Quality of omeprazole purchased via the Internet and personally imported into Japan: comparison with products sampled in other Asian countries.

OBJECTIVE: To evaluate the quality of omeprazole personally imported into Japan via the Internet and to compare the quality of these samples with previously collected samples from two other Asian countries. METHODS: The samples were evaluated by observation, authenticity investigation and pharmacopoeial quality analysis. Quality comparison of some selected samples was carried out by dissolution profiling, Raman spectroscopy and principle component analysis (PCA). RESULTS: Observation of the Internet sites and samples revealed some discrepancies including the delivery of a wrong sample and the selling of omeprazole without a prescription, although it is a prescription medicine. Among the 28 samples analysed, all passed the identification test, 26 (93%) passed the quantity and content uniformity tests and all passed the dissolution test. Dissolution profiling confirmed that all the personally imported omeprazole samples remained intact in the acid medium. On the other hand, six samples from two of the same manufacturers, previously collected during surveys in Cambodia and Myanmar, frequently showed premature omeprazole release in acid. Raman spectroscopy and PCA showed significant variation between omeprazole formulations in personally imported samples and the samples from Cambodia and Myanmar. CONCLUSIONS: Our results indicate that the pharmaceutical quality of omeprazole purchased through the Internet was sufficient, as determined by pharmacopeial tests. However, omeprazole formulations distributed in different market segments by the same manufacturers were of diverse quality. Measures are needed to ensure consistent quality of products and to prevent entry of substandard products into the legitimate supply chain.

Study on health hazards through medicines purchased on the Internet: a cross-sectional investigation of the quality of anti-obesity medicines containing crude drugs as active ingredients.

BACKGROUND: Weight-loss medicines, including crude drugs and herbal supplements disguised as diet-aid products, are readily obtainable and distributed widely, especially in Southeast Asia. Even if such products are unapproved or prescription-only medicines, consumers can purchase them through an agency or directly on the Internet. We evaluated the quality and safety of herbal products purchased on the Internet to reveal their influence on public health. METHODS: Diet-aid products containing Bukuryo (Poria sclerotium), Bakumondo (Ophiopogonis tuber), or Daio (rhubarb rhizome) were purchased through websites that did not provide physical addresses or which advertised misleading medicines (e.g., unapproved Cialis 100 mg tablets, Viagra 100 mg tablets) on websites. We carefully noted details in the descriptions on package inserts or accompanying product characteristics and analyzed the ingredients using qualitative and quantitative methods, namely high-performance liquid chromatography equipped with a photodiode array detector. We requested the respective manufacturers to authenticate their products through a structured questionnaire. RESULTS: We purchased 15 items from 15 Internet sites and imported all 15 items to Japan. One item stated to contain rhubarb rhizome was identified as a prescription medicine; the others were dietary supplements and not medicines. Even though we did not analyze the constituents of all crude drugs, we found some active ingredients in the items. Sibutramine was detected in items confirmed to be supplements, including those containing Poria sclerotium and Ophiopogonis tuber. Each capsule contained ≈ 12 mg of sibutramine, which is the daily dose for anti-obesity medicines. Sibutramine is not approved for use in Japan and its sale has been suspended in Europe and the USA owing to serious adverse effects on the circulatory system. CONCLUSIONS: Our findings indicate that dietary supplements containing injurious ingredients are distributed to Japanese consumers and potentially to a broader international audience, and that purchasing them through unreliable websites bears potential health risks. To avoid potential adverse events, there should be adequate alerts about the risks of taking products without appropriate indications.

Quality Evaluation of Gentamicin Sulfate Reference Standards in Japanese Pharmacopoeia Using Hydrophilic Interaction Chromatography Combined With Tandem Mass Spectrometry.

