RESUMO

Objective: Low HDL-C (high-density lipoprotein cholesterol) is the most frequent dyslipidemia in Mexicans, but few studies have examined the underlying genetic basis. Our purpose was to identify genetic variants associated with HDL-C levels and cardiovascular risk in the Mexican population. Approach and Results: A genome-wide association studies for HDL-C levels in 2335 Mexicans, identified four loci associated with genome-wide significance: CETP, ABCA1, LIPC, and SIDT2. The SIDT2 missense Val636Ile variant was associated with HDL-C levels and was replicated in 3 independent cohorts (P=5.9×10−18 in the conjoint analysis). The SIDT2/Val636Ile variant is more frequent in Native American and derived populations than in other ethnic groups. This variant was also associated with increased ApoA1 and glycerophospholipid serum levels, decreased LDL-C (low-density lipoprotein cholesterol) and ApoB levels, and a lower risk of premature CAD. Because SIDT2 was previously identified as a protein involved in sterol transport, we tested whether the SIDT2/Ile636 protein affected this function using an in vitro site-directed mutagenesis approach. The SIDT2/Ile636 protein showed increased uptake of the cholesterol analog dehydroergosterol, suggesting this variant affects function. Finally, liver transcriptome data from humans and the Hybrid Mouse Diversity Panel are consistent with the involvement of SIDT2 in lipid and lipoprotein metabolism. Conclusions: This is the first genome-wide association study for HDL-C levels seeking associations with coronary artery disease in the Mexican population. Our findings provide new insight into the genetic architecture of HDL-C and highlight SIDT2 as a new player in cholesterol and lipoprotein metabolism in humans.

Assuntos

HDL-Colesterol/sangue , Doença da Artéria Coronariana/genética , Hiperlipoproteinemia Tipo II/genética , Proteínas de Transporte de Nucleotídeos/genética , Polimorfismo de Nucleotídeo Único , Adulto , Idade de Início , Animais , Biomarcadores/sangue , Estudos de Casos e Controles , Criança , Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/diagnóstico , Doença da Artéria Coronariana/epidemiologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Células HEK293 , Fatores de Risco de Doenças Cardíacas , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Hiperlipoproteinemia Tipo II/epidemiologia , Masculino , Análise da Randomização Mendeliana , México/epidemiologia , Camundongos , Pessoa de Meia-Idade , Proteínas de Transporte de Nucleotídeos/metabolismo , Fenótipo , Medição de Risco

RESUMO

AbstractFollowing publication of the original article [1], the author reported their given name have been erroneously tagged as their family names.

RESUMO

BACKGROUND: Fibrosis is a response to chronic liver disease that results in excessive accumulation of extracellular matrix proteins and formation of scar tissue. Fibrosis represents a clinical challenge of worldwide significance. Several studies have demonstrated that many natural products and herbal medicines have activity against liver fibrosis, and extracts of milk thistle such as silymarin and silybin are the natural compounds most commonly prescribed for liver diseases. Therefore, we sought to assess and compare the pharmacokinetic properties and bioavailability of silybin-phosphatidylcholine complex in oily-medium soft-gel capsules and conventional silymarin tablets in healthy Mexican volunteers. METHODS: We enrolled 23 healthy volunteers to participate in a prospective, balanced, blind, single-dose, two-way crossover study with a one-week washout period. Fasting participants received either 45 mg silybin-phosphatidylcholine complex or 70 mg silymarin to assess which formulation provided better bioavailability of silybin. Plasma was obtained and analysed for silybin concentration using a validated ultra-performance liquid chromatography-tandem mass spectroscopy method. Pharmacokinetic parameters were obtained by non-compartmental analysis and values were compared by analysis of variance for a crossover design. Ratios of maximum plasma drug concentration and area under the curve (AUC) were obtained and 90% confidence intervals were calculated. RESULTS: The 23 healthy subjects (11 women, 12 men) who participated in the study were aged 22-31 years old (average: 28), average weight 64.8 kg, height 1.65 m and body mass index 23.5 kg/m2. Plasma levels of silybin were higher after the administration of silybin-phosphatidylcholine complex capsules compared with that after conventional silymarin tablets (P <  0.0001). CONCLUSIONS: The silybin-phosphatidylcholine complex in oily-medium soft-gel capsules seems to provide superior bioavailability. However, clinical studies must be performed to demonstrate its clinical relevance in the treatment of liver diseases. TRIAL REGISTRATION: NCT03440164 ; registered on November 11, 2016.

