Biomedical subjects

Gail D Anderson

Publications and source records attributed to Gail D Anderson.

25 records · Page 2Linked to original sources

PubMed2002

Acetoacetate, acetone, and dibenzylamine (a contaminant in l-(+)-beta-hydroxybutyrate) exhibit direct anticonvulsant actions in vivo.

PURPOSE: To investigate whether ketone bodies are directly anticonvulsant. METHODS: We tested the effects of acetoacetate (ACA), acetone, and both stereoisomers, D-(-)- and L-(+), of beta-hydroxybutyrate (BHB) on sensory-evoked seizures in Frings audiogenic seizure-susceptible mice. RESULTS: We found that these ketone bodies, with the exception of the D-(-)-isomer of BHB, were anticonvulsant in this model. Furthermore, with gas chromatography-mass spectrometry, we confirmed that the activity of L-(+)-BHB was due to dibenzylamine, a chemical contaminant. CONCLUSIONS: Our data indicate that the anticonvulsant efficacy of the ketogenic diet may be due in part to the direct actions of ACA and acetone.

3-Hydroxybutyric Acid↗

PubMed2002

Children versus adults: pharmacokinetic and adverse-effect differences.

Pharmacokinetic differences may play a part in the age-related differences in the incidence of adverse effects. The most common idiosyncratic reaction to lamotrigine (LTG) is rash, affecting 10-20% of patients. Risk factors are young age, concurrent valproate (VPA), high starting dose, and rapid escalation. In children, cytochrome P450 (CYP)-catalyzed metabolism is increased, and uridine diphosphate (UDP)-glucuronosyltransferase (UGT)-catalyzed metabolism is not significantly different from that in adults. A CYP-catalyzed arene oxide intermediate of LTG has been identified. The increase CYP metabolism of LTG in children could result in increased formation of the reactive metabolite and a higher incident of rash. Children often received higher milligram per kilogram doses compared with adults. The higher dose would cause an increased amount of LTG metabolized to the reactive arene oxide intermediate. VPA therapy is associated with a transient elevation in liver-function tests in 15-30% of patients and a rare, fatal hepatotoxicity. Most cases of VPA hepatotoxicity occurred in children younger than 2 years who had preexisting neurologic or other physical defects. Hypotheses regarding the pathogenesis of the hepatotoxicity include preexisting mitochondrial disease or inborn errors of metabolism, VPA inhibition of beta-oxidation, and toxicity from VPA metabolites VPA, 4-ene-VPA, and 2,4-diene-VPA. Infants and children have higher concentration ratios of 4-ene-VPA to VPA. Polytherapy with enzyme inducers increases the formation of the hepatotoxic metabolites. The role of underlying metabolic disorders associated with hepatodegeneration and intractable seizures without VPA is a major confounder in identifying risk factors and demonstrates the difficulty in separating underlying disease factors in rare idiosyncratic reactions.

Adolescent↗

PubMed2002

Pioglitazone: effect on CYP3A4 activity.

Clinical studies demonstrate CYP3A4 enzyme induction with troglitazone, a thiazolidinedione derivative structurally related to pioglitazone. The objective of this prospective, open-label study conducted in healthy volunteers was to evaluate the influence of multiple-dose pioglitazone therapy on the urinary excretion ratio of 6-beta-hydroxycortisol to cortisol, an endogenous marker of CYP3A4 activity. Twelve subjects were given pioglitazone hydrochloride 45 mg daily for 14 days. Urine was collected over a 24-hour period before pioglitazone and after administration of the last tablet. Baseline and posttreatment CYP3A4 activity was assessed with the urinary 6-beta-hydroxycortisol/cortisol ratio. The mean +/- SD 6-beta-hydroxycortisol/cortisol ratios before and after treatment were 8.3 +/- 4.4 and 9.4 +/- 4.0, respectively (p = 0.29). The mean change from baseline was a nonsignificant 20.2%. Nine subjects had a small increase and 3 subjects had a reduction in the ratio. Using the ratio as a marker of CYP3A4 activity, the data support a lack of inductive effect on CYP3A4 by multiple-dose pioglitazone therapy. Thus, administration of pioglitazone should not result in clinically significant effects on the pharmacokinetics of other CYP3A4 substrates.

Adult↗

PubMed2002

Treatment of epilepsy in women of reproductive age: pharmacokinetic considerations.

