Effect of nicotine, silver acetate, and ordinary chewing gum in combination with group counselling on smoking cessation.

Four hundred and ninety six smokers participated in a randomised comparison of the effect of silver acetate, nicotine, and ordinary chewing gum on smoking cessation. All were motivated to stop smoking abruptly and all had smoked at least 10 cigarettes a day for at least five years. Side effects and taste acceptability were related to outcome after six months. The participants attended nine meetings over a year, at which lectures, support, and advice about stopping smoking were given. Tobacco abstinence was confirmed by measurement of carbon monoxide in expired air. The chewing gums were used for 12 weeks. After 12 weeks there was a trend towards more abstainers in the nicotine group (59%) than in the silver acetate (50%) and ordinary (45%) chewing gum groups that was not quite significant (p = 0.07). At 26 and 52 weeks the number of cigarette abstainers was similar in the three treatment groups. Subjects in the nicotine chewing gum group had a longer mean time before relapse than those in the silver acetate and ordinary chewing gum groups. Mean success rates for all subjects combined at 12, 26, and 52 weeks were 52.8%, 39.7%, and 23.3%. The side effects of nicotine and silver acetate chewing gum were generally mild and transient, and unimportant except for mouth irritation from silver acetate, which had a negative effect on outcome, and the low taste acceptability of nicotine, which had a strong negative influence on the success rate. The results suggest a short term effect on nicotine chewing gum on smoking cessation, but the abstinence rates after one year were generally disappointing.     

Percutaneous technique for venovenous bypass including a heat exchanger is safe and reliable in liver transplantation

We have introduced and evaluated several modifications of the conventional venovenous bypass (VVBP) in 29 adult patients undergoing liver transplantation (OLT). A percutaneous technique for insertion of a jugular venous return cannula and a femoral vein cannula was applied. The inferior mesenteric vein (IMV) was used for splanchnic decompression, which facilitated dissection of the recipient liver and allowed portal anastomosis to be performed without disconnecting the portal bypass. A heat exchanger was introduced into the bypass circuit to prevent heat loss. The percutaneous technique prevented complications related to dissection in the axilla and groin. Hemodynamic characteristics corresponded to those found using the traditional technique. Complications related to the VVBP were seen in only one patient in whom the femoral catheter was accidentally introduced into the femoral artery. We conclude that percutaneous cannulas, use of the IMV for splanchnic decompression and the introduction of a heat exchanger offer significant benefits and that they are safe and reliable. Received: 23 August 1996 Received after revision: 14 January 1997 Accepted: 27 January 1997     

Methazolamide-Induced Delirium

A 74-year-old man became delirious 2 days after beginning oral therapy with methazolamide. The delirium was manifested by intermittent psychosis, incontinence of bowel and bladder, lethargy, and disorientation. These symptoms continued for 25 days despite many changes in his drug regimen, and complete laboratory, urologic, and neurologic work-ups. The symptoms resolved completely within 1 week of discontinuing methazolamide. This is the first case reported of delirium associated with methazolamide not accompanied by a metabolic imbalance.     

Atrial natriuretic peptide and blood volume in patients with chronic glomerulonephritis: effects of albumin and frusemide administration

Blood volume, blood pressure, plasma concentrations of atrial natriuretic peptide (ANP), cyclic 3',5'-guanosine monophosphate (cGMP), angiotensin II, aldosterone, and arginine vasopressin (AVP), and urinary excretion rates of cGMP, sodium, and water were determined before and after infusion of human albumin 20%, 3.5 ml/kg body-weight to 12 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 1); and before and after frusemide injection, 0.75 mg/kg to 15 patients with chronic glomerulonephritis and 19 healthy control subjects (Study 2). In Study 1 blood volume was expanded to the same degree in patients (8.8 and 7.5%, medians, after 90 and 180 min) and controls (8.6 and 6.1%). ANP was enhanced in the patients (5.9 to 11.0 pmol/l, P less than 0.01) and the controls (4.9 to 7.1 pmol/l, P less than 0.01), but the elevated level was protracted in the patients simultaneously with a delayed sodium excretion. Plasma cGMP increased, aldosterone decreased and AVP was unchanged in both groups, whereas angiotensin II decreased in the patients (P less than 0.01), but not in the controls. In Study 2 blood volume was reduced to a smaller extent in the patients than in the controls (8.9% versus 9.9%, P less than 0.05). ANP an cGMP decreased, and angiotensin II, aldosterone and AVP increased in both patients and controls. In conclusion, patients with glomerulonephritis respond to albumin- and frusemide induced changes in blood volume with essentially the same counter-regulatory changes in ANP, angiotensin II, aldosterone and AVP as do healthy subjects. The more protracted increase in ANP and the decrease in angiotensin II after albumin, and the smaller blood volume reduction after frusemide suggest an abnormal regulation of blood volume in glomerulonephritis.     

Negative symptoms in schizophrenia: considerations for clinical trials

There is little agreement about the methodology of clinical trials of antipsychotic drugs in patients with negative symptoms. A literature review revealed wide variation in experimental design, rating scales and study duration. This reflects differing views as to the definition and response to treatment of negative symptoms. Some degree of standardization would improve comparability of studies and aid the development of new compounds. Patients included in such studies should have displayed negative symptoms for at least 6 months. Depressive symptoms, positive schizophrenic symptoms and extrapyramidal signs may all influence or be confused with negative symptoms and may respond to treatment; they should be at a low level at baseline and should be measured during the study period. Studies should last at least 8 weeks. Several scales are available for measuring negative symptoms and are reviewed; a global impression score should be used additionally.     

