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1.
Expert Opin Pharmacother ; 25(7): 925-935, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38804904

RESUMO

INTRODUCTION: Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD) is estimated to affect upto 70-80% of people with type 2 diabetes mellitus (T2DM). Although several anti-hyperglycemic drugs have been shown to be effective in such patients, there remains an unmet need for newer drugs. The objective of this meta-analysis was to analyze the effect of ipragliflozin on aspartate aminotransferase (AST), alanine transaminase (ALT), and gamma-glutamyl transpeptidase (GGT) levels in patients with T2DM. METHODS: A literature search on electronic databases was conducted to identify potential randomized clinical trials (RCT) as per predetermined study selection criteria. Mean difference (MD) was calculated using Cochrane review manager. RESULTS: Twelve studies were included in the meta-analysis, including 1349 subjects. Compared to the control group, ipragliflozin as a monotherapy showed a significant reduction in levels of ALT at week 12 (p = 0.02) and at week 24 (p = 0.007), GGT at week 12 (p < 0.00001). Ipragliflozin as an add-on therapy showed significant reduction in levels of AST at week 24 (p < 0.00001), ALT at week 12 (p = 0.002), ALT at week 24 (p < 0.00001), and GGT at week 24 (p < 0.00001). CONCLUSION: Findings suggest the beneficial effects of ipragliflozin on liver enzymes. Further large-scale RCTs are required to confirm ipragliflozin's role for liver-related conditions in T2DM.


Assuntos
Alanina Transaminase , Aspartato Aminotransferases , Diabetes Mellitus Tipo 2 , Glucosídeos , Hipoglicemiantes , Tiofenos , gama-Glutamiltransferase , Humanos , Alanina Transaminase/sangue , Aspartato Aminotransferases/sangue , Aspartato Aminotransferases/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Quimioterapia Combinada , Fígado Gorduroso/tratamento farmacológico , gama-Glutamiltransferase/sangue , Glucosídeos/uso terapêutico , Glucosídeos/administração & dosagem , Hipoglicemiantes/uso terapêutico , Fígado/enzimologia , Fígado/efeitos dos fármacos , Ensaios Clínicos Controlados Aleatórios como Assunto , Inibidores do Transportador 2 de Sódio-Glicose/uso terapêutico , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia , Tiofenos/uso terapêutico
2.
Eur J Clin Pharmacol ; 79(10): 1281-1290, 2023 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-37462748

RESUMO

PURPOSE: Studies have demonstrated a high prevalence of non-alcoholic fatty liver disease (NAFLD) in type 2 diabetes mellitus (T2DM) patients. The aim was to review the effect of tofogliflozin on hepatic outcomes in T2DM patients. METHODS: A literature search in PubMed, Science Direct and Cochrane Central Register of Controlled Trials was conducted for randomised clinical trials of tofogliflozin by applying predetermined inclusion and exclusion criteria. RESULTS: A total number of four randomised clinical trials, including 226 subjects, were included in the review. There was a significant decrease in aspartate aminotransferase (AST) and alanine transaminase (ALT) levels in the tofogliflozin group as compared to the control or active comparator groups. Additionally, gamma-glutamyl transferase (GGT), alkaline phosphatase (ALP) and magnetic resonance imaging proton density fat fraction (MRI-PDFF) levels were also significantly decreased in the tofogliflozin group. However, no significant difference was observed in levels of adiponectin. CONCLUSION: Overall, an improvement in levels of hepatic parameters was observed in T2DM patients with concurrent liver disorders. However, a large number of clinical trials are needed to prove the efficacy of tofogliflozin on hepatic outcomes in patients with T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Hepatopatia Gordurosa não Alcoólica , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Fígado/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Glucosídeos/uso terapêutico , Glucosídeos/farmacologia , Alanina Transaminase
3.
ACS Omega ; 8(17): 14985-15002, 2023 May 02.
Artigo em Inglês | MEDLINE | ID: mdl-37151537

RESUMO

Antidiabetic drugs that have a secondary pharmacological effect on angiogenesis inhibition may help diabetic patients delay or avoid comorbidities caused by angiogenesis including malignancies. In recent studies, saroglitazar has exhibited antiangiogenic effects in diabetic retinopathy. The current study investigates the antiangiogenic effects of saroglitazar utilizing the chicken chorioallantoic membrane (CAM) assay and then identifies its precise mode of action on system-level protein networks. To determine the regulatory effect of saroglitazar on the protein-protein interaction network (PIN), 104 target genes were retrieved and tested using an acid server and Swiss target prediction tools. A string-based interactome was created and analyzed using Cytoscape. It was determined that the constructed network was scale-free, making it biologically relevant. Upon topological analysis of the network, 37 targets were screened on the basis of centrality values. Submodularization of the interactome resulted in the formation of four clusters. A total of 20 common targets identified in topological analysis and modular analysis were filtered. A total of 20 targets were compiled and were integrated into the pathway enrichment analysis using ShinyGO. The majority of hub genes were associated with cancer and PI3-AKT signaling pathways. Molecular docking was utilized to reveal the most potent target, which was validated by using molecular dynamic simulations and immunohistochemical staining on the chicken CAM. The comprehensive study offers an alternate research paradigm for the investigation of antiangiogenic effects using CAM assays. This was followed by the identification of the precise off-target use of saroglitazar using system biology and network pharmacology to inhibit angiogenesis.