BACKGROUND: Through the recent development of analytical technology, antibiotics quantification in the Japanese Pharmacopoeia (JP) has changed from traditional microbiological assays to physicochemical methods with high specificity and precision. However, for several multicomponent antibiotics without typical UV absorption, potency cannot be directly determined using instrumental methods such as high-performance liquid chromatography; therefore, traditional microbiological assays are still used. Gentamicin sulfate (GmS), which consists of three major components, C1, C1a, and C2, is such a typical antibiotic, and its antimicrobial potency continues to be assayed using microbiological methods in JP monographs. Introduction of a physicochemical assay for GmS is needed to help ensure its quality and quantity. OBJECTIVE: This study aimed to develop quality control measures for GmS that could be complementary to quantitative assays and purity tests specified in the JP. METHODS: For each gentamicin C component (C1, C2, and C1a), theoretical potencies were determined based on the quantitative relationship between purity and potency, as measured by quantitative 1H NMR and microbiological assays, respectively. Two lots of the JP reference standard (RS) were used as test samples, with the contents of each component and impurity (sisomicin and garamine) being determined using hydrophilic interaction liquid chromatography-tandem mass spectrometry (HILIC-MS/MS). RESULTS: The ratios of theoretical potency for C1, C2, and C1a were 1.00, 1.21, and 1.80, respectively. The potencies of the GmS JP RSs, which were estimated based on the contents and theoretical potency of each C component, corresponded well with those determined through microbiological assays. Marked differences in impurities (%) between the two RS lots were highlighted by quantifying sisomicin and garamine. CONCLUSIONS: The developed analytical procedure enabled the characterization of two different JP RSs in terms of content ratio, potencies, and impurities. HIGHLIGHTS: Novel analytical procedures useful for routine quality control of GmS were developed using HILIC-MS/MS.

Proton acceleration to 40 MeV using a high intensity, high contrast optical parametric chirped-pulse amplification/Ti:sapphire hybrid laser system.

Using a high-contrast (10(10):1) and high-intensity (10(21) W/cm(2)) laser pulse with the duration of 40 fs from an optical parametric chirped-pulse amplification/Ti:sapphire laser, a 40 MeV proton bunch is obtained, which is a record for laser pulse with energy less than 10 J. The efficiency for generation of protons with kinetic energy above 15 MeV is 0.1%.

[Identification Methods for Pseudo-crystalline Polymorphs of Thiamine Chloride Hydrochloride, Which Transform Easily Depending on the Handling Environment].

Three forms of pseudo-crystalline polymorph of thiamine chloride hydrochloride are dependent on hydration states. We investigated how the measurement environment affects the transition of the pseudo-crystalline polymorph, and aimed to establish a reliable method of identifying the forms clearly by IR spectrophotometry. We prepared three pseudo-crystalline forms and compared their IR spectra. In the IR spectra obtained by the potassium chloride (KCl) disk method, Form II was identified based on its characteristic absorption, but Forms I and III could not be distinguished clearly. Form I transformed to Form III after mixing with undried KCl powder, and Form III transformed to Form I by simply being left in the laboratory environment. These results suggested that the reversible transformation between Forms I and III occurred depending on the hydration status during the process of measurement, as measured by the shift in the absorption wavenumber of the primary alcohol stretching vibration. In addition, Forms I and III could not be distinguished clearly by the X-ray powder diffraction and their crystalline forms were similar plate crystals. However, in the IR spectra by the attenuated total reflection (ATR) method, the three forms could be identified based on each characteristic absorption. In summary, the ATR method does not require pretreatment for sample analysis, can be performed quickly, and is thus suitable to identify crystalline polymorph forms such as pseudo-crystalline polymorphs of thiamine chloride hydrochloride, which transform easily depending on the hydration status in a measurement environment.

Patient safety and public health concerns: poor dissolution rate of pioglitazone tablets obtained from China, Myanmar and internet sites.

BACKGROUND: Poor quality medicines have serious implications for public health. The aim of this study was to explore the quality of the antidiabetic pioglitazone, using samples collected in China and Myanmar, and samples purchased online. METHODS: In this cross-sectional study, we examined samples (n = 163) collected from hospitals in Shanghai, China in 2012 (n = 44), products purchased via the internet and imported into Japan in 2013 (n = 59), and samples purchased in shops in Yangon, Myanmar in 2015 (n = 60). Collected samples were subjected to visual inspection, authenticity investigation and quality testing (potency, content uniformity and dissolution test) by high-performance liquid chromatography. Samples were rated as compliant or non-compliant based on the relevant pharmacopoeial acceptance criteria. RESULTS: Visual inspection of all samples revealed compliant products. However, responses from manufacturers during authenticity investigation were poor. Among the n = 44 samples from China, one was non-compliant in the potency test. Among the n = 59 samples personally imported into Japan, 38% of generic samples were found to be non-compliant. In Myanmar, 13.3% of samples were non-compliant. Non-compliant samples predominantly failed in the dissolution test. All non-compliant samples were generic. CONCLUSIONS: Despite the apparent satisfactory outcome on the samples from China, pioglitazone samples collected in Myanmar and purchased online for personal import into Japan included many substandard products, which failed quality assessment predominantly because of poor dissolution. Internet providers did not comply with Japanese regulations in various respects.