N-acetylaspartate is an axon-specific marker of mature white matter in vivo: a biochemical and immunohistochemical study on the rat optic nerve.

Axonal pathology is a major cause of neurological disability in multiple sclerosis. Axonal transection begins at disease onset but remains clinically silent because of compensatory brain mechanisms. Noninvasive surrogate markers for axonal injury are therefore essential to monitor cumulative disease burden in vivo. The neuronal compound N-acetylaspartate, as measured by magnetic resonance spectroscopy, is currently the best and most specific noninvasive marker of axonal pathology in multiple sclerosis. The possibility has been raised, however, that N-acetylaspartate is expressed also by oligodendroglial lineage cells. In order to investigate N-acetylaspartate specificity for white matter axons, transected rat optic nerves were analyzed by high-performance liquid chromatography and immunohistochemistry. In transected adult nerves, N-acetylaspartate and N-acetyl aspartylglutamate decreased in concordance with axonal degeneration and were undetectable 24 days posttransection. Nonproliferating oligodendrocyte progenitor cells, oligodendrocytes, and myelin were abundant in these axon-free nerves. At 24 days posttransection, N-acetylaspartate was increased (42%; p = 0.02) in nontransected contralateral nerves. After transection at postnatal day 4, total N-acetylaspartate decreased by 80% (P14; p = 0.002) and 94% (P20; p = 0.003). In these developing axon-free nerves, 25 to 33% of oligodendrocyte progenitor cells were proliferating. These data validate magnetic resonance spectroscopy measurements of N-acetylaspartate as an axon-specific monitor of central nervous system white matter in vivo. In addition, the results indicate that neuronal adaptation can increase N-acetylaspartate levels, and that 5 to 20% of the N-acetylaspartate in developing white matter is synthesized by proliferating oligodendrocyte progenitor cells.     

Experience with the P.A.S.-PORT Venous Access Device in Patients with Gynecologic Malignancies

Experience with the P.A.S.-PORT, a peripherally implanted central venous access device, is evaluated in a retrospective review of 154 patients from July 1991 to June 1994. Blood could not be aspirated from six patients. Complications included temporary minor thrombophlebitis in seven patients (4.5%), symptomatic axillary or subclavian vein thrombosis in five patients (3.2%), clotted port in two patients (1.2%), port pocket cellulitis in two patients (1.2%), and fungal sepsis in two patients (1.2%). In six patients (3.8%) the P.A.S.-PORT had to be removed because of complications. The P.A.S.-PORT facilitated delivery of chemotherapy, parenteral nutrition, blood products, antibiotics, hydration, and blood sampling. It was demonstrated that the P.A.S.-PORT may be inserted and used with a low incidence of complications in gynecologic cancer patients.     

Country-specific cost-effectiveness of early intervention with budesonide in mild asthma.

Early intervention with budesonide is an effective strategy for mild persistent asthma, which has been shown to provide additional clinical benefits at a low incremental cost using USA cost data. The present authors analysed whether this strategy would be cost-effective using cost data for other countries. Based on the 3-yr prospective, randomised, double-blind inhaled Steroid Treatment As Regular Therapy (START) in early asthma study (comparing budesonide and placebo combined with usual asthma therapy), the cost-effectiveness was estimated separately for eight different countries, from both healthcare payer and societal perspectives, of adding budesonide to usual asthma therapy. Local unit costs were applied to data for the total trial population. Incremental cost-effectiveness ratios (ICER) were estimated as cost per symptom-free day (SFD) gained. Budesonide increased SFDs by an average of 14.1 days annually. From a healthcare payer perspective, budesonide would reduce the total cost of asthma care in Australia. In Sweden, Canada, France, Spain, UK, China and the USA, the ICER ranged from US$2.4-11.3 per SFD. From a societal perspective, budesonide would be cost-saving in Australia, Canada and Sweden. In conclusion, for countries where costs with budesonide are higher, the policy implication has to be determined by that health system's willingness to pay for an additional symptom-free day. However, where budesonide therapy increases symptom-free days and reduces total costs, the policy conclusion clearly favours early intervention.     

Potency variation of small-molecule chymase inhibitors across species

Chymases (EC 3.4.21.39) are mast cell serine proteinases that are variably expressed in different species and, in most cases, display either chymotryptic or elastolytic substrate specificity. Given that chymase inhibitors have emerged as potential therapeutic agents for treating various inflammatory, allergic, and cardiovascular disorders, it is important to understand interspecies differences of the enzymes as well as the behavior of inhibitors with them. We have expressed chymases from humans, macaques, dogs, sheep (MCP2 and MCP3), guinea pigs, and hamsters (HAM1 and HAM2) in baculovirus-infected insect cells. The enzymes were purified and characterized with kinetic constants by using chromogenic substrates. We evaluated in vitro the potency of five nonpeptide inhibitors, originally targeted against human chymase. The inhibitors exhibited remarkable cross-species variation of sensitivity, with the greatest potency observed against human and macaque chymases, with K_i values ranging from ∼0.4 to 72 nM. Compounds were 10-300-fold less potent, and in some instances ineffective, against chymases from the other species. The X-ray structure of one of the potent phosphinate inhibitors, JNJ-18054478, complexed with human chymase was solved at 1.8 Å resolution to further understand the binding mode. Subtle variations in the residues in the active site that are already known to influence chymase substrate specificity can also strongly affect the compound potency. The results are discussed in the context of selecting a suitable animal model to study compounds ultimately targeted for human chymase.