Chen Hsi Chou

Determination of metformin in human plasma by high-performance liquid chromatography with spectrophotometric detection.

A simple, selective, sensitive and precise high-performance liquid chromatographic plasma assay for the hypoglycemic agent metformin is described. Acidified samples of plasma were deproteinated with acetonitrile, washed with dichloromethane and the resulting supernatant injected. Chromatography was performed at 40 degrees C by pumping a mobile phase of acetonitrile (250 ml) in pH 7, 0.03 M diammonium hydrogen phosphate buffer (750 ml) at a flow-rate of 1 ml/min through a silica column. Metformin and the internal standard (atenolol) were detected at 240 nm and were eluted 7.8 and 6.8 min, respectively, after injection. No endogenous substances were found to interfere. Calibration curves were linear (r>0.999) from 10 to 2000 ng/ml. The absolute recovery of both metformin and atenolol was greater than 76%. The detection limit and limit of quantitation were 2.5 and 10 ng/ml, respectively. The intra- and inter-day precision (C.V.) was 12%, or less, and the accuracy was within 6.2% of the nominal concentration. This method is suitable for clinical investigation and monitoring metformin concentration.

High prevalence of metabolic disturbances in patients with bipolar disorder in Taiwan.

BACKGROUND Both ethnicity and lifestyle may contribute to these abnormalities. High prevalences of obesity and metabolic disturbances in patients with bipolar disorder (BD) have been reported in western countries. However, reports about the prevalences in Asian countries remain scant. METHOD The cross-sectional study included 117 patients diagnosed as BD and treated with lithium (Li), valproate (VPA), or both at a university psychiatric outpatient clinic. Their body mass index and plasma levels of glucose and lipid were measured. The prevalence of metabolic syndrome was determined based on the IDF 2005 criteria. RESULTS 13.7%, 36.8%, 53.0%, 18.6%, and 61.0% of the patients met the criteria for hyperglycemia, hypertriglyceridemia, low high-density lipoprotein cholesterol (HDL-C), hypertension and large waist circumference, respectively. 33.9% of the patients met the IDF 2005 criterion for metabolic syndrome. The prevalence of metabolic abnormalities was significantly higher in patients who have been cotreated with second-generation antipsychotics (SGAs). CONCLUSION This study provides evidence of high prevalence of metabolic syndrome in BD patients in Taiwan. Such metabolic disturbances can increase morbidity and mortality. Further studies that focus on the underlying mechanisms and effective intervention strategies are warranted.

Refractory candidal meningitis in an immunocompromised patient cured by caspofungin

ABSTRACT Candidal meningitis is a rare infectious disease that usually leads to substantial morbidity and mortality. We present a case of candidal meningitis refractory to systemic antifungal therapy (amphotericin B and fluconazole). A 63-year-old female with lymphoblastic lymphoma and myelodysplasia with leukemia transformation developed prolonged fever and headache on the seventh day following intrathecal prophylactic chemotherapy. A lumbar puncture showed neutrophilic pleocytosis, and a cerebrospinal fluid culture yielded Candida albicans. The clinical course was complicated by brain edema, subarachnoid hemorrhage, and hydrocephalus. Parenteral therapy with amphotericin B alone or amphotericin B in combination with fluconazole or intrathecal administration of amphotericin B failed to eradicate C. albicans in the cerebrospinal fluid. After 7 days of caspofungin therapy, however, the cerebrospinal fluid became sterile and the patient gradually regained consciousness. She was discharged 1 month after completing 4 weeks of caspofungin therapy. There were two critical issues we thought to be relevant to the favorable outcome of this case. First, isolation of C. albicans was achieved by inoculating enriched liquid medium with cerebrospinal fluid. Second, there is a potential therapeutic benefit of caspofungin in treating a fungal infection of the central nervous system.

In vitro and in vivo comparison of two diclofenac sodium sustained release oral formulations.

The aim of this study was to investigate the effect of formulation on the pharmacokinetics of diclofenac in two sustained release formulations (formulation A and Voltaren SR) after oral delivery. The dissolution of diclofenac from sustained release formulation was pH-dependent. While drug released from both formulations increased with increased pH, the release kinetics of these two formulations was different. The pharmacokinetic study was conducted in 12 healthy subjects administered with multiple doses of 100mg of diclofenac in a crossover design. There was a significant difference in area under the plasma concentration-time curve [AUC(0-24)] and C(max) observed. The formulation with a reduced diffusion exponent with increased kinetic constant results in increased absorption of diclofenac in vivo. This study demonstrated the impact of release mechanism of the formulation on the absorption in vivo.

Uptake and Dispersion of Metformin in the Isolated Perfused Rat Liver

Although metformin is a widely used oral antihyperglycaemic, the exact mechanisms of its cellular uptake and action remain obscure. In this study the hepatic extraction and disposition kinetics of metformin were investigated by use of an isolated in‐situ rat liver preparation. The liver was perfused in single‐pass mode with protein‐free Krebs bicarbonate medium at a flow rate of 20mLmin−1.

C825T polymorphism of the GNB3 gene on valproate-related metabolic abnormalities in bipolar disorder patients.