Assuntos

Fosfatidilcolinas/farmacocinética , Silibina/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Cápsulas , Estudos Cross-Over , Feminino , Géis , Voluntários Saudáveis , Humanos , Masculino , Silibina/sangue , Método Simples-Cego , Comprimidos , Adulto Jovem

RESUMO

BACKGROUND: Serum uric acid (SUA) is a heritable trait associated with cardiovascular risk factors and coronary artery disease (CAD). Genome wide association studies (GWAS) have identified several genes associated with SUA, mainly in European populations. However, to date there are few GWAS in Latino populations, and the role of SUA-associated single nucleotide polymorphisms (SNPs) in cardiovascular disease has not been studied in the Mexican population. METHODS: We performed genome-wide SUA association study in 2153 Mexican children and adults, evaluated whether genetic effects were modified by sex and obesity, and used a Mendelian randomization approach in an independent cohort to study the role of SUA modifying genetic variants in premature CAD. RESULTS: Only two loci were associated with SUA levels: SLC2A9 (ß = -0.47 mg/dl, P = 1.57 × 10-42 for lead SNP rs7678287) and ABCG2 (ß = 0.23 mg/dl, P = 2.42 × 10-10 for lead SNP rs2231142). No significant interaction between SLC2A9 rs7678287 and ABCG2 rs2231142 genotypes and obesity was observed. However, a significant ABCG2 rs2231142 genotype*sex interaction (P = 0.001) was observed in adults but not in children. Although SUA levels were associated with premature CAD, metabolic syndrome and decreased glomerular filtration rate (eGFR), only ABCG2 rs2231142 was associated with decreased eGFR in the premature CAD group. CONCLUSIONS: SUA elevation was independently associated with premature CAD, metabolic syndrome and decreased eGFR in the Mexican population. However, a Mendelian randomization approach using the lead SUA-associated SNPs (SLC2A9 and ABCG2) did not support a causal role of elevated SUA levels for premature CAD.

Assuntos

Doença da Artéria Coronariana/sangue , Doença da Artéria Coronariana/genética , Estudo de Associação Genômica Ampla/métodos , Polimorfismo de Nucleotídeo Único/genética , Ácido Úrico/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Criança , Doença da Artéria Coronariana/epidemiologia , Feminino , Humanos , Masculino , Análise da Randomização Mendeliana/métodos , México/epidemiologia , Pessoa de Meia-Idade , Adulto Jovem

RESUMO

The aim of the present study was to determine whether tizanidine, an alpha2-adrenoceptor agonist, is able to increase the anti-inflammatory and anti-nociceptive effects of naproxen and ketorolac with a low incidence of gastric injury and spontaneous activity in rats. The anti-inflammatory effect was assayed in a carrageenan test, and oral administration of tizanidine (ED40 =0.94±0.2mg/kg), naproxen (ED40=3.18±0.4mg/kg), and ketorolac (ED40=16.4±1.9mg/kg) showed a dose-dependent effect on inflammation. The anti-nociceptive effect was assayed in the formalin test, and administration of tizanidine (ED40=0.39±0.06mg/kg, p.o.), naproxen (ED40=33.9±3.9mg/kg, p.o.) or ketorolac (ED40=6.49±1mg/kg, p.o.) each showed a dose-dependent anti-nociceptive effect. The effects of combinations of tizanidine/naproxen and tizanidine/ketorolac were determined considering their ED40 at a rate of 1:1. Additionally, the tizanidine/naproxen and tizanidine/ketorolac combinations showed anti-inflammatory and anti-nociceptive effects. The tizanidine/ketorolac combination was more potent than tizanidine/naproxen, in both inflammatory (interaction index=0.03 tizanidine/ketorolac and 0.07 tizanidine/naproxen) and nociceptive (interaction index=0.005 tizanidine/ketorolac and 0.01 tizanidine/naproxen) processes. In both cases, tizanidine improved naproxen and ketorolac gastrointestinal tolerability by 50%. Furthermore, co-administration of tizanidine with naproxen or ketorolac did not modify the spontaneous activity in the same way as individual tizanidine administration. Considering that tizanidine increases the anti-inflammatory and anti-nociceptive effects of naproxen or ketorolac, with an increase in gastric tolerability, tizanidine could provide therapeutic advantages in the clinical treatment of inflammation and pain.

