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1.
J AOAC Int ; 100(4): 1008-1015, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28720173

RESUMO

Tuberculosis is the second most deadly infectious disease, surpassed only by HIV/AIDS, and has resulted in over 1 billion deaths in the last 200 years. The World Health Organization estimates that in 2014, 9.6 million people were infected by this disease and 1.5 million had died. First-choice treatment consists of fixed-dose combination tablets containing rifampicin, isoniazid, pyrazinamide, and ethambutol hydrochloride (4-FDC). There are pharmacopeial protocols available to test 4-FDC, but they are prolonged, two-step methods. One single-step method in the literature performs the simultaneous determination by HPLC, but requires a long acquisition time. In this context, an ultra-HPLC (UHPLC) method was developed based on the HPLC method with the objective of reducing analysis time. A C18 column (1.9 µm particle size) was used with UV-diode-array detection at 238 and 282 nm. The method was found to be selective, linear, exact, precise, and robust. Samples from two batches were analyzed and the results compared with those obtained by the HPLC method, with no statistically significant differences observed (P > 0.05). This UHPLC method reduced the analysis time from 17 to 4 min, with a more than 90% reduction in sample and reagent consumption and a financial economy of almost 50-fold.


Assuntos
Antituberculosos/análise , Cromatografia Líquida de Alta Pressão , Etambutol/análise , Isoniazida/análise , Pirazinamida/análise , Rifampina/análise
2.
J AOAC Int ; 2017 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-28105975

RESUMO

Tuberculosis is the second most deadly infectiousdisease, surpassed only by HIV/AIDS, and hasresulted in over 1 billion deaths in the last200 years. The World Health Organization estimatesthat in 2014, 9.6 million people were infected bythis disease and 1.5 million had died. First-choicetreatment consists of fixed-dose combinationtablets containing rifampicin, isoniazid,pyrazinamide, and ethambutol hydrochloride(4-FDC). There are pharmacopeial protocolsavailable to test 4-FDC, but they are prolonged,two-step methods. One single-step method in theliterature performs the simultaneous determinationby HPLC, but requires a long acquisition time.In this context, an ultra-HPLC (UHPLC) methodwas developed based on the HPLC method withthe objective of reducing analysis time.A C18 column (1.9 µm particle size) was used withUV-diode-array detection at 238 and 282 nm. Themethod was found to be selective, linear, exact,precise, and robust. Samples from two batcheswere analyzed and the results compared with thoseobtained by the HPLC method, with no statisticallysignificant differences observed (<em>P</em> > 0.05). ThisUHPLC method reduced the analysis time from17 to 4 min, with a more than 90% reduction insample and reagent consumption and a financialeconomy of almost 50-fold.

3.
J Alzheimers Dis ; 55(2): 539-549, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27716659

RESUMO

The clinical response to donepezil in patients with mild and moderate dementia was investigated in relation to the drug plasma concentration and APOE and CYP2D6 polymorphisms. In a prospective naturalistic observational study, 42 patients with Alzheimer's disease (AD) and AD with cerebrovascular disease who took donepezil (10 mg) for 12 months were evaluated. Their DNA was genotyped, and the donepezil plasma concentrations were measured after 3, 6, and 12 months. Good responders scored ≥-1 on the Mini-Mental State Examination at 12 months in comparison to the baseline score. The study results indicated the good response pattern was influenced by the concentration of donepezil, but not by APOE and CYP2D6 polymorphisms.


Assuntos
Apolipoproteínas E/genética , Inibidores da Colinesterase/sangue , Inibidores da Colinesterase/uso terapêutico , Citocromo P-450 CYP2D6/genética , Demência , Indanos/sangue , Indanos/uso terapêutico , Piperidinas/sangue , Piperidinas/uso terapêutico , Polimorfismo de Nucleotídeo Único/genética , Cromatografia Líquida de Alta Pressão , Demência/sangue , Demência/tratamento farmacológico , Demência/genética , Donepezila , Feminino , Seguimentos , Humanos , Masculino , Testes de Estado Mental e Demência , Testes Neuropsicológicos , Fatores de Tempo
4.
J AOAC Int ; 98(5): 1234-9, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26525241

