Showing papers in "European Journal of Clinical Pharmacology in 1987"
TL;DR: Evidence of positive effect of calcitonin was derived from the reduced incidence of new fractures occurring during the observation period, and a significant reduction in back pain was a further consequence of the hormone therapy.
Abstract: There is uncertainty about the best treatment for steroid-induced osteoporosis. Thirty-six patients with steroid-dependent, chronic obstructive lung disease and associated steroid osteoporosis have been studied, of whom 18 were treated with salmon calcitonin and the other 18 served as controls. Treatment lasted for 6 months and consisted of 100 I.U. s.c. every other day. In the controls there were significant decrements of 1.4% and 3.5%, respectively, in cortical and cortical and trabecular bone mineral content, whereas in subjects on calcitonin there were increments of 2.6% and 2.7%, respectively. Additional evidence of positive effect of calcitonin was derived from the reduced incidence of new fractures occurring during the observation period. A significant reduction in back pain was a further consequence of the hormone therapy.
141 citations
TL;DR: The results suggest that in man glucuronidation of paracetamol is inducible both by phenobarbital-and 3-methylcholanthrene-type inducers.
Abstract: A simple, noninvasive procedure was developed to monitor glucuronidation and sulphation in patients using paracetamol as the test drug. Urinary paracetamol and its metabolites were determined by UV absorption and electrochemical detection after separation by HPLC. The metabolite to paracetamol ratio (M/P) was used as an approximation of the partial clearance due to metabolite formation. In 14 healthy volunteers, all nonsmokers without medication, M/P was 18 +/- 5 for glucuronides and 12 +/- 4 for sulphate esters. The test was validated in patients treated with enzyme inducers. In 10 patients with epilepsy given phenytoin 0.3 g/day, and in 10 patients with tuberculosis treated with rifampicin 0.6 g/day, the M/P value for glucuronidation was significantly increased to 41 +/- 11 and 35 +/- 7, respectively. In contrast, M/P values for sulphation were not significantly different from untreated controls. In 9 heavy smokers (about 40 cigarettes/day) M/P values for glucuronidation were also significantly increased to 33 +/- 11. However, in 4 moderate smokers (about 10 cigarettes/day) no significant increase was found. The results suggest that in man glucuronidation of paracetamol is inducible both by phenobarbital- and 3-methylcholanthrene-type inducers. Monitoring the ratios of various urinary paracetamol conjugates/paracetamol may be useful as a new tool for the evaluation of factors determining glucuronide and sulphate ester formation in man.
94 citations
TL;DR: The metabolism of morphine in patients with kidney disease is not significantly impaired and the clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
Abstract: The kinetics of morphine and its glucuronidated metabolites were investigated in seven patients with advanced renal failure. The terminal elimination half life of morphine varied between 1.5 and 4.0 h (mean 2.4 h), the volume of distribution between 2.5 and 6.3 l·kg−1 (mean 4.4 l·kg−1) and the total plasma clearance between 13.3 and 31.3 l·min−1·kg−1 (mean 21.1 l·kg−1). There were no statistically significant differences between the pharmacokinetic data in the uraemic patients and in a control group of cancer patients with normal kidney function. The concentrations of the glucuronidated metabolites rapidly rose to levels above those of morphine. The elimination half-life of M3G varied between 14.5 and 118.8 h (mean 49.6 h) in the renal failure patients, which is distinctly different from the 2.4 to 6.7 h (mean 4.0 h) found in patients with normal kidney function. There was a significant correlation between the half-life of M3G and renal function estimated as serum urea. Thus, the metabolism of morphine in patients with kidney disease is not significantly impaired. The clinical importance of the high concentrations of glucuronides in uraemic patients is not known.
86 citations
TL;DR: The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial and the kinetics after the 25 and 50 mg capsules were consistent with dose linearity.
