The pharmacodynamic effects of combined administration of flibanserin and alcohol.

WHAT IS KNOWN AND OBJECTIVE: Flibanserin is a serotonin 5-HT1A agonist and 5-HT2A antagonist approved for the treatment of acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women. Because of the increased risk of hypotension- and syncope-related adverse events (AEs) observed with coadministration of flibanserin and alcohol, alcohol use is contraindicated. To provide a more comprehensive understanding of the interaction between flibanserin and alcohol, the results of a dedicated phase 1 alcohol-interaction study and a pooled analysis of phase 3 studies of premenopausal women with HSDD are presented. METHODS: In the phase 1 study, healthy participants (males [n=23] and females [n=2]) were randomly assigned to one of five sequence groups, which determined the order in which they were to receive flibanserin 100 mg or placebo, with or without ethanol 0.4 g/kg or 0.8 g/kg. Change from baseline in seated blood pressure, orthostatic vital signs, AEs and visual analogue scale sedation outcomes were examined. Blood samples were collected at baseline and for up to 4 hours after dosing to determine flibanserin area under the plasma concentration-time curve from 0 to 4 hours (AUC0-4 ). Pooled data from five phase 3 studies of patients receiving flibanserin 100 mg once daily (n=1543), or placebo (n=1905), were analysed. RESULTS: In the phase 1 study, the incidence of hypotension and syncope increased when flibanserin was coadministered with ethanol. Sedation increased 20% and 27% from baseline with flibanserin plus ethanol 0.4 g/kg and 0.8 g/kg, respectively, at 4 hours post-dose. In the pooled analysis of phase 3 studies, 58.2% and 63.6% of participants receiving flibanserin or placebo, respectively, reported baseline alcohol use. In patients receiving flibanserin, fatigue and dizziness occurred more frequently in patients with vs. without alcohol use. WHAT IS NEW AND CONCLUSION: Results from this study suggest that increased incidence of hypotension- and syncope-related events may result from a pharmacodynamic interaction between flibanserin and alcohol, although the clinical significance of these interactions in real-world populations remains unclear.

Estimating radiation doses from multidetector CT using Monte Carlo simulations: effects of different size voxelized patient models on magnitudes of organ and effective dose.

The purpose of this work is to examine the effects of patient size on radiation dose from CT scans. To perform these investigations, we used Monte Carlo simulation methods with detailed models of both patients and multidetector computed tomography (MDCT) scanners. A family of three-dimensional, voxelized patient models previously developed and validated by the GSF was implemented as input files using the Monte Carlo code MCNPX. These patient models represent a range of patient sizes and ages (8 weeks to 48 years) and have all radiosensitive organs previously identified and segmented, allowing the estimation of dose to any individual organ and calculation of patient effective dose. To estimate radiation dose, every voxel in each patient model was assigned both a specific organ index number and an elemental composition and mass density. Simulated CT scans of each voxelized patient model were performed using a previously developed MDCT source model that includes scanner specific spectra, including bowtie filter, scanner geometry and helical source path. The scan simulations in this work include a whole-body scan protocol and a thoracic CT scan protocol, each performed with fixed tube current. The whole-body scan simulation yielded a predictable decrease in effective dose as a function of increasing patient weight. Results from analysis of individual organs demonstrated similar trends, but with some individual variations. A comparison with a conventional dose estimation method using the ImPACT spreadsheet yielded an effective dose of 0.14 mSv mAs(-1) for the whole-body scan. This result is lower than the simulations on the voxelized model designated 'Irene' (0.15 mSv mAs(-1)) and higher than the models 'Donna' and 'Golem' (0.12 mSv mAs(-1)). For the thoracic scan protocol, the ImPACT spreadsheet estimates an effective dose of 0.037 mSv mAs(-1), which falls between the calculated values for Irene (0.042 mSv mAs(-1)) and Donna (0.031 mSv mAs(-1)) and is higher relative to Golem (0.025 mSv mAs(-1)). This work demonstrates the ability to estimate both individual organ and effective doses from any arbitrary CT scan protocol on individual patient-based models and to provide estimates of the effect of patient size on these dose metrics.

A Monte Carlo based method to estimate radiation dose from multidetector CT (MDCT): cylindrical and anthropomorphic phantoms.

