Pharmacokinetics and beta-blocking effects of timolol in poor and extensive metabolizers of debrisoquin.

We studied the pharmacokinetics and beta-blocking effects of a single, oral 20 mg dose of timolol in six poor metabolizers (PMs) and six extensive metabolizers (EMs) of debrisoquin. The plasma timolol concentration was significantly higher in PMs than in EMs. There was a fourfold difference in mean AUC (1590 +/- 1133 vs. 394 +/- 239 ng X hr/ml; P less than 0.01) and a twofold difference in mean t1/2 (7.5 +/- 3 vs. 3.7 +/- 1.7 hours; P less than 0.01), reflecting differences in oral clearance (13.1 +/- 7.8 vs. 48.5 +/- 23.2 L/hr; P less than 0.01). The degree of beta-blockade was greater in PMs than in EMs at 12 hours (30.9% vs. 18.2%; P less than 0.05) and at 24 hours (28.3% vs. 13.1%; P less than 0.05). In the group as a whole the metabolic ratio correlated positively with both kinetic data and beta-blockade, but some overlap was observed. Hence timolol metabolism appears to be subject to debrisoquin-type polymorphism, which results in interphenotypic variation in plasma concentration and beta-blocking effect.

Oxidative damage to DNA in patients with cystic fibrosis.

Patients with cystic fibrosis (CF) may be more susceptible to oxidative-cell injury due to impaired absorption of dietary-antioxidants. In addition, recurring pulmonary infections regularly subject them to oxidative stress. Our objective was to determine whether the concentration of urinary 8-hydroxydeoxyguanosine (oh8dG), a marker of free radical-induced DNA damage, is elevated in CF patients and to correlate its excretion with clinical status. The first morning void of urine was collected from 13 CF patients and 10 control children of similar age. To determine clinical status, forced expiratory volume (FEV1) and forced ventilatory capacity (FVC) and a Taussing-Schwachman score were obtained for each patient. Urinary oh8dG was measured by high performance liquid chromatography (HPLC) with electrochemical detection and the concentration normalized against creatinine concentration. The mean concentration (+/- SD) of urinary oh8dG was significantly higher in the CF group (2.78 +/- 1.21 vs. 1.51 +/- 0.38 nmol/mmol creatinine). A significant positive correlation was found between urinary oh8dG concentration and plasma alpha-tocopherol concentration in the CF patients (r = 0.947, p = 0.0001), suggesting that vitamin E might be involved in the excretion of oh8dG. However, no correlation was found between urinary oh8dG in CF and markers of lung function or the qualitative index of clinical status. These results confirm that patients with CF are susceptible to oxidative-induced DNA damage, although this appears to be independent of clinical status. Increased DNA damage may explain, in part, why CF patients have a higher incidence of malignancy compared to normal healthy age-matched controls.

Hemodialysis and iopamidol clearance after subclavian venography.

RATIONALE AND OBJECTIVES: The dialyzability of iopamidol is unknown and was investigated in patients undergoing long-term hemodialysis for chronic renal failure. METHODS: Ten patients received 30 ml Niopam 300 (Bracco SpA, Milan, Italy) (identical to 18372 mg iopamidol) intravenously into a forearm vein to investigate for occult subclavian stenosis. RESULTS: The elimination half-life of iopamidol before hemodialysis was 69.6 hours and during 4 hours of hemodialysis was 3.5 hours. A single 4-hour hemodialysis cleared 55.7% (95% Ci 51-5-59.8) of the administered dose, while second and third dialyses cleared 25.3% (95% Ci 21.4-29.1) and 10.1% (95% Ci 7.7-12.6) of the administered dose, respectively. Two patients with significant residual urine excretion excreted more than 10% of the administered dose in the urine. For anuric patients, extrarenal clearance provided total body clearance of up to 0.266 L/hr. CONCLUSIONS: Hemodialysis is a rapid and efficient means of clearing iopamidol provided it is performed soon after the contrast study.

