CNS 7056: A Novel Ultra-short-acting Benzodiazepine

Background: A new benzodiazepine derivative, CNS 7056, has been developed to permit a superior sedative profile to current agents, i.e., more predictable fast onset, short duration of sedative action, and rapid recovery profile. This goal has been achieved by rendering the compound susceptible to metabolism via esterases. The authors now report on the profile of CNS 7056 in vitro and in vivo.

Methods: The affinity of CNS 7056 and its carboxylic acid metabolite, CNS 7054, for benzodiazepine receptors and their selectivity profiles were evaluated using radioligand binding. The activity of CNS 7056 and midazolam at subtypes ([alpha]1[beta]2[gamma]2, [alpha]2[beta]2[gamma]2, [alpha]3[beta]2[gamma]2, [alpha]5[beta]2[gamma]2) of the [gamma]-aminobutyric acid type A (GABAA) receptor was evaluated using the whole cell patch clamp technique. The activity of CNS 7056 at brain benzodiazepine receptors in vivo was measured in rats using extracellular electrophysiology in the substantia nigra pars reticulata. The sedative profile was measured in rodents using the loss of righting reflex test.

Results: CNS 7056 bound to brain benzodiazepine sites with high affinity. The carboxylic acid metabolite, CNS 7054, showed around 300 times lower affinity. CNS 7056 and CNS 7054 (10 [mu]m) showed no affinity for a range of other receptors. CNS 7056 enhanced GABA currents in cells stably transfected with subtypes of the GABAA receptor. CNS 7056, like midazolam and other classic benzodiazepines, did not show clear selectivity between subtypes of the GABAA receptor. CNS 7056 (intravenous) caused a dose-dependent inhibition of substantia nigra pars reticulata neuronal firing and recovery to baseline firing rates was reached rapidly. CNS 7056 (intravenous) induced loss of the righting reflex in rodents. The duration of loss of righting reflex was short (< 10 min) and was inhibited by pretreatment with flumazenil.     

Bimodal dialysis: an integrated approach to renal replacement therapy.

BACKGROUND: Peritoneal dialysis (PD) and hemodialysis (HD) are both widely used as sole therapies for end-stage renal disease (ESRD). There is still controversy over which (if either) is superior in terms of patient outcomes. Peritoneal dialysis offers the advantages of long, slow, continuous ultrafiltration and potentially enhanced protection of residual renal function (RRF). In contrast, HD offers superior solute removal at the cost of undesirable cardiovascular tolerance of high rates of sodium and water removal. The aim of this study was to investigate the clinical feasibility of offering a combined treatment of both modalities [bimodal dialysis (BMD)] to incident patients reaching ESRD. We set out to investigate if it might be possible to utilize the intrinsic advantages of both modalities within a setting of good patient acceptability. METHODS: We prospectively studied 8 patients. They were recruited in the pre-ESRD phase from a specialist low clearance clinic. An arteriovenous fistula was formed and peritoneal catheters were inserted. The BMD consisted of 2, 3-hour, high efficiency, euvolemic HD sessions per week in combination with 2 PD exchanges per day to provide a degree of solute clearance and all of the ultrafiltration. Adequacy was measured independently for each modality. Patients were followed using the standard range of evaluations in addition to RRF (by creatinine clearance and EDTA clearance), echocardiography (left ventricular mass and ventricular performance), treatment outcomes, patient symptoms, and complications. RESULTS: Mean time on BMD was 346 +/- 74.9 (range 245 - 431) days. Peritonitis rate was 21 months per episode (mean 0.6 +/- 0.9, 0 - 2 episodes per patient). Mean peritoneal ultrafiltration volume was 1.58 +/- 0.32 (1.3 - 2.1) L per day. Delivered Kt/V and weekly PD Kt/V did not change significantly. Patients' RRF was maintained over the study period, as were serum albumin and control of serum phosphorus. Blood pressure was controlled with a reduction in the number of antihypertensive agents. Left ventricular mass index reduced over the treatment period, from a mean of 194 +/- 31.2 (161 - 265) to 156 +/- 21.2 (138 - 189) g/m2 (p = 0.05). Ventricular performance remained unchanged over the study [ejection fraction 50.4 +/- 11.1 (38 - 67) % to 48 +/- 8.0 (48 - 67) %]. Mean time during BMD spent on HD alone was 4.2 +/- 6.9 (0 - 16) days, and on PD alone 9.2 +/- 10.6 (0 - 25) days. CONCLUSION: This study suggests that BMD is a feasible treatment for ESRD. It is associated with adequate solute removal and good hemodynamic/volume control, and allows increased treatment flexibility for coping with complications normally requiring recourse to unplanned HD with temporary central venous access.     

Arthroscopic capsulorrhaphy formultidirectional instability

Multidirectional shoulder instability is a common affliction and is increasingly recognized as a debilitating condition in young, athletic patients. Most patients with this condition are in their third decade and have a history of macrotrauma or repetitive microtrauma. Complaints range from frank instability to instability with pain, or to pain alone. These patients may display clinical signs of instability, impingement, or both on physical examination. Generalized ligamentous laxity or shoulder laxity alone are usually present. A positive sulcus sign remains the most sensitive clinical test in distinguishing these patients, even though no data is available on the sensitivity or specificity of this examination. The greater majority of patients are successfully treated with an exercise program stressing rotator cuff and scapular stabilizer strengthening. When patients do not respond to conservative treatment, open capsular shift has been recommended to restore joint stability. Early successes with the arthroscopic treatment of anterior shoulder instability have led to the development of similar procedures for the treatment of multidirectional instability. This paper describes an arthroscopic, multiple suture capsulorrhaphy for the treatment of multidirectional shoulder instability, which is a modification of the procedure advocated by Caspari and reviews the 2-year results of the first 19 patients treated.     

