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1.
Br J Clin Pharmacol ; 89(3): 1127-1138, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-36217901

RESUMO

Dihydroorotate dehydrogenase (DHODH) is a mitochondrial enzyme that is essential for pyrimidine de novo synthesis. Rapidly growing cancer cells and replicating viruses are dependent on host cell nucleotides, the precursors of which are provided by DHODH. Hence, DHODH becomes an ideal target for pharmacological intervention. RP7214 is a potent and selective inhibitor of human DHODH and has shown antiviral and antileukaemic activity in preclinical studies. This paper describes the phase I study that evaluated the safety and pharmacokinetics of single and multiple ascending doses (SAD and MAD) and the food effect of RP7214 in healthy volunteers (HVs). The study was a randomized, double-blind, placebo-controlled trial of single dose (100, 200 and 400 mg QD), multiple doses (200 and 400 mg BID for 7 days) and a food effect study at a single dose of 200 mg. A total of 18, 12 and 12 HVs were enrolled in the SAD, MAD and food effect parts of the study, respectively. RP7214 was well tolerated at all dose levels. There were 20 treatment-emergent adverse events (TEAEs) reported, out of which most were mild to moderate in severity while three TEAEs were grade ≥3. RP7214 showed accumulation on multiple dosing. Steady-state concentrations were reached within about 3-6 days. The mean plasma half-life at steady-state was 12.8 hours (9.9-15.3). Food did not impact the absorption of RP7214. Inhibition of DHODH, as evidenced by increased dihydroorotate levels, was observed, confirming target engagement. The high systemic exposure with a favourable safety profile shows potential for the development of RP7214 in SARS-CoV-2 and acute myeloid leukaemia (NCT04680429).


Assuntos
COVID-19 , Di-Hidro-Orotato Desidrogenase , Humanos , Voluntários Saudáveis , SARS-CoV-2 , Inibidores Enzimáticos/efeitos adversos , Método Duplo-Cego , Relação Dose-Resposta a Droga
2.
J Clin Pharm Ther ; 46(3): 677-687, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33314326

RESUMO

WHAT IS KNOWN AND OBJECTIVE: RP3128, a novel, orally available modulator of calcium released activated calcium (CRAC) channel, is being developed for the potential treatment of autoimmune and inflammatory diseases. RP3128 showed nano-molar potency and activity in a range of in vitro and in vivo models of inflammation. We report a first-in-human study investigating the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of RP3128 in healthy subjects. METHODS: A randomized, double-blind, placebo-controlled trial of single (25, 50, 100, 200 and 400 mg) and multiple (7 days: 25, 100 and 400 mg once daily) doses of RP3128 were performed. Thirty-two and 24 subjects were randomized in the single ascending dose (SAD) and multiple ascending dose (MAD) parts, respectively. RESULTS AND DISCUSSION: RP3128 was well tolerated, with no dose-limiting toxicity at single and multiple doses. Incidence of treatment emergent adverse events (TEAEs) did not increase with ascending RP3128 doses. No changes were seen in cognitive function and ECG parameters. RP3128 was rapidly absorbed. Elimination was slow with a half-life of more than 80 h. Exposures increased with increasing doses. Accumulation was seen on repeated dosing. PD response, as evidenced by lower plasma levels of tumour necrosis factor-alfa (TNFα) and interleukin-4 (IL-4), was seen when compared to pre-dose values or placebo. WHAT IS NEW AND CONCLUSION: The safety, tolerability and PK/PD profile of RP3128 demonstrates its potential to be developed in inflammatory disorders and support further clinical development (ClinicalTrials.gov number: NCT02958982).


Assuntos
Canais de Cálcio Ativados pela Liberação de Cálcio/antagonistas & inibidores , Compostos Orgânicos , Adolescente , Adulto , Doenças Autoimunes/tratamento farmacológico , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Interações Alimento-Droga , Meia-Vida , Voluntários Saudáveis , Humanos , Interleucina-4/sangue , Masculino , Pessoa de Meia-Idade , Compostos Orgânicos/administração & dosagem , Compostos Orgânicos/efeitos adversos , Compostos Orgânicos/farmacocinética , Fator de Necrose Tumoral alfa/sangue , Adulto Jovem
3.
Eur J Med Chem ; 122: 723-730, 2016 Oct 21.
Artigo em Inglês | MEDLINE | ID: mdl-27476117

RESUMO

The structural similarity between an MmpL3 inhibitor BM212, and a cannabinoid receptor modulator rimonabant, prompted us to investigate the anti-tubercular activity of rimonabant and its analogues. Further optimization, particularly through incorporation of silicon into the scaffold, resulted in new compounds with significant improvement in anti-tubercular activity against Mycobacterium tuberculosis (H37Rv). The sila analogue 18a was found to be the most potent antimycobacterial compound (MIC, 31 ng/mL) from this series with an excellent selectivity index.


