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1.
Cochrane Database Syst Rev ; 1: CD012501, 2020 01 25.
Artigo em Inglês | MEDLINE | ID: mdl-31981471

RESUMO

BACKGROUND: Cerivastatin was the most potent statin until it was withdrawn from the market due to a number of fatalities due to rhabdomyolysis, however, the dose-related magnitude of effect of cerivastatin on blood lipids is not known. OBJECTIVES: Primary objective To quantify the effects of various doses of cerivastatin on the surrogate markers: LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides in children and adults with and without cardiovascular disease. The aim of this review is to examine the pharmacology of cerivastatin by characterizing the dose-related effect and variability of the effect of cerivastatin on surrogate markers. Secondary objectives To quantify the effect of various doses of cerivastatin compared to placebo on withdrawals due to adverse effects. To compare the relative potency of cerivastatin with respect to fluvastatin, atorvastatin and rosuvastatin for LDL cholesterol, total cholesterol, HDL cholesterol and triglycerides. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for RCTs up to March 2019: CENTRAL (2019, Issue 3), Ovid MEDLINE, Ovid Embase, the WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov.We also searched the European Patent Office, FDA.gov, and ProQuest Dissertations & Theses, and contacted authors of relevant papers regarding further published and unpublished work. The searches had no language restrictions. SELECTION CRITERIA: RCTs and controlled before-and-after studies evaluating the dose response of different fixed doses of cerivastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without cardiovascular disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility criteria for trials to be included and extracted data. We entered data from RCTs and controlled before-and-after studies into Review Manager 5 as continuous and generic inverse variance data respectively. We collected information on withdrawals due to adverse effects from the RCTs. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. MAIN RESULTS: Fifty trials (19 RCTs and 31 before-and-after studies) evaluated the dose-related efficacy of cerivastatin in 12,877 participants who had their LDL cholesterol measured. The participants were of any age with and without cardiovascular disease and the trials studied cerivastatin effects within a treatment period of three to 12 weeks. Cerivastatin 0.025 mg/day to 0.8 mg/day caused LDL cholesterol decreases of 11.0% to 40.8%, total cholesterol decreases of 8.0% to 28.8% and triglyceride decreases of 9.0% to 21.4%. We judged the certainty of evidence for these effects to be high. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on LDL cholesterol, total cholesterol and triglycerides. When compared to fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin at reducing LDL cholesterol; 233-fold more potent than fluvastatin, 18-fold more potent than atorvastatin and six-fold more potent than rosuvastatin at reducing total cholesterol; and 125-fold more potent than fluvastatin, 11-fold more potent than atorvastatin and 13-fold more potent than rosuvastatin at reducing triglycerides. There was no dose-related effect of cerivastatin on HDL cholesterol, but overall cerivastatin increased HDL cholesterol by 5%. There was a high risk of bias for the outcome withdrawals due to adverse effects, but a low risk of bias for the lipid measurements. Withdrawals due to adverse effects were not different between cerivastatin and placebo in 11 of 19 of these short-term trials (risk ratio 1.09, 95% confidence interval 0.68 to 1.74). AUTHORS' CONCLUSIONS: The LDL cholesterol, total cholesterol, and triglyceride lowering effect of cerivastatin was linearly dependent on dose. Cerivastatin log dose-response data were linear over the commonly prescribed dose range. Based on an informal comparison with fluvastatin, atorvastatin and rosuvastatin, cerivastatin was about 250-fold more potent than fluvastatin, 20-fold more potent than atorvastatin and 5.5-fold more potent than rosuvastatin in reducing LDL cholesterol, and 233-fold greater potency than fluvastatin, 18-fold greater potency than atorvastatin and six-fold greater potency than rosuvastatin at reducing total cholesterol. This review did not provide a good estimate of the incidence of harms associated with cerivastatin because of the short duration of the trials and the lack of reporting of adverse effects in 42% of the RCTs.