Substandard and Falsified Medicines in Myanmar.

Background: substandard and falsified medicines (SFMs) are a threat to public health. The availability of SFMs in Myanmar was reported by the World Health Organization (WHO) in 1999, but there have been few systematic surveys on falsified medicines in Myanmar since then. The aim of this study is to examine the extent of SFMs for sale in Myanmar. Methods: target medicines were tablets of candesartan, metformin, and pioglitazone, and infusions of ciprofloxacin and levofloxacin. Samples were collected from hospitals, pharmacies, and wholesalers located in the Mandalay region in 2015. We carried out observation testing, authenticity investigation, and quality testing to search for SFMs, and analyzed the relationship between SFMs and the price and store type. Results: There were no falsified medicines found in the authenticity check, though there remained a problem due to low response rates from manufacturers and regulatory authorities. In the quality test, some tablets of metformin and pioglitazone made in India failed the dissolution test. Conclusions: although no serious problems were found, some substandard medicines were detected. Regular surveys to monitor SFMs are therefore recommended, together with further regulatory guidance to improve conditions in all medicine manufacturers, distributors, and pharmacies.

A Cross-Sectional Investigation for Verification of Globalization of Falsified Medicines in Cambodia, Indicated by Tablets of Sildenafil Citrate.

Medicine falsification is a global issue. Viagra, an erectile dysfunction therapeutic (EDT) medicine consisting primarily of sildenafil citrate, is the most commonly falsified medicine worldwide. Recently falsified EDTs have been reported multiple times in developing countries. The globalization of falsified EDTs has become a concern. In the present study, we selected sildenafil citrate tablets as an indicator and examined samples from a developing country, Cambodia, to investigate the availability of falsified sildenafil tablets in Cambodia and verify the current globalization status of falsified medicines from the standpoint of a developing country. Six samples of the originator Viagra, and 68 samples of generic sildenafil products were purchased from private drug outlets and wholesalers in Phnom Penh, Svay Rieng, and Battambang. The samples' manufacturers were contacted to authenticate the samples. The quantities and dissolution rates of active ingredients were measured by a high-performance liquid chromatography system with photodiode array. Five generic samples were strongly suspected to be falsified medicines because of their extremely low quality; however, there was little distribution and no falsified medicine alleged to be produced by the originator of Viagra, which charges high prices. That finding indicates that falsification reflects local economic circumstances.

A Cross-Sectional Investigation of the Quality of Selected Medicines for Noncommunicable Diseases in Private Community Drug Outlets in Cambodia during 2011-2013.

Although the issue of substandard and falsified medicines is quite well known, most research has focused on medicines used to treat communicable diseases, and relatively little research has been carried out on the quality of medicines for noncommunicable diseases (NCDs). This study was designed to assess the quality of seven widely used medicines for NCDs in Cambodia during 2011-2013. Medicines were collected from private community drug outlets in Phnom Penh (urban area), by stratified random sampling and in Battambang, Kandal, Kampong Speu, and Takeo (rural areas) by convenience sampling. Samples were subsequently analyzed by visual inspection, authenticity investigation, and pharmacopoeial analysis by high-performance liquid chromatography. Various discrepancies were observed in visual inspection of packages and medicines. Of 372 tablet/capsule samples from 64 manufacturers in 16 countries, the manufacturers confirmed 107 (28.8%) as authentic; the authenticity of other samples could not be verified. Three hundred sixty-four (97.8%) samples were registered in Cambodia. Among all samples, 23.4% (95% CI 19.2-28.0) were noncompliant in one or more of the quality tests: 12.9% (95% CI 9.7-16.7) contained an amount of active pharmaceutical ingredient outside the permitted range, including some showing extreme deviations, 14% (95% CI 10.6-17.9) failed because of content variation, and 10.8% (95% CI 7.8-14.4) failed to meet pharmacopoeial reference ranges in dissolution tests. Pharmaceutical quality appeared to be unrelated to storage conditions. Although no sample was obviously falsified, there is a high prevalence of substandard medicines for NCDs in Cambodia, indicating the need for focused regulatory action, including collaborative initiatives with manufacturers.

