Miriam del Carmen Carrasco-Portugal

Effects of a Cyclooxygenase-2 Preferential Inhibitor in Young Healthy Dogs Exposed to Air Pollution: A Pilot Study

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 1β, 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 IL1β (p = .03), and heart IL1β (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 Aβ42 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.

Evaluation of gender in the oral pharmacokinetics of clindamycin in humans.

Clindamycin is an antimicrobial agent metabolized by CYP3A4. Gender may influence the pharmacokinetics of drugs metabolized by this pathway, however, no information about differences in the pharmacokinetics of clindamycin in men and women is available. The purpose of this study was to evaluate gender differences in clindamycin oral pharmacokinetics. Twenty-four subjects (11 men and 13 women) received an oral 600 mg dose of clindamycin under fasting conditions and plasma concentrations were obtained at selected times during 12 h. Increased plasma levels were observed in women, but when the dose was normalized by the body weight of individuals, these differences disappeared, indicating that gender does not play an important role in the pharmacokinetics of this drug.

Rapid and sensitive determination of levofloxacin in microsamples of human plasma by high-performance liquid chromatography and its application in a pharmacokinetic study

A rapid, sensitive and simple high-performance liquid chromatographic assay with ultraviolet detection was developed for the quantification of levofloxacin in microsamples (100 μL) of human plasma. The extraction procedure included a protein precipitation technique and a short chromatographic running time (4.5 min). Analyses were carried out on a Symmetry C18 column using a mixture of acetonitrile and 0.01 m potassium dihydrogen aqueous solution (pH 3.4; 14:86 v/v) as mobile phase. The method provided specificity and was linear (r ≥ 0.9992) over the concentration range 0.1-12 µg/mL. The average absolute recovery was 93.59%. The intra- and inter-day coefficients of variation were <6%. Additionally, levofloxacin was stable in all evaluations. The usefulness of this method was demonstrated in a pharmacokinetic study of levofloxacin in healthy adult volunteers. The present method offers two main advantages: (a) the use of microsamples reduces the total volume of blood to be collected from patients; and (b) it provides a good cost-effectiveness ratio. It is concluded that the method is rapid, simple, sensitive, economical and suitable for the determination of levofloxacin in human plasma using a small volume of sample.

Gender Differences in the Oral Pharmacokinetics of Fluconazole

AbstractBackground 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.

Further evidence for interethnic differences in the oral pharmacokinetics of meloxicam.

AbstractIntroduction: Meloxicam is a nonsteroidal anti-inflammatory agent used widely in therapeutics. It is mainly metabolised by the cytochrome P450 enzyme (CYP) 2C9, with minor involvement of CYP3A4. So far, no information on the oral pharmacokinetics of this drug in adult Mexicans is available. The purpose of this study was to evaluate the oral pharmacokinetics of meloxicam in Mexican subjects. Methods: Twenty-four healthy male subjects received an oral dose of meloxicam 7.5mg after fasting for 10 hours. Blood samples were drawn from a suitable forearm vein and plasma obtained. The meloxicam concentration was evaluated by a high-performance liquid Chromatographic method and pharmacokinetic parameters were obtained by non-compartmental techniques. Pharmacokinetic parameters obtained in this study were compared with those reported under similar conditions in other populations in order to establish if interethnic differences in the pharmacokinetics of meloxicam exist. Results: After administration of meloxicam, plasma levels increased to a maximum concentration (Cmax) of 0.702 ± 0.027 (mean ± SEM) μg/mL with a time to reach Cmax of 4.77 ± 0.65h. The area under the plasma concentration versus time curve was 24.82 ± 1.23 μg · h/mL. The clearance was about 4.8 mL/min and the volume of distribution 9.8 ± 0.36L. When these parameters were compared with those reported in German and Indian subjects, a reduced clearance and volume of distribution were evident in Mexicans. However, clearance and volume of distribution obtained in this study were very similar to those reported in Chinese subjects. Conclusions: The oral pharmacokinetic parameters of meloxicam in healthy Mexican subjects compared with historic controls reported in other populations showed a reduced clearance and volume of distribution when compared with German subjects, whereas no differences between Mexican and Chinese subjects were observed. These results suggest that there are interethnic differences in the pharmacokinetics of meloxicam.

