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The in vitro lymphocyte response to mitogen stimulation and the in vitro lymphocyte sensitivity to glucocorticoid were examined in 72 kidney transplanted patients before and after administration of high or low doses of glucocorticoid. Administration of 10 mg of prednisone orally to 10 patients did not significantly change the mitogen responses or the lymphocyte sensitivity to methylprednisolone. Likewise, administration of 100-120 mg of methylprednisolone, intravenously to 62 patients did not significantly affect the mitogen responses, but, in contrast, the lymphocyte sensitivity to the immunosuppressive effect of methylprednisolone was clearly increased. This effect was highly significant in both cyclosporine A and azathioprine treated patients. These findings suggest that a change of the lymphocyte sensitivity to the immunosuppressive effect of methylprednisolone may occur after a high dose of glucocorticoid, anaesthesia and surgery, although no changes of the immunefunctions in vitro can be demonstrated by examining the mitogen response of the lymphocyte cultures. No relationship was found in the present study between the individual lymphocyte sensitivity to glucocorticoid and metabolic clearance rate. [ABSTRACT FROM AUTHOR]

1. Inter- and intrasubject variability in the gastric emptying of semisolids and liquids was measured by scintigraphic emptying of radionuclide-labelled semisolid and from paracetamol absorption in ten healthy volunteers of both sexes. 2. The intrasubject variability was not statistically significant for any of scintigraphic or paracetamol absorption parameters. 3. The intersubject variation was significant for all scintigraphic and paracetamol absorption parameters. 4. In women, the gastric emptying rate of semisolid decreased linearly during the menstrual cycle. 5. The lag period and paracetamol absorption parameters were unrelated to the day of the menstrual cycle day. 6. There was no statistically significant relationship between scintigraphic and paracetamol absorption parameters. [ABSTRACT FROM AUTHOR]

1. A sparteine/mephenytoin phenotyping test was carried out in 37 Vietnamese living in Denmark. By visual inspection the urinary S/R-mephenytoin ratio appeared to show a bimodal frequency distribution. Eight putative poor metabolizers of mephenytoin, PMm (22%), had S/R-mephenytoin ratios from 0.79 to 1.12 and 29 putative extensive metabolizers of mephenytoin, EMm, had S/R-mephenytoin ratios < or = 0.55. All of the subjects were extensive metabolizers of sparteine with urinary metabolic ratios from 0.15 to 2.4. 2. The metabolism of the antimalarial prodrug proguanil was studied in 34 of the subjects after a single oral dose of 100 mg. The median 12 h urinary recoveries of the active metabolite cycloguanil and the minor metabolite 4-chlorphenylbiguanide were 5.8 and 1.9% of the dose, respectively, in 26 EMm compared with 1.6 and 0.4%, respectively, in 8 PMm (P < 0.001, Mann-Whitney U-test). 3. There was no statistically significant correlation (Spearmans rs) between any index of proguanil metabolism and the sparteine metabolic ratio.

A sensitive, selective and rapid reversed-phase high-performance liquid chromatographic method was developed for the simultaneous analysis of dapsone, monoacetyldapsone and pyrimethamine in human whole blood and plasma. The procedure involved extraction of the compounds and the internal standard, monopropionyldapsone, with tert.-butylmethyl ether under alkaline conditions. A newly marketed column, Supelcosil LC-ABZ (Supelco, 15 cm x 4.6 mm I.D.), was employed. The mobile phase, consisting of acetonitrile-methanol-phosphate buffer (2:1:7, v/v/v), was delivered at a flow-rate of 1.2 ml/min, and ultraviolet absorbance was monitored at 286 nm. The limit of determination using a 150-microliters sample was 10 ng/ml (40 nM) for dapsone and pyrimethamine and 8 ng/ml (28 nM) for monoacetyldapsone. Given that only a small amount of blood is required in this method, it could now be applied in studies involving blood level monitoring and pharmacokinetics in children on Maloprim (dapsone-pyrimethamine) prophylaxis in malaria endemic areas.

Hyponatremia occurs frequently in patients with severe infections though its cause has not been established. Recent studies have reported that in some patients with septicemia, adrenocortical insufficiency is present. To ascertain whether occurrence of hyponatremia and adrenocortical insufficiency might be related, we studied 40 patients with septicemia (11 in septic shock). A short corticotropin test was used for assessing the adrenocortical function. Though both adrenocortical failure (in 5 patients) and hyponatremia (serum sodium concentration < 125 mmol/l in 3 patients) occurred, there was no apparent relationship between the entities.