The purpose of this work was to extend the verification of Monte Carlo based methods for estimating radiation dose in computed tomography (CT) exams beyond a single CT scanner to a multidetector CT (MDCT) scanner, and from cylindrical CTDI phantom measurements to both cylindrical and physical anthropomorphic phantoms. Both cylindrical and physical anthropomorphic phantoms were scanned on an MDCT under the specified conditions. A pencil ionization chamber was used to record exposure for the cylindrical phantom, while MOSFET (metal oxide semiconductor field effect transistor) detectors were used to record exposure at the surface of the anthropomorphic phantom. Reference measurements were made in air at isocentre using the pencil ionization chamber under the specified conditions. Detailed Monte Carlo models were developed for the MDCT scanner to describe the x-ray source (spectra, bowtie filter, etc) and geometry factors (distance from focal spot to isocentre, source movement due to axial or helical scanning, etc). Models for the cylindrical (CTDI) phantoms were available from the previous work. For the anthropomorphic phantom, CT image data were used to create a detailed voxelized model of the phantom's geometry. Anthropomorphic phantom material compositions were provided by the manufacturer. A simulation of the physical scan was performed using the mathematical models of the scanner, phantom and specified scan parameters. Tallies were recorded at specific voxel locations corresponding to the MOSFET physical measurements. Simulations of air scans were performed to obtain normalization factors to convert results to absolute dose values. For the CTDI body (32 cm) phantom, measurements and simulation results agreed to within 3.5% across all conditions. For the anthropomorphic phantom, measured surface dose values from a contiguous axial scan showed significant variation and ranged from 8 mGy/100 mAs to 16 mGy/100 mAs. Results from helical scans of overlapping pitch (0.9375) and extended pitch (1.375) were also obtained. Comparisons between the MOSFET measurements and the absolute dose value derived from the Monte Carlo simulations demonstrate agreement in terms of absolute dose values as well as the spatially varying characteristics. This work demonstrates the ability to extend models from a single detector scanner using cylindrical phantoms to an MDCT scanner using both cylindrical and anthropomorphic phantoms. Future work will be extended to voxelized patient models of different sizes and to other MDCT scanners.

Hyperbaric oxygen: a means of decreasing ischemic epiphyseal damage in a pediatric rabbit model.

The effect of hyperbaric oxygen on epiphyseal ischemia was evaluated using a pediatric rabbit model. Forty-five animals were compared in this study: 23 from a control pilot study and 22 hyperbaric exposed animals. In each animal the right distal femoral and proximal tibial epiphyses were isolated on a popliteal vascular pedicle. The left leg acted as the control. The growth difference between the rabbit's hindlimbs was the means of comparison throughout the groups established. Warm ischemia was induced by applying a vascular clamp to the right popliteal artery for 12 hours (20 animals) and 7 hours (17 animals). The remaining 8 animals underwent a sham operation without interruption of epiphyseal perfusion. On completion of the ischemic period hyperbaric oxygen therapy (HBOT) was performed on 12 12-hour (12h-HBOT) and 10 7-hour (7h-HBOT) animals at 2 atmospheres for 90 minutes twice per day for 4 postoperative days. The animals were killed on either postoperative day 14 or 90. Measurement of longitudinal bone growth was performed on the 90-day animals from serial radiographs at the time of surgery and then at 1 month, 2 months, and 3 months after surgery. There was no significant difference in longitudinal bone growth between the sham-operated and the 7h-HBOT animals at 1, 2, and 3 months. There was a statistically significant difference, however, between the normal growth of the 7h-HBOT group compared with the abnormal growth of the 7-hour, 12-hour, and 12h-HBOT animals. Histology was consistent, with the bone growth data demonstrating relative normalcy of the 7h-HBOT group epiphyseal plates versus severe architectural aberrance and necrosis of the 12h-HBOT group epiphyses. Our experimental data indicate that a clinical trial should be instituted using HBO for pediatric replantation patients when warm ischemia exceeds 7 hours. (J Hand Surg 2000; 25A:159-165.

Survival of normothermic microvascular flaps after prolonged secondary ischemia: effects of hyperbaric oxygen.

Although hyperbaric oxygen has been shown to improve the survival rate of ischemic grafts and flaps of many types, it has not been studied extensively in free tissue transfer. This study was designed to evaluate the effect of hyperbaric oxygen on flap survival when exposed to critical combinations of primary ischemia, reperfusion, and secondary ischemia times. Unilateral abdominal adipocutaneous island flaps based on the superficial inferior epigastric vessels were raised in 133 Sprague-Dawley rats. Primary normothermic ischemia was induced by applying a microvascular clamp to the vascular pedicle for 6 hours. The clamp was removed for 2 hours of reperfusion and then reapplied for a 6-, 10-, or 14-hour period of secondary ischemia. After completion of the secondary ischemia time, the clamp was removed, and the animals were randomly assigned to one of three treatment regimens. The control animals breathed normobaric air, and the others breathed normobaric 100% oxygen or hyperbaric oxygen (100% oxygen at the equivalent of 33 feet of seawater, 2.0 atmospheres absolute), respectively, for two periods of 90 minutes for 7 days. Flap survival was assessed at postoperative day 7 and was found to be an all-or-none phenomenon. Maximum likelihood-derived survival curves were fitted to the data and used to calculate the secondary ischemic time at which 50% of the flaps survived (D50). The D50 for the air and 100% oxygen groups was 6 hours, whereas that for the hyperbaric oxygen group was 10 hours. This difference in D50 was found to be statistically significant (analysis of variance, p < 0.05). Chi-squared statistical evaluation of pooled data reaffirmed a statistically significant increase in flap survival of the animals treated with hyperbaric oxygen vs. those treated with air or 100% oxygen (p < 0.03 and p < 0.01, respectively). Hyperbaric oxygen enhances the tolerance of normothermic, microvascular flaps to prolonged secondary ischemia. A similar effect was not noted in the 100% oxygen group; therefore the additional expense and technology of a hyperbaric chamber system is necessary to achieve this effect.

