Stroke units could be a valid alternative to intensive care units for patients with low-grade aneurysmal subarachnoid haemorrhage.

BACKGROUND AND PURPOSE: According to current guidelines, patients with aneurysmal subarachnoid haemorrhage (aSAH) are mostly managed in intensive care units (ICUs) regardless of baseline severity. We aimed to assess the prognostic and economic implications of initial admission of patients with low-grade aSAH into a stroke unit (SU) compared to initial ICU admission. METHODS: We reviewed prospectively registered data from consecutive aSAH patients with a World Federation of Neurosurgery Societies grade <3, admitted to our Comprehensive Stroke Centre between April 2013 and September 2018. Clinical and radiological baseline traits, in-hospital complications, length of stay (LOS) and poor outcome at 90 days (modified Rankin Scale score > 2) were compared between the ICU and SU groups in the whole population and in a propensity-score-matched cohort. RESULTS: Of 131 patients, 74 (56%) were initially admitted to the ICU and 57 (44%) to the SU. In-hospital complication rates were similar in the ICU and SU groups and included rebleeding (10% vs. 7%; P = 0.757), angiographic vasospasm (61% vs. 60%; P = 0.893), delayed cerebral ischaemia (12% vs. 12%; P = 0.984), pneumonia (6% vs. 4%; P = 0.697) and death (10% vs. 5%; P = 0.512). LOS did not differ between groups (median [interquartile range] 22 [16-30] vs. 19 [14-26] days; P = 0.160). In adjusted multivariate models, the location of initial admission was not associated with long-term poor outcome either in the whole population (odds ratio [OR] 1.16, 95% confidence interval [CI] 0.32-4.19; P = 0.825) or in the matched cohort (OR 0.98, 95% CI 0.24-4.06; P = 0.974). CONCLUSIONS: A dedicated SU, with care from a multidisciplinary team, might be an optimal alternative to ICU for initial admission of patients with low-risk aSAH.

Effectiveness of a specific follow up program for the management of the mental components of post-intensive care syndrome and chronic pain after COVID-19: results from the PAIN-COVID randomized clinical trial.

BACKGROUND: Critical COVID-19 survivors are at risk of developing Post-intensive Care Syndrome (PICS) and Chronic ICU-Related Pain (CIRP). We determined whether a specific care program improves the quality of life (QoL) of patients at risk of developing PICS and CIRP after COVID-19. METHODS: The PAIN-COVID trial was a parallel-group, single-centre, single-blinded, randomized controlled trial. The intervention consisted of a follow up program, patient education on PICS and pain, and a psychological intervention based on Rehm's self-control model in patients with abnormal depression scores (≥8) in the Hospital Anxiety and Depression Scale (HADS) at the baseline visit. QoL was evaluated with the 5-level EQ 5D (EQ 5D 5 L), mood disorders with the HADS, post-traumatic stress disorder (PTSD) with the PCL-5 checklist, and pain with the Brief Pain Inventory short form, the Douleur Neuropathique 4 questionnaire, and the Pain Catastrophizing Scale. The primary outcome was to determine if the program was superior to standard-of-care on the EQ visual analogue scale (VAS) at 6 months after the baseline visit. The secondary outcomes were EQ VAS at 3 months, and EQ index, CIRP incidence and characteristics, and anxiety, depression, and PTSD at 3 and 6 months after baseline visits. CONCLUSIONS: This program was not superior to standard care in improving QoL in critical COVID-19 survivors as measured by the EQ VAS. However, our data can help establish better strategies for the study and management of PICS and CIRP in this population. TRIAL REGISTRATION: # NCT04394169, registered on 5/19/2020.

Safety of specific immunotherapy using a depigmented and polymerised extract of Dermatophagoides pteronyssinus in children under five years of age.

