α-Monofluoromethyldopa (MFMD) in combination withl-DOPA

Summary We have investigated the interaction of -monofluoromethyldopa (MFMD) with the effects of i.p. injectedl-DOPA (200 mg·kg^–1) on blood pressure and tissue catecholamines in normal and spontaneously hypertensive rats (SHR). MFMD 10 mg·kg^–1 (i.p.) effectively antagonizes thel-DOPA induced increase in heart dopamine (DA). This action is also seen after 15 or 50 mg·kg^–1. The accumulation of DA in the brain is very much reduced by MFMD 50 mg ·kg^–1 while after 15 or, especially, 10 mg·kg^–1 more DA is formed in the rrain than afterl-DOPA alone, probably due to the peripheral decarboxylase inhibition which presents morel-DOPA to the brain. We conclude that MFMD 10 mg ·kg^–1 gives a relatively selective peripheral inhibition of the decarboxylation ofl-DOPA and this dose combination was accordingly found to result in a reduction of blood pressure in conscious animals. This hypotensive response tol-DOPA was attenuated after MFMD 15 mg·kg^–1 and was absent after MFMD 50 mg·kg^–1. Interestingly, the hypotensive effect ofl-DOPA after MFMD 10 or 15 mg·kg^–1 was more pronounced in SHR.     

Comparison of verapamil and bepridil,two slow channel inhibitors,in protection against calcium-induced arrhythmias

Summary Verapamil and bepridil share the common property of antagonizing the slow inward calcium-mediated current, but bepridil has some additional antiarrhythmic properties. The efficacy of these two compounds against CaCl₂-induced arrhythmias has been compared in rats. CaCl₂ was administered i.v. by continuous infusion until death (25 mg·kg^–1·min^–1 or 40 mg·kg^–1·min^–1) or by bolus injection (160 mg·kg^–1). Bepridil (5, 10 mg·kg^–1) or verapamil (2.5,5 mg·kg^–1) were injected 10 min before CaCl₂. Bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1) prolong the survival time during CaCl₂ infusion. After pretreatment, the injection of 160 mg·kg^–1 CaCl₂ is less toxic: 25% of animals are protected by bepridil (5 mg·kg^–1), 41% by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1).At death the myocardial Ca²⁺ level is not different in controls and pretreated animals, thus, the ratio myocardial Ca²⁺/total injected Ca²⁺ is significantly lowered by bepridil (10 mg·kg^–1) or verapamil (5 mg·kg^–1). The efficacy of the two drugs on this model appears related solely to inhibition of slow inward current despite the additional antiarrhythmic profile of bepridil.     

Effects comparés du muscimol et du diazépam sur les inhibitions du comportement induites chez le rat par la nouveauté, la punition et le non-renforcement

Diazepam and muscimol, a direct GABA agonist, were compared on behavioral inhibition induced in rats by (1) novelty, (2) punishment, and (3) nonreward.(1) Muscimol (0.03–0.25 mg·kg^-1 i.p. 30 min before testing, or i.v. immediately before testing) failed to enhance food intake consistently in a nonfamiliar situation and (0.125–0.5 mg · kg^-1 i.p. or i.v.) to increase the ingestion of an unknown food (chocolate); (2) muscimol (0.125–0.5 mg · kg^-1 i.p. or 0.25 i.v. 10 min before testing) was ineffective in reducing the inhibition of lever presses for food elicited by the delivery of an electric shock at every eighth press; (3) muscimol (0.125–0.5 mg · kg^-1 i.p.) failed to attenuate the inhibitory effects on responding induced by the suppression of the reinforcement during extinction.Contrastingly, diazepam (2 mg · kg^-1 i.p. 30 min before testing) was found to reduce each type of behavioral inhibition.These data lend no support to the hypotheses of GABA control of behavioral inhibition and of GABA involvement in the action of benzodiazepines on inhibition induced by novelty, punishment, or nonreward.

     

Penetration of cefoperazone into ascites

Summary The pharmacokinetics of cefoperazone was studied in eleven cirrhotic patients with ascites after i.v. administration of a single dose of 15 mg·kg^–1 (n=7) or after three doses of 15 mg·kg^–1 given at 12 h intervals (n=4). The concentrations of cefoperazone in serum and ascitic fluid were determined by HPLC. The peak serum cefoperazone concentration after a single i.v. injection of 15 mg·kg^–1 was 96.0 mg·l^–1. The serum elimination half-life was longer (5.0 h) than in normal subjects. The penetration of cefoperazone into ascites was satisfactory (32.3% and 58.3% after single and repeated injections, respectively).Ascitic fluid concentrations of cefoperazone exceeded 5.4 mg·ml^–1 from 0.5 to 6 h after the single i.v. injection, levels which are well above the MIC of most pathogens found in spontaneous bacterial peritonitis. Adjustment of the dose of cefoperazone in cases of severe hepatic insufficiency does not appear to be necessary provided that renal function is normal.     

