A randomised feasibility trial comparing needle fasciotomy with limited fasciectomy treatment for Dupuytren's contractures.

PURPOSE: The purpose of this study is to assess the feasibility of conducting a large, multicentre randomised controlled trial (RCT) comparing needle fasciotomy with limited fasciectomy for treatment of Dupuytren's contractures. DESIGN: The design of this study is a parallel, two-arm, multicentre, randomised feasibility trial with embedded QuinteT Recruitment Intervention. PARTICIPANTS: Patients aged 18 years or over who were referred from primary to secondary care for treatment of a hand with Dupuytren's contractures of one or more fingers of more than 30° at the metacarpophalangeal (MCP) and/or proximal interphalangeal (PIP) joints and well-defined cord(s). Patients were excluded if they had undergone previous Dupuytren's contracture surgery on the same hand. METHODS: Potential participants were screened for eligibility. Recruited participants randomised (1:1) to treatment with either needle fasciotomy or limited fasciectomy and followed-up for up to 6 months after treatment. Data on recruitment rates, completion of follow-up, and procedure costs were collected. Four patient reported outcome measures (PROMs) and objective outcome measures were collected before intervention and 6 weeks and 6 months afterwards. RESULTS: One hundred and fifty-three of 267 (57%) primary-care referrals for Dupuytren's contractures met the eligibility criteria for the study. Seventy-one of the 153 (46%) agreed to participate and were randomly allocated to treatment with needle fasciotomy or limited fasciectomy. Sixty-seven of these underwent their allocated treatment, two were crossovers from limited fasciectomy to needle fasciotomy, and two (both allocated limited fasciectomy) received no treatment. Fifty-nine participants (85%) completed 6-month follow-up PROMs. Participants felt the MYMOP, PEM and URAM PROMs allowed them to better describe how their treatment affected their hand function than the DASH PROM. The estimated costs of limited fasciectomy (in an operating theatre) and needle fasciotomy (in a clinic room) were £777 and £111 respectively. CONCLUSION: A large RCT comparing treatment of Dupuytren's contractures by needle fasciotomy and limited fasciectomy is feasible. Data from this study will help determine the number of sites and duration of recruitment required to complete an adequately powered RCT and will assist the selection of PROMs in future studies on the treatment of Dupuytren's contractures. (Level 1 feasibility study). TRIAL REGISTRATION: Trial registered with ISRCTN (registration number: ISRCTN11164292), date assigned - 28/08/2015.

Interactive binocular treatment (I-BiT) for amblyopia: results of a pilot study of 3D shutter glasses system.

PURPOSE: A computer-based interactive binocular treatment system (I-BiT) for amblyopia has been developed, which utilises commercially available 3D 'shutter glasses'. The purpose of this pilot study was to report the effect of treatment on visual acuity (VA) in children with amblyopia. METHODS: Thirty minutes of I-BiT treatment was given once weekly for 6 weeks. Treatment sessions consisted of playing a computer game and watching a DVD through the I-BiT system. VA was assessed at baseline, mid-treatment, at the end of treatment, and at 4 weeks post treatment. Standard summary statistics and an exploratory one-way analysis of variance (ANOVA) were performed. RESULTS: Ten patients were enrolled with strabismic, anisometropic, or mixed amblyopia. The mean age was 5.4 years. Nine patients (90%) completed the full course of I-BiT treatment with a mean improvement of 0.18 (SD=0.143). Six out of nine patients (67%) who completed the treatment showed a clinically significant improvement of 0.125 LogMAR units or more at follow-up. The exploratory one-way ANOVA showed an overall effect over time (F=7.95, P=0.01). No adverse effects were reported. CONCLUSION: This small, uncontrolled study has shown VA gains with 3 hours of I-BiT treatment. Although it is recognised that this pilot study had significant limitations-it was unblinded, uncontrolled, and too small to permit formal statistical analysis-these results suggest that further investigation of I-BiT treatment is worthwhile.

The role of the novel D2/beta2-agonist, Viozan (sibenadet HCl), in the treatment of symptoms of chronic obstructive pulmonary disease: results of a large-scale clinical investigation.

