The steady-state pharmacokinetics and bioequivalence of carprofen administered orally and subcutaneously in dogs.

Eighteen male Beagle dogs were randomized to oral (p.o.) or subcutaneous (s.c.) carprofen administration in a two-sequence, two-period crossover design with a 10-day washout between periods. Twenty-five milligrams of carprofen was administered p.o. or s.c. every 12 h for 7 days. Plasma concentrations of carprofen collected after the first and last treatments were determined by high-performance liquid chromatography. Carprofen concentration data were natural log transformed and geometric means were calculated for maximum plasma concentration (Cmax) and area under the plasma concentration-time curve (AUC0--12) following the first dose and Cmax and AUC0--12 following administration of the last dose. Formulations were considered bioequivalent if the 90% confidence interval (CI) of the mean difference for each variable between formulations were within -20% and 25% of the oral formulation. The mean Cmax and AUC0--12 were 16.9 microg/mL and 73.1 microg. h/mL, respectively, following a single oral dose and 8.0 microg/mL and 64.3 microg x h/mL, respectively, following a single s.c. injection. The 90% CI for Cmax (-56.8 to -48.7%) was outside of the bioequivalence criteria whereas the 90% CI for AUC0--12 (-16.3 to -7.5%) was within the bioequivalence criteria. At steady-state, the mean Cmax and AUC0--12 were 18.7 microg/mL and 101.9 microg x h/mL, respectively, following p.o. administration and 14.7 microg/mL and 111.0 microg x h/mL, respectively, following s.c. injection. The 90% CI was outside the bioequivalence criteria for Cmax (-30.8 to -10.8) but within the bioequivalence criteria for AUC0--12 (2.3-15.9%). The results of this study indicate that peak plasma concentrations of carprofen differ when administered p.o. and s.c., but that total drug exposure following a single dose and at steady-state are bioequivalent.

Assessment of absolute risk of death after myocardial infarction by use of multiple-risk-factor assessment equations: GISSI-Prevenzione mortality risk chart.

AIMS: To present and discuss a comprehensive and ready to use prediction model of risk of death after myocardial infarction based on the very recently concluded follow-up of the large GISSI-Prevenzione cohort and on the integrated evaluation of different categories of risk factors: those that are non-modifiable, and those related to lifestyles, co-morbidity, background, and other conventional clinical complications produced by the index myocardial infarction. METHODS: The 11-324 men and women recruited in the study within 3 months from their index myocardial infarction have been followed-up to 4 years. The following risk factors have been used in a Cox proportional hazards model: non-modifiable risk factors: age and sex; complications after myocardial infarction: indicators of left ventricular dysfunction (signs or symptoms of acute left ventricular failure during hospitalization, ejection fraction, NYHA class and extent of ventricular asynergy at echocardiography), indicators of electrical instability (number of premature ventricular beats per hour, sustained or repetitive arrhythmias during 24-h Holter monitoring), indicators of residual ischaemia (spontaneous angina pectoris after myocardial infarction, Canadian Angina Classification class, and exercise testing results); cardiovascular risk factors: smoking habits, history of diabetes mellitus and arterial hypertension, systolic and diastolic blood pressure, blood total and HDL cholesterol, triglycerides, fibrinogen, leukocytes count, intermittent claudication, and heart rate. Multiple regression modelling was assessed by receiver operating characteristic (ROC) analysis. Generalizability of the models was assessed through cross validation and bootstrapping techniques. POPULATION AND RESULTS: During the 4 years of follow-up, a total of 1071 patients died. Age and left ventricular dysfunction were the most relevant predictors of death. Because of pharmacological treatments, total blood cholesterol, triglycerides, and blood pressure values were not significantly associated with prognosis. Sex-specific prediction equations were formulated to predict risk of death according to age, simple indicators of left ventricular dysfunction, electrical instability, and residual ischaemia along with the following cardiovascular risk factors: smoking habits, history of diabetes mellitus and arterial hypertension, blood HDL cholesterol, fibrinogen, leukocyte count, intermittent claudication, and heart rate. The predictive models produced on the basis of information available in the routine conditions of clinical care after myocardial infarction provide ready to use and highly discriminant criteria to guide secondary prevention strategies. CONCLUSIONS AND IMPLICATIONS: Besides documenting what should be the preferred and practicable focus of clinical attention for today's patients, the experience of GISSI-Prevenzione suggests that periodically and prospectively collected databases on naturalistic' cohorts could be an important option for updating and verifying the impact of guidelines, which should incorporate the different components of the complex profile of cardiovascular risk. The GISSI Prevenzione risk function is a simple tool to predict risk of death and to improve clinical management of subjects with recent myocardial infarction. The use of predictive risk algorithms can favour the shift from medical logic, based on the treatment of single risk factors, to one centred on the patient as a whole as well as the tailoring of medical interventions according to patients' overall risk.

[Assessment of plasma lipid profile in acute coronary syndromes. The use of fibrinolytics and heparin do not affect it significantly]. / Andamento del profilo lipidico plasmatico nelle sindromi coronariche acute. L'uso di fibrinolitici ed eparina non lo modificano significativamente.

