Pharmacogenetic Variants Associated with Fluoxetine Pharmacokinetics from a Bioequivalence Study in Healthy Subjects.

Fluoxetine is one of the most prescribed antidepressants, yet it still faces challenges due to high intersubject variability in patient response. Mainly metabolized by the highly polymorphic gene CYP2D6, important differences in plasma concentrations after the same doses are found among individuals. This study investigated the association of fluoxetine pharmacokinetics (PK) with pharmacogenetic variants. A bioequivalence crossover trial (two sequences, two periods) was conducted with fluoxetine 20 mg capsules, in 24 healthy subjects. Blood samples for fluoxetine determination were collected up to 72 h post-dose. Subjects were genotyped and single nucleotide variants (SNV) were selected using a candidate gene approach, and then associated with the PK parameters. Bioequivalence was confirmed for the test formulation. We found 34 SNV on 10 genes with a quantifiable impact on the PK of fluoxetine in the randomized controlled trial. Out of those, 29 SNVs belong to 7 CYPs (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5), and 5 SNVs to 3 genes impacting the pharmacodynamics and efficacy of fluoxetine (SLC6A4, TPH1, ABCB1). Moreover, decreased/no function SNVs of CYP2D6 (rs1065852, rs28371703, rs1135840) and CYP2C19 (rs12769205) were confirmed phenotypically. Our research contributes to deepening the catalog of genotype-phenotype associations in pharmacokinetics, aiming to increase pharmacogenomics knowledge for rational treatment schemes of antidepressants.

Relative bioavailability of two oral formulations of piroxicam 20 mg: a single-dose, randomized-sequence, open-label, two-period crossover comparison in healthy Mexican adult volunteers.

BACKGROUND: Piroxicam is an NSAID indicated for the treatment of rheumatoid diseases. Although there are generic formulations of oral piroxicam marketed in Mexico, a literature search did not identify published data concerning the bioavailability of these formulations in the Mexican population. OBJECTIVES: The aims of this study were to determine the bioequivalence of a generic (test) and a reference formulation of oral piroxicam 20 mg and to generate data regarding the oral bioavailability of this drug in a Mexican population. METHODS: This single-dose, randomized-sequence, open-label, 2-period crossover study was conducted in healthy Mexican adult volunteers. Subjects were randomly assigned to receive the test formulation followed by the reference formulation, or vice versa, with a 15-day washout period between doses. Study drugs were administered after a 10-hour overnight fast. For pharmacokinetic analysis, blood samples were drawn at 0 (baseline), 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8, 12, 24, 48, 72, 96, 120, and 168 hours after administration. Plasma concentrations of piroxicam were determined using HPLC. The test and reference formulations were to be considered bioequivalent if the 90% CIs for the geometric mean test/reference ratios were within a predetermined range of 80% to 125%. Tolerability was determined using clinical assessment, monitoring of vital signs, laboratory analysis, and subject interviews regarding adverse events (AEs). RESULTS: A total of 28 subjects were enrolled (15 men, 13 women; mean [SD] age, 24 [4] years [range, 19-35 years]; weight, 63.0 [8.9] kg [range, 47.5-81.9 kg]; height, 165 [10] cm [range, 149-179 cm]; and body mass index, 23.2 [1.4] kg/m(2) [range, 20.6-26.0 kg/m(2)]). The 90% CIs for piroxicam C(max), AUC(0-infinity), and AUC(0-infinity)) were 89.98% to 101.04%, 91.46% to 101.19%, and 93.51% to 105.86%, respectively. Thirteen subjects reported a total of 17 AEs during the study. None of the AEs were considered serious or related to the administered formulations. The most common AE was local postvenipuncture ecchymosis, reported in 8 subjects (28.6%). CONCLUSIONS: In this small study in healthy Mexican adult subjects, a single 20-mg dose of the test formulation of orally administered piroxicam met the regulatory requirements to assume bioequivalence, based on the rate and extent of absorption. Both formulations were well tolerated. Mexican national registry code: CE-PEC.0875.

Bioavailability of two oral-tablet and two oral-suspension formulations of naproxen sodium/paracetamol (acetaminophen): single-dose, randomized, open-label, two-period crossover comparisons in healthy Mexican adult subjects.

