Multicenter prospective randomized 52-week trial of calcium hydroxylapatite versus bovine dermal collagen for treatment of stress urinary incontinence.

OBJECTIVES: To evaluate the safety and effectiveness of soft-tissue augmentation of the urethral sphincter with calcium hydroxylapatite (CaHA; Coaptite) compared with glutaraldehyde cross-linked bovine collagen (Contigen) in female patients with stress urinary incontinence due to intrinsic sphincter deficiency and without associated urethral hypermobility. METHODS: This 12-month prospective, randomized, comparative, multicenter, single-blind, parallel, clinical trial of CaHA and collagen for soft-tissue augmentation of the urethral sphincter in the treatment of stress urinary incontinence enrolled 296 women. Up to five injections were performed in the first 6 months of the trial. Twelve-month postinjection efficacy data were available for 231 patients. RESULTS: The results indicated that CaHA and collagen were both well tolerated in this study. No systemic adverse events were observed with either product. We used the Stamey Urinary Incontinence Scale to grade the improvement, which was the primary endpoint of the study. At 12 months, 83 (63.4%) of 131 CaHA patients compared with 57 (57.0%) of 100 collagen patients showed improvement of one Stamey grade or more (P = 0.34). More CaHA patients required only one injection (n = 60; 38.0%) during the study compared with the Contigen patients (n = 36; 26.1%; P = 0.034). Also, the average total volume of material injected during the course of the study was less for CaHA than for collagen (4.0 mL versus 6.6 mL, respectively; P <0.0001). CONCLUSIONS: The results of the study have demonstrated that Coaptite is an appropriate and well-tolerated treatment for patients with incontinence due to intrinsic sphincter deficiency. This new soft-tissue augmentation material has a good safety profile and appears to provide durable improvement.

A meta-analysis comparing the effectiveness of buprenorphine and methadone.

Increases in the use of illicit opiates have refocused attention on these drugs. One outgrowth of this attention has been the increased consideration of pharmacotherapies to provide alternatives to methadone maintenance. Buprenorphine is one new tool used in the attenuation of illicit opiate use. Like methadone, buprenorphine produces cross-tolerance to other opiates. However, it may have advantages over methadone including a longer duration, limited withdrawal syndrome, and increased safety. Buprenorphine's ability to serve as a replacement drug for illicit opiate use is well documented, and efforts have recently been made to compare the drug with methadone. The purpose of this study was to provide a meta-analysis of all available research reporting a controlled comparison of buprenorphine and methadone. This analysis provided a rating of the comparative efficacy of each drug, thus giving clinicians an additional guide when selecting an appropriate course of treatment. Findings suggest a relative equality in the efficacy of buprenorphine and methadone, although patients receiving methadone were less likely to test positive for illicit opiate use. Past experience with methadone maintenance acted as a moderating variable, however, such that those receiving buprenorphine were more likely to stay drug-free in studies that included patients with prior methadone experience.

Laparoscopic evacuation of a subcapsular renal hematoma causing symptomatic hypertension.

We report the case of a subcapsular hematoma following extracorporeal shockwave lithotripsy which presented as symptomatic hypertension. When medical therapy proved ineffective, laparoscopic decompression of the hematoma corrected the hypertension.

Management of stage C adenocarcinoma of the prostate.

A review of numerous clinical series dealing with the treatment of patients with clinical stage C prostate cancer failed to find the treatment or a combination of treatments that is superior to any other. Accurate staging, which was difficult in older studies, and stage migration, which complicates the comparison of recent to older studies, may contribute to this lack of identification. The majority of patients ultimately experience disease progression and are therefore treated with hormonal therapy, the use of which obscures survival data for initial modes of treatment. These observations point to the need for control of randomised clinical trials to identify effective treatments in the future.

Distribution of nerve growth factor-like protein and nerve growth factor receptor in human benign prostatic hyperplasia and prostatic adenocarcinoma.

Recent observations from our laboratory have identified a nerve growth factor (NGF)-like protein in conditioned media of stromal cells and neoplastic epithelial cells of the human prostate which mediates paracrine interactive growth of both cell types in vitro. In order to investigate the location of this NGF-like protein in the human prostate in vivo, and whether a nerve growth factor receptor (NGF-R) could be identified, we have carried out immunocytochemical studies on frozen tissue sections of human benign prostatic hyperplasia (BPH), prostatic adenocarcinoma and normal prostatic tissue. The NGF-like protein localized predominantly to the stromal component of BPH, adenocarcinoma and normal (non-cancerous) prostatic tissue. Conversely, the NGF-R localized predominantly to the epithelial cells of these tissues. Renal tissue provided negative controls for both the NGF-like protein and the NGF-R. The testis provided positive controls for both the NGF-like protein and the NGF-R. These results provide corroborative evidence for a NGF-like protein produced by stromal cells which interacts with a NGF-R on the adjacent epithelial cells thereby mediating paracrine interactive growth regulation of the human prostate.