Assuntos

Clonidina/análogos & derivados , Cetorolaco/efeitos adversos , Cetorolaco/farmacologia , Naproxeno/efeitos adversos , Naproxeno/farmacologia , Analgésicos/efeitos adversos , Analgésicos/farmacologia , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/farmacologia , Clonidina/farmacologia , Relação Dose-Resposta a Droga , Sinergismo Farmacológico , Masculino , Ratos , Ratos Wistar , Estômago/efeitos dos fármacos

RESUMO

The purpose of this study was to assess the effect of the non-selective cholecystokinin receptor antagonist proglumide on the antinociceptive activity of ketorolac and meloxicam in non-diabetic and diabetic rats. Streptozotocin (60 mg/kg) injection caused hyperglycemia which was maintained for 2 weeks. Formalin-evoked flinching was increased in diabetic rats as compared to non-diabetic rats. Local peripheral ipsilateral, but not contralateral, administration of ketorolac and meloxicam produced antinociception in non-diabetic and diabetic rats. However, the antinociceptive effect of both drugs was significantly reduced in diabetic animals. Proglumide was ineffective by itself and it did not affect the antinociception induced by the cyclooxygenase inhibitors in non-diabetic rats. Contrariwise, proglumide reduced formalin-induced nociception and it increased ketorolac- or meloxicam-induced antinociception in diabetic rats. These results suggest that peripheral cholecystokinin plays an important role in diabetes-induced sensitization as well as in the reduction of the antinociceptive effects of ketorolac and meloxicam in diabetic rats. The combination of cholecystokinin receptor antagonists and ketorolac or meloxicam may be a useful strategy to reduce nociception in diabetic patients.

Assuntos

Analgésicos/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Diabetes Mellitus Experimental/fisiopatologia , Formaldeído/efeitos adversos , Proglumida/farmacologia , Prostaglandina-Endoperóxido Sintases/metabolismo , Animais , Anti-Inflamatórios não Esteroides/farmacologia , Comportamento Animal/efeitos dos fármacos , Sinergismo Farmacológico , Cetorolaco/farmacologia , Masculino , Meloxicam , Ratos , Ratos Wistar , Receptores da Colecistocinina/antagonistas & inibidores , Tiazinas/farmacologia , Tiazóis/farmacologia

RESUMO

Residency in cities with high air pollution is associated with neuroinflammation and neurodegeneration in healthy children, young adults, and dogs. Nonsteroidal anti-inflammatory drugs may offer neuroprotection. The authors measured the plasma concentrations of 3-nitrotyrosine and the cerebro-spinal-fluid concentrations of prostaglandin E2 metabolite and the oligomeric form of amyloid derived diffusible ligand; measured the mRNA expression of cyclooxygenase-2, interleukin 1beta, CD14, and Aquaporin-4 in target brain areas; and evaluated brain MRI, cognition, and neuropathology in 8 dogs treated with a preferential cyclooxygenase-2 inhibitor (Nimesulide) versus 7 untreated litter-matched Mexico City dogs. Nimesulide significantly decreased nitrotyrosine in plasma (p < .0001), frontal gray IL1beta (p = .03), and heart IL1beta (p = .02). No effect was seen in mRNA COX2, amyloid, and PGE2 in CSF or the MRI white matter lesions. All exposed dogs exhibited olfactory bulb and frontal accumulation of Abeta(42) in neurons and blood vessels and frontal vascular subcortical pathology. White matter hyperintense MRI frontal lesions were seen in 4/6 non-treated and 6/8 treated dogs. Nonsteroidal anti-inflammatory drugs may offer limited neuroprotection in the setting of severe air pollution exposures. The search for potentially beneficial drugs useful to ameliorate the brain effects of pollution represents an enormous clinical challenge.