Quasi-flow injection analysis for rapid determination of caffeine in tea using the sample pre-treatment method with a cartridge column filled with polyvinylpolypyrrolidone.

The sample pre-treatment method using a polyvinylpolypyrrolidone (PVPP) cartridge column combined with a quasi-flow injection analysis (quasi-FIA) system realized the rapid determination of caffeine in three types of tea, green, oolong and black tea. The measurement time for each tea sample pre-treated using a PVPP cartridge column was shortened to 20s. In the present system, the limits of detection and quantification were 0.3 microM (1.5 pmol injected) and 0.7 microM (3.5 pmol injected), respectively, and a linear calibration curve was afforded up to 800 microM (4 nmol injected). Within-run precision of analysis of standard solutions of 10 and 100 microM caffeine was 0.11 and 0.16% (n=6), respectively. Between-run precision of analysis of the same solutions over 6 days was 0.78 and 0.74% (n=6), respectively. Comparison with the conventional HPLC method indicated that the present quasi-FIA method using sample pre-treatment with a PVPP cartridge column was useful for the simple and precise determination of caffeine in green, oolong and black tea samples.

[Enzymological Studies on the Mechanisms of Pathogenesis of Diabetic Complications].

　Aldose reductase (AR) is involved in the pathogenesis of complications in diabetes. In this study, the enzymatic properties of AR isolated from various sources and a recombinant human AR (rh-AR) were analyzed in detail. The sensitivity of different forms of AR to several AR inhibitors (ARIs) was compared. Our findings enabled us to propose that human AR should be used as the target enzyme in the development of ARIs. An enzyme-linked immunosorbent assay (ELISA) for human AR which employed monoclonal antibodies against rh-AR was created, and this method was used to demonstrate the distribution of AR in human tissues. AR was widely distributed in various organs and blood cell components. The levels of erythrocyte AR (e-AR) were 10.1±1.9 ng/mg Hb and 10.5±3.0 ng/mg Hb in healthy volunteers and diabetic patients, respectively, and thus there was no significant difference between them. The e-AR levels of diabetic patients were assayed using the ELISA developed to investigate the potential correlation between AR levels and the onset of diabetic complications. There were significant correlations between the incidence of diabetic neuropathy and e-AR levels in patients with disease duration of less than 10 years, and between the incidence of diabetic retinopathy and e-AR levels in patients with disease duration of 10-20 years. Our results suggest that measurement of e-AR levels in patients could help optimize drug therapy with ARIs and be a useful method to predict the onset of complications due to the upregulation of the polyol pathway.

An Investigation into the Quality of Medicines in Yangon, Myanmar.

Many poor-quality medicines are supplied to patients mainly in developing countries. No systematic survey on counterfeit medicines has been conducted in Myanmar since 1999. The purpose of this study was to investigate the current situation of substandard or counterfeit medicines in Myanmar. Samples of oral medicines, cefuroxime axetil (CXM), donepezil hydrochloride (DN) and omeprazole (OM), and injections, ceftriaxone sodium (CTRX), and gentamicin sulfate (GM), were collected from pharmacies, hospitals, and wholesalers in Yangon, Myanmar in 2014. Authenticity and quality were verified. There were 221 (94%) foreign medicines among 235 collected samples. Five samples of GM and 1 DN sample were not registered with the Food and Drug Administration, Myanmar. In quality analysis, 36 samples out of 177 (20.3%) did not pass quantity tests, 27 samples out of 176 (15.3%) did not pass content uniformity tests, and 23 out of 128 samples (18.0%) did not pass dissolution tests. Three of the unregistered GM samples failed in both identification and microbial assay tests. Counterfeit GM is being sold in Yangon. Also, the quality of OM is a matter of concern. Poor-quality medicines were frequently found among the products of a few manufacturers. Regular surveys to monitor counterfeit and substandard medicines in Myanmar are recommended.