Abstract: The pharmacokinetics and absolute bioavailability of carvedilol have been studied in 20 male healthy volunteers in a randomised 4-period, cross-over trial. Carvedilol 12,5 mg was given i.v., 50 mg was administered p.o. as a suspension and 25 and 50 mg were given in a capsule formulation. For the 50 mg capsule Cmax was 66 µg·l−1, tmax 1.2 h, t1/2 6.4 h. The t1/2 after i.v. administration was 2.4 h, CL 589 ml/min and Vz 132 l.
82 citations
TL;DR: Loratadine is a promising antihistamine for individuals involved in skilled activity and the anticipated single daily dose of 10 mg is unlikely to impair performance.
Abstract: Effects of loratadine (10, 20 and 40 mg) on visuo-motor coordination, dynamic visual acuity, short-term memory, digit symbol substitution, and on subjective assessments of mood were tested before, and 0.5, 1.5, 3.5 and 5.5 h after ingestion by 6 healthy female adults. There were no effects of 10 or 20 mg loratadine. With 40 mg loratadine the number of substitutions on the digit symbol test was reduced 5.5 h after ingestion, and on dynamic visual acuity response time was increased at 3.5 h and the number of responses missed was increased at 5.5 h. Triprolidine (10 mg) which was used as active control impaired performance on all the tasks and impaired performance was observed at all times after ingestion. Loratadine is a promising antihistamine for individuals involved in skilled activity. The anticipated single daily dose of 10 mg is unlikely to impair performance.
75 citations
TL;DR: It is demonstrated that both obesity and exercise have modified the pharmacokinetics of caffeine in 6 caffeine naive, untrained, nonsmoking, college males.
Abstract: The effects of obesity, exercise, and the interaction of obesity and exercise were examined in 6 caffeine naive, untrained, nonsmoking, college males (3 lean (LV), 3 obese (OV)). Each subject received caffeine (oral, 5.83 mg·kg−1 lean body weight) or placebo (50 mg citrate) prior to 3 h of seated rest and prior to 90 min of treadmill walking (40% of their maximal aerobic power) followed by 90 min of seated recovery. Serum samples were collected at various times and analyzed for caffeine by HPLC. Pharmacokinetic analysis indicated that at rest, OV had a significantly higher absorption rate constant (Ka 0.0757 vs. 0.0397 min−1), lower elimination rate constant (Ke 0.0027 vs. 0.0045 min−1), and longer serum half-life (t1/2 4.37 vs. 2.59 h) in comparison to LV. In exercise, as well as at rest LV and OV had a large difference in the volume of distribution (43.2 vs. 101. 1) (rest, 54.1 vs. 103.1). Exercise consistently resulted in a decrease in the maximal serum concentration of caffeine and the area under the curve in OV while having no consistent effect on LV. The interactive effects of obesity and exercise could not be dissociated. However, these results demonstrate that both obesity and exercise have modified the pharmacokinetics of caffeine.
74 citations
TL;DR: The high clearance and short half-life of budesonide in children are advantageous in reducing the risk of possible systemic side-effects of prophylactic treatment of asthma in childhood.
Abstract: The pharmacokinetics of the glucocorticoid budesonide was studied in 6 children with asthma after i.v. injection of 0.5 mg and oral inhalation of 1 mg as an aerosol. Budesonide is a 1:1 mixture of the epimers 22 S and 22 R, which were assayed separately by HPLC combined with RIA. All pharmacokinetic parameters of the epimers differed except the half-life of about 1.5 h. It was significantly shorter than that reported in adults. Plasma clearance averaged 103 l · h−1 for epimer 22 R and 74 l · h−1 for epimer 22 S; calculated per kg body weight these values were about 50% higher than in adults. The difference was about 40% when calculated per m2 of body surface area. Since budesonide is a high-clearance drug, the data indicate higher liver blood flow · kg−1 body weight and m2 of body surface area in children. The systemic availability of the aerosol was approximately 30% of nominal dose, i.e. the same as in adults. The high clearance and short half-life of budesonide in children are advantageous in reducing the risk of possible systemic side-effects of prophylactic treatment of asthma in childhood.
