RESUMO
OBJECTIVES: Identify the photosensitive drugs included in the hospital pharmacotherapeutic guide and search for stability data on the storage, reconstitution, and dilution of these compounds. METHODS: The data were obtained by referencing technical specifications, information provided by drug laboratories, and in some cases, we performed a more extensive bibliographic search (tertiary sources and conference lectures) for each particular medication. We also performed a data search on the PubMed information database (from 2004 to 2009). The drugs were placed in alphabetical order by brand since the stability of each drug when exposed to light does not depend exclusively on the primary active ingredient. Eight columns describe the principal characteristics of the drugs: brand name, active ingredient, laboratory, storage, reconstitution and dilution conditions, observations, and references. RESULTS: The listing was comprised of 139 photosensitive medicines, of the 1,954 included in the pharmacotherapeutical guide (table 1). CONCLUSIONS: The lack of studies published on the stability of photosensitive medications provided the need for an internal review at our hospital. It is important for drug-producing laboratories to perform photo-sensitivity tests on their products, with the results presented in the technical specifications in order to provide more accessible and reliable information. We believe that this should be required by law.
Assuntos
Estabilidade de Medicamentos , Luz , Preparações Farmacêuticas/efeitos da radiação , Embalagem de Medicamentos/normas , Armazenamento de Medicamentos , Formulários Farmacêuticos como Assunto , FotoquímicaRESUMO
The mixed-function oxidase which activates the carcinogen dimethylnitrosamine (DMN) was determined in the rat liver as a function of animal age. DMN-demethylase activity increased considerably at first to reach a maximum on day 29, and then substantially decreased to day 59; thereafter, enzyme activity remained essentially stable up to at least day 110. Pretreatment with 3-methylcholanthrene, which caused a pronounced decrease in this enzyme activity, did not affect the general shape of the age-dependence curve. The results suggest that rats between weaning and sexual maturity are more susceptible to the carcinogenic effects of pulse doses of DMN than are neonates or adult animals.
Assuntos
Envelhecimento , Dimetilnitrosamina/metabolismo , Fígado/enzimologia , Nitrosaminas/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Animais , Masculino , Metilcolantreno/farmacologia , Microssomos Hepáticos/enzimologia , RatosRESUMO
The effect of administration of beta-naphthoflavone (beta-NF) or pregnenolone-16alpha-carbonitrile (PCN) on the hepatocarcinogenicity of dimethylnitrosamine (DMN) in male SD rats was explored. Both beta-NF and PCN are potent repressors of the low Michaelis constant enzymatic form of DMN-demethylase, a mixed-function oxidase that catalyzes DMN demethylation. DMN-induced hepatocarcinogenesis was inhibited by PCN and was enhanced by beta-NF. Seven liver tumors were found in 45 rats fed DMN plus PCN compared to 14 liver tumors in 43 rats fed DMN alone; 32 liver tumors were found in 43 rats fed DMN plus beta-NF. No liver tumors were detected in rats that received only PCN, beta-NF, or the administration vehicles. Of the 53 liver tumors observed, 53% were angiosarcomas; this type of tumor was found in all 3 groups of rats that received DMN.
Assuntos
Dimetilnitrosamina , Flavonoides/farmacologia , Neoplasias Hepáticas/induzido quimicamente , Nitrosaminas , Carbonitrila de Pregnenolona/farmacologia , Animais , Biotransformação/efeitos dos fármacos , Carcinoma Hepatocelular/induzido quimicamente , Carcinoma Hepatocelular/patologia , Dimetilnitrosamina/antagonistas & inibidores , Interações Medicamentosas , Hemangiossarcoma/induzido quimicamente , Hemangiossarcoma/patologia , Neoplasias Hepáticas/patologia , Masculino , Naftalenos/farmacologia , Neoplasias Experimentais/induzido quimicamente , Nitrosaminas/antagonistas & inibidores , Oxirredutases N-Desmetilantes/antagonistas & inibidores , RatosRESUMO
A comparative study of the effects of the polychlorinated biphenyl mixture Aroclor 1254, 3-methylcholanthrene, and starvation on hepatic dimethylnitrosamine (DMN) demethylase (a repressible enzyme) and azo dye N-demethylase (an inducible enzyme) has been carried out. As previously observed with polycyclic hydrocarbons and phenobarbital, Aroclor in rats is a potent inducer of liver tissue proliferation and of azo dye N-demethylase. However, in mice, although the inducing effect on liver tissue proliferation and azo dye N-demethylase activity is maintained, there is no change in DMN demethylase activity as a result of Aroclor administration. As in rats, 3-methylcholanthrene induces the azo dye N-demethylase in mice. This hydrocarbon, which is known to substantially repress the DMN demethylase in rats, has, however, no effect on this enzyme in mice. While starvation is known to have a substantial inducing effect on DMN demethylase in rats, in mice starvation brings about a moderate induction of DMN demethylase.
