Comparative efficacy of two interventions to discontinue long-term benzodiazepine use: cluster randomised controlled trial in primary care.

BACKGROUND: Benzodiazepines are extensively used in primary care, but their long-term use is associated with adverse health outcomes and dependence. AIMS: To analyse the efficacy of two structured interventions in primary care to enable patients to discontinue long-term benzodiazepine use. METHOD: A multicentre three-arm cluster randomised controlled trial was conducted, with randomisation at general practitioner level (trial registration ISRCTN13024375). A total of 532 patients taking benzodiazepines for at least 6 months participated. After all patients were included, general practitioners were randomly allocated (1:1:1) to usual care, a structured intervention with follow-up visits (SIF) or a structured intervention with written instructions (SIW). The primary end-point was the last month self-declared benzodiazepine discontinuation confirmed by prescription claims at 12 months. RESULTS: At 12 months, 76 of 168 (45%) patients in the SIW group and 86 of 191 (45%) in the SIF group had discontinued benzodiazepine use compared with 26 of 173 (15%) in the control group. After adjusting by cluster, the relative risks for benzodiazepine discontinuation were 3.01 (95% CI 2.03-4.46, P<0.0001) in the SIW and 3.00 (95% CI 2.04-4.40, P<0.0001) in the SIF group. The most frequently reported withdrawal symptoms were insomnia, anxiety and irritability. CONCLUSIONS: Both interventions led to significant reductions in long-term benzodiazepine use in patients without severe comorbidity. A structured intervention with a written individualised stepped-dose reduction is less time-consuming and as effective in primary care as a more complex intervention involving follow-up visits.

The effect of Cecropia glazioui SNETHLAGE on the physical and neurobehavioral development of rats.

This study aimed to determine the LD50, toxic effects on organogenesis/fetal-development, physical aspects, and developmental/neurobehavioral reflexes of litters previously exposed to Cecropia glazioui SNETHL (Cg) extract during the entire gestational period. Swiss mice were submitted to doses of 0.5, 1.0, 2.5 and 5.0 g/Kg/p.o. Female rats received 1.0 g/Kg/day of Cg extract (G1, n = 10) or 1.0 mL/Kg/day of deionized water (G2, n = 10) during pregnancy. The number of successful gestations, pregnant females weight and born/dead-born offsprings were evaluated. Physical development (offspring weight; fluff and hair appearing; ear unsticking and opening; incisor teeth eruption; eyes opening; testis descent; vagina opening; rearing frequency; uprightness latency and negative geotaxis) and the sleeping time (30 mg/Kg/i.p. sodium pentobarbital assay) were also observed. Open field assay evaluated the developmental/neurobehavioral reflexes of pups. LD50 was higher than 5.0 g/Kg. The extract did not affect the gestation number, born/dead-born offspring number and the female weight during pregnancy. The weight and the physical development of both genders pups were not affected (p > 0.05), but the uprightness latency and the negative geotaxis reflexes were enhanced and the rearing frequency decreased (p < 0.05). Ambulation, cleaning activity, sleeping time, and immobility were not affected (p > 0.05). We concluded that Cg extract showed low toxicity to pregnant rats and their litters.

Low-fluoride dentifrice and gastrointestinal fluoride absorption after meals.

A low-fluoride (F) dentifrice has been recommended to reduce the risk of dental fluorosis, but its anti-caries efficacy is questionable compared with that of conventional dentrifices (1000-1100 microg F/g). The tested hypothesis was that conventional dentifrices might be safe if used soon after meals, since food interferes with F absorption. In a crossover, double-blind study, 11 volunteers ingested a dentifrice slurry containing 0 (placebo), 550 (low F), or 1100 microg F/g in 3 gastric content situations: on fasting, or 15 min after breakfast or lunch. F was analyzed in saliva and 24-hour urine samples. The conventional dentifrice ingested after lunch resulted in only 10% higher F absorption than the low-F ingested on fasting. Analysis of the data suggests that the risk of fluorosis could be reduced by the use of either a low-F dentifrice or a conventional dentifrice, if toothbrushing occurred soon after meals.

Antibiotics and pregnancy.

Like anybody else, pregnant women are susceptible to infections. The correct treatment of these women, however, must consider along with pathogens, the infection site and antibiotic pharmacokinetics, the fetus and possible side effects to the child. When prescribing over this special condition, the physician must remember that the prescription will affect two organism and the drug must treat the mother without affecting the fetus. Beta-lactams having a long history of use without significant deleterious effects on the fetuses still are the safest choice during pregnancy. However, considering the constant increase of multi-resistant microorganisms, the physician has been forced to use different antimicrobial agents. Usually, data regarding safety during pregnancy are very limited, which causes serious doubts during prescription. In addition, many studies regarding the safe use of antibiotics during pregnancy are inconclusive or demand more evidence. The present study is a wide revision regarding the use of antibiotics during pregnancy, considering their pharmacokinetics and the clinical experience in recent years. It also intends to assist the physician during prescription and to give information to the pharmacists to help pregnant women.