2.
Cochrane Database Syst Rev ; 3: CD012282, 2018 03 06.
Artigo em Inglês | MEDLINE | ID: mdl-29508377

RESUMO

BACKGROUND: Fluvastatin is thought to be the least potent statin on the market, however, the dose-related magnitude of effect of fluvastatin on blood lipids is not known. OBJECTIVES: Primary objectiveTo quantify the effects of various doses of fluvastatin on blood total cholesterol, low-density lipoprotein (LDL cholesterol), high-density lipoprotein (HDL cholesterol), and triglycerides in participants with and without evidence of cardiovascular disease.Secondary objectivesTo quantify the variability of the effect of various doses of fluvastatin.To quantify withdrawals due to adverse effects (WDAEs) in randomised placebo-controlled trials. SEARCH METHODS: The Cochrane Hypertension Information Specialist searched the following databases for randomised controlled trials up to February 2017: the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 1), MEDLINE (1946 to February Week 2 2017), MEDLINE In-Process, MEDLINE Epub Ahead of Print, Embase (1974 to February Week 2 2017), the World Health Organization International Clinical Trials Registry Platform, CDSR, DARE, Epistemonikos and ClinicalTrials.gov. We also contacted authors of relevant papers regarding further published and unpublished work. No language restrictions were applied. SELECTION CRITERIA: Randomised placebo-controlled and uncontrolled before and after trials evaluating the dose response of different fixed doses of fluvastatin on blood lipids over a duration of three to 12 weeks in participants of any age with and without evidence of cardiovascular disease. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility criteria for studies to be included, and extracted data. We entered data from placebo-controlled and uncontrolled before and after trials into Review Manager 5 as continuous and generic inverse variance data, respectively. WDAEs information was collected from the placebo-controlled trials. We assessed all trials using the 'Risk of bias' tool under the categories of sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, and other potential biases. MAIN RESULTS: One-hundred and forty-five trials (36 placebo controlled and 109 before and after) evaluated the dose-related efficacy of fluvastatin in 18,846 participants. The participants were of any age with and without evidence of cardiovascular disease, and fluvastatin effects were studied within a treatment period of three to 12 weeks. Log dose-response data over doses of 2.5 mg to 80 mg revealed strong linear dose-related effects on blood total cholesterol and LDL cholesterol and a weak linear dose-related effect on blood triglycerides. There was no dose-related effect of fluvastatin on blood HDL cholesterol. Fluvastatin 10 mg/day to 80 mg/day reduced LDL cholesterol by 15% to 33%, total cholesterol by 11% to 25% and triglycerides by 3% to 17.5%. For every two-fold dose increase there was a 6.0% (95% CI 5.4 to 6.6) decrease in blood LDL cholesterol, a 4.2% (95% CI 3.7 to 4.8) decrease in blood total cholesterol and a 4.2% (95% CI 2.0 to 6.3) decrease in blood triglycerides. The quality of evidence for these effects was judged to be high. When compared to atorvastatin and rosuvastatin, fluvastatin was about 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin at reducing LDL cholesterol. Very low quality of evidence showed no difference in WDAEs between fluvastatin and placebo in 16 of 36 of these short-term trials (risk ratio 1.52 (95% CI 0.94 to 2.45). AUTHORS' CONCLUSIONS: Fluvastatin lowers blood total cholesterol, LDL cholesterol and triglyceride in a dose-dependent linear fashion. Based on the effect on LDL cholesterol, fluvastatin is 12-fold less potent than atorvastatin and 46-fold less potent than rosuvastatin. This review did not provide a good estimate of the incidence of harms associated with fluvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 56% of the placebo-controlled trials.