4.
Int J Clin Pract ; 75(12): e14910, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34549867

RESUMO

PURPOSE: Coronavirus disease-2019 (COVID-19) may predispose to venous thromboembolism (VTE) and arterial thromboembolism because of excessive inflammation, hypoxia, immobilisation and diffuse intravascular coagulation. The understanding of the association might be helpful in early vigilant monitoring and better management of COVID-19 patients at high risk. Thus, in this meta-analysis, we aim to assess the association of VTE with the severity of COVID-19 disease. METHODS: A literature search was conducted on PubMed and Cochrane Central Register of Controlled Trials using the keywords "COVID-19 and thromboembolism" and "COVID-19 and embolism," till 20 February 2021. Thirteen studies including 6648 COVID-19 patients were incorporated in this systematic review and exploratory meta-analysis. RESULTS: The analysis revealed nearly three times more risk than intensive care unit (ICU) care in patients with VTE compared to non-VTE patients (RR: 2.78; 95% CI: 1.75-4.39; P < .001; I2 : 65.1%). Patients with pulmonary embolism and deep vein thrombosis are at increased risk of being admitted to ICU (RR: 2.21; 95% CI: 1.86-2.61; P < .001; I2 : 41.2%) and (RR: 2.69; 95% CI: 2.37-3.06; P < .001; I2 : 0.0%), respectively. The quality assessment indicated that the included studies were of fair quality. CONCLUSIONS: Our findings suggest that VTE either deep vein thrombosis or pulmonary embolism may have a negative effect on the health status of COVID-19 patients. This study highlights the need to consider measures for reducing thromboembolism risk amongst COVID-19 patients.


Assuntos
COVID-19 , Embolia Pulmonar , Tromboembolia Venosa , Anticoagulantes , Humanos , Embolia Pulmonar/etiologia , SARS-CoV-2 , Índice de Gravidade de Doença , Tromboembolia Venosa/epidemiologia , Tromboembolia Venosa/etiologia
5.
Minerva Endocrinol (Torino) ; 46(2): 226-232, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34082505

RESUMO

BACKGROUND: Inflammatory cytokines have been reported to be pathogenic factors for the development and progression of diabetic nephropathy (DN). Interleukin (IL)-36α is a newly discovered member of the IL-1 cytokine family that has been implicated in animal models of renal impairment. However, little is known about the role of IL-36α in DN in humans. The purpose of the present study was to assess the levels of IL-36α and IL-18 in type 2 diabetic patients (T2DM) patients with and without DN. METHODS: Subjects were divided into 3 groups: Control (N.=20), T2DM without DN (N.=30), and T2DM with DN (N.=30). Urinary IL-36α and IL-18 levels were assessed using ELISA. Correlation analysis was performed to determine the association of the IL levels with clinical markers of T2DM and DN. RESULTS: IL-36α and IL-18 levels were significantly elevated in T2DM patients with DN, when compared to T2DM patients without DN (P<0.0001, P=0.0025, respectively) and controls (P<0.0001, for both). IL-36α levels showed a positive correlation with urinary albumin excretion (r=0.754, P<0.0001), HbA1c (r=0.433, P=0.0168), fasting plasma glucose (r=0.433, P=0.0168) and negative correlation with glomerular filtration rate (r=-0.852 P<0.0001). CONCLUSIONS: The results highlighted the association of IL-36α with DN. However, further extensive studies are suggested for evaluating the association.


Assuntos
Diabetes Mellitus Tipo 2 , Nefropatias Diabéticas , Biomarcadores , Diabetes Mellitus Tipo 2/complicações , Humanos , Interleucina-18 , Interleucinas
6.
Natl Med J India ; 33(1): 5-9, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33565478

RESUMO

Background: Many people with diabetes, who practise Islam, are passionate about fasting during Ramadan despite their medical condition and exemption from the religion. These patients are at risk of hypoglycaemia, hyperglycaemia, diabetic ketoacidosis, dehydration and thrombosis. We evaluated the acceptability of an individualized management plan for such people. Methods: We conducted a survey to assess the knowledge and ability of patients to manage their diabetes while observing the fast during Ramadan. Then, the acceptance of an educational intervention was assessed among patients, which was provided 1 month before Ramadan. Patients were followed up at 2 weeks into and after Ramadan. Results: Of the survey population, only 14.7% of patients volunteered for pre-Ramadan assessment and 97.5% of patients recollected suffering from symptoms suggestive or hypoglycaemia or hyperglycaemia. Following the intervention, 17 of 50 patients did not fast; 26 patients followed dietary advice, while 7 patients did not. Symptoms suggestive of hypoglycaemia and hyperglycaemia were reported by 21 of 33 patients who fasted and 21 of 28 patients reported lower body weight. Insulin and hypoglycaemic drugs were changed from morning to evening dosing in 41% of patients while 18% of patients had their drugs stopped. Conclusion: An educational intervention generated awareness among the patients and helped 43 of 50 patients in making rational decisions about control of diabetes during Ramadan.


