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The purpose of this study was to design a convenient, small-scale dissolution test for extracting potential substandard and falsified (SF) medicines that require full pharmacopoeial analysis. The probability of metronidazole samples complying with the US Pharmacopoeia (USP) dissolution test for immediate-release tablet formulations was predicted from small-scale dissolution test results using the following criteria: (1) 95% confidence interval lower limit (95% CIlow) of the average dissolution rate of any n = 3 of n = 24 units of each sample, and (2) average and minimum dissolution rates for any n = 3 of n = 24 units. Criteria values were optimized via bootstrap sampling with Thinkeye data-mining software. Compliant metronidazole samples in the USP first-stage and second-stage dissolution test showed complying probabilities of 99.7% and 81.0%, respectively, if the average dissolution rate of n = 3 units is equal to or greater than the monograph-specified amount of dissolved drug (Q; 85% of labeled content for metronidazole). The complying probabilities were 100.0% and 79.0%, respectively, if the average dissolution rate of n = 3 units is 91% or higher and the minimum dissolution rate is 87% or higher. Suitable compliance criteria for the small-scale dissolution test are: average dissolution rate of n = 3 units is Q + 6% or more and minimum dissolution rate is Q + 2% or more.

Comprehensive data are needed to prevent substandard and falsified (SF) medicines as they pose a major risk to human health. To assess the quality of select medicines, samples were collected from random private drug outlets of Dhaka North and South City Corporation, Bangladesh. Sample analysis included visual observation of the packaging, authenticity of the samples, legitimacy and registration verification of the manufacturer, physicochemical analysis, and price. Chemical analysis of the samples was performed using a portable Raman spectroscopy and high-performance liquid chromatography according to the pharmacopoeia. Several discrepancies were noted in the visual observation of samples. Among the 189 collected samples of esomeprazole (ESM), cefixime (CFIX), and amoxicillin-clavulanic acid (CVA-AMPC), 21.2% were confirmed to be authentic, 91.3% manufacturers were confirmed legitimate, and 2.1% of all samples were unregistered. Chemical analysis of the samples revealed that 9.5% (95% CI, 0.057–0.146) of samples were SFs. Falsified samples and quality variation in the same generic branded samples were both detected by Raman spectroscopic analysis. Overall, sample prices were satisfactory relative to the international reference price. Despite the relatively smaller proportions of SFs, this study documents the availability of poor-quality medicines, demonstrating the need for immediate attention by the national medicine regulatory authority.

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.

Objectives To analyse and present the literature describing the health consequences of falsified medicines, focusing on mortality and morbidity, as well as the scale of the issue, the geographic extent, the medicines affected, and the harm caused at both the individual and population levels. Methods We searched for articles in PubMed, using pre-optimized keywords '(counterfeit OR fake OR bogus OR falsified OR spurious) AND (medicine OR drug)'. Searches up to February 2017 yielded 2006 hits, of which 1791 were full-length articles in English. Among them, we found 81 papers that qualitatively or quantitatively described 48 incidents in which falsified medicines caused patients to suffer serious adverse effects, injury, symptoms or death. Results The distribution of incidents was examined according to the economic status of the countries involved, regional location in the world, therapeutic category of the medicines, number of incidents and victims by year, and characteristics of the falsified medicines. Among the 48 reported incidents, 27 (56.3%) occurred in developing countries and 21 (43.7%) in developed countries. These incidents involved a total of approximately 7200 casualties including 3604 deaths. Conclusions Despite the poor quality of much of the reported data, the results of this study indicate that all types of medications have been targeted for falsification, and falsified medicines have had a serious impact on the health of both adults and children worldwide, with similar numbers of incidents in developing and developed countries.

The efficacy of the extraction of polychlorinated biphenyls (PCBs) from varnish-infiltrated insulating papers as a model of solid materials with an aqueous sodium hydroxide (NaOH) by autoclaving at 121°C for 30 min was compared with those for the conventional procedures, i.e., saponification with 1 N ethanolic NaOH in a boiling water bath for 60 min and extraction with benzene in a Soxhlet apparatus. The newly invented autoclaving method was found to be superior to the conventional ones, yielding approximately 5- to 6-fold cumulative PCB congeners without being accompanied by extended decomposition. Therefore, the autoclave-based sample treatment is recommended for more accurate determination of PCBs in the case of PCB-impregnated solid materials such as hardened oils and resin-coated or -infiltrated papers instead of being treated conventionally.

