Daily life of the ancient Maya recorded on murals at Calakmul, Mexico.

Research into ancient societies frequently faces a major challenge in accessing the lives of those who made up the majority of their populations, since the available evidence so often concerns only the ruling elite. Our excavations at the ancient Maya site of Calakmul, Mexico, have uncovered a "painted pyramid:" a structure decorated with murals depicting scenes of its inhabitants giving, receiving, and consuming diverse foods, as well as displaying and transporting other goods. Many are accompanied by hieroglyphic captions that describe the participants, and include spellings of key subsistence items. Collectively, they offer insights into the social mechanisms by which goods were circulated within major Maya centers.

Nasogastric administration of garenoxacin as crushed tablets with and without concomitant enteral feeding in healthy subjects.

BACKGROUND AND OBJECTIVE: Cation-containing drugs have the potential to affect the absorption of quinolones. The current study was conducted to assess whether the bioavailability of garenoxacin was affected by administration as crushed tablets with and without concomitant enteral nutrition. METHODS: This was a randomised, open-label, three-period, single-dose, crossover study carried out in healthy male volunteers who received study treatments at a clinical facility. The study included 18 subjects (mean age 30 +/- 6 years) who were treatment-naive to garenoxacin and had a body mass index of > or =18 kg/m(2) and < or =30 kg/m(2). Subjects received garenoxacin 600 mg orally in three treatments: (A) intact tablets; (B) crushed tablets suspended in water delivered via a nasogastric (NG) tube; and (C) treatment B plus concomitant enteral feeding (Osmolite; 600 mL at 100 mL/h). Serial plasma samples were collected post-dose for pharmacokinetic analysis. Pharmacokinetic parameters were determined by noncompartmental methods. Geometric mean ratio with 90% CI for area under the concentration-time curve from time 0 extrapolated to infinity (AUC(infinity)) and maximum observed plasma concentration (C(max)) were used to assess potential effects of the different conditions of administration. Absence of an effect was concluded if the 90% CIs for the ratio of geometric means for C(max) and AUC(infinity) were within 0.7-1.43 and 0.8-1.25, respectively. The pharmacokinetics (AUC(infinity)and C(max)) and safety of garenoxacin were assessed. RESULTS: Geometric means for C(max) were 8.3, 8.5 and 8.3 microg/mL and for AUC(infinity) were 103.3, 97.2 and 93.4 microg.h/mL for treatments A, B and C, respectively. The 90% CIs for geometric mean ratios for AUC(infinity) and C(max) of garenoxacin administered as crushed tablets and crushed tablets with Osmolite via NG tube relative to intact tablets administered orally were within 0.80-1.25, suggesting that the bioavailability of garenoxacin was not affected by delivery of crushed tablets via NG tube, regardless of concomitant enteral feeding, compared with oral delivery of intact tablets. Half-life (mean range 12-13 hours) was similar for all three groups. CONCLUSIONS: The relative bioavailability of garenoxacin was not affected by administration as crushed tablets, regardless of enteral feeding. Garenoxacin can be administered as crushed tablets in the presence or absence of concomitant Osmolite.

Pharmacokinetics and pharmacodynamics of warfarin when coadministered with pentosan polysulfate sodium.

The effect of pentosan polysulfate sodium on warfarin pharmacokinetics and pharmacodynamics was investigated in healthy subjects. Warfarin was titrated to an international normalized ratio between 1.4 and 1.8. Subjects continued their titrated dose of warfarin and received pentosan polysulfate sodium 100 mg or placebo every 8 hours for 7 days. The Cmax of R- and S-warfarin was approximately 840 to 890 ng/mL and 680 to 730 ng/mL, respectively, and was similar in the absence and presence of pentosan polysulfate sodium. The half-life for R- and S-warfarin was 52 to 56 hours and 36 to 40 hours, respectively. Prothrombin time, partial thromboplastin time, and the international normalized ratio for warfarin + placebo and warfarin + pentosan polysulfate sodium were comparable. The AUC(INR) indicated no treatment effect (P = .772); however, there was a period effect. Analysis of variance for the treatments by period indicated no treatment effect (P > .1). Adverse events were mild and included headache, epistaxis, and rash. Most adverse events were unrelated to treatment and were seen during warfarin titration. Pentosan polysulfate sodium did not affect warfarin pharmacokinetics or pharmacodynamics.