Assuntos
Diabetes Mellitus Tipo 2 , Diabetes Mellitus , Hipoglicemia , Jejum , Humanos , Hipoglicemia/induzido quimicamente , Hipoglicemia/epidemiologia , Hipoglicemia/prevenção & controle , Hipoglicemiantes/uso terapêutico , Islamismo
7.
Life Sci ; 219: 31-39, 2019 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-30625289

RESUMO

AIMS: The study reports preclinical pharmacokinetics (PK) and correlation with pharmacological effect at suprapharmacological dose of orally administered melatonin along with time and dose optimization, which have been lacking in earlier reports of radioprotection using melatonin. METHODS: PK of melatonin in C57BL/6 mice was evaluated after dose of 250 mg/kg using HPLC. Tissue distribution study was conducted in vital organs following oral administration. Plasma total antioxidant capacity (TAC) was determined by ABTS+ radical assay and was correlated to plasma concentrations of melatonin. Using the outcomes of PK and Pharmacodynamics (PD), survival study was conducted for optimization of 'drug radiation gap period' (DRGP). Optimal oral dose for radioprotection was determined using survival as an end point. KEY FINDINGS: PK analysis of melatonin revealed Tmax at 5 min with closely spaced another distinct concentration peak at 20 min. Plasma TAC of melatonin showed similar peaks at 5 min and 45 min, with the highest TAC at 45 min. Survival following a lethal (9 Gy) radiation dose was 20% and 40% after 5 and 45 min of melatonin administration, respectively. DRGP for melatonin was thus 45 min, while optimal oral dose ranged from 125 to 250 mg/kg. PK parameters at 250 mg/kg dose were qualitatively similar to low dose of melatonin, thus preventing chances of unexpected toxicity. SIGNIFICANCE: Survival enhancement at 45 min suggested as probable interval required as 'DRGP'. The optimum oral therapeutic window appears large with no substantial toxicity. The outcomes will be useful in development of radioprotectors as well as other therapeutic applications.


Assuntos
Melatonina/administração & dosagem , Lesões Experimentais por Radiação/prevenção & controle , Protetores contra Radiação/administração & dosagem , Administração Oral , Animais , Cromatografia Líquida de Alta Pressão , Esquema de Medicação , Feminino , Melatonina/farmacocinética , Melatonina/farmacologia , Melatonina/uso terapêutico , Camundongos , Camundongos Endogâmicos C57BL , Protetores contra Radiação/farmacocinética , Protetores contra Radiação/farmacologia , Protetores contra Radiação/uso terapêutico , Distribuição Tecidual
8.
J Pharm Biomed Anal ; 164: 698-705, 2019 Feb 05.
Artigo em Inglês | MEDLINE | ID: mdl-30472588

RESUMO

PURPOSE: In vivo phenotyping of CYP isoforms involved in the metabolism of anti-HIV and antitubercular drugs is important to determine therapeutic dose levels in HIV/AIDS-TB coinfections. In this study, we used a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and N-acetyltransferase-2 (NAT2) in plasma. CYP2B6 is the main catalyst of anti-HIV efavirenz, while NAT2 is involved in antitubercular drug isoniazid metabolism. CYP2C9 has a significant association with antitubercular drug-induced reactions. The activity level of these isoforms has a significant bearing on therapeutic dose in rapid and poor metabolizers. METHODS: Briefly, a cocktail of probe drugs was administered to human volunteers and the drugs and metabolites were determined by an inhouse LC-MS/MS method in 250 µl plasma. The mobile phase and drug/metabolite extraction methods were optimized before analysis. Retention time, Cmax and tmax were calculated from the same sample and the values were used for phenotyping the isoforms. RESULTS: Retention time of drugs and metabolites was calculated. The method was sensitive (4.5-8.2 %CV) and no interfering peak was observed in any batch. %Accuracy of the calibrator and QC was 85-115%. %CV of storage stability testing was within FDA approved limits. Cmax and tmax were comparable to the values reported for individual drugs. CONCLUSIONS: This study advocates the use of a cocktail of bupropion, losartan and dapsone for in vivo phenotyping of CYP2B6, CYP2C9 and NAT2, which is important in determining therapeutic dose levels of anti-HIV and anti-TB drugs in HIV/AIDS-TB coinfections.


