High frequency of potential interactions between direct-acting antivirals and concomitant therapy in HIV/hepatitis C virus-coinfected patients in clinical practice.

OBJECTIVES: The aim of the study was to analyse the frequency and degree of potential drug-drug interactions (DDIs) between direct-acting antivirals (DAAs) and concomitant medication used by HIV/hepatitis C virus (HCV)-coinfected patients, including antiretroviral therapy (ART) and other drugs. METHODS: All patients with HIV infection and viraemic HCV genotype 1, 3 or 4 coinfection attending a tertiary care centre in Spain (November 2014 to November 2015) were included in the study. DDIs were classified as major, i.e. drugs should not be co-administered, or minor, i.e. close monitoring, dosage alteration or change in timing may be required if drugs are co-administered, following the http://www.hep-druginteractions.org database recommendations. RESULTS: A total of 244 patients were included in the study, of whom 224 (92%) were previous injecting drug users. Major DDIs were found for: paritaprevir-r/ombitasvir plus dasabuvir (3D), in 60 (44%) of 138 individuals with genotype 1; paritaprevir-r/ombitasvir (2D), in 22 (37%) of 60 individuals with genotype 4; sofosbuvir/ledipasvir (SOF/LDV), in four (2%) of 198 patients with genotype 1 or 4; simeprevir (SMV) plus SOF, in 160 (81%) of 198 patients with genotype 1 or 4; daclatasvir (DCV) plus SOF, in seven (3%) of 244 patients with genotype 1, 3 or 4 (P < 0.001). Minor DDIs were found for: 3D, in 123 (89%) individuals with genotype 1; 2D, in 52 (87%) individuals with genotype 4; SOF/LDV, in 154 (78%) patients with genotype 1 or 4; SMV plus SOF, in 129 (65%) patients with genotype 1 or 4; DCV plus SOF, in 149 (61%) patients with genotype 1, 3 or 4 (P < 0.001). CONCLUSIONS: Drug-drug interactions between DAAs and ART or other commonly prescribed medications are frequently found among HIV/HCV-coinfected patients. Potential major and minor DDIs are more frequent with 3D, 2D and SMV plus SOF regimens.

Sensory quality of lamb following long-term frozen storage.

The study analysed the effect of frozen storage duration (FSD) on lamb sensory quality. Trained panel evaluated Longissimus lumborum aged for 1d in unfrozen carcass plus 3d in modified atmosphere packaging on thawed (1, 9, 15 or 21 month FSD) or refrigerated (0 month FSD) meat. Consumer acceptability test was performed on leg chops (Semimembranosus) kept in the same conditions but those chops for the visual test were retail displayed up to 10d from packaging. FSD differed on texture variables and fresh meat showed intermediate values among thawed meats for trained evaluators. Consumers gave the lowest acceptability to 21 months FSD and preferred 1 month FSD, being all meats 'acceptable'. A third of the population scored fresh meat with the lowest acceptance after consumption, although its visual score remained 'acceptable' 3d longer than most of thawed meats. As thawed and fresh meats were equally preferred at short display, consumer concerns about thawed meat might be reconsidered.

Meat quality of lamb frozen stored up to 21 months: instrumental analyses on thawed meat during display.

The study analysed the effect of frozen storage duration (FSD: 0, 1, 9, 15 or 21 months) and display duration (DD: 0-24 h post-slaughter-, 3 and 6 days) in modified atmosphere packaging (MAP) on lamb quality. pH, colour, lipid oxidation, water holding capacity and instrumental texture were performed on Longissimus muscle in displayed fresh and thawed meat. FSD affected all the variables showing lower differences between fresh and 1 month storage than among them and longer FSD. Only cooking losses were not affected by DD in thawed meats. It was observed a general decrease in quality (lower redness and water holding capacity; higher yellowness and lipid oxidation) as FSD or DD increased and only texture was improved over DD being thawed meat more tender. In conclusion, lamb storage at -18°C should not exceed 1 month if thawed meat would be later displayed in MAP while meat would have an acceptable quality up to 21 months without subsequent display.

TICAREX: Exposiciones laborales a agentes cancerígenos y plaguicidas en Costa Rica / TICAREX: occupational exposure to carcinogens and pesticides in Costa Rica

