Toxicity of 3′3-ditrifluormethyldiphenyl diselenide administered during intra-uterine development of rats

The aim of this study was to assess the effects of the organoselenium compound, 3′3-ditrifluormethyldiphenyl diselenide [(F₃CPhSe)₂], during the intra-uterine development of Wistar rats. Dams were given repeated doses of 1, 5 or 10 mg/kg (F₃CPhSe)₂ by intragastric route on gestation days 6–15, and cesarean sections were performed on day 20 of pregnancy. The numbers of implantation sites, living and dead fetuses and resorptions were recorded. Fetuses were weighed and stained with Alizarin red S for skeletal evaluation. The placental morphology was also evaluated. In 1 mg/kg (F₃CPhSe)₂ group, neither maternal toxicity nor prenatal growth retardation was observed. Conversely, in 5 and 10 mg/kg groups, there was a decrease in maternal weight gain during pregnancy indicating that (F₃CPhSe)₂ was maternally toxic, without affecting fetuses weight and length. (F₃CPhSe)₂ caused some morphological alterations in placenta of 5 and 10 mg/kg-exposed dams. Results also showed that skeletal variations were produced by (F₃CPhSe)₂ only at doses (10 mg/kg) in which a marked embryolethality was found. We conclude that (F₃CPhSe)₂ was toxic to the dams and induced embryofeto-toxicity at doses equal to 10 mg/kg.     

Daptomycin, a lipopeptide antibiotic in clinical practice

Gram-positive cocci are one of the leading causes of infections in clinical medicine. Since the invention of antibiotic substances, multidrug resistance is a major problem in the treatment of such infections. Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for 60% of nosocomial infections in the US. The first-choice drug used in these cases is the glycopeptide vancomycin; however, vancomycin is associated with a significant number of adverse side effects, such as nephro- and ototoxicity. Thus, the discovery of new drugs against MRSA and other multidrug-resistant cocci is of utmost interest. Daptomycin, a lipopeptide, is one of these new drugs and has been successfully used in the treatment of complicated skin and skin-structure infections and right-sided endocarditis. Because of its potency and pharmacological profile, it is increasingly used for new indications not yet approved by the FDA. The purpose of this article is to provide an overview of daptomycin, with particular emphasis on potential new indications for which it could be used in the future.     

Operative laparoscopy and postoperative pain relief.

OBJECTIVE: To evaluate the immediate postoperative pain and discomfort in patients who underwent operative laparoscopy under general anesthesia with or without peritoneal lidocaine and incisional bupivacaine instillations. DESIGN: Fifty-four participants were prospectively randomized to three groups: group I, intraperitoneal (IP) lidocaine + intraincisional bupivacaine; group II, intraincisional bupivacaine; and group III, no additional drugs after general anesthesia (controls). SETTING: University Hospital, Reproductive Endocrinology and Infertility Clinics. PATIENTS: Private patients needing operative laparoscopy. INTERVENTIONS: One hundred milligrams of lidocaine were instilled with the irrigation device into the peritoneal cavity at the completion of surgery. Twenty-five milligrams of bupivacaine were injected into infraumbilical and suprapubic incisions. MAIN OUTCOME MEASURES: The analgesic use and modified McGill Present Pain Intensity scores were used for pain evaluation. RESULTS: McGill Present Pain Intensity scores for pain, and narcotic use in the recovery room were less in IP lidocaine-instilled group of patients (P less than 0.05). The mean maximum plasma lidocaine level achieved was 1.01 +/- 0.25 micrograms/mL. CONCLUSIONS: Peritoneal lidocaine and incisional bupivacaine use in operative laparoscopy as described after general anesthesia is safe and effective in reducing postoperative pain in the recovery room.     

