Population pharmacokinetics of steady-state carbamazepine in Egyptian epilepsy patients.

WHAT IS KNOWN AND OBJECTIVE: Individualization of carbamazepine (CBZ) dosage regimen in patients with epilepsy based on based on therapeutic drug monitoring (TDM) followed by estimation of pharmacokinetic (PK) parameters can help in better control of epilepsy. Our objective was to establish a population (POP) PK model of CBZ for Egyptian adult and pediatric patients with epilepsy. METHOD: Single steady-state (SS) trough plasma concentrations of CBZ were available for 302 patients with epilepsy (55·6% men and 44·4% women) who were categorized as children (n = 118) and adults (n = 184) with mean age (years) ± SD of 10·6 ± 4·8 and 29·4 ± 9·9, respectively. Carbamazepine was given as an oral suspension (n = 19) or controlled release tablet (n = 283) with average dose of 15·0 ± 7·8 mg/kg per day. A one-compartment model with first-order absorption and elimination for SS conditions (ADVAN2, SS2, TRANS2) was applied using NONMEM 6.2. Separate absorption rate constants were modelled for the two formulations. The mean POP CL, its intersubject variability (ISV), as well as residual error of CBZ concentration were estimated. RESULTS AND DISCUSSION: The POP estimate for CL was 3·5 L/h with coefficient of variation value of 2·6%, which was consistent with literature data. The ISV on CL was 44·5%. The POP PK model was validated by bootstrap re-sampling, and the individual estimates were within the 95% CI of the bootstrap results. Different covariates that might affect CBZ CL have been evaluated but the limited number of samples per individual prevented precise covariate analysis. WHAT IS NEW AND CONCLUSION: The POP PK model we have developed for CBZ shows good predictive performance in Egyptian adult and pediatric patients with epilepsy. Another PK study to better define the effect of different covariates would improve on the model for dosage individualization.

Dihydrotestosterone stimulates amino acid uptake and the expression of LAT2 in mouse skeletal muscle fibres through an ERK1/2-dependent mechanism.

Dihydrotestosterone (DHT) has acute/non-genomic actions in adult mammalian skeletal muscles whose physiological functions are still poorly understood. Therefore, the primary aim of this study was to investigate the acute/non-genomic effects of DHT on amino acid uptake as well as the cellular signal transduction events underlying these actions in mouse fast- and slow-twitch skeletal muscle fibre bundles. 14C-Labelled amino acids were used to investigate the effects of DHT and testosterone (T) on amino acid uptake and pharmacological interventions were used to determine the cellular signal transduction events mediating these actions. While T had no effect on the uptake of isoleucine (Ile) and α-methylaminoisobutyric acid (MeAIB) in both fibre types, DHT increased their uptake in the fast-twitch fibre bundles. This effect was reversed by inhibitors of protein translation, the epidermal growth factor receptor (EGFR), system A, system L, mTOR and MEK. However, it was relatively insensitive to inhibitors of transcription, androgen receptors and PI3K/Akt. Additionally, DHT treatment increased the expression of LAT2 and the phosphorylation of the EGFR in the fast-twitch fibre bundles and that of ERK1/2, RSK1/2 and ATF2 in both fibre types. Also, it decreased the phosphorylation of eEF2 and increased the incorporation of Ile into proteins in both fibre types. Most of these effects were reversed by EGFR and MEK inhibitors. From these findings we suggest that another physiological function of the acute/non-genomic actions of DHT in isolated mammalian skeletal muscle fibres is to stimulate amino acid uptake. This effect is mediated through the EGFR and involves the activation of the MAPK pathway and an increase in LAT2 expression.

Dihydrotestosterone activates the MAPK pathway and modulates maximum isometric force through the EGF receptor in isolated intact mouse skeletal muscle fibres.

It is generally believed that steroid hormones have both genomic and non-genomic (rapid) actions. Although the latter form an important component of the physiological response of these hormones, little is known about the cellular signalling pathway(s) mediating these effects and their physiological functions in adult mammalian skeletal muscle fibres. Therefore, the primary aim of this study was to investigate the non-genomic actions of dihydrotestosterone (DHT) and their physiological role in isolated intact mammalian skeletal muscle fibre bundles. Our results show that treating the fibre bundles with physiological concentrations of DHT increases both twitch and tetanic contractions in fast twitch fibres. However, it decreases them in slow twitch fibres. These changes in force are accompanied by an increase in the phosphorylation of MAPK/ERK1/2 in both fibre types and that of regulatory myosin light chains in fast twitch fibres. Both effects were insensitive to inhibitors of Src kinase, androgen receptor, insulin-like growth factor 1 receptor and platelet-derived growth factor receptor. However, they were abolished by the MAPK/ERK1/2 kinase inhibitor PD98059 and the epidermal growth factor (EGF) receptor inhibitor tyrphostin AG 1478. In contrast, testosterone had no effect on force and increased the phosphorylation of ERK1/2 in slow twitch fibres only. From these results we conclude that sex steroids have non-genomic actions in isolated intact mammalian skeletal muscle fibres. These are mediated through the EGF receptor and one of their main physiological functions is the enhancement of force production in fast twitch skeletal muscle fibres.

Incidence of thyroid malignancy among goitrous thyroid lesions from the Sarawak General Hospital 2000-2004.