Marketing and commercial challenges for anticancer products.

Traditional marketing techniques that are employed by pharmaceutical manufacturers are not adequate in the oncology setting. Many unique characteristics of this therapeutic area create challenges to the marketing and sales teams responsible for selling anticancer and cancer-therapy support products. There is a high burden on those marketing oncology products to provide vast amounts of information about their products, in a timely manner, to various groups of health care providers, while functioning within established legal boundaries. Pharmaceutical companies, through their sales and marketing efforts, are working to provide the information health care providers need to make patient management decisions and prevent the health care environment from restricting physician and patient choices.

Vestibulo-ocular reflex gain as a measure of vestibular function in guinea pigs while in a recompression chamber: apparatus design and effects of nitrogen narcosis.

There are several mechanisms whereby alteration of barometric pressure can produce vertigo in divers or aviators. Development of a reliable measure of vestibular function in an animal model is the first requirement for further study of these mechanisms. This report presents the development of a rotatory table device capable of evoking the vestibulo-ocular reflex (VOR) of a guinea pig while in a hyperbaric chamber. To assess the reproducibility of this response, eight animals were monitored by electronystagmography during rotations at three table velocities (62.4, 83.3, and 100 degrees/s). Two test sessions were performed on each animal with a 6-hour interval between sessions. The VOR gain was calculated by dividing the average peak velocity of the slow phase component of the nystagmus by the peak stimulus velocity. At least eight observations per test speed were averaged; calibration of eye movement was performed prior to each session by forced ocular abduction. Multifactorial analysis of variance revealed no significant differences (p > .05) between the differing rotation speeds nor between test sessions for individual animals. However, there was a significant difference in VOR gain between animals (p < .002). The VOR gain was then measured, using the same techniques, in another group of seven animals before, during, and after an air dive to the equivalent of 200 feet of seawater (7.06 atmospheres absolute) to assess the effects of nitrogen narcosis. Pre- and post-dive VOR gains were significantly greater than those measured at depth (p < .05). These results are consistent with the slow processing model of nitrogen narcosis and the controversial theory that central nervous system depressants decrease the VOR gain. The results also demonstrate the ability of this inexpensive apparatus to provide a sensitive measure of pressure-induced changes of vestibular function in guinea pigs.

Computer-assisted assessment of cochlear nerve fibers.

Quantitative assessment of cochlear nerve fibers, with statistical analysis of histologic specimens, is facilitated by the application of computer image processing techniques. Three algorithms, developed for the evaluation of cochlear sections, are presented, MANUAL, AIDED, and AUTO, in order of increasing degree of automation and decreasing requirement for operator intervention. All three algorithms demonstrate high accuracy and consistency in identifying cochlear nerve fibers and quickly provide statistics regarding the target nerve fiber population. These algorithms have potential utility in the study of cochlear nerve pathologic alterations, as for example, with intracochlear electrical stimulation.

Complement activation during saturation diving.

In this study, the levels of activated complement fragments C3a and C5a were measured on 11 U.S. Navy divers as they performed a 28-day saturation dive to a pressure equivalent of 1,000 feet of seawater (fsw, 31.3 atm abs). Two subjects developed symptoms consistent with the high pressure nervous syndrome (HPNS) and three were treated for type I DCS (joint pain only). These events allowed us to test two hypotheses: a) alterations in C3a or C5a levels during compression are related to the occurrence of HPNS and b) increases in complement fragments are an indicator of decompression stress associated with type I DCS. There was no correlation between changes in C3a and C5a levels during compression and the diagnosis of HPNS. Our results suggest that an increase in C3a and C5a levels during saturation diving correlates with decompression stress and the clinical diagnosis of type I DCS.

Endoscopic carpal tunnel release: a cadaveric study.

