Acute changes of blood ammonia may predict short-term adverse effects of valproic acid.

Valproic acid (VPA) was given to 24 epileptic patients who were already being treated with other antiepileptic drugs. A standardized loading dose of VPA was administered, and venous blood was sampled at 0, 1, 2, 3, and 4 hours. Ammonia (NH3) was higher in patients who, during continuous therapy, complained of drowsiness (7 patients) than in those who were symptom-free (17 patients), although VPA plasma levels were similar in both groups. By measuring VPA-induced changes of blood NH3 content, it may be possible to identify patients at higher risk of obtundation when VPA is given chronically.

Predictive performance of pharmacokinetic methods for phenytoin dosing: a multi-center evaluation in 282 patients with epilepsy.

A retrospective study was conducted in 282 patients with epilepsy to assess the predictive performance of pharmacokinetic methods for individualizing dosage of phenytoin. Two population-based dosing methods (population clearance method and bayesian feedback method) and one individual-based method (the so-called linearized Michaelis-Menten method) were evaluated, when applicable, for single-point and/or 2-point dose predictions of phenytoin. In single-point predictions, we found a generally low percentage of dose calculations falling inside the +/- 10% range (48.9% and 51.1% for the population clearance and the bayesian methods, respectively). In 2-point predictions, the bayesian method was 'accurate' (dose within the +/- 10% range) in approximately 54.3% or 55.0% of cases (depending on the particular method of implementation adopted). An even worse percentage of 'accurate' dose predictions (38.3%) was obtained by using the linearized Michaelis-Menten method. Our data do not confirm results from previous studies indicating a generally good performance of pharmacokinetic methods for predicting phenytoin dosage.

PKRD: a pharmacokinetic program for least-squares and bayesian analysis of repeated-dose pharmacokinetic curves.

A microcomputer program is presented which analyses multiple-dose pharmacokinetic curves using either a least-squares nonlinear analysis or a bayesian fit. The least-squares subroutine is designed to fit retrospective pharmacokinetic curves and can generate the so-called population pharmacokinetic parameters using the Standard Two-Stage method. The bayesian subroutine can instead be used prospectively to individualise the dosage regimen of a patient based on the concentrations measured in the initial phases of the drug treatment. All the pharmacokinetic subroutines of the program use the one-compartment model with either constant-rate intravenous infusion or oral route with zero-order absorption. The program was tested in a series of ten bone marrow transplantation patients treated with cyclosporine. The least-squares estimates of the one-compartment parameters, calculated by the program, were compared with those generated by the SIMKIN program.

[The effects of the acute administration of atrial natriuretic peptide on the mechanisms regulating diuresis and natriuresis in the essential hypertension patient]. / Effetti della somministrazione acuta di peptide atriale natriuretico su alcuni meccanismi di regolazione della diuresi e della natriuresi nell'iperteso essenziale.