Assuntos
Colesterol/sangue , Ácidos Graxos Monoinsaturados/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Indóis/administração & dosagem , LDL-Colesterol/sangue , Estudos Controlados Antes e Depois , Relação Dose-Resposta a Droga , Fluvastatina , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/sangue
3.
Cochrane Database Syst Rev ; (3): CD008226, 2015 Mar 12.
Artigo em Inglês | MEDLINE | ID: mdl-25760954

RESUMO

BACKGROUND: This represents the first update of this review, which was published in 2012. Atorvastatin is one of the most widely prescribed drugs and the most widely prescribed statin in the world. It is therefore important to know the dose-related magnitude of effect of atorvastatin on blood lipids. OBJECTIVES: Primary objective To quantify the effects of various doses of atorvastatin on serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol and triglycerides in individuals with and without evidence of cardiovascular disease. The primary focus of this review was determination of the mean per cent change from baseline of LDL-cholesterol. Secondary objectives • To quantify the variability of effects of various doses of atorvastatin.• To quantify withdrawals due to adverse effects (WDAEs) in placebo-controlled randomised controlled trials (RCTs). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 11, 2013), MEDLINE (1966 to December Week 2 2013), EMBASE (1980 to December Week 2 2013), Web of Science (1899 to December Week 2 2013) and BIOSIS Previews (1969 to December Week 2 2013). We applied no language restrictions. SELECTION CRITERIA: Randomised controlled and uncontrolled before-and-after trials evaluating the dose response of different fixed doses of atorvastatin on blood lipids over a duration of three to 12 weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility criteria for studies to be included and extracted data. We collected information on withdrawals due to adverse effects from placebo-controlled trials. MAIN RESULTS: In this update, we found an additional 42 trials and added them to the original 254 studies. The update consists of 296 trials that evaluated dose-related efficacy of atorvastatin in 38,817 participants. Included are 242 before-and-after trials and 54 placebo-controlled RCTs. Log dose-response data from both trial designs revealed linear dose-related effects on blood total cholesterol, LDL-cholesterol, HDL-cholesterol and triglycerides. The Summary of findings table 1 documents the effect of atorvastatin on LDL-cholesterol over the dose range of 10 to 80 mg/d, which is the range for which this systematic review acquired the greatest quantity of data. Over this range, blood LDL-cholesterol is decreased by 37.1% to 51.7% (Summary of findings table 1). The slope of dose-related effects on cholesterol and LDL-cholesterol was similar for atorvastatin and rosuvastatin, but rosuvastatin is about three-fold more potent. Subgroup analyses suggested that the atorvastatin effect was greater in females than in males and was greater in non-familial than in familial hypercholesterolaemia. Risk of bias for the outcome of withdrawals due to adverse effects (WDAEs) was high, but the mostly unclear risk of bias was judged unlikely to affect lipid measurements. Withdrawals due to adverse effects were not statistically significantly different between atorvastatin and placebo groups in these short-term trials (risk ratio 0.98, 95% confidence interval 0.68 to 1.40). AUTHORS' CONCLUSIONS: This update resulted in no change to the main conclusions of the review but significantly increases the strength of the evidence. Studies show that atorvastatin decreases blood total cholesterol and LDL-cholesterol in a linear dose-related manner over the commonly prescribed dose range. New findings include that atorvastatin is more than three-fold less potent than rosuvastatin, and that the cholesterol-lowering effects of atorvastatin are greater in females than in males and greater in non-familial than in familial hypercholesterolaemia. This review update does not provide a good estimate of the incidence of harms associated with atorvastatin because included trials were of short duration and adverse effects were not reported in 37% of placebo-controlled trials.


Assuntos
Colesterol/sangue , Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Pirróis/administração & dosagem , Atorvastatina , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Estudos Controlados Antes e Depois , Relação Dose-Resposta a Droga , Feminino , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Lipídeos/sangue , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Fatores Sexuais , Triglicerídeos/sangue
4.
Cochrane Database Syst Rev ; (11): CD010254, 2014 Nov 21.
Artigo em Inglês | MEDLINE | ID: mdl-25415541

