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Biomedical subjects

J A Cramer

Publications and source records attributed to J A Cramer.

At least 73 records · Page 4Linked to original sources
PubMed1991

Reproductive function in epilepsy.

The hypothalamic-pituitary-gonadal axis is a complex system within which both positive and negative feedback occur among its elements and higher brain systems. The occurrence of seizures and changes in the secretion of pituitary hormones can affect the feedback loop. Both seizures and antiepileptic drugs can affect the hypothalamic-pituitary-gonadal axis of males and females and cause changes in hormones and sexuality. Reproductive dysfunction has a social impact because of reduced fertility. Once conception occurs, live birth rates are not diminished. Prospective studies of men and women with epilepsy are needed.

Anticonvulsants↗
PubMed1990

In vivo determination of valproate binding constants during sole and multi-drug therapy.

Valproate (VPA) is present in humans and is largely bound to protein. Only free drug is metabolized, and antiepileptic and toxic effects are probably related to free concentrations. By measuring serial free and total serum VPA levels after routine oral doses, we have determined individual in vivo protein binding parameters for 37 patients after a total of 49 separate drug administrations. Binding site concentrations and dissociation constants were fitted using a nonlinear algorithm. On sole VPA (n = 28) the mean dissociation constant was 91 mumol/L, and the mean concentration of binding sites was 1,176 mumol/L. Evidence suggests a second, nonsaturable binding site. Fraction of unbound VPA ranged from 5.4% at low levels up to 38.7%, rising with increasing total concentration. Concurrent therapy with phenytoin (n = 7) or carbamazepine (n = 8) did not cause displacement of VPA. Changes in free fraction were consistently observed during the interdose interval. The data demonstrate that the binding changes are not a factor in decreased VPA levels during coadministration of other antiepileptic drugs.

Binding, Competitive↗
PubMed1990

Compliance declines between clinic visits.

Adherence to prescribed drug dosing regimens declined substantially during the interval between clinic visits and drug level tests. Using microelectronic monitors to observe pill-taking habits, 20 patients averaged 88% compliance before and 86% compliance after the visit, but this dropped to 67% compliance a month later. These data indicate that spot drug levels do not represent long-term "steady-state" drug serum concentrations.

Anticonvulsants↗
PubMed1989

How often is medication taken as prescribed? A novel assessment technique.

The evaluation of the efficacy of medication is confounded when patients do not adhere to prescribed regimens. Overdosing, underdosing, and erratic dosing intervals can diminish drug action or cause adverse effects. Using a new method with epilepsy as a model, we assessed compliance with long-term medications among newly treated and long-term patients. Medication Event Monitor Systems (Aprex Corporation, Fremont, Calif) are standard pill bottles with micro-processors in the cap to record every bottle opening as a presumptive dose. Compliance rates averaged 76% during 3428 days observed: 87% of the once daily, 81% of the twice daily, 77% of the three times a day, and 39% of the four times a day dosages were taken as prescribed. Coefficients of variation of drug serum concentrations had no significant relationship to compliance rates. Pill counts overestimated compliance increasingly as compliance with the prescribed regimen declined. Neither drug serum concentrations nor pill counts would have identified the frequency of missed doses that were revealed with continuous dose observations.

Adult↗
PubMed1989

Barbiturate-related connective tissue disorders.

Development of Dupuytren's contractures, frozen shoulder, Ledderhose's syndrome, Peyronie's disease, fibromas, and general joint pain has been linked in retrospective studies and case reports to the use of antiepileptic drugs. We undertook a prospective survey of the incidence of connective tissue disorders in 622 patients newly treated with carbamazepine, phenobarbital, phenytoin sodium, or primidone. Ten of the 406 patients who were treated for 6 months or more developed connective tissue disorders. All affected patients were taking a barbiturate (primidone, 4 patients; phenobarbital, 6 patients). Seven of the 10 problems occurred during the first year of treatment. These data are prospective evidence of a statistically significant relationship between barbiturate use and the development of connective tissue disorders, and timing of appearance.

Adult↗
PubMed1988

Crossover from polytherapy to monotherapy in primary generalized epilepsy.