The authors investigated the role of atrial natriuretic peptide (alpha-hANP 99-126) in essential hypertension by evaluating some hemodynamic and renal effects of acute peptide infusion (1 micrograms/kg for 1 min + 50 ng/kg for the following 20 min) in fourteen subjects: eight mild to moderate, untreated, essential hypertensives (EH) and six normotensive (N) controls, during 2 hour-clearance periods, the 1st after ANP infusion, the 2nd during placebo (PL) administration. The double-blind study was carried out after the patients had rested and fasted overnight. It showed no significant changes in heart rate (HR); instead, compared with placebo, mean blood pressure (MBP) decreased significantly in both groups, beginning from the 3rd min after ANP infusion was begun (N: PL = 87.04 +/- 1.7 mmHg, ANP = 80.9 +/- 3.7 mmHg, p less than 0.0001; EH: PL = 102.6 +/- 3.2 mmHg, ANP = 97.7 +/- 5.9 mmHg, p less than 0.01). Among the urinary parameters we considered, cyclic GMP (cGMP) increased after ANP infusion in all subjects (N: PL = 129.1 +/- 56.3 pmol/mL, ANP = 199.2 +/- 85.4 pmol/mL; EH: PL = 106.55 +/- 56.2 pmol/mL, ANP = 220.03 +/- 92.7 pmol/mL, p less than 0.05); diuresis showed a prompt and significant increase in EH (N: PL = 837 +/- 368 mL, ANP = 1066 +/- 340 mL; EH: PL = 713 +/- 286 mL, ANP = 1043 +/- 280 mL, p less than 0.005), and so did natriuresis (N: PL = 23 +/- 14.3 mEq/L, ANP = 33 +/- 14.6 mEq/L; EH: PL = 25.6 +/- 8.9 mEq/L, ANP = 41.9 +/- 13.8 mEq/L, p less than 0.01); urinary potassium excretion was significantly reduced in EH (N: PL = 18.7 +/- 12.9 mEq/L, ANP = 14.2 +/- 6.9 mEq/L; EH: PL = 16.5 +/- 7.9 mEq/L, ANP = 10.7 +/- 4.8 mEq/L, p less than 0.005), while no changes were noted in glomerular filtration rate (GFR), estimated as creatinine clearance, urinary magnesium, albumin and aldosterone excretion. To investigate other potential mechanisms involved in renal effects of ANP, the urinary excretion of both prostaglandins 6-cheto PGF1-alpha and thromboxane B2 (TXB2), and dopamine were studied. The results showed only a significant decrease of dopamine urinary excretion in EH after ANP administration (N: PL = 50.4 +/- 28.7 micrograms/L, ANP = 45.0 +/- 29.7 micrograms/L; EH: PL = 47.3 +/- 21.5 micrograms/L, ANP = 27.1 +/- 12.7 micrograms/mL, p less than 0.01).(ABSTRACT TRUNCATED AT 400 WORDS)

External quality assessment in therapeutic drug monitoring: an Italian experience.

Pharmacontrol is an external quality assessment (EQA) for therapeutic drug monitoring initiated in Italy in 1986 on regional basis. Since then, interest and involvement being on a national level, participation has expanded to some 180 laboratories currently. The EQA concerns assays for the drugs most frequently monitored in Italy (seven drugs until 1989, 13 at present). The results obtained in 1989, reported in this paper, indicate a generally satisfactory level of both precision and accuracy.

Pyrrolidone carboxylic acid in acute and chronic alcoholism. Preclinical and clinical studies.

2-Pyrrolidone-5-carboxylic acid (PCA) is a cyclic derivative of glutamic acid, physiologically present in mammalian tissues. We herein report preclinical pharmacology experiments showing that PCA releases GABA from the cerebral cortex of freely-moving guinea-pigs and displays anti-anxiety effects in a simple approach-avoidance conflict situation in the rat. In clinical pharmacology experiments, PCA significantly shortens the plasma half-life of ethanol during acute intoxication. In chronic alcoholics a treatment with PCA (2g/day per 30 days) significantly hastens the recovery to physiological values of plasma gamma-glutamyl transferase activity and of the urinary excretion of glucaric acid, which are considered suitable markers of the trend of the alcoholic disease. The evidence emerging from preclinical and clinical studies strongly suggests that, by combining central anxiolytic actions with the peripheral recovery of the antioxidant defense system in the liver, PCA should be further investigated as an interesting endogenous molecule possibly helpful in the therapy of alcoholism.

[Azlocillin in the treatment of pulmonary infections in patients with cystic fibrosis: plasma concentrations and therapeutic indications]. / L'azlocillina nel trattamento delle infezioni polmonari dei pazienti affetti da fibrosi cistica: concentrazioni plasmatiche e indicazioni terapeutiche.

Azlocillin plasma concentrations have been studied in 10 cystic fibrosis patients suffering from chronic pulmonary infections with Pseudomonas aeruginosa. Patients were given single i.v. doses of 100 e 200 mg/kg body weight as intravenous infusion over 30 minutes. Azlocillin plasma levels have been assayed by a rapid, sensitive and precise high performance liquid chromatographic method. After the dose of 100 mg/kg body weight concentrations of azlocillin decreased below the therapeutic concentrations after three hours; dose of 200 mg/kg was followed by plasma concentrations in the therapeutically desirable range during the 6-8 hours study period. The pharmacokinetic analysis offers further evidence of the dose-dependent nature of azlocillin elimination. Higher dosage of 200 mg/kg body weight and monitoring of plasma drug levels are recommended in the therapy of patients with cystic fibrosis.