Assuntos
Antituberculosos/química , Antituberculosos/farmacologia , Reposicionamento de Medicamentos , Piperidinas/química , Piperidinas/farmacologia , Pirazóis/química , Pirazóis/farmacologia , Antituberculosos/metabolismo , Antituberculosos/toxicidade , Células Hep G2 , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Mycobacterium tuberculosis/efeitos dos fármacos , Piperidinas/metabolismo , Piperidinas/toxicidade , Pirazóis/metabolismo , Pirazóis/toxicidade , Rimonabanto , Relação Estrutura-Atividade
4.
Sci Pharm ; 84(2): 347-59, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27222609

RESUMO

Efficacy assessments using a combination of baricitinib and methotrexate necessitate the development of an analytical method for the determination of both drugs in plasma with precision. A high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of baricitinib and methotrexate in rat plasma. Extraction of baricitinib, methotrexate, and tolbutamide (internal standard; IS) from 50 µL of rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of the analytes was performed on the YMC pack ODS AM (150 mm × 4.6 mm, 5 µm) column under gradient conditions with methanol: 2.0 mM ammonium acetate buffer as the mobile phases at a flow rate of 1 mL/min. The precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated with selective reaction monitoring in positive ionization mode. The method was validated over a concentration range of 0.5-250.00 ng/mL for baricitinib and methotrexate. Mean extraction recoveries for baricitinib, methotrexate, and IS of 86.8%, 89.4%, and 91.8% were consistent across low, medium, and high QC levels, respectively. Precision and accuracy at low, medium, and high quality control levels were less than 15% across the analytes. Benchtop, wet, freeze-thaw, and long-term stability were evaluated for both of the analytes. The analytical method was applied to support the pharmacokinetic study of simultaneous estimation of baricitinib and methotrexate in Wistar rats. Assay reproducibility was demonstrated by reanalysis of 18 incurred samples.

5.
ACS Med Chem Lett ; 6(11): 1105-10, 2015 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-26617962

RESUMO

Therapeutic options for brain infections caused by pathogens with a reduced sensitivity to drugs are limited. Recent reports on the potential use of linezolid in treating brain infections prompted us to design novel compounds around this scaffold. Herein, we describe the design and synthesis of various oxazolidinone antibiotics with the incorporation of silicon. Our findings in preclinical species suggest that silicon incorporation is highly useful in improving brain exposures. Interestingly, three compounds from this series demonstrated up to a 30-fold higher brain/plasma ratio when compared to linezolid thereby indicating their therapeutic potential in brain associated disorders.

6.
J Pharm Biomed Anal ; 107: 151-8, 2015 Mar 25.
Artigo em Inglês | MEDLINE | ID: mdl-25594893

RESUMO

Efficacy assessments using a combination of ibrutinib and lenalidomide necessitate the development of an analytical method for determination of both drugs in plasma with precision. A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of lenalidomide, ibrutinib, and its active metabolite PCI45227 in rat plasma. Extraction of lenalidomide, ibrutinib, PCI45227 and tolbutamide (internal standard; IS) from 50 µl rat plasma was carried out by liquid-liquid extraction with ethyl acetate:dichloromethane (90:10) ratio. Chromatographic separation of analytes was performed on YMC pack ODS AM (150 mm × 4.6 mm, 5 µm) column under gradient conditions with acetonitrile:0.1% formic acid buffer as the mobile phases at a flow rate of 1 ml/min. Precursor ion and product ion transition for analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.72-183.20 ng/ml for ibrutinib, 0.76-194.33 ng/ml for PCI-45227 and 1.87-479.16 ng/ml for lenalidomide. Mean extraction recovery for ibrutinib, PCI-45227, lenalidomide and IS of 75.2%, 84.5%, 97.3% and 92.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability was evaluated for all the analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of lenalidomide, ibrutinib, and its active metabolite PCI-45227 in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples.


