The influence of formulation components on the aerosolisation properties of spray-dried powders.

Dry powders suitable for inhalation containing beta-estradiol, leucine as a dispersibility enhancer and lactose as a bulking agent were prepared by spray-drying from aqueous ethanol formulations. The influence of formulation components on the characteristics of the resultant spray-dried powders was examined through the use of a range of ethanol concentrations (10-50% v/v) in the solvent used to prepare the initial formulations. Additionally, the amount of leucine required to act as a dispersibility enhancer was investigated by varying the amount of leucine added to the formulation prior to spray-drying. Following spray-drying, resultant powders were characterised using scanning electron microscopy, laser diffraction and tapped density measurements, and the aerosolisation performance determined using Twin Stage Impinger and Andersen Cascade Impactor analysis. We demonstrate that selection of appropriate solvent systems and leucine concentration allows the preparation of spray-dried powders that display enhanced aerosolisation properties, and would be predicted to exhibit high deposition in the lower regions of the respiratory tract.     

Protective effects of calcium-magnesium soft gels in morphine tolerant and dependent mice.

The present study was aimed at evaluating the acute effects of Calcium-Magnesium soft gels (CalMag) in morphine tolerant and dependent mice. Mice were rendered tolerant and dependent on morphine by subcutaneous injection of morphine over a fixed time period. Withdrawal signs were precipitated by injecting naloxone 2 h after the final injection of morphine. The tail-pinch assay was used to investigate the effects of various compounds on the development and reversal of morphine tolerance. Acute injection of CalMag (containing 50 mg/kg calcium and 25 mg/kg magnesium) significantly reduced the number of jumps, stands and fast breathing in morphine dependent mice. Co-administration of calcium (50 mg/kg) and magnesium (25 mg/kg) was also effective in preventing the development of morphine tolerance and dependence. Administration of calcium (up to 50 mg/kg) alone did not significantly block the development of tolerance and dependence. The mean latency to pain was significantly increased in animals pretreated with CalMag (containing 50 mg/kg calcium and 25 mg/kg magnesium). The mixture of calcium and magnesium at specific concentrations seem to be critical for preventing the development of morphine tolerance and dependence.     

The acidosis of cholera. Contributions of hyperproteinemia, lactic acidemia, and hyperphosphatemia to an increased serum anion gap

To study the metabolic acidosis that occurs during the diarrhea of cholera, we examined the serum anion gap in 21 patients with hypovolemic shock due to Vibrio cholerae infection. Measurements of serum electrolytes, as well as divalent cations and the anionic contributions of serum proteins, lactate, phosphate, and serum creatinine, were made at the time of admission, after rehydration, and during convalescence. At the time of admission, the mean serum concentration of sodium was 134.8 mmol (meq) per liter, that of chloride was 103.2 mmol per liter, and that of bicarbonate was 11.4 mmol per liter; the mean anion gap was 20.2 mmol per liter. The mean serum creatinine concentration was 2.48 mg per deciliter. The low serum bicarbonate level and the high serum anion gap were corrected by rehydration. The increased serum anion gap was caused by hyperproteinemia, lactic acidemia, and hyperphosphatemia, with anionic contributions to the rise in anion gap estimated as protein, 5.5 meq per liter; lactate, 2.5 meq per liter; and phosphate, 2.5 meq per liter. The hyperproteinemia was attributed to dehydration, the lactic acidemia to shock, and the hyperphosphatemia to acidosis and transient renal failure. The mean concentrations of serum calcium and magnesium were slightly elevated but did not affect the increased anion gap. These results indicate that severe cholera causes acidosis with relatively little change in serum chloride but an increased serum anion gap. The acidosis is more profound than would be expected on the basis of stool losses of bicarbonate, because of superimposed lactic acidemia and renal failure.     

An application of multivariate moment-generating functions to the analysis of signal and noise propagation in radiographic screen-film systems

Previous studies [J. Opt. Soc. Am. 4A 895-901 (1987)] have shown the utility of multivariate moment-generating functions for analyzing the influence of stochastic amplifying and scattering mechanisms on the transfer of signal and noise through multistage imaging systems. Recently, these studies were extended to include cases in which the amplification or scattering parameters are themselves stochastic variables [J. Opt. Soc. Am. 6A, 1156-1164 (1989)]. In this paper we consider a special case in which amplification is followed by scattering such that the same random variable which characterizes the parameters of each amplification process also characterizes the parameters of the subsequent scattering of the amplified output events. In radiographic imaging, this can be used to describe the physics of the depth dependence of emission efficiency and light scatter in x-ray intensifying screens, which was originally treated by Lubberts [J. Opt. Soc. Am. 58, 1475-1483 (1968]). In this work Lubberts' original results are rederived in a more general form. They are then illustrated in terms of a diffusion model [Appl. Opt. 12, 1865-1870 (1973)] for light scatter within the intensifying screen.     