[Pharmacokinetics of oral theophylline. Comparison between asthmatic and cystic fibrosis patients]. / Farmacocinetica della teofillina orale. Confronto tra pazienti asmatici e pazienti con fibrosi cistica.

The pharmacokinetics of oral theophylline at steady-state were comparatively investigated in 13 asthmatic patients and in 10 patients with cystic fibrosis (CF). In all patients, the drug was administered twice daily as slow-release tablets. The total daily dose of theophylline ranged from 10.8 to 29.4 mg/kg/day. For each patient, the time-course of theophylline steady-state plasma levels was studied after the morning dose. Six serial plasma samples were drawn at 0, 2, 4, 6, 8, and 12 h after dosing. Model-independent methods were used for calculating the pharmacokinetics parameters (area under the curve and clearance). The clearance values (mean +/- SD) calculated in the two patient groups were significantly different (asthmatic patients: clearance = 61.2 +/- 15.6 ml/h/kg; CF patients: clearance = 86.3 +/- 22.8 ml/h/kg; P = 0.007). It has previously been shown that the clearance of theophylline after single dose is increased in CF patients. Our study confirms this finding under steady-state conditions and demonstrates that higher theophylline doses are on the average required to treat patients with FC.

The role of lithium carbonate in the management of hemolymphoblastosis: estimation of plasmatic and erythrocyte lithium levels.

Twelve patients affected by hemolymphoblastosis were treated with lithium carbonate in order to attenuate neutropenia induced by anticancer drugs. Controls were chosen among patients who had not received lithium treatment after cytostatic therapy. We estimated plasmatic and erythrocyte lithium levels and determined the Erythrocyte lithium rate (ER), i.e., erythrocyte lithium levels expressed as a percentage of plasmatic levels. A significant correlation was found between granulocyte increase at one week (GIW) and ER. No significant correlation was found between GIW and the other two estimation procedures. Therefore, ER seems to be a reliable index of the efficacy of the treatment, and could be used to monitor lithium administration.

Bioavailability of intramuscular ciclosporin in the pig.

We conducted a cross-over single-dose pharmacokinetic study in 4 pigs to measure the bioavailability of ciclosporin (CS) after intravenous and intramuscular administration. Each animal was given 5 mg/kg i.v. followed by 20 mg/kg i.m. after 1 week. Serial blood samples were taken over 36 h after each dose, and the concentration of CS was assayed by radioimmunologic methods. The pharmacokinetic parameters after intravenous administration were (mean +/- SD; n = 4): clearance = 327 +/- 21 ml/h/kg; volume of distribution = 7.2 +/- 2.8 liters/kg. The same parameters after intramuscular dosing were: clearance = 326 +/- 59 ml/h/kg; volume of distribution = 6.9 +/- 2.1 liters/kg. The percent bioavailability of intramuscular CS was 101.9 +/- 13.3 with a mean absorption time of 10.6 +/- 2.7 h. Our results indicate that following a single dose, the percent bioavailability of intramuscular CS in pigs is considerably greater than that reported in previous studies.

Long-term treatment with sodium valproate: monitoring of venous ammonia concentrations and adverse effects.

