Pharmacokinetics of Moxifloxacin in Rabbits After Intravenous,Subcutaneous and a Long‐acting Poloxamer 407 Gel Formulation Administration

The pharmacokinetics (PK) of moxifloxacin in healthy white New Zealand rabbits was studied following intravenous (IV) and subcutaneous (SC) administration routes as well as a SC long‐acting poloxamer 407 gel formulation (SC‐P407). Moxifloxacin concentrations were determined by high‐performance liquid chromatography assay with fluorescence detection. Mean half‐life for IV, SC and SC‐P407 routes was 2.15, 5.41 and 11.09 h. Clearance value after IV dosing was 0.78 l/kg/h. After SC administration, the mean absolute bioavailability was 117% and the C_max was 1.61 ± 0.49 mg/l. After SC‐P407 administration, the bioavailability was 44% and the C_max 1.83 was ±0.62 mg/l. No adverse effects were observed in any of the rabbits following IV, SC and SC‐P407 administration of moxifloxacin. Minimal inhibitory concentrations of moxifloxacin against different strains of Staphylococcus aureus from different european countries were used to compute the main pharmacodynamic (PD) surrogate markers of efficacy. The high tolerability of this SC‐P407 formulation and the favourable PK behaviour such as the long half‐life, acceptable bioavailability and excellent PK–PD ratios achieved indicate that it is likely to be effective in rabbits.     

Safety considerations for operating room personnel during hyperthermic intraoperative intraperitoneal chemotherapy perfusion.

The new treatment strategy for Peritoneal Surface Malignancy combines a cytoreductive surgery and perioperative intraperitoneal chemotherapy. Cytoreduction removes all macroscopic tumor. Intraperitoneal chemotherapy avoids implantation of microscopic residual tumor cells on intra-abdominal surfaces when it is administered intraoperatively and/or early in the postoperative period. Delivering cytotoxic drugs directly into the peritoneal cavity maximizes dose intensity and minimizes systemic toxicity. Hyperthermia is selectively cytotoxic for malignant cells and potentiates the effect of chemotherapy. Implementation of this procedure makes the perioperative personnel to face a risk of exposure to cytotoxic agents. Furthermore, peritonectomies and electro-evaporation of tumor nodules are performed with high voltage electrocautery, generating a large amount of surgical smoke during several hours. Inhalation of these fumes may be also a risk for healthcare workers. In this article, we analyse in depth these new risks of the operating room personnel, we review the literature, and we give guidelines for secure performance of cytoreductive surgery and hyperthermic intraoperative intraperitoneal chemotherapy, as well as for early postoperative intraperitoneal chemotherapy administration. These new procedures are safe techniques for patients and healthcare workers provided adequate policies are adopted to avoid occupational exposure.     

Effects of intranasal 17beta-estradiol and raloxifene on lipid profile and fibrinogen in hypercholesterolemic postmenopausal women: a randomized, placebo-controlled clinical trial.

AIM: To compare the effects of 17beta-estradiol given intranasally (intranasal E2) and raloxifene on serum lipid profile and fibrinogen in hypercholesterolemic postmenopausal women. METHODS: The study population consisted of 46 women after menopause. The placebo group (n = 11) was given calcium, while the intervention groups were given intranasal E2 (Aerodiol; Servier, Chambray-les-Tours, France) (n = 16) or raloxifene (Evista; Lilly SA, Madrid, Spain) (n = 19). Blood lipids and fibrinogen were compared between groups at baseline and after 3 months of treatment. RESULTS: The group receiving intranasal E2 showed a significant decrease in triglyceride levels (p<0.05) and a marked increase in high-density lipoprotein cholesterol levels (p<0.05). No changes in lipid profile were observed in the raloxifene and placebo groups. Raloxifene caused a significant decrease in fibrinogen levels (p<0.05). CONCLUSION: Intranasal E2 exerts significant effects on lipid profile in hypercholesterolemic postmenopausal women. Raloxifene has a greater impact on fibrinogen than intranasal E2 application.     

Effect of leptin on the regulation of placental hormone secretion in cultured human placental cells.

Placenta is an important source of leptin during pregnancy that contributes to the high plasma leptin levels in pregnant women. Leptin and its functional receptors are synthesized in trophoblast cells that, in turn, secrete gestational hormones supporting a paracrine or autocrine role for leptin in the endocrine activity of the placenta. In the present study we examined the effect of leptin on in vitro release of gestational hormones (human chorionic gonadotropin (hCG), human placental lactogen (hPL), progesterone, estrogens and testosterone) by human term placental cells in culture. Placentas at term were obtained immediately after delivery from mothers with uncomplicated pregnancies. Progesterone, hCG, hPL, estradiol, estrone, estriol and testosterone levels were measured by different assays in culture media of cells maintained in monolayer culture after incubation for 12, 24, 48 or 72 h with leptin or placebo. Incubation with leptin did not modify hCG, hPL, progesterone, estriol and estrone secretion for any of the doses and times assayed. However, leptin led to a dose-dependent decrease in estradiol release. This effect was observed when treatment with recombinant human leptin spanned from 12 to 72 h. At this time an increase in testosterone levels was observed in leptin-treated cells versus placebo. These results indicate that leptin can be considered a gestational hormone implied in the endocrine function of the placenta, with an important role in control of the production of steroid reproductive hormones in placental cells in vitro.     