Patients with primary generalized tonic-clonic seizures can obtain equal or superior seizure control and fewer side effects when managed with valproate than when taking multiple antiepileptic drugs. The conversion from polytherapy to valproate monotherapy must be done carefully if side effects and seizure exacerbation are to be avoided. A gradual crossover, often requiring several months, is usually necessary. A well-developed plan and understanding by the patient, coupled with close follow-up, are essential. The major improvement in quality of life that results for the majority of patients after completing such a conversion fully warrants the extra time and effort required.

Adult↗
PubMed1988

Can categorization of patient background problems be used to determine early termination in a clinical trial?

Many patients entering a long-term clinical study are unable to remain active in the trial (taking medication as prescribed and attending clinic as scheduled) for up to 6 years. We studied a group of 622 patients entering an antiepileptic drug study with maximum possible follow-up period of 6 years. A centralized case validation system was used in this VA Epilepsy Cooperative Study to note problems in patients entering the study. The categories established for pre-entry case status were associated with events occurring during the course of the study that led to noncompletion of the study. The data were reviewed to determine whether pre-entry status can be used to suggest the likelihood that an individual patient will remain in the study to completion or become a non-drug-related loss. Over one-half of all losses were related to failure to return to clinic. Medical problems (18%), medication noncompliance (14%), and psychiatric problems (12%) accounted for the remainder of losses. Pre-entry issues often were the same reason for early loss. However, many patients with problems known at entry were maintained in the study when targeted for extra support. We found some groups of patients had considerably more early terminations whereas others had less loss to the trial than we predicted originally. Thus, case categorization at entry can be used to estimate the likelihood of early termination from a clinical trial.

Actuarial Analysis↗
PubMed1988

Compliance in epilepsy. Strategies to enhance adherence to a medical regimen.

Treatment of medical disorders and prevention of disease are hampered by the all too frequent lack of adherence with the prescribed regimen. Delivery of health care to a broad-based population at reasonable cost and with high quality can be enhanced by use of multiple strategies to aid compliance. No single technique is best for all patients. Education, dose planning, appointment scheduling and monitoring coupled with communication between patient and physician or staff are basic strategies for development of immediate and long-term adherence behavior.

Anticonvulsants↗
PubMed1988

Aspects of compliance: taking drugs and keeping clinic appointments.

Treatment of epilepsy depends on adherence to a drug regimen as prescribed and periodic assessment of progress. Typical problems of compliance to medication and adherence to follow-up in long-term epilepsy treatment in a clinical trial were analyzed. Zero drug levels, subtherapeutic levels, variable levels and delayed dose were measures of non-compliance to the drug regimen. Missed visits and non-drug-related dropouts from the study marked non-adherence. Data from 622 patients participating in a multicenter evaluation of the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin and primidone, showed generally good compliance. Only 5% of patients had zero drug levels or greater than or equal to 24 h since prior dose at 2 or more visits. Good adherence to the protocol was demonstrated by 93% attendance as scheduled. The support structure of the study and the availability of a study assistant helped many patients to prevent potential problems and convert patients into excellent adherers.

Adolescent↗
PubMed1987

Results of a nationwide Veterans Administration Cooperative Study comparing the efficacy and toxicity of carbamazepine, phenobarbital, phenytoin, and primidone.

In 1985 a 5-year multicenter Veterans Administration Cooperative Study was completed that compared the efficacy and toxicity of phenobarbital, carbamazepine, phenytoin, and primidone in a double-blind prospective study design. A total of 622 patients, either previously untreated or undertreated, were entered into the study. Strict exclusion criteria limited confounding factors such as drug or alcohol abuse. Results showed that each of the four drugs used as monotherapy were similarly effective in the treatment of generalized tonic clonic seizures, but carbamazepine was significantly more effective in the treatment of complex partial seizures as measured by 100% control. When the results for all four drugs were combined, the data showed that approximately 80% of the patients were adequately managed on monotherapy. Differences in toxicity were the most significant factor that discriminated between these four drugs. Both carbamazepine and phenytoin were associated with significantly lower incidences of intolerable side effects than were primidone or phenobarbital. A behavioral toxicity battery was performed whenever possible prior to administration of any antiepileptic drug and at 1, 3, 6, and 12 months after initiation of monotherapy. Significant differences in performance on all subtests of the battery were found between patients with epilepsy and a control group matched by age, sex, and education. When the differential effects of all four drugs on behavioral toxicity were compared, few statistically significant differences emerged. However, carbamazepine consistently produced fewer adverse effects on tests of attention/concentration and motor performance than did the other three antiepileptic drugs.