BACKGROUND: Different opinion documents point to a patient age of under five years as a relative contraindication to specific immunotherapy, arguing that this age group has a greater risk of developing anaphylaxis, and that specially trained personnel are needed to deal with the problem if it occurs. However, insufficient evidence exists to support such an affirmation. PATIENTS AND METHODS: A retrospective follow-up observational study was made of patients aged 60 months or younger who had been subjected to specific immunotherapy. We included 77 children with a diagnosis of extrinsic bronchial asthma (n=68), extrinsic spasmodic cough (n=5) and allergic rhinitis (n=4) confirmed by clinical criteria and prick-test, with specific IgE positivity to Dermatophagoides pteronyssinus. All patients received specific immunotherapy with an extract of depigmented D. pteronyssinus polymerised with glutaraldehyde, involving an initial cluster protocol of two weeks and monthly maintenance doses. All observed adverse reactions were recorded, and classified according to European Academy of Allergy and Clinical Immunology (EAACI) criteria. RESULTS: A total of 1837 doses were administered to the 77 patients, with four adverse reactions being observed in three patients. Three reactions (0.16% of the administered doses) were local and immediate, while one was systemic and of grade 2 (0.05% of the administered doses) - consisting of an episode of nocturnal wheezing. CONCLUSIONS: Specific immunotherapy in children under five years of age with the extract used is safe. We consider that further studies are needed, involving other types of extracts, to allow reconsideration of the relative contraindication of patient age for the administration of immunotherapy.

Time-domain induced polarization as a tool to image clogging in treatment wetlands.

During the last decade, treatment (artificial) wetlands have flourished all over Europe for the treatment of sewages from small communities thanks to their low cost of operation. The clogging of the filter of these wetlands is an issue affecting their efficiency and considered as their main operational problem. The present work shows the results of the application of a geophysical method called time-domain induced polarization. It is used to non-intrusively image, in 3D, the clogging of the gravel filters in a quick and efficient way. Induced polarization characterizes the ability of a porous material to reversibly store electrical charges when submitted to an electrical field. The material property characterizing this ability is called normalized chargeability. A set of laboratory experiments allows to determine an empirical relationship between the normalized chargeability and the weight amount of clogging. Induced polarization measurements have been performed in the field over a treatment wetland to get a 3D reconstructed image (tomography) of the normalized chargeability. From this tomography and the previously defined relationship, we are able to image in 3D the distribution of clogging and where it is concentrated in the filter. We can therefore identify the areas requiring preventive measures to minimize this clogging issue.

Patient characteristics, clinical course and factors associated to ICU mortality in critically ill patients infected with SARS-CoV-2 in Spain: A prospective, cohort, multicentre study. / Características, evolución clínica y factores asociados a la mortalidad en UCI de los pacientes críticos infectados por SARS-CoV-2 en España: estudio prospectivo, de cohorte y multicéntrico.

BACKGROUND: The clinical course of COVID-19 critically ill patients, during their admission in the intensive care unit (UCI), including medical and infectious complications and support therapies, as well as their association with in-ICU mortality has not been fully reported. OBJECTIVE: This study aimed to describe clinical characteristics and clinical course of ICU COVID-19 patients, and to determine risk factors for ICU mortality of COVID-19 patients. METHODS: Prospective, multicentre, cohort study that enrolled critically ill COVID-19 patients admitted into 30 ICUs from Spain and Andorra. Consecutive patients from March 12th to May 26th, 2020 were enrolled if they had died or were discharged from ICU during the study period. Demographics, symptoms, vital signs, laboratory markers, supportive therapies, pharmacological treatments, medical and infectious complications were reported and compared between deceased and discharged patients. RESULTS: A total of 663 patients were included. Overall ICU mortality was 31% (203 patients). At ICU admission non-survivors were more hypoxemic [SpO2 with non-rebreather mask, 90 (IQR 83 to 93) vs. 91 (IQR 87 to 94); P<.001] and with higher sequential organ failure assessment score [SOFA, 7 (IQR 5 to 9) vs. 4 (IQR 3 to 7); P<.001]. Complications were more frequent in non-survivors: acute respiratory distress syndrome (ARDS) (95% vs. 89%; P=.009), acute kidney injury (AKI) (58% vs. 24%; P<10-16), shock (42% vs. 14%; P<10-13), and arrhythmias (24% vs. 11%; P<10-4). Respiratory super-infection, bloodstream infection and septic shock were higher in non-survivors (33% vs. 25%; P=.03, 33% vs. 23%; P=.01 and 15% vs. 3%, P=10-7), respectively. The multivariable regression model showed that age was associated with mortality, with every year increasing risk-of-death by 1% (95%CI: 1 to 10, P=.014). Each 5-point increase in APACHE II independently predicted mortality [OR: 1.508 (1.081, 2.104), P=.015]. Patients with AKI [OR: 2.468 (1.628, 3.741), P<10-4)], cardiac arrest [OR: 11.099 (3.389, 36.353), P=.0001], and septic shock [OR: 3.224 (1.486, 6.994), P=.002] had an increased risk-of-death. CONCLUSIONS: Older COVID-19 patients with higher APACHE II scores on admission, those who developed AKI grades ii or iii and/or septic shock during ICU stay had an increased risk-of-death. ICU mortality was 31%.

