Somchai Sriwiriyajan

Comparison of the Pharmacodynamics of Meropenem in Patients with Ventilator-Associated Pneumonia following Administration by 3-Hour Infusion or Bolus Injection

ABSTRACT The time that concentrations in serum are above the MIC (T>MIC) is the pharmacokinetic/pharmacodynamic parameter correlating with the therapeutic efficacy of β-lactam antibiotics. The aim of this study was to demonstrate the T>MIC of meropenem when administered by a 3-h infusion compared with that when administered by bolus injection. The study was conducted with nine patients with ventilator-associated pneumonia. Each subject received meropenem in three regimens consecutively: (i) bolus injection of 1 g every 8 h for 24 h; (ii) 3-h infusion of 1 g every 8 h for 24 h; and (iii) 3-h infusion of 2 g every 8 h for 24 h. Following bolus injection, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 28.33% ± 11.67%, 45.89% ± 22.90%, 57.00% ± 24.82%, and 74.67% ± 17.94% of an 8-h interval, respectively. For the 3-h infusion of 1 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 37.78% ± 20.57%, 58.11% ± 24.38%, 72.67% ± 21.97%, and 93.56% ± 6.84% of an 8-h interval, respectively. For the 3-h infusion of 2 g of meropenem, the percentages of the T>MICs of 16, 8, 4, and 1 μg/ml were 57.89% ± 24.26%, 72.89% ± 22.40%, 85.56% ± 16.42%, and 98.56% ± 3.28% of an 8-h interval, respectively. In conclusion, a 3-h infusion resulted in greater T>MICs than those after a bolus injection. For the treatment of infections caused by pathogens with intermediate resistance, a 3-h infusion of 2 g of meropenem every 8 h can provide concentrations in serum above the MIC of 16 μg/ml for almost 60% of an 8-h interval.

Continuous infusion versus intermittent administration of cefepime in patients with Gram-negative bacilli bacteraemia.

The objective of this study was to compare the pharmacokinetics of cefepime administered by continuous infusion and intermittent injection regimens. A prospective, randomized, cross‐over study of ten patients with Gram‐negative bacilli bacteraemia was conducted. All patients were randomized to receive cefepime either as a 4‐g continuous infusion over 24 h for 48 h or a 2‐g bolus administered intermittently intravenously every 12 h for 48 h. After 48 h the patients received the alternative dose regimen. Cefepime pharmacokinetic studies were carried out during hours 36–48 after the start of both regimens. All of the pathogens isolated from the blood in 7 patients had a minimum inhibitory concentration (MIC) < 1 μg mL−1. In both regimens, the serum cefepime concentrations at all time points were higher than the MIC for the pathogens isolated from this study. For the continuous infusion arm, the highest steady‐state concentration was 49.80±18.40 μg mL−1 and the lowest steady‐state concentration was 41.42±16.48 μg mL−1. The steady‐state concentrations were greater than 4 times the MIC of 8 μg mL−1. For the intermittent injection regimen, the mean trough concentration was 4.74±3.99 μg mL−1. The mean serum cefepime concentration was above 8 μg mL−1 for 81.66% of the dosing interval. Therefore, we conclude that either continuous infusion or intermittent injection can be used as an effective mode of cefepime administration to achieve bactericidal activity.

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective:  Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers.

Anti-cancer effects of Piper nigrum via inducing multiple molecular signaling in vivo and in vitro

ETHNOPHARMACOLOGICAL RELEVANCE Piper nigrum is widely used as a folk medicine including usage for pain relief, fevers, as well as an anti-cancer agent. However the crude extract of piperine free P. nigrum (PFPE), which inhibits breast cancer, and its mechanisms are still being kept secret. This research aims to elucidate the anti-cancer effects of PFPE and its mechanisms. MATERIALS AND METHODS Anti-cancer effects of PFPE were investigated in N-nitroso-N-methylurea (NMU)-induced mammary tumorigenesis rats and breast cancer cell lines MCF-7 and ZR-75-1. Furthermore, the cancer prevention effects of PFPE were investigated in rats. Western blotting was employed to study protein levels induced by PFPE. RESULTS PFPE was found to up-regulate p53, and down-regulate estrogen receptor (ER), E-cadherin (E-cad), matrix metalloproteinase 9 (MMP-9), matrix metalloproteinase 2 (MMP-2), c-Myc, and vascular endothelial growth factor (VEGF) levels in breast cancer rats. Moreover, PFPE decreased protein levels of E-cad, c-Myc, and VEGF in MCF-7 cells. These results suggest that PFPE can enhance breast cancer cell response to phytochemicals, then induce cell cycle arrest, and inhibit cancer cell proliferation resulting in tumor size decrease in the PFPE treated group. It further suggests that PFPE may suppress tumor cell invasion, migration, and angiogenesis. In addition, PFPE possessed cancer prevention effects through generation of reactive oxygen species (ROS) to higher cancer cell cellular stress. CONCLUSIONS PFPE may possess anti-cancer and cancer prevention effects; hence, it deserves further investigation as a novel candidate for breast cancer treatment.