Birth order effects in second-generation alcoholics

The effects of birth-order position (first-, middle- and last-born) in intact families with three children on the psychopathology scores of second-generation alcoholics were examined by administering the MMPI to 90 alcoholic sons of alcoholic parents. Analyses of variance (ANOVAs) applied to the individual MMPI scale scores revealed a consistent pattern of results: first borns evidenced significantly less exaggerated psychopathology scores than both groups of later borns. Most of the extreme scale scores obtained within this population of alcoholics were obtained from the later borns. Implications for previous generalizations about the alcoholic children of alcoholic parents are discussed.     

Anaesthesia monitoring: the human factors component of technology transfer

Resistance to change in monitoring practices from within the anaesthesiology community is a formidable obstacle, and coercive and exhortatory solutions are likely to be unsuccessful in some situations. An analysis of publications about technology transfer and professional obsolescence, and application of this data to the practice of anaesthesia, reveals various stresses that technology transfer from research areas to the workplace may induce in vulnerable anaesthesiologists and account for their attitudes. It is suggested that the invaluable pronouncements of high profile anaesthesiologist groups must be supplemented by supportive behaviour by physicians and administrators at an institutional level. The human factors issues to be addressed include: (i) Monitored data acquisition skills. (ii) Possibility of acting on monitored data. (iii) Assistance for personal insight into attitudinal difficulties that may be encountered. (iv) Data supporting the value of the device. (v) Ergonomically effective integration of the monitor into the work station.Alternatively the perceptions of potential users may accurately reflect changes in their status in the new work situation created by monitors, and decision making aids that may or may not be derived from them. Thus, plans to present job satisfaction in related clinical areas or to associate the proposed new system with evaluation of its effect on patient outcome will be necessary. In this way the clinician becomes involved in clinical research, a quality of personal and quality care development.     

The complement system in human reproduction.

Regulation of the complement system in reproduction is unique inasmuch as reproductive tissues represent the only condition where allogeneic interactions occur naturally. Both allogeneic extraembryonic membranes and semen that contact and interact with maternal cells and tissues must avert complement-mediated damage to ensure reproductive success. Several regulators of complement activation exist. Membrane cofactor protein (MCP) and decay accelerating factor (DAF) inactivate C3 and C5 convertases on cell surfaces. In addition, CD59 inhibits the membrane attack complex (MAC) of the complement cascade. Strong expression of these membrane glycoproteins by trophoblast and amniotic epithelium has been observed. MCP, DAF, and CD59 likely safeguard extraembryonic tissues from complement damage originating from maternal and fetal blood or amniotic fluid. Different reproductive tract fluids vary in complement levels. With the exception of ovarian follicular fluid, these levels are generally much less than those in blood. Endometrial and cervical content of C3 appear to be regulated by hormones. These observations suggest that the effects of complement activation may vary in reproductive tissues. MCP is absent from the surfaces of oocytes. Sperm express MCP and DAF in discrete areas that would not be associated with the known complement-regulatory functions of these proteins. Seminal plasma contains MCP and the MAC inhibitor SP-40,40 but not DAF.SP-40,40 may exemplify how complement-regulatory proteins perform alternative functions as it interacts with molecules other than complement components. We have reviewed aspects of the complement system that relate to allogeneic interactions in reproduction and that suggest fruitful areas for further research.     

A noninvasive method of predicting pulmonary-capillary wedge pressure.

BACKGROUND. The noninvasive prediction of pulmonary-capillary wedge pressure (PCWP) is important for the recognition and treatment of a variety of cardiovascular disorders. The response of the arterial pressure to the Valsalva maneuver has been shown to correlate with the PCWP. We therefore devised a noninvasive method to measure this pressure response at the bedside and correlated these measurements with the PCWP measured directly with a pulmonary-artery catheter. METHODS. Simultaneous, blinded, noninvasive measurements of the ratio of the final amplitude to the initial amplitude of the pulse wave form during the stress phase of the Valsalva maneuver (pulse-amplitude ratio) and direct measurements of the PCWP were obtained in 20 clinically stable patients and in 14 clinically unstable patients who were receiving vasoactive agents, 12 of whom also had endotracheal tubes in place. RESULTS. Using linear regression analysis, we found that the pulse-amplitude ratio strongly correlated with the measured PCWP over a range of base-line values from 4 to 32 mm Hg for the 20 clinically stable patients (R2 = 0.80) and the 14 clinically unstable patients (R2 = 0.85). The method also correctly predicted changes in the PCWP after the administration of nitroglycerin or furosemide and after expansion of the intravascular volume (R2 = 0.79). CONCLUSIONS. These preliminary data indicate that a simple noninvasive method can accurately predict the PCWP and changes in the PCWP in response to medical therapy.     

Solid and papillary epithelial neoplasms of the pancreas: CT findings

Five female patients and one male patient with solid and papillary epithelial neoplasms of the pancreas were examined with computed tomography (CT). The mean age of the patients was 27 years (range, 13-46 years). All cases showed well-encapsulated, round or lobulated masses consisting of both cystic and solid areas. Cystic portions showed CT numbers that suggested hemorrhagic necrosis. There were no internal septations within the masses. In three tumors located in the head of the pancreas, dilatation of the biliary tree was absent or minimal, although the masses were large. Two tumors contained calcifications. One tumor demonstrated metastatic deposits in liver and lymph nodes. Metastatic masses appeared similar to the primary pancreatic mass. Solid and papillary neoplasm of the pancreas should be the primary diagnostic consideration when characteristic CT findings are detected in a young female patient.