Clinical pharmacokinetics of parenteral dexketoprofen trometamol in healthy subjects.

Dexketoprofen trometamol, a highly water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug used for pain relief. Two studies were conducted to determine the pharmacokinetics of the drug in healthy subjects following single intravenous (i.v.) and intramuscular (i.m.) doses of dexketoprofen. In the first study, 6 male and 6 female volunteers received 50 mg dexketoprofen (74 mg dexketoprofen trometamol) by i.v. bolus. In the second one, another 6 male and 6 female subjects received 25 mg and 50 mg of dexketoprofen by the i.m. route. Dexketoprofen plasma concentrations were determined by reverse-phase high-performance liquid chromatography (HPLC). No serious adverse events were observed and all volunteers completed the study. The main pharmacokinetic parameters were determined by a noncompartmental approach. Following the i.v. bolus, mean (+/- SEM) area under the curve AUC0-x and clearance (CL) were 9005 +/- 422 ng.h/ml and 0.089 +/- 0.004 l/h/kg. Volumes of distribution Vi and Vss averaged 0.060 +/- 0.006 l/kg and 0.104 +/- 0.003 l/kg. Mean elimination half-life (t1/2e) and MRT were 1.05 +/- 0.04 h and 1.18 +/- 0.05 h. Following single i.m. 25 mg and 50 mg dexketoprofen, a rapid absorption was observed, with tmax values ranging from 0.17 h to 0.75 h. The corresponding Cmax averaged 1851 +/- 182 ng/ml and 3813 +/- 169 ng/ml, and mean AUC0-x were 3033 +/- 193 ng.h/ml and 5878 +/- 228 ng.h/ml, respectively. No significant differences by gender were obtained following both parenteral routes. A dose proportionality in Cmax and AUC0-x was observed. Dexketoprofen pharmacokinetics following i.v. and i.m. routes, together with the availability of a single 2 ml formulation, allows for a potential advantageous rapid switch to the oral formulation when clinically possible.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in young and elderly subjects.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) widely used for pain relief. This study was conducted to determine the pharmacokinetics of this analgesic agent in elderly subjects and to compare them with young volunteers following single and repeated oral doses. Twelve healthy young and 12 elderly subjects received 25 mg oral dexketo- profen (equivalent to 37 mg of its tromethamine salt) as a single dose (day 1) and 3-day repeated doses (1 dose every 8 h for a total of 10 doses). Serial concentrations of dexketoprofen were determined in plasma and urine by a reverse-phase HPLC/ultraviolet procedure over 24 h on day 1 and after the last 10th repeated t.i.d. dose. Compared to young subjects, elderly subjects showed significant increases in AUC and t1/2,z and decreases in CL/F following single and repeated doses. After single dosing, the corresponding mean +/- SD values were 5106.6 +/- 1873.0 vs. 3605.4 +/- 897.9 ng.h/ml (p = 0.015); 1.59 +/- 0.40 vs. 1.12 +/- 0.20 h (p < 0.001); and 1.11 +/- 0.29 vs. 1.63 +/- 0.36 ml/min/kg (p < 0.001). After the repeated dose, AUC, t1/2,z and CL/F averaged 5067.8 +/- 1373.4 vs. 3194.4 +/- 694.3 ng.h/ml (p < 0.001); 1.65 +/- 0.44 vs. 1.11 +/- 0.29 h (p < 0.005); and 1.12 +/- 0.23 vs. 1.87 +/- 0.42 ml/min/kg (p < 0.001). Median tmax was 0.5 h. Cumulative excretions in urine up to 24 h of unbound, conjugated and total dexketoprofen were similar among the groups. These results suggest that dexketoprofen elimination is reduced in the elderly. Although no drug accumulation in plasma was observed after single and repeated dosing, the renal function decline in elderly patients calls for a cautious dose-adjustment in this population.