RESUMO

Tuberculosis treatment consists of a fixed dose combination of rifampicin (RIF), isoniazid (INH), pyrazinamide (PYZ), and ethambutol hydrochloride (EMB). The combined treatment using various drugs is necessary for patient curing, without recrudescence, and for prevention of drug-resistant mutants, which may occur during treatment. An HPLC-diode array detector (DAD) method for the simultaneous determination of RIF, INH, PYZ, and EMB in fixed dose combination tablets was developed and validated. Chromatographic experiments were performed on an Agilent 1200 HPLC system, and the separation was carried out on a Purospher STAR RP18e (250×4.6 mm id, 5 µm, Merck) analytical column. Gradient elution was carried out with a mobile phase of 20 mM monobasic sodium phosphate buffer with 0.2% triethylamine (pH 7.0) and acetonitrile at a flow rate of 1.5 mL/min. The total run time was 12 min, and the re-equilibration time was 5 min. EMB detection was performed at 210 nm, and RIF, INH, and PYZ were detected at 238 nm, using a DAD. The method proved to be specific, linear (r2>0.99), precise (RSD<2%), accurate, and robust and may be applied to the QC analysis of pharmaceutical formulations.


Assuntos
Antituberculosos/análise , Cromatografia Líquida de Alta Pressão/métodos , Etambutol/análise , Isoniazida/análise , Pirazinamida/análise , Rifampina/análise , Acetonitrilas/química , Combinação de Medicamentos , Etilaminas/química , Análise de Injeção de Fluxo , Humanos , Sensibilidade e Especificidade , Comprimidos
5.
Eur J Pharmacol ; 756: 59-66, 2015 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-25794846

RESUMO

The activities of 2-phthalimidethyl nitrate (PTD-NO) and 2-phthalimidethanol (PTD-OH) were recently demonstrated in models of pain and inflammation. We expanded our investigation by evaluating their activities in models of nociceptive and inflammatory pain and inflammatory edema, the preliminary pharmacokinetic parameter for PTD-NO and the role of opioid and cannabinoid pathways in the activity of analogs. Per os (p.o.) administration of PTD-NO or PTD-OH, 1h before intraplantar injection of formaldehyde, inhibited both phases of the nociceptive response (500 and 750 mg/kg) and paw edema (125, 250, 500 and 750 mg/kg). After p.o. administration of PTD-NO, peak plasma concentrations of PTD-NO and PTD-OH were found 0.92 and 1.13 h, respectively. The plasma concentrations of PTD-NO were higher than those of PTD-OH. Intraperitoneal (i.p.) administration of CB1 (AM251) or CB2 (AM630) cannabinoid receptor antagonists (4 or 8 mg/kg, -30 min) or opioid antagonist naltrexone (5 or 10mg/kg, -30 min) did not affect the antinociceptive activities of the analogs. AM251 (8 mg/kg, i.p., -30 min) attenuated the antiedematogenic activity of both analogs, while naltrexone (10mg/kg, i.p., -30 min) only attenuated the antiedematogenic activity of PTD-NO. The antiedematogenic activities of both analogs were not affected by the CB2 cannabinoid antagonist AM630 (4 or 8 mg/kg, i.p., -30 min). Concluding, we expanded the knowledge on the activities of PTD-NO and PTD-OH by showing that these phthalimide analogs also exhibit marked activity in models of nociceptive and inflammatory pain and inflammatory edema. Opioid and cannabinoid mechanisms partially mediate the anti-inflammatory, but not the antinociceptive activity.


Assuntos
Analgésicos/farmacologia , Edema/induzido quimicamente , Edema/fisiopatologia , Formaldeído/efeitos adversos , Nociceptividade/efeitos dos fármacos , Ftalimidas/farmacologia , Analgésicos/uso terapêutico , Animais , Edema/tratamento farmacológico , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Antagonistas de Entorpecentes/farmacologia , Dor/induzido quimicamente , Dor/tratamento farmacológico , Dor/fisiopatologia , Ftalimidas/uso terapêutico , Receptor CB1 de Canabinoide/antagonistas & inibidores , Receptor CB2 de Canabinoide/antagonistas & inibidores
6.
Malar J ; 14: 29, 2015 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-25626728