Assuntos
Fármacos Anti-HIV/metabolismo , Antituberculosos/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C9/genética , Adulto , Fármacos Anti-HIV/uso terapêutico , Antituberculosos/uso terapêutico , Arilamina N-Acetiltransferase , Bupropiona/administração & dosagem , Bupropiona/sangue , Bupropiona/metabolismo , Bupropiona/farmacocinética , Coinfecção/tratamento farmacológico , Coinfecção/genética , Coinfecção/microbiologia , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2C9/metabolismo , Dapsona/administração & dosagem , Dapsona/sangue , Dapsona/metabolismo , Dapsona/farmacocinética , Combinação de Medicamentos , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Infecções por HIV/microbiologia , Voluntários Saudáveis , Humanos , Inativação Metabólica , Isoenzimas/genética , Isoenzimas/metabolismo , Losartan/administração & dosagem , Losartan/sangue , Losartan/metabolismo , Losartan/farmacocinética , Fenótipo , Polimorfismo Genético , Espectrometria de Massas em Tandem/métodos , Tuberculose/tratamento farmacológico , Tuberculose/genética , Tuberculose/microbiologia , Adulto Jovem
9.
Basic Clin Pharmacol Toxicol ; 122(3): 317-321, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-28889650

RESUMO

There are various factors that contribute to development of antimicrobial resistance. Overuse, inappropriate prescribing and extensive agricultural use of antibiotics are some of the factors which have been identified. Antibiotics are almost always universally packaged by manufacturers in packs that are heavily driven by cost of economies and convenience rather than by any scientific basis or duration of therapy. So, in this study, the correlation of the treatment guidelines with the choice of antibiotics and whether packing size contributes to leftover dosing units when used according to guideline recommendations were assessed.


Assuntos
Antibacterianos/uso terapêutico , Embalagem de Medicamentos , Guias de Prática Clínica como Assunto , Padrões de Prática Médica , Serviços de Saúde Suburbana , Serviços Urbanos de Saúde , Antibacterianos/efeitos adversos , Prescrições de Medicamentos , Registros Eletrônicos de Saúde , Hospitais Urbanos , Humanos , Índia , Infectologia/normas , Atenção Primária à Saúde , Infecções Respiratórias/tratamento farmacológico , Dermatopatias Bacterianas/tratamento farmacológico , Sociedades Médicas , Infecções dos Tecidos Moles/tratamento farmacológico , Estados Unidos , Infecções Urinárias/tratamento farmacológico
10.
Clin Infect Dis ; 62(8): 964-971, 2016 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-26908796

RESUMO

BACKGROUND: Artemisinins, which are derived from plants, are subject to risk of supply interruption due to climatic changes. Consequently, an effort to identify a new synthetic antimalarial was initiated. A fixed-dose combination of arterolane maleate (AM), a new synthetic trioxolane, with piperaquine phosphate (PQP), a long half-life bisquinoline, was evaluated in patients with uncomplicatedPlasmodium falciparummalaria. METHODS: In this multicenter, randomized, double-blind, comparative, parallel-group trial, 1072 patients aged 12-65 years withP. falciparummonoinfection received either AM-PQP (714 patients) once daily or artemether-lumefantrine (A-L; 358 patients) twice daily for 3 days. All patients were followed up until day 42. RESULTS: Of the 714 patients in the AM-PQP group, 638 (89.4%) completed the study; of the 358 patients in the A-L group, 301(84.1%) completed the study. In both groups, the polymerase chain reaction corrected adequate clinical and parasitological response (PCR-corrected ACPR) on day 28 in intent-to-treat (ITT) and per-protocol (PP) populations was 92.86% and 92.46% and 99.25% and 99.07%, respectively. The corresponding figures on day 42 in the ITT and PP populations were 90.48% and 91.34%, respectively. After adjusting for survival ITT, the PCR-corrected ACPR on day 42 was >98% in both groups. The overall incidence of adverse events was comparable. CONCLUSIONS: AM-PQP showed comparable efficacy and safety to A-L in the treatment of uncomplicatedP. falciparummalaria in adolescent and adult patients. AM-PQP demonstrated high clinical and parasitological response rates as well as rapid parasite clearance. CLINICAL TRIALS REGISTRATION: India. CTRI/2009/091/000101.


Assuntos
Antimaláricos/administração & dosagem , Artemisininas/administração & dosagem , Etanolaminas/administração & dosagem , Fluorenos/administração & dosagem , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Malária Falciparum/tratamento farmacológico , Malária Falciparum/parasitologia , Peróxidos/administração & dosagem , Quinolinas/administração & dosagem , Compostos de Espiro/administração & dosagem , Adolescente , Adulto , África/epidemiologia , Idoso , Antimaláricos/uso terapêutico , Artemeter , Artemisininas/uso terapêutico , Ásia/epidemiologia , Criança , Método Duplo-Cego , Quimioterapia Combinada , Etanolaminas/uso terapêutico , Feminino , Fluorenos/uso terapêutico , Meia-Vida , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Humanos , Índia/epidemiologia , Lumefantrina , Malária Falciparum/epidemiologia , Masculino , Pessoa de Meia-Idade , Peróxidos/uso terapêutico , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adulto Jovem
11.
Malar J ; 15: 42, 2016 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-26818020

RESUMO

BACKGROUND: Chloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria. METHODS: Patients aged 13-65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days. RESULTS: In per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100% (140/140) in the FDC of arterolane maleate and PQP group, and 99.3% (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9% (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95% CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4% in the FDC of arterolane maleate and PQP group and 85.4% in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1%), headache (1.3 vs 3.2%) and prolonged QT (1.9 vs 3.2%). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h. CONCLUSIONS: The study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile. Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129.