Prostate specific antigen doubling time after radical prostatectomy: effect of neoadjuvant androgen deprivation therapy

PURPOSE: We determined the predictors of prostate specific antigen (PSA) doubling time in patients with relapse after radical prostatectomy as well as whether PSA doubling time is shorter in those treated versus not treated with neoadjuvant androgen deprivation therapy. MATERIALS AND METHODS: We calculated PSA doubling time in 204 patients with PSA relapse after radical prostatectomy who were or were not treated with neoadjuvant androgen deprivation therapy. Analysis of covariance was used to determine the effect of clinical and pathological parameters on PSA doubling time, and the proportion of variability explained by these parameters. RESULTS: Clinical stage, and combined clinical stage and margin status, clinical stage and androgen deprivation therapy status, androgen deprivation therapy status and time to PSA relapse, and androgen deprivation therapy status and pretreatment PSA were significant predictors of PSA doubling time. Any variable or combination of variables explained up to only 21% of PSA doubling time variability. When stratified by pretreatment PSA, clinical stage and biopsy grade, the difference in doubling times in patients treated with or without neoadjuvant androgen deprivation therapy was significant only for 4.1 to 10 ng./ml. PSA. In this group mean doubling time plus or minus standard deviation in patients receiving neoadjuvant androgen deprivation therapy and those treated only with radical prostatectomy was 7.6+/-1.0 and 15.4+/-2.6 months, respectively. CONCLUSIONS: Our study indicates that it is difficult to predict PSA doubling time in an individual. The small proportion of variability in PSA doubling time explained by the interaction of androgen deprivation therapy status and other variables indicates that these factors are not clinically significant.     

The role of hyperthermia in regional alkylating agent chemotherapy.

The role of hyperthermia during regional alkylating agent chemotherapy is controversial. The aim of this study was to determine the exact contribution of hyperthermia to tumor response during isolated limb infusion with l-phenylalanine mustard. Rats bearing rodent fibrosarcoma on the hindlimb underwent isolated limb infusion with saline, saline plus heat, l-phenylalanine mustard, l-phenylalanine mustard under conditions of normothermia, or l-phenylalanine mustard plus hyperthermia. Heat was administered locally using an in-line hot water circulation loop. Treatment with l-phenylalanine mustard at a concentration of 15 or 50 micrograms/mL was ineffective at producing tumor growth delay (P = 0.24 and 0.41, respectively). Furthermore, thermal enhancement of l-phenylalanine mustard activity was not seen at 15 micrograms/mL. However, administration of high-dose l-phenylalanine mustard, 50 micrograms/mL, with increasing amounts of heat yielded increasing tumor growth delay, increased regressions, and decreased proliferative index. Although l-phenylalanine mustard infusion under normothermia yielded a tumor growth delay of 7.1 days, combination l-phenylalanine mustard + hyperthermia treatment produced tumor growth delay of 27.0 days (P < 0.01; with two of five animals showing a complete response). Four hours after isolated limb infusion, 50.9% of cells in tumor treated with l-phenylalanine mustard + hyperthermia experienced apoptosis, whereas only 18.1, 16, and 4.4% of cells underwent apoptosis after treatment with l-phenylalanine mustard, saline + hyperthermia, or saline. The mean concentration of l-phenylalanine mustard within tumor relative to perfusate following isolated limb infusion was found to be similar among all groups at 0.023, 0.025, and 0.032 in animals undergoing isolated limb infusion with l-phenylalanine mustard, l-phenylalanine mustard + normothermia, and l-phenylalanine mustard + hyperthermia, respectively. These data indicate a synergistic cytotoxic effect of l-phenylalanine mustard + hyperthermia in isolated limb infusion, which is not attributable to enhanced tumor drug uptake.     

Factors predicting recovery of erections after radical prostatectomy

PURPOSE: Because preservation of functioning penile erections is a major concern for many patients considering treatment for localized prostate cancer, we analyzed various factors determined before and after radical retropubic prostatectomy to identify those significantly associated with recovery of erectile function. MATERIALS AND METHODS: Our prospective database of patients undergoing pelvic lymphadenectomy and radical retropubic prostatectomy was used to determine factors predictive of erection recovery after radical prostatectomy. The study included 314 consecutive men with prostate cancer treated with radical retropubic prostatectomy between November 1993 and December 1996. Preoperative potency satisfactory for intercourse and degree of neurovascular bundle preservation during the operation were documented. RESULTS: Patient age, preoperative potency status and extent of neurovascular bundle preservation but not pathological stage were predictive of potency recovery after radical prostatectomy. At 3 years after the operation 76% of men younger than age 60 years with full erections preoperatively who had bilateral neurovascular bundle preservation would be expected to regain erections sufficient for intercourse. Compared to the younger men, those 60 to 65 years old were only 56% (95% confidence interval [CI] 37 to 84) and those older than 65 years were 47% (95% CI 30 to 73) as likely to recover potency. Patients with recently diminished erections were only 63% (95% CI 38 to 100) as likely to recover potency as men with full erections preoperatively, and those with partial erections were only 47% (95% CI 23 to 96) as likely to recover potency. Resection of 1 neurovascular bundle reduced the chance of recovery to 25% (95% CI 10 to 61) compared to preserving both nerves. CONCLUSIONS: Knowledge of preoperative erectile function and patient age before the operation and the degree of neurovascular bundle preservation afterward may aid in patient counseling regarding potency recovery after radical prostatectomy.     

The diagnosis and management of aortic dissection occurring years after open heart surgery

Aortic dissection occurring after open heart surgery is an uncommon but well recognized complication. Unfortunately, it is associated with a high morbidity and mortality. Pre-existing aortic wall pathology, intraoperative aortic manipulations and hypertension are known to predispose to the development of this condition. We report a case of aortic dissection occurring 2 years after coronary artery bypass surgery and complicated by acute saphenous vein graft occlusion and severe mitral insufficiency. We review the diagnosis and management of this complication.