The Disposition of a Human Relaxin (hRlx-2) in Pregnant and Nonpregnant Rats

The pharmacokinetics and tissue distribution of a human relaxin were investigated after intravenous (iv) bolus administration to pregnant or nonpregnant rats. Human gene-2 relaxin (hRlx-2) serum concentrations after iv bolus administration were described as the sum of three exponentials. The pharmacokinetics were comparable in pregnant and nonpregnant rats. The serum clearance (CL) was 7.4–10.2 ml/min/kg at doses of 46–93 µg/kg and was linear in this range. The half-lives were 1.1–2.0, 15.1–16.4, and 53.7–67.9 min, respectively. The volume of the central compartment (V _c) was 48–79 ml/kg and the volume of distribution at steady state (V _ss) was 271–336 ml/kg. Increasing the dose to 463 µg/kg increased the dose-corrected area under the serum concentration–time curve and significantly decreased CL and Vss. The distribution of radioactivity in the tissues of pregnant rats was followed after iv bolus dosing with hRlx-2 internally labeled with ³⁵S-cysteine. Comparison of the extent of organ uptake of radiolabel after ³⁵S-hRlx-2 or ³⁵S-cysteine administration suggested that the kidneys were the principal site of uptake; the liver was of secondary importance. In perfusion experiments utilizing livers isolated from pregnant or nonpregnant rats, 36–52% of the dose of hRlx-2 was cleared from the perfusate in 2 hr. These studies showed that the pharmacokinetics of hRlx-2 in rats appeared to be unaffected by pregnancy and suggested that the kidneys and liver both play a role in the elimination of hRlx-2.     

Liquid Chromatographic Analysis of Di(2-ethylhexyl) Phthalate: Application to Pharmacokinetic Studies in the Mongrel Dog

A high-performance liquid chromatographic (HPLC) assay was developed for the determination of di(2-ethylhexyl) phthalate (DEHP) in serum or plasma. Plasma DEHP concentrations that were measured by HPLC in specimens obtained from hemodialysis patients were in good agreement with corresponding concentrations that were measured by gas chromatography with selected ion monitoring (GC-SIM) (r ² = 0.996). Plasma DEHP concentrations were measured after intravenous DEHP administration (1.2–4.4 mg DEHP/kg body weight) to determine the effect of bilateral ureteral ligation on DEHP elimination in the mongrel dog. DEHP plasma clearance (6.3 ml/min/kg), steady-state distribution volume (0.2l/kg), and terminal half-life (50 min) were unchanged in two dogs following bilateral ureteral ligation. DEHP terminal half-life and steady-state distribution volume were substantially smaller (25- to 70-fold) than reported previously in the rat or dog.     

Distribution of Gacyclidine Enantiomers in Spinal Cord Extracellular Fluid

Purpose. Determination of the pharmacokinetics of gacyclidineenantiomers, a non-competitive NMDA antagonist, in plasma and spinal cordextracellular fluid (ECF) of rats. Methods. Implantation of microdialysis probes in spinal cord (T9).Serial collection of plasma samples and ECF dialysates over 5 hoursafter IV bolus administration of (±)-gacyclidine (2.5 mg/kg). Plasmaprotein binding determined in vivo by equilibrium dialysis. ChiralGC/MS assay. Results. Plasma concentrations of (+)-gacyclidine were 25% higherthan those of (–)-gacyclidine over the duration of the experiment inall animals. Plasma concentrations decayed in parallel in a biphasicmanner (t_1/2 9 min; t_1/2 90 min) with no significant differencebetween enantiomers. Clearance and volume of distribution of(–)-gacyclidine were approximately 20% higher than those of its opticalantipode (CL: 248 vs 197 ml.kg^–1.min^–1;Vd: 31.6 vs 23.5 l/kg).Protein binding (90%) was not stereoselective. Both gacyclidineenantiomers were quantifiable in spinal cord ECF 10 min after drugadministration and remained stable over the duration of the experimentin spite of changing blood concentrations. Penetration of(–)-gacyclidine was significantly higher (40%) than that of (+)-gacyclidine inall animals. Yet, exposure of spinal cord ECF was similar for bothenantiomers, and not correlated with plasma AUCs. Conclusions. The disposition of gacyclidine enantiomers isstereoselective. Both enantiomers exhibit a high affinity for spinal cord tissueand their distribution may involve a stereoselective and active transportsystem. This hypothesis could also explain the discrepancy betweendrug concentrations in plasma and spinal cord ECF.     