Assuntos
Antimaláricos/uso terapêutico , Cloroquina/efeitos adversos , Cloroquina/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Malária Vivax/tratamento farmacológico , Malária/tratamento farmacológico , Maleatos/uso terapêutico , Peróxidos/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Quimioterapia Combinada , Feminino , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Humanos , Masculino , Maleatos/efeitos adversos , Pessoa de Meia-Idade , Peróxidos/efeitos adversos , Quinolinas/efeitos adversos , Compostos de Espiro/efeitos adversos , Adulto Jovem
12.
Malar J ; 14: 469, 2015 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-26608469

RESUMO

BACKGROUND: The World Health Organization (WHO) recommends artemisinin combination therapy (ACT) for the treatment of uncomplicated Plasmodium falciparum malaria. The present study investigated the efficacy and safety of fixed dose combination (FDC) of arterolane maleate 37.5 mg and piperaquine phosphate (PQP) 187.5 mg dispersible tablets in paediatric patients aged 6 months to 12 years. METHODS: Male and female patients aged 6 months to 12 years who were confirmed cases of P. falciparum mono-infection with fever or documented history of fever in the previous 24 h were included. The patients were administered FDC of arterolane maleate and PQP as single daily doses for three consecutive days based on their age. The primary efficacy outcome was proportion of patients with polymerase chain reaction (PCR)-corrected adequate clinical and parasitological response (ACPR) on day 28. Safety was analysed based on adverse events (AE), laboratory abnormalities and abnormalities on electrocardiograph. RESULTS: A total of 141 eligible paediatric patients received FDC of arterolane maleate and PQP in a 42-day follow-up study. All the enrolled patients (141) were included in intention to treat (ITT) and safety analyses, and 126 patients were considered in per protocol (PP) population. The PCR-corrected ACPR on day 28 was achieved in all patients (100 %; 95 % CI 97.11-100) included in PP population. The median parasite clearance time (PCT) and fever clearance time (FCT) were 24 h (95 % CI 18.0-24.0) and 10 h (95 % CI 4.0-18.0), respectively. The most frequently reported clinical AE was vomiting. Majority of the AEs were mild to moderate in severity and resolved without sequelae. No patient was discontinued for any QTc (corrected QT interval) prolongation. No deaths or serious AEs were reported during the study. CONCLUSION: The findings from this study showed that FDC of arterolane maleate and PQP effectively cures P. falciparum malaria and attains acceptable level of cure by day 28 in paediatric patients. The efficacy and safety results observed in children warrants further studies on FDC of arterolane maleate and PQP dispersible tablets. TRIAL REGISTRATION: Clinical Trial Registry India: CTRI/2009/091/000531.


Assuntos
Compostos Heterocíclicos com 1 Anel/uso terapêutico , Malária Falciparum/tratamento farmacológico , Malária/tratamento farmacológico , Peróxidos/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Antimaláricos/uso terapêutico , Criança , Pré-Escolar , Côte d'Ivoire , Combinação de Medicamentos , Feminino , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Índia , Lactente , Recém-Nascido , Masculino , Peróxidos/efeitos adversos , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Quinolinas/efeitos adversos , Quinolinas/farmacologia , Ruanda , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacologia , Comprimidos
13.
J Clin Pharmacol ; 54(4): 386-93, 2014 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-24242999

RESUMO

Arterolane (RBx11160, OZ277) maleate is a rapidly acting synthetic trioxolane anti-malarial. This randomized, placebo controlled study was a phase I study to evaluate the clinical safety and tolerability as well as pharmacokinetics (PKs) of arterolane maleate including food effect. Eight single rising oral doses of arterolane (25, 50, 100, 150, 200, 300, 400, 600 mg), food effect under fed and fasting conditions at 100 mg dose and four multiple oral dose regimens (25, 50, 100, 200 mg) were administered once daily for 7 days in 64 healthy young males (Caucasian). A randomized, placebo-controlled study was also conducted in healthy elderly males and females (Caucasian) to investigate PKs, safety and tolerability of single oral dose (100 mg) of arterolane. All doses were well tolerated after oral administration. The initial peak of arterolane was apparent at 2-3 hours post-dose followed by a secondary peak at approximately 5 hours post-dose. Thereafter, plasma arterolane concentration declined with a geometric mean t1/2 of approximately 2-4 hours. The PKs of arterolane appeared to be time-invariant after repeated once-daily dosing. The incidence of adverse events was similar for placebo and active treatments. Arterolane had similar PKs and tolerability in elderly and younger subjects and between elderly males and females.


