Effects of ibudilast on oxycodone-induced analgesia and subjective effects in opioid-dependent volunteers.

Opioid-induced glial activation is hypothesized to contribute to the development of tolerance to opioid-induced analgesia. This inpatient, double-blind, placebo-controlled, within-subject and between-groups pilot study investigated the dose-dependent effects of ibudilast, a glial cell modulator, on oxycodone-induced analgesia. Opioid-dependent volunteers were maintained on morphine (30mg, PO, QID) for two weeks and received placebo ibudilast (0mg, PO, BID) during the 1st week (days 1-7). On day 8, participants (N=10/group) were randomized to receive ibudilast (20 or 40mg, PO, BID) or placebo for the remainder of the study. On days 4 (week 1) and 11 (week 2), the analgesic, subjective, and physiological effects of oxycodone (0, 25, 50mg/70kg, PO) were determined. Analgesia was measured using the cold pressor test; participants immersed their hand in cold water (4°C) and pain threshold and pain tolerability were recorded. Oxycodone decreased pain threshold and tolerability in all groups during week 1. During week 2, the placebo group exhibited a blunted analgesic response to oxycodone for pain threshold and subjective pain ratings, whereas the 40mg BID ibudilast group exhibited greater analgesia as measured by subjective pain ratings (p≤0.05). Oxycodone also increased subjective drug effect ratings associated with abuse liability in all groups during week 1 (p≤0.05); ibudilast did not consistently affect these ratings. These findings suggest that ibudilast may enhance opioid-induced analgesia. Investigating higher ibudilast doses may establish the utility of pharmacological modulation of glial activity to maximize the clinical use of opioids.

Abuse liability of oxycodone as a function of pain and drug use history.

The relationship between pain and prescription opioid abuse is poorly understood. Determining whether a patient is seeking additional opioid medications in order to alleviate pain or to abuse the drugs can be difficult. The present study was designed to evaluate two variables that may influence the abuse liability of opioids: drug use history and the presence or absence of experimentally induced pain. Eighteen healthy participants completed this outpatient study. One group was abusing prescription opioids (N=9) and one group had used prescription opioids medically but did not abuse them (N=9). All participants completed twelve sessions during which the effects of orally delivered oxycodone (0, 15, 30mg/70kg, PO) were examined. One dose was tested per day under double-blind conditions and sessions were separated by at least 48h. During the first "sample" session each week, participants were given $10 and the dose that was available later that week. During the second "choice" session, participants could self-administer either money or the previously sampled dose. Six sessions involved repeated hand immersions in cold water (4 degrees C) and six sessions involved immersions in warm water (37 degrees C). Most of the positive subjective effects of oxycodone were similar between the groups, but oxycodone self-administration significantly differed between groups. Non-abusers self-administered active doses of oxycodone only when they were in pain while abusers self-administered oxycodone regardless of the pain condition. These data suggest that an assessment of the reinforcing effects of opioids may be a sensitive method for differentiating opioid abusers from non-abusers.

Recombinant human antibody single chain variable fragments reactive with Candida albicans surface antigens.

A combinatorial phage display library expressing human immunoglobulin heavy and light chain variable regions was used to identify phage clones capable of binding to the surface of Candida albicans blastoconidia. Single chain antibody variable fragments (scFv) derived from three clones detected C. albicans antigens by indirect immunofluorescence assay (IFA), enzyme-linked immunosorbent assay (ELISA), and Western blotting. The antigens detected were conserved among different strains of C. albicans and several other Candida species. Two scFv clones detected antigens specifically expressed by C. albicans blastoconidia; the third detected antigens in both blastoconidia and filamentous forms of C. albicans. The antigens containing the epitopes recognized by all three scFv could be extracted from blastoconidia by dithiothreitol, suggesting attachment to the cell wall via sulfhydryl bonds. Epitope detection by the scFv was sensitive to treatment of C. albicans blastoconidia with sodium periodate, but not proteinase K, indicating the cognate epitopes were composed of carbohydrate. Antigenic determinants for each of the three scFv were detected by immunohistochemical staining of skin sections from a model of cutaneous candidiasis, demonstrating expression in vivo. Through selection for the ability to bind intact organisms, the phage display system provides a means to rapidly identify monoclonal binding ligands to Candida surface antigens. Being entirely human, mature antibodies generated from the scFv have potential utility in the treatment of candidiasis.