Pharmacokinetics and safety of ebastine in patients with impaired hepatic function compared with healthy volunteers: a phase I open-label study.

OBJECTIVE: To assess the differences between patients with hepatic insufficiency and healthy subjects with regard to the pharmacokinetics, cardiac safety and overall safety of ebastine and its active metabolite carebastine. DESIGN: Open-label parallel-group study. PARTICIPANTS: 24 patients with varying degrees of hepatic insufficiency, as categorised by the Child-Pugh classification, and 12 healthy volunteers. METHODS: Healthy subjects and patients with Child-Pugh class A (n = 8) or B (n = 8) received ebastine 20 mg once daily for 7 days. Patients with Child-Pugh class C (n = 8) [single or repeated dose] received ebastine 10 mg. Plasma concentrations of ebastine and carebastine were determined for 23.5 hours following the initial dose on day 1 and for 96 hours following the dose on day 7 by using a sensitive liquid chromatography-tandem mass spectrometry assay with a minimum quantifiable limit of 0.05 microg/L for ebastine and 1.00 microg/L for carebastine. Hepatic function was assessed by blood clearance of indocyanine green 0.5 mg/kg administered intravenously on day 2. Cardiac and overall safety parameters were monitored. RESULTS: Overall, the pharmacokinetics of ebastine were not modified by hepatic impairment. No correlation between ebastine pharmacokinetics and hepatic function, as expressed by indocyanine green clearance, was observed. Comparison of the effective half-life of ebastine and carebastine between groups did not show relevant differences. Therefore, no apparent accumulation of ebastine occurred, and steady-state concentrations of ebastine and carebastine were predictable from single-dose pharmacokinetics both in healthy subjects and in hepatically impaired patients. Finally, no apparent difference was noted in the safety of ebastine between patients with hepatic insufficiency and healthy subjects as assessed by evaluation of adverse events, vital signs and laboratory parameters. CONCLUSION: Ebastine can be safely administered to patients with impaired hepatic function, as no clinically important differences can be anticipated from the pharmacokinetics and safety profile of ebastine/carebastine as compared with healthy subjects. Nevertheless, the dosage used in severely impaired patients (10mg daily) was half that used in patients with mild to moderate impairment, and any comedication did not include drugs affecting liver function; in clinical practice, both these factors should be taken into account.

Prevalence of gestational diabetes mellitus: variations related to screening strategy used.

OBJECTIVE: To determine the prevalence of gestational diabetes mellitus in a large general obstetric population and its variations depending on the presence of risk factors, and to evaluate how the gestational diabetes screening strategies applied might modify the observed prevalence in the population. DESIGN: A retrospective cohort study. METHODS: The study population was a total of 2574 pregnant women. Information about risk factors, screening and diagnosis of gestational diabetes was obtained. Frequency of risk factors under the American College of Obstetrics and Gynecologists (ACOG) and the American Diabetes Association (ADA) criteria, and observed and expected prevalence of gestational diabetes mellitus were calculated and compared for statistical significance. RESULTS: Age > or = 30 years, family history of diabetes, obesity and previous fetal macrosomia were the most frequent risk factors. Under ACOG recommendations, 45% of our general obstetric population would have been exempt from gestational diabetes mellitus screening, as compared with only 15.5% under ADA guidelines. Sixty-five patients were diagnosed as having gestational diabetes mellitus, giving an overall prevalence of 2.5% (confidence interval 2.0-3.2). Among the low-risk women, prevalence values were 0.6% and 0.5% respectively under ACOG and ADA criteria, whereas for those presenting one or more risk factors rates were 4% and 2.9% respectively. CONCLUSIONS: In our general obstetric population, gestational diabetes mellitus prevalence was found to be approximately six times lower among low-risk gravidae than among the high-risk subjects, suggesting that selective screening might be beneficial. Nevertheless, selective gestational diabetes mellitus screening under ADA criteria seems to entail the same disadvantages as the selective screening strategies without any apparent benefits.