Assuntos
Arocloros/farmacologia , Microssomos Hepáticos/enzimologia , Oxirredutases N-Desmetilantes/metabolismo , Bifenilos Policlorados/farmacologia , Animais , Compostos Azo , Dimetilnitrosamina , Indução Enzimática , Repressão Enzimática , Masculino , Metilcolantreno/farmacologia , Camundongos , Microssomos Hepáticos/efeitos dos fármacos , Tamanho do Órgão , InaniçãoRESUMO
The effect of in vivo administration of indole and five 3-indolyl derivatives including L-tryptophan, as well as of aminoacetonitrile and 3 of its derivatives, were studied on the carcinogen-metabolizing hepatic mixed-function oxidases dimethylnitrosamine (DMN)-demethylase I and II and aryl hydrocarbon hydroxylase (AHH). Indole, 3-indolylmethanol, 3-indolyl-acetonitrile, 3-indolylacetone and L-tryptophan induce AHH activity from 3- to 6-fold of the control level, whereas beta-3-indolylethanol has no effect; the latter compound produces a 21% decrease of the endoplasmic reticulum content in the tissue. Only L-tryptophan induces DMN-demethylase I and only L-tryptophan and 3-indolylmethanol induce DMN-demethylase II, representing a doubling of enzyme activity in all 3 instances. Aminoacetonitrile is a potent repressor of DMN-demethylase I. Substitutions on the amino group bring about strong decrease or abolishment of mixed-function oxidase repressor activity; thus, iminodiacetonitrile has only about 1/5th the repressor activity of the parent compound, whereas nitrilotriacetonitrile and dimethylaminoacetonitrile appear to be inactive. Aminoacetonitrile and its derivatives studied have no effect on DMN-demethylase II and AHH activities. The mixed-function oxidase-modifying effects of the indole compounds and of aminoacetonitrile and its derivatives illustrate the potential complexity of effects of dietary constituents on the carcinogenic responses.
Assuntos
Acetonitrilas , Aminoacetonitrila/análogos & derivados , Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Indóis/farmacologia , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Aminoacetonitrila/metabolismo , Aminoacetonitrila/farmacologia , Animais , Citocromo P-450 CYP2E1 , Dimetilnitrosamina/antagonistas & inibidores , Indóis/metabolismo , Masculino , Microssomos Hepáticos/enzimologia , RatosRESUMO
Assessment of the potential health hazard of environmental complex chemical mixtures is one of the most difficult and challenging problems in toxicology. In this article, we describe the development of an innovative computerized system for ranking and predicting potential cancer hazard of chemical mixtures. We take into consideration both the additive risk of individual carcinogens present and the projected overall interaction effect of the mixture based on analyzing and integrating the possible interaction effects of all binary pairs of individual constituents of the mixture. Using this system, it can be predicted that a number of mixtures of polycyclic aromatic hydrocarbons should have a carcinogenic risk lower than that calculated by the simple additivity model, whereas the reverse is true for a number of other mixtures. The system can be very useful in hazard ranking and priority setting in dealing with mixture problems such as cleanup of hazardous waste.