BACKGROUND: Neurohormonal and metabolic responses to acute ischemic events associated with thrombolysis and heparin induce substantial changes in the lipid profile (acute phase response). The aim of this study was to assess changes in total cholesterol and triglycerides in patients with acute coronary syndrome, admitted to our Intensive Coronary Care Unit (ICCU). METHODS: The study included 1051 consecutive patients, 316 with unstable angina, 583 with Q wave acute myocardial infarction (AMI) and 152 with non-Q wave AMI. Total cholesterol and triglycerides were measured in all patients at time 0 (admission), at time 1 (the morning following admission), at time 2 (the morning after discontinuation of heparin treatment). RESULTS: The mean value of total cholesterol at admission was 235, 210 and 197 mg% at admission, time 1 and time 2, respectively. Triglyceride levels were 234, 178 and 189 mg%, respectively. In the subgroup of thrombolized AMI the reduction in total cholesterol at time 1 and time 2 resulted similar in comparison with non-thrombolized AMI (p = NS). The decrease in triglycerides showed a similar pattern in the different subgroups. Comparison was also done according to sex, age, and complications. CONCLUSIONS: These data confirm that mean total cholesterol and triglycerides at admission are sharply higher than values considered normal in the literature. Within 24 hours of admission there is a 10.7% drop in total cholesterol which increases to 16.2% after a few days (mean 3.4 days). Total cholesterol determination upon admission in patients with acute coronary syndromes is necessary in order to know the true concomitant lipid profile during the precipitating ischemic events. The decision of initiating early therapy with statins would then appear more justified.

Efficacy of selamectin against experimentally induced tick (Rhipicephalus sanguineus and Dermacentor variabilis) infestations on dogs.

Seven controlled studies were conducted to investigate the efficacy of selamectin against weekly infestations of dogs with Rhipicephalus sanguineus and Dermacentor variabilis. Treatments (selamectin or vehicle alone) were applied topically at weekly, 2-week, or monthly intervals or in a "Monthly Plus" regimen (monthly treatment with an additional treatment at 14 days after the first treatment). Selamectin was supplied in unit dose tubes designed to deliver a minimum dosage of 6mgkg(-1). The studies ranged in duration from 37 to 90 days. Fifty adult ticks (+/-2) were applied approximately weekly, and tick counts were performed 3, 4, and 5 days after each infestation. The efficacy of selamectin was expressed as the percentage reduction in geometric mean tick counts on selamectin-treated dogs compared with those for dogs treated with the vehicle alone (negative-control). In one study, the engorgement of Dermacentor variabilis was assessed by weighing ticks after removal on the fifth day after each infestation. Weekly and 2-week interval treatments with selamectin provided efficacies against R. sanguineus of >89% across the entire study periods, with 100% efficacy being achieved from 21 days after the first dose and thereafter (study duration, 37 days for the weekly regimen and 44 days for the 2-week interval regimen). D. variabilis also was well controlled by the 2-week interval treatment regimen, with >96% efficacy being achieved from 21 days after the first treatment and thereafter until the end of the study (study duration: 90 days). In five of six studies incorporating three treatments at monthly intervals, the percentage reduction in R. sanguineus and D. variabilis counts 5 days after infestation ranged from 90 to 100% in the second and third months after treatment began. In the sixth study, reductions of > or =95% in D. variabilis counts 5 days after infestation were achieved for 2 weeks after each treatment in the second and third months. For the Monthly Plus regimen, from the second treatment (day 14) onwards, selamectin achieved 83-100% reductions in R. sanguineus and D. variabilis counts 3 days after infestation, and 94-100% reductions 5 days after infestation in three of the four studies. In the fourth study, selamectin demonstrated good efficacy against D. variabilis for 2 weeks after each treatment. In all seven studies, the counts from the selamectin-treated dogs were significantly (P< or =0.018) lower than those from the vehicle-treated dogs on 77 of the 80 assessments made 5 days after infestation. Selamectin also significantly (P< or =0.0105) reduced engorgement of female D. variabilis. These studies demonstrated that selamectin, administered topically to the skin in a single spot at a minimum dosage of 6mgkg(-1) at monthly intervals, was effective in the control of experimentally induced R. sanguineus and D. variabilis infestations on dogs.

Isolation and characterization of a gene from the DiGeorge chromosomal region homologous to the mouse Tbx1 gene.

DiGeorge syndrome, velocardiofacial syndrome, conotruncal anomaly face syndrome, and isolated and familial forms of conotruncal cardiac defects have been associated with deletions of chromosomal region 22q11.2. This report describes the identification, cloning, and characterization of the human TBX1 gene, which maps to the center of the DiGeorge chromosomal region. Further, we have extended the mouse cDNA sequence to permit comparisons between human and mouse Tbx1. TBX1 is a member of a phylogenetically conserved family of genes that share a common DNA-binding domain, the T-box. T-box genes are transcription factors involved in the regulation of developmental processes. There is 98% amino acid identity between human and mouse TBX1 proteins overall, and within the T-box domain, the proteins are identical except for two amino acids. Expression of human TBX1 in adult and fetal tissues, as determined by Northern blot analysis, is similar to that found in the mouse. Additionally, using 3 'RACE, we obtained a differentially spliced message in adult skeletal muscle. Mouse Tbx1 has been previously shown to be expressed during early embryogenesis in the pharyngeal arches, pouches, and otic vesicle. Later in development, expression is seen in the vertebral column and tooth bud. Thus, human TBX1 is a candidate for some of the features seen in the 22q11 deletion syndrome.

