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We investigated the efficacy and adverse effects of aminophylline and caffeine citrate in 180 premature neonates for 10 days and nights. Aminophylline (n = 98) and caffeine citrate (n = 82) were equally effective in preventing apnea and bradycardia. The caffeine citrate group had a lower median heart rate on day 3, fewer neonates with tachycardia and a smaller amount of gastric aspirate on day 7. The need for mononasal continuous positive airway pressure and respirator therapy was similar in both groups. We conclude that caffeine citrate is the drug of choice for apnea and bradycardia prophylaxis in premature neonates with a gestational age < or = 33 full weeks.

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In this study, we have measured the plasma concentration of lignocaine and its metabolite, monoethylglycinxylidin, in 19 premature neonates (gestational age < or = 33 weeks) when lignocaine gel was used for lubrication of an intranasal tube (during continuous positive airway pressure treatment) or an endotracheal tube (for intubation). We did not find any correlation between plasma concentration of lignocaine or monoethylglycinxylidin and weight of the infant (range 795-2530 g). None of the neonates had toxic levels of lignocaine. One neonate had an exceptionally high but not toxic plasma level of monoethylglycinxylidin. However, this neonate had been treated for severe seizures with an iv infusion of lignocaine up to 13 h before the study. In conclusion, we found it safe to use moderate amounts of lignocaine (i.e. 0.3 ml/kg of lignocaine gel 20 mg/ml) for lubricating both intranasal and endotracheal tubes.

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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.

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To test the hypothesis that halothane hepatitis is caused by a combination of altered drug metabolism and an immunoallergic disposition, the metabolism of antipyrine, metronidazole, sparteine, phenytoin, and racemic R- and S-mephenytoin was investigated in seven subjects with previous halothane hepatitis. The HLA tissue types and the complement C3 phenotypes were also determined. The metabolism of antipyrine and metronidazole was within normal range in all subjects, and they were all fast or extensive metabolizers of sparteine, mephenytoin, and phenytoin. HLA tissue types were unremarkable. Five of the seven subjects had complement C3 phenotypes F or FS. In the general population phenotype S is the most common, but the difference in complement C3 phenotypes is not statistically significant (p = 0.07). We conclude, although in a limited number of patients, that subjects with previous halothane hepatitis do not appear to be different from controls with regard to drug metabolism and HLA tissue type. The possibility of a higher frequency of complement C3 phenotype F and FS needs further investigation.

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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.

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Myocardial stunning, defined as a reversible decrease in contractility after ischemia and reperfusion, may be a manifestation of reperfusion injury caused by free oxygen radical damage. The aim of this study was to test the hypothesis that pretreatment with coenzyme Q10 (ubiquinone), believed to act as a free radical scavenger, reduces myocardial stunning in a porcine model. Twelve swine were randomized to receive either oral supplementation with coenzyme Q10 or placebo for 20 days. A normothermic open-chest model was used with short occlusion (8 min) of the distal left descending coronary artery followed by reperfusion. Regional contractile function was measured with epicardial Doppler crystals in ischemic and nonischemic segments by measuring thickening fraction of the left ventricular wall during systole. Stunning time was defined as the elapsed time of reduced contractility until return to baseline. Coenzyme Q10 concentrations were measured in blood and homogenized myocardial tissue by high performance liquid chromatography. Plasma levels of reduced coenzyme Q10 (ubiquinol) were higher in swine pretreated with the experimental medication as compared to placebo (mean 0.45 mg/l versus 0.11 mg/l, respectively). Myocardial tissue concentrations, however, did not show any changes (mean 0.79 micrograms/mg dry weight versus 0.74 micrograms/mg). Stunning time was significantly reduced in coenzyme Q10 pretreated animals (13.7 +/- 7.7 min versus 32.8 +/- 3.1 min, P < 0.01). In conclusion, chronic pretreatment with coenzyme Q10 protects ischemic myocardium in an open-chest swine model. The beneficial effect of coenzyme Q10 on myocardial stunning may be due to protection from free radical mediated reperfusion injury. This protective effect seems to be generated by a humoral rather than intracellular mechanism.

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Functional abdominal pain--that is, pain without demonstrable organic abnormalities--has often been associated with psychologic stress. The aim of the present study was to investigate whether sympathetic nervous system response to laboratory stress and basal parasympathetic neural activity were disturbed in 22 patients with functional abdominal pain (functional group) as compared with 14 healthy controls (healthy group) and 26 patients with organic abdominal pain (organic group) due to duodenal ulcer (DU), gallstones, or urinary tract calculi. Plasma adrenocorticotrophic hormone (ACTH) and serum cortisol measurements were included, to assess the pituitary-adrenocortical axis. Heart rate, systolic blood pressure, and plasma adrenaline increased significantly in all groups in response to a stress test (mental arithmetic). Plasma noradrenaline increased in the DU patients only, and plasma ACTH and serum cortisol did not increase at all in any of the groups. As a measure of parasympathetic neural activity, independent of sympathetic neural activity, the beat-to-beat variation of the heart rate was calculated. The functional patients had a significantly higher beat-to-beat variation expressed as the mean square successive differences of the R-R intervals (MSSD), indicating a higher basal parasympathetic neural activity (mean MSSD +/- SEM = 64 +/- 6 msec in the functional group, 46 +/- 6 msec in the healthy group, and 49 +/- 6 msec in the organic group; P = 0.03). A reduced sympathetic neural response as indicated by a lesser stress-induced increment in heart rate, was seen in both patient groups (functional, 13 +/- 2 beats/min; organic, 10 +/- 2 beats/min) as compared with the healthy group (19 +/- 2 beats/min; P = 0.003).(ABSTRACT TRUNCATED AT 250 WORDS)

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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.

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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.

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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.

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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.

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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.

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The efficacy of the lytic cocktail (1 ml contains pethidine 28 mg, promethazine 7 mg, chlorpromazine 7 mg) administered intramuscularly or rectally as premedication was studied in 51 children aged 1-12 years who had minor elective otological surgery. One group received 0.05 ml/kg intramuscularly (maximum dose 2.0 ml) and the other 0.07 ml/kg per rectum (maximum dose 2.8 ml). Most were satisfactorily sedated before operation, but after operation the rectally premedicated children were less sedated, which was in agreement with lower plasma pethidine concentrations in this group. The rectal dose should be increased if prolonged postoperative sedation is desireable.

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Seventy-nine French residents in Dar-es-Salaam, Tanzania, on 3 chemoprophylactic regimens, were included in a prospective study for a mean time of 10.8 +/- 3 months. No malaria attack was observed in the group (n = 32) taking chlorproguanil and chloroquine for chemoprophylaxis. Two attacks were reported in the group (n = 29) using chlorproguanil alone and 5 attacks in the group (n = 20) that was not taking antimalarial chemoprophylaxis. The blood concentration of chlorproguanil and chlorcycloguanil, the active metabolite, were measured, 3 hours (II3), 3 days (D3), and 7 days (D7) after the weekly dose. The urine concentration was measured at D7. The prophylaxis failure with chlorproguanil can be explained either by irregular use of the drug, or insufficiently lasting plasma concentration of chlorcyloguanil, or existence of parasite resistance to dihydrofolate reductase inhibitors.

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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.

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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.

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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.

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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.

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