Adverse effects and venous blood ammonia concentrations were monitored over a period of 7 months in patients with epilepsy treated with valproate (VPA). During the 1st, 4th, 12th, 20th, and 28th weeks of therapy, blood samples for analysis of ammonia and anticonvulsants were taken immediately before the morning dose of VPA as well as 2 h after dosing. In all, 40 patients completed the follow-up; 16 of these (Group 1) received VPA alone, while the remaining 24 (Group 2) were treated simultaneously with VPA and other anticonvulsants (phenobarbital, phenytoin, and/or carbamazepine). In Group 1 patients, a slight though significant increase in ammonia concentrations was found during long-term VPA treatment; this trend was even more pronounced in Group 2 patients. The difference between postdose and predose ammonia levels in Group 2 patients was significant at each of the five follow-up examinations. In contrast, no such difference was demonstrated in patients of Group 1. VPA concentrations were found to be consistently higher in Group 2 patients than in Group 1. Twenty-three patients complained of various long-term adverse effects, while the other 17 remained symptom-free. The adverse effects reported included drowsiness, tremors, weight gain, hair loss, and gastrointestinal symptoms. Our data confirm the previously suggested hypothesis that changes in venous blood ammonia are particularly evident in patients taking VPA in combination with other antiepileptic drugs, such as phenobarbital and phenytoin.

Effect of associated antiepileptic treatment on valproate-induced hyperammonemia.

It has recently been shown that acute changes of venous blood ammonia (NH3) may predict short-term adverse effects of valproic acid (VPA). In the present study, the time course of NH3 concentration after a single oral dose of VPA (800 mg) was monitored in 68 epileptic patients. Patients were classified into four groups: previously untreated patients (group A, n = 21), patients under treatment with either phenobarbital (group B, n = 14) or phenytoin (group C, n = 13) or both (group D, n = 20). In each patient, venous blood for the NH3 assay was taken before the VPA dose (predose level) and at 1, 2, 3, and 4 h after the dose (postdose levels). While in patients receiving only VPA the postdose NH3 concentrations did not differ from the predose level, in each of groups B, C, and D the postdose concentrations appeared to be significantly higher than the predose concentration. The greatest increase was observed in group D. In the light of the data reported in the literature, those patients whose NH3 concentration after the VPA dose exceeds 100 micrograms/dl should be considered at higher risk for short-term, VPA-induced adverse effects during long-term therapy. Thus, our data suggest that caution should be exercised in adding VPA to anticonvulsant treatments including phenobarbital or phenytoin or both.

Effects of oxcarbazepine and carbamazepine on the central nervous system: computerised analysis of saccadic and smooth-pursuit eye movements.

Oxcarbazepine (OXC) is a new anti-epileptic agent structurally related to carbamazepine (CBZ). OXC seems to have a similar efficacy and a better tolerability profile than CBZ. In the present study we compared the subclinical side-effects on the CNS of OXC and CBZ using a computerised analysis of saccadic and smooth-pursuit eye movements. Six healthy male volunteers (mean age 29 yrs) participated in the study, which was conducted by a double-blind cross-over design. Each subject was given a single dose of either CBZ 400 mg or OXC 600 mg (according to the random assignment) after which the drug effects on eye movements were evaluated. One week later, the trial was repeated using the other drug. The parametrisation of both saccadic and smooth-pursuit eye movements was carried out by measuring a series of performance parameters [e.g. the maximum saccade peak velocity (MSPV) and the typical target velocity (TTV)]. OXC was found to induce a lesser degree of alteration on the values of both MSPV (p = 0.07) and TTV (p less than 0.03) than CBZ. In particular, the TTV values were virtually unaffected by OXC administration, while the effects of CBZ on both variables were particularly evident at 8 and 10 h after dosing which correspond to the time at which the plasma concentrations of CBZ and of its 10,11-epoxide reach the peak. In conclusion, our preliminary results indicate that OXC induces negligible alterations, if any, on the eye movement parameters evaluated in our study.

Usefulness of basal catecholamine plasma levels and clonidine suppression test in the diagnosis of pheochromocytoma.