The single dose kinetics of chloroquine and its major metabolite desethylchloroquine in healthy subjects

Summary The kinetics and disposition of chloroquine (CQ) and its metabolite monodesethylchloroquine (CQM) were investigated in 5 healthy volunteers after incremental (150–300–600 mg CQ base) single oral doses of CQ. The analytical method used (HPLC and fluorescence detection) is the most sensitive known method for CQ and CQM. Plasma and whole blood concentrations of CQ, CQM and a third metabolite, bidesethylchloroquine (CQMM), were determined. The kinetics of CQ was found to be unique. The best fit was obtained by a multicompartmental model. The biological half-life appeared to be between 30–60 days; the volume of distribution (V_d) was 800l/kg, and the clearance 11/h/kg when calculated from plasma data. The whole blood concentrations were 8–10 times higher than in plasma, and consequently the V_d and whole blood clearance were 10 times lower. The kinetics changed as the dose was increased. An indication of capacity-limited steps in CQ disposition was found, as the rate constants decreased even though the clearance remained the same. The intrinsic half-life of CQM was 1/4 of that of CQ, but was prolonged after the highest dose of CQ. The present knowledge of CQ kinetics could provide a basis for revision of current dosage regimens in malaria suppression and rheumatoid disease to ensure efficacious and safe therapy.     

Plasma levels and β-blocking effect of α-hydroxymetoprolol—Metabolite of metoprolol—in the dog

The plasma levels and the - blocking effect of metoprolol and its active metabolite - hydroxymetoprolol have been studied after i.v. bolus injections of the substances to dogs. For both substances the - blockade increased with the dose, and there was a linear relationship between percent reduction in exercise heart rate and the logarithm of plasma concentration. The dose of the metabolite, however, had to be 5 times higher than that of metoprolol to induce the same degree of - blockade. Because of differences in the volume of distribution, 2.0 liters/kg for - OH-metoprolol and 3.5 liters/kg for metoprolol, the 5 times higher dose of - OH-metoprolol resulted in 10 times higher plasma levels of the metabolite than of metoprolol. - OH-Metoprolol was more slowly eliminated (t_1/27.0 hr, total body clearance 3.5 ml-kg^–1-min^–1) than metoprolol (t_1/22.0 hr, total body clearance 20.0 ml-kg^–1-min^–1). Approximately 5% of an i.v. dose of metoprolol was metabolized to - OH-metoprolol. The half-life of the endogenously formed metabolite was the same as after an i.v. dose of the compound.     

Valve movement response of the mussel Dreissena polymorpha -- the influence of pH and turbidity on the acute toxicity of pentachlorophenol under laboratory and field conditions

The Dreissena-Monitor is a biological early warning system for the continuous monitoring of water quality, based on the computer assessment of valve movements in two groups of 42 zebra mussels (Dreissena polymorpha). In the laboratory, two series of toxicity tests were conducted with PCP. (1) At neutral pH conditions only the concentration of PCP was altered. The dose--response relationship revealed 15 g l–1 PCP for the number of valve movements and 20 g l–1 PCP for the percentage of open mussels. (2) At 50 g l–1 PCP the pH value was altered from 6.5 to 8.4, demonstrating an inverse relationship between the toxicity of PCP and the pH. The detection limits evaluated from a series of toxicity tests under the field conditions of the River Rhine at Koblenz were nearly ten times higher than those from the laboratory. During a second series of toxicity tests under the field conditions of the River Rhine at Bad Honnef, the toxicity of PCP seemed to be reduced in relation to the increasing turbidity. The differences between the results obtained under laboratory and field conditions are discussed with respect to the influence of the pH and turbidity at the toxicity of PCP on D. polymorpha     