Assuntos

Poluição do Ar/efeitos adversos , Inibidores de Ciclo-Oxigenase 2/farmacologia , Ciclo-Oxigenase 2/metabolismo , Cães/metabolismo , Sulfonamidas/farmacologia , Peptídeos beta-Amiloides/metabolismo , Animais , Aquaporina 4/metabolismo , Encéfalo/anatomia & histologia , Encéfalo/patologia , Distribuição de Qui-Quadrado , Ciclo-Oxigenase 2/genética , Inibidores de Ciclo-Oxigenase 2/farmacocinética , Lobo Frontal/metabolismo , Imuno-Histoquímica , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Receptores de Lipopolissacarídeos/metabolismo , Imageamento por Ressonância Magnética , México , Mucosa Nasal/metabolismo , Ozônio/efeitos adversos , Projetos Piloto , Prostaglandinas E/metabolismo , Estatísticas não Paramétricas , Sulfonamidas/farmacocinética , Tirosina/metabolismo

RESUMO

Omeprazole is a very widely used proton-pump inhibitor. Currently, there are several branches available in Mexico, however, limited information about their bioavailabilities is available. The purpose of this study was to compare the bioavailability of two of them, Losec and Omelcid. Twenty-eight healthy volunteers were enrolled in this study that was carried out following the recommendations of the Declaration of Helsinki. Subjects read the protocol that was approved by the institutional research and ethics committees and gave written consent for participation. After an overnight fast, volunteers received an oral dose of 20 mg omeprazole (formulation A or B) and blood samples were obtained at selected times during 8 hours. Plasma was obtained by centrifugation and stored frozen until analyzed by a validated HPLC method. Pharmacokinetic parameters were obtained by non-compartmental analysis and values (+/- s.e.m.) obtained were as follows: Cmax 354.28 +/- 51.57 and 308.95 +/- 44.42 ng/ml, t(max) 2.26 +/- 0.22 and 2.63 +/- 0.24 h and AUC(8h) 701.01 +/- 109.34 and 774.13 +/- 132.84 ngh/ml for formulations A and B respectively. Log transformed Cmax and AUC(8h) were compared by analysis of variance and 90% confidence limits of the parameters ratios (B/A) were 72.73-106.34% and 90.32-124.96%, for Cmax and AUC(8h) respectively. As confidence intervals did not exceed the 70-142.9% limits for Cmax and 80-125% for AUC(8h), it is concluded that the formulations tested are bioequivalent.

Assuntos

Antiulcerosos/farmacocinética , Omeprazol/farmacocinética , Administração Oral , Adulto , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Humanos , Masculino , Omeprazol/administração & dosagem , Omeprazol/química

RESUMO

Fluconazole and itraconazole are antimycotics widely used in Mexico. However, limited information about their pharmacokinetics is available. It has been reported that physicochemical characteristics of these compounds are disparate, leading to different pharmacokinetic profiles. Moreover, it has been suggested that pharmacokinetics of some drugs may vary in Mexicans when compared with Caucasians due to reduced metabolism by CYP3A4. Based on these distinctions, it is important to carry out local studies in order to establish dosage regimens according the characteristics of each population. The purpose of this study was to compare the oral pharmacokinetics of fluconazole and itraconazole in Mexicans and to compare our results with those reported in other populations. Two groups of 16 subjects volunteered for this study that was approved by the Institutional Research and Ethics Committees. All subjects gave written informed consent for participation. After an overnight fast, volunteers received an oral dose of 100 mg fluconazole or itraconazole and blood samples were obtained at selected times over 96 hr. Plasma was obtained and analyzed by HPLC and pharmacokinetic parameters were obtained. As expected, fluconazole plasma levels were higher than itraconazole due to a lower volume of distribution. Additionally, less variability was observed for fluconazole. When data obtained in Mexicans was compared with those obtained in other populations, no differences were observed, suggesting that there are not interethnic differences in the pharmacokinetics of fluconazole and itraconazole.

