Fluconazole pharmacokinetics in burn patients

The pharmacokinetics of fluconazole in nine adult patients with severe (30 to 95% total body surface area) burns were studied. There was no significant difference in half-life (t1/2), clearance (CL), or volume of distribution (V) over time in five patients on days 3 and 8 of the study (P > 0.05). Combined parameter estimates (means +/- standard deviations) for all nine patients for the two study periods were as follows: t1/2, 24.4 +/- 5.8 h; CL, 0.36 +/- 0.09 ml/min/kg; and V, 0.72 +/- 0.12 liters/kg. These estimates of t1/2 and CL in burn patients were approximately 13% shorter and 30% more rapid, respectively, than the most extreme estimates reported for other populations.     

Is the inversion from R- to S-ketoprofen concentration dependent? Investigations in rats in vivo and in vitro

The effects of dose on the pharmacokinetics of ketoprofen (KT) enantiomers were investigated in rats in vivo and in hepatoma cells in continuous culture in vitro following administration of the optically pure enantiomers and the racemate of KT. With the exception of AUC (area under the curve) no pharmacokinetic differences could be found following i.v. administration of various doses of KT enantiomers (2.5, 5 and 10 mg/kg) and of racemic KT (5, 10 and 20 mg/kg) and between single enantiomer and racemate administration in rats in vivo. Independent of the dose administered the fraction inverted was about 66%. In line with the findings in vivo good correlation between incubation concentration and AUC of R- and S-KT was found in the hepatoma cells in vitro. The ratios of AUC(S)/AUC(R) were not significantly affected by concentration after R-KT (2.5-20 micrograms/mL) and racemate incubation (5-40 micrograms/mL) in the concentration ranges investigated. However, unlike in rats in vivo enhanced inversion was observed following racemate as compared to single enantiomer incubation in vitro.     

Pharmacokinetic differences between lansoprazole enantiomers in rats

Because limited information is available about potential differences between the pharmacokinetics and pharmacodynamics of the enantiomers of lansoprazole, the enantioselective pharmacokinetics of the compound have been investigated in rats. There was a noticeable difference between the serum levels of the enantiomers of lansoprazole and of their metabolites, 5-hydroxylansoprazole enantiomers, after oral administration of the racemate (50 mg kg(-1)) to rats. Cmax (maximum serum concentration) and AUC (area under the serum concentration-time curve) for (+)-lansoprazole were 5-6 times greater than those for (-)-lansoprazole, whereas for (+)-5-hydroxylansoprazole both values were significantly smaller than those for the (-) enantiomer. CLtot/F values (where CLtot is total clearance and F is the fraction of the dose absorbed) for (+)-lansoprazole were significantly smaller than those for the (-) enantiomer. There was no significant difference between the absorption rate constants of the lansoprazole enantiomers in the in-situ absorption study. The in-vitro protein-binding study showed that binding of (+)-lansoprazole to rat serum proteins was significantly greater than for the (-) enantiomer. The in-vitro metabolic study showed that the mean metabolic ratio (45.9%) for (-)-lansoprazole was significantly greater than that (19.8%) for the (+) enantiomer in rat liver microsomes at 5.6 microM lansoprazole. These results show that the enantioselective disposition of lansoprazole could be a consequence of the enantioselectivity of plasma-protein binding and the hepatic metabolism of the enantiomers.     

Differential effects of specific delta and kappa opioid receptor antagonists on the bidirectional dose-dependent effect of systemic naloxone in arthritic rats, an experimental model of persistent pain