Overall pharmacokinetics during prolonged treatment of healthy volunteers with digoxin andβ-methyldigoxin

Summary Five healthy volunteers received digoxin 0.4 mg or -methyldigoxin 0.4 mg i. v., daily for 14 days, in a randomized cross-over arrangement. By monitoring minimal plasma concentrations during multiple dosing, it was found that the steady state pharmacokinetics of digoxin and -methyldigoxin could be estimated even better by a one-compartment than by a two-compartment model. The following mean parameters were calculated: the half life of digoxin of 1.54±0.31 days was significantly shorter than the half life of 2.29±0.34 days for -methyldigoxin. The distribution volume of 807±187 liters for digoxin was not significantly larger than the 735±227 liters for -methyldigoxin. Renal digoxin clearance of 191±25 ml/min was significantly higher than both the renal clearance of -methyldigoxin of 111±23 ml/min and also the creatinine clearance, which indicates tubular secretion of digoxin. There was a 2.8-fold accumulation of -methyldigoxin injected once a day, which was significantly higher than the 1.8-fold accumulation of digoxin.Abbreviations of parameters D dose - EST estimated disposition rate constant (day^–1) semilog curve fit - KTOT total disposition rate constant (day^–1) NONLIN fit - KREN renal disposition rate constant (day^–1) NONLIN fit - VOL volume of distribution (liters) NONLIN fit - CTOT total clearance (ml/min) - CREN renal clearance (ml/min) - BMIN body stores (µg) before next dose in steady state - CCR creatinine clearnace (ml/min) - CR/CT fraction renally excreted - CR/CCR renal drug clearance versus creatinine clearance - T/2 half life (days) - BMIN/D extent of accumulation This study was supported by Bundesministerium für Jugend, Familie und Gesundheit, Federal Republic of Germany.     

Effect of α2-adrenoceptor agonists on the expression of morphine-withdrawal in rats

Summary Previous studies using clonidine indicate that ₂-adrenoceptors are involved in suppressing opiate-withdrawal symptoms. However, clonidine may act as a partial agonist at ₂-adrenoceptors and it also possesses significant ₁-receptor agonist activity.The aim of this study was to determine the role of ₂-adrenoceptors in the expression of opiate withdrawal signs using morphine-dependent rats. A range of agonists were selected for study on the basis of their differential preferences for -adrenoceptors.Hooded Wistar rats were made physically dependent on morphine (s.c. injection of an emulsion releasing a total of 250 mg/kg of morphine base over 48 h). Test drugs were injected s.c. followed by naloxone (10 mg/kg i.p.) 20 min later. The incidence of 5 selected withdrawal signs was recorded during the following 20 min. The ₂-adrenoceptor agonists displayed different profiles of activity. Azepexole (1–10 mg/kg) reduced all signs. Clonidine (80–800 g/kg) reduced all signs except paw shakes while guanfacine (25–250 g/kg) reduced all except jumping and diarrhoea. Talipexole (0.1–1 mg/kg) reduced all signs except diarrhoea which was not affected and jumping which was markedly enhanced. UK 14,304 (80–800 g/kg) reduced jumps, potentiated paw shakes but did not affect body shakes, teeth chattering or diarrhoea. The results suggest that there are subpopulations of ₂-adrenoceptors that modulate the expression of opiate withdrawal signs and/or that some of the drugs used affect receptors other than ₂-adrenoceptors.     