B-vitamin Mixture Improves the Analgesic Effect of Diclofenac in Patients with Osteoarthritis: A Double Blind Study

According to the high consumption of the mixture of B vitamins and diclofenac in several countries, this combination has constituted a frequently used option in pain therapy from inflammatory origin. Although the evidence obtained from inflammatory pain animal models has shown the existence of analgesic synergy between diclofenac and the B vitamins mixture, the corresponding clinical evidence is scarce. A double-blind, randomized clinical trial study was designed to characterize the analgesic effect and safety of diclofenac and B vitamins against diclofenac alone in patients with severe osteoarthritis. Forty eight patients programmed to total knee arthroplasty with a pain level ≥7 in a 1-10 cm visual analogue scale were allocated to receive a single intramuscular injection of sodium diclofenac (75 mg) alone or combined with thiamine (100 mg), pyridoxine (100 mg) and cyanocobalamin (5 mg), and the pain level was evaluated during 12 h post-injection. Diclofenac+B vitamins mixture showed a superior analgesic effect during the assessed period and also a better assessment of the pain relief perception by patients than diclofenac alone. This study constitutes a clinical support on the improvement of the analgesic effect of diclofenac by B vitamins in patients with osteoarthritis programmed to total knee arthroplasty, as a clinical model of inflammatory pain.

RAPID AND SENSITIVE DETERMINATION OF KETOPROFEN IN MICRO-WHOLE BLOOD SAMPLES BY HIGH-PERFORMANCE LIQUID CHROMATOGRAPHY AND ITS APPLICATION IN A PHARMACOKINETIC STUDY IN RATS

A new simple and sensitive method for determination of ketoprofen in micro-whole blood samples was developed, and its usefulness was demonstrated by the characterization of the oral pharmacokinetics of this drug in rats. Whole blood samples were added with perchloric acid to precipitate proteins, and supernatant was injected into the chromatographic system. Separation of compounds was achieved with a Symmetry C18 column eluted with a mixture of acetonitrile and 0.1 M potassium dihydrogen phosphate solution pH 3.5 (48:52 v/v) as the mobile phase at flow rate of 1.0 mL/min. Detection was carried out by absorbance at 260 nm. Under these conditions the method was linear in the range 0.1–15 µg/mL. In order to demonstrate the usefulness of this method, oral pharmacokinetics of ketoprofen after administration of 1, 3.2, and 10 mg/kg was evaluated in rats. Blood samples were obtained at selected times during 24 hr and successfully analyzed by the method described. It is concluded that the method is suitable for pharmacokinetic studies of ketoprofen using small volume of sample.

Relationship Between Blood Levels and the Anti-Hyperalgesic Effect of Ketoprofen in the Rat

Preclinical Research

Evaluation of the interaction between tramadol and diclofenac in several models of nociception in the rat

Diclofenac and tramadol are drugs widely used for the treatment of pain. However, side effects may limit their use. As both drugs produce side effects that are dose‐dependent, it seems appropriate to combine them in order to reduce the requirements for efficacy and, consequently, side effects. The purpose of this study was to evaluate the possible synergistic effect of these drugs in three experimental models of nociception in the rat. Dose‐response curves for diclofenac and tramadol were constructed in three models, thermal hyperalgesia, formalin, and hot plate. From these curves, ED40 or ED30 (according to the model employed) values were obtained and isobolographic analyses were carried out based on 0.5:0.5 proportions. Synergistic interactions were observed in the thermal hyperalgesia and hot plate models and an additive interaction was obtained in the formalin test. These results suggest a good therapeutic potential of this combination in the treatment of pain. Drug Dev Res 72: 391–396, 2011.

Genetic contributors to serum uric acid levels in Mexicans and their effect on premature coronary artery disease

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 (β = -0.47 mg/dl, P = 1.57 × 10-42 for lead SNP rs7678287) and ABCG2 (β = 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.