71 citations
TL;DR: New methods to measure inducibility in man involve new lymphocyte bioassays and mRNA determinations, while in vivo biotransformation studies of caffeine allow estimates of the state of induction of members of one of the cytochrome families.
Abstract: Studies in rodents indicate that the cytochrome P-450 system consists of a superfamily of heme proteins, produced by clusters of structural genes on different chromosomes. Equivalent P-450s of different species show more homologies than members of different P-450 families within a species. The Ah receptor serves the induction of members of one of the cytochrome families. The human structural gene for the methylcholanthrene-inducible P1-450 is located on Chromosome 15. This gene has been completely sequenced. The human Ah receptor is also measurable. New methods to measure inducibility in man involve new lymphocyte bioassays and mRNA determinations, while in vivo biotransformation studies of caffeine allow estimates of the state of induction. Structural genes for phenobarbital-inducible cytochromes have been localized to Chromosome 19. The deficiency of biotransformation of debrisoquine and sparteine continues to be explored intensely. Linkage studies indicate the gene for the variable cytochrome P-450 to be located on Chromosome 22. The deficiency is more likely due to structural variation than absence of the cytochrome. Inhibiting drugs can mimic the genetic defect. Many pharmacological and toxicological consequences of the deficiency have been defined. The main characteristics of the genetic deficiencies affecting the metabolisms of mephenytoin, phenytoin, tolbutamide, nifedipine and of methyl cysteine were outlined briefly.
71 citations
TL;DR: Body fat and stature may account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.
Abstract: We have compared diazepam pharmacokinetics in 16 Chinese and 18 white Caucasian healthy male volunteers, resident in Hong Kong and have correlated them with physical attributes. Serum concentrations of diazepam and desmethyldiazepam were measured in venous blood by an enzyme-linked immunoassay (0-3 h samples) and HPLC (3-72 h samples). Pharmacokinetic parameters were derived assuming a two compartment model, distribution phase less than 6 h, and 100% oral systemic availability. Compared with the Chinese the white Caucasians were older, heavier, taller, and fatter, as judged by skin fold thickness (SFT) and total body weight to 'Ideal' body weight (TBW/IBW) ratio; respective mean differences being 16%, 27%, 4%, 26%, and 15% (p less than 0.05). Mean diazepam apparent volume of distribution (V) and V/IBW were larger in the white Caucasians (52% & 39% respectively, p = 0.002). SFT and TBW/IBW ratio yielded the best correlations with V, V/TBW and V/IBW (0.50-0.75, p less than 0.05). Obesity indices contributed most to the overall regressions (R2 up to 0.52), and for V there was a further small effect (2%, partial F test) due to ethnic group, possibly reflecting stature. Mean peak diazepam concentration (Cmax) was similar in both ethnic groups. Time to Cmax (tmax) was more often prolonged in the Chinese (chi 2 test, p = 0.01). Body fat and stature may thus account for these inter-ethnic differences in the apparent volume of distribution of diazepam, a highly lipid-soluble drug.
71 citations
TL;DR: The results suggest that yohimbine is eliminated primarily through metabolism since the rapid plasma clearance of yohimine was not the result of renal elimination or sequestration by RBC.
Abstract: The kinetic disposition of yohimbine was examined in eight young male subjects following a single oral dose of 10 mg yohimbine hydrochloride. The drug was rapidly absorbed (absorption half-time 0.17±0.11 h) and rapidly eliminated from the plasma (elimination half-life 0.60±0.26 h).
68 citations
TL;DR: It is demonstrated that beneficial effects, already well-recognized after chronic administration of 20 mg three times a day, also occur after a single administration equivalent to the normal daily dose of 60 mg trimetazidine.
Abstract: A single dose of 60 mg trimetazidine (the normal daily dose) improved exercise capacity in angina pectoris, as reflected by an increase in the duration of exercise, total work performed, and improvement in ECG signs of ischaemia. All these effects occurred without any detectable chronotropic or vasomotor effect. The importance of this study is to demonstrate that these beneficial effects, already well-recognized after chronic administration of 20 mg three times a day, also occur after a single administration equivalent to the normal daily dose.