Comparison of visual results in initial and re-treatment laser in situ keratomileusis procedures for myopia and astigmatism

PURPOSE: To report the results of initial and re-treatment laser in situ keratomileusis procedures for myopia and astigmatism. METHODS: A total of 1161 consecutive inital and retreatment laser in situ keratomileusis procedures in 697 patients performed between September 19, 1996, and June 20, 1998, were retrospectively analyzed. Baseline and postoperative best spectacle-corrected visual acuity, uncorrected visual acuity, spherical and cylindrical refractions, computerized video keratography, and biomicroscopy were measured or performed on each eye. RESULTS: Of 1,071 eyes, 900 (84%) underwent a single-laser in situ keratomileusis procedure, and 171 of 1,071 eyes (16%) underwent one or two re-treatment procedures. The preoperative mean +/- SD spherical equivalent was -5.09 +/- 3.15 diopters (range, -0.75 to -14.38 diopters) and the cylinder was 0.97 +/- 1.09 diopters (range, 0.00 to 3.25 diopters) in the group that underwent a single laser in situ keratomileusis treatment. The preoperative mean +/- SD spherical equivalent was -6.26 +/- 3.04 diopters (range, -1.75 to -12.88 diopters) and the cylinder was 1.53 +/- 1.11 diopters (range, 0.00 to 3.50 diopters) in the group that underwent re-treatment. Before re-treatment, 110 eyes (64.3%) in the group that underwent re-treatment achieved 20/40 or better uncorrected visual acuity and 23 eyes (13.5%) achieved 20/25 or better. Three months after re-treatment, 155 eyes (90.6%) achieved 20/40 or better, and 80 eyes (46.8%) achieved 20/25 or better. In the single-procedure group, uncorrected visual acuity at 3 months revealed 20/40 vision or better in 856 eyes (95.1%) and 20/25 vision or better in 572 eyes (63.6%). In this study group, 23.6% of eyes with a preoperative spherical equivalent greater than -6.0 diopters underwent re-treatment compared with 11.8% of eyes with a preoperative spherical equivalent of -6.0 diopters or less. CONCLUSIONS: Laser in situ keratomileusis appears to be an effective procedure for mild, moderate, and severe myopia. In eyes with residual refractive error, re-treatment laser in situ keratomileusis procedures can result in good visual outcomes.     

Mg2+ efflux from the isolated perfused rabbit heart is mediated by two states of the beta1-adrenergic receptor

The non-selective beta-adrenergic receptor agonist isoproterenol stimulates Mg(2+) efflux from the perfused heart. The beta-adrenergic receptor subtype governing Mg(2+) efflux was determined in rabbit hearts perfused by the method of Langendorff with Mg(2+)-free Krebs Henseleit buffer. Magnesium efflux was examined during infusion of isoproterenol (a non-selective beta-adrenergic agonist), dobutamine (beta(1)-selective), salbutamol (beta(2)-selective), BRL37344 in the presence of 200 nM propranolol (beta(3)-selective conditions) or CGP12177 (beta(3)/low affinity state beta(1)-selective). Isoproterenol increased Mg(2+) efflux in a dose-dependent manner, and was the most potent and efficacious agent used. Dobutamine and CGP12177 each significantly increased Mg(2+) efflux, but with markedly different time characteristics. Dobutamine induced significantly less Mg(2+) release than isoproterenol. Although the maximal effect of CGP12177 on Mg(2+) release was 30% less than that of isoproterenol, the difference was not statistically significant. Neither salbutamol nor BRL37344 had any effect on Mg(2+) efflux. These results suggest that isoproterenol-induced Mg(2+) efflux is mediated by both the high and low affinity states of the beta(1)AR, with the low affinity state making the larger contribution.     