Organic halogens (OX) extractable with a water-miscible organic solvent in samples from municipal solid waste incinerators (MSWIs) were determined quantitatively using apparatus for measuring total organic halogens in drinking water. Besides OX, polychlorinated dibenzo-p-dioxins (PCDD) and polychlorinated dibenzofurans (PCDF) in samples from MSWI were analyzed separately to compare their behavior in MSWI. OX was generated both in flue gas and the electrostatic precipitator and exhibited a linear correlation with both PCDD and PCDF, implying that PCDD and PCDF were derived from OX. These results show that OX is a useful surrogate marker for PCDD and PCDF in MSWIs.

The effect of wearing of sand in the furnaces of fluidized bed incinerators (FBIs) on the formation of polychlorinated dibenzo-p-dioxin (PCDD), polychlorinated dibenzofuran (PCDF) and their related compounds from polychlorinated biphenyl (PCB) and 1,2,3-trichlorobenzene (1,2,3-T3CBz) was studied experimentally using a pyrolysis apparatus consisting of an injection unit; a stainless steel tube, in which packed was either unused sand (virgin sand) or used for two months in FBI (worn-out sand), heated to 650°C by an electric furnace; and a sampling unit. Furthermore, polychlorinated diphenyl ether (PCDE) was pyrolyzed on worn-out sand in order to compare the formation mechanisms of PCDD and PCDF with those from PCBs. Besides the generation of PCDD and PCDF, the hydroxylation of the starting compounds occurred. PCB was detected in the pyrolyzed samples of 1,2,3-T3CBz on both types of sand. In all cases, PCDF was in much higher yield than PCDD and pyrolysis on worn-out sand was more favorable for the formation of PCDD, PCDF and their relatives than pyrolysis on virgin sand. There was marked difference in metal concentrations between virgin and worn-out sand, implicating that the increased metal concentrations in sand would promote the formation of PCDD, PCDF and their related compounds in FBIs.

In a fluidized bed incinerator (FBI), municipal solid waste incinerated with the help of sand which had been repeatedly used for two months (worn-out sand) yielded one-order higher concentrations of polychlorinated dibenzo-p-dioxins (PCDDs), polychlorinated dibenzofurans (PCDFs), polychlorinated benzenes (PCBzs) and polychlorinated phenols (PCPs) in comparison with that incinerated on unused (fresh) sand. As metal concentrations in sand increased after each cycle of incineration, the worn-out sand used contained one to two-order higher amount of metals than the sand used for the first time. Taken together, these findings might imply that the accumulation of metals in worn-out sand is responsible for the increase in the amounts of polychlorinated compounds.

The qualitative analysis of moderately polar organic compounds in fly ash from a municipal solid waste incinerator (MSWI) was carried out by GC/MS. NINETY SEVEN oxygenated polycyclic aromatic hydrocarbons (oxy-PAHs), including known toxic substances were detected. They were classified into five groups by their structures. Aldehydes and most ketones detected had already been reported as oxy-PAHs in fly ash; however, most quinones and pyrones and all dicarboxylic acid anhydrides were found for the first time.

In a municipal solid waste incinerator (MSWI), the flue gas at the temperature of about 900°C was cooled to 3 stages in 300–400°C at the outlet of furnace by regulated water spray (Exp.I). In another MSWI, the flue gas at the temperature of about 280°C was cooled to about 160°C by water spray, and filtered by a fabric filter (FF) after dry lime powder spray into the cooled gas flow (Exp.II). Gas samples were collected before and after water spray (Exp.I and II) and at outlet of FF (Exp.II). Polychlorinated dibenzo- p -dioxins (PCDDs) and polychlorinated dibenzofurans (PCDFs) in the gas samples were investigated for the variation of their amounts, constitutions of the homologous compounds and distributions to the gaseous and solid phases. Further, the removal efficiency of PCDDs and PCDFs in the cooled flue gas by FF was also determined in Exp.II. When water was sprayed into the high temperature gas flow in Exp.I, the amounts of PCDDs and PCDFs in gaseous phase decreased accompanied with increasing amount of sprayed water, but those in solid phase showed similar levels with any amount of sprayed water. In the case of Exp.II, amounts of PCDDs and PCDFs in gaseous phase decreased similarly to those in Exp.I, but those in solid phase remarkably increased after water spray. The removal efficiency of total PCDDs and PCDFs by FF was 95.7–97.5% in cooled gas, and 84.0–92.9% of those in the gaseous phase, after cooling with water spray. At the outlet of a furnace and inlet of a dust removing equipment in the flue gas flow of MSWI, the water spray affected on decrease of amounts of PCDDs and PCDFs in the gaseous phase. Furthermore, the gas treatment by the combination of water spray, lime powder spray and filtration by FF showed high efficiency for decrease of PCDDs and PCDFs in the gas to be discharged to atmosphere.

