RESUMEN
Development of new, safe, and effective microbicides to prevent human immunodeficiency virus HIV sexual transmission is needed. Unfortunately, most microbicides proved ineffective to prevent the risk of HIV-infection in clinical trials. We are working with G2-S16 polyanionic carbosilane dendrimer (PCD) as a new possible vaginal topical microbicide, based on its short reaction times, wide availability, high reproducibility, and quantitative yields of reaction. G2-S16 PCD exerts anti-HIV activity at an early stage of viral replication, by blocking gp120/CD4/CCR5 interaction, and providing a barrier against infection for long periods of time. G2-S16 PCD was stable at different pH values, as well as in the presence of seminal fluids. It maintained the anti-HIV activity against R5/X4 HIV over time, did not generate any type of drug resistance, and retained the anti-HIV effect when exposed to semen-enhanced viral infection. Importantly, G2-S16 PCD did not modify vaginal microbiota neither in vitro or in vivo. Histopathological examination did not show vaginal irritation, inflammation, lesions, or damage in the vaginal mucosa, after administration of G2-S16 PCD at different concentrations and times in female mice and rabbit animal models. Based on these promising data, G2-S16 PCD could become a good, safe, and readily available candidate to use as a topical vaginal microbicide against HIV.
Asunto(s)
Alcanosulfonatos/uso terapéutico , Fármacos Anti-VIH/uso terapéutico , Dendrímeros/uso terapéutico , Infecciones por VIH/prevención & control , Compuestos de Organosilicio/uso terapéutico , Administración Intravaginal , Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/efectos adversos , Animales , Fármacos Anti-VIH/administración & dosificación , Fármacos Anti-VIH/efectos adversos , Dendrímeros/administración & dosificación , Dendrímeros/efectos adversos , Evaluación Preclínica de Medicamentos , Femenino , Infecciones por VIH/transmisión , Humanos , Masculino , Compuestos de Organosilicio/administración & dosificación , Compuestos de Organosilicio/efectos adversosRESUMEN
The most common complications in patients with type-2 diabetes are hyperglycemia and hyperlipidemia that can lead to cardiovascular disease. Alleviation of these complications constitutes the major therapeutic approach for the treatment of diabetes mellitus. Agonists of peroxisome proliferator-activated receptor (PPAR) alpha and PPARγ are used for the treatment of hyperlipidemia and hyperglycemia, respectively. PPARs belong to the nuclear receptors superfamily and regulate fatty acid metabolism. PPARα ligands, such as fibrates, reduce circulating triglyceride levels, and PPARγ agonists, such as thiazolidinediones, improve insulin sensitivity. Dual-PPARα/γ agonists (glitazars) were developed to combine the beneficial effects of PPARα and PPARγ agonism. Although they improved metabolic parameters, they paradoxically aggravated congestive heart failure in patients with type-2 diabetes via mechanisms that remain elusive. Many of the glitazars, such as muraglitazar, tesaglitazar, and aleglitazar, were abandoned in phase-III clinical trials. The objective of this review article pertains to the understanding of how combined PPARα and PPARγ activation, which successfully targets the major complications of diabetes, causes cardiac dysfunction. Furthermore, it aims to suggest interventions that will maintain the beneficial effects of dual PPARα/γ agonism and alleviate adverse cardiac outcomes in diabetes.