The pharmacokinetics of d-sotalol and d,l-sotalol in healthy volunteers

Summary The pharmacokinetics of d-sotalol has been studied in six healthy volunteers given single doses of 0.25, 0.50, 1, 2 mg·kg^–1 i.v. and one 100 mg oral dose in comparison with the kinetics of 1 mg·kg^–1 i.v. of dlsotalol.There was no significant difference in the disposition of the d-enantiomer and the racemate.The terminal half-life averaged 7.2 h, and the kinetics was linear, with a mean total clearance of 0.13 l·h^–1·kg^–1. Renal clearance of d-sotalol represented 56 to 77% of total clearance. The absolute systemic availability of oral d-sotalol was close to 100% and the elimination half-life of the oral-d-enantiomer was similar to that of the i.v. form (7.5 h).     

Cardiovascular effects of clonidine in an avian species,Larus argentatus

Summary Blood pressure and heart rate were recorded in the sea gull, Larus argentatus, under light pentobarbitone anaesthesia. Clonidine 10^–7 and 10^–8 mol·kg^–1 (27 and 2.7 g·kg^–1) i.v. produced a biphasic effect on blood pressure, a brief initial increase being followed by a prolonged hypotensive response. There was an immediate reduction in heart rate which persisted throughout the hypotensive phase. After spinal transection at the level of C 4, clonidine administration elicited hypertension and bradycardia.Bilateral vagotomy abolished the effect of clonidine on heart rate but did not alter the blood pressure response.Vagotomy in combination with spinal transection abolished the effect of clonidine on heart rate but the hypertensive response was accentuated.Yohimbine 10^–7 or 10^–6 mol·kg^–1 (0.039 or 0.39 mg·kg^–1) given 5 min after clonidine 10^–7 mol·kg^–1 (27 g·kg^–1) effectively antagonized the cardiovascular effects of clonidine, while prazosin 10^–7 or 10^–6 mol·kg^–1 (0.042 or 0.42 mg·kg^–1) had no such effect.We conclude that clonidine acts in the central nervous system of the sea gull to produce a lowering of blood pressure and heart rate. These effects are mediated by central inhibition of sympathetic activity and, in the case of the heart rate, mostly by central activation of vagal activity to the heart. This central action of clonidine involves activation of -adrenoceptors which are blocked by yohimbine but not by prazosin and therefore may belong to the ₂ subtype.     

Analysis of the heart rate effects of 5-hydroxytryptamine in the cat; mediation of tachycardia by 5-HT1-like receptors

