Kazuko Kimura

Effect of Meropenem on Disposition Kinetics of Valproate and Its Metabolites in Rabbits

AbstractPurpose. We investigated the effect of meropenem (MEPM) on the disposition kinetics of valproate (VPA) and its metabolites in rabbits. Methods. Rabbits were given 75 mg/kg VPA intravenously with or without 300 mg/kg MEPM. Results. The plamsa total clearance of VPA was significantly increased to about 1.5 times the control (6.09 mL/min/kg vs. 4.28 mL/min/kg) by MEPM (P < 0.05). The values of the area under the plasma concentration-time curve (AUC) of 2-en-VPA, a product of β-oxidation, and VPA-glucuronide (VPA-G) were significantly decreased to about 55% and 78% of the control, respectively (P < 0.05). The cumulative urinary excretions of VPA in the control and MEPM-treated groups were 0.54% and 0.62% of the dose, respectively, whereas those of VPA-G were 45.6% and 62.5%, respectively. The urinary excretion of VPA-G was significantly increased by MEPM (P < 0.05). Further, in the case of 33.8 mg/kg VPA-G administered intravenously the AUC value of VPA-G was unchanged by MEPM, whereas that of the generated VPA was significantly decreased to about half of the control. Conclusions. The increase of the total clearance of VPA caused by MEPM appears to be a consequence of increased renal clearance of VPA-G, as well as suppression of VPA-G hydrolysis in the liver.

Prevalence of counterfeit anthelminthic medicines: a cross-sectional survey in Cambodia

Objectives  To assess the prevalence of counterfeit anthelminthic medicines in Cambodia, and to determine influential factors.

Associations of depressive symptoms with serum proportions of palmitic and arachidonic acids, and α-tocopherol effects among male population--a preliminary study.

BACKGROUND & AIMS Recent years, inflammation and oxidative stress have been addressed in relation to interactions between fatty acid (FA) and depression. To study the associations between FAs and depressive symptoms in men, serum FA proportion was compared with perceived depression. We also measured α-tocopherol (a-Toc) levels to investigate the associations with FA functions. METHODS A cross-sectional study was performed on 113 male workers recruited from a software development company in Japan. Depressive symptoms were assessed according to the 20-item Center for Epidemiologic Studies Depression (CES-D) scale. Twenty-four FAs in the serum from the peripheral blood were examined. RESULTS CES-D scores were significantly positively correlated with the serum percentage of palmitic acid (PA), while they were negatively correlated with arachidonic acid (AA). The CES-D scores were not correlated with the serum ratio of docosahexaenoic acid or eicosapentaenoic acid (n-3 poly-unsaturated FAs (PUFAs)). CES-D scores were significantly negatively correlated with a-Toc/PA ratio (correlation: adjusting for possible confounders). CONCLUSIONS Although no associations were found between depressive symptoms and n-3 PUFA proportions in male population, depressive symptoms were positively correlated with PA percentages and negatively correlated with AA percentages. PA may increase neural vulnerability and AA may decrease the severity of depression. Moreover, a-Toc may have protective effects against depressive symptoms.

Counterfeit Medicines in Cambodia—Possible Causes

The use of counterfeit medicines present a world-wide public health crisis (1). Although few reports are available on the global consequences of counterfeit medicines, the consequences of the issue are enormous, and people could be at considerable risk if they use counterfeit medicines (2,3). The epidemiology data is often limited. Data compilation and comparison is difficult due to the fact that different methods are used to produce the estimates. In developed countries, less than 1% of medicines are estimated to be counterfeits; however, the evidence suggests that the percentage is much higher in developing countries, where regulatory systems and their enforcements are weakest (4). The prevalence of counterfeit and substandard medicines reported in Cambodia ranges from 4% to as high as 90% from 2001 to the present (5–8). To tackle the situation, the Ministry of Health of Cambodia initiated a collaborative project with Kanazawa University and Japan Pharmaceutical Manufacturers Association (JPMA), Japan in 2006 to assess the prevalence of counterfeit pharmaceutical products and to investigate factors that influence counterfeiting.