TL;DR: The authors' studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion, and TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.
Abstract: The effect of hypothermia on the disposition of fentanyl was evaluated in 18 children undergoing corrective cardiac surgery. They received a bolus of fentanyl followed by a continuous infusion which was stopped when cardiopulmonary bypass was established and profound hypothermia was achieved (18 °C–25 °C). Fentanyl plasma concentration remained essentially unchanged during hypothermia (6.45 ng/ml 5 min into hypothermia and 5.26 ng/ml 100–140 min later; p>0.1). In subsequent experiments, the effect of hypothermia on the pharmacokinetics of fentanyl was studied in 4 piglets serving as their own controls. Both distribution volume (Vz) and total body clearance (CL) were significantly smaller during hypothermia. Our studies indicate that being a drug with a large distribution volume and a high hepatic extraction ratio, both CL and Vz are significantly reduced by hypothermia-induced hypoperfusion. In addition, TBC is influenced by the temperature-dependent hepatic metabolism of fentanyl.
TL;DR: Patients receiving treatment with carbamazepine, phenytoin or sodium valproate alone all performed similarly to each other and to those patients taking anticonvulsant polypharmacy.
Abstract: Using a battery of simple tests, psychomotor performance was assessed in 11 healthy subjects, 14 untreated epileptic patients and 66 epileptics on chronic anticonvulsant medication. Significant differences were found between controls and untreated patients for choice reaction time, card sorting and Simple Simon memory game. Treated patients performed less well than both untreated epileptics and controls in choice reaction time (p<0.05; p<0.001), card sorting (p<0.01; p<0.001), Simple Simon (p<0.05; p<0.001) and finger tapping (p<0.05; p<0.001). Patients with centrencephalic epilepsy were slower than those with discrete focal EEG abnormalities in reaction time and card sorting. Patients receiving treatment with carbamazepine, phenytoin or sodium valproate alone all performed similarly to each other and to those patients taking anticonvulsant polypharmacy. Monotherapy patients with potentially “toxic” plasma anticonvulsant concentrations did no worse than those within or below the “therapeutic” range. Both the disease and its treatment reduce psychomotor performance. All major anticonvulsants appear to cause a similar degree of impairment across a wide range of concentrations. The effect of chronic anticonvulsant medication on “quality of life” should not be neglected in the pursuit of perfect seizure control.
TL;DR: Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered, which led to unchanged or even to elevated plasma levels of the metabolites.
Abstract: The mechanism of the theophylline-enoxacin interaction has been studied in six healthy subjects. Theophylline 250 mg was administered p.o., twice daily for 11 days in a sustained release dosage form. On the 4th day of treatment, blood samples were taken every 2 h and urine was collected over 1 dose interval. From Days 5 to 11 coated tablets of enoxacin 400 mg b.i.d. were coadministered. On Day 11 blood and urine were collected as on Day 4. The mean plasma theophylline concentration rose from 4.4 to 15.1 mg/l, corresponding to a 73.6% reduction in total clearance. The urinary excretion of unchanged theophylline increased from 12.7 to 35.3%, whereas the production of metabolites was reduced (1-demethylation 81.4%; 3-demethylation 83.1%, 8-hydroxylation 74.6%). The results indicate that the theophylline-enoxacin interaction may be due to inhibition of the cytochrome P-450 isozymes responsible for theophylline metabolism. Unexpectedly, the renal clearance of theophylline metabolites was found to be drastically reduced when enoxacin was coadministered. This led to unchanged or even to elevated plasma levels of the metabolites. The mechanism of this interaction is still to be elucidated, but it may be due to competition for renal tubular secretion.
TL;DR: Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the Pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantomer, possibly due to metabolic inhibition of this species.