Viozan (sibenadet HCl, AR-C68397AA) is a novel dual D2 dopamine receptor, beta2-adrenoceptor agonist, developed specifically to treat the key symptoms of chronic obstructive pulmonary disease (COPD), breathlessness, cough and sputum. The dual sensory nerve modulation and bronchodilator effects of sibenadet have been demonstrated in initial dose-ranging studies of patients with COPD and large-scale clinical evaluation has now been completed. Sibenadet efficacy was determined by assessing symptomatic changes, as defined by the novel assessment tool, the Breathlessness, Cough and Sputum Scale (BCSS). The findings of two placebo-controlled studies are reported. These multicentre, double-blind, placebo-controlled studies recruited over 2000 patients with stable COPD, randomized to receive sibenadet (500 microg) or placebo, pressurized metered-dose inhaler (pMDI) (three times daily) for a period of 12 or 26 weeks. Diary cards were completed daily by patients throughout the study to record BCSS scores, peak expiratory flow (PEF), study drug and rescue bronchodilator usage, changes in concomitant medication and adverse events. The primary endpoints were defined as change from baseline to the final 4 weeks of the treatment period in mean BCSS total score, and forced expiratory volume in one second (FEV1) measured 1 hour after administration of the final dose of study drug and expressed as a percentage of the predicted FEV1. In addition, clinic assessments were made to determine changes in pulmonary function, health-related quality of life, perception of treatment efficacy and adverse events. Despite initial improvements in mean daily BCSS total scores in patients receiving sibenadet, the difference in the change from baseline to the final 4 weeks of the treatment period between the two treatment groups was neither statistically significant, nor considered to be of clinical importance. Although marked bronchodilator activity was seen early on with sibenadet treatment, the duration of effect diminished as the studies progressed. Sibenadet use was not associated with any safety concerns. These studies, utilizing the novel BCSS, have clearly illustrated that, despite initial symptomatic improvement with sibenadet therapy, this clinical benefit was not sustained over the course of the study.

Antibody-mediated stripping of CD4 from lymphocyte cell surface in patients with rheumatoid arthritis.

OBJECTIVE: Keliximab studies have provided evidence of the therapeutic potential of a non-depleting CD4 monoclonal antibody (mAb) in the treatment of rheumatoid arthritis (RA). Clenoliximab, an immunoglobulin G4 derivative of keliximab, has substantially reduced potential to deplete CD4 cells. In initial studies of clenoliximab, we investigated the hypothesis that the decrease in cell surface CD4 is the result of antibody-mediated stripping from the cell surface. METHODS: Patients received single or multiple intravenous infusions of clenoliximab as follows: 0.05, 0.2, 1, 5, 10 or 15 mg/kg (n=3-5/group); 150 or 350 mg weekly x 4; or 350 or 700 mg every other week x 2 (n=12/group). Blood was collected for up to 16 weeks and pharmacokinetic and pharmacodynamic assessments were conducted using immunoassay and flow cytometry. RESULTS: CD4 count was largely unaffected by clenoliximab treatment. Dose-dependent CD4 coating, down-modulation and stripping were observed. Maximal down-modulation persisted for an increasing period as dose increased, while soluble CD4-clenoliximab complexes accumulated. The amount of CD4 in soluble complex was as much as 20 times the amount of cell-associated CD4. For the same total dose, administration of higher doses, less frequently, resulted in pharmacodynamic profiles similar to those of lower doses administered more frequently. CONCLUSION: Decrease in the density of CD4 on the T-lymphocyte surface is caused by antibody-mediated stripping.

Pharmacokinetics and tissue distribution of SB-251353, a novel human CXC chemokine, after intravenous administration to mice.

The pharmacokinetics and tissue distribution of SB-251353, a novel truncated form of the human CXC chemokine growth-related gene product beta, were studied after intravenous administration to the mouse (0.1--250 mg/kg). At the lowest dose, the clearance exceeded blood flow to the kidney. As the dose increased, clearance approached the glomerular filtration rate in the mouse. Clearance of this chemokine may be mediated by its pharmacologic receptor, CXCR2, via endocytosis with subsequent lysosomal degradation, as has been observed for several growth and hematopoietic factors. Apparent distribution volumes were high (> or =1 l/kg). Moderate binding to the Duffy antigen/receptor for chemokines on erythrocytes was observed. Consistent with the pharmacokinetic analysis, microscopic autoradiography showed uptake into renal proximal tubule epithelial cells. Limited excretion of SB-251353 in the urine (<2%) was consistent with catabolism of the chemokine in the tubules. Binding to hepatic sinusoids and connective tissue in the dermis was observed. This possibly reflected interaction of SB-251353 with heparin sulfate proteoglycan and may explain the large distribution volumes. This first study of the disposition of a chemokine provides insight into mechanism of action and physiological factors that may influence chemokine pharmacodynamics.

Anti-psychotic drug prescribing trends in primary care in Scotland 1994-97.