Assuntos
Substâncias Perigosas , Sistemas de Informação , Software , Interações Medicamentosas , Medição de RiscoRESUMO
Analysis by gas chromatography (GC) of the volatile compounds present in the urine from rats administered dioxane, a hepatic carcinogen to this species, revealed a major metabolite. The appearance of the metabolite was pH-dependent, undetectable at high pH; reacidification of the urine sample brought about the reappearance of the metabolite. The amount excreted was dose-dependent and time-dependent, reaching a maximum between 20 and 28 h after dioxane administration. Diethylene glycol administered to rats gave rise to the same metabolite. When isolated and purified from lyophilized urine by preparative GC, the metabolite exhibited an intense carbonyl band at 1750 cm-1 in the infrared spectrum. Nuclear magnetic resonance spectrum showed two triplets and one singlet with equal intensity at delta 3.85, 4.48 and 4.37, respectively. GC-mass spectrometric studies indicated a parent peak at m/e 102. The metabolite was identified as p-dioxane-2-one. Synthetic reference compound exhibited identical IR, NMR, and GC-mass spectra as the metabolite. The tentative pathway and the biological significance of dioxane metabolism are discussed.
Assuntos
Dioxanos/urina , Dioxinas/urina , Animais , Biotransformação , Fenômenos Químicos , Química , Etilenoglicóis/metabolismo , Masculino , Ácido Oxâmico/metabolismo , RatosRESUMO
Evidence is presented that the previously observed decrease of the Vmax of hepatic microsomal demethylation of dimethylnitrosamine (DMN), following pretreatment of rats with 3-methylcholanthrene (MC), is not due to increase in the rate of breakdown but to decrease of de novo synthesis. Determinations of Vmax at time intervals in the transition from the high steady-state level induced by a carbohydrate-devoid casein diet, down to the low steady-state level of carbohydrate-containing basal diet, yielded two consecutive slopes; descent from the basal diet level to the lower steady-state level following pretreatment with MC yielded one slope. Plotting these slopes against the initial Vmax values gave a typical exponential curve (or straight line if the logs of slopes are used) indicating that the rate of enzyme decay in the MC-treated animals is not greater than that expected from normal enzyme catabolism. A multiplicity of effector sites appears to be involved in the repressor action of different structural types; for example, repression by MC (46.6%) and by phenobarbital (23.9%) in combination are approximately additive (62.0%), rather than competitive, indicating that the two agents act at different sites. A P-450 type cytochrome is involved in the demethylation of DMN. DMN-demethylase is inhibited by carbon monoxide, but the susceptibility to CO is far greater than that observed previously with 3,4-benzopyrene hydroxylation; inhibition of DMN-demethylase as a function of CO concentration follows typical enzyme kinetics. However, while both phenobarbital and MC powerfully repress the DMN-demethylase, we have confirmed that they are strong inducers of the synthesis of P-450 and P-448, respectively, as estimated from the difference spectra.
