Recombinant Mycobacterium bovis BCG is a promising platform to develop vaccines against Trypansoma cruzi infection.

Chagas disease, caused by the hemoflagelate parasite Trypanosoma cruzi, is one of the most prevalent endemic parasitoses, affecting 7-8 million people. Due to the complexity of the infection, no vaccines are available at present. The extraordinary adjuvant capacity of bacille Calmette-Guérin (BCG) was explored in this work to develop a vaccine candidate to protect against T. cruzi infection using the recombinant BCG (rBCG) vaccine platform. Three antigens of the parasite corresponding to the N and C terminal fragments of the enzyme trans-sialidase (NT-TS and CT-TS, respectively) and a fragment of the cruzipain enzyme (CZf) were cloned into the vectors pUS997 and pUS2000 and transformed into the BCG Pasteur strain. In vaccinated mice, rBCG expressing NT-TS in pUS2000 plasmid provided the highest protection and the lowest parasitemia after challenging BALB/c mice with a 50% lethal dose of parasites. When mice vaccinated with pUS2000-NT-TS were challenged with a 100% lethal dose of parasite, high levels of protection were also obtained, together with a low degree of cardiac lesions 120 days after infection. In immunized mice with pUS2000-NT-TS/rBCG clone, the proliferation of CD4+ cells from splenocytes stimulated with the TS antigen was significant; this stimulation increased interferon (IFN)-γ and interleukin (IL)-17 within CD4⁺ T lymphocytes (LTCD4+ ) cells and IFN-γ and CD107 expression within LTCD8+ cells. Therefore, pUS2000-NT-TS/rBCG conferred high levels of protection, which correlated with an immune response orientated towards a T helper type 1 (Th1)/Th17 profile, together with an LTC-specific response, indicating that rBCG is a promising platform to develop vaccines against T. cruzi.

Cardiovascular complications and drug prescriptions in subjects with and without diabetes in a Northern region of Italy, in 2002 and 2012.

BACKGROUND AND AIMS: In contrast to the well-documented global prevalence of diabetes, much less is known about the epidemiology of cardiovascular (CV) complications in recent years. We describe the incidence of major CV events, deaths and drug prescribing patterns from 2002 to 2012 in subjects with (DM) or without diabetes mellitus (No DM). METHODS AND RESULTS: Subjects and outcomes were identified using linkable health administrative databases of Lombardy, a region in Northern Italy. A logistic regression model was used to compare myocardial infarction (MI), stroke, major amputation and death between DM and No DM in 2002 and 2012 and between the two index years in each population. The interaction between years and diabetes was introduced in the model. From 2002 to 2012 the incidence of major CV complications and death fell in both groups with a larger reduction among DM only for CV events: OR (95% CI) for the interaction 0.86 (0.79-0.93) for MI, 0.89 (0.82-0.96) for stroke, 0.78 (0.57-1.06) for major amputations. CV prevention drugs rose considerably from 2002 to 2012 particularly in DM and a switch towards safer antihyperglycemic drugs was also observed. CONCLUSIONS: Major CV complications and death declined from 2002 to 2012 in both DM and No DM. This might be due to a larger increase in prescriptions of CV drugs in DM and a relevant change toward recommended antihyperglycemic drugs.

Lithium use from 2000 to 2010 in Italy: a population-based study.

INTRODUCTION: Lithium is a highly specific and evidence-supported drug for the acute and maintenance treatment of bipolar disorder. METHODS: The purpose of this study was to calculate the prevalence and incidence of lithium use and to investigate the prescribing patterns of other mood-stabilizing agents in lithium users. We analyzed lithium utilization from 2000 to 2010 in a large area in Italy on the basis of dispensing data drawn from the regional administrative database. For each calendar year those who had at least one recorded dispensation of lithium were defined as lithium users. Those who received more than 4 dispensations per year were defined as lithium-treated. RESULTS: Rates of lithium utilization did not change during the observation period, but the amount of drug prescribed increased as a result of longer treatment and higher doses. The prevalence of use showed an initial increase of 8% (2000-2002), followed by a 13% decrease (2002-2006) and a subsequent rise of 11% (2006-2010). The prevalence of treatment grew by 38% during the whole observation period. The proportion of former lithium users who received other drugs or discontinued any treatment increased from 41% in 2002 to 52% in 2006, and then fell to 40% in 2010. CONCLUSION: The initial decline (2002-2006) and the subsequent rise (2006-2010) of lithium use can be explained by a fall and rise of new prescriptions. This finding together with a similar but opposite change in prescriptions of the other mood-stabilizing agents suggests a temporary change in prescribing attitudes which was subsequently reconsidered.