Celecoxib does not affect the antiplatelet activity of aspirin in healthy volunteers.

Celecoxib is a novel cyclooxygenase-2-specific inhibitor for the management of acute pain, primary dysmenorrhea, and the signs and symptoms of arthritis. This double-blind, placebo-controlled study in 16 healthy volunteers evaluated whether celecoxib alters the effect of concomitant aspirin on platelet function. Volunteers received celecoxib (400 mg/day) or placebo for 4 days. On day 5, they also received a single 325 mg dose of aspirin with either 200 mg celecoxib or placebo. Thromboxane and platelet aggregation response to adenosine 5'-diphosphate (ADP), collagen, and arachidonic acid were measured before the first dose of celecoxib or placebo (baseline) and before dosing and 2 and 8 hours post dose on day 5. There was no significant difference in thromboxane inhibition between the two groups (percent inhibition: placebo 99.4%, celecoxib 99.0%; p = 0.555). There was also no significant difference in the effect of aspirin on platelet aggregation due to ADP, collagen, or arachidonic acid between the groups. Therefore, these data indicate that celecoxib does not alter the effects of aspirin on platelet function.

Pharmacokinetics and safety of the ketolide telithromycin in patients with renal impairment.

The pharmacokinetics and safety of the ketolide telithromycin were evaluated in two separate studies after single and repeat oral dosing in patients with varying degrees of renal impairment and in subjects with normal renal function. The single-dose study was an open-label, nonrandomized, parallel-group design in which all 40 patients received a single oral dose of telithromycin 800 mg. The repeat-dose study was an open-label study with a randomized, balanced, incomplete three-block treatment crossover design. In this study, each of the 36 patients received two of three telithromycin regimens (400, 600, or 800 mg once daily for 5 days), with a washout period of >/= 7 days between treatments. Telithromycin was well tolerated. Adverse events were generally mild in severity, and no serious drug-related adverse events were reported. Plasma exposure to telithromycin (C(max), AUC) showed a tendency to increase with increasing severity of renal impairment in both studies. In patients with severe renal impairment (CL(CR) < 30 mL/min) receiving telithromycin 800 mg in the repeat-dose study, C(max,ss) and AUC((0-24 h)ss) increased 1.5-fold (p < 0.05) to 2.0-fold (p = 0.0005), respectively, compared with healthy subjects. The percentage of dose excreted in urine and renal clearance (CL(R)) of telithromycin was found to decrease significantly with increasing severity of renal impairment in both studies, and CL(R) was found to be independent of telithromycin dose in the repeat-dose study. In conclusion, telithromycin dosage adjustment is not necessary in patients with mild to moderate renal impairment (CL(CR) >/= 30 mL/min). In patients with severe renal impairment (CL(CR) < 30 mL/min), dosage adjustment could be considered.

Pharmacokinetics in Non-Insulin-Dependent Diabetics of the Aldose Reductase Inhibitor, Zopolrestat.

The pharmacokinetics of zopolrestat have been examined in non-insulin-dependent diabetic patients after oral administration of a single dose of 1000 mg zopolrestat. T(max) ranged from 2 to 4 h with a mean C(max) of 100 &mgr;g ml(minus sign1). Mean plasma half-life of zopolrestat was 26.9 h. The same patients were also administered oral doses of 1000 mg day(minus sign1) for 10 consecutive days. Mean T(max) was 4.3 h and mean C(max) was 208 &mgr;g ml(minus sign1). Plasma accumulation, the ratio of AUC((0--24)) for the last dose to AUC((0--24)) for the first dose, was 2.67. Apparent oral clearance was 5.71 ml min(minus sign1) and apparent volume of distribution was 12.9 L. The mean urinary excretion of unchanged drug over the 24-h period following the last dose was 36% of the dose while another 7% of the dose appeared in the urine as an acylglucuronide of zopolrestat. Renal clearance of zopolrestat was 1.82 ml min(minus sign1). Binding of zopolrestat to plasma proteins exceeded 99% and was concentration dependent.