Asunto(s)
Enfermedades Cardiovasculares/inducido químicamente , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Metabolismo Energético/efectos de los fármacos , Hipoglucemiantes/efectos adversos , PPAR alfa/agonistas , PPAR gamma/agonistas , Alcanosulfonatos/efectos adversos , Animales , Cardiotoxicidad , Enfermedades Cardiovasculares/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Diabetes Mellitus Tipo 2/metabolismo , Glicina/efectos adversos , Glicina/análogos & derivados , Humanos , Oxazoles/efectos adversos , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Fenilpropionatos/efectos adversos , Medición de Riesgo , Factores de Riesgo , Transducción de Señal , Tiofenos/efectos adversosRESUMEN
OBJECTIVE: Evaluate the safety and efficacy of RVT-1502, a novel oral glucagon receptor antagonist, in subjects with type 2 diabetes inadequately controlled on metformin. RESEARCH DESIGN AND METHODS: In a phase 2, double-blind, randomized, placebo-controlled study, subjects with type 2 diabetes (n = 166) on a stable dose of metformin were randomized (1:1:1:1) to placebo or RVT-1502 5, 10, or 15 mg once daily for 12 weeks. The primary end point was change from baseline in HbA1c for each dose of RVT-1502 compared with placebo. Secondary end points included change from baseline in fasting plasma glucose (FPG) and safety assessments. RESULTS: Over 12 weeks, RVT-1502 significantly reduced HbA1c relative to placebo by 0.74%, 0.76%, and 1.05% in the 5-, 10-, and 15-mg groups (P < 0.001), respectively, and FPG decreased by 2.1, 2.2, and 2.6 mmol/L (P < 0.001). The proportions of subjects achieving an HbA1c <7.0% were 19.5%, 39.5%, 39.5%, and 45.0% with placebo and RVT-1502 5, 10, and 15 mg (P ≤ 0.02 vs. placebo). The frequency of hypoglycemia was low, and no episodes were severe. Mild increases in mean aminotransferase levels remaining below the upper limit of normal were observed with RVT-1502 but were reversible and did not appear to be dose related, with no other liver parameter changes. Weight and lipid changes were similar between RVT-1502 and placebo. RVT-1502-associated mild increases in blood pressure were not dose related or consistent across time. CONCLUSIONS: Glucagon receptor antagonism with RVT-1502 significantly lowers HbA1c and FPG, with a safety profile that supports further clinical development with longer-duration studies (NCT02851849).
Asunto(s)
Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/efectos adversos , Benzamidas/administración & dosificación , Benzamidas/efectos adversos , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/administración & dosificación , Hipoglucemiantes/efectos adversos , Receptores de Glucagón/antagonistas & inhibidores , Adulto , Anciano , Glucemia/efectos de los fármacos , Glucemia/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Resistencia a Medicamentos/efectos de los fármacos , Quimioterapia Combinada , Femenino , Humanos , Masculino , Metformina/uso terapéutico , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
Dual peroxisome proliferator-activated receptor (PPAR)α/γ agonists that were developed to target hyperlipidemia and hyperglycemia in type 2 diabetes patients, caused cardiac dysfunction or other adverse effects. We studied the mechanisms that underlie the cardiotoxic effects of a dual PPARα/γ agonist, tesaglitazar, in wild type and diabetic (leptin receptor deficient - db/db) mice. Mice treated with tesaglitazar-containing chow or high fat diet developed cardiac dysfunction despite lower plasma triglycerides and glucose levels. Expression of cardiac peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α), which promotes mitochondrial biogenesis, had the most profound reduction among various fatty acid metabolism genes. Furthermore, we observed increased acetylation of PGC1α, which suggests PGC1α inhibition and lowered sirtuin 1 (SIRT1) expression. This change was associated with lower mitochondrial abundance. Combined pharmacological activation of PPARα and PPARγ in C57BL/6 mice reproduced the reduction of PGC1α expression and mitochondrial abundance. Resveratrol-mediated SIRT1 activation attenuated tesaglitazar-induced cardiac dysfunction and corrected myocardial mitochondrial respiration in C57BL/6 and diabetic mice but not in cardiomyocyte-specific Sirt1-/- mice. Our data shows that drugs, which activate both PPARα and PPARγ lead to cardiac dysfunction associated with PGC1α suppression and lower mitochondrial abundance likely due to competition between these two transcription factors.