Cerebellar Purkinje's cell degeneration and coat color dilution in a family of Rhodesian Ridgeback dogs.

A syndrome of cerebellar Purkinje's cell degeneration and coat color dilution was diagnosed in a family of Rhodesian Ridgeback dogs. One male and 1 female from the same litter and 1 female from a different litter were evaluated for growth retardation, inability to ambulate, and progressive ataxia. On physical examination, lateral recumbency, severe ataxia, tremors, and diluted coat color were identified. Littermates with nondiluted coat color were neurologically normal. Results of routine laboratory tests, urine metabolic screenings, and karyotype analyses were normal. Histopathologic abnormalities at necropsy included cerebellar Purkinje's cell degeneration, reduced granular cell layer thickness, and uneven distribution of macromelanosomes within hair shafts. Pedigree analysis suggested an autosomal recessive mode of inheritance. This is the first description of a genetic syndrome affecting the central nervous system and associated with coat color dilution in dogs.

Evaluation of exercise-induced Q-wave amplitude changes and their clinical value.

We studied the influence of exercise level, severity of coronary artery disease (CAD), presence of previous myocardial infarction (MI), anterior or diaphragmatic, on the clinical value of exertional Q wave changes (Delta-Q). We retrospectively evaluated the exercise electrocardiograms of 62 patients without angiographic evidence of CAD and 133 patients with CAD; 28 of them had single (SVD) and 105 multivessel disease (MVD). Forty-one patients had a previous diaphragmatic MI and 23 anterior. The sensitivity, specificity and predictive value of Delta-Q were compared to the ST criterion. The exercise level affected Delta-Q. ST and Delta-Q had similar specificity and predictive values. The extent of CAD did not affect the sensitivity of Delta-Q and this method was better than ST to detect SVD patients. The Delta-Q criterion was equally as efficient as ST in MVD patients without MI and with diaphragmatic MI. The loss of septal forces on resting electrocardiograms made useless Delta-Q analysis on patients with anterior MI. The improvement of sensitivity in SVD patients by Delta-Q might be of clinical value since these latter are frequently not diagnosed by the ST criterion.

[Diagnostic value of changes in the Q wave induced by exertion]. / Valore diagnostico delle modificazioni dell'onda Q indotte dallo sforzo.

In order to evaluate the diagnostic value of exercise-induced Q wave changes and its relationship with the extent of coronary involvement and presence and location of a previous myocardial infarction, we examined the stress electrocardiograms of 188 consecutive patients with chest pain. Coronary arteriography shoved single vessel disease (SV) in 28 patients and multivessel disease (MV) in 130 patients; a previous myocardial infarction was present in 64 patients. The Q wave amplitude was measured as average of ten values in CM5 at rest and at peak exercise; a Delta-Q less than 0, i.e. reduction or no change of Q wave at peak exercise, was considered a positive response for coronary artery disease. The Delta-Q criterion shoved a significantly better sensitivity than ST depression, as a whole, but this improvement was nullified when patients with anterior myocardial infarction were excluded; as well specificity of Delta-Q although better than ST, did not allow a significant improvement for the diagnostic value of stress test. We also evaluated the diagnostic accuracy for multivessel coronary artery disease of both criteria positive was 78% whereas the negative predictive value of both criteria negative was 91%. We concluded that the exercise-induced Delta-Q less than 0 is a good indicator of coronary artery disease, although not superior to ST depression; the negativity of both criteria seems to be highly reliable for the exclusion of multivessel coronary artery disease.

Hypocholesterolaemic activity of suloctidil: double-blind, crossover short-term and long-term treatment trial.

Two studies were carried out in patients with primary hyperlipidaemia to investigate the effect of suloctidil (200 mg 3-times daily) on serum cholesterol levels and other lipidaemic variables. The first study was a double-blind, crossover comparison of suloctidil and placebo in 23 patients. Patients were allocated at random to receive one or other treatment for 4 weeks, after a wash-out period of 4 weeks on placebo, and were then crossed over to the alternative medication for the following 4 weeks. Patients were kept on a controlled diet throughout the trial. In the second, long-term study, 28 patients were treated, after an initial washout period of 8 weeks on placebo, with suloctidil for periods of up to 1 year. As in the short-term trial, patients were maintained on a controlled diet. The results showed that suloctidil produced a statistically significant reduction in total serum cholesterol and serum triglycerides in the short-term and this reduction was maintained over the longer period of the second study. In addition, there was a concomitant and approximately proportional increase in HDL-cholesterol. Suloctidil was well tolerated and no serious side-effects were reported.