Inhibition of human and rabbit platelet aggregation by chlorophenoxyacid herbicides

Inhibition of human platelet aggregation by eight chlorophenoxyacid herbicides was studied in vitro. Thrombocyte aggregation in the platelet-rich plasma was induced by 1.0–32.0 M adenosine diphosphate (ADP), 0.32–32.0 M adrenaline or 7.5–30.0 g/ml collagen with and without chlorophenoxyacid (0.05–2.0 mg/ml). Platelet aggregation by each inducer was inhibited dose dependently by all the eight chlorophenoxyacids at concentrations between 0.1 and 2.0 mg/ml. Increasing the concentrations of ADP and collagen but not of adrenaline inhibited the antiaggregatory action of chlorophenoxy-acids. No essential differences in inhibitory effect were found between different chlorophenoxyacids varying in respect of their ring substituents and the length of the carboxylic side chain. In the platelet-rich plasma prepared from rabbits 2.5 h after subcutaneous injection of 2,4-dichlorophenoxyacetic acid or 4-chloro-2-methylphenoxy-acetic acid (100–150 mg/kg), platelet aggregation by ADP was inhibited 20–30%, compared to plasma taken from the rabbits before the chlorophenoxyacid treatment. The inhibition had disappeared by 20–23 h after administration. The results indicate that chlorophenoxyacid herbicides inhibit human platelet aggregation. Furthermore, the inhibition is probably involved in haemorrhages known to occur in various tissues of animals intoxicated by chlorophenoxyacid herbicides.     

Kinetics and metabolism of 2,2-diethylallylacetamide in dog and man

Summary In dogs, slow intravenous injection of 100 mg of diethylallylacetamide (DA) resulted in maximal blood levels of 10–14 g/ml, and a rapid phase of elimination during 90 min with a half life of 45 min, followed by a slower elimination rate with a half life of 80–90 min.After oral application of 30 mg DA/kg to female beagle dogs, maximal blood levels of 14 g/ml were observed after 90–120 min. The blood concentrations declined with a mean half life of 5 h.In human volunteers, oral doses of 250 mg DA, or rectal application of 300 mg DA produced highest mean blood levels of 4.8 g/ml (orally), and 5.4 g/ml (rectally) after 180 min. The mean blood half life was 7.2 h (orally), and 9.2 h (rectal application). Undesirable effects such as nausea, vomiting, and disorientation began to appear at blood levels above 5 g/ml.In the urine of dogs and human volunteers, only 2–3% of unchanged DA was recovered, and less than 1% of 2,2-diethyl-4,5-dihydroxypentanoic acid--lactone (DA-lactone) was identified. Acid hydrolysis of the human urine liberated a total of 14–16% of DA-lactone. This percentage was not increased by splitting the urinary conjugates with glucuronidase and glusulase. Small amounts of 2,2-diethylallylacetic acid, 2,2-diethyl-4-one-pentanoic acid, and 2,2-diethyl-4,5-dihydroxypentanamide were detected.The new metabolites described were synthetized and fully characterized.Abbreviations used in the text AIA allylisopropylacetamide - DA 2,2-diethylallylacetamide (2,2-diethyl-4-penteneamide) - DA-acid 2,2-diethylallylacetic acid (2,2-diethyl-4-pentenoic acid) - DA-lactone 2,2-diethyl-4,5-dihydroxypentanoic acid--lactone - DA-glycol 2,2-diethyl-4,5-dihydroxypentanamide The results were presented at the 17th Spring Meeting of the German Pharmacological Society (Brinkschulte-Freitas and Uehleke, 1976). Parts of the results are included in the dissertation of Brinkschulte (1975)     

Metabolisches Verhalten von kolloidalem Ferrihexacyanoferrat(II)

Summary Intestinal absorption, distribution, and excretion of ferrihexacyanoferrate(II), labeled by⁵⁹Fe at the Fe(III)- and Fe(II)-atoms, respectively, was studied in rats. Following i.v. injection, the compound is separated at 60% into Fe³⁺ and [Fe(CN)₆]^4–, the residual fraction being retained by the reticuloendothelial system. [Fe(CN)₆]^4– is excreted rapidly and virtually completely by the kidneys. With oral administration the disintegration amounts to 7%, and 2% of [Fe(CN)₆]^4– is absorbed from the gut. No evidence was obtained for decomposition of [Fe(CN)₆]^4–. No toxic side-effects were observed after chronic administration of ferrihexacyanoferrate(II).