Asunto(s)
Insuficiencia Cardíaca/metabolismo , PPAR alfa/metabolismo , PPAR gamma/metabolismo , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/metabolismo , Peroxisomas/metabolismo , Sirtuina 1/metabolismo , Alcanosulfonatos/efectos adversos , Animales , Glucemia , Línea Celular , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Dieta Alta en Grasa/efectos adversos , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mitocondrias/metabolismo , Miocitos Cardíacos/metabolismo , PPAR alfa/agonistas , PPAR gamma/agonistas , Coactivador 1-alfa del Receptor Activado por Proliferadores de Peroxisomas gamma/genética , Fenilpropionatos/efectos adversos , Receptores de Leptina/metabolismo , Sirtuina 1/genética , Factores de Transcripción , TranscriptomaAsunto(s)
Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Alcanosulfonatos/efectos adversos , Ensayos Clínicos Fase II como Asunto , Diabetes Mellitus Tipo 2/complicaciones , Glicina/efectos adversos , Glicina/análogos & derivados , Humanos , Hipoglucemiantes/farmacología , Oxazoles/efectos adversos , Oxazoles/farmacología , Oxazoles/uso terapéutico , PPAR alfa/fisiología , PPAR gamma/fisiología , Fenilpropionatos/efectos adversos , Tiofenos/farmacología , Tiofenos/uso terapéuticoRESUMEN
PX-18 and PX-13 are new secreted phospholipase A2 inhibitors. An increased expression of secreted phospholipase A2 in psoriatic epidermis and dermis was reported in the literature, hence the dermal application of PX-18 and PX-13 seems to be a promising approach for psoriasis treatment. Both compounds are practically insoluble in aqueous media and hard to formulate using conventional techniques. Therefore, nanosuspensions were prepared by high pressure homogenization. Pre-clinical skin and eye irritation tests were performed with PX-18 and PX-13 bulk material and 5% (w/w) PX-18 and PX-13 nanosuspensions using the EPISKIN and the HET-CAM test to aid safety assessment and to facilitate the design of safe and efficient human studies. It could be shown that nanosuspensions with an active content of 5% (w/w) with a particle size well in the nanometer range can be produced applying high pressure homogenisation. The results of the EPISKIN test allow the classification of PX-18 and PX-13 bulk material and the according nanosuspensions as non irritant to the skin. According to the test protocol applied for the HET-CAM test, the bulk material of the new secreted phospholipase A2 inhibitors as well as the nanosuspensions can be classified as non/slightly irritant to the eye.
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Alcanosulfonatos/efectos adversos , Ácidos Alcanesulfónicos/efectos adversos , Proteínas Sanguíneas/administración & dosificación , Portadores de Fármacos/efectos adversos , Ojo/efectos de los fármacos , Nanopartículas/efectos adversos , Ácidos Oléicos/efectos adversos , Piel/efectos de los fármacos , Animales , Pollos , Ojo/patología , Humanos , Piel/patología , SuspensionesRESUMEN
This randomised, double-blind, parallel-group study assessed the effects of addition of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist, tesaglitazar, for 24 weeks to the therapeutic regimen of 392 poorly controlled (glycosylated haemoglobin [HbA1C] 7.5-10%) insulin-treated, type 2 diabetes patients. At 24 weeks, tesaglitazar 0.5 mg resulted in a 0.66% (95% confidence intervals: -0.85, -0.47; p<0.0001) reduction from baseline in HbA1C, and reduced fasting plasma glucose (p<0.0001) and daily insulin dose (p=0.014) versus placebo. After 24 weeks, tesaglitazar caused greater improvements from baseline in triglycerides (p<0.0001), high-density lipoprotein cholesterol (HDL-C) (p<0.001), non-HDL-C (p<0.05), apolipoprotein (apo)A-I (p<0.05) and apoB levels (p<0.01) than placebo. Tesaglitazar was generally well tolerated but was associated with a greater increase in serum creatinine level than placebo. The clinical development of tesaglitazar is no longer continuing; its effects on the glucose and lipid abnormalities of type 2 diabetes suggest that the concept of dual PPARalpha/gamma agonism is worthy of further investigation.
