Pierpaola Benetello

Pharmacokinetic Optimisation of Tricyclic Antidepressant Therapy

SummaryPharmacokinetics has greatly contributed to the elucidation of the variability in clinical response to antidepressants in terms of differences in plasma concentrations due to genetic constitution, age, associated diseases and drug interactions. Despite no general agreement, therapeutic and toxic concentrations have been suggested for some tricyclic antidepressants (TCAs) [ami-triptyline, nortriptyline, imipramine, desipramine]. Predictive techniques may be implemented on the basis of which starting TCA dosages may be selected to reach more rapidly those concentrations at which efficacy is more probable. Therapeutic drug monitoring may thereafter assist the clinician in refining the individualisation of the dosage regimen.

Oral gabapentin disposition in patients with epilepsy after a high-protein meal.

Summary: Purpose: To study the interaction between gaba‐pentin (GBP) and high‐protein meals, 12 patients with epilepsy were administered this drug both while in a fasting state and after a high‐protein meal.

Plasma Levels of Levodopa and Its Main Metabolites in Parkinsonian Patients after Conventional and Controlled-Release Levodopa-Carbidopa Associations

The paper reports plasma levels of levodopa (LD), its main metabolites [dopamine, dihydroxyphenylacetic acid, homovanillic acid, 3-O-methyldopa (3-O-MD)] and carbidopa in 14 parkinsonian patients first treated with Sinemet and thereafter with Sinemet-CR4. A good relationship was observed between LD plasma levels and pharmacological effects. While the LD area under the curve increased after Sinemet-CR4, the same was not observed with metabolites, except with 3-O-MD. The experiments in volunteer subjects confirmed the increase in 3-O-MD in plasma after Sinemet-CR4. Higher levels were observed also in the CSF with a reduction of LD concentrations. This seems to corroborate the hypothesis of an interference with LD passage through the blood-brain barrier in humans.

The pharmacokinetics of tricyclic antidepressant drugs in the elderly.

Antidepressants, especially tricyclic agents (TCAs), are increasingly used in geriatric patients since depression is a common mood disorder in the elderly and the size of elderly population is increasing. Notwithstanding the importance of kinetics to better use of drugs, its study in the elderly (regarding TCAs) is not sufficiently developed. The present paper briefly reviews the available data on amitriptyline, nortriptyline, protriptyline, imipramine, desipramine and clomipramine kinetics in the elderly.

Therapeutic drug monitoring of lamotrigine in patients suffering from resistant partial seizures

Sixty patients, all potential candidates for ongoing lamotrigine (LTG) treatment as add-on therapy for resistant partial seizures and receiving carbamazepine (CBZ) and/or valproate (VPA) treatment, were submitted to therapeutic drug monitoring (TDM). The aim was to evaluate the possible relation between serum levels and the clinical effect of LTG, to verify whether CNS toxicity has to be considered the result of a pharmacokinetic or a pharmacodynamic interaction with CBZ, and to investigate whether possible changes in the clinical response during long-term treatment are dependent on LTG serum level variations. Sixteen patients achieved complete control, 26 a ≧50% reduction in seizures, the remainder did not respond. Mean LTG serum concentrations were higher in responders than in nonresponders, the difference being statistically insignificant. The best results were observed in VPA-cotreated patients with the highest LTG blood levels. CNS toxicity occurred after giving LTG to subjects who subsequently developed the highest LTG concentrations, whereas CNS toxicity seemed unrelated to CBZ and CBZ-epoxide serum concentrations. No decrease in LTG, CBZ and VPA serum levels was observed even in patients showing a reduction in the response during long-term treatment.

Steady-state serum concentrations of imipramine, its main metabolites and clinical response in primary enuresis

Thirty-seven children (6-13 years old), receiving a flexible dosage of imipramine (IMI) for nocturnal enuresis, were evaluated. After a mean time of 8.5 +/- 7.0 weeks of therapy, 40.5% no longer wet the bed; 32.4% had a mean benefit of 80%; 27.01% had a negligible response. The best relationship observed was between clinical effect and drug serum concentrations rather than with drug daily dose, the most satisfactory being that with IMI seric values (P = 0.019). Responders (effect higher than 50%) had higher IMI serum concentrations (P less than 0.05) than poor responders. At 3 and 6 months after stopping the drug, over 90% of the responders maintained the maximum response reached during treatment. The side-effects observed were irritability, reduction of appetite, headache, a mild increase of blood pressure.

NEW ANTIEPILEPTIC DRUGS

Notwithstanding pharmacokinetics has greatly increased the rational approach to the drug treatment of epilepsies, about 25% of the patients do not respond to the therapy. Therefore, a great effort has been made to discover new antiepileptic drugs effective in refractory seizures. On the basis of increased knowledge of seizure pathophysiology two principal groups of drugs have been developed: the first enhancing brain GABA activity (vigabatrin); the second inhibiting excitatory amino-acids (lamotrigine and felbamate). Oxcarbazepine has the same mechanism of action as carbamazepine, whereas gabapentins mechanism is still uncertain. The major clinical indications of these new antiepileptic drugs are represented by partial complex seizures. Side effects (mostly regarding the central nervous system) appear mild, and clinical interactions have little importance. The role of therapeutic drug monitoring for these substances is at present not well established.

Chlorpromazine Disposition in Relation to Age in Children

SummaryThe pharmacokinetics of chlorpromazine after intravenous infusion were studied in 25 children.The pharmacokinetic parameters studied are markedly different from those reported for adults. A clear relationship was demonstrated between age, serum terminal half-life (r = 0.75) and systemic clearance (r = -0.43). It appears that the pharmacokinetics of chlorpromazine are more rapid in children than in adults.

Carbamazepine and carbamazepine-epoxide serum concentrations in some resistant cases of complex partial seizures

Sir, In epileptic patients on carbamazepine (CBZ) therapy a worsening of seizures may sometimes be observed after a limited period of apparent response. Autoinduction [1, 2] may be the cause of this. In order to verify this hypothesis we carried out an investigation in 6 patients (3 males and 3 females) from 17 to 25 yrs, affected by complex partial seizures apparently resistant to anticonvuisants. None had hepatic or renal diseases. At the beginning, the patients were on polytherapy (5 CBZ+phenobarbital; 1 CBZ+primidone), CBZ being administered 3 times a day. After steady-state serum level determination, the first step was to increase CBZ dosage until a better control of seizures was reached. Thereafter associated drugs were gradually withdrawn so that all patients were on CBZ monotherapy. At this point, when seizures became more numerous, the CBZ dose was increased until a total daily dosage of 30 mg/Kg was reached. Finally if complete control was not achieved notwithstanding the high CBZ dosage, phenytoin was added. During monotherapy, when a decrease of seizures was observed only for a brief period following CBZ dose increments, weekly sampling was performed in order to test for a possible relationship between weekly serum level variations of CBZ, its main metabolite CBZ-epoxide (CBZ-E), and the number of seizures. Blood samples were drawn before morning dose. Seizure frequency was recorded in diaries kept by relatives. CBZ and CBZ-E serum concentrations were determined in duplicate by HPLC [3]. Of the 6 patients studied 2 were controlled by CBZ monotherapy. The other 4 patients had limited benefit from an increase of CBZ doses but not complete control of seizures, which subsided only after administration of phenytoin. In these patients, after the first increment of CBZ dose during monotherapy, we observed an improvement lasting for about 2-3 weeks, after