Summary The effects of 5-hydroxytryptamine (5-HT) on heart rate in anaesthetized cats were analysed both in intact animals and after spinal section plus vagotomy.The intact cat responded to 5-HT (3, 10 and 30 g·kg^–1, i.v.) with a brief, but intense, bradycardia and a longerlasting hypotension. Administration of MDL 72222, a selective antagonist of M-type 5-HT receptors, blocked bradycardia elicited by 5-HT without affecting that caused by stimulation of the vagus nerve.In spinal cats the same doses of 5-HT increased heart rate and blood pressure. These effects remained essentially unchanged after bilateral adrenalectomy, guanethidine, propranolol and burimamide, suggesting that 5-HT acted directly on the myocardium and blood vessels. The tachycardic responses to 5-HT in spinal cats were little affected by 0.5 mg·kg^–1 doses of MDL 72222 or of the 5-HT₂ receptor antagonists, ketanserin, ritanserin or cyproheptadine. In contrast, the non-selective 5-HT receptor antagonist, methysergide, which binds to both 5-HT₁ and 5-HT₂ recognition sites in rat brain membranes, potently antagonized the 5-HT-induced tachycardia in doses of 0.05 to 0.5 mg·kg^–1. However pizotifen and mianserin, two other 5-HT₂ antagonists which show poor affinity for 5-HT₁ recognition sites, were also effective against the tachycardic response to 5-HT in doses of 0.5–4.5 mg·kg^–1. The pressor responses to 5-HT in the spinal cat were markedly inhibited by all six 5-HT₂ antagonists at a dose of 0.5 mg·kg^–1.5-Carboxamido-tryptamine, which has a high and selective affinity for 5-HT₁ recognition sites, elicited marked tachycardia in doses of 0.1–10 g/kg^–1 in spinal cats treated with saline. These responses were not affected in animals treated with 4.5 mg·kg^–1 of ketanserin, which was able to shift the dose-response curve for 5-HT to the right. On the other hand, methysergide (0.5 mg·kg^–1) displaced the dose-response curves for both 5-carboxamidotryptamine and 5-HT to a similar extent.Unlike on the dog saphenous vein, methysergide showed no agonist effects on heart rate in the spinal cat.On the basis of the above results, we conclude that: (i) the reflexogenic bradycardic response elicited by 5-HT overshadows its direct tachycardic response on heart rate in the intact cat; (ii) M-type 5-HT receptors mediate the bradycardic response; (iii) the pressor response to 5-HT in the spinal cat involves 5-HT₂ receptors; (iv) tachycardia by 5-HT in the spinal cat is mediated mainly by 5-HT₁-like receptors, but an additional, though less important, non-5-HT₁ mechanism may also be involved; (v) the cardiac 5-HT₁ receptors are similar, but perhaps not identical, to those delineated in the dog saphenous vein or rat brain membrane preparations; and (vi) the tachycardic responses to 5-HT and, in particular the more selective, 5-carboxamidotryptamine may be conveniently utilized to characterize new chemical compounds designed for potential 5-HT₁ receptor antagonist activity.     

Dose-dependent absorption and elimination of cefadroxil in man

Summary The pharmacokinetic behaviour of cefadroxil was dose-dependent in healthy male volunteers following the oral administration of single doses of 5, 15, and 30 mg · kg^–1.As the dose of cefadroxil increased from 5 to 15 and 30 mg · kg^–1, the peak plasma concentrations, normalized to 5 mg · kg^–1, decreased significantly from 15.1 to 10.7 and 7.6 mg·l^–1, while the corresponding normalized areas under the plasma concentration-time curves from 0 to 2 h decreased significantly from 1258 to 946 and 801 min·mg·l^–1.When the same subjects were given 5 mg·kg^–1 of cefadroxil together with 45 mg·kg^–1 of cephalexin, the absorption of cefadroxil was slowed to a similar or greater extent than with the high dose of cefadroxil.Although the absorption rate decreased as the dose increased, the systemic availability of cefadroxil was essentially complete at all doses, as judged by the 24 h urinary recoveries of the antibiotic. Kinetic analysis of the plasma concentration-time curves gave the best fit with a zero-order followed by a first-order absorption process, consistent with saturable intestinal absorption of cefadroxil.The elimination rate of cefadroxil was directly related to dose and plasma concentrations, and the clearance at the dose of 5 mg·kg^–1 was significantly increased by the simultaneous administration of high-dose cephalexin.The renal clearance of cefadroxil ranged from 98 ml·min·l^–1 at total plasma cephalosporin (cefadroxil + cephalexin) concentrations less than 2.5 mg·l^–1 to 156 mg·l^–1 at concentrations greater than 40 mg·l^–1. These findings are consistent with saturable active gastrointestinal absorption and renal tubular reabsorption of cefadroxil, with competitive inhibition of both processes by cephalexin.     

Action of the competitive angiotensin II antagonist saralasin during the initial phase of glycerol-induced acute renal failure of the rat

Summary The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml ·kg^–1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure.In healthy rats saralasin (6 g·kg^–1·min^–1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng·kg^–1·min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.Supported by Deutsche Forschungsgemeinschaft     

Pharmacokinetics of ethanol in plasma and whole blood: estimation of total body water by the dilution principle

Summary The pharmacokinetics of ethanol in plasma and whole blood have been investigated and the results used to estimate the volume of total body water (TBW) by means of the dilution principle. Fifteen men (mean age 62 y) were given 0.6 g ethanol/kg body weight as an intravenous infusion over 1 h.The peak concentration of ethanol in plasma was 120 mg·dl^–1 compared to 108 mg·dl^–1 for whole blood. The disappearance rate of ethanol from plasma was 18.6 mg·dl^–1·h^–1 compared to 17.0 mg·dl^–1·h^–1 for the whole blood concentration-time data. The apparent volume of distribution of ethanol (V_z) was 0.54 l·kg^–1 according to plasma kinetics compared to 0.59 l·kg^–1 for the kinetics derived from whole blood. The mean area under the curve (AUC) was 294 mg·dl^–1×h for plasma kinetics compared to 266 mg·dl^–1×h for whole blood. The TBW was 40.9 l or 50.9% of body weight for the plasma concentration-time data. This agreed well with the 40.3 l or 50.1% of body weight obtained using whole blood.     