OBJECTIVE: To describe trends in the use of anti-psychotic drugs prescribed in Primary Care in Scotland. DESIGN: Information on prescription numbers and costs were obtained from the Pharmacy Prescribing Division. SETTING: Scotland 1994-1997. Results Prescriptions for anti-psychotic drugs in Primary Care in Scotland increased by 28% in the period April 1994-December 97. In the same period, quarterly costs increased from 523,971 Pounds to 1,339,215 Pounds, an increase of 155%. Ninety per cent of the increase is accounted for by use of the five drugs risperidone, sertindole, olanzapine, clozapine and quetiapine. Health Board areas vary markedly in their uptake of the new drugs. CONCLUSION: The use of new anti-psychotic drugs in Scotland represents a substantial additional investment in mental health care. This has happened with little discussion or debate. Scotland needs to make explicit decisions on the place of newer anti-psychotics in treatment, and on the balance between investing in these drugs and investing in other aspects of mental health services.

Phototimer setup for CR imaging.

A study was performed to investigate the feasibility of using the standard deviation (sigma) of the pixel values in a computed radiography (CR) image and a measure of the median incident exposure on the imaging plate (IP) as parameters for setting up phototimers in a CR system. Slabs of Lucite 4-, 6-, and 8-in.-thick were imaged with a CR system at 70, 90, and 125 kVp at various mA s values both with grid and without grid. Incident IP exposures were measured with an ionization chamber. Images were analyzed on a workstation. The sigma's in the "flat field" images were found to be approximately related to the mean incident exposure E by the relationship: sigma is proportional to E(-1/2), indicating the quantum-noise-limited operation of the system. Derived relationships between the reading sensitivity of the (IP) reader (S number) and sigma can be used to obtain images with a specific noise level. At our institution, where a 400 speed screen-film system is used for general radiography and 200 speed for chest radiography, radiologists generally find CR image quality acceptable when sigma < or = 11 (S< or =400) for general radiography (50-90 kVp), and sigma < or =8 (S< or =200) for chest radiography (125 kVp). However, factors other than the amount of x-ray quanta that form the useful image, such as the image processing mode and the amount of collimation, may affect both the sensitivity value and the image quality.

PD 90780, a non peptide inhibitor of nerve growth factor's binding to the P75 NGF receptor.

Nerve growth factor is a peptide that supports the survival and differentiation of discrete neuronal populations in the peripheral and central nervous systems. NGF binds to both trkA, a tyrosine kinase receptor, and to the p75 nerve growth factor receptor, a protein lacking a consensus signalling sequence. We have identified a substituted pyrazoloquinazolinone, PD 90780, which inhibits binding of nerve growth factor to the p75 receptor. This inhibition of binding occurs due to PD 90780 binding to nerve growth factor, not to the p75 receptor. This compound may be useful in identifying the region(s) of nerve growth factor involved in binding to the p75 receptor and in clarifying the role of p75 receptor in the actions of the neurotrophins.

Preclinical pharmacokinetic evaluation of the respiratory syncytial virus-specific reshaped human monoclonal antibody RSHZ19.

A preclinical evaluation of RSHZ19, a respiratory syncytial virus-specific reshaped human monoclonal antibody (IgG1 framework), has included pharmacokinetic studies in rats, adult cynomolgus macaques, and infant baboons after intravenous (iv), subcutaneous, or intramuscular (im) administration. After iv administration to rats and monkeys (1 mg/kg dose), a biphasic decline in plasma concentration was observed. The dominant terminal phase was characterized by an 11-day half-life in rats and a 21- to 24-day half-life in monkeys. Plasma clearances of 0.3 ml/hr/kg in the rat and 0.1-0.2 ml/hr/kg in the monkey were estimated. In the macaque, based on area under the curve, no evidence of significant nonlinearity in the pharmacokinetics was observed over a 200-fold dose range (1-200 mg/kg). In rat and monkey, absorption after extravascular administration was rapid relative to elimination (apparent half-lives < or = 24 hr), and bioavailability was high (> or = 82%). After iv or im administration to macaques (> or = 40 mg/kg), 1 of 3 animals in each group developed anti-RSHZ19 antibodies, and this resulted in rapid elimination of RSHZ19 from plasma. After the administration of a second im dose to macaques, no additional animals developed anti-RSHZ19 antibodies. Multiple-dose iv kinetics (5-day repeat dose) in infant baboons were modeled accurately by adult macaque data, suggesting that these species handled RSHZ19 similarly. The pharmacokinetic characteristics of RSHZ19 should support a convenient regimen for treatment or prophylaxis of human respiratory syncytial virus infection.

Renal catabolism of recombinant human soluble CD4 after intravenous administration to male Sprague-Dawley rats.