RESUMO

BACKGROUND: Rosuvastatin is one of the most potent statins and is currently widely prescribed. It is therefore important to know the dose-related magnitude of effect of rosuvastatin on blood lipids. OBJECTIVES: Primary objective To quantify the effects of various doses of rosuvastatin on serum total cholesterol, low-density lipoprotein (LDL)-cholesterol, high-density lipoprotein (HDL)-cholesterol, non-HDL-cholesterol and triglycerides in participants with and without evidence of cardiovascular disease. Secondary objectives To quantify the variability of the effect of various doses of rosuvastatin.To quantify withdrawals due to adverse effects (WDAEs) in the randomized placebo-controlled trials. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) Issue 10 of 12, 2014 in The Cochrane Library, MEDLINE (1946 to October week 5 2014), EMBASE (1980 to 2014 week 44), Web of Science Core Collection (1970 to 5 November 2014) and BIOSIS Citation Index (1969 to 31 October 2014). No language restrictions were applied. SELECTION CRITERIA: Randomized controlled and uncontrolled before-and-after trials evaluating the dose response of different fixed doses of rosuvastatin on blood lipids over a duration of three to 12 weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility criteria for studies to be included and extracted data. WDAEs information was collected from the placebo-controlled trials. MAIN RESULTS: One-hundred and eight trials (18 placebo-controlled and 90 before-and-after) evaluated the dose-related efficacy of rosuvastatin in 19,596 participants. Rosuvastatin 10 to 40 mg/day caused LDL-cholesterol decreases of 46% to 55%, when all the trials were combined using the generic inverse variance method. The quality of evidence for these effects is high. Log dose-response data over doses of 1 to 80 mg, revealed strong linear dose-related effects on blood total cholesterol, LDL-cholesterol and non-HDL-cholesterol. When compared to atorvastatin, rosuvastatin was about three-fold more potent at reducing LDL-cholesterol. There was no dose-related effect of rosuvastatin on blood HDL-cholesterol, but overall, rosuvastatin increased HDL by 7%. There is a high risk of bias for the trials in this review, which would affect WDAEs, but unlikely to affect the lipid measurements. WDAEs were not statistically different between rosuvastatin and placebo in 10 of 18 of these short-term trials (risk ratio 0.84; 95% confidence interval 0.48 to 1.47). AUTHORS' CONCLUSIONS: The total blood total cholesterol, LDL-cholesterol and non-HDL-cholesterol-lowering effect of rosuvastatin was linearly dependent on dose. Rosuvastatin log dose-response data were linear over the commonly prescribed dose range. Based on an informal comparison with atorvastatin, this represents a three-fold greater potency. This review did not provide a good estimate of the incidence of harms associated with rosuvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 44% of the placebo-controlled trials.


Assuntos
Fluorbenzenos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Hiperlipidemias/tratamento farmacológico , Lipídeos/sangue , Pirimidinas/administração & dosagem , Sulfonamidas/administração & dosagem , Doenças Cardiovasculares/sangue , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , Hiperlipidemias/sangue , Ensaios Clínicos Controlados Aleatórios como Assunto , Rosuvastatina Cálcica , Triglicerídeos/sangue
5.
J Med Chem ; 57(5): 2013-32, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24521299

RESUMO

The biphenyl derivatives 2 and 3 are prototypes of a novel class of NS5A replication complex inhibitors that demonstrate high inhibitory potency toward a panel of clinically relevant HCV strains encompassing genotypes 1-6. However, these compounds exhibit poor systemic exposure in rat pharmacokinetic studies after oral dosing. The structure-activity relationship investigations that improved the exposure properties of the parent bis-phenylimidazole chemotype, culminating in the identification of the highly potent NS5A replication complex inhibitor daclatasvir (33) are described. An element critical to success was the realization that the arylglycine cap of 2 could be replaced with an alkylglycine derivative and still maintain the high inhibitory potency of the series if accompanied with a stereoinversion, a finding that enabled a rapid optimization of exposure properties. Compound 33 had EC50 values of 50 and 9 pM toward genotype-1a and -1b replicons, respectively, and oral bioavailabilities of 38-108% in preclinical species. Compound 33 provided clinical proof-of-concept for the NS5A replication complex inhibitor class, and regulatory approval to market it with the NS3/4A protease inhibitor asunaprevir for the treatment of HCV genotype-1b infection has recently been sought in Japan.