INTRODUCTION: Thyroid cancer is the most common among all endocrine malignancies. The worldwide prevalence of goitre in the general population is estimated at 4-7 percent and the incidence of malignancy in goitrous thyroid is about ten percent. It is postulated that goitrous thyroid is a precursor lesion to the development of malignant thyroid diseases. As Sarawak is a state well known for endemic goitre, this study focused on establishing the incidence of thyroid malignancy among goitrous thyroid swellings. METHODS: This study was a hospital-based retrospective study on the archived collection of the surgically-removed thyroid specimens from the Sarawak General Hospital, Malaysia. Cases were grouped into cancer and non-cancer groups. The cancer group included papillary thyroid carcinoma (PTC), PTC follicular variant, follicular carcinoma and anaplastic carcinoma (ANA). RESULTS: A total of 820 thyroid cases which underwent surgical removal in years 2000 to 2004 were collected. Of these, 143 (17.4 percent) were male and 677 (82.6 percent) female. It was observed that the highest prevalence of thyroid swelling cases occurred in the age group 41-60 years while the lowest prevalence occurred in the age group under 21 years, 371 (45.2 percent) vs. 31 (3.8 percent). By ethnicity, the Ibans and Malays were found to have a higher prevalence at 275 (33.5 percent) and 196 (23.9 percent), respectively, while the lowest prevalence was observed in Indians, 11 (1.3 percent). 55 cases (6.7 percent) were found to be cancerous and the rest (93.3 percent) were non-cancerous thyroid swellings. Histologically, the highest incidence of carcinoma was PTC (4.0 percent) and the lowest was ANA (0.2 percent). CONCLUSION: Based on our observations, although goitrous thyroid swelling is quite a common problem in Sarawak, thyroid malignancy is not a major issue. Among thyroid malignancies, PTC is the most common histological type of malignancy.

Estimation of lithium clearance from routine clinical data in Egyptian bipolar patients. A population pharmacokinetic approach.

Population pharmacokinetics (PK) of lithium as a mood stabilizer was investigated in Egyptian patients with bipolar affective disorders (n = 50) of whom 31 were suffering from lithium toxicity. The mean (+/- SD) age and body weight of patients were 33 +/- 10 years and 67 +/- 3.6 kg, respectively. Patients selected were maintained on lithium carbonate controlled release tablets at doses of 400 mg/12 hours (n = 43) or 200 mg/12 hours (n = 7) respectively. In 19 patients who continued lithium therapy, 1 blood sample/patient was withdrawn for lithium level determination before the morning dose of the drug was given while for 31 patients who suffered from lithium-related toxicity and cessation of drug intake was therapeutically decided, a single blood was drawn at variable time (36, 48 or 72 h) following the last administered dose of the drug. The data was subjected to population PK analysis using NONMEM and a two-compartment model was used. Due to single point sparse data, not all parameters and their between subject variability (BSV) could be determined. Therefore, lithium clearance (CL) and BSV were estimated while other PK parameters were fixed using available literature information. First order (FO) estimation method was used in the analysis. Covariates were evaluated by univariate analysis using likelihood ratio test. The most significant covariate on lithium CL was found to be creatinine clearance (CrCL). The population CL of lithium in the final model was expressed as CLpop = 0.51 x (CrCL/105.3)0.44. The final population PK parameters estimates of lithium were: CL = 0.51 l/h with 12.7% BSV, V1 (Fixed) = 15.2 l, Q (Fixed) = 7.44 l/h, and V2 (Fixed) = 6.7 l. The mean value of lithium concentration at 12 hours as predicted by the final model in the patients with drug toxicity was 1.3 +/- 0.1 mmol/l versus 0.8 +/- 0.14 mmol/l in patients without toxic signs. External validation of the final model on another group of adult bipolar patients (n = 12) maintained on lithium therapy showed a predictive ability of -35 to 65% as represented by% error for the predictions.

Expression of Galectin-3 and Galectin-7 in thyroid malignancy as potential diagnostic indicators.

INTRODUCTION: It has been suggested that Galectin-3 (Gal-3) and Galectin-7 (Gal-7) are potential tumour markers for differentiating thyroid carcinoma from its benign counter part. Galectins are beta-galactoside-binding proteins with Gal-3 being a redundant pre-mRNA splicing factor. They are supposed to be p53-related regulators in cell growth and apoptosis, being either anti-apoptotic or pro-apoptotic. Although the value of Gal-3 has been studied extensively, there is little knowledge regarding the expression of Gal-7 in thyroid malignancy. METHODS: We initiated an immunohistochemical (IHC) study on the expression of Gal-3 and Gal-7 on various thyroid lesions. Formalin-fixed paraffin embedded thyroid tissues were stained for IHC expression of Gal-3 and Gal-7 using monoclonal anti-human Gal-3 antibody and anti-human Gal-7 antibody (R&D Systems Inc, MN, USA). Gal-3 and Gal-7 expressions were measured semiquantitatively on their distribution and staining intensity. RESULTS: A total of 95 cases were collected, including 32 benign and 63 malignant thyroid lesions. These contained 37 cases of papillary thyroid carcinoma, nine cases of papillary thyroid carcinoma follicular variant, 16 cases of follicular carcinoma, one case of anaplastic carcinoma, 14 cases of follicular adenomas and 18 cases of nodular goitre. Gal-3 expression was significantly strong in cancer cases compared to non-cancer cases (p-value is 0.000), while no significant difference was noted with Gal-7 expression (p-value is 0.870). CONCLUSION: Our findings suggested that the IHC localisation of Gal-3 is a useful marker in conjunction with routine haematoylin and eosin staining in differentiating benign from malignant thyroid lesions, while there is no significant adjunct diagnostic value in Gal-7 for thyroid malignancy.