The effect of milk on plasmatic and tissue levels of macrolides: in vivo study in rats

The ingestion of milk with drugs, particularly some antibiotics, is frequently recommended in order to decrease possible gastrointestinal discomfort. The objective of this sutdy was to assess the interference of milk in the absorption and tissue levels of macroline antibiotics (erythromycin, clarithromycin, roxithromycin and azithromycin). Forty female rats received surgically-implanted PVC sponges on their backs. One week later, granulomatous tissue was observed and the animals were divided into eight groups, which received erythromycin, clarithromycin, roxithromycin and azithromycin with and without milk. One hour after administration of antibiotic, the animals were sacrificed. The serum and tissue samples were submitted to microbiological assay with Micrococcus luteus ATCC 9341, in order to determine drug concentration. Milk did not cause any reduction in the serum and tissue levels of azithromycin and clarithromycin (p>0.05, t-test). However, ingestion of milk reduced by approximately 28.7% the roxithromycin (p<0.0001, t-test) and by 34.1% the rythromycin (p<0.0001, t-test) serum concentrations. Similar effects were observed on tissue levels. Milk ingestion caused a reduction of approximately 20.8% in the roxithromycin (p<0.0001, t-test) and 40% in the erythromycin (p<0.0001, t-test) tissue levels. We concluded that erythromycin and roxithromycin should be not administered with milk

Bioassay of amoxicillin in rats.

Few reports are available about tissue concentration of amoxicillin. The techniques used to measure tissue concentration usually require rupture and are expensive. The objective of the present study is to assess the utility of an animal model to predict tissue concentration of amoxicillin using induced granulomatous tissue. We used 160 rats with four polyurethane sponges previously implanted in their backs. At 7, 14, 21 and 28 d after sponge introduction, groups of eight animals each received 3.5, 7.0, 40.0 or 80.0 mg/kg of amoxicillin (p.o.) or 1 ml of 0.9% NaCl solution (control group). One hour after drug administration, 10 microl of serum and granulomatous tissue were obtained. Tissue and serum were placed on different plates containing Mueller Hinton agar inoculated with 10(8) cfu (colony forming unit) of Staphylococcus aureus (ATCC 25923), and the diameters of the inhibition zones were measured after 18 h of incubation. Analysis of variance showed no statistically significant differences (p>0.05) among time periods for the same dose of amoxicillin. These results suggest that the pharmacokinetics of amoxicillin did not change in relation to the development of granulomatous tissue; therefore this method is valid to measure the tissue concentration of amoxicillin.

Evaluation in an animal model and in vitro of the combination clavulanic acid and cephalosporins against beta-lactamase producing and nonproducing Staphylococcus aureus strains.

Beta-lactamase enzymes are the most common cause of bacterial resistance to Beta-lactam antibiotics. They hydrolyze the amide bound in the Beta-lactam ring and produce acidic derivatives that have no antibacterial properties. The aim of this study was to evaluate a combination of clavulanic acid with cephalosporins against Beta-lactamase-producing and nonproducing strains of Staphylococcus aureus using in vitro tests and a rat animal model. In vitro tests (MIC) of the drug combination were done using standard methods. In an animal model, rats were submitted to surgical implantation of polyurethane sponges in their backs to induce granulomatous tissue. After seven days, the animals received cephalexin, cephalexin with clavulanic acid, ceftriaxone, ceftriaxone with clavulanic acid or clavulanic acid alone. One hour after the drug administration, granulomatous tissue was removed and placed in Petri dishes previously inoculated with 10(8) cfu of producing or non-producing Beta-lactamase Staphylococcus aureus. After 24h at 37 degrees C, the inhibition zones formed by granulomatous tissue was measured and scored for statistical analysis. Both tests (ex vivo ¿animal model¿ and in vitro) showed that the cephalexin was more active than ceftriaxone against non-producing Beta-lactamase S.aureus (p<0.01). Against Beta-lactamase producing S.aureus, ceftriaxone was more active than cephalexin, which was inactive. Combinations of clavulanic acid with cephalexin or ceftriaxone had similar antimicrobial activity against non-producing Beta-lactamase S.aureus compared to the cephalosporins used alone. When tested using Beta-lactamase producing strains, the combination of clavulanic acid with cephalosporins showed synergism. We conclude that the combination of cephalosporins with clavulanic acid could be useful in staphylococcal infections caused by Beta-lactamase producing strains.