Evidence for the involvement of oxygen-derived free radicals in ischaemia-reperfusion injury.

Six patients undergoing vascular reconstructive surgery were examined for evidence of oxygen-derived free radical (ORF) damage to the protein, immunoglobulin G (IgG). OFR damage was determined as an increase in the fluorescence (ex 360 nm em 454 nm) to ultraviolet absorption (280 nm) ratio of IgG, representing N-Formyl kynurenine and other as yet unidentified fluorophores. The IgG ratio was found to increase slightly during ischaemia and to undergo marked elevation upon reperfusion (275 +/- 405% baseline value at 40 min post-clamp; mean +/- sd). A high ratio was maintained post-reperfusion, even after 60 min reperfusion. Determination of thromboxane B2, (TXB2), leukotriene B4, (LTB4) and 6-keto prostaglandin F1 alpha, (PGF1a), revealed a decrease in their concentrations during ischaemia and a transient, marked increase on reperfusion. Only TXB2 concentrations were found to correlate with the IgG ratio (negative correlation, p < 0.05). No correlation was observed between von Willebrand antigen factor, a marker of endothelial cell damage and fluorescent IgG ratio. However, levels of the factor increased slightly during ischaemia and more sharply upon reperfusion. These preliminary results therefore suggest that a more likely source of the OFRs responsible for IgG damage is endothelial cell xanthine oxidase, rather than cyclo-oxygenase or lipoxygenase.

Reverse phase partition HPLC for determination of plasma purines and pyrimidines in subjects with gout and renal failure.

A reverse phase partition mode of high pressure liquid chromatography was developed for the estimation of purine, pyrimidine and pyrazolopyrimidine nucleosides and bases. This method has been applied to the investigation of purine and pyrimidine metabolism in subjects with gout and/or renal failure during allopurinol therapy. Plasma levels of hypoxanthine and xanthine were quantitated in all subjects. No significant differences were observed between healthy males and gouty subjects with or without allopurinol medication. There was a significant increase in xanthine levels in patients with gout and renal failure, or renal failure on allopurinol, and plasma levels of oxipurinol were increased, but no correlation with glomerular filtration rate (GFR) was observed. The separation method was also used to examine urines from patients with known abnormalities of purine and pyrimidine metabolism in an attempt to evaluate its usefulness as a urine screening technique.

Effects of food on the bioavailability of sustained-release pinacidil in humans.

The effects of a standard breakfast meal on the bioavailability of a sustained-release tablet formulation of pinacidil [(+/-)-2-cyano-1- (4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate) were investigated in eight healthy volunteers. Concomitant food intake resulted in significantly increased maximum measured serum pinacidil concentrations, Cmax, (172 +/- 21 versus 102 +/- 49 ng/mL, p less than 0.05), and relative bioavailability, measured as AUCo-infinity (904 +/- 189 versus 697 +/- 279 ng.h/mL, p less than 0.05). The time to maximum serum concentration (tmax) was not affected by food (2.3 +/- 1.3 versus 3.3 +/- 1.2 h, p greater than 0.05), and the terminal elimination half-life, (t1/2z) was significantly decreased (4.7 +/- 2.2 versus 2.3 +/- 0.4 h, p less than 0.05).

Effects of formulation on the pharmacokinetics of orally administered pinacidil in humans.

Serum concentrations, relative bioavailability, and urinary excretion of pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl) guanidine monohydrate] from two sustained-release oral formulations (tablet and capsule) were compared in 12 healthy volunteers. Maximum measured serum concentrations (Cmax) from the sustained-release tablet and capsule did not differ significantly (75 +/- 17 versus 70 +/- 14 ng/mL, p greater than 0.05), but the time to achieve maximum concentration (tmax), was longer for the capsule (2.4 +/- 1.8 versus 0.98 +/- 0.5 h, p less than 0.05). There was no significant difference in bioavailability between the formulations, as measured by the area under the concentration-time curve (AUC0-8 h; 279 +/- 99 versus 311 +/- 85 ng.h/mL, p greater than 0.05). Twenty-four hour urinary excretion of both pinacidil and its major metabolite, pinacidil pyridine-N-oxide, was similar for both tablet and capsule preparations (3.9 +/- 1.2 and 55 +/- 19% versus 4.4 +/- 1.0 and 55 +/- 14%, respectively, of the administered dose, p greater than 0.05).