In an attempt to determine the opioid receptor class(es) which underly the two opposing effects of naloxone in models of persistent pain, we tested the action of the selective delta antagonist naltrindole, and that of the kappa antagonist MR-2266 on the bidirectional effect of systemic naloxone in arthritic rats. As a nociceptive test, we used the measure of the vocalization thresholds to paw pressure. The antagonists were administered at a dose (1 mg/kg i.v. naltrindole, 0.2 mg/kg i.v. MR-2266), without action per se but which prevents the analgesic effect of the delta agonist DTLET (3 mg/kg, i.v.) or the kappa agonist U-69,593 (1.5 mg/kg, i.v.) respectively, and does not influence the effect of morphine (1 mg/kg i.v.) or the mu agonist DAMGO (2 mg/kg, i.v.) in these animals. In arthritic rats injected with the delta antagonist, the paradoxical antinociceptive effect produced by 3 micrograms/kg i.v. naloxone was not significantly modified (maximal vocalization thresholds (% of control) were 146 +/- 9% versus 161 +/- 7% in the control group). By contrast, the hyperalgesic effect produced by 1 mg/kg i.v. naloxone was significantly reduced (maximal vocalization thresholds were 87 +/- 4% versus 69 +/- 5% in the control group). In rats injected with the kappa antagonist, the antinociceptive effect of the low dose of naloxone was almost abolished (mean vocalization thresholds were 115 +/- 3% versus 169 +/- 7%) whereas the hyperalgesic effect of naloxone 1 mg/kg i.v. was not significantly modified (mean vocalization thresholds = 70 +/- 3% and 65 +/- 3%, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacokinetics of a new carbapenem, DA-1131, after intravenous administration to rats with uranyl nitrate-induced acute renal failure

Because the physiological changes that occur in patients with acute renal failure could alter the pharmacokinetics of the drugs used to treat the disease, the pharmacokinetics of DA-1131, a new carbapenem antibiotic, were investigated after 1-min intravenous administration of the drug (50 mg/kg of body weight) to control rats and rats with uranyl nitrate-induced acute renal failure (U-ARF rats). The impaired kidney function was observed in U-ARF rats on the basis of physiological parameters observed by microscopy of the kidney and obtained by chemical analysis of the plasma. After a 1-min intravenous infusion of DA-1131, the concentrations in plasma and the total area under the plasma concentration-time curve from time zero to time infinity increased significantly in U-ARF rats compared with those in control rats (13,000 versus 4,400 microg x min/ml). This was due to the significantly slower total body clearance (CL) of DA-1131 (3.84 versus 11.4 ml/min/kg) from U-ARF rats than from control rats. The significantly slower CL of DA-1131 from U-ARF rats was due to both significantly slower renal clearance (0.000635 versus 4.95 ml/min/kg because of a significant decrease in the 8-h urinary excretion of unchanged DA-1131 [1.54 versus 43.8% of the intravenous dose] due to impaired kidney function, as proved by the significant decrease in creatinine clearance [0.0159 versus 4.29 ml/min/kg]) and significantly slower nonrenal clearance (3.80 versus 6.34 ml/min/kg because of a significant decrease in the metabolism of DA-1131 in the kidney) in U-ARF rats. The amounts of DA-1131 recovered from all tissues studied (except the kidneys) were significantly higher for U-ARF rats than for control rats; however, the ratios of the amount in tissue to the concentration in plasma (except those for the kidney, small intestine, and spleen) were not significantly different between the two groups of rats, indicating that the affinity of DA-1131 for rat tissues was not changed considerably in U-ARF rats.     

Tenoxicam: acute dose-dependent disposition studies in rats

Single intravenous bolus doses of tenoxicam of 2.5, 5, and 10 mg/kg were administered to male Wistar rats to determine the effects of dose on tenoxicam pharmacokinetics. Predicted apparent volume of distribution at steady state (Vdss) and total plasma clearance (CL) were, respectively, 42 and 45% higher in the animals given 10-mg/kg dose than the animals given 2.5- and 5-mg/kg doses. Binding of tenoxicam to plasma proteins showed saturability, with a 33% higher unbound fraction of tenoxicam in plasma when total drug concentration in plasma was 36 mg/L (high dose group) in comparison with animals given the low doses (12 and 20 mg/L). The blood-to-plasma concentration ratio of tenoxicam was concentration independent and therefore did not account for the observed dose-dependent changes in Vdss and CL.     