     

Pharmacokinetics of exogenous adenosine in man after infusion

Summary The plasma kinetics of adenosine was investigated in healthy volunteers after a 1 minute infusion of 2.5, 5 and 10 mg (38, 79 and 148 g·kg^–1 respectively) and after infusion of 200 g·kg^–1 in 10 min followed by 400 g·kg^–1 in 10 min.As the dose in the 1 min infusion study was increased the mean CL of adenosine decreased (10.7, 4.70 and 4.14 l·min^–1, respectively), its mean half-life increased (0.91, 1.24 and 1.86 min, respectively), and the mean volume of distribution did not show any clear trend (8–13 l).After the 20 minute infusion the plasma level of adenosine reached a peak value comparable to that observed after infusion of 5 mg in 1 min (about 0.5 g·ml^–1), but the mean clearance and half-life were significantly different (12.1 l·min^–1 and 0.63 min respectively).In all the subjects the plasma concentration of adenosine had returned to the baseline value in 5–15 min after the end of the infusion.     

In Vivo Saturation of the Transport of Vinblastine and Colchicine by P-Glycoprotein at the Rat Blood–Brain Barrier

Purpose. To determine concentration-dependent P-gp-mediated efflux across the luminal membrane of endothelial cells at the blood-brain barrier (BBB) in rats. Methods. The transport of radiolabeled colchicine and vinblastine across the rat BBB was measured with or without PSC833, a well known P-gp inhibitor, and within a wide range of colchicine and vinblastine concentration by an in situ brain perfusion. Thus, the difference of brain transport achieved with or without PSC833 gives the P-gp-mediated efflux component of the compound transported through the rat BBB. Cerebral vascular volume was determined by coperfusion with labeled sucrose in all experiments. Results. Sucrose perfusion indicated that the vascular space was close to normal in all the studies, indicating that the BBB remained intact. P-gp limited the uptake of both colchicine and vinblastine, but the compounds differ in that vinblastine inhibited its own transport. Vinblastine transport was well fitted by a Hill equation giving IC₅₀ at 71 M, a Hill coefficient (n) 2, and a maximal efflux velocity J_max of 9 pmol s^–1 g^–1 of brain. Conclusions. P-gp at the rat BBB may carry out both capacity-limited and capacity-unlimited transport, depending on the substrate, with pharmacotoxicologic significance for drug brain disposition and risk of drug-drug interactions.     

Pharmacokinetics of ketamine and two metabolites in the dog

The plasma concentrations of ketamine, N-demethylketamine (I), and the cyclohexene metabolite (II) formed by oxidation of I were determined at various times after rapid i.v. administration of 15 mg of ketamine HCl/kg of body weight to dogs. A pharmacokinetic model that included two compartments for ketamine and one compartment for each metabolite was developed. Ketamine distributed rapidly with (t _1/2 averaging 1.95 min. The apparent volumes of the central and peripheral compartments for ketamine averaged 542 and 1940 ml/kg of body weight, respectively, and the (t _1/2 ) averaged 61 min. The model indicated that 62% of ketamine was transformed to I and that 11% of I was converted to II. The apparent volumes of distribution of I and II averaged 61% and 59% of body weight, respectively. The total body clearances (plasma) of ketamine, I, and II averaged 32.2, 89.4, and 8.54 ml/min/kg, respectively. Plasma protein binding was determined by equilibrium dialysis; it averaged 53.5% for ketamine (concentration range 0.34– 19.5 g/ml), 60.3% for I (0.05– 19.6 g/ml), and 70.1% for II (0.09– 0.58 g/ml). A minimum anesthetic concentration of 3 g ketamine HCl/ml plasma was used with the model to predict that the duration of ketamine anesthesia after an i.m. dose would not be significantly affected if the absorption t_1/2 varied from 0.48 to 31 min. The model also predicted that accumulation of I and II would not interfere with ketamine anesthesia that was prolonged by repeated doses, each dose administered i.v. on termination of anesthesia from the previous dose.     