Assuntos
Antivirais/farmacologia , Inibidores Enzimáticos/farmacologia , Hepacivirus/efeitos dos fármacos , Imidazóis/farmacologia , Proteínas não Estruturais Virais/antagonistas & inibidores , Replicação Viral/efeitos dos fármacos , Animais , Antivirais/química , Antivirais/farmacocinética , Área Sob a Curva , Cães , Descoberta de Drogas , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Hepacivirus/enzimologia , Hepacivirus/fisiologia , Imidazóis/química , Imidazóis/farmacocinética , Espectroscopia de Ressonância Magnética , Ratos , Espectrometria de Massas por Ionização por Electrospray , Relação Estrutura-Atividade
6.
J Med Chem ; 57(5): 1730-52, 2014 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-24564672

RESUMO

The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor of the NS3/4A enzyme is currently in phase III clinical trials for the treatment of hepatitis C virus infection. The discovery of 24 was enabled by employing an isolated rabbit heart model to screen for the cardiovascular (CV) liabilities (changes to HR and SNRT) that were responsible for the discontinuation of an earlier lead from this chemical series, BMS-605339 (1), from clinical trials. The structure-activity relationships (SARs) developed with respect to CV effects established that small structural changes to the P2* subsite of the molecule had a significant impact on the CV profile of a given compound. The antiviral activity, preclincial PK profile, and toxicology studies in rat and dog supported clinical development of BMS-650032 (24).


Assuntos
Antivirais/uso terapêutico , Hepatite C/tratamento farmacológico , Isoquinolinas/uso terapêutico , Inibidores de Proteases/uso terapêutico , Sulfonamidas/uso terapêutico , Proteínas não Estruturais Virais/antagonistas & inibidores , Animais , Antivirais/sangue , Antivirais/química , Cães , Humanos , Isoquinolinas/sangue , Isoquinolinas/química , Modelos Moleculares , Inibidores de Proteases/sangue , Inibidores de Proteases/química , Coelhos , Ratos , Sulfonamidas/sangue , Sulfonamidas/química
7.
Cochrane Database Syst Rev ; 12: CD008226, 2012 Dec 12.
Artigo em Inglês | MEDLINE | ID: mdl-23235655

RESUMO

BACKGROUND: Atorvastatin is one of the most widely prescribed drugs and the most widely prescribed statin in the world. It is therefore important to know the dose-related magnitude of effect of atorvastatin on blood lipids. OBJECTIVES: To quantify the dose-related effects of atorvastatin on blood lipids and withdrawals due to adverse effects (WDAE). SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) on The Cochrane Library Issue 4, 2011, MEDLINE (1966 to November 2011), EMBASE (1980 to November 2011), ISI Web of Science (1899 to November 2011) and BIOSIS Previews (1969 to November 2011). No language restrictions were applied. SELECTION CRITERIA: Randomised controlled and uncontrolled before-and-after trials evaluating the dose response of different fixed doses of atorvastatin on blood lipids over a duration of 3 to 12 weeks. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. WDAE information was collected from the placebo-controlled trials. MAIN RESULTS: Two hundred fifty-four trials evaluated the dose-related efficacy of atorvastatin in 33,505 participants. Log dose-response data revealed linear dose-related effects on blood total cholesterol, low-density lipoprotein (LDL)-cholesterol and triglycerides. Combining all the trials using the generic inverse variance fixed-effect model for doses of 10 to 80 mg/day resulted in decreases of 36% to 53% for LDL-cholesterol. There was no significant dose-related effects of atorvastatin on blood high-density lipoprotein (HDL)-cholesterol. WDAE were not statistically different between atorvastatin and placebo for these short-term trials (risk ratio 0.99; 95% confidence interval 0.68 to 1.45). AUTHORS' CONCLUSIONS: Blood total cholesterol, LDL-cholesterol and triglyceride lowering effect of atorvastatin was dependent on dose. Log dose-response data was linear over the commonly prescribed dose range. Manufacturer-recommended atorvastatin doses of 10 to 80 mg/day resulted in 36% to 53% decreases of LDL-cholesterol. The review did not provide a good estimate of the incidence of harms associated with atorvastatin because of the short duration of the trials and the lack of reporting of adverse effects in 37% of the placebo-controlled trials.