El sistema europeo de datos CAREX (CARcinogen Exposure) considera la fuerza laboral de un país agrupada en 55 sectores económicos según la Clasificación Internacional de Actividades Económicas de las Naciones Unidas, segunda revisión de 1968, y mediante la aplicación de proporciones de trabajadores expuestos a partir de datos generados en estudios de higiene industrial para 139 agentes carcinógenos, los convierte en fuerza laboral expuesta y número de trabajadores expuestos a agentes carcinogénicos, según rama de actividad. En este artículo se describe una modificación y extensión del sistema CAREX para calcular los números de trabajadores expuestos a agentes cancerígenos y plaguicidas en Costa Rica. Esta primera aplicación de CAREX fuera de Europa (TICAREX) fue realizada en Costa Rica, Centroamérica, para 27 agentes cancerígenos y 7 grupos de plaguicidas, considerados de interés para el país, realizando estimaciones por separado para mujeres y hombres. Los agentes cancerígenos más frecuentes a los que se expone la fuerza laboral de Costa Rica de 1.3 millones fueron la radiación solar (333,000 trabajadores), las emisiones de diesel (278,000), paraquat y diquat (175,000), el humo de tabaco ambiental (71,000), los compuestos de cromo hexavalente (55,000), el benceno (52,000), mancozeb, maneb y zineb (49,000), clorotalonil (38,000), el polvo de madera (32,000), el cuarzo (27,000), benomil (19,000), el plomo y sus compuestos inorgánicos (19,000), tetracloroetileno (18,000), y los compuestos aromáticos policíclicos (17,000). En los hombres, la distribución se mantuvo muy ajustada a los anteriores rangos, sin embargo en las mujeres, debido a su diferente distribución en los sectores, el formaldehído, el radón y el cloruro de metileno superaron a los plaguicidas, el cromo (VI), el polvo de madera y el cuarzo. La agricultura, la construcción, los servicios personales y domésticos, el transporte terrestre y acuático y los servicios asociados al transporte, la fabricación de productos cerámicos y similares, la manufactura de productos de madera, la minería, la silvicultura, la pesca, la fabricación de maquinaria y aparatos eléctricos, bares y restaurantes fueron sectores de donde las exposiciones son frecuentes. Una reducción drástica de exposiciones laborales y ambientales a estos agentes daría por resultado mejoras sustanciales en los niveles de salud pública y ocupacional. La vigilancia de las exposiciones laborales y de la salud en el trabajo son esenciales para el control de la contaminación y de las exposiciones a los agentes cancerígenos

The European data system CAREX takes the workforce of a country grouped into 55 economic sectors according to the International Economic Activity Classification of the United Nations, the second 1968 revision and through the application of proportions of workers exposed to 139 carcinogenic agents based on data from industrial hygiene studies, converting it into the total workforce exposed to carcinogens by sector. . In this article we describe a modification and extension of of the CAREX system in order to calculate the number of workers exposed to carcinogens in Costa Rica. It is the first use of CAREX outside Europe (TICAREX) in Costa Rica, Central America, for 27carcinogens and 7 groups of pesticides thought to be of interest for the country, with separate estimations for men and women. The most frequent agents of exposure for the 1.3 million workers of Costa Rica were solar radiation (333,000 workers); diesel exhaust (278,000); paraquat and diquat (175,000); environmental tobacco smoke (71,000); hexavalent chromium compounds (55,000); benzene (52,000); mancozeb, maneb and zineb (49,000); chlorothalonil (38,000); wood dust (32,000); quartz (27,000); benomyl (19,000); lead and its inorganic compounds (19,000); tetrachloroethylene (18,000); and polycyclic aromatic hydrocarbons (17,000). Owing to the different occupational distribution between the genders, exposures to formaldehyde, radon and methylene chloride were more frequent than pesticides, hexavalent chromium, wood dust, and quartz in women. Agriculture, construction, personal and domestic services, manufacture of wood products, mining, forestry, fishing, manufacture of electrical products, and bars and restaurants were sectors with frequent exposures. Substantial reduction of occupational and environmental exposures to these agents would significantly improve public and occupational health. Reduction of occupational exposures is usually also followed by improvement of environmental quality. Monitoring of exposures and health of workers and the general public is an essential element in the control of environmental contamination and human exposures

Pesticide-related illness and injuries among banana workers in Costa Rica: a comparison between 1993 and 1996.

An intervention program considerably decreased systemic poisonings on banana plantations in Costa Rica in the early 1990s. Nevertheless, pesticide safety continues to be controversial. To examine the determinants of acute pesticide-related illness on banana plantations, the authors surveyed occupational injuries and illness among banana workers in the Atlantic Region of Costa Rica that were reported during 1993 and 1996 to the National Insurance Institute. Incidence rates were calculated for categories of pesticides and types of medical problems, for all and subgroups of banana workers. Between 1993 and 1996, an overall 35% decrease in injuries was observed, attributable to a marked decline in topical injuries (3.3 vs 1.9 per 100 workers), whereas systemic poisonings remained the same (0.7 per 100 in both years). The decrease concerned selectively milder skin conditions, indicating underreporting of less severe health effects. In both years, paraquat was the pesticide most frequently associated with injuries, mostly skin and eye lesions. Workers at highest risk per unit time of exposure were nematocide applicators, herbicide applicators, and cleaners of packing plants. Despite control measures, further reduction of systemic illness had not been achieved. The decrease of topical injuries may be partly explained by improved work conditions, but possible underreporting hinders interpretation. Pesticide-related illness on banana plantations is a persistent problem.

Chronic nervous-system effects of long-term occupational exposure to DDT.

Dichlorodiphenyltrichloroethane (DDT) is a compound with moderate toxicity that is judged to be safe for occupational use, although little is known about its long-term effects on the human nervous system. We investigated chronic nervous-system effects of long-term occupational exposure to DDT by comparing the neurobehavioural performance of retired malaria-control workers with a reference group of retired guards and drivers. DDT-exposed workers did worse on tests assessing various neurobehavioural functions than controls; performance significantly deteriorated with increasing years of DDT application. Our results could not be explained by exposure to cholinesterase-inhibiting pesticides or other potential confounding factors.