Assuntos
Antimaláricos , Compostos Heterocíclicos com 1 Anel , Peróxidos , Compostos de Espiro , Administração Oral , Adolescente , Adulto , Idoso , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Antimaláricos/sangue , Antimaláricos/farmacocinética , Estudos Cross-Over , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Voluntários Saudáveis , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/sangue , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Masculino , Pessoa de Meia-Idade , Peróxidos/administração & dosagem , Peróxidos/efeitos adversos , Peróxidos/sangue , Peróxidos/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/efeitos adversos , Compostos de Espiro/sangue , Compostos de Espiro/farmacocinética , Adulto Jovem
14.
Eur J Drug Metab Pharmacokinet ; 38(4): 275-82, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23446815

RESUMO

Identification of polymorphism of cytochrome P450 2C9 (CYP2C9) enzymes in different ethnic populations is important to understand the differences in clinical responses to drugs. This study determines the CYP2C9 genetic polymorphism in Indian National Capital Region and correlates the phenotype-genotype. Losartan (25 mg) was administered to 107 volunteers to assess CYP2C9 activity, and, on the basis of results, volunteers were categorized as rapid and poor metabolizers. Molecular typing of CYP2C9*1 (wild type), CYP2C9*2, and CYP2C9*3 (the most common variant) was carried out by single-base primer extension technology for 37 subjects, of which 9 were poor metabolizers, and 28 were rapid metabolizers. 14.28 % of the studied population was identified as poor metabolizer for the category of drugs metabolized by CYP2C9. Significant difference was observed between the mean ratio (drug/metabolite) of poor (11.38 ± 5.88) and rapid (1.18 ± 1.11) drug metabolizers. The study suggests that phenotyping of CYP2C9 is desirable before enrollment of subjects for clinical trials or for deciding drug dose regimen as 14.28 % of study population was found to be poor metabolizer for the category of drugs metabolized by CYP2C9. This study establishes phenotype-genotype correlation, and proposes to use genotyping or phenotyping to evaluate the status of drug metabolizing capacity of CYP2C9 as a primary screening procedure before enrolling subjects in clinical trials or in clinical practice.


Assuntos
Hidrocarboneto de Aril Hidroxilases/genética , Bloqueadores do Receptor Tipo 1 de Angiotensina II/metabolismo , Hidrocarboneto de Aril Hidroxilases/metabolismo , Povo Asiático , Ácidos Carboxílicos/metabolismo , Citocromo P-450 CYP2C9 , Primers do DNA , Frequência do Gene , Genótipo , Humanos , Índia/epidemiologia , Losartan/metabolismo , Preparações Farmacêuticas/metabolismo , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Nucleotídeo Único
15.
Clin Infect Dis ; 55(5): 663-71, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22586253

RESUMO

BACKGROUND: Artemisinin-based combination therapy is the first-line treatment for uncomplicated falciparum malaria. This study assessed the antimalarial efficacy and safety of a combination of 150 mg of arterolane maleate and 750 mg of piperaquine phosphate (AM-PQP) in comparison to Coartem (artemether and lumefantrine) in patients with acute uncomplicated P. falciparum malaria. METHODS: In this open-label, randomized, multicentric, parallel group clinical trial, 240 patients were randomized to receive AM-PQP (160 patients) or Coartem (80 patients). Patients with P. falciparum monoinfection and initial parasite densities ranging from 1000 to 100 000 asexual parasites/µL of blood were followed for 28 days. Polymerase chain reaction-corrected adequate clinical and parasitologic response on day 28, parasite clearance time, and fever clearance time were evaluated. RESULTS: A total of 151 (94.4%) of 160 patients in the AM-PQP group completed the trial, while 77 (96.3%) of 80 patients in the Coartem group completed the trial. No treatment failure was noted in the AM-PQP group, while one patient receiving Coartem failed treatment on day 28. There was no difference in the median parasite clearance time (30 hours in both groups) or median fever clearance time (24 hours in both groups) after administration of the 2 study treatments. CONCLUSIONS: The available data support the evaluation of a drug combination in a larger population as a fixed-dose combination. Clinical Trials Registration. CTRI/2007/091/000031.