Steady-state levels of pefloxacin and its metabolites in patients with severe renal impairment

Summary Twenty patients (aged 26–70 years) with severely impaired renal function received pefloxacin twice daily for 5 days as 12 mg·kg^–1 administered as a 1 h i.v. infusion, or 800 mg administered as tablets.On Day 5 the minimal and maximal plasma concentrations were 5.9 and 11.5 mg·l^–1 respectively, after the infusion, and 8.0 and 10.4 mg·l^–1, respectively, after oral administration. The steady-state level of the N-desmethyl metabolite ranged from 0.9 (infusion) to 1.2 mg·l^–1 (oral route), and that of the N-oxide metabolite ranged from 6.2 (infusion) to 9.0 mg·l^–1 (oral route). The minimal concentration of unchanged drug was related to the age of the patients (infusion), but the N-oxide concentration was influenced by the degree of renal impairment (both routes).The pefloxacin levels were similar to those achieved in healthy subjects, but reduced renal function leads accumulation of its biotransformation products, especially of the N-oxide metabolite which lacks antibacterial activity.     

Drug monitoring of quinine by HPLC in cerebral malaria with acute renal failure treated by haemofiltration

Summary The monitoring of quinine by HPLC in 3 patients suffering from cerebral malaria with acute renal failure and treated by haemofiltration is reported.The recommended dose of quinine in this situation is reduced to 10 to 15 mg·kg^–1·day^–1. However, in the first patient, when given quinine 10 mg kg^–1·day^–1 the plasma concentration was mainly below the recommended therapeutic range of 5 to 15 mg/l. In consequence, the dose of quinine in the second patient was elevated to quinine dihydrochloride 15.1 mg·kg^–1·day^–1 which produced plasma concentrations in the low therapeutic range. In the third patient, an unreduced dose of quinine dihydrochloride 25.7 mg·kg^–1·day^–1 was employed, resulting in plasma concentrations above 15 mg/l, which is generally assumed to be toxic, although, no sign of acute quinine toxicity was seen.The antimalarial effect in all three patients was satisfactory. Quinine was estimated in the haemofiltrate in two patients and was found to be below the limit of sensitivity (0.25 mg/l). Plasma quinine did not change during or shortly after haemofiltration.It is concluded that in case of acute renal failure in cerebral malaria the dose of quinine should be reduced, but that the common recommendation of 10 to 15 mg·kg^–1·day^–1 may be too low, and that haemofiltration has no marked influence on the total body clearance of quinine.     

Oxolinic acid and diazepam: Their reciprocal antagonism in rodents

The stimulant effects of oxolinic acid were investigated in rats and mice. This drug, given orally, consistantly induced, in doses ranging from 16 to 256 mg·kg^-1, locomotor stimulation and stereotyped behavior.These effects were antagonized by pimozide (1 mg·kg^-1), -methyltyrosine (64 mg·kg^-1) or reserpine (4 mg·kg^-1, 24 h before testing) pretreatment, suggesting a facilitatory role of oxolinic acid on catecholaminergic processes.Diazepam (4–16 mg·kg^-1) reduced the stimulant effects induced by oxolinic acid but not those induced by amphetamine; oxolinic acid (8 mg·kg^-1) markedly reduced the antipunishment effect elicited in rats by diazepam (2 mg·kg^-1). Since benzodiazepines have been reported to enhance GABA functioning, these data suggest that oxolinic acid may impair GABA transmission. However, neither muscimol (0.5–1 mg·kg^-1) or -acetylenic-GABA (16–64 mg·kg^-1) selectively reduced the stimulant effects elicited by oxolinic acid. Therefore, the possible facilitation exerted by this drug on catecholaminergic systems may not derive from the release of an inhibitory GABAergic control.     