In the present paper we report our experience on the utility of basal plasma catecholamine (CA) measurement and of the clonidine-suppression test in the diagnosis of pheochromocytoma. Basal noradrenaline (NA) and adrenaline (A) were assayed in plasma samples of 27 subjects affected by pheochromocytoma. When compared to basal values obtained in hypertensive patients without pheochromocytoma, one or both the CA resulted pathologically elevated in all patients except one. The response to the clonidine-suppression test was evaluated in 41 hypertensive patients suspected of having a pheochromocytoma measuring plasma NA and A in basal conditions and 2 and 3 h after oral administration of 300 micrograms clonidine. Extensive laboratory and instrumental findings confirmed the presence of pheochromocytoma only in 12 patients. Among the other 29 patients basal plasma CA resulted higher than normal in 4 patients. In patients without pheochromocytoma clonidine induced a significant fall in both NA and A plasma levels. The decrease in NA was observed in each patient. The 12 patients with pheochromocytoma showed a pathological elevation of one or both the CA. In this group clonidine did not significantly suppress plasma CA. The individual responses were extremely variable. Our data confirm the validity of plasma CA measurement as a diagnostic tool for the diagnosis of pheochromocytoma. The results of the clonidine-suppression test were generally confirmatory of the basal CA plasma values but in the 4 hypertensive patients without pheochromocytoma who showed basal plasma CA higher than normal clonidine resulted a useful tool in excluding the presence of pheochromocytoma.

Aminophylline and respiratory muscle interaction in normal humans.

The effects of intravenous infusion of aminophylline on respiratory muscle interaction were examined in seven normal subjects breathing at rest. Rib cage (RC-Ap) and abdominal (AB-Ap) volume displacements, pleural (Ppl), gastric (Pg), and transdiaphragmatic (Pdi) pressure swings, and electromyographic activity of the diaphragm (Edi) and the parasternal (Eps) muscles were measured under control and during infusion of either aminophylline or placebo in a double-blind randomized manner. Compared with placebo, aminophylline induced an increase in ventilation (p < 0.01) that was mainly accounted for by an increase in tidal volume (p = 0.01). Aminophylline induced a significant and similar increase in RC-Ap and AB-Ap as associated with increased Ppl and Pg swings (p = 0.002, and p < 0.01, respectively). On the contrary, no changes in end-expiratory RC and AB volume and in Ppl and Pg at end-expiration were observed, indicating that expiratory muscles did not contribute to the increase in tidal volume. Edi and Eps increased significantly with aminophylline, whereas Pdi/Edi ratio remained unchanged. We conclude that in normal humans breathing at rest: (1) aminophylline increases ventilation, promoting larger tidal volume; (2) this effect is due to increased neural drive to inspiratory muscles; (3) aminophylline does not promote any appreciable expiratory muscle recruitment and distortion in the pattern of chest wall motion.

Comparative analysis of the pharmacokinetic techniques available for individualizing phenytoin dosage.

Over the past few years, numerous pharmacokinetic techniques based on Michaelis-Menten principles have been proposed to individualize PHT dosage and predict plasma levels. The choice of one of these techniques for clinical use depends on the number of steady state concentration-versus-dose (Css-D) data pairs that are known in the patient for whom the predictive technique is to be applied. The most frequent clinical situations in which these predictions are made can be divided into three groups for each patient considered--Case A: only one previous Css-D data pair is known; Case B: two previous Css-D data pairs are known; Case C: three previous Css-D data pairs are known. Of the available techniques that can be applied in case A, we compared the population clearance (PC) method and the Bayesian feedback (BF) method. The procedure for comparing the predictive capabilities of these methods was very similar to that adopted in a recent report by Vozeh et al. Our findings showed that the PC method should be preferred for clinical use under this circumstance. Two predictive techniques suitable for use in Case B (BF and Mullen & Foster methods) were compared. In this case, the BF method was shown to be more accurate. As regards Case C, three pharmacokinetic techniques were compared: the Mullen and Foster method, the iterative least-squares (ILS) technique, and the BF method. The ILS technique was found to be the most accurate in this case. Finally, we describe a programmable calculator procedure which uses the PC, BF or ILS methods in Cases A, B and C respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

A new programmable calculator procedure for individualizing phenytoin dosage.

A programmable calculator procedure allowing nonlinear least-squares fit to pharmacokinetic data conforming to the Michaelis-Menten model is described. Model parameter estimation is performed according to the iterative Gauss-Newton technique as modified by Hartley. This procedure thus employs the same theoretical approach used by most pharmacokinetic computer programs. No programming skill is needed to run the program described. The proposed procedure is discussed in detail and applied to some sets of pharmacokinetic data.