Elevated risk of death and major cardiovascular events in subjects with newly diagnosed diabetes: findings from an administrative database.

AIMS: To investigate the incidence of major cardiovascular complications and mortality in the first years of follow-up in patients with newly diagnosed diabetes. METHODS AND RESULTS: We examined incidence rates of hospitalization for cardiovascular reasons and death among new patients with diabetes using the administrative health database of the nine million inhabitants of Lombardy followed from 2002 to 2007. Age and sex-adjusted rates were calculated and hazard ratios (HR) were estimated with a matched population without diabetes of the same sex, age (± 1 year) and general practitioner. There were 158,426 patients with newly diagnosed diabetes and 314,115 subjects without diabetes. Mean follow-up was 33.0 months (SD ± 17.5). 9.7% of patients with diabetes were hospitalized for cardiovascular events vs. 5.4% of subjects without diabetes; mortality rate was higher in patients with diabetes (7.7% vs. 4.4%). The estimated probability of hospitalization during the follow up was higher in patients with diabetes than in subjects without for coronary heart disease (HR 1.4, 95% CI 1.3-1.4), cerebrovascular disease (HR 1.3.95% CI 1.2-1.3), heart failure (HR 1.4, 95% CI 1.3-1.4) as was mortality (HR 1.4, 95% CI 1.4-1.4). Younger patients with diabetes had a risk of death or hospital admission for cardio-cerebrovascular events similar to subjects without diabetes ten years older. CONCLUSIONS: The elevated morbidity and mortality risks were clear since the onset of diabetes and rose over time. These data highlight the importance of prompt and comprehensive patients care in addition to anti-diabetic therapy in patients with newly diagnosed diabetes.

Reducing the costs of paediatric antibiotic prescribing in the community by implementing guideline recommendations.

WHAT IS KNOWN AND OBJECTIVE: Italian children receive a high number of antibiotic prescriptions, and the use of second-choice antibiotics is common. A few studies in other countries have demonstrated that the implementation of international guidelines for the most common paediatric diseases may reduce the associated costs. A cost analysis of the expenditure for antibiotic prescriptions in outpatient children in the Lombardy region (Italy) and for each of the region's local health units (LHUs) was performed using a pharmacoepidemiological approach. The safety and cost impact associated with a quali-quantitative improvement in antibiotic prescribing was estimated. METHODS: The data source was the Lombardy region's prescription database (year 2008) for outpatient children <14 years old. The average total expenditure for each package, and per capita, was calculated for each active substance considered and for each LHU. An estimate of the possible cost reduction was elaborated using, as a reference, the prescription profile of a group of paediatricians that has been involved in initiatives concerning care for years. The hospital admission rates for acute respiratory infections (ARI) and their major complications were evaluated at the regional level and in the group of children followed by the reference paediatricians. RESULTS AND DISCUSSION: The cost reduction estimate reveals a possible decrease in antibiotic expenditure of about 3·6 million euros (-19·5%) in the Lombardy region. Large variability was observed between different LHUs (-33·3 to +9·2% of difference). The hospital admission rate was not different when comparing the group of children followed by the reference paediatricians to the rest of the study population, but the hospital admission rate for ARI was lower in the reference group (χ(2) = 16·4, P < 0·001). WHAT IS NEW AND CONCLUSION: This is the first Italian study to evaluate the costs related to a specific prescription profile, which already exists in the real setting, hypothesizing its application in a large outpatient child population of the same geographical area. The results show that by improving prescribing appropriateness, it is possible to reduce the expenditure associated with antibiotic prescriptions to outpatient children in the Lombardy region by about one-fifth. The lower rate of hospital admissions for ARI suggests that the adopted profile is also beneficial to children's health.