Age and sex differences in the risk of causing vehicle collisions in Spain, 1990 to 1999.

This retrospective, paired case-control study was designed to estimate crude and adjusted effects of age and sex on the risk of causing collisions between vehicles with four or more wheels in Spain during the period from 1990 to 1999. We selected all 220284 collisions registered from 1990 to 1999 in the Spanish Dirección General de Tráfico (DGT) traffic crash database in which only one driver committed any infraction. Information was collected about age, sex and several confounding factors for both the responsible and paired-by-collision nonresponsible drivers. Crude and adjusted odds ratios (aORs) were calculated for each age and sex category. For men, the lowest risk was seen for drivers aged 25-49 years. Below the age of 35 years the crude odds ratio (cOR) was highest in the 18-24-year-old group (1.61; CI: 1.57-1.65). The risk increased significantly and exponentially after the age of 50 years, to a maximum odds ratio of 3.71 (3.43-4.00) for drivers aged >74 years. In women, the lowest risk values were found for the 25-44-year-old age group. In older women the risk increased significantly with age to a maximum odds ratio of 3.02 (2.31-3.97) in the oldest age group. aOR estimates tended to be lower than crude estimates for drivers younger than 40 years of age, but the opposite was seen for drivers 40 years old and older. Regarding sex differences, among younger drivers crude and aORs for men were higher than for women. Our results suggest that the risk of causing a collision between vehicles with four or more wheels is directly dependent on the driver's age.

Impact of different levels of carbohydrate intolerance on neonatal outcomes classically associated with gestational diabetes mellitus.

OBJECTIVE: To compare the influence of different levels of carbohydrate intolerance on neonatal outcomes. STUDY DESIGN: The cohort constituted by the 1962 pregnant women screened for gestational diabetes who gave birth at the University Hospital of Granada (Spain) in the year 1995 was followed retrospectively. Women were classified into three groups: diagnosis of gestational diabetes, positive screen but non-gestational diabetes, and negative screen. Frequency of adverse newborn outcomes were quantified for each group and compared for statistical significance. RESULTS: Gestational diabetes was associated with a greater incidence of high birth weight, hypoglycemia and hypocalcemia. Adequate metabolic control of the illness reduced the risk of adverse outcomes. Birth weight traced a positive slope with respect to the degree of carbohydrate intolerance. Regardless of carbohydrate intolerance, macrosomia was always higher among gravidae with gestational diabetes risk factors than among women without them. CONCLUSION: Both maternal gestational diabetes risk factors and greater carbohydrate intolerance in gravidae are associated with an increase in adverse newborn outcomes.

[An assessment of the effect of helmet use among cyclists and the risk of head injury and death in Spain, 1990 to 1999]. / Valoración del efecto del uso de casco en los ciclistas sobre el riesgo de sufrir lesiones craneales y de morir en España, entre 1990 y 1999.

BACKGROUND AND OBJECTIVE: This study aimed to assess the protective effect of helmet use by cyclists on risk of suffering head injury or dying as a consequence of a traffic crash. SUBJECTS AND METHOD: 26,832 cyclists involved in traffic crashes with victims registered in the Dirección General de Tráfico database from 1990 to 1999 in Spain were studied. From this database, variables relating to each cyclist (i.e., age, sex, presence of head trauma, severity of lesions) and those related with the crash (i.e., place, date, type of crash), were collected. The odds ratio and the proportion of the population attributable risk for non-use of a helmet by cyclist were estimated. RESULTS: An adjusted odds ratio of 2.45 (2.19-2.73) for the association between non-use of a helmet and the risk of head injury was obtained. As death of the cyclist as the outcome, the corresponding odds ratio was 1.35 (1.09-1.67). The values of proportion of the population attributable risk were 0.51 (0.47-0.55) and 0.22 (0.07-0.36), for head injury and death, respectively. CONCLUSIONS: This study confirms that helmet use among cyclists significantly decreased the risk of head injury and, to a lesser extent, death. These results constitute a strong argument for increasing in the frequency of helmet use among cyclists in Spain.