Depletion of intracellular sulfhydryl groups has been considered a main reason for the development of nitrate tolerance during sustained nitrate therapy. Although administration of N-acetyl-cysteine, a sulfhydryl donor, potentiates the acute hypotensive effect of nitroglycerin (NTG), its role in the reversal of nitrate tolerance is controversial. In the present study, we developed a conscious in vivo rat model to study nitrate tolerance and nitrate-thiol interactions. Tolerance to NTG, as assessed by the blood pressure reduction in response to i.v. NTG bolus doses, developed after 24 h of i.v. NTG infusion. After 3 and 5 days of 0.2 mg/h NTG i.v., the dose-response relations for NTG-induced reduction in blood pressure were shifted to 25-fold higher doses (P less than .01). Infusion of N-acetylcysteine (0.245, 1.225 and 6.125 mmol/kg/h for 4 h) and, to a lesser extent, equimolar doses of reduced glutathione, but not N-acetylserine, significantly potentiated the hypotensive effect of NTG, in a dose-dependent manner (P less than .05). However, complete reversal of tolerance was not achieved. This animal model of nitrate tolerance is suitable for further investigations of nitrate-thiol interactions and shares similarities with nitrate tolerance development in humans. The results suggest that sulfhydryl supplementation may enhance the hypotensive effect of NTG in a dose-dependent manner. This effect is more likely to be achieved with N-acetylcysteine than with glutathione and may be related to differences in membrane permeability.

Failures in the prophylactic effect of the antimalarial biguanide chlorproguanil (Lapudrine) may be caused by insufficient levels of its active metabolite chlorcycloguanil. Concentrations of chlorproguanil, chlorcycloguanil and a second metabolite, dichlorophenylbiguanide, in plasma, erythrocytes and urine, were followed in 13 volunteers, using a HPLC assay. In an initial study the basic kinetics were investigated after an oral dose of 2 mg kg-1. In the main study, the concentration-time curves were followed for 1 week after an oral dose of 20 or 80 mg chlorproguanil, respectively, after either a single dose or one weekly dose for 5 weeks. Higher concentrations of all three compounds were found in erythrocytes than in plasma. The active substance, chlorcycloguanil, was below the probably effective concentration in erythrocytes 24 h after 20 mg chlorproguanil and 72 h after 80 mg. The urinary recovery was about 45% of the dose and t1/2 31-44 h, both higher than previously reported. The apparent clearance was 0.52-0.82 l h-1 kg-1, which is lower than previously found. It is suggested that improved dose regimens, e.g. a higher dose given once a week, should be clinically tested on basis of these kinetic results.

A mental arithmetic test (the stressor; 15 min) significantly increased systolic and diastolic blood pressure, heart rate and plasma adrenaline by 11%, 12%, 28% and 152% respectively, with a prompt return to resting values after the test. Plasma noradrenaline and serum cortisol did not increase significantly during the 15 min of stress. Afterwards, however, the concentrations of both hormones increased, resulting in a total and significant increase averaging 19% and 23%, respectively. Plasma adrenocorticotrophic hormone (ACTH) did not rise significantly, but it was only measured before and at the end of the stressor. As a measure of parasympathetic nervous function, the beat-to-beat variation of heart rate, expressed as the mean successive square difference (MSSD), was employed. Four to 14 months later, the investigation was repeated, and resting values of all measures were found to be stable. The increments in systolic blood pressure and heart rate were significantly lower at retest. MSSD at stress, but not at rest, was significantly lower at retest. The mental arithmetic stress test as described here produces a sufficient autonomic response to make it viable for laboratory stress research. However, if repeated examinations are desired, the lower response at retest should be taken into consideration.

The release pattern, bioavailability, and kinetics of a 5-aminosalicylic acid tablet with sustained release were studied in humans. Six ileostomy patients received a single dose (500 mg). Eight and 48 h later, respectively, 58% and 65% of the dose was recovered in the ileostomy effluents, either as 5-aminosalicylic acid still retained in the preparation, free 5-aminosalicylic acid or acetyl-5-aminosalicylic acid. Fourteen healthy volunteers took 1500 mg of 5-aminosalicylic acid per day for 6 days and a steady state plasma acetyl-5-aminosalicylic acid concentration was reached on day 5 (1.1-2.9 microgram/ml). 5-Aminosalicylic acid was not detected in the plasma. At steady state, 40% of the 24-h dose was recovered from feces, and 53% from the urine. The sustained-release preparation studied provides sufficient amounts of 5-aminosalicylic acid to all parts of the gut and its curative effect in ulcerative colitis and Crohn's disease should be examined in controlled trials.