A cross-sectional investigation of the quality of selected medicines in Cambodia in 2010

BackgroundAccess to good-quality medicines in many countries is largely hindered by the rampant circulation of spurious/falsely labeled/falsified/counterfeit (SFFC) and substandard medicines. In 2006, the Ministry of Health of Cambodia, in collaboration with Kanazawa University, Japan, initiated a project to combat SFFC medicines.MethodsTo assess the quality of medicines and prevalence of SFFC medicines among selected products, a cross-sectional survey was carried out in Cambodia. Cefixime, omeprazole, co-trimoxazole, clarithromycin, and sildenafil were selected as candidate medicines. These medicines were purchased from private community drug outlets in the capital, Phnom Penh, and Svay Rieng and Kandal provinces through a stratified random sampling scheme in July 2010.ResultsIn total, 325 medicine samples were collected from 111 drug outlets. Non-licensed outlets were more commonly encountered in rural than in urban areas (p < 0.01). Of all the samples, 93.5% were registered and 80% were foreign products. Samples without registration numbers were found more frequently among foreign-manufactured products than in domestic ones (p < 0.01). According to pharmacopeial analytical results, 14.5%, 4.6%, and 24.6% of the samples were unacceptable in quantity, content uniformity, and dissolution test, respectively. All the ultimately unacceptable samples in the content uniformity tests were of foreign origin. Following authenticity investigations conducted with the respective manufacturers and medicine regulatory authorities, an unregistered product of cefixime collected from a pharmacy was confirmed as an SFFC medicine. However, the sample was acceptable in quantity, content uniformity, and dissolution test.ConclusionsThe results of this survey indicate that medicine counterfeiting is not limited to essential medicines in Cambodia: newer-generation medicines are also targeted. Concerted efforts by both domestic and foreign manufacturers, wholesalers, retailers, and regulatory authorities should help improve the quality of medicines.

Effects of packaging and storage conditions on the quality of amoxicillin-clavulanic acid – an analysis of Cambodian samples

BackgroundThe use of substandard and degraded medicines is a major public health problem in developing countries such as Cambodia. A collaborative study was conducted to evaluate the quality of amoxicillin–clavulanic acid preparations under tropical conditions in a developing country.MethodsAmoxicillin-clavulanic acid tablets were obtained from outlets in Cambodia. Packaging condition, printed information, and other sources of information were examined. The samples were tested for quantity, content uniformity, and dissolution. Authenticity was verified with manufacturers and regulatory authorities.ResultsA total of 59 samples were collected from 48 medicine outlets. Most (93.2%) of the samples were of foreign origin. Using predetermined acceptance criteria, 12 samples (20.3%) were non-compliant. Eight (13.6%), 10 (16.9%), and 20 (33.9%) samples failed quantity, content uniformity, and dissolution tests, respectively. Samples that violated our observational acceptance criteria were significantly more likely to fail the quality tests (Fisher’s exact test, p < 0.05).ConclusionsImproper packaging and storage conditions may reduce the quality of amoxicillin–clavulanic acid preparations at community pharmacies. Strict quality control measures are urgently needed to maintain the quality of amoxicillin–clavulanic acid in tropical countries.

Perceptions and practices of pharmaceutical wholesalers surrounding counterfeit medicines in a developing country: a baseline survey