Primary leiomyosarcoma of adrenal gland. Case report with immunohistochemical and ultrastructural study.

A primary leiomyosarcoma of the right adrenal gland is reported in a 49-year-old male who presented with progressive flank pain. This is the second case in the English language literature and the first to have documentation of malignant behavior. The tumor measured 11 cm in diameter and showed marked necrosis with prominent mitotic activity (average 15 per 10 high-power fields). Smooth muscle differentiation was apparent ultrastructurally and confirmed by positive immunostaining for muscle-specific and alpha-smooth muscle actin. Bony metastases developed; following palliative treatment with radiation and chemotherapy, the patient is alive with tumor 9 months later. Origin from smooth muscle associated with the central adrenal vein or its tributaries is proposed.

Alpha- and beta-adrenergic stimulation of parenchymal cell Ca2+ influx. Influence of extracellular pH.

Stimulation of parenchymal cell alpha- and beta-adrenergic receptors, with either epinephrine or the specific alpha-agonist phenylephrine or the beta-agonist isoproterenolol, promoted a net Ca2+ influx when the pH of the external medium was greater than pH 7.7. The effect was both time- and dose-dependent. At the elevated pH of 8.1, alpha-adrenergic receptors were still able to mobilize intracellular Ca2+, since when the external Ca2+ concentration was reduced to 0.05 mM, epinephrine promoted net Ca2+ efflux. The data suggest the existence of a Ca2+/H+ antiport or a Ca2+/OH- symport in the plasma membrane which can be stimulated by either alpha- or beta-adrenergic receptors. It is proposed that the Ca2+ influx mediated by alpha-adrenergic receptors helps maintain the elevated cytosolic [Ca2+]i for longer time periods after the initial mobilization from intracellular Ca2+ stores.

The effects of digoxin and dopamine on the oxygen consumption, lactate production and haemodynamic performance of an isolated, perfused, working guinea-pig heart.

We have adapted an established technique for perfusing the isolated, working rat heart to the guinea-pig heart and characterized its biochemical and haemodynamic performance. After 20 min of anoxia the heart recovers about 50% of its pre-anoxic performance ('post-anoxic cardiac failure') and after 90 min of continuous work total cardiac output falls to 50% of its initial, stable value ('spontaneous cardiac failure'). We have studied the effects of digoxin (10(-7) M and 2 x 10(-7) M) and dopamine (10(-5) M) on these two forms of cardiac failure and shown that digoxin improves the haemodynamic performance of the heart without altering its metabolism and therefore increases its efficiency. In contrast dopamine improves the haemodynamic performance of the heart at the expense of increased aerobic and anaerobic metabolism. The preparation is of value in studying the effects of cardioactive drugs on hearts subjected to constant pre-load and after-load.

Midazolam and diazepam: maternal and fetal effects in the pregnant ewe.

Maternal and fetal hemodynamic effects and placental transfer of midazolam (RO 21-3981, Hoffman-LaRoche) and diazepam were studied in chronically instrumented pregnant ewes. Diazepam administration resulted in greater increases of maternal and fetal heart rates and maternal blood pressure, and greater alteration of total uterine blood flow than did administration of comparable doses of midazolam. Neither drug altered fetal mean arterial pressure or maternal and fetal respiratory gases. Although the absolute blood concentrations were higher, the fetal:maternal drug concentration ratios were consistently less for midazolam than for diazepam, suggesting less placental permeability of midazolam.

Nitroprusside and the duration of tubocurarine and pancuronium.

Seventy-six patients in whom sodium nitroprusside was administered in order to induce hypotension received either 0.2 mg/kg tubocurarine or 0.04 mg/kg pancuronium bromide. The duration of action of these two drugs was assessed. In contrast to previous studies in the dog, sodium nitroprusside, given concurrently with either tubocurarine or pancuronium bromide, did not result in significantly prolonged neuromuscular blockade (33.0 vs 28.6 min for tubocurarine and 39.3 vs 39.6 min for pancuronium bromide; P greater than 0.1). These findings suggest that the prolonged neuromuscular blockade which is sometimes associated with trimetaphan-induced hypotension in man, is not encountered with sodium nitroprusside.

Lorazepam, hyoscine and atropine as i.v. surgical premedicants.

Lorazepam 2 and 4 mg alone and in combination with atropine 0.4 mg and hyoscine 0.4 mg were studied as i.v. surgical premedicants in 150 patients. Relief of anxiety, sedation, patient acceptance, lack of recall and side-effects were evaluated. Hyoscine was found to improve the relief of anxiety and sedation associated with lorazepam, but did not significantly increase lack of recall or patient acceptance. The addition of atropine to lorazepam did not significantly alter its effects. A high frequency of agitation and restlessness in patients receiving lorazepam and hyoscine make this combination undesirable for surgical premedication.

Directional spinals in obstetric analgesia.

