This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for... more
This paper provides compound-specific toxicology limits for 20 widely used synthetic reagents and common by-products that are potential impurities in drug substances. In addition, a 15 μg/day class-specific limit was developed for monofunctional alkyl bromides, aligning this with the class-specific limit previously defined for monofunctional alkyl chlorides. Both the compound- and class-specific toxicology limits assume a lifetime chronic exposure for the general population (including sensitive subpopulations) by all routes of exposure for pharmaceuticals. Inhalation-specific toxicology limits were also derived for acrolein, formaldehyde, and methyl bromide because of their localized toxicity via that route. Mode of action was an important consideration for a compound-specific toxicology limit. Acceptable intake (AI) calculations for certain mutagenic carcinogens assumed a linear dose-response for tumor induction, and permissible daily exposure (PDE) determination assumed a non-line...
A genotoxic carcinogen, N‐nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N‐nitrosamines, such as N‐nitrosodiethylamine (NDEA), were later detected in other sartan products.... more
A genotoxic carcinogen, N‐nitrosodimethylamine (NDMA), was detected as a synthesis impurity in some valsartan drugs in 2018, and other N‐nitrosamines, such as N‐nitrosodiethylamine (NDEA), were later detected in other sartan products. N‐nitrosamines are pro‐mutagens that can react with DNA following metabolism to produce DNA adducts, such as O6‐alkyl‐guanine. The adducts can result in DNA replication miscoding errors leading to GC>AT mutations and increased risk of genomic instability and carcinogenesis. Both NDMA and NDEA are known rodent carcinogens in male and female rats. The DNA repair enzyme, methylguanine DNA‐methyltransferase can restore DNA integrity via the removal of alkyl groups from guanine in an error‐free fashion and this can result in nonlinear dose responses and a point of departure or “practical threshold” for mutation at low doses of exposure. Following International recommendations (ICHM7; ICHQ3C and ICHQ3D), we calculated permissible daily exposures (PDE) for...
La utilizacion de medicamentos bajo condiciones de uso no aprobadas en el registro de comercializacion o uso off-label, es una practica clinica comun y poco regulada normativamente, cuya magnitud, efectos y resultados no han sido... more
La utilizacion de medicamentos bajo condiciones de uso no aprobadas en el registro de comercializacion o uso off-label, es una practica clinica comun y poco regulada normativamente, cuya magnitud, efectos y resultados no han sido suficientemente estudiados en poblacion adulta. La presente investigacion desarrollo una revision sistematica de la literatura de estudios observacionales, que estimaron la frecuencia y/o establecieron los factores asociados al uso de medicamentos en condiciones no autorizadas en poblacion adulta. Para esto, se recurrio a las bases de datos PubMed, Embase, LILACS, Science Direct, CINAHL, ProQuest y Cochrane, en busca de articulos publicados en relacion al tema de investigacion. Aquellos articulos que cumplieron con los criterios de inclusion fueron sometidos a evaluacion de calidad metodologica.