The control of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs) formation was investigated in a municipal waste incinerator equipped with the electrostatic precipitator (EP). The simultaneous control of combustion, hydrogen chloride (HCl) concentration level in the flue gas and the gas temperature proved very effective in the control of PCDDs/Fs formation, reducing the concentration levels of PCDDs/Fs in the flue gas at the EP outlet to 0.2 ng/Nm3 as 2,3,7,8-tetrachlorodibenzo-p-dioxin when evaluated by the international toxicity equivalent factors.

In order to predict how much polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDDs/Fs) are leached from fly ash by rain water when fly ash is disposed, leaching of PCDDs/Fs from a fly ash obtained from a municipal solid waste incinerator (MSWI) was investigated by packing the ash in a column and eluting with water. In the beginning of the elution, PCDDs/Fs associated with water-soluble particulates in the ash were eluted, whereas in the latter half, those associated with water slightly soluble particles were eluted, judging from the comparison of PCDDs/Fs in eluate fractions with those transferred to solutions from the original ash by stepwise batch methods with water and 2N hydrochloric acid. The amounts of PCDDs/Fs eluted from the ash column were 2.9% and 1.7% of those extracted from the original ash, respectively, while large amounts of PCDDs/Fs were contained in the fly ash in the column after the elution, suggesting that PCDDs/Fs in water-insoluble particulates of the ash would not be eluted by water.

For mapping brain acetylcholinesterase (AchE) in vivo , seven radioactive acetylcholine analogs, N -[ 14 C]methylpiperidyl-3-and 4-acetates, propionates, isobutyrates, and 3-butyrate were newly synthesized and evaluated in mice. The esters readily entered the brain and were hydrolyzed into the hydrophilic metabolite, which was trapped. In brain homogenates, the esters showed a wide range of enzymatic reactivity (about 40-fold), and high specificity for AchE (more than 82%) except the butyrate. Intra-brain distribution of the esters reflected a pattern of AchE activity.

The metabolites, metabolizing organs of oxybutynin and its effect on the induction of drug metabolizing enzymes were investigated in rat, dog and human after oral administrations of oxybutynin and following the results were obtained.1. Eight metabolites of oxybutynin and their glucuronide were identified in the dog and human urine after oral administration.2. About 18 %, and 8.7 to 27.5 % of the administrated dose were excreted as a metabolites to urine in dogs and humans, respectively.3. It was presumed that oxybutynin was metabolized by the following four pathways; a) de-ethylation b) hydrolysis of ester c) hydroxylation at 3' and 4' positions on cyclohexyl ring and d) conjugation of each metabolites.4. The highest metabolic activity for oxybutynin was shown in the rat liver.5. The induction of drug metabolizing enzymes by oxybutynin, administered orally every day for 8 days, was not found.

PCDD and PCDF in flue gas and ash were determined when municipal solid waste was burnt in a rotary combustor (RC) and PCDD and PCDF were measured by GC/MS/SIM. PCDD and PCDF in the boiler outlet gas showed higher concentration levels than did those in the boiler inlet gas at the combustion of several amounts of refuse. PCDD and PCDF in the ashes and the gases showed low concentrations by the operation of the RC even over its capacity. The concentrations of PCDD and PCDF in the EP outlet gas and EP ash of the RC were observed lower than in those found in other incinerators in Japan. In the RC, the combustion of refuse was operated with good control of the carbon monoxide level. The formation of PCDD and PCDF in flue gas can be controlled by control of the carbon monoxide and with high temperaure conbustion in the RC.