Abstract: Stereochemical aspects of the potential interaction between the oral anticoagulant warfarin and the H2-antagonists, cimetidine and ranitidine, were investigated. A single 25 mg oral dose of racemic warfarin was administered on Day 4 of a randomised 9-day multiple dosing regimen of either cimetidine (800 mg o.d.) ranitidine (300 mg o.d.) or placebo. The degree of anticoagulation produced by warfarin was quantificated by the determination of both the prothrombin and Factor VII clotting times. Ranitidine had no effect on the pharmacodynamics of warfarin or the pharmacokinetics of the individual warfarin enantiomers. Cimetidine whilst producing no statistically significant change in the pharmacodynamics of warfarin or in the pharmacokinetics of the pharmacologically more potent (S) enantiomer, did produce a statistically significant decrease in the clearance of the (R) enantiomer, possibly due to metabolic inhibition of this species.
TL;DR: Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in dose-independent half-life of 12.2 h and mean urinary recovery and renal clearance were almost identical with the values after iv administration.
Abstract: Cotinine, the main metabolite of nicotine, was administered intravenously to healthy male non-smoking volunteers in doses of 5, 10 and 20 mg, and orally in doses of 10 and 20 mg.
TL;DR: While statistically significant differences in lag time and time to peak concentration were noted among the various oral preparations, the drug is rapidly absorbed in all three dosage forms and the observed differences are unlikely to be of clinical significance.
Abstract: Salbutamol was administered to sixteen healthy male volunteers intravenously and by mouth in liquid, tablet, and capsule form using a Latin-Squares design.
TL;DR: Single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin during up to three consecutive cycles of cancer chemotherapy are given.
Abstract: We have given single high doses of dexamethasone phosphate by intravenous infusion as an antiemetic to 15 cancer patients receiving regimens containing cisplatin and/or doxorubicin. The patients received graded doses of dexamethasone phosphate, in the range 40–200 mg, dependent upon nausea and vomiting scores, during up to three consecutive cycles of cancer chemotherapy. Plasma and urine concentrations of dexamethasone (dexamethasone alcohol) were measured by HPLC. The plasma concentration-time data were described by an open two-compartment model. The pharmacokinetic variables were independent of the dose of dexamethasone over the range studied. The terminal half-time was 4.0±0.4 h and the total body clearance was 3.5±0.4 ml·min−1·kg−1. The volume of the central compartment and the total apparent volume of distribution were 0.23±0.03 and 1.0±0.1 l·kg−1 respectively. Approximately 8% of the dose was excreted into the urine as dexamethasone.
TL;DR: The in vitro findings were confirmed by a pharmacokinetic study in volunteers given [14C] teicoplanin i.v., in whom the fraction of teioplanin bound to serum protein ranged between 87.6 and 90.8%.
Abstract: The interaction between the main components of the new glycopeptide antibiotic teicoplanin, A2–2, A2–3, A2–4, A2–5 and A3–1, and human serum albumin has been studied in vitro by equilibrium dialysis (pH 7.4, 37°C). From Scatchard analysis of the data, the calculated association constants (Ka) were: A2–2, 2.47×104, A2–3, 2.86×104, A2–4, 2.95×104 and A2–5, 3.87×104 mol·l−1. The number of binding sites per albumin molecule ranged between 1.23 to 1.31. A3–1 had a lower affinity with a Ka of about 5×103 mol·l−1. Extrapolated to the in vivo situation, the data suggested that about 90–95% of A2 components will be bound to serum albumin, and about 68–72% of A3–1. The in vitro findings were confirmed by a pharmacokinetic study in volunteers given [14C] teicoplanin i.v., in whom the fraction of teicoplanin bound to serum protein ranged between 87.6 and 90.8%.
TL;DR: Three schedules (alternate days, weekly, daily) of the conventional prophylactic dose of 10 mg/kg per week were compared in six other healthy subjects and there were significant differences in the plasma monodesethylamodiaquine levels between the three schedules.