Concurrent substance use and outcome in combined behavioral and naltrexone therapy for opiate dependence.

UNLABELLED: The effect of concurrent nonopiate drug use on outcome of treatment for opiate dependence. METHOD: Forty-seven opiate-dependent patients received a 6-month course of outpatient treatment with naltrexone and cognitive-behavioral therapy (behavioral naltrexone therapy, BNT) at a university-based research clinic. Opiate-negative urines and naltrexone ingestion were rewarded with monetary vouchers. Abstinence from other drugs was encouraged verbally, but no contingencies were placed on nonopiate drug use. The proportions of all urines (collected twice weekly) positive for cocaine, cannabis, and benzodiazepines over the course of treatment were evaluated as predictors of outcome of opiate dependence treatment, as measured by proportion of opiate-positive urines, days retained in treatment, and proportion of naltrexone doses taken, using Pearson product moment correlations and one-way analysis of variance (ANOVA). RESULTS: The majority of patients (78%) used a nonopiate drug at least once during the trial. There were no significant correlations between concurrent drug use measures and opiate dependence treatment outcomes, indicating no simple linear relationship between these measures. However, when concurrent drug use was trichotomized into abstinent, intermittent, and heavy use groups, groups with intermittent use had superior outcome compared to both abstinent and heavy use groups in several contrasts. CONCLUSIONS: Intermittent use of nonopiate drugs is common during outpatient treatment for opiate dependence and may be a favorable prognostic indicator. This may support a "harm reduction" approach as opposed to a strict abstinence-oriented approach. Further research is needed to identify the optimal therapeutic stance toward other drug use during treatment for opiate dependence.

Attention deficit/hyperactivity disorder and substance abuse. Diagnostic and therapeutic considerations.

Patterns of association between attention deficit hyperactivity disorder (ADHD) and substance-use disorders are considered. Recent investigations have found that up to 50% of individuals with continuing ADHD symptoms have a substance-use disorder. ADHD appears to represent an independent risk factor for substance abuse. We review clinical challenges posed by the diagnosis of ADHD in substance-abusing populations. Nicotine dependence is also substantially more common among adults with ADHD (40%) than in the general population (26%). While several classes of substances of abuse may ameliorate various symptoms of ADHD, individuals with ADHD may also be vulnerable to substance use because of poor judgment or impulsive behavior in social settings. Evidence is reviewed from genetic studies examining the role of the dopamine D2 (DRD2) gene in the etiology of ADHD. The presence of ADHD may affect the course of adolescent substance abuse in several ways: predicting earlier age of onset, longer duration of substance-use disorder, and progression of alcohol abuse to another drug-use disorder. Individuals with ADHD have been noted to have a shorter interval between the onsets of drug abuse and drug dependence. Such individuals are also at greater risk for treatment failure, as their disruptive behaviors interfere with treatment access and response. Lastly, we review advances in pharmacotherapeutic agents used for treating ADHD and consider the impact of these interventions on comorbid substance-use disorders. We suggest promising areas of focus for clinical research trials targeting the subpopulation of substance abusers with concurrent ADHD.

Dose escalation in non-small-cell lung cancer using three-dimensional conformal radiation therapy: update of a phase I trial.

PURPOSE: High-dose radiation may improve outcomes in non-small-cell lung cancer (NSCLC). By using three-dimensional conformal radiation therapy and limiting the target volume, we hypothesized that the dose could be safely escalated. MATERIALS AND METHODS: A standard phase I design was used. Five bins were created based on the volume of normal lung irradiated, and dose levels within bins were chosen based on the estimated risk of radiation pneumonitis. Starting doses ranged from 63 to 84 Gy given in 2.1-Gy fractions. Target volumes included the primary tumor and any nodes >or= 1 cm on computed tomography. Clinically uninvolved nodal regions were not included purposely. More recently, selected patients received neoadjuvant cisplatin and vinorelbine. RESULTS: At the time of this writing, 104 patients had been enrolled. Twenty-four had stage I, four had stage II, 43 had stage IIIA, 26 had stage IIIB, and seven had locally recurrent disease. Twenty-five received chemotherapy, and 63 were assessable for escalation. All bins were escalated at least twice. Although grade 2 radiation pneumonitis occurred in five patients, grade 3 radiation pneumonitis occurred in only two. The maximum-tolerated dose was only established for the largest bin, at 65.1 Gy. Dose levels for the four remaining bins were 102.9, 102.9, 84 and 75.6 Gy. The majority of patients failed distantly, though a significant proportion also failed in the target volume. There were no isolated failures in clinically uninvolved nodal regions. CONCLUSION: Dose escalation in NSCLC has been accomplished safely in most patients using three-dimensional conformal radiation therapy, limiting target volumes, and segregating patients by the volume of normal lung irradiated.