Asunto(s)
Alcanosulfonatos/uso terapéutico , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Insulina/uso terapéutico , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alcanosulfonatos/efectos adversos , Glucemia/efectos de los fármacos , HDL-Colesterol/sangre , Diabetes Mellitus Tipo 2/metabolismo , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Quimioterapia Combinada , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversos , Factores de Tiempo , Triglicéridos/sangreRESUMEN
OBJECTIVE: The Glucose and Lipid Assessment in Diabetes (GLAD) trial examined the dose-response relationship of the dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist tesaglitazar in type 2 diabetic patients. STUDY DESIGN: GLAD was a 12-week, multicenter, international, randomized, parallel-group trial. Five-hundred men and women aged 30-80 years with type 2 diabetes (fasting plasma glucose [FPG] > or = 126 mg/dL [> or = 7.0 mmol/L]) received once-daily, double-blind placebo or tesaglitazar (0.1 mg, 0.5 mg, 1.0 mg, 2.0 mg, or 3.0 mg) or open-label pioglitazone (45 mg), included as a therapeutic benchmark. MAIN OUTCOME MEASURES: Placebo-corrected changes from baseline in FPG (primary end point), plasma lipids, and insulin-resistance measures. RESULTS: At baseline, the mean patient age was 56.1 years, 57.5 years, and 58.9 years for placebo, across tesaglitazar groups, and for pioglitazone, respectively. For the corresponding groups, mean body mass index was 30.6 kg/m2, 30.9 kg/m2, and 29.7 kg/m2, and mean HbA1c was 7.0%, 7.2%, and 7.0%, respectively. At 12 weeks, tesaglitazar 0.5 mg, 1.0 mg, 2.0 mg, and 3.0 mg produced statistically significant reductions in FPG (-30.3 mg/dL, -41.1 mg/dL, -55.0 mg/dL, -60.9 mg/dL; p < 0.0001), triglycerides (-17.2%, -32.9%, -41.0%, -40.9%; p < 0.01), and apolipoprotein B (-15.0%, -15.7%, -21.0%, -22.3%, respectively; p < 0.0001). Tesaglitazar at doses > or = 1.0 mg significantly increased high-density lipoprotein-cholesterol (HDL-C) (15.0%, 13.0%, 12.9%; p < 0.001), and reduced non-HDL-C (-13.2%, -22.2%, -25.0%; p < 0.0001), very-low-density lipoprotein-cholesterol (VLDL-C) (-36.9%, -49.8%, -52.5%; p < 0.0001), and total cholesterol (-6.8%, -14.1%, -15.5%, respectively; p < 0.01). Tesaglitazar > or = 0.5 mg improved insulin-resistance measures. Although no formal statistical analyses were performed between active treatments, improvements in efficacy measures with tesaglitazar 1.0 mg were numerically similar to or greater than those with pioglitazone. Similar numbers of adverse events occurred in the tesaglitazar < or = 1.0 mg, placebo, and pioglitazone arms, but there was an increasing frequency of discontinuations due to pre-specified hematologic and clinical-chemistry criteria with tesaglitazar doses > or = 1.0 mg. CONCLUSIONS: In type 2 diabetic patients, tesaglitazar dose-dependently reduced FPG levels at doses > or = 0.5 mg. Other markers of glycemic control, atherogenic dyslipidemia, and measures associated with insulin resistance were improved at doses > or = 0.5 mg or > or = 1.0 mg. Study limitations included that the majority of patients were white, patients had good glycemic control at baseline, and the increased number of early withdrawals in the tesaglitazar 2.0 mg and 3.0 mg doses limits conclusions about the efficacy of these doses. The 0.5 mg and 1.0 mg tesaglitazar doses were identified for further investigation.