Mechanism of lipid bilayer perturbation by bactericidal membrane-active small molecules.

Membrane-active small molecules (MASMs) are small organic molecules designed to reproduce the fundamental physicochemical properties of natural antimicrobial peptides: their cationic charge and amphiphilic character. This class of compounds has a promising broad range of antimicrobial activity and, at the same time, solves some major limitations of the peptides, such as their high production costs and low in vivo stability. Most cationic antimicrobial peptides act by accumulating on the surface of bacterial membranes and causing the formation of defects when a threshold is reached. Due to the drastically different structures of the two classes of molecules, it is not obvious that small-molecule antimicrobials act in the same way as natural peptides, and very few data are available on this aspect. Here we combined spectroscopic studies and molecular dynamics simulations to characterize the mechanism of action of two different MASMs. Our results show that, notwithstanding their simple structure, these molecules act just like antimicrobial peptides. They bind to the membrane surface, below the head-groups, and insert their apolar moieties in the core of the bilayer. Like many natural peptides, they cause the formation of defects when they reach a high coverage of the membrane surface. In addition, they cause membrane aggregation, and this property could contribute to their antimicrobial activity.

Prevalence, incidence and mortality of diagnosed diabetes: evidence from an Italian population-based study.

AIMS: To describe trends in diagnosed diabetes prevalence, incidence and mortality from 2000 to 2007 in the most heavily populated Italian region. METHODS: We examined the prevalence and incidence rates of Type 1 and Type 2 diabetes and yearly mortality rates among individuals with diabetes from 2000 to 2007 using an administrative health database of prescription, disease-specific exemption and hospitalization records of more than 9 million inhabitants of Lombardy. Age- and sex-specific rates were calculated and temporal trends for subjects aged ≥ 30 years were analysed. RESULTS: The crude point diabetes prevalence rose from 3.0% in 2000 to 4.2% in 2007, a 40% increase. The incidence remained stable during the study period with a rate of 4/1000 per year. Overall mortality declined from 43.2/1000 in 2001 to 40.3/1000 in 2007 (6.7% decrease) at a rate slightly higher than that of the general population (4.8% decrease). Our projection in subjects aged ≥ 30 years indicates that the prevalence will rise continuously over the next years, reaching 11.1% in 2030. CONCLUSIONS: The prevalence of diabetes increased substantially between 2000 and 2007, mainly because there are more patients with a new diagnosis each year than those who die. The increase observed by 2007 almost reached the World Health Organization prediction for 2030. Our analyses suggest that the increase will continue over the next few decades. These data are important for defining the burden of diabetes in the near future, to help in planning health services and ensure proper allocation of resources.

Differences in outpatient antibiotic prescription in Italy's Lombardy region.

OBJECTIVES: We assessed the antibiotic patterns of use and geographical distribution of prevalence and consumption by age in 15 Local Health Units (LHUs) of Italy's Lombardy region. METHODS: A retrospective analysis of reimbursement data for the community-dwelling population in 2005 was performed. Prescriptions reimbursed by the National Health System and consumption as defined daily doses (DDD) per 1,000 inhabitants per day (DID) were analyzed. A logistic regression was performed to evaluate the association between antibiotic drug prescription and age, gender, and LHU of residence of the population. RESULTS: During 2005, a total of 3,120,851 people (34% of the population) received at least one antibiotic drug prescription. The highest prescription prevalence was observed in the 0-17 and 80 or more years age ranges (41.6 and 41.9%, respectively). Large differences were found in the prevalence rates between different LHUs (ranging from 28.7% in Milan to 39.4% in Brescia) and in DID (ranging from 12.6 DID in Sondrio to 18.9 DID in Brescia). The age and residence of the population were the main determinants of drug exposure. In particular, patients aged <18 years (odds ratio [OR] = 1.73; 95% confidence interval [CI] 1.73, 1.74), aged 65 years or older (OR = 1.64; 95% CI 1.63, 1.65), and those that live in Brescia (OR = 1.66; 95% CI 1.65, 1.66) had a statistically significant higher risk of antibiotic drug exposure. CONCLUSIONS: The observed intra-regional differences underline the need for a careful monitoring with the aim to reduce antibiotic resistance and improve the rational use of drugs.