Adult↗
PubMed1986

Use of oral contraceptives by women with epilepsy.

Oral contraceptives have not been associated with exacerbation of epilepsy despite warnings in package inserts. No clinical study has provided scientific evidence of worsening of seizures in epileptic women who use oral contraceptives, and improvement in seizure control has occurred in some cases. The main concern about use of oral contraceptives in this population is their effectiveness in preventing conception. Failure rates are higher in groups of women taking enzyme-inducing antiepileptic drugs. The degree of increased metabolism of estrogen and progestin components is highly variable and unpredictable among individuals. Use of higher doses increases protection against conception but also increases the risk of side effects, particularly in patients in whom no enzyme induction occurs. The strength of hormones in the pill should be selected individually when initiating use. Some women may require higher doses for full contraceptive effect.

Animals↗
PubMed1986

Variable free and total valproic acid concentrations in sole- and multi-drug therapy.

Total and free valproic acid (VPA) serum concentrations differ between patients on sole therapy (SOLE Group) and those taking multiple drugs (MULTI Group). We found significantly higher total and free VPA levels and free fractions in 25 SOLE patients than in 29 MULTI patients, both at morning predose (minimum) and postdose (maximum) testing. Results in SOLE versus MULTI patients were, respectively, as follows: total minimum 70.5 vs. 50.2 micrograms/ml (p less than 0.01); total maximum 106.8 vs. 89.5 micrograms/ml (p less than 0.05); free minimum 9.8 vs. 4.4 micrograms/ml (p less than 0.001); free maximum 18.9 vs. 12.0 micrograms/ml (p less than 0.01). The wide variation in total and free levels suggests the need to monitor VPA levels carefully. Not only does use of other drugs influence VPA kinetics, but the time since last dose also affects levels. Nonlinear binding causes large increases in free levels as total VPA concentration rises. We monitor free and total VPA at minimum and maximum along with evaluation of side effects and seizures for better interpretation of dosage requirements.

Adult↗
PubMed1985

Comparison of carbamazepine, phenobarbital, phenytoin, and primidone in partial and secondarily generalized tonic-clonic seizures.

We conducted a 10-center, double-blind trial to compare the efficacy and toxicity of four antiepileptic drugs in the treatment of partial and secondarily generalized tonic-clonic seizures in 622 adults. Patients were randomly assigned to treatment with carbamazepine, phenobarbital, phenytoin, or primidone and were followed for two years or until the drug failed to control seizures or caused unacceptable side effects. Overall treatment success was highest with carbamazepine or phenytoin, intermediate with phenobarbital, and lowest with primidone (P less than 0.002). Differences in failure rates of the drugs were explained primarily by the fact that primidone caused more intolerable acute toxic effects, such as nausea, vomiting, dizziness, and sedation. Decreased libido and impotence were more common in patients given primidone. Phenytoin caused more dysmorphic effects and hypersensitivity. Control of tonic-clonic seizures did not differ significantly with the various drugs. Carbamazepine provided complete control of partial seizures more often than primidone or phenobarbital (P less than 0.03). Overall, carbamazepine and phenytoin are recommended drugs of first choice for single-drug therapy of adults with partial or generalized tonic-clonic seizures or with both.

Adolescent↗
PubMed1985

Epilepsy, sex hormones, and antiepileptic drugs.

Many factors associated with hormone function have an impact on the course of epilepsy. Patients with epilepsy may have disturbances in sexual function such as anovulatory cycles in women and decreased libido and potency in men. Data indicate seizures, especially those arising in the limbic system, may influence the hypothalamic pituitary axis. Antiepileptic drugs also influence sexual function through direct brain effects as well as through induced changes in pharmacokinetics of the sex steroid hormones. Pregnancy has been reported to be a time of increased seizures; however, this has often been associated with low drug levels, for reasons that include inadequate drug dose, possible changes in pharmacokinetics, and noncompliance. Some evidence suggests that hormones affect seizure frequency. Changes in seizures during the menstrual cycle (catamenial epilepsy) have been found in some women: seizures were fewer during the luteal phase but increased when progesterone levels declined. Some improvement in seizure frequency has been shown in pilot studies using medroxyprogesterone acetate, a synthetic progesterone. Current concepts of the interrelationship among epilepsy, sex hormones, and antiepileptic drugs are discussed.

Anovulation↗