A comprehensive review, evaluating 51 randomized double-blind controlled studies, covering different aspects of epileptology, is presented. Trials were grouped according to the investigated topic and for each group an attempt was made to derive an overall conclusion. The majority of studies investigated antiepileptic drug treatments. Other topics were: psychotropic effect of antiepileptic drugs, folic acid and vitamin D administration in epilepsy, and EEG investigations. A cross-sectional analysis of items such as designs, patient sampling principles, recording of effect parameters and side effects, concomitant treatments, and statistical evaluations demonstrated that cross-over designs, investigating fixed dosage schedules, were extensively used. Less than half of these studies included a washout period between treatments, complicating the interpretation of the obtained results. The vast majority of studies involved only chronic patients; and marked heterogeneity in patient selection with respect to age, seizure type, and mental status, and severity of epilepsy was observed. Classifications of seizures varied between the studies. The most prominent effect parameter was seizure frequency. The use of heterogeneous patient samples frequently necessitated equalization of widely different seizure types in order to perform statistical analyses. The mean duration of trials was 6 months, precluding evaluation of chronic toxicity. The majority of studies recorded side effects, but data collection was rather unsystematic and statistical evaluation was seldom applied. Most studies were add-on trials, and since concomitant treatment was frequently changed during the investigations, it was difficult to evaluate the influence of this variable. A correlation analysis across trials demonstrated, among other things, that the common assumption that short controlled trials provide too optimistic results, could not be substantiated. This survey provides no firm indication of which drug is more suitable for which seizure type.

The effect of 3 antimalarial quinoline derivatives, chloroquine, mefloquine and quinine on human blood mononuclear cells in vitro was studied. High concentrations profoundly suppressed the proliferation of mitogen- and antigen-stimulated lymphocytes, as indicated by decreased 14C-thymidine incorporation. On a weight base, the most potent drug was mefloquine. At clinically relevant doses, chloroquine and mefloquine did not affect the response to malaria antigens, but mefloquine decreased the response to phytohaemagglutinin; quinine suppressed the response to all mitogens (with the exception of pokeweed mitogen) and antigens studied, including P. falciparum merozoites. The drugs' potential adverse effect on the immune system is discussed.

Eighteen controlled studies investigating the psychotropic effect of anti-epileptic drugs are critically reviewed. The neurochemical evidence for existence of psychotropic properties is still speculative. It seems questionable on the basis of this survey that there exist genuine psychotropic effects of antiepileptic drugs, which are not related to antiepileptic efficacy and/or differences in toxicity.

In 1982, 2 of 14 Plasmodium falciparum infections acquired in East Africa and diagnosed in Copenhagen were resistant to treatment with sulfadoxine plus pyrimethamine (Fansidar), while in 1983, 6 of 18 were so. The in vivo tests were supplemented by determinations of drug concentrations in serum, and 4 isolates from in vivo-sensitive cases and 6 from in vivo-resistant cases were selected for in vivo tests. These were performed in ordinary RPMI 1640 medium and in a medium with physiological p-aminobenzoic acid and folic acid concentrations. Pharmacokinetic aberrations were found to be of possible importance in only 2 of the in vivo-resistant cases. In vitro susceptibility to sulfadoxine was found to be uniformly low in all isolates. Testing with a combination of sulfadoxine and pyrimethamine in the medium with physiological concentrations of cofactors probably reflects the in vivo situation most accurately, but in all but 1 of the isolates studied in vitro the in vivo susceptibility to Fansidar would be predicted by in vitro susceptibility to pyrimethamine in either medium. The concentration of p-aminobenzoic acid in serum, quantitated by high performance liquid chromatography, was found to be subject to wide variation, and this may have implications for in vitro testing.

Arterial and venous concentrations of phenobarbital, phenytoin, clonazepam, and diazepam were followed for 12 hr after a rapid intravenous injection. Initial blood samples were collected at intervals of only 5 sec. The arterial curves were initially much higher and steeper than the venous. For all four drugs the arterial curves could be described as triexponential functions. The initial part of the arterial curves were used in determining the initial supply to and uptake rate in the organs.

The effects of phenobarbital (PB) and carbamazepine (CZ) on the ethanol withdrawal reaction in the rat were investigated in a blind study including an untreated control group. Physical ethanol dependence was established by intragastric intubation during a 4-day period. Both the degree of intoxication and the withdrawal reaction were assessed by standardised assessment instruments. Treatment with PB (40-60 mg/kg) and CZ (80-120 mg/kg) was initiated 10 h after the last ethanol dose and continued during the first 24 h of withdrawal. Serum concentrations of the drugs were measured. Both PB and CZ significantly reduced the ethanol withdrawal reaction compared to controls, and PB was significantly more effective than CZ. The degree of drug intoxication signs assessed by the same rating scale as the degree of ethanol intoxication indicated that maximum tolerable drug doses were used. PB probably exerts its treatment effect through the mechanism of cross dependence with ethanol, while CZ may exert a more specific effect on limbic structures responsible for central nervous system excitability.