Tolerance to nicotine in mice lacking α7 nicotinic receptors

Rationale Previous studies have suggested that a knockout of the gene coding for 7 nicotinic receptor subunits influences the behaviour of undrugged mice but not the acute effect of nicotine on locomotor activity.Objectives The present studies extend these observations to nicotine tolerance assessed by means of schedule-controlled behaviour.Methods Groups of 7^–/– and 7^+/+ mice were trained to press levers under an FR20 schedule of food reinforcement. The acute response rate-depressant effects of nicotine were determined in both genotypes and the mice were then subdivided into groups treated daily with nicotine (1.2 mg/kg/day) or saline. After 39 days of exposure to this regimen, the dose–response curves were re-determined.Results Knockout of the 7 gene had no consistent effect on the lever-pressing behaviour of undrugged mice and did not influence the acute, dose-related, response rate-depressant effect of nicotine (0.2–1.2 mg/kg). When dose–response curves for nicotine (0.4–2.0 mg/kg) were re-determined after daily dosing with the drug, both wild-type and knockout mice developed similar tolerance to nicotine, as shown by 2.5-fold shifts to the right of the dose–response curves.Conclusions Nicotinic receptors containing the 7 subunit do not play a significant role in the regulation of the lever-pressing behaviour studied or in the acute behavioural depressant effect of nicotine and the development of tolerance to that effect. Such results contrast with previous reports suggesting profound impairments in sensitivity to nicotine in nicotinic receptor 2^–/– mice.C. Naylor and D. Quarta are listed alphabetically and contributed equally to the work.     

Partial Maintenance of Taurocholate Uptake by Adult Rat Hepatocytes Cultured in a Collagen Sandwich Configuration

Purpose. This study was designed to characterize taurocholate uptake properties in primary cultures of rat hepatocytes maintained under different matrix conditions. Methods. Hepatocytes isolated from male Wistar rats (230–280 g) were cultured on a simple collagen film, on a substratum of gelled collagen or between two layers of gelled collagen (sandwich configuration). Hepatocyte morphology, taurocholate uptake properties, and expression of the sinusoidal transport protein, Na⁺/taurocholate-cotransporting polypeptide (Ntcp) were examined in these cultures at day 0 and day 5. Results. By day 5, monolayer integrity had deteriorated in simple collagen cultures. In contrast, cell morphology was preserved in hepatocytes maintained in a sandwich configuration. At day 5, taurocholate accumulation at 5 min in hepatocytes cultured on a simple collagen film, on a substratum of gelled collagen, and in a sandwich configuration was 13%, 20% and 35% of day-0 levels, respectively, and occurred predominately by a Na⁺-dependent mechanism. The initial taurocholate uptake rate vs. concentration (1-200 M) profile was best described by a combined Michaelis-Menten and first-order function. In all cases, the estimated apparent K_m values were comparable for day-0 and day-5 hepatocytes (32–41 M). In contrast, the V_max values of hepatocytes cultured on a simple collagen film, on gelled collagen and in a sandwich configuration were 5, 6 and 14% of the values at day 0, respectively; values for the first-order rate constant were 5-, 3- and 2-fold lower, respectively. Immunoblot analysis indicated that at day 5 Ntcp expression in hepatocytes cultured in a sandwich configuration was greater than in hepatocytes cultured on a simple collagen film. Conclusions. A collagen sandwich configuration reestablishes normal morphology and partially restores bile acid uptake properties in primary cultures of rat hepatocytes.     