Potentially severe drug interactions in elderly outpatients: results of an observational study of an administrative prescription database.

PURPOSE: To estimate the prevalence of potentially severe drug-drug interactions (DDIs) and their relationship with age, sex and number of prescribed drugs. METHODS: We analysed all prescriptions dispensed from 1 January 2003 to 31 December 2003 to individuals aged 65 or more registered under the Local Health Authority of Lecco, a northern Italian province with a population of almost 330 000 persons. Elderly who received at least two co-administered prescriptions were selected to assess the presence of DDIs. RESULTS: The prevalence of potentially severe DDIs was 16%, and rose with increasing patient's age and number of drugs prescribed. At multivariate analysis, the adjusted odds ratios rose from 1.07 (95% CI 1.03-1.11) in patients aged 70-74 to 1.52 (95% CI 1.46-1.60) in those aged 85 or older. Elderly taking more than five drugs on a chronic basis had a statistically significant higher risk of sever DDIs than those receiving less than 3 or 3-5 such drugs. CONCLUSIONS: The elderly constitutes a population at high risk of DDIs. As physicians still have some difficulty in managing this problem, it is essential to highlight for them, which factors raise the risk of DDIs.

Erectile dysfunction in diabetic subjects in Italy. Gruppo Italiano Studio Deficit Erettile nei Diabetici.

OBJECTIVE: Our objective was to analyze the prevalence and risk factors for erectile dysfunction (ED) in men with diabetes in Italy in a cross-sectional study. RESEARCH DESIGN AND METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of IDDM or NIDDM who were observed on randomly selected days in 178 diabetes centers in Italy. ED was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: Of the 9,868 diabetic men interviewed, 3,534 (35.8%) reported ED. The prevalence increased with age, from 4.6% in men aged 20-29 to 45.5% in those aged > or =60 years (test for trend, P = 0.0001). After taking into account the confounding role of age, men with NIDDM reported ED less frequently than did men with IDDM (odds ratio [OR], 0.7; 95% CI 0.6-0.8). In comparison with men reporting diabetes lasting < or =5 years, the ORs for ED were 1.3 and 2.0 for subjects with diabetes lasting 6-10 and 11-30 years, respectively. In comparison with men with good metabolic control, the ORs for ED were 1.7 and 2.3 in men with fair and poor control, respectively. A history of diabetes-related arterial, retinal, or renal diseases and neuropathy was associated with an increased risk of ED. Finally, in comparison with never-smokers, the ORs for ED were 1.5 (95% CI 1.3-1.6) for current smokers and 1.4 (95% CI 1.3-1.6) for ex-smokers. The OR increased with number of cigarettes smoked per day: in comparison with men smoking <12 cigarettes per day, the OR was 1.5 (95% CI 1.3-1.7) for those smoking > or =30 cigarettes day. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and of its main risk factors in Italian men with diabetes.

Erectile dysfunction in type 1 and type 2 diabetics in Italy. On behalf of Gruppo Italiano Studio Deficit Erettile nei Diabetici.

BACKGROUND: Several studies reported data on the increased risk of erectile dysfunction (ED) in populations of diabetic men, but few presented data separately for Type 1 and Type 2 subjects. No comparison data for these diabetic subgroups are available with regard to risk factors for ED. METHODS: Eligible for the study were men aged 20-69 years with a diagnosis of insulin-dependent (Type 1) or non-insulin-dependent (Type 2) diabetes who were observed on randomly selected days in 178 diabetes centres in Italy. Erectile dysfunction was defined as a failure to achieve and maintain an erection sufficient for satisfactory sexual performance. RESULTS: The study population consisted of 1383 Type 1 and 8373 Type 2 men. The prevalence of ED increased with age for both groups. After taking into account the effect of age Type 2 men (37/100 men) tend to report ED less frequently than Type 1 men (51/100 men). A significant positive relationship was reported between ED and poor metabolic control and smoking for both Type 1 and Type 2 men, whereas high body mass index (BMI) increased only the risk of ED in Type 1 cases. CONCLUSIONS: The study offers a quantitative estimate of the prevalence of ED and its main risk factors in Type 1 and Type 2 diabetic subgroups.