RESUMO

BACKGROUND: Chloroquine and primaquine are the first-line treatment recommended by World Health Organization for malaria caused by Plasmodium vivax. Since the problem of counterfeit or substandard anti-malarials is well established all over the world, the development of rapid and reliable methods for quality control analysis of these drugs is essential. Thus, the aim of this study was to develop and validate a novel UPLC-DAD method for simultaneously quantifying chloroquine and primaquine in tablet formulations. METHODS: The UPLC separation was carried out using a Hypersil C18 column (50 × 2.1 mm id; 1.9 µm particle size) and a mobile phase composed of acetonitrile (A) and 0.1% aqueous triethylamine, pH 3.0 adjusted with phosphoric acid (B), at a flow rate 0.6 mL/min. Gradient elution was employed. UV detection was performed at 260 nm. UPLC method was fully validated and the results were compared to a conventional HPLC-DAD method for the analysis of chloroquine and primaquine in tablet formulations. RESULTS: UPLC method was shown to be linear (r2 > 0.99), precise (CV < 2.0%), accurate (recovery rates from 98.11 to 99.83%), specific, and robust. No significant differences were observed between the chloroquine and primaquine contents obtained by UPLC and HPLC methods. However, UPLC method promoted faster analyses, better chromatographic performance and lower solvent consumption. CONCLUSIONS: The developed UPLC method was shown to be a rapid and suitable technique to quantify chloroquine and primaquine in pharmaceutical preparations and may be successfully employed for quality control analysis.


Assuntos
Antimaláricos/análise , Técnicas de Química Analítica/métodos , Cloroquina/análise , Cromatografia Líquida/métodos , Primaquina/análise , Comprimidos/química , Controle de Qualidade , Fatores de Tempo
7.
J Alzheimers Dis ; 45(2): 609-20, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25589728

RESUMO

BACKGROUND: Naturalistic studies evaluate individuals in their usual way of living, presenting more "real-life" data regarding patients and their diseases. OBJECTIVE: To investigate demographic, clinical, and genetic factors that could be predictive of good response to cholinesterase inhibitors (ChEI) treatment in Alzheimer's disease (AD) and AD + cerebrovascular disease (CVD). PATIENTS AND METHODS: A total of 129 patients were diagnosed with AD or AD + CVD and with mild-to-moderate dementia. After a 12-month treatment, 97 patients completed the study. They were evaluated at baseline and after three, six, and 12 months of ChEI (donepezil or rivastigmine or galantamine) use. APOE genotype and CYP2D6 polymorphisms were determined for all of the participants. In each visit, we used cognitive, functional, mood, and behavior scales. We classified patients according to their scores in the Mini-Mental State Examination (MMSE). Good responders were defined as those scoring ≥2 in the MMSE at 12 months. RESULTS: The rate of good clinical response was 27.8%. In a longitudinal analysis, the patients with mild AD and also good responders at three months were considered to be good responders at 12 months. There was no correlation between ChEI dose, APOE and CYP2D6 polymorphisms, and the pattern of clinical response. CONCLUSION: A higher rate of good response was observed in this study compared to that in previous investigations. The pharmacogenetic aspects do not seem to have an influence in the response.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Inibidores da Colinesterase/uso terapêutico , Demência/tratamento farmacológico , Demência/genética , Farmacogenética , Idoso , Idoso de 80 Anos ou mais , Apolipoproteínas E/genética , Citocromo P-450 CYP2D6/genética , Feminino , Testes Genéticos , Humanos , Estudos Longitudinais , Masculino , Escalas de Graduação Psiquiátrica , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento
8.
Bioorg Med Chem ; 22(9): 2783-90, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24685703

RESUMO

Nicorandil (N-(2-hydroxyethyl)nicotinamide nitrate) is an antianginal drug, which activates guanylyl cyclase and opens the ATP-dependent K(+) channels, actions that have been suggested to mediate its vasodilator activity. We synthesized nicorandil and its two isomers, which vary in the positions of the side chain containing the nitric oxide (NO) donor, and also their corresponding denitrated metabolites. The activities of these compounds were evaluated in an experimental model of pain in mice. Pharmacokinetic parameters of nicorandil and its isomers, as well as the plasma concentrations of the corresponding denitrated metabolites and also nicotinamide and nitrite were determined. Nicorandil exhibited the highest antinociceptive activity, while the ortho-isomer was the least active. Nicorandil and para-nicorandil, which induced higher plasma concentrations of nitrite, exhibited higher antinociceptive activity, which suggests that the release of NO may mediate this activity.