Assuntos
Adenina/análogos & derivados , Plasma/química , Pirazóis/sangue , Pirazóis/química , Pirimidinas/sangue , Pirimidinas/química , Talidomida/análogos & derivados , Adenina/sangue , Adenina/química , Animais , Calibragem , Cromatografia Líquida de Alta Pressão/métodos , Estabilidade de Medicamentos , Lenalidomida , Extração Líquido-Líquido/métodos , Masculino , Piperidinas , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Espectrometria de Massas em Tandem/métodos , Talidomida/sangue , Talidomida/química , Tolbutamida/sangue , Tolbutamida/química
7.
Bioorg Med Chem Lett ; 24(14): 3088-91, 2014 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-24863744

RESUMO

DDD-028 (4), a novel pentacyclic pyridoindolobenzazepine derivative was evaluated in vitro for receptor binding affinity and in vivo for analgesic activity using rodent models of neuropathic and inflammatory pain. DDD-028 does not bind to opioid, cannabinoid, dopamine, or histamine receptors. DDD-028 is very active even at the low oral dose of 1-5 mg/kg in both neuropathic, (spinal nerve ligation and chronic constriction injury) and inflammatory (Complete Freund's Adjuvant Induced) models of pain. DDD-028 appears to be about 6-fold more potent than pregabalin and indomethacin. Visual observation of all the animals used in these studies indicated that DDD-028 is well tolerated without any sedation. Thus, DDD-028 seems to be a promising candidate for the treatment of neuropathic and inflammatory pain without the possible side effects or abuse potential associated with opioid or cannabinoid activities.


Assuntos
Analgésicos/uso terapêutico , Anti-Inflamatórios não Esteroides/uso terapêutico , Azepinas/farmacologia , Carbolinas/farmacologia , Constrição Patológica/tratamento farmacológico , Inflamação/tratamento farmacológico , Neuralgia/tratamento farmacológico , Nervos Espinhais/efeitos dos fármacos , Analgésicos/administração & dosagem , Analgésicos/química , Animais , Anti-Inflamatórios não Esteroides/administração & dosagem , Anti-Inflamatórios não Esteroides/química , Azepinas/administração & dosagem , Azepinas/química , Carbolinas/administração & dosagem , Carbolinas/química , Doença Crônica , Camundongos , Estrutura Molecular , Medição da Dor , Ratos , Nervos Espinhais/patologia
8.
J Pharm Biomed Anal ; 94: 125-31, 2014 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-24561338

RESUMO

Efficacy assessments using a combination of ruxolitinib and nilotinib necessitate the development of a high precision analytical method for determination of both drugs in plasma. A high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed for the simultaneous determination of ruxolitinib and nilotinib in rat plasma. Extraction of ruxolitinib, nilotinib and dasatinib (internal standard; IS) from 50µl rat plasma was carried out by protein precipitation with methanol. Chromatographic separation of analytes was performed on YMC pack ODS AM (150mm×4.6mm, 5µm) column under gradient conditions with acetonitrile:2.0mM ammonium acetate buffer as the mobile phase at a flow rate of 1ml/min. Precursor ion and product ion transition for both analytes and IS were monitored on a triple quadrupole mass spectrometer, operated in the selective reaction monitoring with positive ionization mode. Method was validated over a concentration range of 0.16-247ng/ml for ruxolitinib and 0.86-219ng/ml for nilotinib. Mean extraction recovery for ruxolitinib, nilotinib, and IS of 99.6%, 97.6% and 90.3% were consistent across low, medium, and high QC levels. Precision and accuracy at low, medium and high quality control levels were less than 15% across analytes. Bench top, wet, freeze-thaw and long term stability were evaluated for both analytes. The analytical method was applied to support a pharmacokinetic study of simultaneous estimation of ruxolitinib and nilotinib in Wistar rat. Assay reproducibility was demonstrated by re-analysis of 18 incurred samples.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Pirazóis/sangue , Pirazóis/química , Pirimidinas/sangue , Pirimidinas/química , Espectrometria de Massas em Tandem/métodos , Animais , Feminino , Nitrilas , Pirazóis/farmacocinética , Pirimidinas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Espectrometria de Massas por Ionização por Electrospray/métodos
9.
Artigo em Inglês | MEDLINE | ID: mdl-24463402