Asunto(s)
Alcanosulfonatos/uso terapéutico , Glucemia/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Lípidos/sangre , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Alcanosulfonatos/efectos adversos , HDL-Colesterol/sangre , VLDL-Colesterol/sangre , Femenino , Hemoglobina Glucada/metabolismo , Humanos , Resistencia a la Insulina , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversosRESUMEN
Tesaglitazar is a dual peroxisome proliferator-activated receptor (PPAR) alpha/gamma agonist in development to treat lipid and glucose abnormalities associated with type 2 diabetes. This study evaluated the effects of food on tesaglitazar pharmacokinetics. In an open, randomized, 2-way crossover study, 20 healthy men received tesaglitazar 1 mg during fasting and after a high-fat, high-calorie breakfast. Blood samples were taken to assess pharmacokinetic variables. Systemic exposure to tesaglitazar was unaffected by food intake. Estimated ratios were 0.99 (90% confidence interval [CI], 0.94-1.04) for fed/fasted area under plasma concentration-time curve and 0.82 (90% CI, 0.78-0.86) for fed/fasted maximum plasma concentration (C(max)). Mean C(max) was approximately 18% lower (0.41 [95% CI, 0.38-0.43] versus 0.50 [95% CI, 0.47-0.53] mumol/L), and median time to C(max) was increased (2.00 vs 0.75 h) in fed versus fasted state. The median difference of t(max) was 1.25 h (P = .0001, signed-rank test). Tesaglitazar was well tolerated. Tesaglitazar pharmacokinetics is unaffected by food intake, allowing once-daily administration of tesaglitazar with or without food in clinical practice.
Asunto(s)
Alcanosulfonatos/farmacocinética , Alimentos , PPAR alfa/agonistas , PPAR gamma/agonistas , Fenilpropionatos/farmacocinética , Adulto , Alcanosulfonatos/efectos adversos , Alcanosulfonatos/sangre , Salud , Humanos , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversos , Fenilpropionatos/sangreRESUMEN
AIMS/HYPOTHESIS: Insulin resistance is associated with abnormalities in lipid and glucose metabolism, which are major components of metabolic syndrome and risk factors for vascular disease. This study examined the effect of tesaglitazar (Galida), a novel, dual-acting peroxisome proliferator-activated receptor alpha/gamma agonist, on lipid and glucose metabolism in patients with evidence of insulin resistance. METHODS: A 12-week, multicentre, randomised, double-blind, placebo-controlled, dose-finding study compared the efficacy and safety of oral tesaglitazar (0.1, 0.25, 0.5 and 1.0 mg/day) and placebo in 390 non-diabetic patients with hypertriglyceridaemia (plasma triglyceride concentration >1.7 mmol/l) and abdominal obesity (waist-to-hip ratio >0.90 for men and >0.85 for women). RESULTS: A 1.0-mg dose of tesaglitazar reduced fasting triglycerides (the primary endpoint) by 37% (95% CI: -43% to -30%; p<0.0001), non-HDL-cholesterol by 15% (95% CI: -20% to -10%; p<0.0001) and NEFA by 40% (95% CI: -51% to -27%; p<0.0001), and increased HDL-cholesterol by 16% (95% CI: 8 to -24%; p<0.0001). At the end of treatment there was a dose-dependent increase in patients with pattern A LDL particle diameter (40% at baseline vs 87% at 12 weeks for tesaglitazar 1.0 mg). Tesaglitazar produced significant reductions in fasting insulin concentration (-35%; p<0.0001) and plasma glucose concentration (-0.47 mmol/l; p<0.0001). Respiratory infection and gastrointestinal symptoms were the most common adverse events and were similarly frequent in all groups. CONCLUSIONS/INTERPRETATION: Tesaglitazar was well tolerated and produced significant, dose-dependent improvements in lipid and glucose metabolism and insulin sensitivity. Tesaglitazar may have the potential to prevent vascular complications and delay progression to diabetes in these patients.