Effect of the menstrual cycle and oral contraceptives on aromatase and cyclooxygenase-2 expression in adenomyosis.

OBJECTIVES: To determine whether aromatase expression in the eutopic endometrium and adenomyotic foci is affected by previous use of oral contraceptives containing gestodene, and to determine whether changes in cyclooxygenase-2 (COX-2) expression occur in adenomyosis during the menstrual cycle. PATIENT AND METHODS: This was a retrospective cohort study carried out in paraffin-embedded endometrial tissue obtained from patients with a histological diagnosis of adenomyosis obtained during the proliferative (n = 25) and luteal (n = 10) phases of the menstrual cycle and following the use of continuous oral contraception with gestodene/ethinyl estradiol (n = 7). COX-2 and aromatase expression were measured in both eutopic endometrium and adenomyotic foci using immunohistochemical methods. RESULTS: Aromatase expression was detected in 80% of the endometrial slices by immunohistochemistry. In positive cases, aromatase was mainly detected in the stromal cells of the eutopic endometrium, whereas in the adenomyotic foci this expression was negative in the majority of the cases. Oral contraceptives containing gestodene, on the other hand, were effective in suppressing aromatase expression in both eutopic and ectopic endometrium. COX-2 expression was detected by immunohistochemistry in the glandular epithelium of both eutopic endometrium and adenomyotic foci and there were no significant changes in its intensity throughout the menstrual cycle. CONCLUSION: Aromatase expression in the eutopic endometrium and adenomyotic foci is suppressed by oral contraceptives containing gestodene. Increased aromatase activity may be responsible for the persistent COX-2 expression during the luteal phase.     

Left pulmonary artery evaluation through transesophageal echocardiography.

INTRODUCTION: Transesophageal echocardiography (TEE) has become increasingly useful in the study of patients with suspected pulmonary thromboembolism. OBJECTIVE: The aim of this study was to prospectively evaluate the usefulness of TEE in the study of the distal part of the left pulmonary artery (LPA) as well as the influence of this procedure on total echocardiographic exam duration. METHODOLOGY: A prospective study in two groups of consecutive patients referred for TEE with a one- year interval between evaluation of Group A: 33 patients, 17 male, mean age 54 +/- 24 years, and Group B: 42 patients, 20 male, mean age 48 +/- 27 years (p = NS). The procedure was considered long when it took more than 3 min to evaluate the distal part of the LPA. RESULTS: In group A we were able to visualize the distal part of the LPA in 24 patients (73%) without significant prolongation of total exam duration in 16 patients (48% of group A). In one of the patients with suspected pulmonary thromboembolism thrombi were only observed in the distal part of the LPA. In group B we were able to visualize the distal part of the LPA in 36 patients (86%) without significant prolongation of total exam duration in 26 patients (61% of group B). CONCLUSIONS: 1. Visualization of the distal part of the LPA was possible in more patients, and with TEE time prolongation in less patients, in group B. These differences can be accounted for by the training of the operator in this technique. 2. The importance of visualization of this part of the LPA in guiding treatment in the subset of patients with pulmonary thromboembolism confirms the usefulness of this specific procedure.     

Neuropeptides in idiopathic chronic constipation (slow transit constipation)

Tissue specimens from the large bowel of 18 patients with long-standing slow transit constipation were investigated to determine the distribution and density of several neuropeptides and amines in the enteric nerve system, and also of endocrine cells in comparison to normal individuals. CGRP (calcitonin gene-related peptide), galanin, glucagon, GRP (gastrin-releasing peptide), metenkephalin, motilin, neuropeptide Y (NPY), PACAP, peptide YY (PYY), serotonin, somatostatin, substance P and VIP were studied by immunohistochemistry. Tissue concentrations of VIP, substance P and galanin were also measured by radioimmunoassay. Significantly increased VIP, SP and galanin contents were found in specimens from the ascending colon. Levels of VIP and galanin were also increased in the transverse colon. Immunohistochemistry revealed only marginal changes with an increased density of PACAP nerve fibres in the smooth muscle and of VIP and PACAP nerves in the myenteric plexus of the transverse colon. In the descending colon substance P and NPY immunoreactivity were also increased in the myenteric plexus while the density of VIP nerve fibres was reduced in the mucosa/submucosa. The frequency of PYY-containing cells and the 5-HT-containing cells in the ascending colon was significantly increased in the constipated patients.