Pharmacokinetics of dexketoprofen trometamol in subjects with mild and moderate chronic renal insufficiency.

The influence of mild to moderate chronic renal insufficiency on the pharmacokinetics of dexketoprofen trometamol was evaluated. Dexketoprofen was administered to volunteers with mild (n = 8) or moderate (n = 8) renal impairment and to healthy subjects (n = 8), as a single 12.5 mg oral dose (equivalent to 18.5 mg of the tromethamine salt). All subjects completed the study and no serious adverse events were recorded. Mild and moderate renal insufficiency increased Cmax by approximately 22% and 37%, respectively, as related to normal subjects (p < 0.05 for moderate renal dysfunction). No statistically significant differences between groups were obtained for tmax, AUC, CL/F, renal CL and V/F. The cumulative urinary excretion of unchanged dexketoprofen, assessed up to 24 hours postdose, was similar in all groups (median values of 7.0%, 8.1% and 9.7% of the administered dose). On the contrary, cumulative urinary excretions of conjugated dexketoprofen decreased in subjects with mild or moderate renal insufficiency when compared to healthy controls (median and 95% CI for differences: -3.3% (-14.8% to 2.6%) and -7.3% (-22.2% to -0.2%), respectively). Conservatively, a dose adjustment of dexketoprofen in patients with impaired renal function is recommended.

Single and repeated dose pharmacokinetics of dexketoprofen trometamol in patients with impaired liver function.

Dexketoprofen trometamol, a high water-soluble salt of the active enantiomer of rac-ketoprofen, is a nonsteroidal antiinflammatory drug (NSAID) used for pain relief. This study compared the pharmacokinetics of dexketoprofen in patients with impaired liver function and normal subjects following single and repeated oral dosing. Subjects with normal liver function (n = 6) and with Child-Pugh A (n = 7) or Child-Pugh B (n = 5) hepatic impairment scores completed this open-label and parallel study. They received 25 mg dexketoprofen (equivalent to 37 mg of its tromethamine salt) as a single (day 1) and a 3-day repeated dose (1 dose every 8 hours for a total of 10 doses). Dexketoprofen concentrations were determined in plasma and urine by reverse-phase high performance liquid chromatography (HPLC). Model-independent pharmacokinetic parameters were obtained. All subjects completed the study. No serious adverse events were recorded. Following the single dose, mean (+/- SEM) Cmax were 3027.7 +/- 429.3 ng/ml (healthy subjects), 2856.3 +/- 340.3 ng/ml (Child-Pugh A) and 1937.2 +/- 328.0 ng/ml (Child-Pugh B). Median tmax were 0.49 h (0.33-0.68) h, 0.50 h (0.33-0.67) h and 0.67 h (0.33-1.50) h. AUC0-x averaged 3778.0 +/- 439.0 ng.h/ml, 4890.4 +/- 539.1 ng.h/ml and 3985.0 +/- 712.0 ng.h/ml. Mean CL/F were 101.1 +/- 11.3 ml/h/kg, 73.3 +/- 9.9 ml/h/kg and 88.8 +/- 15.5 ml/h/kg and V/F averaged 0.192 +/- 0.018 l/kg, 0.162 +/- 0.006 l/kg and 0.214 +/- 0.044 l/kg. Following the repeated administration, similar results were obtained showing no drug accumulation. As related to the administered dose, median excretions of unchanged and conjugated dexketoprofen in urine were 2.1% and 67.1% in healthy subjects, 2.8% and 60.9% in Child-Pugh A subjects and 4.4% and 47.7% in Child-Pugh B volunteers. A trend towards a reduced urinary excretion of conjugated dexketoprofen in hepatic patients, more evident in the Child-Pugh B than in the Child-Pugh A groups, was observed when compared with healthy volunteers (median and 95% CI for differences: -5.4% [-19.9% to 2.0%] and -19.4% [-45.6% to 0.4%]). Conservatively, a dose adjustment of dexketoprofen trometamol in patients with impaired hepatic function is recommended.