Recombinant soluble CD4 (sT4; mol. wt. 45,000) has been studied extensively in Sprague-Dawley rats, and substantial renal processing has been indicated. In rats and monkeys, renal filtration and precipitation of sT4 in the distal nephron caused tubular cast nephropathy. Intravenous pharmacokinetics in the rat demonstrated that sT4 plasma clearance exceeded the glomerular filtration rate. In an effort to determine quantitatively the extent to which kidney and other tissues were responsible for sT4 catabolism, sT4 was labeled with trace amounts of dilactitol-[125I]tyramine and administered intravenously to Sprague-Dawley rats (1 mg/kg). Dilactitol-tyramine accumulates in lysosomes at the site of protein degradation. It has been used primarily to demonstrate hepatic catabolism of endogenous proteins. Blood samples were drawn for pharmacokinetic analysis, and selected tissues were removed to assess radiolabel distribution. Comparison of pharmacokinetic parameters derived from total plasma radiolabel and functional ELISA were not significantly different. Thus, covalent modification of sT4 with dilactitol-tyramine did not appreciably change the rate of clearance. From 3 to 24 hr after intravenous administration, 81.5 +/- 0.1% of the total administered radioactivity was found in the kidney. Approximately 8-13% of the administered dose was recovered in the liver. Macroscopic autoradiography of the kidney demonstrated accumulation of radiolabel in the cortex. Light microscopic autoradiography of the kidney following intravenous administration of directly radioiodinated sT4 confirmed cortical processing, because radiolabel was located primarily in epithelial cells of P1 and P2 segments of the proximal tubule after low intravenous doses (0.4-4 mg/kg). At 40 mg/kg, distal tubules and cortical collecting ducts were labeled as well. Thus, sT4 was filtered by the glomerulus, reabsorbed in the proximal tubule, and degraded in the lysosomal compartment.

Evaluation of the protective efficacy of reshaped human monoclonal antibody RSHZ19 against respiratory syncytial virus in cotton rats.

Reshaped human MAb RSHZ19, which is specific for the surface fusion protein of respiratory syncytial virus (RSV) is in clinical development for the prevention and treatment of RSV-induced disease in human infants. The current studies profile lung virus clearance and evaluate lung histopathology in MAb-treated, RSV-infected cotton rats, a well characterized model of RSV infection. The highest dose of this MAb (10 mg/kg) administered parenterally 24 h before infection decreased subgroup A or B RSV lung titers to below detectable levels (> or = 2.3 log10 reduction), and significantly reduced lung virus titers (> or = 2.0 log10 reduction) when administered 96 h postinfection. Prophylactic administration of 10 mg/kg RSHZ19 was significantly more protective than 1000 mg/kg conventional human immune serum globulin (HSIg), and protective serum-neutralizing titers in MAb-treated animals (1:32, which correlated with approximately 40 micrograms/ml determined by anti-idiotype ELISA) were significantly lower than those reported previously for HSIg or for convalescent human serum (1:200-1:400). MAb concentration in lung lavages was determined by ELISA to be approximately 1% of the serum MAb concentration, but was not detectable by neutralization assay. The degree of lung histopathology in MAb-treated cotton rats was proportional to lung virus titer, and inversely proportional to the RSHZ19 dose administered. There was no evidence of exacerbated disease in the lungs of MAb-treated animals. These studies thus support the potential clinical utility of RSHZ19 MAb in the prevention and treatment of RSV-induced disease in humans.

Purification of acetylcholinesterase by tacrine affinity chromatography.

Acridine ligand affinity chromatography is an effective means of acetylcholinesterase (AChE) purification. However, the synthesis of these resins is laborious and expensive. We have developed an acridine ligand affinity resin that is easy to produce, inexpensive, and selective for AChE over butyrylcholinesterase. The resin is produced in a single synthetic step by attaching the aminoacridine tacrine to epoxy-activated Sepharose. AChE from bovine serum (59% yield), Torpedo electric organ (27-60% yield), and two commercial sources of eel AChE (> 92% yield) is purified using the affinity resin. One commercial source of eel AChE contains two proteins with molecular weights of 80 and 55 kDa upon purification, while two proteins with molecular weights of 55 and 25 kDa are isolated from the other commercial source, presumably representing degraded AChE. The degradation state of the commercially available eel AChE preparations did not influence their specific activities. The isolation of AChE from bovine serum results in a single 80-kDa protein. However, butyrylcholinesterase is not purified from the serum. Using the tacrine affinity resin, and 80-kDa AChE, solubilized from Torpedo electric organ membranes by protease digestion, can also be purified. Velocity sedimentation analysis of the Torpedo AChE reveals that the molecular forms isolated are either tetrameric or asymmetric when solubilized by collagenase or trypsin, respectively. Overall, the tacrine affinity resin which is simple and inexpensive to produce allows for the selective isolation of AChE from diverse biological matrices.