Stereoselectivity of biliary excretion of 2-arylpropionates in rats

To examine the stereoselectivity of biliary excretion, the optically pure enanatiomers of ketoprofen (KT), ibuprofen (IBU), and flurbiprofen (FLU) were intravenously administered to normal and bile duct-cannulated rats at 10 mg/kg. The recovery of total KT in bile was significantly higher after administration of (S)-KT than after (R)-KT [90.1 +/- 3.5% vs 68.8 +/- 8.2%, n = 3, P < 0.05]. In normal rats the terminal half-life of (R)-KT was significantly shorter than that of (S)-KT after administration of (R)-KT (2.2 +/- 0.6 h vs 14.3 +/- 4.9 h, n = 3, P < 0.05). The terminal half-life of both enantiomers was significantly shorter in rats with continuous bile drainage as compared to normal rats. No significant differences in pharmacokinetic parameters could be found between both enantiomers in bile duct-cannulated animals. The total amount of IBU in bile was slightly higher after administration of (S)-IBU than after (R)-IBU administration. The percentage of (R)-IBU after (R)-IBU administration, however, was very low [(R)-IBU: 1.5 +/- 0.9%, (S)-IBU: 23.4 +/- 5.8%]. In normal rats the clearance of (R)-IBU was significantly higher as compared to (S)-IBU. Differences in pharmacokinetic parameters between normal and bile duct-cannulated rats were not statistically significant due to high interindividual variability. The total recovery of FLU, which was excreted in bile to a lower extent than either KT or IBU, also tended to be greater after S-enantiomer administration. Only small amounts of (S)-FLU could be recovered in bile after (R)-FLU administration.(ABSTRACT TRUNCATED AT 250 WORDS)     

A case of Buerger''s disease solitary involved in the left subclavian and axillary artery

The pharmacokinetics of ceftazidime have been investigated in eight patients with chronic renal failure undergoing continuous ambulatory peritoneal dialysis. Each subject was given ceftazidime 1 g intravenously and 1 g intraperitoneally at an interval of 1 week. Ceftazidime was assayed by high-pressure liquid chromatography. After intravenous administration, the pharmacokinetic parameters of ceftazidime were: elimination plasma half-life (t1/2 beta) = 24.6 +/- 4.6 hours; apparent volume of distribution (V(area)): 0.37 +/- 0.09 1/kg, total plasma clearance (CL): 11.9 +/- 3.3 mL/minute, peritoneal clearance (CLp): 1.7 +/- 0.3 mL/minute. Over 72 hours, only 15.6 +/- 4.7% of the dose was eliminated by the peritoneal route. After intraperitoneal administration, ceftazidime appeared in the plasma rapidly, and the peak plasma concentration of 24.5 +/- 5.2 mg/L was achieved at the fourth hour; the elimination half-life (t1/2ke) was 20.8 +/- 1.7 hours. The absorption of ceftazidime from the peritoneal space was 74.1 +/- 7.4%. These data suggest that ceftazidime has bidirectional exchange characteristics through the peritoneal membrane. A single 1-g intraperitoneal dose led to serum and dialysate concentrations of ceftazidime above the minimum concentrations for susceptible pathogen germs for 24 hours.     

Effects of P-glycoprotein modulators on etoposide elimination and central nervous system distribution

In this study, P-glycoprotein modulator effects on pharmacokinetics and central nervous system distribution of the chemotherapeutic agent etoposide were evaluated. The multidrug resistance transporter P-glycoprotein is expressed in normal tissues, and its physiological function is thought to be an excretory and/or protective one. To examine this further, we evaluated etoposide under steady-state and bolus dose conditions. In microdialysis infusion studies, etoposide 15 mg/kg/hr was administered to 12 rats. Rats received sodium cyanide (1 or 100 mM), trifluoperazine (30 mM) or cyclosporine (4.14 mM) via microdialysis probe at 3.5 hr after etoposide infusion initiation. High-dose sodium cyanide (100 mM) increased the etoposide BBR,corr from 0.09 +/- 0.03 to 0.85 +/- 0.35. Similarly, trifluoperazine significantly increased the BBR,corr (0.05 +/- 0.02 vs. 1.30 +/- 0.43), whereas cyclosporine had no effect. In bolus studies, etoposide (10-12 mg/kg) was given alone or concomitant to cyclosporine (5 mg/kg) or tamoxifen (13.5 mg/kg). Control etoposide total systemic clearance (ml/min/kg) was 29.3 +/- 13.0 vs. 16.0 +/- 1.9 and 22.6 +/- 5.3 for cyclosporine and tamoxifen treatments, respectively. Etoposide nonrenal clearance (ml/min/kg) values for cyclosporine (12.0 +/- 1.6) and tamoxifen (18.1 +/- 3.6) treatments was also decreased from controls (23.5 +/- 10.5). Etoposide renal clearance (ml/min/kg) values (5.7 +/- 2.5) were not significantly different from cyclosporine (4.0 +/- 0.7) or tamoxifen (4.6 +/- 1.7) treatments, respectively. In this study, the ability of sodium cyanide and trifluoperazine to alter etoposide BBR,corr, demonstrated that etoposide distribution into brain is partly controlled by an active transport process. Similarly, the results indicate cyclosporine inhibits etoposide transport at the canalicular membrane and/or etoposide P-450 metabolism.     