Identificación por catálogo y detección molecular de bovinos Holstein portadores de braquiespina en Uruguay / Identification through sire catalogues analysis and molecular detection of brachyspina carriers in Uruguayan Holstein

Resumen El síndrome de braquiespina es una condición genética de la raza Holstein, detectada en el año 2006. Es causado por una deleción de 3.3 Kb en el gen FANCI localizado en el cromosoma bovino 21. La mutación fue identificada en poblaciones de Holstein de Europa, América del Norte y Asia. Dada la importancia económica del defecto y su amplia distribución mundial, el objetivo de este trabajo ha sido la identificación de animales portadores en el núcleo de selección genética de la raza en Uruguay y el diagnóstico molecular del alelo deletéreo en animales del rodeo nacional. En el presente estudio se analizaron 2598 registros de toros Holstein del catálogo de padres del sistema de evaluación genética lechera, los registros de toros pertenecientes a los catálogos de semen Holstein disponible para Uruguay de los años 2014 al 2018; y 71 vacas pertenecientes al rodeo general. Se encontraron 28 toros portadores de braquiespina de un total de 377 toros con información genética del catálogo de padres y cuatro vacas portadoras de un total de 71 genotipificadas en nuestro laboratorio. Se demostró una disminución en el ingreso de semen de animales portadores al país entre los años 2014 y 2018. La frecuencia significativa de animales portadores en Uruguay evidencia la necesidad de implementar estrategias que permitan eliminar gradualmente el defecto de la población.

Abstract Brachyspina syndrome is a hereditary recessive disease of recent identification in the Holstein breed. It is caused by a deletion of 3.3Kb in the FANCI gene located in the bovine chromosome 21. The mutation was identified in Holstein populations of Europe, North America and Asia. Given the economic importance of the defect and its wide distribution, the objective of this work was the identification of carrier animals in the genetic selection nucleus of the breed in Uruguay and the molecular verification of the deleterious allele in animals of the national herd. In the present study, 2598 records of Holstein bulls were analyzed from the list of parents of the dairy genetic evaluation system, records of bulls belonging to the Holstein semen catalogs available for Uruguay from 2014 to 2018; and 71 cows belonging to the general herd. Twenty-eight brachyspina carrier bulls were found of a total of 377 bulls with genetic information from the list of parents and four carrier cows of a total of 71 genotyped in our laboratory. A decrease in the income of semen from carrier animals to the country between 2014 and 2018 was demonstrated. The significant frequency of carrier animals in Uruguay evidences the need to implement strategies to gradually eliminate the population defect.

Preclinical and clinical development of dexketoprofen.

Dexketoprofen trometamol is a water-soluble salt of the dextrorotatory enantiomer of the nonsteroidal anti-inflammatory drug (NSAID) ketoprofen. Racemic ketoprofen is used as an analgesic and an anti-inflammatory agent, and is one of the most potent in vitro inhibitors of prostaglandin synthesis. This effect is due to the S(+)-enantiomer (dexketoprofen), while the R(-)-enantiomer is devoid of such activity. The pharmacokinetic profile of ketoprofen and its enantiomers was assessed in several animals species and in human volunteers. In humans, the relative bioavailability of oral dexketoprofen trometamol (12.5 and 25 mg, respectively) is similar to that of oral racemic ketoprofen (25 and 50 mg, respectively), as measured in all cases by the area under the concentration-time curve values for S(+)-ketoprofen. Dexketoprofen trometamol, given as a tablet, is rapidly absorbed, with a time to maximum plasma concentration (tmax) of between 0.25 and 0.75 hours, whereas the tmax for the S-enantiomer after the racemic drug, administered as tablets or capsules prepared with the free acid, is between 0.5 and 3 hours. Peak plasma concentrations of 1.4 and 3.1 mg/L are reached after administration of dexketoprofen trometamol 12.5 and 25 mg, respectively. From 70 to 80% of the administered dose is recovered in the urine during the first 12 hours, mainly as the acyl-glucuronoconjugated parent drug. No R(-)-ketoprofen is found in the urine after administration of dexketoprofen [S(+)-ketoprofen], confirming the absence of bioinversion of the S(+)-enantiomer in humans. in animal studies, the anti-inflammatory potency of dexketoprofen was always equivalent to that demonstrated by twice the dose of ketoprofen. Similarly, animal studies showed a high analgesic potency for dexketoprofen trometamol. The R(-)-enantiomer demonstrated a much lower potency, its analgesic action being apparent only in conditions where the metabolic bioinversion to the S(+)-enantiomer was significant. The gastric ulcerogenic effect of dexketoprofen at various oral doses (1.5 to 6 mg/kg) in the rat do not differ from those of the corresponding double doses (3 to 12 mg/kg) of racemic ketoprofen. Repeated (5-day) oral administration of dexketoprofen as the trometamol salt causes less gastric ulceration than was observed after the acid form of both dexketoprofen and the racemate. In addition, single dose dexketoprofen as the free acid at 10 to 20 mg/kg does not show a significant intestinal ulcerogenic effect in rats, while racemic ketoprofen 20 or 40 mg/kg is clearly ulcerogenic to the small intestine. The analgesic efficacy of oral dexketoprofen trometamol 10 to 20 mg is superior to that of placebo and similar to that of ibuprofen 400 mg in patients with moderate to serve pain after third molar extraction. The time to onset of pain relief appeared to be shorter in patients treated with dexketoprofen trometamol than in those treated with ibuprofen 400 mg. Dexketoprofen trometamol was well tolerated, with a reported incidence of adverse events similar to that of placebo.

Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated oral doses.

The pharmacokinetics of dexketoprofen trometamol were evaluated in two studies using healthy volunteers. In the first study, the relative bioavailability of a single oral capsule of dexketoprofen free acid 25 mg or dexketoprofen trometamol 25 mg (given as 37 mg of the trometamol salt) was compared to ketoprofen 50 mg in 18 healthy volunteers. In the second study, the pharmacokinetics and tolerability of oral dexketoprofen trometamol in tablet form were evaluated after either a single 25 mg dose (24 volunteers) or a repeated dose of 25 mg twice daily for 7 days (12 volunteers). The absorption of dexketoprofen from dexketoprofen trometamol capsules was bioequivalent to that of ketoprofen. On the other hand, the extent of absorption of dexketoprofen free acid was significantly lower than that for ketoprofen. Dexketoprofen trometamol showed the most rapid absorption rate, with highest Cmax and shortest t(max) values, whereas dexketoprofen free acid had the slowest absorption rate, and ketoprofen had an intermediate absorption rate. After repeated-dose administration of dexketoprofen trometamol, the pharmacokinetic parameters were similar to those obtained after single doses, indicating that no drug accumulation occurred. Dexketoprofen trometamol was well tolerated, with no clinically relevant adverse events reported.

Clinical comparison of dexketoprofen trometamol, ketoprofen, and placebo in postoperative dental pain.

The efficacy and tolerability of single doses of dexketoprofen trometamol 12.5 mg, 25 mg, and 50 mg and ketoprofen 50 mg were compared in this double-blind, randomized, placebo-controlled study of 210 patients with moderate to severe pain after removal of one mandibular impacted third molar tooth. Pain intensity and pain relief were monitored for 6 h after administration of medication using visual analogue and verbal rating scales. All four active treatments were significantly more effective than placebo (P < 0.001). Dexketoprofen 25 mg and 50 mg produced an analgesic effect within 30 min of administration and their effect persisted for 6 h. Ketoprofen 50 mg produced a level of analgesia similar to those of the higher doses of dexketoprofen trometamol, but it had a slower onset. The 12.5-mg dose of dexketoprofen trometamol was significantly superior to placebo but produced a lower level and shorter duration of analgesia compared to the other active treatments. There were no significant differences between 25 and 50 mg of dexketoprofen trometamol in any measure of analgesic efficacy. No serious adverse events were observed and there were no significant differences in the incidence of adverse events among treatment groups. These results demonstrate that dexketoprofen trometamol 25 mg is at least as effective as the racemic ketoprofen 50 mg in the treatment of postsurgical dental pain. The more rapid onset of action compared to ketoprofen suggests that dexketoprofen trometamol is more appropriate for treatment of acute pain.

The effect of food and an antacid on the bioavailability of dexketoprofen trometamol.

This randomized three-way, crossover pharmacokinetic study was performed to determine whether food or an antacid alters the bioavailability of dexketoprofen trometamol. A total of 24 healthy volunteers received three single 25 mg doses of dexketoprofen trometamol administered either in fasting condition, after an antacid (Maalox), or after a high-fat breakfast. Each volunteer received the three treatments in a randomized order, with a 7-day washout period between treatments. Blood samples were taken at regular intervals up to 24 h after dose. Plasma dexketoprofen concentrotions were determined by HPLC and the main outcome measures were area under curve of concentration vs. time (AUC0-infinity), maximal plasma concentration (Cmax), and time to reach maximal concentration (t(max)). Administration of an antacid 10 min before dexketoprofen trometamol had no clinically relevant effect on any of the pharmacokinetic parameters. Food did not alter the extent of absorption of dexketoprofen trometamol, but t(max) was significantly increased and C(max). significantly decreased compared with the fasting state. In conclusion, we can state that neither antacid nor food has a significant effect on the overall bioavailability of dexketoprofen trometamol.