Asunto(s)
Alcanosulfonatos/uso terapéutico , Glucemia/metabolismo , PPAR alfa/antagonistas & inhibidores , PPAR gamma/antagonistas & inhibidores , Fenilpropionatos/uso terapéutico , Alcanosulfonatos/efectos adversos , Glucemia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Ácidos Grasos no Esterificados/sangre , Femenino , Humanos , Insulina/sangre , Lípidos/sangre , Masculino , Persona de Mediana Edad , Fenilpropionatos/efectos adversos , Placebos , Seguridad , Triglicéridos/sangreRESUMEN
Alkylating agents are widely used in high-dose chemotherapy regimens in combination with hematological support. Knowledge about the pharmacokinetics and pharmacodynamics of these agents administered in high doses is critical for the safe and efficient use of these regimens. The aim of this review is to summarize the clinical pharmacology of the alkylating agents (including the platinum compounds) in high-dose chemotherapy. Differences between conventional and high doses will be discussed.
Asunto(s)
Antineoplásicos Alquilantes/farmacología , Antineoplásicos Alquilantes/farmacocinética , Alcanosulfonatos/administración & dosificación , Alcanosulfonatos/efectos adversos , Alcanosulfonatos/farmacocinética , Alcanosulfonatos/farmacología , Antineoplásicos Alquilantes/administración & dosificación , Antineoplásicos Alquilantes/efectos adversos , Aziridinas/administración & dosificación , Aziridinas/efectos adversos , Aziridinas/farmacocinética , Aziridinas/farmacología , Humanos , Compuestos de Mostaza Nitrogenada/administración & dosificación , Compuestos de Mostaza Nitrogenada/efectos adversos , Compuestos de Mostaza Nitrogenada/farmacocinética , Compuestos de Mostaza Nitrogenada/farmacología , Compuestos de Nitrosourea/administración & dosificación , Compuestos de Nitrosourea/efectos adversos , Compuestos de Nitrosourea/farmacocinética , Compuestos de Nitrosourea/farmacología , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/farmacocinética , Compuestos Organoplatinos/farmacología , Triazenos/administración & dosificación , Triazenos/efectos adversos , Triazenos/farmacocinética , Triazenos/farmacologíaRESUMEN
The biological activity of skin-sensitizing chemicals can be expressed in terms of physicochemical properties which relate to the propensity of those chemicals to behave as electrophiles and which describe their ability to partition into the epidermis and between compartments within it. For defined series of chemicals, it has proved possible to express such structure-activity relationships quantitatively. Such quantitative relationships can provide valuable insights into the mechanisms of skin sensitization and/or are of use in predictive toxicology. In the present work the quantitative structure-activity relationship (QSAR) previously derived for a series of alkyl transfer agents based on alkanesulfonate leaving groups has been critically examined in the light of skin sensitization data obtained for new members of that series and also for alkyl transfer agents based on different leaving groups. The QSAR predictions were broadly accurate, but demonstrated that further refinement was both necessary and possible. In particular, the physicochemical parameters which relate to the disposition of the chemical in the epidermis, i.e., its penetration through the stratum corneum, cell surface/cytoplasmic distribution and the associated dynamics, will need to be understood more fully in order to enhance the precision of the QSAR and its predictive power.
Asunto(s)
Alcanosulfonatos/efectos adversos , Dermatitis Alérgica por Contacto/etiología , Alcanosulfonatos/química , Animales , Bromuros/efectos adversos , Bromuros/química , Evaluación de Medicamentos , Ésteres/efectos adversos , Ésteres/química , Cobayas , Piel/química , Piel/fisiopatología , Pruebas Cutáneas , Relación Estructura-ActividadAsunto(s)
Detergentes/efectos adversos , Productos Domésticos/efectos adversos , Tensoactivos/efectos adversos , Alcanosulfonatos/efectos adversos , Derivados del Benceno/efectos adversos , Técnicas de Apoyo para la Decisión , Monitoreo del Ambiente/métodos , Filipinas , Técnicas de Planificación , Factores de Riesgo , Dodecil Sulfato de Sodio/efectos adversosRESUMEN
The suspicion that a newly developed detergent ingredient, sodium iso-nonanoyl oxybenzene sulphonate (SINOS), was inducing asthma among a workforce led to a series of inhalation challenge tests to determine the specificity and dose response characteristics of its asthma provoking properties. Three previously exposed workers, three non-exposed non-asthmatic controls, and three non-exposed asthmatic controls were challenged with SINOS 0.01-100 micrograms and another chemically similar surface active detergent ingredient, linear alkyl benzene sulphonate (LAS) 0.01-100 micrograms. Asthmatic symptoms, late falls in FEV1, and increases in non-specific bronchial responsiveness were seen after the inhalation of SINOS in all three workers, confirming SINOS as a cause of occupational asthma. No changes were seen after the inhalation of SINOS in either group of control subjects nor after LAS in any subject. These findings suggest that SINOS causes asthma through a specific hypersensitivity mechanism unrelated to its surface active properties.