Pharmacokinetics, oral bioavailability, and metabolic disposition in rats of (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine, a nucleoside analog active against human immunodeficiency virus and hepatitis B virus

The pharmacokinetics and metabolism of the potent anti-human immunodeficiency virus and anti-hepatitis B virus compound, (-)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl] cytosine (FTC), were investigated in male CD rats. Plasma clearance of 10 mg of FTC per kg of body weight was biexponential in rats, with a half-life at alpha phase of 4.7 +/- 1.1 min (mean +/- standard deviation) and a half-life at beta phase of 44 +/- 8.8 min (n = 5). The total body clearance of FTC was 1.8 +/- 0.1 liters/h/kg, and the oral bioavailability was 90% +/- 8%. The volume of distribution at steady state (Vss) was 1.5 +/- 0.1 liters/kg. Increasing the dose to 100 mg/kg slowed clearance to 1.5 +/- 0.2 liters/kg/h, lowered the Vss to 1.2 +/- 0.2 liters/kg, and reduced the oral bioavailability to 65% +/- 15%. FTC in the brains of rats was initially less than 2% of the plasma concentration but increased to 6% by 2 h postdose. Probenecid elevated levels of FTC in plasma as well as in brains but did not alter the brain-to-plasma ratio. The urinary and fecal recoveries of unchanged FTC after a 10-mg/kg intravenous dose were 87% +/- 3% and 5% +/- 1.6%, respectively. After a 10-mg/kg oral dose, respective urinary and fecal recoveries were 70% +/- 2.5% and 25% +/- 1.6%. Two sulfoxides of FTC were observed in the urine, accounting for 0.4% +/- 0.03% and 2.7% +/- 0.2% of the intravenous dose and 0.4% +/- 0.06% and 2.5% +/- 0.3% of the oral dose. Also observed were 5-fluorocytosine, representing 0.4% +/- 0.06% of the intravenous dose and 0.4% +/- 0.07% of the oral dose, and FTC glucuronide, representing 0.7% +/- 0.2% of the oral dose and 0.4% +/- 0.2% of the intravenous dose. Neither deaminated FTC nor 5-fluorouracil was observed in the urine (less than 0.2% of dose). The high oral availability and minimal metabolism of FTC encourage its further preclinical development.     

Arteriolar reactivity in conscious diabetic rats: influence of aminoguanidine treatment

The effect of 6 weeks' streptozotocin (STZ)-induced (70 mg/kg) diabetes and aminoguanidine (AG) treatment (50 mg/kg s.c. or 250-750 mg/l given in drinking water) on arteriolar reactivity to vasoactive substances was investigated in conscious rats. Studies were performed in untreated control rats (n = 13), STZ-induced diabetic rats (n = 11), AG-treated control rats (n = 12), and AG-treated diabetic rats (n = 12). Rats were provided with a dorsal microcirculatory chamber that allowed intravital microscopy of striated muscle arterioles of varying diameter (A1, large; A2, intermediate; and A3, small arterioles) in conscious animals. The mean arterial pressure (MAP) and arteriolar diameter responses to intravenous infusion of the following drugs were examined: the endothelium-dependent vasodilator acetylcholine (ACh; 3, 10, and 30 microg x kg(-1) x min(-1)), the potassium-channel opener levcromakalim (LC; 30 microg/kg), and the vasoconstrictor agents ANG II (0.1 and 0.3 microg x kg(-1) x min(-1)) and norepinephrine (NE; 0.2, 0.6, and 2.0 microg x kg(-1) x min(-1)). Baseline MAP was lower in both diabetic groups versus the nondiabetic groups (P < 0.05). AG treatment had no influence on baseline MAP. The absolute change in MAP after drug infusion tended to be lower in the diabetic rats than in their nondiabetic littermates. Arteriolar vasodilatory responses to ACh and LC were attenuated in the diabetic animals (1 +/- 7 vs. 19 +/- 7% [P < 0.05] and 7 +/- 3 vs. 34 +/- 8% [P < 0.01] in A2, respectively). AG treatment of diabetic animals did not prevent the development of this disturbance. Vasoconstrictor responses were not influenced by the diabetic state. In the intermediate arterioles of AG-treated control rats, a hyperresponse was observed after ANG II infusion (-10 +/- 2 vs. -2 +/- 2%; P < 0.05) and a hyporesponse was observed after ACh and LC infusion (2 +/- 3 and 15 +/- 6%, respectively; P < 0.05 vs. untreated control rats). These data indicate that 6 weeks of experimental diabetes is associated with a decreased endothelium-dependent and -independent vasodilatation. AG treatment had no beneficial effect on this disturbance.     