Solarization in clinical imaging.

X-ray exposure levels at which solarization occurs were determined for a new screen-film system and its predecessor, both from the same manufacturer and both with a speed class of 400. Solarization (contrast reversal [lead markers imaged as black on a lighter back-ground]) was clearly evident with the new system at a cassette exposure level of 132 mR (3.4 x 10(-5) C/kg). No solarization was exhibited by the old system even at five times this exposure. In rare cases, solarization can obscure bone and soft-tissue detail, thereby degrading the diagnostic accuracy of the radiograph.

Investigation of the substrate binding and catalytic groups of the P-C bond cleaving enzyme, phosphonoacetaldehyde hydrolase.

Kinetic studies with substrate analogs and group-directed chemical modification agents were carried out for the purpose of identifying the enzyme-substrate interactions required for phosphonoacetaldehyde (P-Ald) binding and catalyzed hydrolysis by P-Ald hydrolase (phosphonatase). Malonic semialdehyde (Ki = 1.6 mM), phosphonoacetate (Ki = 10 mM), phosphonoethanol (Ki = 10 mM), and fluorophosphate (Ki = 20 mM) were found to be competitive inhibitors of the enzyme but not substrates. Thiophosphonoacetaldehyde and acetonyl phosphonate underwent phosphonatase-catalyzed hydrolysis but at 20-fold and 140-fold slower rates, respectively, than did P-Ald. In the presence of NaBH4, acetonyl-phosphonate inactivated phosphonatase at a rate exceeding that of its turnover. Sequence analysis of the radiolabeled tryptic peptide generated from [3-3H]acetonylphosphonate/NaBH4-treated phosphonatase revealed that Schiff base formation had occurred with the catalytic lysine. From the Vm/Km and Vm pH profiles for phosphonatase-catalyzed P-Ald hydrolysis, an optimal pH range of 6-8 was defined for substrate binding and catalysis. The pH dependence of inactivation by acetylation of the active site lysine with acetic anhydride and 2,4-dinitrophenyl acetate evidenced protonation of the active site lysine residue as the cause for activity loss below pH 6. The pH dependence of inactivation of an active site cysteine residue with methyl methanethiol-sulfonate indicated that deprotonation of this residue may be the cause for the loss of enzyme activity above pH 8.

Investigation of the Bacillus cereus phosphonoacetaldehyde hydrolase. Evidence for a Schiff base mechanism and sequence analysis of an active-site peptide containing the catalytic lysine residue.

Reaction of Bacillus cereus phosphonoacetaldehyde hydrolase (phosphonatase) with phosphonoacetaldehyde or acetaldehyde in the presence of NaBH4 resulted in complete loss of enzymatic activity. Treatment of phosphonatase with NaBH4 in the absence of substrate or product had no effect on catalysis. Inactivation of phosphonatase with [3H]NaBH4 and phosphonoacetaldehyde, NaBH4 and [14C]acetaldehyde, or NaBH4 and [2-3H]phosphonoacetaldehyde produced in each instance radiolabeled enzyme. The nature of the covalent modification was investigated by digesting the radiolabeled enzyme preparations with trypsin and by separating the tryptic peptides with HPLC. Analysis of the peptide fractions revealed that incorporation of the 3H- or 14C-radiolabel into the protein was reasonably selective for an amino acid residue found in a peptide fragment observed in each of the three trypsin digests. Sequence analysis of the 3H-labeled peptide fragment isolated from the digest of the [2-3H]phosphonoacetaldehyde/NaBH4-treated enzyme identified N epsilon-ethyllysine as the radiolabeled amino acid. The ability of the phosphonatase competitive inhibitor (Ki = 230 +/- 20 microM) acetonylphosphonate to protect the enzyme from phosphonoacetaldehyde/NaBH4-induced inactivation suggested that the reactive lysine residue is located in the enzyme active site. Comparison of the relative effectiveness of phosphonoacetaldehyde and acetaldehyde as phosphonatase inactivators showed that the N-ethyllysine imine that is reduced by the NaBH4 is derived from the corresponding N-(phosphonoethyl) imine. On the basis of these findings, a catalytic mechanism for for phosphonatase is proposed in which phosphonoacetaldehyde is activated for P-C bond cleavage by formation of a Schiff base with an active-site lysine. Accordingly, an N-ethyllsysine enamine rather than the high-energy acetaldehyde enolate anion is displaced from the phosphorus.