Assuntos

Antifúngicos/farmacocinética , Fluconazol/farmacocinética , Itraconazol/farmacocinética , Administração Oral , Etnicidade , Fluconazol/administração & dosagem , Humanos , Itraconazol/administração & dosagem , Masculino , México

RESUMO

BACKGROUND AND OBJECTIVE: Fluconazole is a triazole derivative widely used for the treatment of mycoses. It has been established that several factors are able to modify its pharmacokinetics, including the bodyweight of the patient; however, there is controversy about the influence of gender on the pharmacokinetics of fluconazole. In order to clarify this controversy we decided to evaluate the pharmacokinetics of fluconazole in males and females. METHODS: Fifty-nine subjects (26 males and 33 females) were enrolled in this study. Volunteers received an oral dose of fluconazole 100mg under fasting conditions and blood samples were collected at selected times over a period of 96 hours. Plasma was obtained and analysed by a high-performance liquid chromatography method. RESULTS: The plasma fluconazole concentrations obtained in women were higher than those obtained in men. This was reflected in differences in most pharmacokinetic parameters. However, when parameters were normalised according to the bodyweight of subjects, differences were reduced, indicating that this factor plays a role in the differences observed. Notwithstanding, differences in other parameters, such as normalised maximum plasma concentration, time to reach maximum plasma concentration, volume of distribution and half-life, remained. CONCLUSION: Fluconazole pharmacokinetics are influenced by both bodyweight and gender, most likely because of differences in total body water between males and females. Although the clinical impact on efficacy and safety of the pharmacokinetic differences observed in this study was not established, it is desirable that fluconazole dosage regimens take into account both the gender and the bodyweight of the patient.

Assuntos

Antifúngicos/farmacocinética , Peso Corporal , Fluconazol/farmacocinética , Administração Oral , Água Corporal , Cromatografia Líquida de Alta Pressão , Feminino , Meia-Vida , Humanos , Masculino , Fatores Sexuais , Fatores de Tempo , Distribuição Tecidual

RESUMO

The effects of cholecystokinin (CCK-8) and the CCK receptor antagonist proglumide, on antinociception induced by local peripheral (subcutaneous) injected morphine in non-diabetic (ND) and streptozotocin-induced diabetic (D) rats, were examined by means of the formalin test. Morphine induced dose-dependent antinociception both in ND and D rats. However, in D rats, antinociceptive morphine potency was about twofold less than in ND rats. Pre-treatment with CCK-8 abolished the antinociceptive effect of morphine in a dose-dependent manner in both groups of rats. Additionally, proglumide enhanced the antinociceptive effect induced by all doses of morphine tested. Both CCK-8 and proglumide had no effect on flinching behaviour when given alone to ND rats. Unlike ND rats, in D rats proglumide produced dose-dependent antinociception and CCK-8 enhanced formalin-evoked flinches, as observed during the second phase of the test. In conclusion, our data show a decrease in peripheral antinociceptive potency of morphine when diabetes was present. Additionally, peripheral CCK plays an antagonic role to the peripheral antinociceptive effect of morphine, additional to the well known CCK/morphine interaction at spinal and supraspinal level.

Assuntos

Colecistocinina/metabolismo , Morfina/uso terapêutico , Entorpecentes/uso terapêutico , Neuralgia/tratamento farmacológico , Animais , Área Sob a Curva , Colecistocinina/administração & dosagem , Colecistocinina/antagonistas & inibidores , Diabetes Mellitus Experimental/complicações , Relação Dose-Resposta a Droga , Interações Medicamentosas , Formaldeído/efeitos adversos , Masculino , Neuralgia/etiologia , Medição da Dor , Limiar da Dor/efeitos dos fármacos , Fragmentos de Peptídeos/administração & dosagem , Proglumida/administração & dosagem , Ratos , Ratos Wistar

RESUMO

The possible pronociceptive role of peripheral cholecystokinin (CCK-8) as well as CCK(A) and CCK(B) receptors in diabetic rats was assessed. Subcutaneous injection of 0.5% formalin induced a greater nociceptive behavior in diabetic than in non-diabetic rats. Moreover, local peripheral injection of CCK-8 (0.1-100 microg) significantly increased 0.5% formalin-induced nociceptive activity in diabetic, but not in non-diabetic, rats. This effect was restricted to the formalin-injected paw as administration of CCK-8 into the contralateral paw was ineffective. Local peripheral administration of CCK-8, in the absence of formalin injection, produced a low level of, but significant increase in, flinching behavior in diabetic compared to non-diabetic rats. In addition, local peripheral administration of the non-selective CCK receptor antagonist proglumide (1-100 microg), CCK(A) receptor antagonist lorglumide (0.1-100 microg) or CCK(B) receptor antagonist CR-2945 (0.1-100 microg), but not vehicle or contralateral administration of CCK receptor antagonists, significantly reduced 0.5% formalin-induced flinching in diabetic rats. CR-2945 was the most effective drug in this condition. These effects were not observed in non-diabetic rats. The local peripheral pronociceptive effect of CCK-8 (100 microg) was significantly reduced by proglumide (100 microg), lorglumide (100 microg), and CR-2945 (100 microg). Results suggest that diabetes-induced peripheral sensitization could be due to a local peripheral release of CCK-8, which in turn would act on CCK(B), mainly but also in CCK(A), receptors located on the primary afferent neurons.

