Chronic Monotherapy Research Articles

Chewable Versus Regular Carbamazepine

A comparison of chewable and regular carbamazepine (CBZ tablets) in 44 children receiving chronic CBZ monotherapy is reported from the IWK Children’s Hospital, Halifax, Nova Scotia.

The Pharmacology of Chewable Versus Regular Carbamazepine in Chronically Treated Children With Epilepsy

We report the first comparison of Chewable and Regular Carbamazepine (CBZ) tablets in children with epilepsy. Forty-four children receiving chronic monotherapy CBZ participated. In month 1 children received regular CBZ; in month 2, the same dose of Chewable CBZ. Once per week fasting predose CBZ and CBZ epoxide serum levels were determined. In a subset of 15 children, at the end of each month serum levels were obtained every 2 hours for 12 hours beginning pre-dose. Standards for CBZ and CBZ epoxide were tested in each centre. Overall, weekly levels showed no consistent differences between the month on chewable CBZ and regular CBZ. Seizure control and rates of reported side effects were similar. In five patients chewable CBZ produced higher peak CBZ levels while five had higher peaks with regular CBZ. In conclusion, regular and chewable CBZ often have unpredictable differences in peak but not trough levels of CBZ suggesting that peak level side effects with one form of CBZ might be alleviated by changing to the other.

Acetazolamide Monotherapy for Myoclonic Epilepsy

Chronic acetazolamide monotherapy controlled generalized tonic-clonic seizures in 14 of 31 patients with juvenile myoclonic-86-epilepsy treated in the Department of Neurology, Columbia University College of Physicians and Surgeons, New York, NY, and the Department of Neurology, Stamford Hospital, Stamford, CT.

バルプロ酸単独服用患者における血清蛋白との結合

Valproic acid is highly bound to serum protein, mainly albumin. Valproic acid exhibits concentration-dependent protein binding, which partly accounts for considerable variability in the unbound fraction, even within the therapeutic range. Therefore, valproic acidprotein interaction and determination of the corresponding binding parameters should be considered. In the present study, we investigated the binding characteristics in epileptic adults and children under valproic acid chronic monotherapy, and determined the binding parameters of valproic acid to serum protein.There was a curvilinear relationship between total and unbound concentrations orunbound fraction, using a second-degree polynomial equation. The unbound fraction increased curvilinearly in proportion to the increase in total concentration . Averages of unbound fraction obtained from adults and children were not significantly different from each other (P>0.05). The unbound fraction ranged from 4.1 to 16 .7% (adults), and from 5.6 to 16.7% (children). There were marked about three-fold variations of unbound fraction in both adults and children.On the other hand, as the Scatchard plot was shown to be linear in both adults and children, valproic acid was bound to only one class of binding sites on the protein molecule. The binding parameters calculated by Scatchard plot were as follows: association constants (Ka) were 1. 14×104l/mol (adults) and 1.44×104l/mol (children), total number of binding sites (n (Pt)) was 1.36×10-3mol/l (adults) and 1. 20×10-3mol/l (children). There was no significant difference in the two parameters between adults and children (P>0 .05). Therefore, we determined the binding parameters from all samples (n=96) by using Langmuir plot. These results showed that dissociation constant (Kd) was 3 .89×10-5mol/l, total number of binding sites (n (Pt)) was 8.46×10-4 mol/l.These results suggested that valproic acid had the same binding characteristics in both adults and children. The molecular interaction between valproic acid and serum albumin involved one class of binding sites within the investigated range.

Serum binding of nifedipine and verapamil in patients with ischaemic heart disease on monotherapy.

Serum free fractions of nifedipine, verapamil and some of their metabolites were measured in patients with ischaemic heart disease receiving single oral dose and chronic monotherapy and were compared with those obtained in vitro. The percentages of unbound nifedipine and verapamil in vitro (concentration range 50-200 and 150-400 ng ml-1, respectively) were 2.51 and 7.23%, respectively, and did not differ from those found on monotherapy with these drugs (2.05 and 8.08%, respectively), and after single dosing. It is suggested that, during treatment with nifedipine or verapamil, their serum metabolites do not affect binding of the parent drugs to serum proteins.

P-513 - Protein binding of valproic acid in epileptic children under chronic monotherapy

P-513 - Protein binding of valproic acid in epileptic children under chronic monotherapy

Effects of long-lasting antiepileptic therapy on brainstem auditory evoked potentials.

The brainstem auditory evoked potentials of 84 epileptic patients in chronic monotherapy with carbamazepine (n = 36), phenobarbital (n = 19), Na-valproate (n = 20) or progabide (n = 9) were studied. The mean values of I-III and I-V interpeak latencies (IPLs) were respectively 2.16 +/- 0.11 and 4.03 +/- 0.17 in the control group, 2.31 +/- 0.09 and 4.17 +/- 0.16 in the valproic group, 2.30 +/- 0.17 and 4.19 +/- 0.20 in the carbamazepine group, 2.17 +/- 0.16 and 4.10 +/- 0.18 in the phenobarbital group and 2.16 +/- 0.11 and 4.12 +/- 0.17 in the progabide group. The prolongation of I-III and I-V IPLs was statistically significant only for the valproic acid and carbamazepine groups. Neither duration of the epilepsy and treatment and frequency of seizures nor the serum drug levels were correlated with I-V IPL values.