Facilitation of shock-induced fighting following intraventricular 5,7-dihydroxytryptamine and 6-hydroxydopa

Immobilization of albino rats for 2 h showed ambient temperature-dependent changes in rectal temperature, hypothermia at temperatures below 30° C, and hyperthermia at 35° C and above. Adrenalectomized (Adre) rats showed more hypothermia compared to sham operated controls at 25±2° C. The increased hypothermia in adrenalectomized rats was reversed by 10 mg/kg IP or 100 g/rat ICV of hydrocortisone. Groups of rats pretreated with desmethylimipramine (DMI, 25 mg/kg IP) and 6-hydroxydopamine (6-HD, 100 g/rat ICV) or methyl ester of parachlorophenylalanine (ME-PCPA, 100 g/rat ICV for 3 days) or 5,6-dihydroxytryptamine (DHT, 75 g/rat ICV) showed significantly less hypothermia at the end of 2 h of immobilization. Applying analysis of variance test, the hypothermia in Adre, ME-PCPA and DHT groups, was found to be not significantly different from their respective control groups between 0 to 45 min of immobilization but was significantly different between 45 to 120 min of immobilization. DMI-6-HD group however, showed significant difference between 0–45 min only and not between 45–120 min of immobilization. The results suggest that the early phase of immobilization induced hypothermia between 0–45 min is dopamine and the late phase of hypothermia between 45–120 min is 5-hydroxytryptamine mediated.     

Methyl mercury reduces voltage-activated currents of rat dorsal root ganglion neurons

Methyl mercury (MeHg) is a widespread toxicant with major actions on the nervous system. Since the function of neurons depends on voltage gated ion channels, we examined the effects of micromolar concentrations of methyl mercury on voltage-activated calcium, potassium and sodium channel currents of cultured rat dorsal root ganglion (DRG) neurons. The cells, which were obtained from 2–4 day old rat pups, were whole-cell patch-clamped. Currents were separated by selective intra-and extracellular solutions as well as specific depolarizing voltage steps. We did not distinguish between different calcium, potassium or sodium channel subtypes.All three types of voltage-activated currents were irreversibly reduced by McHg in a concentration dependent manner. Voltage-activated calcium and potassium channel currents were more sensitive to MeHg (Calcium: IC₅₀ = 2.6±0.4 M; Potassium: IC₅₀ = 2.2±0.3 M) than voltage-activated sodium channels (IC₅₀ = 12.3±2.0 M). The Hill coefficients for the reduction of the currents were calculated as 1 for calcium and potassium channel currents and as 1.7 for sodium currents. In the cases of the voltage-activated calcium and sodium channel currents the reduction was clearly use dependent. Higher concentrations of McHg ( 5 M) resulted in a biphasic change in the holding membrane current at the potential of –80 mV in 25% of the cases.     

Disposition kinetics of ethambutol in man

Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 g/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The phase in these subjects had a mean half-life of 8.6 min while the half-life of the phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the phase estimated from plasma data points between 12 and 24 hr averaged 11.2±3.6 hr. A terminal t_1/2 of 15.4±1.7 hr was calculated from 12–72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 9.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.This work was supported in part by NIH Grant GM 26551.     

Kinetics and efficacy of theophylline in the treatment of apnea in the premature newborn

Summary Aminophylline (theophylline-ethylenediamine) was administered to 27 premature newborns to prevent apneic spells. Of the 22 patients monitored for theophylline concentration, a therapeutic blood level was reached in 19 in 1–2 days, and 3 stayed below it. Toxic blood levels (20 µg/ml) were reached in 3 cases, one of whom showed signs of toxicity. Theophylline treatment was not efficient in the prevention of apnea when a serious underlying disease was present. Theophylline blood half-life (mean : 27.0 h) and clearance (mean 12.9 ml/h/kg) confirmed the slow elimination pattern of the drug in the premature infant.