Assuntos
Antimaláricos/uso terapêutico , Compostos Heterocíclicos com 1 Anel/uso terapêutico , Malária Falciparum/tratamento farmacológico , Peróxidos/uso terapêutico , Quinolinas/uso terapêutico , Compostos de Espiro/uso terapêutico , Adolescente , Adulto , Antimaláricos/efeitos adversos , Antimaláricos/farmacocinética , Feminino , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/farmacocinética , Humanos , Estimativa de Kaplan-Meier , Malária Falciparum/metabolismo , Malária Falciparum/parasitologia , Masculino , Peróxidos/efeitos adversos , Peróxidos/farmacocinética , Quinolinas/efeitos adversos , Quinolinas/farmacocinética , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacocinética , Estatísticas não Paramétricas
16.
Springerplus ; 1: 34, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23961363

RESUMO

Identification of poor and rapid metabolizers for the category of drugs metabolized by cytochrome P450 2B6 (CYP2B6) is important for understanding the differences in clinical responses of drugs metabolized by this enzyme. This study reports the prevalence of poor and rapid metabolizers in North Indian population residing in the National Capital Territory. The prevalence of poor and rapid metabolizers was determined in the target population for the category of drugs metabolized by CYP2B6 by measuring plasma bupropion, a drug metabolized by CYP2B6, and its metabolite. Bupropion (75 mg) was administered to 107 volunteers, and the drug (bupropion) and its metabolite (hydroxybupropion) were determined simultaneously by LCMS/MS in the plasma. CYP2B6 activity was measured as hydroxybupropion/bupropion ratio, and volunteers were categorized as rapid or poor metabolizers on the basis of cutoff value of log (hydroxybupropion/bupropion). Significant differences were observed between the mean metabolite/drug ratio of rapid metabolizers (Mean = 0.59) and poor metabolizers (Mean = 0.26) with p<0.0001. Results indicate that 20.56% individuals in the target population were poor metabolizers for the category of drugs metabolized by CYP2B6. Cutoff value defined in this study can be used as a tool for evaluating the status of CYP2B6 using bupropion as a probe drug. The baseline information would be clinically useful before administering the drugs metabolized by this isoform.

17.
J Clin Pharmacol ; 51(12): 1655-64, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21415286

RESUMO

The authors compared US Food and Drug Administration (FDA) and 9 pharmacologically guided approaches (PGAs; simple allometry, maximum life span potential [MLP], brain weight, rule of exponent [ROE], two 2-sp methods and 3 one-sp methods) to determine the maximum recommended starting dose (MRSD) for first-in-human clinical trials in adult healthy men using 10 drugs. The ROE method as suggested by Mahmood and Balian1 gave the best prediction accuracy for a pharmacokinetic (PK) parameter. Values derived from clearance were consistently better than volume of distribution (Vd)-based methods and had lower root mean square error (RMSE) values. A pictorial method evaluation chart was developed based on fold errors for simultaneous evaluation of various methods. The one-sp method (rat) and the US FDA methods gave the highest prediction accuracy and low RMSE values, and the 2-sp methods gave the least prediction accuracy with high RMSE values. The ROE method gave more consistent predictions for PK parameters than other allometric methods. Despite this, the MRSD predictions were not better than US FDA methods, probably indicating that across-species variation in clearance may be higher than variation in no observed adverse effect level (NOAEL) and that PGA methods may not be consistently better than the NOAEL based methods.


Assuntos
Avaliação Pré-Clínica de Medicamentos/métodos , Farmacocinética , United States Food and Drug Administration , Adulto , Animais , Cães , Haplorrinos , Humanos , Masculino , Taxa de Depuração Metabólica , Nível de Efeito Adverso não Observado , Preparações Farmacêuticas/administração & dosagem , Preparações Farmacêuticas/metabolismo , Ratos , Estados Unidos
18.
J Clin Pharmacol ; 51(11): 1519-28, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21148048

RESUMO

Arterolane (RBx 11160) maleate is a novel, rapidly acting synthetic trioxolane antimalarial compound being developed by Ranbaxy Research Laboratories (Haryana, India). It is presently under phase III in combination with piperaquine phosphate. The present work reports the relationship between pharmacokinetic (PK) parameter (AUC(0-8h) on day 0/day 6) and indices of pharmacodynamic (PD) response (50% parasite clearance [PC(50)], 90% parasite clearance [PC(90)], parasite clearance time [PCT], recrudescence) from a phase II, double-blind, multicenter, randomized, parallel-group, dose-ranging trial. Patients with acute uncomplicated P. falciparum malaria were randomized to 1 of 3 arterolane maleate (50, 100, and 200 mg) doses for 7 consecutive days. Plasma concentration data were available from 78, 76, and 75 patients receiving a 50-, 100-, and 200-mg dose, respectively. Based on PD modeling, its limitations and assumptions, minimum 150-mg dose arterolane maleate was recommended to optimize the probability of maximum therapeutic benefits for an adult. Doses higher than 100 mg are unlikely to reduce the probability of recrudescence. This study re-stresses the need of combining short and long-acting drugs to prevent resistance development and minimize recrudescence.