Role of aldose reductase in the peritoneal changes of patients undergoing peritoneal dialysis.

BACKGROUND/AIMS: The mesothelium of patients undergoing peritoneal dialysis (PD) is exposed to glucose in dialysate. Glucose metabolites 3-deoxyglucosone and advanced glycation endproducts (AGEs) in the PD fluid induce peritoneal damage. Circulating factors also affect the peritoneum in the uremic model and predialysis patients. Aldose reductase (AR) generates precursors of 3-deoxyglucosone. We have reported AR acceleration in uremic patients. Therefore, AR acceleration might affect the peritoneum. The purpose of this study was to evaluate the AR level in PD patients and to determine the factors that change the peritoneum of these patients. METHODS: We measured the PD effluent (eff-) concentration of cancer antigen 125 (CA125) as a marker of mesothelial viability in PD patients. Erythrocyte AR, eff-, and plasma (p-) concentrations of 3-deoxyglucosone, AGEs, and malondialdehyde were also studied in 30 PD patients, 18 patients undergoing hemodialysis, and 8 control subjects. RESULTS: In the PD group, AR, p-3-deoxyglucosone, p-AGEs, and p-malondialdehyde were higher than in the control group. The predictors for eff-CA125 were not only PD duration and eff-3-deoxyglucosone, but also AR. CONCLUSION: AR was upregulated in PD patients. AR acceleration may affect the peritoneum in these patients. Further studies are needed to clarify the role of AR in PD patients.

Erroneous formulation of delayed-release omeprazole capsules: alert for importing countries.

BACKGROUND: Poor drug quality is a matter of serious concern, especially in countries where drug regulation and law enforcement are constrained by limited resources. This study was carried out to investigate the cause of quality failure of omeprazole in Cambodia in 2010 and Myanmar in 2014. METHODS: We conducted pharmacopoeial quantity, content uniformity and dissolution tests of 156 samples of omeprazole capsules collected in Cambodia in 2010 and Myanmar in 2014. High failure rates were found, especially in dissolution testing, and detailed investigation of several unacceptable samples was carried out by means of in-vitro dissolution profiling, scanning electron microscopy (SEM) and X-ray computed tomography (X-ray CT) to identify the cause of failure. RESULTS: Dissolution profiling with and without the acid stage showed that acid caused premature omeprazole release, indicating that the enteric coating of the omeprazole granules was ineffective. SEM examination of two failed samples revealed cracked and broken granules mixed with apparently intact omeprazole granules in the capsule. X-ray CT examination indicated that some granules of failed samples completely lacked enteric coating, and others had incomplete and non-uniform enteric coating or malformation. CONCLUSIONS: Omeprazole capsules collected in Myanmar and Cambodia showed high failure rates in pharmacopoeial tests, especially dissolution tests. Some samples were found to have ineffective or absent enteric coating of the granules, resulting in premature dissolution and degradation in acidic conditions. This is a potentially serious public health issue that needs to be addressed by regulatory authorities in Cambodia and Myanmar, possibly through a collaborative initiative with manufacturers.

Correlation between adult diabetic cataracts and red blood cell aldose reductase levels.

PURPOSE: To investigate the correlation between adult diabetic cataracts and levels of aldose reductase (AR) in red blood cells (RBCs). METHODS: The study involved 337 eyes of 337 patients with diabetes. The extent and severity of lens opacity was assessed according to the Lens Opacities Classification System III (LOCS III). The AR levels within RBCs were determined with an ELISA. The relationship between the AR level in RBCs and the prevalence of nuclear cataract, cortical cataract, and posterior subcapsular cataract in patients with diabetes was examined. RESULTS: There were no significant alterations in AR level in RBCs in patients with a diabetes duration of < or = 10 years and patients < 60 years of age. In each subgroup, a higher amount of AR levels in RBCs significantly correlated with the prevalence of posterior subcapsular cataracts. A significant association between cortical cataract and AR level in RBCs was also seen in a subgroup of patients younger than 60 years. CONCLUSIONS: AR emerges as an important factor affecting the onset of posterior subcapsular cataracts at the early stages of diabetes mellitus. This raises the possibility that AR inhibitors could play a useful role in treatment of adult diabetic cataract through its inhibition of AR activities.