RESUMO

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) method was developed and validated for simultaneous quantification of idelalisib, fludarabine and lenalidomide using tolbutamide as an internal standard. Analytes were recovered by liquid-liquid extraction and separated on a reverse phase C18 column (150mm×4.6mm i.d., 5µm) using methanol:0.1% formic acid buffer (70:30) as mobile phase at a flow rate of 1mL/min in isocratic mode. Selective reaction monitoring was performed using the transitions, i.e. m/z 416.25/176.48, 286.11/154.10, 260.15/149.15, and 271.14/155.06 to quantify idelalisib, fludarabine and lenalidomide and tolbutamide, respectively. The method was validated over the concentration range of 1.15-576.84ng/mL for idelalisib, 0.95-476.25ng/mL for fludarabine and 0.97-486.19ng/mL for lenalidomide. Intra and inter-day accuracy and precision of validated method were within the acceptable limits of <15%. Coefficients of correlation (r(2)) for the calibration curves were >0.998 for all analytes. The method was successfully applied for simultaneous estimation of idelalisib, fludarabine and lenalidomide in a pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Purinas/sangue , Quinazolinonas/sangue , Espectrometria de Massas por Ionização por Electrospray/métodos , Talidomida/análogos & derivados , Vidarabina/análogos & derivados , Animais , Estabilidade de Medicamentos , Lenalidomida , Masculino , Purinas/química , Purinas/farmacocinética , Quinazolinonas/química , Quinazolinonas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espectrometria de Massas em Tandem/métodos , Talidomida/sangue , Talidomida/química , Talidomida/farmacocinética , Vidarabina/sangue , Vidarabina/química , Vidarabina/farmacocinética
10.
J Pharm Pharmacol ; 64(11): 1638-45, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-23058051

RESUMO

OBJECTIVES: Atorvastatin (ATV) and cilostazol (CLZ) are often co-prescribed to treat conditions such as peripheral arterial disease. In the present study, the drug-drug interaction potential of multi-dose CLZ on both pharmacokinetics and the lipid-lowering ability of single-dose ATV is demonstrated. METHOD: The pharmacokinetic parameters of ATV were determined in Wistar rats after per-oral pre-treatment with CLZ for 7 days in order to assess the interaction potential between ATV and CLZ. In-vitro metabolic inhibition and everted gut sac studies were conducted to elucidate the mechanism of this interaction. Biochemistry analyser was used to estimate lipid profiles in Wistar rats. A validated LC-MS/MS method was employed to simultaneously quantify both ATV and CLZ in rat plasma matrix. KEY FINDINGS: A statistically significant increase in systemic exposure to ATV after a single dose was observed in CLZ pre-treated rats. In-vitro metabolism studies using rat liver microsome (RLM) demonstrated statistically significant inhibition of ATV metabolism when co-incubated with CLZ. No change in apparent permeability of ATV was observed in the presence of CLZ. The blood lipid profile study after ATV administration indicated a statistically significant decrease in total cholesterol, triglycerides and LDL-cholesterol. CONCLUSIONS: Multi-dose administration of CLZ influences the pharmacokinetics and lipid-lowering properties of ATV. Collectively, an apparent interaction between selected drugs was evident.


Assuntos
Ácidos Heptanoicos/farmacocinética , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacocinética , Pirróis/farmacocinética , Tetrazóis/farmacologia , Vasodilatadores/farmacologia , Animais , Atorvastatina , Colesterol/sangue , LDL-Colesterol/sangue , Cromatografia Líquida de Alta Pressão , Cilostazol , Interações Medicamentosas , Ácidos Heptanoicos/farmacologia , Inibidores de Hidroximetilglutaril-CoA Redutases/farmacologia , Masculino , Microssomos Hepáticos/metabolismo , Pirróis/farmacologia , Ratos , Ratos Wistar , Espectrometria de Massas em Tandem , Tetrazóis/administração & dosagem , Triglicerídeos/sangue , Vasodilatadores/administração & dosagem
11.
Sci Pharm ; 80(3): 633-46, 2012.
Artigo em Inglês | MEDLINE | ID: mdl-23008811

RESUMO

A new method for the simultaneous determination of celecoxib, erlotinib, and its active metabolite desmethyl-erlotinib (OSI-420) in rat plasma, by liquid chromatography/tandem mass spectrometry with positive/negative ion-switching electrospray ionization mode, was developed and validated. Protein precipitation with methanol was selected as the method for preparing the samples. The analytes were separated on a reverse-phase C(18) column (50mm×4.6mm i.d., 3µ) using methanol: 2 mM ammonium acetate buffer, and pH 4.0 as the mobile phase at a flow rate 0.8 mL/min. Sitagliptin and Efervirenz were used as the internal standards for quantification. The determination was carried out on a Theremo Finnigan Quantam ultra triple-quadrupole mass spectrometer, operated in selected reaction monitoring (SRM) mode using the following transitions monitored simultaneously: positive m/z 394.5→278.1 for erlotinib, m/z 380.3→278.1 for desmethyl erlotinib (OSI-420), and negative m/z -380.1→ -316.3 for celecoxib. The limits of quantification (LOQs) were 1.5 ng/mL for Celecoxib, erlotinib, and OSI-420. Within- and between-day accuracy and precision of the validated method were within the acceptable limits of < 15% at all concentrations. The quantitation method was successfully applied for the simultaneous estimation of celecoxib, erlotinib, and desmethyl erlotinib in a pharmacokinetic study in Wistar rats.