Assuntos
Antimaláricos/administração & dosagem , Antimaláricos/farmacocinética , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Compostos Heterocíclicos com 1 Anel/farmacocinética , Malária Falciparum/tratamento farmacológico , Malária Falciparum/metabolismo , Peróxidos/administração & dosagem , Peróxidos/farmacocinética , Compostos de Espiro/administração & dosagem , Compostos de Espiro/farmacocinética , Administração Oral , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Antimaláricos/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/sangue , Humanos , Malária Falciparum/sangue , Malária Falciparum/parasitologia , Masculino , Maleatos , Pessoa de Meia-Idade , Peróxidos/efeitos adversos , Peróxidos/sangue , Plasmodium falciparum , Compostos de Espiro/efeitos adversos , Compostos de Espiro/sangue , Adulto Jovem
19.
Clin Infect Dis ; 51(6): 684-91, 2010 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-20687837

RESUMO

BACKGROUND: Drug-resistant Plasmodium falciparum malaria necessitates development of novel drugs for treatment.The present study assessed the efficacy and safety of 3 dose levels of arterolane (RBx 11160), a synthetic trioxolane, for treatment of acute uncomplicated falciparum malaria. METHODS: In this randomized, double-blind, multicenter, parallel-group, dose-finding, phase II trial, 230 patients from 4 centers in Thailand, India, and Tanzania (mainland and Zanzibar) received either 50 mg (n=78), 100mg (n=76), or 200 mg (n=76) of arterolane once daily for 7 days. Patients (aged 13-65 years) with asexual parasite density of 1000-100,000 parasites/microL were included and were followed up for 28 days. The median time to 90% parasite clearance (PC90) was evaluated. RESULTS: The median PC90 was longer in the group receiving the 50-mg dose (19.4 h), compared with the groups receiving the 100-mg dose (12.8 h) and 200-mg dose (12.6 h) (P < .01). The polymerase chain reaction-corrected adequate clinical and parasitological responses on day 28 were 63%, 71%, and 72% for the groups receiving the 50-mg, 100-mg, and 200-mg doses, respectively, by intention-to-treat analysis (odds ratio, 1.55; 95%confidence interval, 0.78-3.06, for comparison of the 200-mg and 50-mg dose groups). Treatment was generally well tolerated. No patient died or experienced any serious adverse event. Mild complaints were reported in <10%of the patients and were similar in the 3 groups. Biochemistry and hematological analyses did not show any signof drug toxicity in any patient. CONCLUSION: Arterolane at daily doses of 100 and 200 mg is a rapidly acting, effective, and safe synthetic antimalarial drug, which may potentially represent an alternative to artemisinin derivatives in antimalarial combination therapy. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00362050.


Assuntos
Antimaláricos/administração & dosagem , Compostos Heterocíclicos com 1 Anel/administração & dosagem , Malária Falciparum/tratamento farmacológico , Peróxidos/administração & dosagem , Plasmodium falciparum/isolamento & purificação , Compostos de Espiro/administração & dosagem , Adolescente , Adulto , Idoso , Antimaláricos/efeitos adversos , Antimaláricos/farmacologia , Método Duplo-Cego , Feminino , Compostos Heterocíclicos com 1 Anel/efeitos adversos , Compostos Heterocíclicos com 1 Anel/farmacologia , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Peróxidos/efeitos adversos , Peróxidos/farmacologia , Plasmodium falciparum/efeitos dos fármacos , Compostos de Espiro/efeitos adversos , Compostos de Espiro/farmacologia , Tanzânia , Tailândia , Resultado do Tratamento , Adulto Jovem
20.
J Clin Pharmacol ; 48(2): 166-75, 2008 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-18199893

RESUMO

Piperaquine phosphate is an orally active bisquinolone antimalarial drug that has been used for the past 3 decades. The authors report the safety, tolerability, and pharmacokinetics of piperaquine from a classical controlled phase I study. It was a double-blind, randomized, parallel-group, placebo-controlled, and single- and multiple-dose study. During the rising single-dose study, single ascending oral doses of 500, 750, 1000, 1250, and 1500 mg of piperaquine phosphate were administered, whereas in rising multiple-dose study, once-daily ascending oral doses of 500, 750, 1000, and 1500 mg were administered for 3 consecutive days. Pharmacokinetic analysis for both the rising single- and multiple-dose studies was done using the noncompartmental approach. The mean apparent terminal half-life ranged from 11 to 23 days. Increase in exposure was less than dose proportional and linear. Piperaquine concentrations were measurable up to 60 days postdose. Multiple peaks were observed in the plasma piperaquine concentration-time profiles and exhibited 3- to 7-fold accumulation following multiple dosing. Piperaquine was well tolerated following single and multiple doses.


Assuntos
Antimaláricos/farmacocinética , Quinolinas/farmacocinética , Administração Oral , Adulto , Antimaláricos/administração & dosagem , Antimaláricos/efeitos adversos , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Relação Dose-Resposta a Droga , Método Duplo-Cego , Meia-Vida , Cefaleia/induzido quimicamente , Humanos , Masculino , Taxa de Depuração Metabólica , Pessoa de Meia-Idade , Quinolinas/efeitos adversos , Quinolinas/sangue , Comprimidos , Espectrometria de Massas em Tandem , Fatores de Tempo , Resultado do Tratamento , Vômito/induzido quimicamente
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