Proceedings of the Western Pharmacology Society最新文献

Tacrolimus, a macrolide immunosuppressant agent, is indicated for the prophylaxis of organ rejection in patients receiving allogenic liver or kidney transplantation. Successful therapy is complicated by both intra- and inter-patient variability in drug absorption, coupled with the drug's narrow therapeutic index. Moreover, clearance, is significantly affected by co-administration with food and with additional factors such as length of posttransplantation time. At the National Institute of Cardiology, Mexico, the measure of tacrolimus levels is carried out as a common analysis on patients who have been transplanted as a measure to make empiric doseage adjustments. The purpose of this study was to investigate whether tacrolimus levels exceed the desired therapeutic range in adult patients being initiated on a dosage regimen and to establish the use of pharmacokinetic concepts to avoid organ rejection and other complications related to tacrolimus over-exposure. The patients were followed from 1 week to 6 months after transplantation and a mean of 12 samples were collected (11.92 +/- 2.59 ng/mL) from each patient. Modeling was used to establish the correlation between the doses administered per kilogram of body weight, the tacrolimus level measured and the post-transplantation time. Of 155 tacrolimus measurements, only 48.4% were found within the therapeutic range (5-10 ng/mL); 7.1% below and 44.5% with elevated levels. Tacrolimus has proven its usefulness in solid organ transplants, but this study demonstrates that it is essential to carry out close monitoring through the application of pharmacokinetic concepts to optimize therapy.

17beta-aminoestrogens (AEs) decrease luteinizing hormone levels, increase uterine weight, activate transcription through ERalpha and ERbeta receptors and induce progesterone receptor expression in the anterior pituitary. This work evaluates the influence of single and multiple administration of a homologous series of the AEs: prolame, butolame and pentolame on rat female sexual behavior to explore their capability of inducing lordosis by themselves. In a reversed cycle the animals received one or three subcutaneous (s.c.) injections at 8:00 hr of: 7.5 microg E2/day (approximately 30 microg/kg), or 10 microg BE/day (approximately 40 microg/kg), or 1 mg/day prolame, butolame, pentolame (approximately 4000 microg/kg), or 300 microL/day of corn oil (approximately 1.2 ml/kg). Twenty-four hr following treatment, progesterone (P; 1 mg/0.1 ml of corn oil/rat) was administered; and 5 to 7 hr later, rats were tested for sexual receptivity and the lordosis quotient (LQ) was estimated (number of lordosis displays/number of mounts x 100). Single administration by themselves did not facilitate lordosis, 24 hr after the second injection, AEs-LQs values were: 24, 30, 21, E2 = 13 and EB = 11. administrations of three AEs increased LQs to: 48, 50, 45 E2 = 33 and EB = 57. The sequential P administration facilitated lordosis; after one injection: LQs 50-90 (p<0.01), meanwhile E2 and BE inducing LQs of 43 and 81 respectively. After the second and third injections and P administration the AEs LQs were 92-100 (p<0.01) similarly to E2 (95; p<0.01) and BE (96; p<0.01). The facilitation of sexual behavior by AEs was time and dose-dependent.

It has been shown that acupuncture can modify circulating levels of subpopulations of leukocytes. There have been few investigations on the effect of acupuncture on prostaglandins metabolism. Aspirin is capable of inhibiting the metabolism of prostaglandins and to produce several pharmacological effects. The objective of this study was to determine whether prior administration of aspirin could modify the action of acupuncture on levels of circulating leukocytes. Fourteen healthy males (age: 19-23 years) were recruited from a university student population. This study was a placebo-controlled, prospective, cross-over design. Subjects were randomly assigned into A or B groups. Group A received aspirin 500 mg and group B placebo, after 1 week of a washout period, group A received placebo and group B aspirin. Subjects were given acupuncture with manual needling in GV14 (Dazhui) acupoint 2 hr after receiving medication. The needle was stimulated for 10 sec and was kept in place for 5 min. Leukocytes and their subpopulations were quantified in blood samples taken immediately before and 2 hr after acupuncture treatment. In each subject pre-acupuncture values were compared to those post-acupuncture. The results showed that acupuncture significantly increased overall leukocytes (p=0.006) and neutrophils (p<0.001). Aspirin partially inhibited these effects. The data suggest that the effect of acupuncture on leukocytes may be related to levels of prostaglandins.

The exposure of 8 to 29-day-old mouse pups to midazolam (MDZ) produces the same type of histological alterations in the cerebral cortex as those caused in mice by exposure in utero to diazepam (DZ) from day 6 to 17 of gestation. Two groups of 10 each ICR (Harlan Mexico) strain male mice were injected: the first with a single daily MDZ dose (2.0 mg/kg/bw, s.c.) at the age of 8 to 29 days. The control group (C), received saline solution. All mice were sacrificed with a CO2 atmosphere at day 30. The brain was fixed in 2.5% glutaraldehyde, post-fixed in 1% OsO4, and embedded in epoxy resin. Semifine sections were stained with toluidine blue and observed under the light microscope. In the MDZ group, the cerebral cortex was thinner than in the control group. Ventricular, subventricular and cortex show delayed differentiation and higher nuclear density per area (p<0.05). The nuclei showed clumps of heterochromatin. In the MDZ group, cells of the cerebral cortex were altered. The neuropile was scarce, coarse and disoriented and few myelin fibers were observed. Control animals depicted a normal cerebral cortex. MDZ could be inhibiting mitosis during prometaphase and actin and myosin synthesis, as well as modifying the metabolic pathways mediated by central and peripheral type benzodiazepine receptors. Results showed that MDZ administration to mouse pups over 21 days induced histological changes in the cerebral cortex of 30-day old mice as those observed in mice prenatally exposed to diazepam.