[The effect of age, sex, and experience on the risk of causing a car collision in drivers aged 18-24 years old]. / Efecto de la edad, el sexo y la experiencia de los conductores de 18 a 24 años sobre el riesgo de provocar colisiones entre turismos.

OBJECTIVE: To assess the separate effects of age, sex, and experience on the risk of drivers aged 18-24 years being actively involved in a car collision in Spain from 1990 to 1999. METHODS: For this matched case-control study, data were obtained from the Spanish Register of Traffic Crashes with Victims held by the General Directorate of Transport. The study population comprised all drivers involved in car collisions in which only one of the drivers committed a traffic infraction. Drivers who committed infractions constituted the case group while non-infracting drivers involved in the same collision were their corresponding matched controls. Drivers with incomplete or inconsistent data were excluded and a total of 123,586 cases and 140,482 controls was studied. Crude and adjusted (for the effect of potential confounders) odds ratio (OR) were obtained for each combination of driver age (from 18 to 24 years old), sex and years in possession of a driving license (from 0 to 7). RESULTS: For each category of age and years in possession of a driving license, OR estimates for men were usually higher than those for women. In men, crude and adjusted OR significantly decreased with increasing number of years in possession of a driving license for each age group. A similar but less clear trend was also observed for female drivers. After adjustment for the effect of the number of years in possession of a driving license, driver age did not seem to be strongly associated with the risk of being actively involved in a car collision. CONCLUSIONS: Our results suggest that the effect of inexperience is more important than that of age in explaining the higher risk of being involved in a traffic crash in the youngest drivers.

Selenium-induced antioxidant protection recruits modulation of thioredoxin reductase during excitotoxic/pro-oxidant events in the rat striatum.

Selenium (Se) is a crucial element exerting antioxidant and neuroprotective effects in different toxic models. It has been suggested that Se acts through selenoproteins, of which thioredoxin reductase (TrxR) is relevant for reduction of harmful hydroperoxides and maintenance of thioredoxin (Trx) redox activity. Of note, the Trx/TrxR system remains poorly studied in toxic models of degenerative disorders. Despite previous reports of our group have demonstrated a protective role of Se in the excitotoxic/pro-oxidant model induced by quinolinic acid (QUIN) in the rat striatum (Santamaría et al., 2003, 2005), the precise mechanism(s) by which Se is inducing protection remains unclear. In this work, we characterized the time course of protective events elicited by Se as pretreatment (Na(2)SO(3), 0.625 mg/kg/day, i.p., administered for 5 consecutive days) in the toxic pattern produced by a single infusion of QUIN (240 nmol/µl) in the rat striatum, to further explore whether TrxR is involved in the Se-induced protection and how is regulated. Se attenuated the QUIN-induced early reactive oxygen species formation, lipid peroxidation, oxidative damage to DNA, loss of mitochondrial reductive capacity and morphological alterations in the striatum. Our results also revealed a novel pattern in which QUIN transiently stimulated an early TrxR cellular localization/distribution (at 30 min and 2 h post-lesion, evidenced by immunohistochemistry), to further stimulate a delayed protein activation (at 24 h) in a manner likely representing a compensatory response to the oxidative damage in course. In turn, Se induced an early stimulation of TrxR activity and expression in a time course that "matches" with the reduction of the QUIN-induced oxidative damage, suggesting that the Trx/TrxR system contributes to the resistance of nerve tissue to QUIN toxicity.