12.
J Mass Spectrom ; 47(12): 1612-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-23280750

RESUMO

A sensitive and reliable high-performance liquid chromatography-mass spectrometry (LC-MS/MS) was developed and validated for simultaneous quantification IC87114, roflumilast (RFM), and its active metabolite roflumilast N-oxide (RFN) using tolbutamide as an internal standard. The analytes were extracted by using liquid-liquid extraction and separated on a reverse phase C(18) column (50 mm × 3 mm i.d., 4.6 µ) using methanol: 2 mM ammonium acetate buffer, pH 4.0 as mobile phase at a flow rate 1 mL/min in gradient mode. Selective reaction monitoring was performed using the transitions m/z 398.3 > 145.9, 403.1 >186.9, 419.1 > 187.0 and 271.1 > 155.0 to quantify quantification IC87114, RFM, RFN and tolbutamide, respectively. The method was validated over the concentration range of 0.1-60 ng.mL(-1) for RFM and RFN and 6 to 2980 ng.mL(-1) for IC87114. Intra- and inter-day accuracy and precision of validated method were within the acceptable limits of <15% at all concentrations. Coefficients of correlation (r(2) ) for the calibration curves were >0.99 for all analytes. The quantitation method was successfully applied for simultaneous estimation of IC87114, RFM and RFN in a pharmacokinetic drug-drug interaction study in Wistar rats.


Assuntos
Adenina/análogos & derivados , Aminopiridinas/sangue , Benzamidas/sangue , Cromatografia Líquida de Alta Pressão/métodos , Quinazolinas/sangue , Espectrometria de Massas em Tandem/métodos , Adenina/sangue , Adenina/química , Adenina/farmacocinética , Aminopiridinas/química , Aminopiridinas/farmacocinética , Animais , Benzamidas/química , Benzamidas/farmacocinética , Ciclopropanos/sangue , Ciclopropanos/química , Ciclopropanos/farmacocinética , Estabilidade de Medicamentos , Modelos Lineares , Masculino , Quinazolinas/química , Quinazolinas/farmacocinética , Ratos , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
13.
Arzneimittelforschung ; 58(6): 288-96, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18677971

RESUMO

A high performance liquid chromatographic (HPLC) method for simultaneous determination of rosiglitazone, CAS 122320-73-4, RSG), cilostazol (CAS 73963-72-1, CLZ) and its active metabolite 3, 4-dehydro-cilostazol (DCLZ), using pioglitazone (PIO) as internal standard (IS), in rat plasma is described. The plasma was extracted with methyl t-butyl ether, the dry extract was reconstituted in mobile phase and the aliquot was injected. The eluent drugs were detected by UV at dual wavelength of 226 nm (RSG and DCLZ) and 257 nm (CLZ). The mobile phase consisting of acetonitrile:potassium di-hydrogen phosphate buffer (35:65 v/v) was used at the flow rate of 1.2 ml/min on a reverse phase C18 column. The absolute recovery was above 90% of all analytes over the concentration range of 25-2500 ng/ml for RSG and CLZ and 20-2000 ng/ ml for DCLZ. The relative standard deviation (RSD) of the inter-day and intra-day precision ranged from 2.8 to 8.4% and 0.9 to 5.9%, respectively. The method is simple, rapid, accurate and sensitive and was applied to pharmacokinetic studies.


Assuntos
Hipoglicemiantes/sangue , Hipoglicemiantes/farmacocinética , Inibidores da Agregação Plaquetária/sangue , Inibidores da Agregação Plaquetária/farmacocinética , Tetrazóis/sangue , Tetrazóis/farmacocinética , Tiazolidinedionas/sangue , Tiazolidinedionas/farmacocinética , Animais , Área Sob a Curva , Cromatografia Líquida de Alta Pressão , Cilostazol , Interações Medicamentosas , Meia-Vida , Masculino , Controle de Qualidade , Ratos , Ratos Wistar , Padrões de Referência , Reprodutibilidade dos Testes , Rosiglitazona , Espectrofotometria Ultravioleta
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