Clinical effects at three different serum levels of sodium valproate (VPA) were compared in a triple-blind, multiple crossover trial comprising 13 epileptic inpatients. Patients were selected regardless of seizure type, and all were in concomitant antiepileptic treatment, which was kept constant throughout the study. A significant relationship between the decrease in number of seizures and increasing VPA serum level was demonstrated. The relationship between VPA dose and serum level was curvilinear. Statistical evaluation of patients by seizure type in relation to clinical effect of VPA was only possible for secondary generalized seizures. Between phenytoin, phenobarbital, and carbamazepine and the different VPA serum levels no interactions could be demonstrated. Recorded side effects were always mild and transient. No obvious correlation between side effects and VPA serum level was established.

The pharmacokinetics of proguanil and its metabolites cycloguanil and p-chlorophenylbiguanide were studied in five healthy volunteers taking 200 mg orally for 14 days. A highly sensitive and specific high-performance liquid chromatographic assay was applied, clearly identifying all three compounds in plasma extracts as separate peaks. In four subjects peak plasma concentrations of proguanil (500 to 600 nmol/l) were reached after two to three hours, while cycloguanil and p-chlorophenylbiguanide showed a plateau after three and six hours, respectively. In the fifth subject peak concentrations of proguanil and cycloguanil appeared after seven hours. Trough concentrations (pre-dose in the morning) of proguanil and cycloguanil were about 200 and 100 nmol/l, respectively. Mean half-life of proguanil was estimated to approximately 20 h. The active metabolite cycloguanil constituted 30% of the total plasma drug concentration. The concentration of proguanil was higher in erythrocytes than in plasma, while that of cycloguanil was lower. Relevant clinical studies correlating plasma concentrations to the suppressive activity against malaria will be possible to perform based on the applied method and presented kinetic data.

Flunitrazepam (Rohypnol) 2.0 mg was given as a single dose by the oral or sublingual route to ten volunteers using a cross-over design. Plasma concentrations of the drug were measured by gas-liquid chromatography for up to 6 hours after administration. The highest mean concentration occurred 45 min after administration irrespective of route. No significant differences were found between the two treatments at any time. Since the sublingual route compares favorably with other routes of administration, these findings suggest that sublingual flunitrazepam is valuable for premedication.

A mixture containing 3 g of boric acid and 300 mg of cinchocaine chloride prescribed due to painful dental protrusion was accidentally ingested by a 12-month-old girl. She developed violent vomiting and coughing. Irritability, tremor, seizures and a delirious reaction. She was treated with diazepam, intubated, sedated and ventilated. Her diuresis was stimulated with furosemide and fluid. Within the first 24 h she was treated with haemodialysis twice on femoral catheters. Her renal function was unaffected. In two days she fully recovered. The maximum measured levels of boric acid and cinchocaine chloride approximately 6 h after ingestion were 26 micrograms/ml and 71 ng/ml respectively. The plasma half-life of boric acid was 7.0 h and decreased to 3.6 and 4.4 h during the two haemodialyses. The total body clearance of boric acid increased correspondingly from 21 ml/min to 41 and 34 ml/min. The in vitro clearance of boric acid of the dialyser was later determined to be 18 ml/min. It is concluded that haemodialysis is valuable in the treatment of boric acid intoxication because it increases the elimination of the drug even in patients without any sign of renal toxicity.

We measured the fluctuations in plasma pyridostigmine concentration from day to day on 3 consecutive days and hour to hour during 1 day in 11 myasthenic patients, by studying their usual dosage regime. Plasma pyridostigmine was measured by gas chromatography/mass spectrometry. The intraindividual day-to-day variation in plasma pyridostigmine levels was small. A highly significant relationship was found between the oral pyridostigmine dose and the area under the plasma concentration/time curve. The bioavailability of oral pyridostigmine was 3.6%, estimated by replacing one dose with an intravenous dose amounting to 1/30 of the oral dose. The relatively stable kinetic behavior of pyridostigmine is in contrast to the interpatient variability in dose requirement, indicating that monitoring of plasma pyridostigmine levels should be reserved for special cases.