Background: Valproate (VPA) is a mood stabilizer for treating patients with bipolar disorder (BD). It may cause metabolic abnormalities in certain bipolar patients. However, the genetic factors that influence the susceptibility remain unclear. Genetic polymorphism of the G-protein &bgr;3 subunit (GNB3) is reported to be associated with metabolic phenotypes. In the current study, we investigated the possible associations between the GNB3 variation and VPA-induced metabolic abnormalities. Methods: Subjects (n = 96) who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria for BD were recruited from the National Cheng Kung University Hospital. Their metabolic indices were measured. Results: The variation of GNB3 C825T showed an association with higher plasma total cholesterol (P = 0.037), triglyceride (P = 0.014), and leptin (P < 0.001) levels in BD patients treated with VPA. After adjusting for age, sex, types of BDs, and serum concentration of VPA, the variation of GNB3 C825T remained significantly associated with the levels of serum leptin and body mass index (BMI; P < 0.001 and P = 0.030, respectively). In addition, the GNB3 C825T showed significant drug-single-nucleotide polymorphism interactions with insulin levels (P = 0.033), triglyceride levels (P = 0.013), leptin levels (P = 0.013), and BMI (P = 0.018). These results indicated that the T allele may be associated with lower serum leptin levels and BMI in BD patients treated with VPA. Conclusions: The current study provides evidence that BD patients who are T allele carriers of the GNB3 C825T polymorphism have a lower risk for VPA-induced metabolic abnormalities. Further studies about the underlying mechanisms of G protein in VPA-induced metabolic abnormalities are warranted.

High risk of cross-reactivity between vancomycin and sequential teicoplanin therapy

What is known and Objective:  Teicoplanin and vancomycin show similar clinical and bacteriological efficacy in clinical trials. Teicoplanin has been reported to have a lower adverse drug reaction (ADR) rate than vancomycin. Cross‐reactivity between these two glycopeptides is controversial. Our aim was to study the cross‐reactivity between teicoplanin and vancomycin through an assessment of all the reported ADRs of these drugs in our University hospital.

Teicoplanin-induced hypersensitivity syndrome with a preceding vancomycin-induced neutropenia: a case report and literature review

Hypersensitivity syndrome associated with teicoplanin has rarely been reported. We report a case with a preceding episode of vancomyin‐related neutropenia. A 47‐year‐old female with cervical spine infection was treated with vancomycin. Neutropenia occurred after 17 days of vancomycin therapy. Vancomycin was changed to teicoplanin, and the neutropenia resolved 4 days later. After 11 days of teicoplanin therapy, a new episode of hypersensitivity syndrome manifested as fever, bilateral neck lymphadenopathy, mild wheezing, hepatitis and increased CRP occurred. Neutropenia and thrombocytopenia developed 3 days later. The patient’s symptoms settled over 1 week following withdrawal of teicoplanin. Naranjo’s ADR algorithm categorized the neutropenia associated with vancomycin and the hypersensitivity syndrome associated with teicoplanin as ‘probable’.

Association between ABCB1 Polymorphisms and Antidepressant Treatment Response in Taiwanese Major Depressive Patients.

Objective The multidrug resistance 1 (ABCB1, MDR1) gene, encoding P-glycoprotein, is extensively distributed and expressed in various tissues, such as a blood-brain barrier transporter. P-glycoprotein plays an important role in controlling the passage of substances between the blood and brain. The current study aimed to investigate possible associations of functional ABCB1 polymorphisms (C3435T, G2677T and C1236T) with response to antidepressant treatment and serum cortisol levels in Taiwanese patients with major depressive disorder (MDD). Methods We recruited 112 MDD patients who were randomized to fluoxetine (n=58, mean dose: 21.4±4.5 mg/day) or venlafaxine (n=54, 80.2±34.7 mg/day) treatment for 6 weeks. The 21-item Hamilton Depression Rating Scale (HDRS) was administered initially and biweekly after treatment, and cortisol levels were assessed initially and after 6-week antidepressant treatment. Results The initial HDRS scores and the HDRS scores after six weeks of antidepressant treatment were not significantly different among the different genotypes in each polymorphism of ABCB1. The percentage changes of HDRS scores over time were significantly different in the polymorphisms of ABCB1 G2677T (p=0.002). MDD patients with the G/G genotype of ABCB1 G2677T had a worse antidepressant treatment response. However, the polymorphisms of ABCB1 genotypes were not significantly associated with cortisol levels before and after antidepressant treatment in MDD patients. Conclusion The results suggested that the variants of ABCB1 may influence the short-term antidepressant response in MDD patients. Further details of the underlying mechanisms of ABCB1 in antidepressant treatment remain to be clarified.

Determination of delavirdine in very small volumes of plasma by high-performance liquid chromatography with fluorescence detection.

Delavirdine is a newly developed anti-HIV-1 drug for AIDS therapy. This study describes a sensitive high-performance liquid chromatographic method for the determination of delavirdine in 50 microl of plasma. Samples were deproteinized with 150 microl of a solution of internal standard (cisapride 10 microg/ml) in acetonitrile. An aliquot of the supernatant was injected onto the column. HPLC separation was achieved on a C18 column with the mobile phase of acetonitrile-50 mM sodium dihydrogen phosphate (60:40, v/v) at a flow-rate of 1 ml/min. The eluants were measured by fluorescence detection with excitation at 295 nm and emission filtration at 425 nm. The retention time was about 5.3 min for delavirdine and 6.5 min for cisapride. The specificity was demonstrated, as there were no interferences from plasma samples of different batches in the regions of peak interest. Calibration curves were linear from 25 to 25000 ng/ml. The limit of quantitation was 25 ng/ml. The within- and between-day precision (C.V.) was 9.3%, or less, and the accuracy was within 9.2% of the nominal concentration. The small sample volume needed is especially advantageous for the application both in pharmacokinetic studies in HIV-infected adults and pediatric patients, and in small animals, where limited samples are available.