Neurological, psychological and educational sequelae of low birth weight.

In a prospective study of 501 infants of low birth weight (LBW) who mostly weighed 2,041 g (4 1/2 lb) or less, and of 203 control infants of full birth weight (FBW > 2,500 g), 335 LBW and 139 FBW children were followed beyond the age of 6 years and 6 months. The incidence of neurological defects was negatively correlated with birth weight, and the mean "global" IQ of different birth weight groups retained a direct relationship. While the relationship of birth weight to IQ gradually became less marked, the effect of social class was increasingly evident from the age of 2 years and 6 months. The preterm children whose birth weight was appropriate for gestational age (AGA) attained a slightly higher mean IQ and significantly better grade placement in the third school year than the children who were unduly light for their gestational age. Details of the neurological and ophthalmological defects are given, and the predictive significance of neonatal variables is analyzed.

Clearance of iopamidol, a non-ionic contrast medium, by CAPD in patients with end-stage renal failure.

In normal healthy subjects radiographic contrast media are cleared by the kidneys with a half-life of approximately 2 h and a total body clearance of 8 l/h. The mechanism of contrast clearance has not been previously investigated in chronic renal failure patients undergoing continuous ambulatory peritoneal dialysis (CAPD). A study was undertaken to investigate the pharmacokinetics of a non-ionic water soluble radiographic contrast medium (iopamidol) in 10 patients stabilized on CAPD. All patients (eight male, two female) aged 22-68 years (median 53 years) had injection of 30 ml of iopamidol 300 via a forearm vein to investigate subclavian vein patency following previous cannulation for haemodialysis. Venous blood samples, CAPD dialysate and urine were collected for seven days post injection. The mean plasma half-life was 37.9 h (SD 10.6) (range 24.1-57.2 h) for the CAPD patients and was greatly prolonged in comparison to healthy subjects. The total body clearance of iopamidol was also greatly reduced (0.377 l/h). CAPD removed an average of 53.6% of the administered dose (range 36.3-80.8%) whilst an average of 26.9% was excreted in the urine (range 1.3-56.3%). The combined renal and dialysate clearance was up to 93% of the administered dose over the period of the study. There is therefore some evidence for a small extra renal clearance of iopamidol in end-stage renal failure patients. This study has shown for the first time that patients with end-stage renal failure undergoing CAPD have significantly delayed elimination of contrast medium. This should be taken into consideration when extensive or prolonged investigations using contrast medium are proposed.

Purine excretion in complete adenine phosphoribosyltransferase deficiency: effect of diet and allopurinol therapy.

1. Abnormal amounts of adenine, 8-hydroxyadenine and 2,8-dihydroxyadenine are found in the urine of homozygotes for APRTase deficiency and are diagnostic of this condition. 2. The renal complication is due to the excessive amounts of 2,8-dihydroxyadenine excreted since it is removed by allopurinol which blocks 2,8-dihydroxyadenine formation. 3. Uric acid metabolism and the excretion of the other minor purine bases is normal, at least in childhood, in homozygotes for APRTase deficiency. 4. Patients with the defect appear to be very sensitive to dietary purine. At least some of the adenine metabolites may have a dietary origin.

Maternal cigarette smoking during pregnancy and the child's subsequent development: I. Physical growth to the age of 6 1/2 years.