Assuntos
Analgésicos/síntese química , Nicorandil/química , Analgésicos/farmacocinética , Analgésicos/uso terapêutico , Animais , Modelos Animais de Doenças , Feminino , Meia-Vida , Isomerismo , Camundongos , Nicorandil/farmacocinética , Nicorandil/uso terapêutico , Dor/tratamento farmacológico
9.
Pharmacol Biochem Behav ; 106: 85-90, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23537730

RESUMO

Nicorandil (2-nicotinamide ethyl nitrate), an antianginal drug characterized by the coupling of nicotinamide with a nitric oxide (NO) donor, activates guanylyl cyclase and opens ATP-dependent K(+) channels. In the present study, we investigated the effects induced by per os (p.o.) administration of nicorandil (12.5, 25 or 50 mg/kg) or equimolar doses (corresponding to the highest dose of nicorandil) of N-(2-hydroxyethyl) nicotinamide (NHN), its main metabolite, or nicotinamide in the model of nociceptive response induced by formaldehyde in mice. Nicorandil, but not NHN or nicotinamide, inhibited the second phase of the nociceptive response. This activity was observed when nicorandil was administered between 30 and 120 min before the injection of formaldehyde. Ipsilateral intraplantar injection of nicorandil (125, 250 or 500 µg/paw) did not inhibit the nociceptive response. After p.o. administration of nicorandil (50 mg/kg), peak plasma concentrations of this compound and NHN were observed 0.63 and 4 h later, respectively. Nicotinamide concentrations were not increased after administration of nicorandil. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ; 1 or 2 mg/kg), a guanylyl cyclase inhibitor, partially attenuated the antinociceptive activity of nicorandil. However, this activity was not changed by glibenclamide (30 or 60 mg/kg), an inhibitor of ATP-dependent K(+) channels. In conclusion, we demonstrated the antinociceptive activity of nicorandil in a model of pain that exhibits both a nociceptive and an inflammatory profile. This activity is not mediated by nicotinamide or NHN. The coupling of an NO-donor to nicotinamide results in a compound with an increased potency. The NO-cGMP pathway, but not ATP-dependent K(+) channels, partially mediates the antinociceptive activity of nicorandil.


Assuntos
Analgésicos/farmacologia , Modelos Animais de Doenças , Formaldeído/toxicidade , Nicorandil/farmacologia , Dor/prevenção & controle , Analgésicos/sangue , Animais , Relação Dose-Resposta a Droga , Glibureto/farmacologia , Masculino , Camundongos , Nicorandil/sangue , Oxidiazóis/farmacologia , Dor/induzido quimicamente
10.
Malar J ; 11: 202, 2012 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-22704680