Abstract: The disposition of monodesethylamodiaquine was studied in four healthy subjects after a single oral dose of 10 mg/kg amodiaquine base
TL;DR: The systemic availability of fentanyl by this route is approximately 30% of that found using the intravenous route, and the transdermal absorption of tritiated fentanyl and sufentanil citrate is studied.
Abstract: We have studied the transdermal absorption of tritiated fentanyl (citrate and base) and sufentanil citrate.
TL;DR: Data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke, as indicated by a decrease of the haematocrit and a shift towards higher values after ten days treatment.
Abstract: In 21 patients with ischaemic strokes we have monitored plasma viscosity, total plasma concentration, numeric average molecular weight (Mn), and weight average molecular weight (Mw) of Dextran 40 (dextran) and hydroxyethylstarch 200/0.5 (HES) during 10 days of treatment (days 1–4, 2×500 ml; days 5–10, 1×500 ml). Plasma concentrations of dextran increased during the first 4 days (8.3 mg·ml−1 on the first day to 18.0 mg·ml−1 on the fifth day), reached an apparent steady state of 17.2 mg·ml−1 during the next 6 days, and declined subsequently with a half-time (t1/2) of 4.03 days. After ten days treatment Mn and Mw were shifted towards higher values. Plasma viscosity increased from 1.26 mPas to 1.69 mPas on Day 10 (p<0.01) and was linearly correlated with the total plasma concentration of dextran (p<0.001; r=0.88). Total plasma concentrations of HES averaged 11.7 mg·ml−1 on Day 1 and 12.4 mg·ml−1 on Day 5. The molecular weight distribution did not change during the infusions but decreased in comparison with the administered solution. Plasma viscosity fell from 1.40 mPas to 1.30 mPas at Day 10 (p<0.05) and was not related to the concentration of HES. The haemodiluting effect, as indicated by a decrease of the haematocrit, was 22% and 16.8% for dextran and HES respectively. These data suggest several advantages of HES compared with dextran in haemodilution therapy of ischaemic stroke.
TL;DR: It is concluded that omeprazole in the dose likely to be used for peptic ulcer has no significant effect on the kinetics or action of propranolol.
Abstract: In a randomised double-blind cross-over study, 8 normal subjects received propranolol 80 mg twice daily with omeprazole 20 mg or identical placebo each morning. Propranolol kinetics were measured on day 8 of both treatment periods.
TL;DR: The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.
Abstract: Actions and interactions of buprenorphine (BUP) and amitriptyline (AMI) on performance and respiration were studied double-blind and cross-over in 12 healthy volunteers. After one-week pretreatments with AMI or placebo, the subjects received on Day 8 placebo, BUP or AMI so that the final treatments were 1) placebo, 2) acute AMI 50 mg, 3) acute BUP, 4) subchronic AMI + acute BUP and 5) subchronic AMI. The subacute treatments were started at two-week intervals. A Mapleson D rebreathing circuit including a pneumotachograph and an infrared capnograph was employed to study drug effects on respiration. Minute volume and end-tidal carbon dioxide as well as psychomotor performance were measured and the blood samples taken on Day 8 before the drug intake and 2 and 4 h thereafter. The performance tests included tracking, choice reaction, flicker fusion, exophoria, nystagmus, digit symbol substitution and the subjective assessment of mood. BUP depressed respiration, and subchronic AMI increased this depression. Both BUP and acute AMI 50 mg each alone impaired various measures of performance and rendered the subjects drowsy, feeble, mentally slow and muzzy but subchronic AMI did not enhance BUP effects. BUP increased plasma prolactin levels similarly after both pretreatments. The results suggest that both BUP and AMI moderately affect psychomotor performance but the interaction between these agents is mild and restricted mainly to respiration.
TL;DR: The haemodynamic effects of both doses of human CRF were accompanied by significant increases in plasma noradrenaline concentrations, which were significantly greater after the higher dose.
