Mohamed E. E. Shams

CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine.

Background:  Venlafaxine (V) is a mixed serotonin and noradrenaline reuptake inhibitor used as a first‐line treatment of depressive disorders. It is metabolized primarily by the highly polymorphic cytochrome P450 (CYP) enzyme CYP2D6 to yield a pharmacologically active metabolite, O‐desmethylvenlafaxine (ODV), and to a lesser extent by CYP3A4, to yield N‐desmethylvenlafaxine (NDV).

Type 2 Diabetes Mellitus-Induced Hyperglycemia in Patients with NAFLD and Normal LFTs: Relationship to Lipid Profile, Oxidative Stress and Pro-Inflammatory Cytokines.

Type 2 diabetes mellitus is associated with dyslipdemia, insulin resistance and non alcoholic fatty liver disease. The purpose of the current study was to assess whether type 2 diabetes mellitus-induced hyperglycemia has an effect on the lipid profile and release of oxidative stress markers and inflammatory mediators in patients with non alcoholic fatty liver disease and normal liver function tests which may in turn lead to enhancing the pathogenicity of this liver disease. For this purpose, one hundred and five outpatients, matched in age and weight, were classified into two groups: the first group consisted of patients with non alcoholic fatty liver disease and the second group consisted of patients with non alcoholic fatty liver disease in conjunction with hyperglycemia due to the presence of type 2 diabetes mellitus. In all patients, lipid profile, oxidative stress, and inflammatory mediators were assessed by measuring serum concentrations of triglycerides, low density lipoprotein, hydrogen preroxide, malondialdehyde, tumor necrosis factor-alpha and interleukin-6, respectively. In the studied population, it was found that the presence of type 2 diabetes mellitus-induced hyperglycemia significantly impaired lipid profile, and significantly enhanced the formation of hydrogen preroxide and malondialdehyde as well as significantly increased the release of tumor necrosis factor-alpha and interleukin-6 in the second group of patients. In addition, plasma glucose level showed significant positive correlation with hydrogen peroxide, malondialdehyde, tumor necrosis factor-alpha and interleukin-6. From the previous results, it was concluded that the presence of type 2 diabetes mellitus-induced hyperglycemia results in significant increase in lipid profile, oxidative stress markers and inflammatory mediators in patients with non alcoholic fatty liver disease and normal liver function tests. For this reason, further research studies may be essential to evaluate the benefit of adding suitable antioxidant and anti-inflammatory drugs to the treatment regimen for this group of patients. In addition, regular monitoring of blood glucose levels and liver function tests should be advised to this category of patients to reduce liver fat deposition and avoid the development of non alcoholic steatohepatitis, cirrhosis or liver cancer and their related complications.

Protective effects of arjunolic acid against cardiac toxicity induced by oral sodium nitrite: Effects on cytokine balance and apoptosis

AIMS Sodium nitrite, a preservative used in meat products, helps in the production of free radicals, leading to increased lipid peroxidation, which plays a vital role in posing toxic effects in different body organs. On the other hand, arjunolic acid possesses antioxidant properties and plays protective roles against chemically induced organ pathophysiology. We investigated the effect of sodium nitrite on cardiac tissue in rats on the inflammatory cytokine balance and the type of induced apoptosis, and we analyzed the protective role of arjunolic acid. MAIN METHODS Sixty adult male Sprague-Dawley rats were injected with 80mg/kg sodium nitrite in the presence/absence of arjunolic acid (100 and 200mg/kg). Cardiac pro-inflammatory cytokines (TNF-α and IL-1β), c-reactive protein (CRP) and anti-inflammatory cytokines (IL-4 and IL-10) were measured by ELISA. Cardiac mitochondrial activity (cytochrome-C-oxidase), JNK activation and apoptosis (caspase-3, caspase-8 and caspase-9) were assessed. KEY FINDINGS Sodium nitrite resulted in increased TNF-α (1.6-fold), IL-1β (3.7-fold) and CRP (2.4-fold) levels accompanied by 52%, 59% and 40% reductions in IL-10, IL-4 and cytochrome-C-oxidase, respectively, as well as enhanced JNK, caspase-3, caspase-8 and caspase-9 activities. Arjunolic acid markedly ameliorated these effects. SIGNIFICANCE Arjunolic acid attenuated sodium nitrite-induced cardiac damage in rats and restored the normal balance between pro- and anti-inflammatory cytokines. Moreover, arjunolic acid protected cardiac tissues from both extrinsic and intrinsic cell death pathways.

Therapeutic drug monitoring of the antidepressant mirtazapine and its N-demethylated metabolite in human serum.

