antifibrotic and hepatoprotective properties in several animal models, has been investigated in cirrhotic patients. Nine patients with cirrhosis of various aetiologies and severity, and 4 healthy volunteers, participated in a pharmacokinetic study. After a single dose of 500 mg malotilate p.o. peak malotilate plasma concentration measured by GC-MS was 35 times higher in patients (median 0.70 micrograms/ml) than in controls (median 0.019 micrograms/ml). The median apparent oral clearance was approximately 50 times lower in cirrhotics (median 2.21/min) than in healthy volunteers (1181/min). The apparent oral clearance was significantly correlated with indicators of portal-systemic shunting, such as the 2-h postprandial serum bile acids and the bioavailability of oral nitroglycerine. Urinary output of the glucuronidated metabolite-(M3), measured by HPLC, was normal in patients, whereas recovery of metabolite-M6 (resulting from ring opening and loss of sulphur) was reduced. Six patients in an open 6-month trial received malotilate 200 mg t.i.d. for 2 months and 400 mg t.i.d. for 4 months. The thrombocyte count increased and serum ferritin level fell in all patients, and serum cholinesterase rose and IgA decreased in 5 of 6. The other indicators of liver function did not show a significant change. Dry skin was the only possible adverse effect. It is concluded that first-pass elimination of malotilate is dramatically reduced in cirrhotics, and that a smaller amount of the drug reaches the liver in such patients. Malotilate was well tolerated, even in patients with advanced disease.

Absolute bioavailability of glyceryl trinitrate from a transdermal system, assessed by digital plethysmography.

The absolute bioavailability of glyceryl trinitrate from a transdermal therapeutic system (Nitroderm TTS, 20 cm2) was assessed with a new method in 6 healthy volunteers. Instead of measuring plasma concentrations the pharmacological effects of glyceryl trinitrate were followed by digital plethysmography. Each experiment consisted of the establishment of an intravenous dose response curve which was followed by a 1-hour application of the transdermal system and a second intravenous dose response curve. The investigations were repeated after pretreatment of each subject with 0.4 mg pindolol i.v. The results show a satisfactory overall consistency of the data and indicate a release rate of 4.4 +/- SD 1.7 micrograms/min of bioavailable glyceryl trinitrate during the first hour of application of this transdermal system. This corresponds to 75 +/- 29% of the release rate obtained by analysis of residual amounts in the TTS.

[Transcortin concentrations in the plasma of normal persons and patients with kidney and liver diseases]. / Transcortinkonzentrationen im Plasma von Normalpersonen und Patienten mit Nieren- oder Lebererkrankungen.

The purpose of the study was to assess the influence of chronic kidney and liver diseases on the transcortin concentrations in plasma. The mean (+/- SD) plasma concentration of transcortin was 45.0 +/- 6.7 mg/l in women not taking oral contraceptive steroids and 41.2 +/- 6.7 mg/l in healthy male volunteers. Patients with the nephrotic syndrome had low transcortin concentrations (females: 20.9 +/- 8.5 mg/l; males: 26.0 +/- 6.0 mg/l). Abnormally low concentrations were measured in females treated for endstage renal disease with chronic ambulant peritoneal dialysis (CAPD) (30.8 +/- 7.5 mg/l). Patients on hemodialysis or with a functioning renal allograft had normal transcortin concentrations in plasma. Females suffering from a primary biliary cirrhosis had normal transcortin concentrations and male patients with an alcoholic cirrhosis had abnormally low mean transcortin concentrations in plasma (32.6 +/- 7.4 mg/l). The transcortin concentrations in patients with a Gilbert syndrome were normal. Among patients with a kidney or liver disease, the large variability of the transcortin concentration in plasma indicates that the knowledge of the transcortin concentration or the unbound steroid concentration in plasma is mandatory for the interpretation of total glucocorticoid concentrations in plasma.

[Automatic finger plethysmography as a human pharmacologic research tool. A methodologic study]. / Die automatisierte Fingerplethysmographie als human pharmakologisches Forschungsinstrument. Eine methodologische Untersuchung.

In view of the use of an electronically processed digital plethysmography as a noninvasive pharmacological tool - particularly to measure effects of organic nitrates - 9 healthy young volunteers were examined. The purpose of the investigation was to study baseline recordings and to assess the effects of several well defined exogenous influences. The electronic processor calculated the D/H-ratio of each plethysmographic pulse wave, where D represents the depth of the dicrotic minimum measured from the apex of the systolic maximum and H the total hight of the plethysmographic wave. The D/H-ratio was not significantly influenced by a hot beverage, but fell after a cold drink. In undisturbed volunteers the D/H-ratio had a tendency to fall slightly during a 3-h period of observation. This tendency could be eliminated by small doses of pindolol or dihydroergotamine, but individual fluctuations of the curves were still visible. It appears therefore that a fully automated evaluation of plethysmographic recordings yields best results if the findings in a group of volunteers are averaged.

[1st use of lactitol in the treatment of porto-systemic encephalopathy]. / Erstmalige Anwendung von Lactitol in der Behandlung der porto-systemischen Enzephalopathie.

Lactitol (beta-galactosido-sorbitol) is not absorbed in the small bowel but metabolized by colonic bacteria, and should therefore be as effective in the treatment of portal-systemic encephalopathy as lactulose (beta-galactosido-fructose). This hypothesis was tested in a 61-year-old alcoholic with an end-to-side portacaval anastomosis and chronic portal-systemic encephalopathy. Under controlled conditions he was switched from optimized treatment with lactulose to several regimens with lactitol (40-68 g/day), after which he was maintained on the new treatment for 1 year. On lactitol his condition was at least as good as on lactulose, but lactitol produced no taste aversion because it is less sweet. In addition, the patient no longer had nausea after taking the drug because lactitol can be supplied in a nonhygroscopic, chemically pure, crystalline form and therefore is less hyperosmotic than lactulose, which is supplied with contaminations of galactose and lactose. Obviously the data in single case represent only a feasibility study. Nevertheless, the outcome in this patient, together with the advantages of the new sugar, justify the planning of controlled clinical trials.

Determination of chromium sesquioxide in faeces by a spectrophotometric method.

Chromium sesquioxide Cr2O3, present as a non-absorbable marker in faeces, may be determined spectrophotometrically as chromate ion in aqueous solution after ashing and alkaline fusion. Recovery of this substance is excellent. The method described is simpler, more suited to the clinical laboratory and less hazardous than previously reported methods.