BACKGROUND: Naproxen sodium/paracetamol (acetaminophen) is a combination for the treatment of symptomatic pain and fever marketed both as a prescription and an over-the-counter product in Mexico. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability and to determine the bioequivalence of 2 test formulations (an oral-tablet formulation containing the combination of naproxen sodium/paracetamol 275/300 mg and an oral-suspension formulation containing the combination of naproxen sodium/paracetamol 375/300 mg per 15 mL) with their corresponding listed reference-drug formulations in Mexico (a list issued by Mexican health authorities). METHODS: Two separate, single-dose, randomized, open-label, 2-period crossover, postmarketing studies were conducted. For each study, a different set of eligible subjects was selected comprising healthy Mexican adults of either sex, and subjects were randomly assigned to receive 1 test formulation of the combination of naproxen sodium/paracetamol followed by the corresponding reference-drug formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour overnight fast, subjects received a single dose of naproxen sodium/paracetamol 275/300-mg tablet or naproxen sodium/paracetamol 375/300 mg per 15 mL suspension, depending on the study. For the analysis of pharmacokinetic parameters, including C(max), AUC from time 0 (baseline) to 48 hours (AUC(0-48)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline and at 0.16, 0.33, 0.5, 0.75, 1, 1.25, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 24, and 48 hours after administration. The formulations were considered bioequivalent if the geometric mean ratios (test/reference) of the C(max) and AUC were within the predetermined range of 80% to 125%. Tolerability was determined by clinical assessment, monitoring vital signs, laboratory analysis results, and subject interviews regarding adverse events. RESULTS: A total of 26 subjects (15 men, 11 women; mean [SD] age, 29 [8] years [range, 20-50 years]; weight, 63.1 [9] kg [range, 51.4-84.4 kg]; height, 164 [9] cm [range, 149-179 cm]; and body mass index [BMI], 23.53 [2.18] kg/m(2) [range, 18.54-26.82 kg/m(2)]) were enrolled to receive the suspension-dosage formulation; 13 subjects received the suspension-test formulation first. A total of 26 subjects (13 men, 13 women; mean [SD] age, 29 [8] years [range, 18-43 years]; weight, 64.3 [7.7] kg [range, 50.6-80.7 kg]; height, 165 [9] cm [range, 151-181 cm]; and BMI, 23.64 [2.43] kg/m(2) [range, 18.02-26.42 kg/m(2)]) were enrolled to receive the tablet-dosage formulation; 13 subjects received the tablet-test formulation first. No significant period or sequence effects were detected based on analysis of variance. For the suspension-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 93.06% to 104.00%, 93.50% to 98.44%, and 92.14% to 98.99%, respectively, and were 90.09% to 105.90%, 88.58% to 99.34%, and 91.43% to 101.55%, respectively, for paracetamol. For the tablet-dosage formulation, the 90% CIs for naproxen C(max), AUC(0-48), and AUC(0-infinity) were 102.83% to 117.15%, 96.59% to 104.26%, and 96.01% to 102.90%, respectively, and were 94.04% to 121.09%, 95.48% to 105.64%, and 96.64% to 105.42%, respectively, for paracetamol. CONCLUSIONS: In these 2 small studies in healthy Mexican adult subjects, a single dose of naproxen sodium/paracetamol 275/300 mg of the test formulation of the tablet-dosage formulation or a single dose of naproxen sodium/paracetamol 375/300 mg per 15 mL of the test formulation of the suspension-dosage formulation was found to be bioequivalent to the corresponding reference formulations according to the regulatory definition of bioequivalence based on the rate and extent of absorption. All formulations were generally well tolerated.

Bioavailability of two oral suspension and two oral tablet formulations of acyclovir 400 mg: two single-dose, open-label, randomized, two-period crossover comparisons in healthy Mexican adult subjects.

BACKGROUND: Acyclovir is an important antiviral drug, used extensively for treatment of herpes simplex and varicella zoster. Six oral generic formulations of acyclovir are available in Mexico; however, a literature search failed to identify data information concerning the bioavailability of these formulations in the Mexican population. OBJECTIVE: The aim of these 2 studies was to compare the bioavailability of 4 oral formulations of acyclovir 400 mg--2 tablet formulations and 2 suspension formulations--with their corresponding listed drug references in Mexico (a list issued by Mexican Health Authorities). METHODS: Two separate, single-dose, open-label, randomized, 2-period crossover studies were conducted at the Centro de Estudios Científicos y Clínicos Pharma, S.A. de C.V. (clinical unit), Mexico City, Mexico. For each study, a different set of eligible subjects were selected. They included healthy Mexican volunteers of either sex. For each study, subjects were randomly assigned to receive 1 test formulation of acyclovir 400 mg followed by the reference formulation, or vice versa, with a 1-week washout period between doses. After a 12-hour (overnight) fast, subjects received a single 400-mg dose (tablet or 10-mL suspension) of the corresponding formulation. For the analysis of pharmacokinetic properties, including C(max), AUC from time 0 (baseline) to time t (AUC(0-t)), and AUC from baseline to infinity (AUC(0-infinity)), blood samples were drawn at baseline, 0.25, 0.5, 0.75, 1.0, 1.25, 1.5, 1.75, 2, 3, 4, 6, 8, 12, and 24 hours after dosing. The formulations were considered bioequivalent if the natural logarithm (ln)-transformed ratios of Cmax and AUC were within the predetermined equivalence range of 80% to 125% and if P