The aim of this study was to determine whether or not ribavirin provides protection against varicella in those who come in contact with the virus. In a double blind placebo study, ribavirin (20 mg/kg/day, p.o.) or placebo was administered to children who had contact with varicella. Treatment was administered to 61 children (Group 1) within the first 3 days of contact, 45 of them were immunocompetent and 16 were immunodepressed. Treatment was given to 54 children on the 7th day after contact (Group 2); 48 of them were immunocompetent and 6 immunodepressed. In group 1, 11 (50%) of the immunocompetent treated with ribavirin developed chicken pox while 11 (50%) were asymptomatic. For seroconversion, there was no significant difference (p=0.586). In group 2, we did not find varicella in immunocompetent patients receiving ribavirin (0/24), for placebo there were 2 (2/24) cases of varicella. Varicella was not observed in immunodepressed patients in Group 2. A difference was not observed with the administration of ribavirin at day 3 or 7 versus placebo to prevent development of varicella. This study may have implications for the public health efforts in the prophylaxis of chicken pox.

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.

A major directive of Pharmaceutical Research and Development (R&D) is to efficiently advance potential new chemical entities (NCEs) from the Discovery therapeutic area into Global Preclinical Development (GPCD), where a safety profile can be established. To facilitate the transition a comprehensive toxicity evaluation is required. In order to support both the R&D Discovery teams and GPCD, investigative (non-GLP) tolerance/dose range finding studies are conducted. These studies are designed to provide a quality toxicological and toxicokinetic assessment of potential NCEs early in the drug development process. During tolerance evaluations, compounds are first assessed in a single dose escalation (SDE) phase where rodents (or canines) receive a single dose anticipated to achieve relevant multiples of the efficacious dose. Data from this phase evaluates NCE absorption, and assists in estimating the maximum tolerated dose for a single administration and establish doses for a repeat dose (RD) phase. Data from the RD phase are used to determine potential target tissues of toxicity and also select doses for future GLP Toxicology studies. Thus, a rapid assessment of the toxicological profile of the NCE can be made to establish initial safety facilitating conduct of subsequent regulatory Toxicological studies and potentially earlier entry into clinical trials.

Inhalant abuse constitutes an important public health problem in Mexico that is more prevalent among children and adolescents. Commercial products that are abused are complex mixtures of solvents containing mainly toluene, in association with other solvents like benzene and xylene. Epidemiological evidence indicates that chronic solvent abuse exposure can cause loss of appetite among other unwanted effects. The mechanisms by which loss of appetite is produced are unknown. It is a matter of interest to determine if loss of appetite is related to changes in taste perception. One of the basic flavors detected by the taste system is umami taste (monosodium glutamate) and it has been proposed that glutamatergic receptors can play an important role in umami taste transduction and perception. It is unknown however, if chronic solvent abuse exposure can induce alterations in umami taste perception. The purpose of this work was to determine if chronic solvent exposure in rats causes alterations in glutamate solution consumption. Rats were exposed to solvents (6000 ppm) in a static chamber for 2 months, as follows: a toluene group, a benzene group, a xylene group and a control group. During the treatment, glutamate solution (120 mM) consumption, food intake and rat weights were measured. The results show that glutamate solution intake was increased in rats chronically exposed to solvents, with differences in consumption patterns between solvents. In addition, chronically exposed animals had a lower weight increase compared with unexposed rats. These data suggest that solvent inhalation originates feeding behavior alteration in rats.

Vancomycin, a glycopeptide antibiotic, was developed-and released in the 1950's for the treatment of aerobic gram-positive infections and has been widely used mainly in the treatment of methicillin-resistant Staphylococcus aureus infections. Early reports regarding the possibility of nephrotoxicity and ototoxicity led to concern about the use of vancomycin and the need to monitor serum concentrations. In Mexico, the National Institute of Cardiology measures serum level of some drugs, such as vancomycin on a routine basis. Nevertheless, although a large number of measurements are made, the quantification of drug in serum is only used by physicians as a empiric parameter for dose adjustment. The aim of this work was to know whether dosing was appropriate taking the therapeutic interval as a commonly accepted baseline and to propose viable alternatives in the case dosing was inadequate. Peak and through vancomycin levels were analyzed retrospectively (n=295), in patients from 18 to 65 yr old with diagnosis of sepsis. The relationship between administered dose and measured blood levels was established. The equation that characterizes the study population was obtained based on a single compartment model considering the proportional relationship between vancomycin and creatinine clearance. The analysis shows that only 44% of C(trough) and 47% of C(peak) values represented therapeutic levels, with the remainder either toxic or ineffective.

The main objective of the present study was to investigate the use of drugs in the pediatric intensive care units (PICUs) at a pediatric hospital. Data were equally collected from charts of PICUs of the Hospital del Niño DIF, Pachuca, Hidalgo, Mexico in 2007. The data included demographic, clinical data and those on drugs usage. A total of 45 patients were included at the study, all (100%) of whom received one or more drugs. Data were collected and 57 different drugs were given to the pediatric patients. The median number of drugs/inpatient was 6.9 (1-17). The therapeutic class most prescribed was anti- infective (30.6 % of all the prescriptions), followed by electrolytes (13.3 % of all the prescriptions) and gastrointestinal agents (12.9 % of all the prescriptions). KCI was the drug most commonly used (64.4 % of all the patients) followed by ranitidine and amikacin (both with 51.1 % of all the patients). As in many studies, the therapeutic class most used was the anti-infectives. Substantial variation exists in hospitalists' reported management of common pediatric conditions. To decrease undesirable variation in care, a stronger evidence base for inpatient pediatric care must be built.