Calcium antagonist induced vasodilation in peripheral, coronary and cerebral vasculature as important factors in the treatment of elderly hypertensives.

Increased arteriolar tone is the pathophysiological hallmark of essential hypertension and is determined by the intracellular free calcium concentration in the vascular smooth muscle cell. Calcium influx is an important determinant of vasoconstriction and excess calcium influx-dependent vasoconstriction has been shown by plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower BP by reducing calcium influx, calcium concentration and peripheral resistance. The degree of the attendant sympathetic nerve reflex activation and counter-regulatory mechanisms determines the antihypertensive response of the individual. Chronic monotherapy with a calcium antagonist results in an antihypertensive response, which is directly related to the patient's age and pretreatment BP and indirectly related to plasma renin levels. The resulting reduction in after-load neither leads to reduced cerebral blood flow in hypertensive patients, nor aggravates congestive heart failure. Calcium antagonists are a useful alternative to diuretics, primarily in older patients with low renin levels, either alone or combined with any other antihypertensive drug, and provide effective and safe control of blood pressure.

Effects of chronic nitrendipine on casual (office) and 24-hour ambulatory blood pressure.

To assess the clinical efficacy of chronic nitrendipine therapy in mild to moderate essential hypertension, we studied blood pressure (BP) and heart rate responses in 22 subjects receiving maintenance nitrendipine therapy. Ten subjects (45%) whose hypertension was controlled with chronic monotherapy had an 11/12 mm Hg decrease in supine BP (P less than 0.05) with a mean (+/- SD) dose of 71 +/- 15 mg/day. The 12 (55%) subjects whose hypertension was not controlled with monotherapy had a comparatively higher baseline BP than the other 10 (156/105 +/- 10/6 compared with 150/98 +/- 15/4 mm Hg; P less than 0.05). Eight of the 10 subjects demonstrating office BP control with chronic nitrendipine monotherapy who also had full-time employment underwent continuous ambulatory BP monitoring before and after maintenance monotherapy. Nitrendipine induced a reduction in the mean 24-hour BP and mean BP at home, but did not reduce the BP during work or while asleep. These data suggest that nitrendipine lowers BP when assessed by casual office methods. The ambulatory BP monitor data demonstrate that the hypotensive response to chronic nitrendipine is modified during work periods, which are generally associated with increased adrenergic activity. Ambulatory BP monitoring may be superior to office (casual) monitoring in the assessment of the overall efficacy of antihypertensive drugs.

Position of Calcium Antagonists in Antihypertensive Therapy

More than 20 years ago calcium antagonists were shown to lower elevated blood pressure. Today's worldwide recognition, at least in part, is due to rising research interest in cellular ion regulation abnormalities in essential hypertension. Using the human platelet as a model for the vascular smooth muscle cell, a direct relationship was observed between intracellular free calcium concentration and the height of blood pressure before as well as during different antihypertensive treatments. Calcium influx is an important determinant of vasoconstriction, and excess calcium influx-dependent vasoconstriction was shown with plethysmographical studies in patients with essential hypertension. Calcium antagonists acutely lower blood pressure by reducing intracellular calcium and peripheral vascular resistance. The degree of the attendant sympathetic nerve reflex activation and counterregulatory mechanisms codetermine the antihypertensive result of the individual. Chronic monotherapy with calcium antagonists results in an antihypertensive response that is related directly to the patient's age and pretreatment blood pressure and indirectly to renin. These studies led to a new treatment concept: calcium antagonists can be used as alternatives to diuretic drugs primarily in the older and low-renin patients and beta-blockers or converting enzyme inhibitors can be used in the younger or high-renin patients with greater efficacy. With the appropriate choice, calcium antagonists alone or combined with any other antihypertensive drug provide good blood pressure control with little subjective and objective adverse effects.

Valproic Acid Free Fraction in Epileptic Children Under Chronic Monotherapy

The total and free (nonprotein-bound) concentration of valproic acid (VPA) was determined in plasma samples collected at two different times of the day (before the morning dose and 3 h later) in 62 epileptic children receiving maintenance single-drug therapy with sodium valproate. Both the total and the free concentrations were lower in the early than in the late morning samples (total VPA: 394.4 +/- 150.0 vs. 556.9 +/- 175.2 mumol/L; free VPA: 20.1 +/- 11.1 vs. 31.3 +/- 17.4 mumol/L). The average free fraction of the drug was also lower in the early morning (4.8 +/- 1.3 vs. 5.4 +/- 1.6%, p less than 0.001). At both sampling times, the free fraction was positively correlated (p less than 0.01) with the total concentration. Evidence is presented that, at equal total plasma VPA concentration, the free fraction of the drug is significantly (p = 0.01) higher in the early than in the late morning samples. The rise in plasma free fatty acids (acting as displacing agents) after the overnight fast is probably responsible for this difference in free fraction. The implications of these findings with respect to the monitoring of free plasma VPA levels are discussed.