Evidence that toxicity of lipopolysaccharide upon cholinergic basal forebrain neurons requires the presence of glial cells in vitro

The cholinergic system of the basal forebrain is affected in brains of dementia patients and during neuroinflammation. The aim of this study was to establish a method to cultivate basal forebrain cholinergic neurons in dissociated, pure neuronal cultures and to apply this method to study the effect of acute and chronic experimentally-induced inflammation using lipopolysaccharide. Purity of the cultures, degrees of neuronal dissociation, connectivity and neuronal survival were investigated by immunocytochemistry for microtubule-associated protein-2 (neurons), glial fibrillary acidic protein (astroglia), complement receptor 3 (microglia), choline acetyltransferase and the neurotrophin receptor p75 (cholinergic neurons). Neuronal cultures only contained <7% astrocytes and <1% microglia when using a "sandwich-technique". Acute (1, 10 microg/ml) as well as chronic (0.1, 1 microg/ml) treatment with lipopolysaccharide did neither affect total number of neurons, nor number of p75-positive neurons or enhance expression of major histocompatibility complex I or II. Our results suggest that lipopolysaccharide-induced degeneration of both microtubule-associated protein-2-like immunoreactive as well as specific killing of cholinergic forebrain neurons in vitro are mediated by glial cells.     

Use of diffusion-weighted magnetic resonance imaging in differentiating purulent brain processes from cystic brain tumors

OBJECT: Brain abscesses and other purulent brain processes represent potentially life-threatening conditions for which immediate correct diagnosis is necessary to administer treatment. Distinguishing between cystic brain tumors and abscesses is often difficult using conventional imaging methods. The authors' goal was to study the ability of diffusion-weighted (DW) magnetic resonance (MR) imaging to differentiate between these two pathologies in patients within the clinical setting. METHODS: Diffusion-weighted MR imaging studies and calculation of the apparent diffusion coefficient (ADC) values were completed in a consecutive series of 16 patients harboring surgically verified purulent brain processes. This study group included 11 patients with brain abscess (one patient had an additional subdural hematoma and another also had ventriculitis), two with subdural empyema, two with septic embolic disease, and one patient with ventriculitis. Data from these patients were compared with similar data obtained in 16 patients matched for age and sex, who harbored surgically verified neoplastic cystic brain tumors. In patients with brain abscess, subdural empyema, septic emboli, and ventriculitis, these lesions appeared hyperintense on DW MR images, whereas in patients with tumor, the lesion was visualized as a hypointense area. The ADC values calculated in patients with brain infections (mean 0.68 x 10(3) mm2/sec) were significantly lower than those measured in patients with neoplastic lesions (mean 1.63 x 10(3) mm2/sec; p < 0.05). CONCLUSIONS: Diffusion-weighted MR imaging can be used to identify infectious brain lesions and can help to differentiate between brain abscess and cystic brain tumor, thus making it a strong additional imaging modality in the early diagnosis of central nervous system purulent brain processes.     

Antiplasmodial and antitrypanosomal activity of new esters and ethers of 4-dialkylaminobicyclo[2.2.2]octan-2-ols

Only three drugs are available for the treatment of East African trypanosomiasis. Patients suffer from painful application, severe side effects and increasing resistance against these drugs. Malaria tropica kills more than 2 million people every year mainly due to growing drug resistance. 4-Dialkylaminobicyclo[2.2.2]octan-2-ols and some of their esters have shown activity against both the causative organisms, Trypanosoma brucei rhodesiense and Plasmodium falciparum. Ethers and new esters with markedly higher lipophilicity were prepared in three-step procedures from acyclic synthons. The new compounds were screened for their antiprotozoal activities against T. b. rhodesiense (STIB 900) and P. falciparum K1 (resistant to chloroquine and pyrimethamine), and for their cytotoxicity with l-6 cells by means of in vitro microplate assays. The results were compared to those of the parent compounds indicating that higher lipophilicity increases the antiprotozoal activities. The pivalate 10a showed the highest antitrypanosomal activity. The 4-chlorobenzoate 9b exhibited good antiplasmodial activity and low cytotoxicity. The most active antiplasmodial agent was the benzhydryl ether 13c which was nearly as active as chloroquine against sensitive strains.