Clinical comparison of dexketoprofen trometamol and dipyrone in postoperative dental pain.

A total of 125 outpatients with moderate to severe pain after surgical removal of one impacted third molar were randomly assigned to receive dexketoprofen trometamol 12.5 or 25 mg or dipyrone 575 mg. For first-dose assessments, patients rated their pain intensity and its relief at regular intervals. From 60 min post dose to the end of the 6-h observation period, both doses of dexketoprofen trometamol had higher pain relief scores than dipyrone: Between 3 and 6 h the differences were statistically significant. In addition, peak measures (PIDmax and PARmax) were statistically superior after both doses of dexketoprofen trometamol compared to dipyrone. The overall efficacy assessed at the end of the first-dose phase was rated as good or excellent by 90%, 83.3%, and 70% of patients receiving dexketoprofen trometamol 25 mg, dexketoprofen trometamol 12.5 mg, and dipyrone, respectively. The number of patients who required remedication during the 6-h period was significantly lower in both dexketoprofen groups. Repeated-dose data were also obtained. No significant differences were found in the efficacy after repeated doses, the number of doses taken, or the mean time elapsed between doses. The overall efficacy at the end of the repeated-dose phase was rated as good or excellent by 84.2%, 66.7%, and 70% of patients receiving dexketoprofen trometamol 25 mg, dexketoprofen trometamol 12.5 mg, and dipyrone, respectively. The frequency of adverse events was similar for all treatments and no serious adverse events were reported during the study.

Comparison of the efficacy and tolerability of dexketoprofen and ketoprofen in the treatment of primary dysmenorrhea.

Dexketoprofen, the pure S(+)-enantiomer of ketoprofen, is a promising new analgesic, but few clinical trials have yet examined its efficacy and tolerability. In this study, patients with a history of primary dysmenorrhea were treated with dexketoprofen doses of 12.5 and 25 mg, ketoprofen 50 mg, and placebo using a randomized, four-way crossover design. Efficacy analyses showed that dexketoprofen 12.5 and 25 mg and racemic ketoprofen 50 mg significantly reduced pain intensity compared with placebo from 1 h after dose to 4-6 h after dose. Interestingly, dexketoprofen at 12.5 mg was significantly superior to placebo at 30 min after dose. Mean pain relief scores also demonstrated that both doses of dexketoprofen and racemic ketoprofen were significantly superior to placebo at 1-6 h after the first dose. No indices of analgesic efficacy showed any significant differences between the two doses of dexketoprofen or between dexketoprofen and ketoprofen. After repeated dose administration, similar results were obtained. There were no significant effects of any treatment on activities of daily living, menstrual flow, or associated symptoms. Dexketoprofen was effective, well tolerated, and had no difference in the incidence of adverse events compared to ketoprofen or placebo.

Comparison of dexketoprofen trometamol and ketoprofen in the treatment of osteoarthritis of the knee.

Dexketoprofen, the active enantiomer of the racemic compound ketoprofen, is a new nonsteroidal antiinflammatory drug (NSAID) of the arylpropionate family. The efficacy and safety of dexketoprofen trometamol were compared with the equivalent enantiomeric dose of ketoprofen in a multicenter, randomized, double-blind 3-week trial of adult outpatients with pain due to osteoarthritis of the knee. After a washout period of 7-15 days, patients were randomly assigned to receive either dexketoprofen trometamol 25 mg tid (N = 89) or ketoprofen 50 mg tid (N = 94). Of the 183 patients enrolled, two were lost to follow-up. At the end of treatment (3 weeks), the main efficacy outcome measures were significantly better in the dexketoprofen trometamol group than in the ketoprofen group. In addition, overall physician assessment indicated that 75% of the dexketoprofen group had improved compared with 50% of the ketoprofen patients. There were fewer adverse events in the dexketoprofen treatment group, but the difference did not reach statistical significance. These results demonstrate that dexketoprofen trometamol 25 mg tid is more effective than ketoprofen 50 mg tid in short-term symptomatic treatment of knee osteoarthritis and suggest that the tolerability of dexketoprofen trometamol is more favorable than ketoprofen. Therefore, the substitution of dexketoprofen for racemic ketoprofen may be advantageous in clinical practice.