Assuntos

Complicações do Diabetes/fisiopatologia , Hiperalgesia/fisiopatologia , Limiar da Dor/efeitos dos fármacos , Receptor de Colecistocinina A/metabolismo , Receptor de Colecistocinina B/metabolismo , Sincalida/administração & dosagem , Sincalida/metabolismo , Animais , Relação Dose-Resposta a Droga , Combinação de Medicamentos , Resistência a Medicamentos , Formaldeído , Hiperalgesia/induzido quimicamente , Ratos

RESUMO

The possible participation of the nitric oxide (NO)-cyclic GMP-protein kinase G (PKG) pathway on gabapentin-induced spinal antiallodynic activity was assessed in spinal nerve injured rats. Intrathecal gabapentin, diazoxide or pinacidil reduced tactile allodynia in a dose-dependent manner. Pretreatment with NG-L-nitro-arginine methyl ester (L-NAME, non-specific inhibitor of NO synthase NOS), 7-nitroindazole (neuronal NO synthase inhibitor), 1H-[1,2,4] -oxadiazolo [4,3-a] quinoxalin-1-one (ODQ, guanylyl cyclase inhibitor) or (9S, 10R, 12R)-2,3,9,10,11,12-hexahydro-10-methoxy-2,9-dimethyl-1-oxo-9,12-epoxy-1H-diindolo-[1,2,3-fg:3',2',1'-kl]pyrrolo[3,4-i][1,6]benzodiazocine-10-carboxylic acid methyl ester (KT-5823, specific PKG inhibitor), but not NG-D-nitro-arginine methyl ester (D-NAME) or okadaic acid (protein phosphatase 1 and 2 inhibitor) prevented gabapentin-induced antiallodynia. Pinacidil activity was not blocked by L-NAME, D-NAME, 7-nitroindazole, ODQ, KT-5823 or okadaic acid. Moreover, KT-5823, glibenclamide (ATP-sensitive K+ channel blocker), apamin and charybdotoxin (small- and large-conductance Ca2+-activated K+ channel blockers, respectively), but not margatoxin (voltage-gated K+ channel blocker), L-NAME, 7-nitroindazole, ODQ or okadaic acid, reduced diazoxide-induced antiallodynia. Data suggest that gabapentin-induced spinal antiallodynia could be due to activation of the NO-cyclic GMP-PKG-K+ channel pathway.

Assuntos

Aminas/farmacologia , Ácidos Cicloexanocarboxílicos/farmacologia , Dor/prevenção & controle , Transdução de Sinais/fisiologia , Ácido gama-Aminobutírico/farmacologia , Aminas/administração & dosagem , Analgésicos/administração & dosagem , Analgésicos/farmacologia , Animais , Apamina/farmacologia , Carbazóis/farmacologia , Charibdotoxina/farmacologia , GMP Cíclico/antagonistas & inibidores , GMP Cíclico/metabolismo , Proteínas Quinases Dependentes de GMP Cíclico/antagonistas & inibidores , Proteínas Quinases Dependentes de GMP Cíclico/metabolismo , Ácidos Cicloexanocarboxílicos/administração & dosagem , Diazóxido/administração & dosagem , Diazóxido/farmacologia , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Feminino , Gabapentina , Glibureto/farmacologia , Indazóis/farmacologia , Indóis/farmacologia , Injeções Espinhais , NG-Nitroarginina Metil Éster/química , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/antagonistas & inibidores , Óxido Nítrico/metabolismo , Óxido Nítrico Sintase/antagonistas & inibidores , Óxido Nítrico Sintase/metabolismo , Ácido Okadáico/farmacologia , Oxidiazóis/farmacologia , Dor/fisiopatologia , Pinacidil/administração & dosagem , Pinacidil/farmacologia , Bloqueadores dos Canais de Potássio/farmacologia , Canais de Potássio/fisiologia , Inibidores de Proteínas Quinases/farmacologia , Quinoxalinas/farmacologia , Ratos , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Nervos Espinhais/lesões , Nervos Espinhais/fisiopatologia , Estereoisomerismo , Fatores de Tempo , Vasodilatadores/administração & dosagem , Vasodilatadores/farmacologia , Ácido gama-Aminobutírico/administração & dosagem