Prevention of glomerular dysfunction in diabetic rats by treatment with d-alpha-tocopherol

Because d-alpha-tocopherol (vitamin E) has been shown to decrease diacylglycerol (DAG) levels and prevent the activation of protein kinase C (PKC), which is associated with retinal and renal dysfunctions in diabetes, the study presented here characterized the effect of d-alpha-tocopherol treatment to prevent glomerular hyperfiltration and increased albuminuria as well as PKC activities in streptozotocin (STZ)-induced diabetic rats. Two weeks after the induction of diabetes, total DAG content and PKC activity in glomeruli were significantly increased in diabetic rats by 106.4 +/- 16.8% and 66.4 +/- 8.4%, respectively, compared with control rats. Intraperitoneal injection of d-alpha-tocopherol (40 mg/kg of body weight) every other day prevented the increases in total DAG content and PKC activity in glomeruli of diabetic rats. Glomerular filtration rate (GFR) and filtration fraction (FF) were significantly elevated to 4.98 +/- 0.34 mL/min and 0.36 +/- 0.05, respectively, in diabetic rats, compared with 2.90 +/- 0.14 mL/min and 0.25 +/- 0.02, respectively, in control rats. These hemodynamic abnormalities in diabetic rats were normalized to 2.98 +/- 0.09 mL/min and 0.24 +/- 0.01, respectively, by d-alpha-tocopherol. Albuminuria in 10-wk diabetic rats was significantly increased to 9.1 +/- 2.2 mg/day compared with 1.2 +/- 0.3 mg/day in control rats, whereas d-alpha-tocopherol treatment improved albumin excretion rate to 2.4 +/- 0.6 mg/day in diabetic rats. To clarify the mechanism of d-alpha-tocopherol's effect on DAG-PKC pathway, the activity and protein levels of DAG kinase alpha and gamma, which metabolize DAG to phosphatidic acid, were examined. Treatment with d-alpha-tocopherol increased DAG kinase activity in the glomeruli of both control and diabetic rats, by 22.6 +/- 3.6% and 28.5 +/- 2.3% respectively, although no differences were observed in the basal DAG kinase activity between control and diabetic rats. Because immunoblotting studies did not exhibit any difference in the protein levels of DAG kinase alpha and gamma, the effect of d-alpha-tocopherol is probably modulating the enzyme kinetics of DAG kinase. These findings suggest that the increases in DAG-PKC pathway play an important role for the development of glomerular hyperfiltration and increased albuminuria in diabetes and that d-alpha-tocopherol treatment could be preventing early changes of diabetic renal dysfunctions by normalizing the increases in DAG and PKC levels in glomerular cells.     