Drug treatment of hypertension: compliance and adverse reactions in a cohort of hypertensive patients in a primary care setting.

OBJECTIVES: The primary was to assess the frequency of therapeutic non-compliance due to ADRs in a cohort of patients with recently diagnosed systemic hypertension. The secondary objectives were to evaluate the blood pressure control during the follow-up in the whole cohort and in patients who received non-steroidal anti-inflammatory drugs (NSAIDs). METHODS: A cohort of 73 recently diagnosed ambulatory hypertensive patients was followed-up for 6 months. Validated questionnaires for identification of therapeutic scheme changes and ADRs were applied monthly, during each medical visit. RESULTS: Family physicians selected monotherapy in 79% of patients. The frequency of therapeutic non-compliance was 44%; non-compliance secondary to ADR was 7%. Systolic and diastolic blood pressure at the beginning of the study were 140 +/- 15/90 +/- 15 mm Hg for the whole cohort. At the end of the study the figures were 130 +/- 11/85 +/- 6 (p < 0.001). Patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) had higher blood pressure levels than the groups of patients not receiving such kind of drugs (134 +/- 10 vs. 128 +/- 8 mm Hg, p = 0.025 and 88 +/- 7 vs. 83 +/- 5 mm Hg, p = 0.05). CONCLUSIONS: The drugs used in the present study as monotherapy are considered acceptable choices for hypertension treatment. The frequency of therapeutic non-compliance was within the limits reported in the literature and the frequency of therapeutic non-compliance secondary to ADRs in this cohort was lower than that reported in the literature. Higher blood pressure was found in the group of patients receiving NSAIDs.

Gastric emptying effect by 4-aminopyridine in patients with chronic spinal cord injury.

BACKGROUND: 4-Aminopyridine (4-AP) given to patients with chronic spinal cord injury (SCI) has shown beneficial effects in some somatic and autonomic functions, although patients often develop dyspeptic symptoms. 4-AP is a potassium-channel blocker capable of altering gastro-pyloric functions as demonstrated experimentally. Our objective was to examine the influence of 4-AP treatment on gastric emptying in patients with chronic SCI. METHODS: Gastric emptying was measured by the acetaminophen absorption test in 18 patients (9 with cervical and 9 with thoracic injury), and 9 healthy volunteers. Patients received increasing oral doses, 5 mg day(-1) of oral 4-AP (5-30 mg day(-1)), for 12 weeks. Patients were studied before and at the end of the last week of 4-AP treatment, whereas healthy volunteers (without 4-AP treatment) were studied only once. Whole blood samples of 2.5 mL were drawn at 0 (before 1 g of oral acetaminophen) and at 15, 30, 45, 60, 75, 90, 105 and 120 min postdose. Acetaminophen concentration in plasma was determined by high-pressure liquid chromatography. RESULTS: Treatment with 4-AP significantly delayed stomach emptying in patients with chronic SCI, considering the significant decreasing of acetaminophen absorption (t paired test, p <0.05). This effect did not correlate either to the level or ASIA score of the injury (linear regression correlation analysis, r(2) = 0.003 and 0.015, respectively). No significant differences were observed by comparing data of patients before 4-AP treatment with healthy volunteers. CONCLUSIONS: 4-AP intake in patients with chronic spinal cord injury significantly slowed gastric emptying regardless of level and ASIA score of the injury.