RESUMO

The current requirement of the Mexican Authorities to demonstrate the interchangeability of ranitidine formulations is to establish that the dissolution profile of the drug shows similarity. In order to establish if this requirement is adequate, the bioavailability of two formulations that did not meet this similarity were compared. Twenty-five female volunteers received 150 mg ranitidine (Azantac or Midaven) under fasting conditions in two separate sessions using a cross-over design. Plasma samples were obtained at selected times for a period of 12 h and stored frozen at -80 degrees C until analysed. Ranitidine plasma levels were determined and pharmacokinetic parameters were obtained. Values (mean+/-SEM) were: Cmax 528.85+/-25.34 and 563.03+/-33.25 ng/ml, tmax 2.76+/-0.19 and 2.79+/-0.18 h, and AUC12 h 2694.94+/-99.50 and 2648.51+/-133.38 ng.h/ml, for Azantac or Midaven, respectively. No statistically significant difference was obtained in the parameters evaluated. Moreover, 90% confidence limits were 96.6%-116.2% and 90.7%-105.1% for Cmax and AUC12 h ratios, respectively, indicating that the formulations tested are bioequivalent, despite the dissimilarity in the dissolution profile of the formulations. These results suggest that the comparative dissolution profile is not an adequate test to demonstrate the interchangeability of ranitidine formulations.

Assuntos

Antagonistas dos Receptores H2 da Histamina/farmacocinética , Ranitidina/farmacocinética , Administração Oral , Adulto , Disponibilidade Biológica , Química Farmacêutica/legislação & jurisprudência , Química Farmacêutica/normas , Feminino , Antagonistas dos Receptores H2 da Histamina/administração & dosagem , Antagonistas dos Receptores H2 da Histamina/química , Humanos , México , Ranitidina/administração & dosagem , Ranitidina/química , Solubilidade , Equivalência Terapêutica

RESUMO

Vitamin B2 (riboflavin) has been proposed as a prophylactic therapy of migraine. However, so far there are no preclinical studies about the analgesic properties of this vitamin. The current study was designed to investigate the possible antinociceptive, antihyperalgesic and antiallodynic effect of riboflavin in formalin, carrageenan-induced thermal hyperalgesia, and spinal nerve ligation models, respectively. Oral riboflavin produced a dose-related antinociceptive (6.25-50 mg/kg), antihyperalgesic (25-150 mg/kg) and anti-inflammatory (50-150 mg/kg) effect. Gabapentin (100 mg/kg, positive control), but not riboflavin (150-600 mg/kg), reduced tactile allodynia in neuropathic rats. Riboflavin-induced antinociception in the formalin test was reversed by pretreatment with NG-L-nitro-arginine methyl ester and glibenclamide, but not by NG-D-nitro-arginine methyl ester or naloxone. Our results indicate that riboflavin is able to produce antinociception and anti-inflammatory, but not antiallodynic, effect in the rat. The effect of riboflavin could be due to the activation of K+ channels or nitric oxide release, but not activation of opioid mechanisms.