Pharmacokinetic modelling of intravenous tobramycin in adolescent and adult patients with cystic fibrosis using the nonparametric expectation maximization (NPEM) algorithm

The availability of personal computer programs for individualizing drug dosage regimens has stimulated the interest in modelling population pharmacokinetics. Data from 82 adolescent and adult patients with cystic fibrosis (CF) who were treated with intravenous tobramycin because of an exacerbation of their pulmonary infection were analysed with a non-parametric expectation maximization (NPEM) algorithm. This algorithm estimates the entire discrete joint probability density of the pharmacokinetic parameters. It also provides traditional parametric statistics such as the means, standard deviation, median, covariances and correlations among the various parameters. It also provides graphic-2- and 3-dimensional representations of the marginal densities of the parameters investigated. Several models for intravenous tobramycin in adolescent and adult patients with CF were compared. Covariates were total body weight (for the volume of distribution) and creatinine clearance (for the total body clearance and elimination rate). Because of lack of data on patients with poor renal function, restricted models with non-renal clearance and the non-renal elimination rate constant fixed at literature values of 0.15 L/h and 0.01 h-1 were also included. In this population, intravenous tobramycin could be best described by median (+/-dispersion factor) volume of distribution per unit of total body weight of 0.28 +/- 0.05 L/kg, elimination rate constant of 0.25 +/- 0.10 h-1 and elimination rate constant per unit of creatinine clearance of 0.0008 +/- 0.0009 h-1/(ml/min/1.73 m2). Analysis of populations of increasing size showed that using a restricted model with a non-renal elimination rate constant fixed at 0.01 h-1, a model based on a population of only 10 to 20 patients, contained parameter values similar to those of the entire population and, using the full model, a larger population (at least 40 patients) was needed.     

Atrial natriuretic peptide metabolism during pregnancy in the rat

OBJECTIVE: Our purpose was to determine whether plasma clearance rates and production rates of atrial natriuretic peptide 99-126 are altered during pregnancy in the rat. STUDY DESIGN: Twelve virgin and 12 late-pregnant chronically instrumented, conscious, unrestrained Sprague-Dawley rats were studied. Mean arterial pressure, heart rate, and plasma atrial natriuretic peptide levels were measured before and during a 40-minute continuous infusion of atrial natriuretic peptide (10 ng/kg/min). RESULTS: Control mean arterial pressure was 106 +/- 5 mm Hg in virgin rats versus 97 +/- 4 mm Hg in pregnant rats. Atrial natriuretic peptide infusion did not significantly affect mean arterial pressure in either group of animals but decreased heart rate in virgin rats. Basal plasma atrial natriuretic peptide levels were significantly higher in virgin than in pregnant rats (107 +/- 10 vs 78 +/- 7 pg/ml, respectively, p < 0.05). Atrial natriuretic peptide infusion significantly increased plasma levels in both groups to similar (183 +/- 19 and 154 +/- 14 pg/ml, virgin vs pregnant rats). Calculated plasma clearance rates were similar in virgin and pregnant rats (166 +/- 27 vs 155 +/- 17 ml/kg/min). Estimated production rates of atrial natriuretic peptide were higher in virgin then in pregnant rats (15.1 +/- 1.4 vs 11.4 +/- 1.1 ng/kg/min, p < 0.05). CONCLUSIONS: Plasma atrial natriuretic peptide levels are lower in chronically instrumented near-term pregnant rats compared with levels in virgin rats. This is not related to differences in plasma atrial natriuretic peptide clearance rates but rather to a decrease in production rates in late pregnancy.     

Effects of diabetes and hyperglycemia on disaccharidase activities in the rat

BACKGROUND AND METHODS: To elucidate the effect of hyperglycemia on disaccharidase activities, the specific and total activities of the disaccharidases were measured in the intestinal mucosa and kidney cortex of diabetic and hyperglycemic rats. The diabetes was induced with an intraperitoneal injection of streptozotocin (60 mg/kg). The rats were made hyperglycemic with an intravenous instillation of a solution containing 40% dextrose monohydrate at a rate of 1.5 ml/h for 24 h. RESULTS: The blood glucose level was 387+/-45 mg/dl and 382+/-35 mg/dl (mean +/- standard deviation) in diabetic and hyperglycemic rats, respectively. In diabetic rats the intestinal maltase, sucrase, and lactase activities were significantly higher than those in control rats. Similarly, disaccharidase activities in hyperglycemic rats were significantly higher than those in control rats. The renal maltase activity in diabetic rats was significantly lower than that in control rats. The maltase activity in hyperglycemic rats, however, was not significantly different from that in control rats. CONCLUSIONS: These results suggest that 1) hyperglycemia directly increases the activities of intestinal maltase, sucrase, and lactase; 2) hyperglycemia does not influence renal maltase activity; and 3) hyperglycemia is partly responsible for increased activities of intestinal disaccharidases in diabetes mellitus.     