Takotsubo syndrome associated with myasthenic crisis. A case report / Síndrome de takotsubo asociado a crisis miasténica. Presentación de un caso

Abstract: Introduction: The takotsubo syndrome is a rare clinical entity commonly associated with elderly women (ratio 6:1), easily confused with an acute ischemic syndrome, strangely associated with a myasthenic crisis. It is characterized with chest pain, elevated biomarkers, ST segment elevation, absence of coronary flow obstruction, and a characteristic deformity (anteroapical dyskinesia) of the left ventricle; these changes associated with a stressor. Case report: A woman of 69 years, diagnosed with myasthenia gravis six years ago, who entered in the intensive care unit with a suspected diagnosis of acute coronary syndrome and respiratory failure which required mechanical ventilation. Coronary angiography discarded a coronary disease. Ventriculography revealed a systolic anteroapical deformation. Treatment was initiated with acetylcholinesterase inhibitors and plasmapheresis with partial response, it required the use of vasoactive amines, with a suitable progressive cardiovascular and neurological outcome, with echocardiographic resolution. Conclusions: The takotsubo syndrome can be associated with myasthenia gravis and myasthenic crisis. The prognosis depends on early diagnosis, appropriate differential diagnosis, immediate treatment of myasthenic crisis, and management of the hemodynamic consequences of the takotsubo syndrome.

Resumen: Introducción: El síndrome de takotsubo es una entidad clínica poco frecuente asociada comúnmente con las mujeres de edad avanzada (relación 6:1), puede fácilmente confundirse con un síndrome isquémico agudo, extrañamente asociado con una crisis miasténica. Se caracteriza por dolor torácico, biomarcadores elevados, elevación del segmento ST, ausencia de obstrucción del flujo coronario, y una deformidad característica (discinesia anteroapical) del ventrículo izquierdo; estos cambios asociados con un factor de estrés. Caso clínico: Una mujer de 69 años, con diagnóstico de miastenia gravis hace seis años, que ingresó en la Unidad de Cuidados Intensivos con un diagnóstico de sospecha de síndrome coronario agudo e insuficiencia respiratoria que requirió de ventilación mecánica. La angiografía descartó una enfermedad coronaria. La ventriculografía reveló una deformación anteroapical sistólica. Se inició el tratamiento con inhibidores de la acetilcolinesterasa y plasmaféresis con respuesta parcial, se requirió el uso de aminas vasoactivas, con un resultado progresivo cardiovascular y neurológico adecuado, con resolución ecocardiográfica. Conclusiones: El síndrome de takotsubo puede estar asociada con miastenia gravis y la crisis miasténica. El pronóstico depende del diagnóstico precoz, el diagnóstico diferencial adecuado, el tratamiento inmediato de la crisis miasténica, y la gestión de las consecuencias hemodinámicas del síndrome takotsubo.

Factors associated with psychiatric morbidity in Spanish schoolteachers.

BACKGROUND: The relationship between psychiatric morbidity and characteristics of the work environment has been well-documented, and one of the professional groups in which psychiatric symptoms are most common is schoolteachers. AIMS: The present study was designed to evaluate the association between psychiatric morbidity [measured with General Health Questionnaire (GHQ)-28 score] and workplace-, sociodemographic- and personality-related variables in schoolteachers. METHODS: A sample of 498 non-university teachers in the city of Granada (southern Spain) were studied with a questionnaire comprising items that covered work-related variables (work and professional variables, as well as job perceptions), sociodemographic characteristics of the teachers and personality, evaluated with the Temperament and Character Inventory (TCI-125). The dependent variable was psychiatric morbidity, measured as scores >6 on the GHQ-28. Crude and adjusted odds ratios between each independent variable and psychiatric morbidity were obtained. RESULTS: In the adjusted analysis, psychiatric morbidity was associated with heavy workload, physical assault from pupils, low appraisal by superiors, low job satisfaction, high stress, female gender and (regarding personal characteristics) high scores for harm avoidance and novelty seeking and low scores for self-directedness. CONCLUSIONS: When personality characteristics are taken into account, the effect of workplace and sociodemographic variables was limited, although workload, poor job satisfaction and female sex remained associated with psychiatric morbidity.