The effect of chloroquine on human blood mononuclear cells was studied. High concentrations of chloroquine in vitro profoundly suppressed the proliferation of mitogen- and antigen-stimulated cells, as indicated by decreased 14C-thymidine incorporation. Lower concentrations of chloroquine increased the response to pokeweed mitogen. The response to concanavalin A and to various antigens was suppressed, especially the response to large particulate antigens. Oral intake of 300 mg of chloroquine base/week did not affect the lymphocyte proliferative responses. 600 mg of base/week decreased the response to large particulate antigens; the response to small antigens was not affected. The mode of action of chloroquine and the possible consequences of the findings for dosage of chloroquine when used for malaria prophylaxis is discussed.

Plasma concentration-time curves of pethidine and norpethidine were studied in 25 children allocated after operation to three groups to receive pethidine 1 mg kg-1 i.v., i.m. or rectally. Peak concentrations occurred after 5 +/- 1, 10 +/- 2, and 60 +/- 10 min, respectively, while the maximum concentrations amounted to 2800 +/- 462, 1609 +/- 367 and 531 +/- 179 nmol litre-1, respectively. The area under the curve (0-240 min) was similarly reduced in the group with rectal administration (P less than 0.05). Compared with the i.v. data, approximately 40% systemic availability occurred after rectal application, although considerable individual variation was noted. In one child very high plasma concentrations were observed after rectal administration, possibly as a result of redistribution/recirculation phenomena. The average results are similar to those obtained when other opioids are given rectally.

Phenytoin (PHT) disposition was studied in Greenland Eskimos and in Caucasians (Danes) in order to reveal possible ethnic differences in the pharmacokinetics. PHT was administered i.v. as a single, subsaturation does to healthy adult volunteers and determined in plasma by thin-layer chromatography. Based on the time/concentration curves obtained, the half-life, volume of distribution, the area under the curve, and the total body clearance were calculated. The protein binding was measured by ultrafiltration. Three groups were studied: Group 1 were Eskimos living in East Greenland, group 2 were Eskimos living in Denmark, and group 3 were comparable Caucasians, as a reference group. The total body clearance of PHT per kg body weight was almost twice as high in Eskimos, irrespective of place of living or sex, compared with the Danish group. The volume of distribution was larger in the Eskimo group, but the protein binding did not differ. The reason for the differences in clearance and volume of distribution between the two ethnic groups is not clear, but the results emphasize that ethnic differences in pharmacokinetics can be of significance. The total body clearance values for PHT in Caucasians found in the present study agreed with results from other European investigations that used the same dose, but different analytical assays.

The effects of ketoconazole (Kcnz) on cyclosporine A (CyA) serum levels and CyA-nephrotoxicity were studied. To rats later anesthetized with pentobarbital sodium, CyA 12.5 and Kcnz 20 mg/kg/day (n = 20), or CyA 12.5 mg/kg and Kcnz-vehicle (n = 21), was dosed. To rats anesthetized with etomidate (n = 14), CyA 12.5 mg/kg and Kcnz-carrier was dosed. S-CyA was monitored during 14 days, and then the rats were investigated with clearance (C) methods (inulin [(in), lithium (Li)], sodium, and potassium), and liver (L) and kidney (K) CyA was measured. Kcnz increased S-CyA, L-CyA and K-CyA (+50 -80%). There were significant (p less than 0.05) correlations between S- and L- or K-CyA. Kcnz increased CyA nephrotoxicity: Mean Cin was 1.012 ml/min/gKW (kidney weight) after CyA treatment (a subnormal value), but decreased to 0.556 ml/min/gKW in the group also given Kcnz (p less than 0.001). CLi decreased from 0.135 to 0.048 ml/min/gKW (p less than 0.001), and absolute proximal tubular reabsorption decreased from 0.877 to 0.508 ml/min/gKW (p less than 0.001), while the fractional reabsorption in the proximal tubule (FPR), expressed as a percentage of GFR, increased from 86.9 to 91.6% (p less than 0.005). Thus, after Kcnz treatment to rats given CyA 12.5 mg/kg/day, their renal function was indistinguishable from that in rats given CyA 25 mg/kg/day.(ABSTRACT TRUNCATED AT 250 WORDS)

In eight epileptic patients receiving chronic antiepileptic treatment, a study of the excretion in sweat of phenytoin, phenobarbitone and carbamazepine was performed. All three drugs were found to be present in sweat. Phenytoin sweat concentration was found to correspond to the free fraction in plasma and to be independent of sweat flow. Phenobarbitone sweat concentration was found to increase with increasing sweat flow. Regarding drug level monitoring it is proposed that under changing climatic conditions the phenomenon may be of clinical significance.