The effect of asphyxia on the pharmacokinetics of ceftazidime in the term newborn

The multiple-dose pharmacokinetics of ceftazidime (CAZ) (administered twice daily in a 50 mg/kg of body weight i.v. dose) were studied in 10 severely asphyxiated term infants with suspected septicemia on d 3 of life. Nine term infants with suspected septicemia but without asphyxia served as controls. Blood samples were collected from an arterial catheter at 0, 0.5, 1, 2, 4, 8, and 12 h after an i.v. bolus injection. A high performance liquid chromatography method was used to determine CAZ concentrations from serum. CAZ pharmacokinetics followed a one-compartment open model. The GFRs of all infants were simultaneously studied by means of the 24-h continuous inulin infusion technique. Elimination serum half-life (5.86 +/- 1.13 h versus 3.85 +/- 0.40 h) and serum trough concentrations (46 +/- 14 mg/L versus 23 +/- 7 mg/L) of CAZ were significantly (p < 0.001) increased in the asphyxiated newborn, whereas total body clearance of CAZ (128.4 +/- 25.1 mL/h versus 205.7 +/- 55.4 mL/h), CAZ clearance per kg (40.9 +/- 6.1 mL/h/kg versus 60.8 +/- 8.3 mL/h/kg), and the GFR expressed in mL/min (3.14 +/- 0.43 versus 4.73 +/- 0.89) were significantly (p < 0.001) decreased in the asphyxiated newborn. We conclude that twice daily administration of 50 mg/kg of body weight CAZ given to asphyxiated term newborns in the first days of life results in significantly higher serum trough levels in comparison with control infants. The impaired CAZ clearance is a result of a significantly decreased GFR.     

Effect of experimental diabetes mellitus on gentamicin-induced acute renal functional changes in the anaesthetized rat

1. Rats with streptozotocin (STZ) diabetes are protected from gentamicin (GEN) nephrotoxicity. Because the chronic renal damage from GEN is preceded by acute renal functional changes (notably hypercalciuria), the present study aims to determine whether diabetes may also protect against the acute effects of the drug. If there is a link between the rapid physiological actions of GEN and its subsequent nephrotoxicity, the former may also be affected by the diabetic condition. 2. Standard renal clearance techniques were performed on anaesthetized rats that had been injected with STZ or vehicle 2 weeks previously. All animals were infused with 0.9% NaCl for 5 h and then either GEN (0.28 mg/kg per min) or 0.9% NaCl alone for 2 h. 3. Baseline fractional calcium excretion (FE(Ca)) of diabetic rats was three-fold that of control animals (6.6+/-0.2 vs 2.2+/-0.2%, respectively; P<0.01, MANOVA). Following GEN infusion, a comparable increase in FE(Ca) occurred in control and diabetic rats (5.3+/-0.6 vs 5.3+/-0.8%, respectively; NS). 4. Streptozotocin diabetes, therefore, does not alter the acute hypercalciuric response to GEN. This may suggest that the acute effects of GEN on renal calcium handling do not contribute to the subsequent nephrotoxicity. However, the higher baseline FE(Ca) seen in diabetic rats may afford protection against the renal injury caused by gentamicin.     

Substance P in the ventral pallidum: projection from the ventral striatum, and electrophysiological and behavioral consequences of pallidal substance P