Directional characteristics of spinal injections delivered via a 22 gauge Whitacre needle were confirmed in twenty-one obstetric patients undergoing elective Caesarean section. Caudad injection was inadequate for elective Caesarean section, while cephalad or lateral injection provided good sensory levels for the duration of the surgery. It is speculated that along with the low incidence of postspinal headache and ease of administering the block with a more rigid 22 gauge needle, low dose caudally directed injections may provide a superior means of administering saddle block analgesia for obstetric patients.

Pain and clinical thrombophlebitis following intravenous diazepam and lorazepam.

Eighty-seven per cent of surgical patients receiving undiluted diazepam experienced pain on injection while 6-16%, depending on the dose, manifested evidence of clinical thrombophlebitis. This was improved when diazepam, 10 mg, was diluted to 20-40 ml with intravenous solution. In contrast, lorazepam appeared to have minimal irritative or injurious effects on veins whether undiluted or diluted. In view of these results and clinical studies reporting a higher patient acceptance of lorazepam than diazepam, lorazepam may be a superior drug for use in anaesthesia.

RO 21-3981 for intravenous surgical premedication and induction of anesthesia.

RO 21-3981, a new water soluble benzodiazepine, was studied in 24 patients both as an intravenous premedicant and to induce anesthesia. The premedicant dose of 5 mg produced lack of recall and marked sedation within 1 to 2 minutes after injection and persisted for at least 32 minutes. Subsequent induction of anesthesia required an additional 5 to 25 mg of RO 21-3981. However, anesthesia was not induced in 1 patient with 25 mg and was accomplished only with inhalation anesthesia. Loss of lid reflex was unreliable as a sign of induction for patients in whom tracheal intubation was planned. Although decreases in blood pressure of 10 to 30 mm Hg were noted after administration of RO 21-3981, systolic pressure was not recorded below 90 mm Hg. RO 21-3981, because of its amnesic, sedative, and anxiolytic properties, appears to be an excellent premedicant although the 5 mg dose studied was probably larger than necessary. For induction of anesthesia, RO 21-3981 may be an effective alternative to thiopental.

Histopathology of veins after intravenous lorazepam and RO 21-3981.

A previously established rat model has been utilized to demonstrate that an acute inflammatory response occurs after high intravenous doses of lorazepam. This occurs only with high concentrations of drug equivalent to 20 times the normal clinical dosage in man. In contract, water soluble RO 21-3981 produces no vascular pathology in any dosage evaluated. It appears that propylene glycol may play a role in the pathogenesis of the intravascular injury observed.

Thrombophlebitis after intravenous diazepam--can it be prevented?

Although pain and subsequent thrombophlebitis are complications in patients receiving intravenous (IV) diazepam, the mechanism and accompanying histology are unknown. To further elucidate the pathogenesis for this and determine whether it can be minimized, adult female rats received IV diazepam, diazepam vehicle, lidocaine, a combination of lidocaine and diazepam, or N saline solution, and underwent subsequent tissue light microscopy. Vascular tissue from animals receiving IV diazepam alone revealed marked inflammation with inflammatory edema and intramural polymorphonuclear-cell infiltration. Intravascular thrombosis and complete vein-wall destruction were also present in some animals as early as 48 hours after IV diazepam. Diazepam vehicle and diluted diazepam produced similar morphologic alterations. Lidocaine or saline IV resulted in no histologic alterations, while lidocaine added to diazepam did not reduce the inflammatory response. These results represent the first systematic morphologic evaluation of vein response to intravascular diazepam and suggest that it produces rapid and detrimental morphologic alterations. The dilution of diazepam or combination with lidocaine does not appear to alter these findings, and diazepam vehicle appears to assume a role in the production of the vascular injury.

Some histological and metabolic properties of an isolated perfused rat brain preparation with special reference to monoamine metabolism.

A method is described for perfusing the rat head which results in perfusion of the brain, its covering and the bony skull only. Dye and latex injection studies showed that there was no perfusion of extracranial tissue and thus it was not necessary to remove the lower jaw and facial tissues as described by previous authors. Perfusion with fluorescein demonstrated that the whole brain was perfused. Light microscopy after two hours of perfusion revealed no deterioration in brain-structure. Electron microscopy showed a small increase in the extracellular space and the perivascular space with good preservation of subcellular organelles. Glucose and acetoacetate removal were very similar to those reported for the adult rat in vivo as measured by arterio-venous differences. The concentrations of 5-hydroxytryptamine, dopamine and noradrenaline are maintained at values close to those in vivo during a 2-hr perfusion with a basal medium and the preparation will maintain linear rates of 5-hydroxytryptamine synthesis for 2 h when the medium contains L-tryptophan and tranylcypromine, at rates similar to those measured in vivo. The rate of uptake of L-tryptophan into the brain is similar to that reported after L-tryptophan loading in vivo. The histological and metabolic properties of the preparation are close to those observed in vivo. The method could provide a way in which monoamine metabolism in particular could be studied using an experimental model closer in its properties to the in vivo situation than tissue preparations such as slices or homogenates.