Effect of repeated oral administrations of the oral adsorbent AST-120 on serum creatinine and other markers of renal function. A randomized controlled study in patients with chronic kidney disease.

BACKGROUND: AST-120 is an orally administered adsorbent used in Japan for prolonging time to initiation of hemodialysis and improving uremic symptoms in patients with chronic kidney disease (CKD). As AST-120 is suspected to reduce the progression of CKD by adsorbing renal toxins in the gastrointestinal tract, the objective of the current study was to determine whether binding of AST-120 to creatinine in the intestines could acutely alter creatinine balance, thereby limiting the utility of serum creatinine (sCr) as a measure of progression of renal function. Such information may be critical for the design of future studies to assess the efficacy of AST-120 in CKD patients. METHODS: Patients with CKD (n = 20) received oral doses of AST-120(3 g t.i.d.) and placebo in a two-way crossover study. Blood and urine were collected for determination of sCr, 24-hour urinary creatinine (UcrV), creatinine clearance (Ccr), and urea nitrogen clearance (URCL). Differences between treatments were assessed using an ANCOVA model. RESULTS: Following AST-120 and placebo treatments, mean sCr (1.73 and 1.79 mg/dl, respectively) and UcrV (1,264.73 and 1,286.05 mg) values were not significantly different. No significant differences were observed for Ccr and URCL. CONCLUSION: These results indicate that AST-120 has no acute impact on creatinine balance in patients with CKD. Consequently, sCr and other markers of renal function are acceptable measures for assessing changes in renal function following AST-120 treatment.

Steady-state pharmacokinetics, pharmacodynamics and tolerability of donepezil hydrochloride in hepatically impaired patients.

AIMS: To evaluate the pharmacokinetics (PK), pharmacodynamics (PD), tolerability and safety of donepezil HCl 5 mg following oral doses for 1 and 24 days in hepatically impaired patients compared with healthy controls under steady-state, multiple-dose conditions. METHODS: In this single-centre, multiple-dose, open-label study, patients with impaired hepatic function (Child-Pugh grade A or B) and healthy controls (matched by gender, age and weight to the hepatically impaired patients) received a single 5 mg dose of donepezil on day 1 and then donepezil HCl 5 mg once daily from days 6 to 29. PK and PD (determination of erythrocyte acetylcholinesterase inhibition) parameters were evaluated on days 1 and 29. Treatment-emergent adverse events (AEs), vital signs, physical examination and clinical laboratory test parameters were monitored throughout the study. RESULTS: A total of 35 subjects (18 patients with hepatic impairment and 17 healthy controls) were enrolled and 32 subjects (16 in each group) completed the study. On day 1 (following a single dose) hepatically impaired patients showed a significant decrease in T(max), while t((1/2)) and AUC(0-infinity) were significantly increased compared with the healthy controls. On day 29 (following multiple doses), AUC(0-24 h), C(max), t((1/2)), C(SS), and R(A) were significantly increased in hepatically impaired patients compared with healthy controls. AUC(0-24 h) increased by 47.6% in the patients with hepatic impairment compared with the healthy controls. There were no significant differences in PD between the groups, although at steady state, the mean AChE inhibition was 16.2% higher in the hepatically impaired patients. No serious AEs were reported and no subject withdrew from the study due to AEs. The most common AEs in both groups were headache and diarrhoea. No clinically significant changes from baseline were observed in vital signs, physical examination findings or electrocardiograms. There was a significant difference in the number of hepatically impaired subjects with abnormalities in serum glucose compared with healthy subjects. However, these elevations were not associated with AEs. CONCLUSIONS: The results of this study suggest that patients with AD and mild to moderate hepatic impairment (Child-Pugh grade A or B) can be safely given donepezil 5 mg once daily and that this dose is associated with a nonsignificantly higher AChE inhibition than age-matched volunteers.