1. Piroximone was administered orally (p.o.) and intravenously (i.v.) to male Beagle dog. In vitro, piroximone was incubated with dog liver microsomes. 2. Piroximone was metabolized in vivo to five metabolites (1-5) representing approximately 20% of the total administered dose. 3. The parent drug and its metabolites were totally eliminated in urine. 4. Reduced piroximone (piroximole), representing approximately 10% of the administered dose, was identified as the major metabolic product in vivo. 5. In vitro, piroximone was metabolized by dog liver microsomes to isonicotinic acid (1) and piroximole (4), with the same ratio as in vivo (1:4 = 0.2). The Michaelis-Menten parameters were determined for piroximole formation and were: Kmapp = 733 microM and Vmax app = 232 pmol/mg protein/min. 6. Comparison of the pharmacokinetics of piroximone and piroximole revealed that both compounds were very well absorbed (F = 93 +/- 7 and 89 +/- 8% respectively), slightly distributed (Vd app = 0.78 +/- 0.04 and 1.02 +/- 0.09 l/kg p.o., and 0.95 +/- 0.05 and 0.76 +/- 0.13 1/kg i.v. respectively) and excreted into urine to the same extent (UEx = 54.7 +/- 1.2 and 53.2 +/- 12.6% p.o., and 59.1 +/- 5.3 and 51.2 +/- 5.7% i.v. respectively), except that the clearance of piroximone was two-fold higher than that observed for piroximole (ClT = 7.77 +/- 1.35 and 4.12 +/- 0.44 ml/min/kg p.o., and 7.68 +/- 1.25 and 4.06 +/- 0.51 ml/min/kg i.v. respectively).     

Pharmacokinetics of gentamicin at traditional versus high doses: implications for once-daily aminoglycoside dosing

Two doses of gentamicin (2 and 7 mg/kg of body weight) were administered to 11 healthy volunteers in a randomized, crossover single-dose study to compare their pharmacokinetics. Doses were infused over 1 h with a syringe infusion pump, and 14 concentrations in sera were obtained over an 8-h period. Concentration in serum versus time data were fitted to a two-compartment pharmacokinetic model. In addition, to mimic the clinical setting, subjects' data were fitted by the Sawchuk-Zaske method. Distributional and postdistributional peak concentrations, along with the last obtained concentration in serum, were utilized to compare the following pharmacokinetic variables: volume of distribution at steady state (Vss), half-life, clearance (CL), and maximum concentration in serum (Cmax). With two-compartment pharmacokinetic fitting, significant differences in distribution half-life (average, 21.8 and 41.6 min [P < or = 0.05]) and gentamicin CL (76.6 +/- 6.6 and 67.2 +/- 4.2 ml/min/1.73 m2 [P < or = 0.001]) were found between traditional-dose and high-dose groups, respectively. When the data for concentrations in sera were fitted to a one-compartment pharmacokinetic model by using either the distributional or the postdistributional Cmax, statistically significant differences (P < or = 0.001) were found between Vss, half-life, CL, and Cmax values for both dosage groups. The results show that the pharmacokinetics of gentamicin at a large dose differ significantly from those at the traditional dose. This information has direct implications for once-daily aminoglycoside (ODA) literature when the Cmax values reported are distributional and therefore show falsely high Cmax/MIC ratio estimates. In addition, ODA nomogram dosing tools developed with distributional Cmax values are probably inaccurate.     

Alterations in urinary bladder synaptosomal neurotransmitter concentrations in two-week streptozotocin-induced diabetic rats

Three-month-old male Wistar rats were rendered diabetic with a single intravenous injection of streptozotocin (60 mg/kg body weight). Two weeks after induction of diabetes, synaptosome-rich fractions were prepared from urinary bladder tissue homogenate of the diabetic rats and control rats by differential centrifugation (1000 x g, 17,000 x g and 100,000 x g) with discontinuous sucrose gradient. Synaptosomal acetylcholine, norepinephrine, epinephrine and dopamine were measured by the method of high-performance liquid chromatography. The respective neurotransmitter concentrations for the diabetic rats were 1537.8 +/- 65.3, 4757.7 +/- 361.9, 3720.7 +/- 276.1, and 2447.8 +/- 196.8 pmol/mg synaptosomal protein, respectively; those for the control rats were 338.1 +/- 25.0, 1009.0 +/- 54.6, 645.3 +/- 52.2, and 1426.1 +/- 123.9 pmol/mg protein, respectively. Thus, the synaptosomal concentrations for all the measured neurotransmitters were significantly higher in the diabetic rats (P < 0.05 for each comparison). In conclusion, it has been demonstrated that the vesicle-bound acetylcholine and catecholamines in the synaptosome-rich fraction of the urinary bladder were significantly increased in 2-week diabetic rats. This finding would suggest impaired neurotransmitter release from both the bladder sympathetic and parasympathetic efferent nerve endings in early streptozotocin-induced diabetes.