Anticancer and Cancer Prevention Effects of Piperine-Free Piper nigrum Extract on N-nitrosomethylurea-Induced Mammary Tumorigenesis in Rats

Piper nigrum (P. nigrum) is commonly used in traditional medicine. This current study aimed to investigate the anticancer and cancer preventive activity of a piperine-free P. nigrum extract (PFPE) against breast cancer cells and N-nitrosomethylurea (NMU)–induced mammary tumorigenesis in rats. The cytotoxic effects and the mechanism of action were investigated in breast cancer cells using the MTT assay and Western blot analysis, respectively. An acute toxicity study was conducted according to the Organization for Economic Co-operation and Development guideline. Female Sprague-Dawley rats with NMU-induced mammary tumors were used in preventive and anticancer studies. The results showed that PFPE inhibited the growth of luminal-like breast cancer cells more so than the basal-like ones by induction of apoptosis. In addition, PFPE exhibited greater selectivity against breast cancer cells than colorectal cancer, lung cancer, and neuroblastoma cells. In an acute toxicity study, a single oral administration of PFPE at a dose of 5,000 mg/kg body weight resulted in no mortality and morbidity during a 14-day observation period. For the cancer preventive study, the incidence of tumor-bearing rats was 10% to 20% in rats treated with PFPE. For the anticancer activity study, the growth rate of tumors in the presence of PFPE-treated groups was much slower when compared with the control and vehicle groups. The extract itself caused no changes to the biochemical and hematologic parameters when compared with the control and vehicle groups. In conclusion, PFPE had a low toxicity and a potent antitumor effect on mammary tumorigenesis in rats. Cancer Prev Res; 9(1); 74–82. ©2015 AACR.

Effect of indinavir on the pharmacokinetics of rifampicin in HIV-infected patients*

Indinavir, an antiretroviral agent, has an influence on the pharmacokinetics of other drugs by acting as an inhibitor of cytochrome P450‐mediated drug metabolism. The incidence of tuberculosis has increased dramatically in the past decade because of an epidemic of HIV infection. Rifampicin is still one of the most valuable drugs for the standard treatment of tuberculosis. The objective of this study was to investigate the effects of indinavir on the pharmacokinetics of rifampicin in man. Our study was conducted in eleven HIV‐infected patients. All patients received a 600‐mg single dose of oral rifampicin on day 1 and 15‐ and 800‐mg oral indinavir three times a day from day 2 to day 15. Rifampicin pharmacokinetic studies were carried out on day 1 and day 15. The results showed that rifampicin concentrations were higher when it was administered with indinavir than when it was administered alone. With concomitant indinavir medication, the mean AUC0–24 of rifampicin was increased by 73%. Therefore, we conclude that indinavir has an inhibitory effect on the metabolism of rifampicin.

Pharmacokinetic Interactions between Ciprofloxacin and Itraconazole in Healthy Male Volunteers

Objective. To investigate the pharmacokinetic interaction between ciprofloxacin and itraconazole in healthy male volunteers. Methods. Ten healthy male volunteers were assigned into a 2‐sequence, 3‐period pharmacokinetic interaction study. In phase 1, all subjects were randomly assigned to receive 500 mg of ciprofloxacin alone and 200 mg of itraconazole alone twice daily for 7 days with a 14 day wash‐out period in a crossover design. Phase 2 was performed 14 days after finishing phase 1, all subjects received 500 mg of ciprofloxacin in combination with 200 mg of itraconazole twice daily for 7 days. Ciprofloxacin and itraconazole pharmacokinetics were studied and adverse effects noted. Results. Ciprofloxacin significantly increased the Cmax and AUC0 − ∞ of itraconazole by 53.13% and 82.46%, respectively. The half‐life and CL of itraconazole were not changed significantly. The combination of itraconazole and ciprofloxacin could therefore result in an increase in adverse drug reactions. Conversely, itraconazole had no significant effect on the pharmacokinetics of ciprofloxacin. Conclusion. Ciprofloxacin decreases the metabolism of itraconazole, most likely through inhibition of CYP3A4. The dosage of itraconazole should be reduced and its therapeutic outcome should be monitored closely when these two agents are concomitantly administered. Copyright