Assuntos
Ácidos Heptanoicos/administração & dosagem , Inibidores de Hidroximetilglutaril-CoA Redutases/administração & dosagem , Lipídeos/sangue , Pirróis/administração & dosagem , Atorvastatina , Colesterol/sangue , HDL-Colesterol/sangue , LDL-Colesterol/sangue , Relação Dose-Resposta a Droga , Humanos , Hiperlipidemias/sangue , Hiperlipidemias/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Triglicerídeos/sangue
8.
Chem Res Toxicol ; 23(4): 749-55, 2010 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-20356072

RESUMO

Drug-induced phospholipidosis (PLD) is an adaptive histologic alteration that is seen with various marketed drugs and often encountered during drug development. Various in silico and in vitro cell-based methods have been developed to predict the PLD-inducing potential of compounds. These methods rely on the inherent physicochemical properties of the molecule and, as such, tend to overpredict compounds as PLD inducers. Recognizing that the distribution of compounds into tissues or tissue accumulation is likely a key factor in PLD induction, in addition to key physicochemical properties, we developed a model to predict PLD in vivo using the measures of basicity (pK(a)), lipophilicity (ClogP), and volume of distribution (V(d)). Using sets of PLD inducers and noninducers, we demonstrate improved concordance with this method. Furthermore, we propose a screening paradigm that includes a combination of various methods to predict the in vivo PLD-inducing potential of compounds, which may be especially useful in lead identification and optimization processes in drug discovery.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Lipidoses/induzido quimicamente , Algoritmos , Animais , Humanos , Lipidoses/fisiopatologia , Modelos Moleculares , Modelos Estatísticos , Fosfolipídeos/metabolismo , Ratos
9.
Toxicol In Vitro ; 23(6): 1170-8, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19523510

RESUMO

Proximal tubules of the kidneys are one of the most common targets of nephrotoxic drugs and chemicals. Screens to predict nephrotoxic potential of compounds with insights to mechanisms of toxicity facilitate lead optimization, guide structure-activity relationships, minimize risks of clinical nephrotoxicity and therefore are valuable in the process of drug discovery. We developed and characterized an in vitro assay multiplexed to measure several endpoints of cytotoxicity using HK-2 cells. Assays for lactate dehydrogenase, cellular caspase 3/7 activation, resazurin dye reduction and Hoechst 33342 DNA staining were multiplexed to maximize the ability to detect cell injury. Assays were performed after 5- or 24-h incubations to further enhance the sensitivity of detection of toxicity. Individual assays were optimized for cell density, assay linearity and assay performance under multiplexed conditions. Inducers of apoptosis (staurosporine) and necrosis (perhexiline) were used to validate the mechanistic aspects of cell death. Nephrotoxic compounds (5-fluorouracil, gentamicin, cisplatin, acetaminophen, para-aminophenol, potassium dichromate, ibuprofen, doxorubicin, cyclosporine, citrinin, puromycin) were used to determine the potential of this method to detect proximal tubule toxicity of compounds. Overall, this cost-effective multiplexed platform is more sensitive than a single endpoint assay, provides mechanistic cues of toxicity and is amenable for higher throughput screening.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Túbulos Renais Proximais/efeitos dos fármacos , Testes de Toxicidade/métodos , Apoptose/efeitos dos fármacos , Células Cultivadas , Análise Custo-Benefício , Humanos , Túbulos Renais Proximais/citologia , Túbulos Renais Proximais/metabolismo , Necrose/induzido quimicamente , Perexilina/toxicidade , Estaurosporina/toxicidade , Fatores de Tempo , Testes de Toxicidade/economia
10.
Toxicol Sci ; 103(1): 28-34, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18281259