Asunto(s)
Ácidos Alcanesulfónicos , Asma/inducido químicamente , Bencenosulfonatos/efectos adversos , Industria Química , Detergentes/efectos adversos , Enfermedades Profesionales/inducido químicamente , Tensoactivos/efectos adversos , Adulto , Alcanosulfonatos/efectos adversos , Pruebas de Provocación Bronquial , Fenómenos Químicos , Química , Método Doble Ciego , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Masculino , Subtilisinas/efectos adversosRESUMEN
A murine model for in vivo and in vitro studies of contact sensitization to methyl alkanesulphonate derivatives has been developed. Contact sensitivity was quantified in vivo by measuring the ear thickness increase, and the influence of the alkyl chain length (hexyl, dodecyl, hexadecyl) was investigated. Long chain methyl alkanesulphonates (dodecyl and hexadecyl) are strong sensitizers, while the shorter alkyl chain, methyl hexanesulphonate, is a weak sensitizer. In vitro lymphocyte blastogenesis was measured by the 3H-thymidine uptake and exhibited a stimulation index between 2 and 8. The results nicely parallelled the in vivo sensitization measurements, except for methyl dodecanesulphonate. This could be explained by the cytotoxic activity of this compound, the most toxic of the three methyl alkanesulphonates tested. Thus, murine sensitization to methyl alkanesulphonates provides a good model system for preliminary investigations of delayed type hypersensitivity mechanisms.
Asunto(s)
Alcanosulfonatos/farmacología , Dermatitis por Contacto/patología , Hipersensibilidad a las Drogas/patología , Alcanosulfonatos/efectos adversos , Animales , Modelos Animales de Enfermedad , Epidermis/efectos de los fármacos , Epidermis/metabolismo , Epidermis/patología , Femenino , Activación de Linfocitos/efectos de los fármacos , Ratones , Ratones Endogámicos BALB C , Timidina/metabolismo , TritioRESUMEN
Nested case-control studies of non-Hodgkin's lymphoma (52 cases), multiple myeloma (20 cases), nonlymphocytic leukemia (39 cases), and lymphocytic leukemia (18 cases) were conducted within a cohort of employed men from two chemical manufacturing facilities and a research and development center. Exposure odds ratios were examined in relation to 111 work areas, 21 specific chemicals, and 52 chemical activity groups. Associations were observed for a maintenance and construction subgroup (non-Hodgkin's lymphoma) and a chlorohydrin production unit (nonlymphocytic leukemia). The odds ratio for the association of "foremen and others" with non-Hodgkin's lymphoma was 3.2 (CI95 = 1.47-7.2) based on 11 cases. A duration-response trend was observed for the chlorohydrin unit with three of four cases assigned 5+ years to that unit. An association between non-Hodgkin's lymphoma and assignment to strong acid alcohol production units (OR = 8.3; CI95 = 2.3-30.7) was not supported by a duration-response trend. Two highly correlated chemical groups, antioxidants (five cases) and nitriles (four cases), were over-represented among multiple myeloma cases. A duration effect was observed. However, examination of work histories did not reveal common jobs or departments among these cases.