Assuntos
Dimetilnitrosamina/metabolismo , Hemeproteínas/metabolismo , Microssomos Hepáticos/enzimologia , Nitrosaminas/metabolismo , Oxirredutases N-Desmetilantes/metabolismo , Animais , Monóxido de Carbono/farmacologia , Caseínas , Sistema Enzimático do Citocromo P-450/metabolismo , Proteínas Alimentares , Repressão Enzimática/efeitos dos fármacos , Cinética , Masculino , Metilcolantreno/farmacologia , Microssomos Hepáticos/efeitos dos fármacos , Fenobarbital/farmacologia , RatosRESUMO
In vivo administration to rats of the mixed-function oxidase modifiers 3-methylcholanthrene (MC), pregnenolone-16 alpha-carbonitrile (PCN) or beta-naphthoflavnoe (beta-f) inhibits the hepatic microsome-catalyzed in vitro binding of dimethylnitrosamine (DMN) to DNA. This parallels their effect on DMN-demethylase I, regarded to be the sole activating step in DMN carcinogenesis and fails to account for the previously observed anomaly that MC and PCN inhibit, while beta-NF enhances, the hepatocarcinogenic activity of DMN. The in vitro binding of DMN is clearly dependent on microsomes and NADPH, and is strongly enhanced by soluble cytoplasmic proteins; the presence of the latter has no effect. however, on the relative response to pretreatment by the modifiers. In mice beta-NF enhances and PCN inhibits DMN-demethylase I; beta-NF has no effect on either the cytochrome P-450 level or on the LD50, while PCN strongly increases the cytochrome P-450 level but without influencing the LD50. Neither of the two modifiers has any effect in mice on the host-mediated mutagenicity of DMN in a dose-response study, except for the highest dose of DMN (200 mg/kg) where PCN pretreatment significantly enhanced mutagenicity. To account for the anomalous observations, other potential pathways of DMN metabolism have been explored. Whole rat liver nuclei or isolated nuclear membrane fractions contain no DMN-demethylase or diethylnitrosamine-deethylase activity. In a microsomal mixed-function amine-oxidase assay system neither purified enzyme preparations nor whole microsomes catalyze NADPH oxidation in the presence of DMN as substrate. In addition, the purified enzyme does not catalyze formaldehyde production in the DMN-demethylase assay system. Benzylamine, a typical inhibitor of mitochondrial monoamine oxidase (MAO), is a potent inhibitor of DMN-demethylase activity, but microsomes are devoid of MAO activity. Furthermore, purified MAO has no DMN-demethylase activity. The differential effect of modifiers on the carcinogenicity of DMN probably involves pathways other than DMN metabolism.
Assuntos
Dimetilnitrosamina/metabolismo , Microssomos Hepáticos/enzimologia , Oxirredutases N-Desmetilantes/metabolismo , Biotransformação/efeitos dos fármacos , Núcleo Celular/metabolismo , DNA/metabolismo , Dimetilnitrosamina/toxicidade , Flavonoides/farmacologia , Mutagênicos , Oxirredutases atuantes sobre Doadores de Grupo CH-NH/metabolismo , Carbonitrila de Pregnenolona/farmacologiaRESUMO
Since the inception of Section 5 (Premanufacturing/Premarketing Notification, PMN) of the Toxic Substances Control Act (TSCA), structure-activity relationship (SAR) analysis has been effectively used by U.S. Environmental Protection Agency's (EPA) Structure Activity Team (SAT) in the assessment of potential carcinogenic hazard of new chemicals for which test data are not available. To capture, systematize and codify the Agency's predictive expertise in order to make it more widely available to assessors outside the TSCA program, a cooperative project was initiated to develop a knowledge rule-based expert system to mimic the thinking and reasoning of the SAT. In this communication, we describe the overall structure of this expert system, discuss the scientific bases and principles of SAR analysis of chemical carcinogens used in the development of SAR knowledge rules, and delineate the major factors/rules useful for assessing the carcinogenic potential of fibers, polymers, metals/metalloids and several major classes of organic chemicals. An integrative approach using available short-term predictive tests and non-cancer toxicological data to supplement SAR analysis has also been described.
Assuntos
Carcinógenos/toxicidade , Sistemas Inteligentes , Relação Estrutura-Atividade , Animais , Carcinógenos/química , Humanos , Medição de Risco , Estados Unidos , United States Environmental Protection AgencyRESUMO
The acute toxicity of p-dioxane may be enhanced up to 1000-fold by chlorination of the compound. The effect was stereoselective. Of the stereoisomers tested, tetrachloro-p-dioxane, isomer I (2r, 3t, 5t, 6c) was over 80 times more toxic than isomer II (2r, 3c, 5t, 6t). The latter compound was also a potent repressor of hepatic dimethylnitrosamine-demethylase I (DMN-d) and aryl hydrocarbon hydroxylase (AHH).