PIP: The growth of 81 "small-for-dates" (SFD) and 99 "truly premature" children of low birth weight, and of 146 controls of full birth weight (FBW) was analyzed with respect to maternal smoking during pregnancy. Shortly after birth, a history was obtained from the mother pertaining to factors which could be related to the pregnancy outcome. Physical examination, developmental tests, and psychological tests were performed on the children up to the age of 6 1/2 years. There was a highly significant excess in the percentage of smokers among the mothers of SFD children as compared to FBW control children. At 6 1/2 years, the children of nonsmoking mothers had a slightly greater mean weight and height in all categories. Statistically significant differences in favor of nonsmokers' children were seen only in the FBW children. Mean social class was lower in children of nonsmoking mothers. Other factors influencing growth, such as maternal height and weight, and childrens' sex were not significantly different in the 2 groups of children. Although the trends of the results indicate that cigarette smoking in pregnancy may negatively affect the child's growth, the trends rarely reached statistical significance, and larger numbers are required for detailed factorial analysis.^ieng

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the dog.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in dogs and also eliminated rapidly with a short half-life. Following single intravenous doses, dexloxiglumide was characterised as a drug having a high clearance (30.7 and 27.0 ml/min/kg in males and females respectively), a low volume of distribution (Vss, 0.34 and 0.27 L/kg in males and females respectively) and a moderate systemic availability (about 33%). It was extensively bound to plasma proteins (89%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the kidney, liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. 14C concentrations generally peaked at 0.25h and declined rapidly during 24h being present only in a few tissues (such as the kidney, liver and gastrointestinal tract) at 24h. Single intravenous or oral doses were mainly excreted in the faeces (77-89%), mostly during 24h. Urine contained up to 7.5% dose. Mean recoveries during 7 days ranged between 93-97%. Biliary excretion of 14C was prominent (64% dose during 24h) in the disposition of 14C which was probably also subjected to some limited enterohepatic circulation. Unchanged dexloxiglumide was the major component in plasma. Urine and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. about 55% dose in faeces). LC-MS/MS of urine and bile extracts showed that dexloxiglumide was metabolised mainly by O-demethylation and by conjugation with glucuronic acid.

Absorption, distribution, metabolism and excretion of the cholecystokinin-1 antagonist dexloxiglumide in the rat.

Single oral doses of 14C-dexloxiglumide were rapidly and extensively absorbed in rats, and eliminated more slowly by females than by males. The respective half-lives were about 4.9 and 2.1 h. Following single intravenous doses, dexloxiglumide was characterised as a drug having a low clearance (6.01 and about 1.96 ml/min/kg in males and females respectively), a moderate volume of distribution (Vss, 0.98 and about 1.1 L/kg in males and females respectively) and a high systemic availability. It was extensively bound to plasma proteins (97%). Dexloxiglumide is mainly cleared by the liver. Its renal clearance was minor. In only the liver and gastrointestinal tract, were concentrations of 14C generally greater than those in plasma. Peak 14C concentrations generally occurred at 1-2 h in males and at 2-4 h in females. Tissue 14C concentrations then declined by severalfold during 24 h although still present in most tissues at 24 h but only in a few tissues (such as the liver and gastrointestinal tract) at 168 h. Decline of 14C was less rapid in the tissues of females than in those of males. Single intravenous or oral doses were mainly excreted in the faeces (87-92%), mostly during 24 h and more slowly from females than from males. Urines contained less than 11% dose. Mean recoveries during 7 days when 14C was not detectable in the carcass except in one female rat ranged between 93-101%. Biliary excretion of 14C was prominent (84-91% dose during 24 h) in the disposition of 14C which was also subjected to facile enterohepatic circulation (74% dose). Metabolite profiles in plasma and selected tissues differed. In the former, unchanged dexloxiglumide was the major component whereas in the latter, a polar component was dominant. Urine, bile and faeces contained several 14C-components amongst which unchanged dexloxiglumide was the most important (eg. up to 63% dose in bile). LC-MS/MS showed that dexloxiglumide was metabolised mainly by hydroxylation in the N-(3-methoxypropyl)pentyl sidechain and by O-demethylation followed by subsequent oxidation of the resulting alcohol to a carboxylic acid.