Drug treatment of hypertension: compliance and adverse reactions in a cohort of hypertensive patients in a primary care setting / Tratamiento farmacológico antihipertensivo: Cumplimiento y reacciones adversas en una cohorte de pacientes hipertensos en atención primaria

Objectives. The primary was to assess the frequency of therapeutic non-compliance due to ADRs in a cohort of patients with recently diagnosed systemic hypertension. The secondary objectives were to evaluate the blood pressure control during the follow-up in the whole cohort and in patients who received non-steroidal anti-inflammatory drugs (NSAIDs). Methods. A cohort of 73 recently diagnosed ambulatory hypertensive patients was followed-up for 6 months. Validated questionnaires for identification of therapeutic scheme changes and ADRs were applied monthly, during each medical visit. Results. Family physicians selected monotherapy in 79% of patients. The frequency of therapeutic non-compliance was 44%; non-compliance secondary to ADR was 7%. Systolic and diastolic blood pressure at the beginning of the study were 140 ± 15/90 ± 15 mm Hg for the whole cohort. At the end of the study the figures were 130 ± 11/85 ± 6 (p < 0.001). Patients receiving non-steroidal anti-inflammatory drugs (NSAIDs) had higher blood pressure levels than the groups of patients not receiving such kind of drugs (134 ± 10 vs. 128 ± 8 mm Hg, p = 0.025 and 88 ± 7 vs. 83 ± 5 mm Hg, p = 0.05). Conclusions. The drugs used in the present study as monotherapy are considered acceptable choices for hypertension treatment. The frequency of therapeutic non-compliance was within the limits reported in the literature and the frequency of therapeutic non-compliance secondary to ADRs in this cohort was lower than that reported in the literature. Higher blood pressure was found in the group of patients receiving NSAIDs.

Objetivos. El objetivo primario fue evaluar la frecuencia de falta de cumplimiento terapéutico debido a la presencia de reacciones adversas a medicamentos (RAMs) con el uso de antihipertensivos; los objetivos secundarios fueron evaluar el control de la presión arterial durante el seguimiento y en aquellos pacientes que recibieron fármacos antiinflamatorios no esteroideos. Métodos. Se integró una cohorte de 73 pacientes hipertensos de reciente diagnóstico, a los que se les vigiló durante seis meses. En cada visita médica mensual se les aplicaron cuestionarios validados, para identificar cambios en el esquema terapéutico y RAMs. Resultados. Los médicos familiares emplearon monoterapia en 79% de los pacientes. La falta de cumplimiento terapéutico se presentó en 44%; el incumplimiento terapéutico secundario a RAMs se observó en 7% de los casos. En todos los pacientes la presión arterial sistólica y diastólica al inicio del estudio fue 140 ± 15/90 ± 15 mm Hg y al final del estudio las cifras fueron 130 ± 11 / 85 ± 6 (p < 0.001). Los pacientes que recibieron fármacos antiinflamatorios no esteroideos (AINEs) tuvieron cifras de presión arterial más elevadas que pacientes que no recibieron este tipo de fármacos (134 ± 10 vs. 128 ± 8, p = 0.025 y 88 ±7 vs. 83 ± 5 mm Hg, p - 0.05). Conclusiones. Los fármacos empleados en este estudio como monoterapia son fármacos aceptados para el tratamiento de la hipertensión. La frecuencia de falta de cumplimiento terapéutico se ubicó dentro de los límites descritos en la literatura y la falta de cumplimiento terapéutico secundario a RAMs fue menor que lo informado en la literatura. Se observaron cifras de presión arterial elevadas en pacientes que recibieron AINEs.

[Comparative clinical multicenter study to evaluate analgesic effectiveness of intramuscular etofenamate and diclofenac in patients with post-surgical pain]. / Estudio multicéntrico comparativo para evaluar la eficacia analgésica de etofenamato y diclofenaco por vía intramuscular en pacientes con dolor postquirúrgico.

OBJECTIVE: The analgesic efficacy of intramuscular etofenamate (1 g/day) and intramuscular diclofenac (75 mg/day) was assessed in post-surgical pain relief during a period of 3 days. MATERIAL AND METHODS: One hundred ten hospitalized patients undergoing elective surgery were evaluated in an open-label, comparative, randomized, parallel-group, multicenter study. Fifty five patients received etofenamate and 55 patients diclofenac, 1 h before surgery. The doses were administered after 24 and 48 h. Baseline evaluations were carried out 30 min after anesthesia recovery and the clinical efficacy variables were assessed at 1, 6, 12, 24, 36, 48, 60 and 72 h. The efficacy variables were Pain Visual-Analogue Scale (VAS), Pain Analogous Verbal Scale (AVERS), and Well-Being Scale. Adverse events were documented. RESULTS: Patients in both groups showed similar values in post-surgical pain relief (VAS, AVERS). According to VAS, etofenamate at 24 h had a better analgesic action than diclofenac even though it was not statistically significant. Both drugs demonstrated to be safe. Patients in both groups reported nausea, vomiting, flatulence, and pain at injection site. CONCLUSIONS: We find that both etofenamate and diclofenac were safe, tolerable, and effective treatments for the relief of post-surgical pain.