RESUMO

The Critical Path Institute recently established the Predictive Safety Testing Consortium, a collaboration between several companies and the U.S. Food and Drug Administration, aimed at evaluating and qualifying biomarkers for a variety of toxicological endpoints. The Carcinogenicity Working Group of the Predictive Safety Testing Consortium has concentrated on sharing data to test the predictivity of two published hepatic gene expression signatures, including the signature by Fielden et al. (2007, Toxicol. Sci. 99, 90-100) for predicting nongenotoxic hepatocarcinogens, and the signature by Nie et al. (2006, Mol. Carcinog. 45, 914-933) for predicting nongenotoxic carcinogens. Although not a rigorous prospective validation exercise, the consortium approach created an opportunity to perform a meta-analysis to evaluate microarray data from short-term rat studies on over 150 compounds. Despite significant differences in study designs and microarray platforms between laboratories, the signatures proved to be relatively robust and more accurate than expected by chance. The accuracy of the Fielden et al. signature was between 63 and 69%, whereas the accuracy of the Nie et al. signature was between 55 and 64%. As expected, the predictivity was reduced relative to internal validation estimates reported under identical test conditions. Although the signatures were not deemed suitable for use in regulatory decision making, they were deemed worthwhile in the early assessment of drugs to aid decision making in drug development. These results have prompted additional efforts to rederive and evaluate a QPCR-based signature using these samples. When combined with a standardized test procedure and prospective interlaboratory validation, the accuracy and potential utility in preclinical applications can be ascertained.


Assuntos
Testes de Carcinogenicidade/métodos , Genômica , Animais , Perfilação da Expressão Gênica , Masculino , Ratos , Ratos Sprague-Dawley
11.
J Pharmacol Toxicol Methods ; 55(3): 279-88, 2007.
Artigo em Inglês | MEDLINE | ID: mdl-17222568

RESUMO

INTRODUCTION: The properties and potential liabilities of drug candidate are investigated in detailed ADME assays and in toxicity studies, where findings are placed in context of exposure to dosed drug and metabolites. The complex nature of biological samples may necessitate work-up procedures prior to high performance liquid chromatography-mass spectrometric (HPLC-MS) analysis of endogenous or xenobiotic compounds. This concept can readily be applied to biological fluids such as blood or urine, but in localized samples such as organs and tissues potentially important spatial, thus anatomical, information is lost during sample preparation as the result of homogenization and extraction procedures. However, the localization of test article or spatial identification of metabolites may be critical to the understanding of the mechanism of target-organ toxicity and its relevance to clinical safety. METHODS: Tissue imaging mass spectrometry (IMS) by matrix-assisted laser desorption ionization (MALDI) and ion trap mass spectrometry (MS) with higher order mass spectrometric scanning functions was utilized for localization of dosed drug or metabolite in tissue. Laser capture microscopy (LCM) was used to obtain related samples from tissue for analyses by standard MALDI-MS and HPLC-MS. RESULTS: In a toxicology study, rats were administered with a high dosage of a prodrug for 2 weeks. Birefringent microcrystalline material (10-25 microm) was observed in histopathologic formalin-fixed tissue samples. Direct analysis by IMS provided the identity of material in the microcrystals as circulating active drug while maintaining spatial orientation. Complementary data from visual cross-polarized light microscopy as well as standard MALDI-MS and HPLC-MS experiments on LCM samples validated the qualitative results obtained by IMS. Furthermore, the HPLC-MS analysis on the LCM samples afforded a semi-quantitative assessment of the crystalline material in the tissue samples. DISCUSSION: IMS by MALDI ion trap MS proved sensitive, specific, and highly amenable to the image analysis of traditional small molecule drug candidates directly in tissue.


Assuntos
Preparações Farmacêuticas/análise , Pró-Fármacos/análise , Espectrometria de Massas por Ionização e Dessorção a Laser Assistida por Matriz/métodos , Toxicologia/métodos , Animais , Birrefringência , Cromatografia Líquida de Alta Pressão , Cristalização , Feminino , Masculino , Microscopia Confocal , Microscopia de Polarização , Preparações Farmacêuticas/metabolismo , Pró-Fármacos/metabolismo , Ratos , Ratos Sprague-Dawley , Sensibilidade e Especificidade , Distribuição Tecidual
12.
J Forensic Sci ; 48(2): 404-8, 2003 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-12665001