Abstract: The haemodynamic effects of i.v. bolus injections of 100 and 200 µg ovine CRF and human CRF in man have been compared. Neither ovine CRF 100 µg nor human CRF 100 µg caused a significant change in blood pressure, although the pulse rate was increased in all the subjects tested. The mean maximum increase in pulse rate after human CRF was almost twice that after ovine CRF (21 vs 12 beats·min−1;p<0.05). After 200 µg ovine CRF in all subjects the diastolic blood pressure declined gradually from 77 mm Hg to a nadir of 67 mm Hg at 22 min (p<0.002). After 200 µg human CRF diastolic blood pressure fell from 78 mm Hg to a nadir of 61 mm Hg at 6 min (p<0.002); the fall after human CRF was significantly greater than after ovine CRF (p<0.05). After 200 µg ovine CRF there was a slight increase in pulse rate lasting for 6 min, and after 200 µg human CRF there was a marked (reflex) tachycardia for 30 min. Only after the highest dose of human CRF did a slight increase in systolic blood pressure occur. The haemodynamic effects of both doses of human CRF were accompanied by significant increases in plasma noradrenaline concentrations, which were significantly greater after the higher dose.
TL;DR: Oral pefloxacin would seem to be a convenient and useful treatment of spontaneous, gram-negative, bacterial peritonitis in cirrhosis, but the decreased hepatic metabolism of the drug leads to a marked accumulation in plasma and ascites after repeated doses, and a reduced dose is required in these patients.
Abstract: Plasma and ascitic fluid concentrations of pefloxacin in 10 cirrhotic patients and 8 healthy volunteers were determined following administration of a single oral dose of 400 mg. The mean elimination half-life was significantly increased in the patients (29.0 h) compared to in 8 healthy volunteers (12.3 h). In patients, the total plasma clearance (2.71 vs 6.85 l/h) and volume of distribution (1.12 vs 1.67 l/kg) were decreased. Estimated by the ratio of the AUC in peritoneal fluid and plasma, ascitic fluid penetration was 68% after one oral dose, and pronounced accumulation of pefloxacin in ascites was found after repeated doses. Oral pefloxacin would seem to be a convenient and useful treatment of spontaneous, gram-negative, bacterial peritonitis in cirrhosis. However, the decreased hepatic metabolism of the drug leads to a marked accumulation in plasma and ascites after repeated doses, and a reduced dose is required in these patients.
TL;DR: It is demonstrated that 5-FU degrades when incubated in whole blood, which most likely reflects metabolism in red blood cells or other blood-formed elements since5-FU was stable in plasma.
Abstract: The nonlinear disposition kinetics of 5-fluorouracil (5-FU) were investigated in 6 patients with colorectal carcinoma. Each patient randomly received two single, intravenous doses of 5-FU (7.5 and 15 mg/kg) on separate days. Venous blood and urine samples were collected just prior to and for 5 h after drug administration. In addition to the kinetic studies, the in vitro whole blood/plasma concentration ratio and stability of 5-FU at 37°C were determined in whole blood from normal volunteers and from 5 patients with colorectal carcinoma. A disproportionate increase in area under the curve and corresponding decrease in total body clearance with increasing dose was observed suggesting dose-dependent behavior of 5-FU. Doubling the dose was accompanied by a 36% decrease in nonrenal clearance but no apparent change in renal clearance. Therefore, the mechanism for dose-dependent elimination appears to be primarily associated with nonrenal processes. The mean 5-FU half-life following the high dose was nearly twice as long as that observed for the low dose (12.3 versus 6.2 min). The log-linear decline in plasma concentrations and increase in half-life with dose suggest the potential role of product-inhibition as an explanation for the observed nonlinearity in 5-FU elimination. The present study demonstrates that 5-FU degrades when incubated in whole blood. This most likely reflects metabolism in red blood cells or other blood-formed elements since 5-FU was stable in plasma. Although degradation in whole blood occurs, the estimated whole blood clearance does not contribute significantly to the observed total body clearance value. These findings suggest the possibility of pulmonary clearance of 5-FU.
TL;DR: The oral administration of [14C]PN 200-110 prescribed in the present study was safe and well tolerated and the pharmacokinetic characteristics appeared to be linear in the 5 to 20-mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as the parent drug.