[The Nazis, guide of the International Conference of Harmonization and ethics committees]. / Los Nazis, la guía de la Conferencia Internacional de Armonización (ICH) y los comités de ética.

This article begins with the basic ethical principles in clinical research. The four moral principles of autonomy, beneficence, non-maleficence, and justice are reviewed. Likewise, a historical review of the participation of German physicians and the medical establishment that carried out the policies of the Third Reich is examined, and delineates several moral failures attributable to these physicians during the dark period of history known as the Holocaust. Medical ethics were completely ignored during that period, and thus, the Nuremberg Code was enacted for regulating human research by means of informed consent. A historical vision of the universal documents for ethics in clinical research has been reviewed from the Declaration of Helsinki in 1964 to the ICH Guideline (International Conference of Harmonisation) for Good Clinical Practice (GCP) in 1996. The ICH Guideline is an international ethical and scientific quality standard for designing, conducting, recording, and reporting trials that involve participation of human subjects. The guide was developed with consideration of the current GCP of the European Union, Japan, and the U.S. Finally, we establish the composition, functions, and operations of the Ethic Committees that ensure the rights, safety, well-being, and confidentiality statement of subjects who participate in clinical research studies and document that protection by reviewing and approving/rejecting a study protocol, and evaluate research personnel, the research site, and materials and methods used for obtaining and recording informed consent protocol from subjects participating in the study.

[Levosimendan: a new option in the pharmacologic management of cardiac insufficiency]. / Levosimendan: una nueva opción en el manejo farmacológico de la insuficiencia cardíaca.

The congestive heart failure is a pathological process characterized by the incapacity of the heart to maintain an adequate cardiac perfusion for the tissue metabolism, and that can be secondary to diverse causes, that give as result, alterations in the lusitropism, inotropism or in the cronotropism. Over 4.6 persons per hundred in the United States alone carry this diagnosis, and it is the cause of death in several hundred thousand patients each year, with a 35% mortality over 5 years. In the last years, have existed important advances in the pharmacological treatment of this disease in it's terminal stages. The increase in the knowledge on the physiopathology of the heart failure, has taken place for the use of new schemes of treatment, where it excels the use of vasoactive amines, Angiotensin Converting Enzyme Inhibitors, angiotensin II receptor AT1 antagonists, etc; nevertheless we whereupon that most of these drugs that at the present display a favorable answer to the disease, has the disadvantage of increasing the consumption of oxygen by the own myocardium tissue. Levosimendan has a better profile of security than its predecessors (amrinone and milrinone), improves the haemodynamics parameters of special significant form in the cardiac output, the systolic pressure of the pulmonary artery and the telediastolic pressure of the left ventricle, without significantly increasing the consumption of oxygen by the myocardium. Levosimendan is a new and relevant calcium sensitizer developed for the short-term intravenous treatment of congestive heart failure.

Anatomical differences in uterine sensitivity to prostaglandin F(2alpha) and serotonin in non-pregnant rats.

The ovarian steroids regulate the sensitivity of a population of uterine receptors to prostaglandin F(2alpha), serotonin and oxytocin. However, the uterine sensitivity to prostaglandin F(2alpha) and oxytocin does not coincide with the estrogen-induced increase in the number of receptors. Anatomical differences affect the uterine sensitivity to agonists. We investigated whether anatomical differences between ovarian and cervical uterine regions modulate the hormone-regulated sensitivity to prostaglandin F(2alpha), serotonin and oxytocin. Non-cumulative concentration-response curves for these agonists were recorded for ovarian and cervical uterine segments from adult ovariectomized rats treated with 17beta-estradiol, 17beta-estradiol+progesterone, or vehicle. The ovarian segments displayed a higher maximal response (E(max)) to prostaglandin F(2alpha) and a lower E(max) to serotonin than the cervical segments. Both uterine segments displayed a similar sensitivity to oxytocin. The ovariectomized controls displayed the highest E(max) and the lowest effective concentration 50 (EC(50)) for oxytocin and prostaglandin F(2alpha). Anatomical differences between ovarian and cervical uterine regions modulate the hormonal regulation of uterine sensitivity to serotonin and prostaglandin F(2alpha) in the non-pregnant rat uterus.