Plasma 3-deoxyglucosone elevation in chronic renal failure is associated with increased aldose reductase in erythrocytes.

BACKGROUND: Serum concentrations of 3-deoxyglucosone (3DG), a highly reactive dicarbonyl compound, are elevated in uremic patients. Aldose reductase (AR) is an enzyme involved in both the detoxification of 3DG and producing precursors of 3DG. METHODS: We examined the relationship between plasma 3DG and erythrocyte AR content in uremic patients. Patients were divided into three groups: (1) progressive renal disease without hemodialysis (HD; chronic renal failure [CRF] group), (2) patients without diabetes mellitus (DM) treated with maintenance HD (HD group), and (3) patients with DM treated with maintenance HD (DM-HD group). High-performance liquid chromatography was used to measure 3DG, and erythrocyte AR was measured by means of enzyme-linked immunosorbent assay. RESULTS: Both 3DG and erythrocyte AR levels were significantly greater in the CRF, HD, and DM-HD groups than in healthy controls. These results did not change after HD sessions in the HD or DM-HD groups. Serum creatinine levels correlated with 3DG and erythrocyte AR levels in the control and CRF groups (3DG: r = 0.67; P < 0.001; erythrocyte AR: r = 0.71; P < 0.001). Both erythrocyte AR and 3DG levels then increased as renal function declined. A positive correlation was seen between 3DG and erythrocyte AR levels in all groups (r = 0.65; P < 0.001), and also between plasma osmolality and erythrocyte AR level (r = 0.46; P < 0.001). CONCLUSION: Both erythrocyte AR and 3DG levels are increased in uremic patients, and these increases could possibly contribute to the development of uremic symptoms.

[Fluorometholone Reference Standard (control 011) of National Institute of Health Sciences].

The raw material of fluorometholone was examined for the preparation of the "Fluorometholone Reference Standard (Control 011)". The analytical data obtained were: optical rotation, [alpha]20D = .5 degrees; UV spectrum, lambda max of 240 nm and specific absorbance in methanol at 240 nm = 350.7; IR spectrum, same as that of the Fluorometholone Reference Standard (Control 864); high-performance liquid chromatography (HPLC), total amount of impurities estimated to be less than 0.5%; loss on drying, 0.01%. Based on the above results, the raw material was authorized as the Fluorometholone Reference Standard (Control 011) of the National Institute of Health Sciences.

[Tocopherol Succinate Reference Standard (Control 021) of National Institute of Health Sciences].

The raw material of tocopherol succinate was tested for the preparation of the "Tocopherol Succinate Reference Standard (Control 021)". Analytical data obtained were as follows: infrared spectrum, same as that of the Tocopherol Succinate Reference Standard (Control 981); specific absorbance, E1% 1 cm (286 nm) = 40.7; thin-layer chromatography, no impurities were detected until 50.0 micrograms; high-performance liquid chromatography (HPLC), four impurities were detected and the amount of tocopherol succinate was estimated to be 99.0%; loss on drying, 0.11%. Based on the above results, the raw material was authorized as the Japanese Pharmacopoeia Reference Standard (Control 021).

[Glycyrrhizinic Acid Reference Standard (Control 0211 and 0221) of National Institute of Health Sciences].

The raw material of glycyrrhizinic acid was examined for preparation of the "Glycyrrhizinic Acid Reference Standard". The analytical data obtained were: UV spectrum: lambda max, 251 nm; and specific absorbance (E1% 1 cm) in ethanol at 251 nm, 149.6 (Control 0211) and 145.7 (Control 0221); IR spectrum, specific absorptions of raw material were consistent with that of Standard (Control 001). Also, thin-layer chromatography, no impurity was detected; high-performance liquid chromatography, several impurities were detected. The amount of each impurity was estimated at less than 0.2% and total amount of impurities was less than 0.6%. Based on the above results, the candidate materials were authorized as the Glycyrrhizinic Acid Reference Standard (Control 0211 and 0221) of the National Institute of Health Sciences.