Abstract: The pharmacokinetics of PN 200-110 (isradipine), a new calcium channel blocking agent, have been studied in 18 normal male volunteers who received orally a single 5-mg dose, a single 20-mg dose, or repeated administration of 5 mg every 8 h for 13 doses of [14C]PN 200-110. PN 200-110 was rapidly and almost completely (90-95%) absorbed from the gastrointestinal tract, although the estimated bioavailability was only 17% due to extensive first-pass metabolism. The pharmacokinetics of PN 200-110 appeared to be linear in the 5 to 20-mg dose range, as indicated by the dose-proportional blood levels of total radioactivity as well as the parent drug. Absorbed PN 200-110 was completely metabolized prior to excretion. The recovery of radioactivity after both the 5 and the 20-mg dose was virtually complete within the experimental period, with a renal:fecal excretion ratio of ca. 70:30. Repeated administration of [14C]PN 200-110 showed no change in pharmacokinetic characteristics. During the 5 mg thrice daily regimen, steady-state blood levels of parent drug were reached in 2 days while those of total radioactivity were reached in approximately 4 days. PN 200-110 and total radioactivity accumulated in blood by a factor of 2.1 and 3.4, respectively, indicating effective half-lives of 8.8 h and 16 h. The oral administration of [14C]PN 200-110 prescribed in the present study was safe and well tolerated.
TL;DR: Increases in half-life during the third trimester were highly significant, suggesting that theophylline partitions into the enlarged tissue spaces during pregnancy and post-partum, suggesting an ongoing suppression relative to pre-pregnancy levels.
Abstract: The effects of pregnancy on the disposition of theophylline were assessed in 10 patients throughout pregnancy and post-partum. The clearance relative to total theophylline concentrations was only slightly affected during the first two trimesters (2.61 +/- 0.63 l/h and 2.85 +/- 1.05 l/h), while a statistically significant reduction was evident late in pregnancy (2.05 +/- 0.49 l/h). Post-partum clearance values (2.16 +/- 2.81 l/h) suggest an ongoing suppression relative to pre-pregnancy levels. A similar pattern was evident with clearance values based on free theophylline plasma concentrations (p = 0.12). Absolute volume of distribution increased in concert with gestation, suggesting that theophylline partitions into the enlarged tissue spaces. In addition, theophylline binding to plasma proteins decreased, albeit insignificantly, during the second (fraction bound = 29%) and third (32%) trimesters compared to post-partum values (41%). Increases in half-life during the third trimester (13.00 +/- 2.31 h vs 9.53 +/- 3.53 h post-partum) were highly significant. This change reflects the net effect of reduced clearance and increased distribution. Breast feeding had no effect on the disposition of theophylline, although the transfer of this compound into breast milk was confirmed.
TL;DR: The aqueous solution of SMS was rapidly absorbed from the gastrointestinal tract after local application, and it was well tolerated, suggesting that oral delivery of the polypeptide may eventually be possible for long-term treatment of a variety of disorders.
Abstract: To determine the local gastrointestinal absorption of a new synthetic somatostatin analogue (SMS 201-995 = Sandostatin), an intestinal tube was passed in eight healthy volunteers and on different days an aqueous solution was administered at four different locations: stomach, proximal duodenum, ligament of Treitz and jejunum In a follow-up study, an oro-ileal tube was passed in six of the original volunteers and the drug solution was administered in to the terminal ileum The aqueous solution of SMS was rapidly absorbed from the gastrointestinal tract after local application, and it was well tolerated Absorption of the drug from the different sites was comparable, although there was a tendency to decreased peptide absorption after ileal administration Absorption of the drug was quite variable between the subjects and the different locations The dose-corrected systemic availability relative to subcutaneous administration in another study was 028% However, significant plasma SMS concentrations were achieved, suggesting that oral delivery of the polypeptide may eventually be possible for long-term treatment of a variety of disorders