RESUMO

BACKGROUND: Ensuring the quality of malaria medicines is crucial in working toward malaria control and eventual elimination. Unlike other validated tests that can assess all critical quality attributes, which is the standard for determining the quality of medicines, basic tests are significantly less expensive, faster, and require less skilled labour; yet, these tests provide reproducible data and information on several critical quality attributes, such as identity, purity, content, and disintegration. Visual and physical inspection also provides valuable information about the manufacturing and the labelling of medicines, and in many cases this inspection is sufficient to detect counterfeit medicines. The Promoting the Quality of Medicines (PQM) programme has provided technical assistance to Amazon Malaria Initiative (AMI) countries to implement the use of basic tests as a key screening mechanism to assess the quality of malaria medicines available to patients in decentralized regions. METHODS: Trained personnel from the National Malaria Control Programmes (NMCPs), often in collaboration with country's Official Medicine Control Laboratory (OMCL), developed country- specific protocols that encompassed sampling methods, sample analysis, and data reporting. Sampling sites were selected based on malaria burden, accessibility, and geographical location. Convenience sampling was performed and countries were recommended to store the sampled medicines under conditions that did not compromise their quality. Basic analytical tests, such as disintegration and thin layer chromatography (TLC), were performed utilizing a portable mini-laboratory. RESULTS: Results were originally presented at regional meetings in a non-standardized format that lacked relevant medicines information. However, since 2008 information has been submitted utilizing a template specifically developed by PQM for that purpose. From 2005 to 2010, the quality of 1,663 malaria medicines from seven AMI countries was evaluated, mostly collected from the public sector, 1,445/1,663 (86.9%). Results indicate that 193/1,663 (11.6%) were found not to meet quality specifications. Most failures were reported during visual and physical inspection, 142/1663 (8.5%), and most of these were due to expired medicines, 118/142 (83.1%). Samples failing TLC accounted for 27/1,663 (1.6%) and those failing disintegration accounted for 24/1,663 (1.4%). Medicines quality failures decreased significantly during the last two years. CONCLUSIONS: Basic tests revealed that the quality of medicines in the public sector improved over the years, since the implementation of this type of quality monitoring programme in 2005. However, the lack of consistent confirmatory tests in the quality control (QC) laboratory, utilizing methods that can also evaluate additional quality attributes, could still mask quality issues. In the future, AMI countries should improve coordination with their health authorities and their QC lab consistently, to provide a more complete picture of malaria medicines quality and support the implementation of corrective actions. Facilities in the private and informal sectors also should be included when these sectors constitute an important source of medicines used by malaria patients.


Assuntos
Antimaláricos/farmacologia , Antimaláricos/normas , Técnicas de Química Analítica , Preparações Farmacêuticas/química , Preparações Farmacêuticas/normas , Antimaláricos/química , Humanos , Malária/tratamento farmacológico , Controle de Qualidade , América do Sul
11.
Ther Drug Monit ; 34(1): 59-66, 2012 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-22210098

RESUMO

BACKGROUND: A liquid chromatography-tandem mass spectrometry method for the simultaneous quantitation of endogenous uracil (U) and dihydrouracil (UH2) was developed and tested in a Brazilian population of patients with gastrointestinal cancer previously exposed to 5-fluorouracil (5FU). METHODS: The analytes were extracted by a liquid-liquid method using 5-clorouracil as internal standard. The separation was performed on a reversed-phase XTerra C18 column with a mobile phase composed of methanol and aqueous 0.1% ammonium hydroxide (15:85). Mass spectrometry detection was carried out using negative electrospray ionization and selected reaction monitoring. Bovine serum albumin was employed as an alternative matrix to prepare the calibration standards, aiming to avoid the measurement of physiologic U and UH2. Calibration curves were constructed over the range of 5-200 ng/mL for U and 10-500 ng/mL for UH2. RESULTS: The mean RSD values in the intrarun precision were 6.5% and 10.0% and in the interrun precision were 7.8% and 9.0% for U and UH2, respectively. The mean accuracy values were within the range of 90%-110% for both analytes. The analytes were stable in plasma under different conditions of temperature and time. The validated method was successfully applied to determine the plasma concentrations of U and UH2 in patients with gastrointestinal cancer (n = 32) previously treated with 5FU and for whom clinical toxicity was well documented. U concentrations varied from 21.8 to 56.6 ng/mL, whereas UH2 concentrations varied from 57.7 to 271.5 ng/mL. UH2/U ratio ranged from 1.56 to 6.18. CONCLUSIONS: The method has proved to provide a quick, reliable, and reproducible quantitation of the plasma concentrations of U and its metabolite UH2. The UH2/U ratios did not discriminate patients previously exposed to 5FU with and without severe toxicities, possibly due to the small sample. Further studies in a larger population are desirable.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Fluoruracila/efeitos adversos , Espectrometria de Massas por Ionização por Electrospray/métodos , Espectrometria de Massas em Tandem/métodos , Uracila/análogos & derivados , Uracila/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/sangue , Feminino , Fluoruracila/sangue , Fluoruracila/química , Neoplasias Gastrointestinais/sangue , Neoplasias Gastrointestinais/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Estrutura Molecular , Uracila/química
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