Mirtazapine is a novel antidepressant that acts by enhancing serotonergic and noradrenergic neurotransmission. Because very little is known about serum concentrations in relation to clinical effects, the use of therapeutic drug monitoring is so far unclear. A rapid automated HPLC method with fluorescence detection was developed for routine quantification of mirtazapine and its demethylated metabolite N-desmethylmirtazapine in human serum. The precision of the method was suitable because the day-to-day (n = 7) coefficient of variation (CV) of mirtazapine was 9.8, 4.2, and 5.1% for concentrations of 10, 40, and 80 ng/mL, respectively, and the CV for N-desmethylmirtazapine were 11.6, 10.3, and 9.5% for 5, 20, and 40 ng/mL, respectively. The bias ranged between 0.7 and 4.2 ng/mL and between 0.9 and 2.0 ng/mL for mirtazapine and N-desmethylmirtazapine, respectively. Serum samples of 100 patients, aged between 18 and 93 years, were analyzed. There was wide interindividual variability of serum concentrations on each dose level, and the median (25th to 75th percentiles) of the mirtazapine and N-desmethylmirtazapine concentrations was 19.5 (11.0–28.7) and 9.0 (6.0–17.0) ng/mL, respectively. Women had higher dose-corrected concentrations (C/Ds, ng/mL/mg) of mirtazapine [median (25th–75th percentiles) 0.6 (0.4–0.9) vs 0.4 (0.3–0.6) and N-desmethylmirtazapine [0.4 (0.2–0.6) vs 0.2 (0.1–0.4)] than men. Patients over 60 years of age (mean age ± SD was 72.2 ± 7.1) had higher C/Ds of mirtazapine and N-desmethylmirtazapine [0.7 (0.4–1.2) vs 0.53 (0.4–0.8) and 0.5 (0.2–0.9) vs 0.3 (0.2–0.9), respectively] than younger patients (mean age ± SD was 43.3. ± 10.6). Patients with N-desmethylmirtazapine/mirtazapine ratios less than 0.4 had significantly more side effects (P < 0.05) than those having higher ratios. Comedications were assessed for drug–drug interaction, and significantly (P < 0.05) lower N-desmethylmirtazapine/mirtazapine ratios were found under concomitant medications of the antidepressant sertraline and the antipsychotic amisulpride.

Fish oil improves lipid metabolism and ameliorates inflammation in patients with metabolic syndrome: Impact of nonalcoholic fatty liver disease

Context: Nonalcoholic fatty liver disease (NAFLD) is increasingly prevalent in Egypt, in parallel with increasing obesity. NAFLD can lead to liver inflammation, fibrosis and cirrhosis. NAFLD appears tightly linked with metabolic syndrome (MetS). Objective: Examine the impact of dietary fish oil on human patients with MetS and NAFLD. Materials and methods: One hundred and forty patients were enrolled in the current study and classified into two groups: patients with both MetS and NAFLD and patients with MetS alone. Sixty-four patients were treated with daily supplementation of 2 g of fish oil for 6 months. Markers of hyperlipidemia and oxidative stress, hydrogen peroxide (H2O2) and malondialdhyde (MDA), as well as proinflammatory cytokines, tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), were analyzed. Results: Patients without fish oil exhibited significant increases in triglycerides (TGs), low-density lipoprotein (LDL), H2O2 and MDA that were associated with significantly elevated TNF-α and IL-6 compared to controls. Furthermore, patients with both NAFLD and MetS showed significant increase in H2O2, MDA, TNF-α and IL-6 levels compared with MetS group (p < 0.05). Treatment with fish oil reduced serum level of TG, LDL-cholesterol (LDL-C), H2O2, MDA, TNF-α and IL-6 levels in patients and did not affect the control levels. Discussion and conclusion: Patients with NAFLD had bad lipid profile through a mechanism that involved developed redox imbalance, characterized by boosted free-radical activity and lipid peroxidation enhancing the release of proinflammatory cytokines leading to increased MetS risk and liver damage. However, daily treatment of patients with fish oil for 6 months improved lipid profile and blocked the oxidative stress and cytokines release.

Phenotyping and Genotyping of Drug Metabolism to Guide Pharmacotherapy in Psychiatry

In psychiatry, around 130 drugs are available which have been detected and developed during the last 60 years. These drugs are effective and essential for the treatment of many psychiatric disorders and symptoms. Therapeutic outcomes, however, are still far from satisfactory for many patients. One major reason underlying insufficient response or problems of tolerability or toxicity is considerable interindividual variability in the pharmacokinetic properties of the patients. At the exact same dose, a more than 20-fold interindividual variation in steady state concentrations of the drugs in the body may result. Patients differ in their ability to absorb, distribute, metabolize and excrete drugs due to concurrent disease, age, concomitant medication or genetic peculiarities. A valuable tool for tailoring the dosage of the prescribed medication(s) to the individual characteristics of a patient is therapeutic drug monitoring (TDM). For a considerable number of psychopharmacologic compounds, TDM has become a clinical routine for dose adjustment. The benefits of TDM regarding optimization of psychopharmacotherapy can be further enhanced by genotyping of cytochrome P450 enzymes (CYP). These enzymes are highly polymorphic and involved in the metabolism of most psychotherapeutic drugs. Genotyping related information may be supportive especially for drugs that are predominantly metabolized by CYP2C19 or CYP2D6. The in vivo activity of CYP isoenzymes can be determined using probe drug assays. When used appropriately, phenotyping and genotyping methods are most helpful for problem solving and improvement of the outcomes of psychopharmacotherapy for many patients.