The object of this study was to know how the formation of PCDDs and PCDFs in fluidized bed incinerators could be controlled. Therefore the relationship between levels of hydrogen chloride in flue gas in municipal waste combustion and PCDDs and PCDFs formed thereby was investigated. In order to decrease the concentration of formed hydrogen chloride in the gas, Dolomite was supplied into the furnace. When the supplied amounts of Dolomite were increased, the concentration of hydrogen chloride in the gas at the outlet of the electrostatic precipitator (EP) were clearly decreased. PCDDs and PCDFs in the boiler and the EP ash samples and in the gas samples were found at lower levels in proportion to the decrease of levels of hydrogen chloride in the gas.

14C-Labeled diethylene glycol was synthesized from radioactive ethylene glycol with a good yield and specific radioactivity.As a result of animal experiments using this labeled compound, the following findings were made:1) After single oral administration, the peak of radioactivity in blood was found at 1h, and, thereafter, the radioactivity decreased slowly. The radioactivity in tissues and organs persisted for a long period. A high radioactive concentration was detected in stomach and just relatively high concentrations were observed in liver, pancreas and kidney. About 55% of the dose was excreted in urine by 24h after administration.2) The radioactivity in tissues distributed evenly after repeated oral administration, as in the case of single administration, and accumulation in any particular tissue or organ was not observed. In every tissue and organ of 24h after final repeated administration, each radioactive concentration was found to be higher than the corresponding value at 24h after a single oral administration.3) Transference of radioactivity to milk occurred, and the peak of concentration in milk was observed at 6h after oral administration; however, its ratio to the concentration in dam blood increased with time until 24h.4) Transference of radioactivity in bile began just after oral administration, but the amount was small.5) About 21% of the dose was excreted in expiration by 24h after single oral administration.6) Percutaneous absorption took place in animals with abraded skin much more than in animals with normal skin.7) In the dialysis experiment, 14C-diethylene glycol did not combine with normal plasma, but binding of radioactivity to plasma was noted in plasma 1h and 24h after oral administration.8) About 93% of radioactive urinary metabolites were identified as intact dethylene glycol, and the remaining 7% as oxalic acid. All radioactive expiration was the form of carbon dioxide.

^ C-2-Chloroethyl benzoate (14C-CEB) was given to animal to investigate its fate in the body, and the following results were observed ; The absorption rate of 14C-CEB was so fast that a radioactivity in blood was observed 15 min after a single oral administration. Relatively higher distributions of radioactivity were noted in the liver and kidney comparing with other many organs. Almost all radioactivity of dose was excreted only in the urine 12 h after the administration, and its accumulation was not recognized in any region of the body. The rate of distribution to tissues after a cutaneous application was also fast, and the radioactivity was rapidly excreted as well as in the case of oral dosing. The amount of radioactivity transferred into the bile was only 0.8% of the dose 24 h after an intravenous injection. The urinary metabolite corresponding to 99.3% of the radioactivity in the rat urine was identified to be hippuric acid by thin-layer chromatography (TLC) and isotope dilution method. Additionally, p-hydroxybenzoic acid was also detected in the hydrolyzed rat urine.

The biodistribution of [3H]Ro 15-1788 in control and stress-loaded mice (forced swimming) was compared. In control mice, carrier-free [3H]Ro 15-1788 was selectively and highly distributed in Bz receptor rich brain regions, while radioactivity in the brain was very low following administration of carrier-added tracer, which suggested that in vivo non-specific binding of this tracer was very low. Significant changes in biodistribution of carrier-free [3H]Ro 15-1788 were observed in stress-loaded mice, which strongly indicated that in vivo binding availability of Bz receptor in the brain was rapidly and reversibly reduced by acute stress. The degree of these changes was very dependent upon the stressful conditions, such as swimming duration and water temperature, and a significant alteration in biodistribution of [3H]Ro 15-1788 was particularly observed in the cerebral cortex. Simplified Scatchard analysis of in vivo binding of this tracer was performed, and results suggested that these alterations were mainly caused by changes in the Kd value rather than the Bmax value.