Cisapride treatment changes the evolution of infant asthma with gastroesophageal reflux.

Gastroesophageal reflux has been named as a possible etiologic factor in infant asthma. We studied 28 boys and six girls aged 19.4 +/- 4.8 months whose asthma began at the age of 7.5 months (1 to 28 months). A common protocol including allergy tests and 24-h intraesophageal pH monitoring (IEpHM) was used. Patients with pathologic 24-h IEpHM were treated with cisapride while the rest were considered the control group. Symptoms score and drug consumption were evaluated in both groups, and 24-h IEpHM was repeated at 4 months. IEPHM was pathologic in 65.6% of the infants. In the cisapride group, wheezing crisis frequency decreased from 4.9 +/- 2 to 0.75 +/- 1.2 (p < 0.0002), and only 10% of patients needed basic pharmacologic treatment. The second IEpHM was normal in eight cases, pathologic in six and was not performed in seven. In the controls, wheezing crisis frequency decreased from 4.6 +/- 2.4 to 0.75 +/- 1.8 (p < 0.01), but 44% needed basic pharmacologic treatment (p < 0.05). In conclusion, gastroesophageal reflux is a frequent but not universal finding in infants with asthma; and cisapride treatment spectacularly reduces wheezing crisis frequency and antiasthmatic drug consumption in these patients.

ITS-2 rDNA sequencing of Gnathostoma species (Nematoda) and elucidation of the species causing human gnathostomiasis in the Americas.

From several gnathostome species the complete internal transcribed spacer ITS-2 ribosomal DNA (rDNA) repeat sequence and a fragment of the 5.8S rDNA were obtained by direct polymerase chain reaction cycle-sequencing and silver-staining methods. The size of the complete ITS-1 sequence in agarose gel electrophoresis was also obtained. The ITS-2 enabled the differentiation of Gnathostoma spinigerum from Thailand and Gnathostoma binucleatum from Mexico and Ecuador and confirmed the validity of the latter. Gnathostoma turgidum, Gnathostoma sp. I (=Gnathostoma procyonis sensu Almeyda-Artigas et al., 1994), and Gnathostoma sp. II (=G. turgidum sensu Foster, 1939 pro parte), all from Mexico, proved to be independent species, but Gnathostoma sp. III, also from Mexico, could not be differentiated from G. turgidum. In Mexico and Ecuador, gnathostomes involved in human infection and that had been classified as G. spinigerum belong to G. binucleatum. The 5.8S rDNA sequences of the 6 Gnathostoma species studied were identical. The results of the ITS-1 agreed with those results of ITS-2.

[Epidemiological study of healthy carriers of Australia antigen. Analysis of contagiousness, and mechanism of spread of the infection (author's transl)]. / Estudio epidemiológico de los portadores sanos de antíaeno Australia. Análisis de su infecto-contagiosidad y mecanismo de aparición de nuevos casos.

Epidemiological studies in healthy carriers of HB Ag show variable results that might depend on the geographical area, ethnic group, and socio-economic level analyzed. For that reason an study was undertaken in the Spanish population with the purpose of analysing contagiousness of healthy carriers and mechanism of spread of the infection. The incidence of HB Ag and HB Ab was determined by radioimmunoassay in 211 relatives of 76 healthy carriers; all members of the family could be studied in 51 cases. The results were compared to those of a sizeable sample of the normal population. The overall incidence of HB Ag (13.1 %), and of HB Ab (18.9 %) in the probands was significantly higher than in the normal population (0.8 %, and 9 %, respectively). The distribution of new cases of HB Ag positivity in the 51 families in which the members could be studied demonstrated a significantly higher frequency in children of a carrier mother (28.9 %) than in those of a carrier father (10.8 %). In conclusion, the contagiousness of healthy carriers for their families can not be disregarded. It is likely that the mechanism of spread of the infection depends on a multifactorial inheritance of the genetic alteration of the selective immunologic response to the HB Ag, compounded by environmental factors.