Bioequivalence study of a generic quetiapine in healthy male volunteers

AIM To study the bioequivalence of a generic quetiapine (Quantia 200, manufactured by the Unison Laboratories Co., Ltd., Bangkok, Thailand) and the innovator product (Seroquel, AstraZeneca, Macclesfield, UK). VOLUNTEERS AND METHODS The study was a randomized, 2-way crossover design with a 2-week washout period in 24 healthy Thai male volunteers. After a single 200 mg oral dosing, serial blood samples were collected at appropriate interval up to 48 h. Plasma quetiapine concentrations were determined by high-performance liquid chromatography (HPLC). Pharmacokinetic parameters were estimated using the WinNonlin software with noncompartment model analysis. Comparative bioequivalence between the two formulations was determined by analysis of variance (ANOVA) for 2-way crossover design. RESULTS The mean +/- SD of maximum plasma concentration (Cmax), the area under the plasma concentration-time curve from 0 - 48 h (AUC0-48) and the area under the plasma concentration-time curve from 0 to infinity (AUC0-inf) of Quantia 200 vs. Seroquel were 886.60 +/- 356.50 vs. 811.34 +/- 323.37 ng/ml; 3,754.41 +/- 1,453.00 vs. 3,420.00 +/- 1,229.6 ng x h/ml and 4,015.35 +/- 1,528.25 vs. 3,769.45 +/- 1,296.69 ng x h/ml, respectively. Time to reach Cmax (tmax) of Quantia 200 and Seroquel were 1.08 +/- 0.778 and 1.10 +/- 0.79 h, respectively, and thus not significantly different. The 90% confidence interval of the ratios of the logarithmically transformed of Cmax, AUC0-48 and AUC0-inf were 98.21 - 124.37%, 94.43 - 117.03% and 94.77 - 116.61%, respectively, which were within the acceptable range of 80 - 125%. Power of the test for Cmax, AUC0-48 and AUC0-inf was 92.1%, 96.9% and 97.4%, respectively. CONCLUSION Quantia 200, used in this study, was bioequivalent to Seroquel in terms of both the rate and extent of absorption.

(−)-Kusunokinin and piperloguminine from Piper nigrum: An alternative option to treat breast cancer

Several studies have reported that active compounds isolated from Piper nigrum possess anticancer properties. However, there are no data on anticancer activity of (-)-kusunokinin and piperlonguminine. The purposes of this study were to isolate active compounds from P. nigrum and identify the molecular mechanisms underlying growth and apoptosis pathway in breast cancer cells. Two bioactive compounds, (-)-kusunokinin and piperlonguminine, were isolated from P. nigrum. Cytotoxicity and the molecular mechanism were measured by methyl thiazolyl tetrazolium (MTT) assay, flow cytometry and Western blot analysis. We found that the active compounds, which effect cancer cell lines were (-)-kusunokinin and piperlonguminine. These compounds have potent cytotoxic effects on breast cancer cells (MCF-7 and MDA-MB-468) and colorectal cells (SW-620). (-)-Kusunokinin demonstrated a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.18 and 1.62μg/mL, respectively. Piperlonguminine had a cytotoxic effect on MCF-7 and MDA-MB-468 with IC50 values of 1.63 and 2.19μg/mL, respectively. Both compounds demonstrated lower cytotoxicity against normal breast cell lines with IC50 values higher than 11μg/mL. Cell cycle and apoptotic analysis using flow cytometry, showed that the (-)-kusunokinin and piperlonguminine induced cell undergoing apoptosis and drove cells towards the G2/M phase. Moreover, both compounds decreased topoisomerase II and bcl-2. The increasing of p53 levels further increased p21, bax, cytochrome c, caspase-8, -7 and -3 activities, except caspase-9. These results suggest that the (-)-kusunokinin and piperlonguminine have been shown to have potent anticancer activities through extrinsic pathway and G2/M phase arrest.

Development of an analytical method for cefpirome in plasma by simplified HPLC technique and its applications

The objective of this study was to develop a rapid and simplified, reliable high-performance liquid chromatography (HPLC) method for quantification of cefpirome (CAS 98753-19-6) in plasma. After precipitation of the plasma containing the internal standard, hydrochlorothiazide, with 5% trichloroacetic acid (TCA), the analysis of the cefpirome level in the plasma samples was carried out using a reverse-phase C18 column with the ultraviolet detector set at a wavelength of 258 nm. The chromatographic separation was accomplished with an isocratic mobile phase consisting of acetonitrile-acetate buffer pH 5. The proposed method was specific and sensitive with a lower limit of quantitation (LLOQ) of 0.5 microg/ml. This HPLC method was validated by examining the precision and accuracy for inter- and intra-day analysis in the concentration range 0.5-64.0 microg/ml. The relative standard deviation in the inter- and intra-day validation was less than 3%. Analytical recovery was more than 84%, and cefpirome was found to be stable in human plasma during both the storage and assay procedures. A satisfactory pharmacokinetic study of cefpirome was carried out in rabbits using the devised procedure.