Assuntos
Hidrocarboneto de Aril Hidroxilases/antagonistas & inibidores , Dioxanos/toxicidade , Dioxinas/toxicidade , Oxirredutases N-Desmetilantes/antagonistas & inibidores , Animais , Carcinógenos Ambientais/metabolismo , Fenômenos Químicos , Química , Cloro/toxicidade , Dimetilnitrosamina/metabolismo , Indução Enzimática , Masculino , Dibenzodioxinas Policloradas/farmacologia , Ratos , Estereoisomerismo , Relação Estrutura-AtividadeRESUMO
C57Bl/6J mice, which are inducible for both hepatic and pulmonary aryl hydrocarbon hydroxylase (AHH), and DBA/2J mice, which are noninducible for hepatic AHH but moderately inducible for pulmonary AHH, received dimethylnitrosamine (DMN) i. p., or methylcholanthrene (MCA) orally, or a combination of both agents, for 10 weeks; the animals were observed for an additional 26 weeks. The dosing schedule and total dose of DMN or MCA or DMN + MCA received were identical to those used by other investigators in their syncarcinogenesis bioassay study in Swiss mice. The lung lesions induced in the present experiments were alveologenic tumors and adenomatosis. Alveologenic tumors were induced in a much larger number of DBA/2J mice than in C57Bl/6J mice (87.9% versus 14.0%). If, however, the sum of alveologenic tumors and adenomatous nodules is considered and is expressed per lung lesion bearing mouse, then these ratios are for the control, MCA, DMN and MCA + DMN groups: 2.7, 1.5, 3.5, and 5.4 in the DBA/2J mice and 1.0, 1.3, 2.7, and 3.6 in the C57Bl/6J mice, respectively. This suggests a relatively greater susceptibility of the C57Bl/6J strain if the ratios are compared to the respective control values. This greater susceptibility of the C57Bl/6J is best seen by comparing the percent increase of the ratio for the MCA + DMN groups; the net increase is 100% for DBA/2J and 260% for C57Bl/6J. In the DBA/2J strain more extrapulmonary tumors (hemangioendotheliomas, liver and kidney tumors) were induced than in the C57Bl/6J strain by DMN or MCA + DMN, but not by MCA alone.
Assuntos
Dimetilnitrosamina/administração & dosagem , Neoplasias Pulmonares/induzido quimicamente , Metilcolantreno/administração & dosagem , Adenoma/induzido quimicamente , Adenoma/patologia , Animais , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Neoplasias Experimentais/induzido quimicamente , Especificidade da EspécieRESUMO
OBJECTIVES: To analyse therapeutic regimens including bortezomib used in our centre for the treatment of multiple myeloma, to evaluate its effectiveness and safety in clinical practice in our hospital, and to assess the appropriateness of the indications described in guidelines. MATERIAL AND METHODS: Retrospective analysis of patients diagnosed with multiple myeloma in the period between January 2008 and December 2009 (24 months) that received treatment with a regimen including bortezomib. We analysed demographic variables (age, sex), disease characteristics (type of multiple myeloma, stage, and clinical cytogenetic abnormalities), concomitant drugs, response, and side effects of the regimen including bortezomib. RESULTS: We included 59 patients who were diagnosed with multiple myeloma (25 males and 34 females) with an average age of 63 years (range 30-82 years). The overall response rate for patients who received first-line regimens with bortezomib ranged between 69% (vincristine, carmustine, cyclophosphamide, melphalan and prednisone/vincristine, carmustine, doxorubicin, and dexamethasone plus bortezomib) and 82% (bortezomib, melphalan and oral prednisone). When we analysed the salvage treatment regimens: Bortezomib-Dexamethasone, Bortezomib-Cyclophosphamide-Dexamethasone and bortezomib, doxorubicin, melphalan alternating with thalidomide, cyclophosphamide, and dexamethasone achieved overall response rates of 72%, 77% and 89%, respectively. Adverse reactions to bortezomib or a treatment regimen that included it occurred in 32 (54%) patients, highlighting neurotoxicity in 19 patients (32%) and gastrointestinal toxicity in 12 (20%). CONCLUSIONS: The results of our study show the important role of bortezomib in the treatment of multiple myeloma, with response rates and side effects comparable to published data, although the conditions for using it in clinical practice are not yet recognized in the guidelines for use.