Perfluorocarbon broncho-alveolar lavage and liquid ventilation versus saline broncho-alveolar lavage in adult guinea pig experimental model of meconium inhalation.

OBJECTIVE: This study compares perfluorocarbon broncho-alveolar lavage (PFC-BAL) with isotonic saline broncho-alveolar lavage (saline-BAL) in an experimental model of meconium aspiration in adult guinea pigs. DESIGN: Prospective controlled experimental study. PATIENTS AND METHODS: Ten male guinea pigs were given 1 ml of human meconium, diluted to 10% in isotonic saline, via tracheostomy and then artificially ventilated. After stabilization, five animals (control group) underwent BAL with 10 ml/ kg isotonic saline solution. After bronchial suctioning, a further BAL with 2 ml/kg saline was performed. The other five animals (study group) underwent BAL with 100 ml/kg of PFC (RIMAR 101). Bronchosuction was effected at 5 min and then a BAL with PFC 2 ml/kg was performed. Both groups received conventional mechanical ventilation during the lavage procedures. Within 20 min all the saline-BAL treated animals died, whereas the PFC-BAL treated animals survived and were then treated with total liquid ventilation (TLV) by gravity. MEASUREMENTS AND RESULTS: After meconium inhalation in both groups, a large alveolar-arterial oxygen difference, hypercarbia, severe acidosis and tachycardia were noticed. In PFC treated animals, an improvement in blood gases was noted and acid-base balance remained stable compared to saline-BAL treated animals. No haemodynamic change was observed during or after PFC-BAL, while during saline-BAL there was evidence of bradycardia, hypotension and respiratory failure, which led to the death of the animals. The histological lung sections in the PFC-BAL group showed evidence of normal alveolar expansion with a minimal presence of meconium debris in the small bronchioles. In saline-BAL treated animals, the lung structure appeared severely compromised with the presence of meconium in bronchioles and alveoli, intra-alveolar oedema and haemorrhagic areas. CONCLUSIONS: This study confirms the detrimental effects of meconium aspiration and the impairment of lung function following saline-BAL. By contrast, PFC-BAL and TLV by gravity seemed to prevent absorption of meconium, facilitate its removal, improve gas exchange and reduce lung barotrauma.

Current drug use as risk factor for erectile dysfunction: results from an Italian epidemiological study.

Several drugs have been associated with an increased risk of erectile dysfunction (ED). We analysed the role of pharmacological treatments on the risk of ED using data from a cross-sectional study on prevalence and risk factors for ED in the general population in Italy. A total of 2450 men aged more than 18 years were randomly identified by 143 general practioners (GP) among their registered patients and invited to a confidential interview by their GP. Patients were asked 'about their ability to achieve and maintain an erection sufficient for satisfactory sexual performance'. If they were dissatisfied, they were defined as having ED. Out of the 2450 men identified, 440 (18%) refused to participate. The present analysis therefore includes information on 2010 men. After adjustment for related pathologies, anxiolytics and antidepressants showed insignificantly higher odds ratio (ORs, respectively, 1.7 and 2.1); antipsychotic drug use significantly increased the risk of ED (OR 9.0, 95% confidence interval, CI 1.8-44.4). Diuretics (OR 3.1, 95% CI 1.4-6.9) and anticholinergic drugs (OR 12.8, 95% CI 2.7-60.1) were associated with ED risk. No association emerged between ED and H2 antagonists, anticholesterolemic or hypoglycemic drugs. In conclusion, after taking account of related pathologies, our results suggest that men treated with antipsychotic, diuretic and anticholinergic drugs are at greater risk of ED.

Kinetics and metabolism of theobromine in male and female non-pregnant and pregnant rabbits.