Pharmacokinetics of intravenous bisoprolol in obese and non-obese volunteers

Summary The pharmacokinetics of a single i. v. dose of dlbisoprolol 0.16 mg·kg^–1 ideal body weight has been studied in 8 obese women (mean weight 91 kg; 161% of ideal body weight) and 8 non-obese women (51 kg; 94% of ideal body weight).Compared to the controls, the obese subjects showed an increase in the total apparent volume of distribution (V_z) (182 vs 135 1) and a decrease in V_z per kg body weight (2 vs 2.7 l·kg^–1). There was a negative correlation between V_z l·kg^–1 and the percentage of ideal body weight (r=–0.672). Total body clearance was increased, but t_1/2 and renal clearance was unchanged.It is concluded that tissue diffusion of bisoprolol in obese subjects is limited, despite its lipophilicity, possibly because of alteration in the blood flow to adipose tissue produced by bisoprolol.     

Pharmacokinetics of ibuprofen in febrile children

Summary Ibuprofen may be an alternative to acetaminophen to control fever in children but little is known about its pharmacokinetics in pediatric patients. We studied 17 patients (age 3–10 yr) with fever; the most prevalent diagnoses were streptococcal pharyngitis and otitis media. Ibuprofen liquid was given as a single dose, 5 mg/kg (9 patients) or 10 mg/kg (8 patients). Multiple blood samples were collected over 8 hours and analyzed by HPLC.The maximum observed serum concentrations of ibuprofen ranged from 17–42 m·ml^–1 at 5 mg·kg^–1 and 25–53 m·ml^–1 at 10 mg·kg^–1 doses. Pharmacokinetics did not appear to be affected by ibuprofen dose. Mean t_max, oral clearance and elimination half life were 1.1 h, 1.2 ml·min^–1·kg^–1, and 1.6 h, respectively in patients at 5 mg·kg^–1 doses; the corresponding values were 1.2 h, 1.4 ml·min^–1·kg^–1, and 1.6 h in those receiving 10 mg·kg^–1 doses. There was no relationship between age and ibuprofen kinetics. No adverse effects occurred in any patients.These data suggest that ibuprofen pharmacokinetics may not be affected by dose between 5 and 10 mg/kg or age between 3 and 10 years.     

Influence of hyperlipidic food on the kinetics of slow-release formulations of theophylline

Summary A cross-over study of kinetics has been undertaken in 12 healthy adults volunteers using two sustained-release theophylline products that allow once a day dosing (Theo-Dur tablets and Dilatrane A.P. bead filled capsules) to compare the i.v. pharmacokinetic profiles when taken with an hyperlipidic meal and a balanced standard meal. Each subject took part in four phases in randomised order, corresponding to all possible combinations of the products and the types of meal. Each phase involved a single dose of 9 to 11 mg·kg^–1 theophylline administered at 20.00 h, at the beginning of the meal, with 100 ml water.The two formulations were found to be bioequivalent with both types of meal. Taken with a balanced meal, the mean parameters were similar; for Theo-Dur and Dilatrane A.P. they were respectively:C_max: 11.32 mg·l^–1 which plateaued from 8 to 10 h after dosing and 10.9 mg·l^–1, which plateaued after 6 to 10 h; AUC 230 mg·h·l^–1 and 220 mg·h·l^–1; and MRT 18.2 h and 17.7 h. After the hyperlipidic meal the values for Theo-Dur and Dilatrane A.P. respectively, were: C_max 10.9 mg·l^–1 at 12 h and 11.3 mg·l^–1 at 10 h; AUC 237 mg·h·l^–1 and 227 mg·h·l^–1; and MRT 19.2 h and 18.9 h.In spite of a decrease in the absorption rate, which led to a shift to the right of about 2 h of the plasma concentration-time curve, the bioavailability of both formulations were not significantly modified by a hyperlipidic meal as compared to a balanced meal. The shift of the curve with fatty food was not clinically important, as there was no dumping effect.The main difference between the two formulations was seen during the absorption phase, which was linear and less variable with Dilatrane A.P. and sigmoidal with Theo-Dur. This was observed with both types of meal.     

Pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus infection

The objective of this study was to determine the pharmacokinetics of fluconazole after oral administration in children with human immunodeficiency virus (HIV) infection. After an overnight fast, a single dose of either 2 mg·kg^–1 or 8 mg·kg^–1 was administered in a suspension; five children received 2 mg·kg^–1 and four 8 mg·kg^–1 (ages 5–13 years). Blood samples were collected at various times on day 1, and once daily on days 2–7 after the dose. Fluconazole serum concentrations were measured by gas chromatography. At the dose of 2 mg·kg^–1, the C_max, AUC (0–), and t_1/2 ranged from 2.3–4.4 g·ml^–1, 84.9–136 g·h·ml^–1, and 19.8–34.8 h, respectively. At the dose of 8 mg·kg^–1 the C_max, AUC (0–), and t_1/2 ranged from 5.4–12.1 g·ml^–1, 330–684 gh·ml^–1, and 25.6–42.3 h, respectively. When compared with published data in healthy adults, fluconazole achieved similar serum concentrations in the present group of children, indicating a nearly complete degree of absorption.     

Treatment of persistent fetal circulation syndrome of the newborn. Comparison of different doses of tolazoline

Summary The effects of two doses of tolazoline have been compared in 2 groups of newborns suffering from the persistent fetal circulation syndrome. The effects on PaO₂ and AaDO₂ were similar in the 2 groups who received either a bolus of 1 or 0.5 mg·kg^–1 tolazoline, followed by a continuous infusion of 1 or 0.5 mg·kg^–1·h^–1. The observed changes did not differ significantly from those previously observed in babies treated with 2 mg·kg^–1. A rise in PaO₂ and a reduction in AaDO₂ were usually observed shortly after the bolus injection and at plasma levels between 1.5 and 4 µg·ml·^–1. A progressive rise in plasma level over time occurred after 1 mg·kg^–1 (and in the previous study of 2 mg) but not with 0.5g/kg tolazoline. The elimination half-life of tolazoline in 6 patients was 5 to 13 h. The data suggest that continuous infusion of tolazoline is not necessarily required and that the dose of 0.5 mg/kg is more appropriate and safer than the higher doses usually proposed.     

Interaction between clonidine and physostigmine in normal rats and in rats after sinoaortic denervation

Summary Clonidine (3–30 g · kg^–1, i.v.) induced a fall in mean arterial pressure in rats after sinoaortic denervation but not in sham-operated animals. Moreover, sinoaortic denervation reduced the bradycardic action of this antihypertensive drug. Pressor and tachycardic response to physostigmine (60 g · kg^–1, i.v.) were greater in denervated than in sham-operated rats. The increase of mean arterial pressure was 26.2 ± 2.2 mm Hg in sham-operated rats (n = 12) and 53.8 ± 2.0 mm Hg in denervated rats (n = 12, P < 0.005).Pretreatment with 3 g · kg^–1 (i. v.) of clonidine did not alter the pressor response to physostigmine (60 g · kg^–1) in either of the two groups; 10 and 30 g · kg^–1 of clonidine reduced the physostigmine-induced increase of mean arterial pressure in sham-operated rats but enhanced the pressor response in denervated animals. Furthermore, an ineffective dose of physostigmine (30 g - kg^–1 i.v.) induced a pressor response after pretreatment with clonidine (10 gg · kg^–1) in denervated rats.Clonidine (10 g · kg^–1) did not affect the pressor effect of 1,1 dimethyl-4-phenylpiperazinium iodide (DMPP: 50 g · kg^–1 i.v.) or phenylephrine (4 g · kg ^–1, i.v.) in either group.The anticholinergic effect of clonidine in sham-operated rats may be explained by an inhibitory action on the release of acetylcholine in several brain structures but the facilitatory effect of clonidine observed in denervated animals is not clear. The results did not suggest a peripheral involvement in this facilitatory effect. Send offprint requests to M. A. Enero at the above address     

Steady state pharmacokinetics of piroxicam in children with rheumatic diseases

Summary Ten children with rheumatoid arthritis, aged 7–16 y and weighing 20–63 kg, were treated with piroxicam mean dose 0.4 mg·kg^–1 once daily for 2 weeks. On Day 15, blood was sampled from 2–120 h after the last dose.The C_max for piroxicam ranged from 3.6 to 9.8 (mean 6.6) mg·l^–1 and its half-life by log linear computation was 22 to 40 (mean 32.6) h. The volumes of distribution and the total body clearance were estimated as the ratio of actual volumes of distribution and actual clearances to availability. The volumes of distribution (V/F) were 0.12 to 0.25 (mean 0.16) l·kg^–1, and the total body clearances (CL/F) were 2.1 to 5.0 (mean 3.4) ml·kg^–1·^–1.Thus, piroxicam clearance in these patients was higher and its half-life was shorter than those previously reported in young adults, yet V appeared similar.