Determination of blood dexmedetomidine in dried blood spots by LC-MS/MS to screen therapeutic levels in paediatric patients.

Dexmedetomidine is an imidazole derivative, with high affinity for α2 adrenergic receptors, used for sedation, analgesia and adjuvant anaesthesia. In this study, an analytical method for the quantification of dexmedetomidine in dried blood spots was developed, validated and applied. The drug was extracted from dried blood spot by liquid extraction; the separation was carried out by ultra high-resolution liquid chromatography in reverse phase coupled to tandem mass spectrometry method. An X Select cyano 5 µm HSS column (2.1 X 150 mm, Waters) and a mobile phase composed of 0.1% formic acid: acetonitrile [50:50 v/v], were used. The test was linear over the concentration range of 50 to 2000 pg/mL. The coefficients of variation for the intra and interday trials were less than 15%. The drug was stable under the conditions tested. The method was successfully applied for the quantification of 6 patients, aged 0 to 2 years, with classification ASA I, who underwent ambulatory surgeries, receiving a dose of 1 µg/Kg dexmedetomidine IV. The drug concentrations in the different sampling times were in the range of 76 to 868 pg/mL.

Population Pharmacokinetics and Pharmacodynamics of Dexmedetomidine in Children Undergoing Ambulatory Surgery.

BACKGROUND: Dexmedetomidine (DEX) is an α-2 adrenergic agonist with sedative and analgesic properties. Although not approved for pediatric use by the Food and Drug Administration, DEX is increasingly used in pediatric anesthesia and critical care. However, very limited information is available regarding the pharmacokinetics of DEX in children. The aim of this study was to investigate DEX pharmacokinetics and pharmacodynamics (PK-PD) in Mexican children 2-18 years of age who were undergoing outpatient surgical procedures. METHODS: Thirty children 2-18 years of age with American Society of Anesthesiologists physical status score of I/II were enrolled in this study. DEX (0.7 µg/kg) was administered as a single-dose intravenous infusion. Venous blood samples were collected, and plasma DEX concentrations were analyzed with a combination of high-performance liquid chromatography and electrospray ionization-tandem mass spectrometry. Population PK-PD models were constructed using the Monolix program. RESULTS: A 2-compartment model adequately described the concentration-time relationship. The parameters were standardized for a body weight of 70 kg by using an allometric model. Population parameters estimates were as follows: mean (between-subject variability): clearance (Cl) (L/h × 70 kg) = 20.8 (27%); central volume of distribution (V1) (L × 70 kg) = 21.9 (20%); peripheral volume of distribution (V2) (L × 70 kg) = 81.2 (21%); and intercompartmental clearance (Q) (L/h × 70 kg) = 75.8 (25%). The PK-PD model predicted a maximum mean arterial blood pressure reduction of 45% with an IC50 of 0.501 ng/ml, and a maximum heart rate reduction of 28.9% with an IC50 of 0.552 ng/ml. CONCLUSIONS: Our results suggest that in Mexican children 2-18 years of age with American Society of Anesthesiologists score of I/II, the DEX dose should be adjusted in accordance with lower DEX clearance.

Difusión de cotrimoxazol a través de un expansor tisular: Estudio in vitro / Cotrimoxazole diffusion through a tissue expanders: In vitro study