The kinetics and metabolism of theobromine (3,7- DMX ) were investigated in male rabbits after a single oral dose and 14 days oral dosing at 1, 5, 10, 50 and 100 mg/kg/day. Female non-pregnant and pregnant rabbits were also studied after single oral doses of 1, 5 and 50 mg/kg. No significant difference was found in the pharmacokinetic profile of 3,7- DMX due to either sex, pregnancy or after chronic oral administration for 14 days. Intravenous (i.v.) administration of 3,7- DMX at 1 and 5 mg/kg resulted in calculated kinetic parameters in close agreement with oral doses. Irrespective of sex, there was a reduction in the absorption rate constant as the dose increased, coupled with a linear dose-related increase in AUC values. No qualitative difference in the metabolism of 3,7- DMX in the rabbit was observed as linked to sex, pregnancy or treatment schedule. Twenty-five percent of the administered dose of 3,7- DMX was excreted unchanged, the major metabolite being 7-methylxanthine (40%). There appeared to be a shift in the metabolic pathway at 100 mg/kg/day in the males and at 50 mg/kg/day in the females with more unchanged 3,7- DMX excreted. Only at these highest doses (100 mg/kg for males and 50 mg/kg for pregnant rabbits) was there a tendency toward accumulation.

The cost of urinary incontinence in Italian women. A cross-sectional study. Gruppo di Studio Incontinenza.

OBJECTIVE: To offer cost estimates of urinary incontinence (UI) in the general population based on prospectively collected data. DESIGN: We analyzed individual costs in a sample of women with UI who were identified in the framework of a cross-sectional study on the prevalence of UI in women aged > 40 years. SETTING: Six areas in Italy. INTERVENTION: Home interview. PATIENTS AND PARTICIPANTS: Women were identified among the patients registered with a network of general practitioners operating in each area using computer-generated random number lists. RESULTS: A total of 2767 women were identified. Of these, 408 (14.7%) reported UI during the year before the interview and 229 underwent a detailed interview on UI-related costs. On the basis of this information, we estimated the direct costs associated with UI from the perspective of the Italian National Health Service (INHS). The lifetime cost per patient of diagnosis was 80,131 Italian lire (L) (exchange rate: $US1 = L1618). Consultations accounted for only 20% of the diagnostic cost, diagnostic tests for 36% and hospital admissions for diagnostic procedures accounted for 44%. The diagnosis cost estimate seems low, partly because several women did not request either consultations or diagnostic tests (the overall rate per patient was 0.76 for consultations and 0.39 for diagnostic tests). The only appreciable treatment cost, according to the INHS perspective, was for diapers. The annual cost per patient for diapers was L255,519. The prevalence of UI in women aged > 40 years in Italy is estimated in the study at 9.3%. Thus, combining this information with the cost estimates, the annual treatment cost of UI in Italian women aged > 40 years is L351,800 billion, considering diapers and drugs only. CONCLUSION: This study has estimated the individual cost of UI in the general population. These figures may be useful when designing economic evaluations of UI.

Caffeine distribution in acute toxic response among inbred mice.

The median lethal dose (LD50) and the median lethal concentration (LC50) of caffeine administered intravenously (i.v.) and orally (p.o.) were calculated in adult male CD2F1/Crl BR mice. Acute toxic behavioral responses to the drug were observed after administration via the two routes. Deaths followed severe tetanic convulsions: some animals had transient convulsions and survived, and others presented no acute toxicity. In a further study, the LD50 of caffeine was given i.v. and by gavage to animals randomly paired. At the death of one of the two mice the other was killed and caffeine assayed in blood and tissues of both. Different patterns of distribution were observed inter- and intra-route of administration, animals which died always having higher drug levels, although they had received the same dose. These findings suggest that besides the well-known factors affecting acute toxic response to exogenous compounds, drug distribution also has to be taken into account in a multifactorial toxicological investigation.

Bioavailability of intramuscular vitamin E acetate in rabbits.

The bioavailability of alpha-tocopherol acetate and alpha-tocopherol (vitamin E) was assessed in male rabbits given 50 mg kg-1 doses according to a randomized design. After intramuscular injection of alpha-tocopherol acetate in colloidal aqueous solution, a mean absolute bioavailability of 65% was calculated for the acetate and 35% for the physiologically active compound, alpha-tocopherol. Comparison of the kinetic profiles after intravenous and intramuscular administration of the acetate and intravenous injection of alpha-tocopherol, revealed absorption of alpha-tocopherol acetate from the site of injection and hydrolysis of the acetate to be potential limiting steps in the bioavailability of alpha-tocopherol. Intramuscularly injected alpha-tocopherol acetate in olive oil (the only formulation available in a few European countries) proved completely bio-unavailable. It thus appears necessary to re-assess the utility of current vitamin E supplementation, since the only formulations available offer poor bioavailability.