Five surgeons performed endoscopic (Dyonics) carpal tunnel releases on 24 fresh cadaver wrists. In 50% of the specimens, transection of the transverse carpal ligament was incomplete. The average amount of incomplete release was 31% (range, 0% to 53%). Three types of incomplete release were noted: (1) release of Guyon's canal release--one, (2) incomplete distal ligament release--five, and (3) incomplete central or superficial release--six. Other technical errors were noted in nine of 24 specimens. There were no nerve lacerations. Endoscopic carpal tunnel release is either a technically demanding procedure, commonly results in incompletely released ligaments, or both. Proper training, followed by practice on several cadaver specimens before its clinical use, is recommended.

Management of herniated intervertebral disks during saturation dives: a case report.

During research saturation dives at 5.0 and 5.5 atm abs, 2 divers developed an acute herniation of the nucleus pulposus of the L5-S1 intervertebral disk. In both cases the pain was severe enough to require intravenous morphine or intramuscular meperidine. Although the symptoms presented by these divers are frequently considered to be an indication for immediate surgical consultation, we decided that emergency decompression posed an unacceptable risk that decompression sickness (DCS) would develop in the region of acute inflammation. In both cases strict bedrest and medical therapy were performed at depth. In the first case, 12 h was spent at depth before initiating a standard U.S. Navy saturation decompression schedule with the chamber partial pressure of oxygen elevated to 0.50 atm abs. In the second case, a conservative He-N2-O2 trimix decompression schedule was followed to the surface. In both cases, no initial upward excursion was performed. The required decompression time was 57 h 24 min from 5.5 atm abs and 55 h 38 min from 5.0 atm abs. During the course of decompression, the first diver's neurologic exam improved and he required decreasing amounts of intravenous narcotic; we considered both to be evidence against DCS. The second diver continued to have pain and muscle spasm throughout decompression, however he did not develop motor, reflex, or sphincter abnormalities. Both divers have responded well to nonsurgical therapy.

Morphologic and electrophysiologic effects of cochlear implantation and electrical stimulation.

The nondeafened guinea pig model was utilized in this study to assess the functional and morphologic effects of cochlear implantation and electrical stimulation. Auditory brainstem responses (ABRs) were recorded prior to and following intrascalar implantation of a 3M-House cochlear electrode (n = 41 ears), as well as after electrical stimulation (n = 23 ears). The experimental population was divided into the following groups according to implantation and stimulation parameters: 200 microA for 3 hours (group I); 200 microA for 24 hours (group II); 400 microA for 3 hours (group III); implanted, but not stimulated (group IV); and nonimplanted, not stimulated ears (group V). Of those cochleae that sustained the trauma of implantation, 32 percent had no detectable ABR to 110 dB SPL clicks, while only 7 percent additionally failed to respond to 130 dB SPL clicks. No significant difference (one-way ANOVA with repeated measures at the 95 percent confidence limit) could be detected when comparing those ears that retained ABRs according to experimental grouping. Morphologic analysis was performed on 29 cochleae. Spiral ganglion "packing densities" were not found to be significantly different among the groups (ANOVA). The status of the organ of Corti was significantly better in groups II and V in comparison to the other groups (Kruskal-Wallis test with pairwise comparisons, p less than 0.05); there was no discernible dose-response relationship. Morphologic and electrophysiologic changes correlated with insertion trauma and infection rather than with electrical stimulation at the levels tested in this study.(ABSTRACT TRUNCATED AT 250 WORDS)

The effects of estrogen and progesterone on glycogen and the enzymes involved in its metabolism in the cat uterus.

In the endometrium of the spay cat, estradiol treatment causes a drastic reduction in glycogen content. The initiation of simultaneous progesterone treatment causes a replenishment of glycogen with the levels surpassing those observed in the spayed animal. The effect of the hormones on glycogen synthetase I follows the same pattern as the changes in glycogen content, while the effect on phosphorylase a is the mirror image. The total content of glycogen synthetase and phosphorylase do not show appreciable changes with the same hormone treatment. The possible reproductive role of these changes in glycogen content are discussed.

The glucagonoma syndrome.

The glucagonoma syndrome is characterized by necrolytic migratory erythema, glossitis, ungual dystrophy, diabetes mellitus, anemia, weight loss, elevated plasma glucagon levels and an alpha-cell glucagon-secreting neoplasm of the pancreas. We are reporting a case of this syndrome in a middle-aged woman, in whom the first complaints and signs were cutaneous. The recognition of the distinctive skin manifestations of the syndrome led to early diagnosis and treatment of the underlying malignant pancreatic tumor.

Ulcers of the leg in thalassemia.

Four patients had thalassemia and leg ulcers. In three patients the hematologic diagnosis of thalassemia had not been previously made; the presenting symptom was the leg ulcer. The diagnosis of thalassemia should be considered in patients who have unexplained chronic leg ulcers; the incidence of this complication of thalassemia may be higher than previously reported.