Paraquat in developing countries.

The herbicide paraquat is considered safe by industry and the bulk of regulators worldwide. However, determinants of exposure from 30 years ago persist in developing countries. Little is known about systemic absorption from occupational exposures. The relationships between exposure determinants, levels of external exposure, biomarkers of exposure, and outcomes are not clear. High rates of severe acute poisonings have been documented. In addition, topical injuries occur in as many as 50% of exposed workers. Non-worker populations are also at risk, particularly children. Long-term and delayed health effects include Parkinson's disease, lung effects, and skin cancer. Regulatory agencies have not fully recognized either the inherent toxicity of paraquat or the particular risks derived from exposures in developing countries. Independent risk assessment in the developing-country context and application of the precautionary principle are necessary to prevent adverse effects of dangerous pesticides in susceptible populations.

Hazardous pesticides in Central America.

Pesticides are an extensively documented occupational and environmental hazard in Central America. Yet, severe problems persist. Toxic pesticide use in the Region increased during 1985-1999. High exposure levels and ineffectiveness of personal protective equipment evidence the difficulties for risk reduction. Acute poisonings remain a severe problem. Delayed and/or long-lasting health effects include dermatoses, cancer, and genotoxic, neurotoxic, and respiratory effects. The use of hazardous pesticides persists through deficiencies in government-driven assessment and risk management; excessive focus on regional harmonization; short-term economic interests; strong links between industry and governments; aggressive marketing; weak trade unions; and failure of universities to reach decision makers. Regulation based on local data is lacking. An agreement of the Ministries of Health for restricting the most toxic pesticides in Central America has potential for progress. The most effective way to reduce risk is to greatly reduce pesticide use. Actions needed include development of multidisciplinary strategies for local studies on health and environmental impact of pesticides; development of sustainable nonchemical agricultural technologies; evaluation of interventions; extending and sharing of expertise within the Region; strengthening of unions and communities; and redefining the role of industry toward development of safer products, with responsible marketing and reliable information.

Dihydrochalcone metabolism in the rat: phloretin.

The metabolism of phloretin (2',4',6',4-tetrahydroxydihydrochalcone) was studied in rats. Approx. half of the intragastric dose (0.75 mmol/kg) was excreted in the urine, mainly within two days. Small initial amounts of phloretin were found, however most of the metabolites were degradation products. The latter included phloroglucinol and, in larger amounts, phloretic acid and related metabolites formed by its dehydrogenation, beta-oxidation and glycine conjugation. Phloroglucinol, administered in similar experiments, was rapidly (90% within 24 h) excreted in the urine, either unchanged or as conjugates (glucuronide/sulphate). Incubation of phloretin and its glucoside phloridzin with rat-caecal micro-organisms resulted in the formation of phloroglucinol and phloretic acid. The degradative pathways of metabolism of dihydrochalcones and other flavonoids are discussed.

p-Cymene metabolism in rats and guinea-pigs.

The metabolism of p-cymene was studied in rats and guinea-pigs. Following intragastric or inhalation dosage (100 mg/kg) urinary metabolite excretion was nearly complete within 48 h, amounting to 60-80% dose. The inhalation experiments gave the lowest values. 18 urinary metabolites were detected and identified. Of these, rats did not excrete two and guinea-pigs did not excrete a third. No ring-hydroxylation of p-cymene was detected in rats, but guinea-pigs formed small amounts of carvacrol and hydroxycarvacrol. Oxidation of both the methyl and isopropyl groups of p-cymene occurred extensively in both species. The following types of metabolites were formed: monohydric alcohols, diols, mono- and di-carboxylic acids and hydroxyacids. Conjugation with glycine of the cumic acid formed was extensive in guinea-pigs.

Storage of blood samples containing alcohol.

The storage of blood alcohol samples was studied. The samples were analysed and then frozen and kept at -20 degrees for 6 months before reanalysis. The results from this reanalysis did not deviate to any significant extent from those originally obtained. The process of freezing and thawing the same samples before analysis was repeated three times without any significant difference from the results with the fresh blood samples.

The metabolism of zingerone, a pungent principle of ginger.

1. The metabolism of 4-(4-hydroxy-3-methoxyphenyl)butan-2-one (zingerone), a pungent principle of ginger, has been investigated in rats. 2. Oral or intraperitoneal dosage (100mg/kg) of zingerone resulted in the urinary excretion of most metabolites within 24 h, mainly as glucuronide and/or sulphate conjugates. While zingerone itself accounted for roughly 50-55% of the dose, reduction to the corresponding carbinol (11-13%) also occurred. Side chain oxidation took place at all three available sites and oxidation at the 3-position, giving rise to C6-C2 metabolites, predominated. About 95-97% of the dose was accounted for. 3. Appreciable (40% in 12 h) biliary excretion occurred. Biliary studies and studies in vitro using caecal micro-organisms indicated that several O-demethylated metabolites found in the urine are of bacterial origin.