Assuntos

Analgésicos/farmacologia , Hiperalgesia/tratamento farmacológico , Inflamação/tratamento farmacológico , Riboflavina/farmacologia , Animais , Carragenina , Inibidores Enzimáticos/farmacologia , Feminino , Glibureto/farmacologia , Inflamação/induzido quimicamente , Atividade Motora/efeitos dos fármacos , NG-Nitroarginina Metil Éster/farmacologia , Naloxona/farmacologia , Antagonistas de Entorpecentes/farmacologia , Medição da Dor/efeitos dos fármacos , Limiar da Dor/efeitos dos fármacos , Bloqueadores dos Canais de Potássio/farmacologia , Ratos , Ratos Wistar

Assuntos

Diabetes Mellitus Tipo 2/metabolismo , Glibureto/farmacocinética , Hipoglicemiantes/farmacocinética , Metformina/farmacocinética , Idoso , Área Sob a Curva , Disponibilidade Biológica , Química Farmacêutica , Cromatografia Líquida de Alta Pressão , Estudos Cross-Over , Feminino , Meia-Vida , Humanos , México , Espectrofotometria Ultravioleta , Comprimidos

RESUMO

The purpose of this work was to study tolmetin plasma protein binding in an experimental model of hypoalbuminemia in the rat. Hypoalbuminemia was produced by repetitive plasmapheresis, achieving a 26.2 +/- 4.6% reduction in albumin circulating levels. Rats then received a 100 mg/kg oral tolmetin dose. Control rats received oral tolmetin 10, 56 or 100 mg/kg. Tolmetin plasma protein binding was determined by an ultrafiltration technique using an in vivo pharmacokinetic approach. Plasma protein binding data for the 3 doses studies in control animals could be described considering a single binding site with Kd = 21.9 +/- 2.1 microM and N = 0.98 +/- 0.05 sites per molecule of albumin. For hypoalbuminemic rats Kd was significantly increased (p < 0.05), while there was no significant change in the number of binding site per albumin molecule (Kd = 131.6 +/- 38.1 microM and N = 1.58 +/- 0.77). Our results show that hypoalbuminemia produces a disproportionate increase in the free fraction of tolmetin, not only by reducing albumin concentration, but also by a decrease in affinity. The mechanism responsible of such changes in affinity remains to be elucidated.

Assuntos

Albumina Sérica/metabolismo , Tolmetino/metabolismo , Animais , Ligação Proteica , Ratos , Ratos Wistar , Tolmetino/farmacocinética

RESUMO

The pharmacokinetics of oral ranitidine were studied in 24 Mexican male healthy volunteers. Subjects received a tablet containing 150 mg of ranitidine (Azantac TM, Glaxo de Mexico, Mexico, City) after an overnight fast and blood samples were drawn at several times for a period of 24 h. Ranitidine concentration in plasma was measured by high performance liquid chromatography and pharmacokinetic parameters were determined by non-compartmental analysis. Ranitide plasma concentration increased with time, reaching a maximum of (mean ñ SEM) 484 ñ 34 ng/ml in 2.7 ñ 0.2 h. Plasma levels then decayed with a terminal half-life of 4.8 ñ 0.3 h. The area under the plasma concentration against time curve was 2440 ñ 126 ngh/ml. Oral ranitidine pharmacokinetic parameters in mexicans appeared to be similar to those previously reported for caucasians

Assuntos

Adulto , Humanos , Masculino , Cromatografia , Cloreto de Metileno , Nizatidina , Farmacocinética , Plasma/efeitos dos fármacos , Ranitidina/farmacocinética

RESUMO

Oral pharmacokinetics of rifampin were studied in eight Mexican young healthy male volunteers after administration of a 600 mg oral dose. After and overnight fast, subjects received medication and blood samples were drawn at selected time over a 24-h period. Rifampin plasma levels were determined by HPLC. Pharmacokinetic parameters (mean ñ SEM) were: Cmax 13.514 ñ 1.775 µg/ml, tmax 1.88 ñ 0.30 h, AUC 73.61 ñ 9.48 µg.h/ml anf half-life 2.98 ñ 0.29 h. Results were compared with those obtained for the other populations under similar conditions in order to explore the possibility of interethnic variability, since it has been reported that rifampin pharmacokinetics in Indonesian subjects differ from those found in Europeans. Pharmacokinetic data found in Mexican were comparable with those observed in Brithis, Indian, Japanese and Italian individuals. As the parmacokinetics of rifampin seem to be similar different populations, it is concluded that ethnic origin does not a appear to play and important role. Therefore, dosing regimens designed for Caucasians can be extrapolated for other populations

Assuntos

Etnicidade/classificação , Rifampina/farmacocinética , Comportamento Sexual Animal/efeitos dos fármacos , Interpretação Estatística de Dados