Goserelin acetate to avoid hysterectomy in pre-menopausal women with fibroids requiring surgery.

OBJECTIVE: To obtain information on the efficacy of repeated short cycles of GNRH agonist treatment in order to avoid hysterectomy in near-menopausal women with symptomatic fibroids. STUDY DESIGN: 72 pre-menopausal women (mean age 50 years) with one or more uterine fibroids >10 cm in diameter, symptomatic menorrhagia lasting three months or more and haemoglobin=9 g/dl entered the study. The patients were randomized with ratio of approximately 1:4 to: (a) immediate surgery; or (b) treatment with goserelin acetate. Patients randomized to goserelin acetate received a first cycle of 3.6 mg depot once every 28 days for four months. They were followed-up for three years. If menorrhagia was observed during the follow-up the woman was given goserelin acetate 3.6 mg depot for another three months. In case of further menorrhagia, a third cycle of goserelin acetate 3.6 mg depot for three months was given. After the third cycle of therapy if there was still menorrhagia, the patient underwent hysterectomy plus bilateral oophorectomy. RESULTS: A total of 13 women were assigned to the immediate surgery group and 59 to goserelin. Three years after trial entry a total of 23 women allocated to goserelin acetate treatment had undergone hysterectomy. CONCLUSION: This study suggests that GNRH agonists are efficacious for avoiding hysterectomy in women near menopause with uterine fibroids.

Monitoring of blood gas parameters and acid-base balance of pregnant and non-pregnant rabbits (Oryctolagus cuniculus) in routine experimental conditions.

Blood gas parameters and acid-base balance values were determined in adult pregnant New Zealand rabbits (Oryctolagus cuniculus) in standard laboratory housing conditions and during anaesthesia with an association of ketamine-chlorpromazine, administered before surgical procedures. All the variables were also studied in adult non-pregnant female, used as controls. No differences in pH, sO2c, O2Hb, COHb, sO2m and a-vDO2 were found between pregnant and non-pregnant rabbits in physiological conditions and during anaesthesia. Ketamine-chlorpromazine and pregnancy seemed to change the other parameters used to assess the acid-base balance and the oxygenation conditions. Anaesthesia affected only Hb, O2Ct, O2Cap, CcO2 and P50. The additive effect of pregnancy and anaesthesia modified pCO2, pO2, HCO3-, TCO2, BEb, SBC, BEecf, A-aDO2, RI, MetHb, RHb, CaO2 and CvO2. The patterns described are close to those of other species, suggesting the New Zealand rabbit might be a reliable animal model for monitoring selected variables.

Pharmacokinetic and pharmacodynamic modelling of metoprolol in rabbits with liver failure.

The pharmacokinetic and pharmacodynamic profiles of metoprolol were studied in adult male rabbits given 3.2 mg/kg i.v. before and during liver failure. The partition of metoprolol between blood cells and plasma averaged 1.14 in both conditions. Plasma protein binding, concentration-independent, was 32% and 17% in normal and pathological status, respectively. With normal liver function the terminal elimination half-life for the drug was 0.54-0.96 h, rising to 1.0-2.1 h in liver failure. Differences of the same order were observed for total plasma drug clearance (average 3.7 vs 1.5 1/h/kg), MRT (0.77 vs 1.92 h), AUC (0.9 vs 2.2 mg h/l) and k10 (3.17 vs 1.80 h-1). Liver impairment did not affect the volume of distribution of the central compartment, the steady-state volume of distribution and the other intercompartmental rate constants. Although metoprolol was eliminated in the urine, the amount excreted was low (1.5% of the administered dose) in both conditions. The pharmacokinetic model was extended by an 'effect compartment', which has no influence on the predetermined mass of drug in the body, to analyse the relationship between heart rate fall and changes in metoprolol plasma concentrations. After drug administration, heart rate fell rapidly about 90 beats in both states. The mean unbound plasma concentration producing 50% of this reduction was double during liver failure compared to normal condition (0.03 vs 0.07 mg/l), but the temporal aspects of drug equilibration with site of action were similar.