Blocking of responses to endotoxin by E5564 in healthy volunteers with experimental endotoxemia.

E5564 is a second-generation synthetic analogue of the lipid A component of endotoxin (lipopolysaccharide [LPS]). The ability of E5564 to block the toxic activity of LPS was assessed in a double-blind, placebo-controlled study. A bolus infusion of endotoxin (4 ng/kg) was administered to healthy subjects to induce a mild transient syndrome similar to clinical sepsis. Single E5564 doses of 50-250 microg ameliorated or blocked all of the effects of LPS in a dose-dependent manner. All E5564 dose groups had statistically significant reductions in elevated temperature, heart rate, C-reactive protein levels, white blood cell count, and cytokine levels (tumor necrosis factor-alpha and interleukin-6), compared with placebo (P<.01). In doses of > or = 100 microg, E5564 acted as an LPS antagonist and completely eliminated these signs. E5564 also blocked or ameliorated LPS-induced fever, chills, headache, myalgia, and tachycardia (P<.01). These results demonstrate that E5564 blocks the effects of LPS in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Extended in vivo pharmacodynamic activity of E5564 in normal volunteers with experimental endotoxemia [corrected].

E5564 (alpha-D-glucopyranose) is a synthetic antagonist of bacterial endotoxin that has been shown to completely block human endotoxin response. Low doses of E5564 (0.35-3.5 mg) have a long pharmacokinetic half-life, but a surprisingly short ex vivo and in vivo pharmacodynamic half-life (generally less than several hours). To determine whether extended antagonistic activity can be achieved in vivo, this study assesses the pharmacodynamic activity of 4- and 72-h infusions of E5564 into normal volunteers. Administration of 3.5 mg of E5564/h x 72 h completely blocked effects of endotoxin challenge at the end of dosing (72 h), and at 48 and 72 h postdosing. Similarly, a 4-h infusion of E5564, 3 mg/h completely blocked endotoxin administered 8 h postdosing. A lower dose of E5564, 0.5 mg/h x 4 h, ameliorated but did not block most effects of endotoxin 8 h postdosing (p <0.05). Finally, the effect of varying plasma lipoprotein content on E5564 activity was studied in subjects having high or low cholesterol levels (>180 or <140 mg/dl) after 72-h infusion of 252 mg of E5564. No differences were observed. These results demonstrate that E5564 blocks the effects of endotoxin in a human model of clinical sepsis and indicate its potential in the treatment and/or prevention of clinical sepsis.

Infección experimental con trypanosoma cruzi en machos y hembras de tres cepas de ratones / Trypanosoma cruzi: experimental infection in males and females from three mouse strains

Se inocularon 3 cepas de ratones, machos y hembras, con 2.000 trypomastigotes sanguíneos del clon Dm 28c de Trypanosoma cruzi. Los ratones HTI de ambos sexos se comportaron como resitentes, en cambio, murió el 100 por ciento de los animales de las cepas A/Sn y AKR entre los 30 y 50 días post-infección, respectivamente. En las tres situaciones se observaron diferencias significativas en los niveles máximos de parasitemia entre machos y hembras, teniendo los primeros, niveles más altos. Los sueros de los ratones infectados obtenidos a distintos tiempos post-infección, se probaron con una batería de antígenos recombinantes de T. cruzi. Los sueros de los ratones A/Sn y AKR mostraron reactividad preferencial con los antígenos recombinantes SAPA y 13. Los sueros de los ratones HTI reconocieron ademßs de SAPA y 13, al antígeno recombinante 36 y tardíamente al antígeno 1. En cuanto al sexo, la técnica diferencia parece ser los niveles de parasitemias, pero este hecho no se refleja en diferencias a nivel de susceptibilidad o resistencia, como tampoco en el reconocimiento de los antígenos recombinantes