Introducción: La principal complicación del uso de los expansores titulares (ET) son las infecciones. Una alternativa para evitarla, es agregar antibióticos que se difundan a través de la pared de un ET y eviten la colonización bacteriana. El objetivo de este trabajo fue evaluar la eficacia de una presentación nacional de cotrimoxazol, para difundirse a través de un ET en diferentes volúmenes de expansión. Material y método: Se realizó un experimento longitudinal con 12 ET, llenados a 50,100, 150 o 200% de su capacidad nominal, con solución fisiológica y cotrimoxazol a una concentración de 800/4000 ug/mL de trimetoprin/sulfametoxazol (TMX/SMX), sumergidos posteriormente en un sistema cerrado. Se midió la presión en el interior del ET, al inicio y al final del experimento. En los cuatro grupos se cuantificó la concentración de cotrimoxazol en la solución del contenedor, durante nueve días consecutivos. Los resultados se compararon mediante ANOVA de dos vías. Resultados: El SMX se precipitó dentro del ET. Las concentraciones de TMX en la solución del contenedor fueron diferentes en función del tiempo y el porcentaje de expansión. No hubo correlación entre el porcentaje de expansión y la presión dentro del ET. Conclusiones: La sinergia de cotrimoxazol de uso endovenoso disponible en nuestro país, no es una buena opción a emplearse en un ET a las dosis utilizadas, ya que el coeficiente de solubilidad de SMX se saturó y se formaron cristales. El incremento de difusión de TMX estuvo asociado con un mayor porcentaje de expansión, lo que es una ventaja, considerando que las infecciones son más frecuentes al final del proceso de expansión.

Introduction: Infection associated with tissue expansion is one of the main complications and force to take away the tissue expander. An alternative to avoid this action is to dilute antibiotics inside it. The aim of this experiment was to quantify the concentration of cotrimoxazole diffused through a tissue expander at different expansion and pressure volumes. Material and methods: A test was performed with 12 tissue expanders immersed in a closed system. These were divided in 4 sets according to the introduced expansion rate. Three independent variables were considered: percentage of lumen volume introduced into the expander, pressure inside the expander, and experiment duration. The concentration of the drug diffused through the expander was taken as dependent variable. The solution in which the expander was immersed was continuously sampled and drug concentration was determined by High Performance Liquid Chromatography (HPLC). ANOVA was used to determine differences between concentrations measured of every variable applied. Results: Only trimethoprim (TMX) diffused. No lineal correlation was observed between expansion rate and pressure inside the expander. The difference with respect to time and concentration of the drug outside the expander was statistically significant among the 4 sets of expanders (p = 0.0000). Conclusion: Sulfametoxazole (SMX) did not diffuse and crystallized inside the expander because of the different pk of the two drugs (SMX-TMX) respect to pH of dilution which was similar to pK of trimethoprim. The expansion rate had a proportional effect on TMX concentration outside the expander: an over-expansion of the system greater than 200% increases diffusion highly.

Effects of mesocaval shunt on the pharmacokinetics of metronidazole in young rats.

Prophylactic and therapeutic management of portosystemic encephalopathies is based on protein restriction in the diet, and the use of lactulose and antibiotics such as metronidazole. These actions intend to reduce the main source of intestinal ammonia production and release into the systemic circulation. The aim of this study was to evaluate the medium-term effects of mesocaval shunt on the pharmacokinetics of metronidazole in rats with healthy livers. Male Lewis rats were divided into two groups. The first group was subjected to mesocaval shunt (MCS) and the other employed as a control. The following tests were carried out in both groups: metronidazole pharmacokinetics, determination of ALT, AST, albumin, urea and ammonium, liver weight and histomorphology. A loss in body and liver weight was registered in rats subjected to MCS. AST levels also increased compared to controls. Significant differences in almost all pharmacokinetic parameters were detected between MCS and control rats, especially in Kel, AUC and Cmax. Modifications in metronidazole pharmacokinetics and liver weight changes without microstructural modification secondary to MCS were found. We suggest that individual drug-monitoring and pharmacokinetic analysis must be carried out in metronidazole medicated patients with modifications in portal circulation with or with out macro or micro liver structural alterations.

Effect of age on the pharmacokinetics of ranitidine in healthy Mexican volunteers.