BackgroundRecent investigations by the Ministry of Health of Cambodia suggest that counterfeit medicines have been introduced into the pharmaceutical market in tampered packaging. To further explore this possibility, an interview survey was conducted at the wholesaler level to investigate the medicinal supply chain in Cambodia.MethodsManaging executives of 62 (83.8%) registered wholesalers of modern medicines in Cambodia were interviewed in 2009 on their knowledge of, perception on, and practices related to counterfeiting issues through a semi-structured questionnaire.ResultsAccording to our findings, 12.9% of the wholesalers had encountered counterfeit medicine. However, they demonstrated a variety of perceptions regarding this issue. A majority (59.7%) defined counterfeit medicines as medicines without registration, while other definitions included medicines that were fraudulently manufactured, medicines without a batch/lot number, those containing harmful ingredients or a reduced amount of active ingredients, and expired medicines. Additionally, 8.1% responded that they did not know what counterfeit medicines were.During procurement, 66.1% of the wholesalers consider whether the product is registered in Cambodia, while 64.5% consider the credibility and quality of the products and 61.3% consider the reputation of the manufacturers. When receiving a consignment, 80.6% of wholesalers check the intactness of medicines, 72.6% check the specification and amount of medicines, 71% check Cambodian registration, 56.5% check that the packaging is intact, 54.8% check batch and lot numbers, 48.4% check the dates of manufacture and expiration, and 9.7% check analytical certificates.Out of 62 wholesalers, 14.5% had received medicines that arrived without packages or were separated from their packaging and had to be repacked before distribution. Significant statistical association was found between wholesalers who received medicines separately from their packs/containers and who consider their belief on reliability of pharmaceutical products of certain manufacturing country during procurement (Chi-square: 12.951, P = 0.002). When wholesalers divide medicines from larger packs into smaller ones, 54.8% use packaging purchased from local markets.ConclusionA number of wholesalers think counterfeit medicines are medicines without registration, and/or do not have any uniform ideas on the issue and what to do, when they find or suspect counterfeits. Furthermore, their strict adherence to anti-counterfeiting measures is urgently needed.

Kinetic phenotypic diagnosis of N-acetylation polymorphism in patients based on ratio of urinary metabolites of salicylazosulfapyridine.

We found that N-acetylation polymorphism can be evaluated from the disposition kinetics of sulfapyridine (SP) and 5-aminosalicylic acid (5-ASA) and their acetylated metabolites generated by N-acetyltransferase (NAT2) after oral administration of salicylazosulfapyridine (SASP). In 126 Japanese subjects, the homozygote of NAT2*4 was the most frequent (40%), followed by heterozygotes of NAT2*4 and mutant genes (28% NAT2*4/*6A, 15% NAT2*4/*7B, and 2% NAT2*4/*5B). Combinations of mutant genes accounted for 16%. When the relationship between the molar ratio of N-acetyl-SP (Ac-SP)/SP or N-acetyl-5-ASA(Ac-5-ASA)/5-ASA in serum and five genotypes of polymorphic NAT2* was examined in patients who received multiple doses of SASP, the molar ratios of Ac-SP/SP, rather than Ac-5-ASA/5-ASA tended to decrease according to the classification of genotype. We calculated the pharmacokinetic parameters in healthy subjects with various genotypes of polymorphic NAT2* after a single p.o. administration of SASP, according to a model of the SP metabolic pathways. The molar ratios of Ac-SP/SP in serum and urine were simulated using these parameters, and the molar ratio of Ac-SP/SP in urine at 4 days after the first administration could be categorized into ranges that were specific to various NAT2* genotypes. Thus, we were able to predict the N-acetylation polymorphic genotypes of patients by measuring the molar ratio of Ac-SP/SP in urine, after administration of SASP.

High failure rate of the dissolution tests for 500-mg amoxicillin capsules sold in Cambodia: is it because of the product or the test method?

Objectives  During the survey of substandard medicines in Cambodia in 2007, it was found that more than 90% of 500‐mg amoxicillin (AMPC) capsules failed the United States Pharmacopeia (USP) 30 TEST 1 dissolution test. In the USP, several monographs provide multiple methods for performing the dissolution test. By using the 500‐mg AMPC capsule as an example, we aimed to identify the problems and implications of the USP methods adopted for the dissolution test as a global standard.

Investigation Into the Antinfluenza Agent Oseltamivir Distributed via the Internet in Japan

This study evaluated the quality and authenticity of the anti-influenza agent oseltamivir acquired via the Internet in Japan. The brand name drugs Tamiflu and Antiflu were obtained via the Internet using a search engine. The authenticity and legitimacy of the medicines were verified with the samples’ manufacturers and the regulatory authorities of the country of origin, respectively. In addition, quantitative and dissolution tests were carried out using high-performance liquid chromatography. No counterfeits were detected among the samples. Additionally, all samples passed qualitative and quantitative tests according to the US Pharmacopeia monograph. However, different sorts of mismanagement were observed in the distribution channels. Through the Internet, oseltamivir can be purchased in quantities larger than the permissible amount in Japan. Furthermore, maintenance of medicine quality cannot be guaranteed. In addition, insufficient information and lack of quality control in some samples may cause unwanted health problems in patients.