RESUMO

Malaria is the world's most important parasitic disease, accounting for an estimated 300 to 500 million new cases and between 1.5 and 2.7 deaths annually. The majority of these deaths occur in sub-Saharan Africa where malaria is endemic and are the result of infection with Plasmodium falciparum. The number of deaths in the United States due to malaria is comparably much lower and involves so-called "imported" cases in which U.S. travelers acquire the infection upon travel to endemic areas and subsequently return to the United States or in which infected foreign citizens travel to the United States. There were a total of 118 deaths due to malaria in the United States between 1979 and 1998 with an average of 5.9 deaths per year. Specific epidemiological data provided by the CDC regarding the 40 deaths that occurred between 1992 and 1998 yielded the following results. Deaths occurred in patients ranging from 9 months to 89 years of age (median, 53 years). Thirty-eight (95%) of these were due to P. falciparum and two (5%) due to P. vivax. Anti-malarial chemoprophylaxis was taken in 40% of cases, not taken in 45% of cases, and unknown in 15% of cases. Twenty-four (60%) of the cases involved U.S. travelers to endemic areas, of whom 59% traveled to Africa, 25% to South America, 8% to India, 4% to Haiti, and 4% to unspecified areas. The remaining cases included eleven foreign travelers to the U.S. (27.5%), three induced cases (7.5%), and two undetermined cases (5%). Thirty-nine (98%) of the cases were diagnosed antemortem and only one case was known to have come to the attention of the medical examiner/coroner. An illustrative case report demonstrates many of the features associated with fatal malaria infections in the United States. The case involves a U.S. student who was studying in Africa and who, by report, had not taken antimalarial chemoprophylaxis. Despite seeking medical attention, the patient was not diagnosed with P. falciparum infection and cerebral malaria until the time of medico-legal autopsy, where the classic gross and microscopic features of cerebral malaria were identified. This case represents one of the few cases of P. falciparum infection in the United States not diagnosed antemortem. Given the worldwide prevalence of the disease, increasing international travel, and rapidly developing drug resistance, malaria will continue to be an important disease and should be considered in cases of sudden, unexplained deaths. By reviewing the major epidemiological features of malaria-related deaths in the United States and by presenting the major gross and microscopic features of cerebral malaria, an attempt is made at raising the awareness of the forensic community to the potential of malaria-related deaths.


Assuntos
Malária Cerebral/mortalidade , Malária Falciparum/mortalidade , Adulto , Encéfalo/parasitologia , Encéfalo/patologia , Eritrócitos/parasitologia , Eritrócitos/patologia , Feminino , Humanos , Malária Cerebral/patologia , Estados Unidos/epidemiologia
13.
J Pharm Biomed Anal ; 27(1-2): 327-34, 2002 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-11682240

RESUMO

In early safety assessment studies with the experimental anti-neoplastic drug XP315, a toxic reaction was observed in dogs immediately after intravenous (iv) infusion. The reaction was characterized by severe erythema around the ears, eyes, face and body; ocular hyperemia; head shaking; swelling around the eyes, face, paws, head, neck and legs; scratching; and reddened gums, which lasted several hours after dosing. By fractionating the drug substance using preparative HPLC and then infusing the residues into dogs by iv, this reaction was traced to an impurity in the drug substance. Following the preparative isolation of the toxic impurity, characterization was performed using a combination of NMR and mass spectral methods. The proposed impurity was found to be structurally related and nearly twice the molecular weight of XP315, resulting from a dimerization by ring fusion of two 3-aminonaphthalene fragments during the synthetic process. This paper details the steps taken to isolate the toxic impurity and characterize its structure using off-line methods.


Assuntos
Antineoplásicos/análise , Etilaminas/análise , Imidas/análise , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/toxicidade , Cromatografia Líquida de Alta Pressão/métodos , Cães , Avaliação Pré-Clínica de Medicamentos , Etilaminas/toxicidade , Compostos Heterocíclicos/análise , Compostos Heterocíclicos/toxicidade , Imidas/toxicidade , Injeções Intravenosas , Espectroscopia de Ressonância Magnética , Espectrometria de Massas , Estrutura Molecular , Peso Molecular , Controle de Qualidade
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