UNLABELLED: Numerous reports in the literature have demonstrated changes in drug pharmacokinetics that result with age. Ranitidine is a drug commonly used in Mexico. However no reports on the pharmacokinetics of ranitidine in the Mexican population are available in the literature. The objective of this clinical trial was to evaluate the effect of age on the pharmacokinetics of ranitidine in healthy Mexican volunteers. METHODS: Twenty-one healthy Mexican volunteers were included, who were divided into three groups G1 (18-30 y), G2 (31-50 y) and G3 (51-60 y). The volunteers were given a single oral dose of 300 mg of ranitidine and blood samples were obtained, and some pharmacokinetic parameters were correlated with age. RESULTS: Statistically significant differences were noted in the distribution volume (4.00 +/- 1.11 L/kg in G1, vs 2.15 +/- 1.12 L/kg in G3) of the drug. Clearance was faster among the G1 (1.11 +/- 0.12 mL/hr) group compared to the G3 group (0.58 +/- 0.19 mL/hr). Differences for AUC, t1/2 and Cmax are more evident between G1 and G3. DISCUSSION: The results of our study indicated that in patients over 50 years of age who are treated with ranitidine, the dosage of this agent should be appropriately adjusted in order to avoid adverse effects that may develop with prolonged use of the drug. However it is very important to consider that our result only reflect observations made from a single dose study, thus it is necessary to carry out study under chronic dosage treatment.

Reliable method for the determination of ranitidine by liquid chromatography using a microvolume of plasma.

The aim of the present study was to develop a simple method to measure ranitidine, using 100 microL of plasma, by high-performance liquid chromatography with a Symmetry C(18) column and UV detection at 313 nm. Linearity was assessed in the range from 50 to 1500 ng ml(-1) and had a correlation coefficient of 0.999. The inter- and intra-day coefficients of variation were less than 7%. The limits of detection and quantitation were 5 and 15 ng ml(-1), respectively. Drug levels were determined satisfactorily in three patients. A simple and reliable method was developed which uses a microvolume of plasma, particularly useful in low-weight children.

Effects of gender and phase of the menstrual cycle on the kinetics of ranitidine in healthy volunteers.

The present study was undertaken to determine if differences exist in the pharmacokinetic parameters of oral ranitidine caused by gender and stage of the menstrual cycle. The study was performed in two steps, in the first a pharmacokinetic study was performed on 10 men (average age 35.5 yrs) and 10 women (average age 34.7 yrs) during the follicular phase, and in the second the pharmacokinetic study was performed only on the same women in their luteal phase. Subjects received a tablet dose of 300 mg ranitidine, and blood samples were drawn at several times after its ingestion. Plasma ranitidine concentration was determined by high performance liquid chromatography. Comparison of the pharmacokinetic parameters of women and men revealed statistically significant differences both in distribution volume (Vd) with values of 2.0 and 6.3 l/kg, Area Under Curve (AUC) with values of 7312.15 and 11471.94 ng/ml/h, and clearance (CLt) with values of 0.65 and 0.59 l/kg/h, respectively. Several pharmacokinetic parameters in women were different in the follicular compared to the luteal phase; for example, Vd was 2.0 and 5.6 l/kg, AUC was 7312.15 and 5195.83 ng/ml/h, and CLt was 0.65 and 0.97 l/kg/h, in the respective phases. Moreover, the maximum concentration (Cmax) was 1086 ng/ml in the follicular vs. 864 ng/ml in the luteal phase. The first study detected differences between men and women in several pharmacokinetic parameters, mainly those indicative of drug availability, for example, Vd, AUC, and CLt. Comparison of data obtained in the follicular phase with those obtained in the luteal phase revealed differences in most pharmacokinetic parameters, which is seemingly indicative of the characteristic physiological changes associated with the luteal phase that largely affect the kinetics and availability of drugs such as ranitidine. Although it has been postulated that hormonal fluctuation within the menstrual cycle phase is the primary cause of documented gender differences in the pharmacokinetics and pharmacodynamics of drugs, further study of related factors is required to understand how gender and menstrual cycle rhythms affect the phannacokinetic process in their entirety.