Although epilepsy affects men and women equally, there are many women's health issues in epilepsy, especially for women of childbearing age. These issues, which include menstrual cycle influences on seizure activity (catamenial epilepsy), interactions of contraceptives with antiepileptic drugs (AEDs), pharmacokinetic changes during pregnancy, teratogenicity and the safety of breastfeeding, challenge both the woman with epilepsy and the many healthcare providers involved in her care. Although the information in the literature on women's issues in epilepsy has grown steeply in recent years, there are many examples showing that much work is yet to be done. The purpose of this article is to review these issues and describe practical considerations for women of childbearing age with epilepsy. The article addresses the established or "first-generation" AEDs (phenobarbital, phenytoin, primidone, carbamazepine, ethosuximide and valproic acid) and the "second-generation" AEDs (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin and zonisamide). Although a relationship between hormones and seizure activity is present in many women, good treatment options for catamenial epilepsy remain elusive. Drug interactions between enzyme-inducing AEDs and contraceptives are well documented. Higher dosages of oral contraceptives or a second contraceptive method are suggested if women use an enzyme-inducing AED. Planned pregnancy and counselling before conception is crucial. This counselling should include, but is not limited to, folic acid supplementation, medication adherence, the risk of teratogenicity and the importance of prenatal care. AED dosage adjustments may be necessary during pregnancy and should be based on clinical symptoms, not entirely on serum drug concentrations. Many groups have turned their attention to women's issues in epilepsy and have developed clinical practice guidelines. Although the future holds promise in this area, many questions and the need for progress remain.

Abnormalities, Drug-Induced↗

PubMedDate not supplied

Sex and racial differences in pharmacological response: where is the evidence? Pharmacogenetics, pharmacokinetics, and pharmacodynamics.

The Food and Drug Administration (FDA) reviewed 300 new drug applications between 1995 and 2000. Of the 163 that included a sex analysis, 11 drugs showed a >40% difference in pharmacokinetics between males and females, which was listed on the product label, yet no dosing recommendations were made based on sex. Female sex has been shown to be a risk factor for clinically relevant adverse drug reactions. Would simply dosing females based on their different pharmacokinetics decrease the incidence of adverse events? The answer is not known. Sex-dependent pharmacodynamic effects have been identified. The role of pharmacokinetics vs. pharmacodynamics is unclear, as is the impact of pharmacogenetics on both. This review highlights a few specific examples in each area in which sex differences in pharmacokinetics and pharmacodynamics are important and provides recommendations for additional needed research.

Biological Availability↗

PubMedDate not supplied

Ginkgo biloba: evaluation of CYP2C9 drug interactions in vitro and in vivo.

Ginkgo biloba extract is one of the most widely used herbal products in the United States. However, bleeding episodes in patients taking Ginkgo biloba and warfarin have been documented. Therefore, in vitro and in vivo inhibition studies were done to ascertain the influence of ginkgo on CYP2C9, the P-450 isozyme responsible for the metabolism of the most potent warfarin enantiomer, (S)-warfarin. Ginkgo extract inhibited human liver microsomal CYP2C9 with an apparent Ki=14.8 microg/mL, and the inhibition was increased by acid hydrolysis (apparent Ki=9.1 microg/mL). Two open-label, crossover pharmacokinetic studies in healthy subjects were performed using tolbutamide and diclofenac as probe CYP2C9 substrates. In contrast to the in vitro inhibition of CYP2C9, no interactions between Ginkgo biloba extract and CYP2C9 probe substrates were observed in vivo as evidenced by the lack of effect on the steady-state pharmacokinetics of diclofenac or on the urinary metabolic ratio of tolbutamide.

Adult↗

PubMedDate not supplied

Sex differences in drug metabolism: cytochrome P-450 and uridine diphosphate glucuronosyltransferase.

The two most common families of enzymes involved in drug metabolism are the cytochrome P-450 (CYP) and the uridine diphosphate glucuronosyltransferase (UGT) enzymes. The activity of these enzymes depends on genetic, physiologic, and environmental effects. Because the genes involved in the CYP and UGT proteins are not X-linked, the incidence of poor metabolizers would not be expected to be sex-dependent. However, genetics also controls the amount (or activity) of the enzymes. Sex-dependent differences have been demonstrated for several CYP isoenzymes and for UGT. Ethnicity also appears to play a role in the activity of these enzymes.

Age Factors↗