Acetyl-CoA carboxylase 2-/- mutant mice are protected against fatty liver under high-fat, high-carbohydrate dietary and de novo lipogenic conditions.

Hepatic fat accumulation resulting from increased de novo fatty acid synthesis leads to hepatic steatosis and hepatic insulin resistance. We have shown previously that acetyl-CoA carboxylase 2 (Acc2(-/-)) mutant mice, when fed a high-fat (HF) or high-fat, high-carbohydrate (HFHC) diet, are protected against diet-induced obesity and maintained whole body and hepatic insulin sensitivity. To determine the effect of an ACC2 deletion on hepatic fat metabolism, we studied the regulation of the enzymes involved in the lipogenic pathway under Western HFHC dietary and de novo lipogenic conditions. After completing the HFHC regimen, Acc2(-/-) mutant mice were found to have lower body weight, smaller epididymal fat pads, lower blood levels of nonesterified fatty acids and triglycerides, and higher hepatic cholesterol than wild-type mice. Significant up-regulation of lipogenic enzymes and an elevation in hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) protein were found in Acc2(-/-) mutant mice under de novo lipogenic conditions. The increase in lipogenic enzyme levels was accompanied by up-regulation of the transcription factors, sterol regulatory element-binding proteins 1 and 2, and carbohydrate response element-binding protein. In contrast, hepatic levels of the PPAR-γ and PPAR-α proteins were significantly lower in the Acc2(-/-) mutant mice fed an HFHC diet. When compared with wild-type mice fed the same diet, Acc2(-/-) mutant mice exhibited a similar level of AKT but with a significant increase in pAKT. Hence, deleting ACC2 ameliorates the metabolic syndrome and protects against fatty liver despite increased de novo lipogenesis and dietary conditions known to induce obesity and diabetes.

Grapefruit juice and drug interactions. Exploring mechanisms of this interaction and potential toxicity for certain drugs.

Concomitant administration of grapefruit juice can increase the plasma concentration of numerous drugs in humans and decrease the concentration of a few others. Such elevations of drug plasma concentrations have, on occasion, resulted in adverse clinical effects. Increased concentrations are primarily mediated by chemicals in grapefruit juice, which inhibit the CYP 3A4 drug-metabolizing enzyme in the small intestines. This inhibition decreases the first-pass metabolism of drugs using the CYP 3A4 intestinal system and increases the bioavailability and maximal plasma drug concentrations (Cmax) of the CYP 3A4 substrates. The effect of grapefruit juice on drug metabolism is most pronounced in drugs with a high first-pass metabolism (eg, felodipine, amiodarone), in which it inhibits the first-pass metabolism of the CYP 3A4 substrates leading to an increase in Cmax and area under the concentration time curve (AUC). The use of grapefruit juice with a few specific drugs (eg, fexofenadine, digoxin) may lower plasma drug concentrations by inhibiting drug absorption catalyzed by the organic anion transporting polypeptide (OATP).

Herb-drug interactions. Interactions between saw palmetto and prescription medications.

Patients over age 50 typically present with one chronic disease per decade. Each chronic disease typically requires long-term drug therapy, meaning most older patients require several drugs to maintain health. Simultaneously, use of complementary and alternative medicine (CAM) has increased in the United States in the last 20 years, reaching 36% in 2002; herbal medicine use accounts for approximately 22% of all CAM use. Older adults often add herbal medicines to prescription medications, yet do not always inform their physicians. The drug metabolizing enzyme systems process all compounds foreign to the body, including prescription and herbal medications. Therefore use of both medicinals simultaneously has a potential for adverse interactions. This review, which discusses saw palmetto, is the last in a series covering the documented interactions among the top 5 efficacious herbal medicines and prescription drugs.

Herb-drug interactions: interactions between kava and prescription medications.

Patients over age 50 typically present with one chronic disease per decade. Each chronic disease usually requires long-term drug therapy, meaning most older patients require several drugs to control their conditions and/or maintain their health. Simultaneously, the use of complementary and alternative medications (CAM) has increased in the United States over the last 20 years, reaching 36% in 2002; herbal medicine use accounts for approximately 22% of all CAM use. Older adults often add herbal medicines to medications prescribed by their physicians, yet do not always inform the physician. The drug metabolizing enzyme systems process all compounds foreign to the body including prescription drugs and herbal medications. Therefore use of both medicinals simultaneously has a potential for interactions of an adverse nature. This review, which will discuss kava, is one in a series covering the documented interactions between herbal medicines with proven efficacy and prescription drugs.

Herb-drug interactions: interactions between Ginkgo biloba and prescription medications.

Geriatric patients typically present with one chronic disease per decade over age 50. Each chronic disease typically requires long-term drug therapy, meaning most older patients require several drugs to control their conditions and/or maintain their health. Simultaneously, the use of complementary and alternative medications (CAM) has increased in the United States over the last 20 years, reaching 36% in 2002; herbal medicine use accounts for approximately 22% of all CAM use. Older adults often add herbal medicines to the medications prescribed by their physicians, yet do not always inform their physicians. The drug metabolizing enzyme systems process all compounds foreign to the body, including prescription drugs and herbal medications. Therefore, use of both medicinals simultaneously has a potential for interactions of an adverse nature. This review, which will discuss ginkgo biloba, is the first of a continuing series covering the documented interactions between herbal medicines with proven efficacy and prescription drugs.

Multisite inhibition by phenylacetate of PC-3 cell growth.

Phenylacetate (PA) is a reversible inhibitor of tumor cell growth and an inhibitor of mevalonate pyrophosphate decarboxylase (MPD). We hypothesized that MPD inhibition should lower rates of protein accumulation and accretion of cell number in all cell lines regardless of tumorigenic status or origin of the cell lines. PA treatment inhibited growth of MCF-7, NIH-3T3, Detroit 551, UT-2, NCTC-929, COS-1 and PC-3 cell lines. NCTC-929 cells lack cadherins and Cos-1 cells are deficient in PPARalpha and PPARgamma, proteins suggested to be central to the action of PA. Oxidative metabolism was not impeded by PA treatment. One-dimensional and two-dimensional FACS analysis of BrdU incorporation failed to demonstrate a redistribution of nuclei in the cell cycle or that the rate of cells entering S phase had changed. Time-lapse photo-microscopy studies reveal a process that left condensed nuclei with little or no cytoplasm. However, negative TUNEL assay results and failure to block cell loss with z-VAD-fmk suggest this type of cell death is not typical apoptosis, but cell death is responsible for the lower rates of cell and protein accumulation. Supplementation studies with mevalonate pathway intermediates during inhibition of the mevalonate pathway of cholesterol biosynthesis by lovastatin confirmed MPD as a site of PA inhibition of growth, but in the presence of lovastatin with or without farnesyl pyrophosphate plus geranylgeranyl pyrophosphate, additive inhibition by PA revealed additional site(s). The existence of site(s) in addition to MPD suggests effective PA-based agents might be developed that would not inhibit MPD.

Principles of drug therapy for the elderly patient.

Physicians will treat larger numbers of elderly patients as the US population ages. Being treated simultaneously for more than 1 condition with multiple prescription drugs is only 1 reason why elderly patients are at greater risk of experiencing adverse drug reactions. The need for physicians to minimize the incidence of these reactions has become incumbent on both physicians and administrators. We review the underlying reasons why the elderly population is at risk of adverse drug reactions and summarize the principles of drug-drug interaction, metabolism, and distribution, which can help elderly patients receive proper pharmacological treatment.