Defining the atherogenicity of large and small lipoproteins containing apolipoprotein B100.

Apo-E-deficient apo-B100-only mice (APOE:(-/-)APOB:(100/100)) and LDL receptor-deficient apo-B100-only mice (LDLR:(-/-)APOB:(100/100)) have similar total plasma cholesterol levels, but nearly all of the plasma cholesterol in the former animals is packaged in VLDL particles, whereas, in the latter, plasma cholesterol is found in smaller LDL particles. We compared the apo-B100-containing lipoprotein populations in these mice to determine their relation to susceptibility to atherosclerosis. The median size of the apo-B100-containing lipoprotein particles in APOE:(-/-)APOB:(100/100) plasma was 53.4 nm versus only 22.1 nm in LDLR:(-/-)APOB:(100/100) plasma. The plasma levels of apo-B100 were three- to fourfold higher in LDLR:(-/-)APOB:(100/100) mice than in APOE:(-/-)APOB:(100/100) mice. After 40 weeks on a chow diet, the LDLR:(-/-)APOB:(100/100) mice had more extensive atherosclerotic lesions than APOE:(-/-)APOB:(100/100) mice. The aortic DNA synthesis rate and the aortic free and esterified cholesterol contents were also higher in the LDLR:(-/-)APOB:(100/100) mice. These findings challenge the notion that all non-HDL lipoproteins are equally atherogenic and suggest that at a given cholesterol level, large numbers of small apo-B100-containing lipoproteins are more atherogenic than lower numbers of large apo-B100-containing lipoproteins.

Overall survival after prostate-specific-antigen-detected recurrence following conformal radiation therapy.

PURPOSE: To study the significance, in terms of overall and cause-specific survival, of biochemical failure after conformal external-beam radiation therapy (RT) for prostate cancer. METHODS AND MATERIALS: Of the 1844 patients in the Radiation Oncology prostate cancer database, 718 were deemed eligible. Patients excluded were those with N1 or M1 disease, those treated after radical prostatectomy, those who received hormone therapy before radiation therapy, and those who died, failed clinically, or had no PSA response in the first 6 months after RT. Patients included were required to have a minimum of 2 post-RT PSAs separated by at least 1 week. Biochemical relapse was defined as 3 consecutive PSA rises. This resulted in 154 patients with biochemical failure. Survival was calculated from the third PSA elevation. The rate of rise of PSA was calculated by fitting a regression line to the four rising PSAs on a ln PSA vs. time plot. RESULTS: There were 41 deaths among the 154 patients with failure in 23 of the 41 due to prostate cancer. The overall survival after failure was 58% at 5 years, while the cause-specific failure was 73% at 5 years. Among the 154 failures, several factors were evaluated for an association with overall survival: age at failure, pre-RT PSA, PSA at second rise, PSA nadir, time from RT to failure, time to nadir, Gleason score, T-stage, and rate of rise, both from the nadir and from the beginning of the rise. None of these factors were significantly associated with an increased risk of death. As expected, the group of patients with biochemical failure have significantly worse prognostic factors than those without biochemical failure: median pre-RT PSA 15.9 vs. 9.0 (p < 0.001), and Gleason score of 7 or greater for 48% of subjects vs. 40% (p = 0.1). Relative PSA rise and slope of ln PSA vs. time were associated with cause-specific mortality (p < 0.001 and p = 0.007, respectively). CONCLUSION: Overall survival after conformal radiotherapy for prostate cancer remains high 5 years after biochemical failure. This high survival rate occurs even though the group of patients with biochemical failure has worse than average adverse preradiation prognostic factors. Thus, although biochemical failure can identify patients who have recurrent disease after RT, the ultimate relationship between this endpoint and death remains to be better defined.

Power Doppler imaging: initial evaluation as a screening examination for carotid artery stenosis.

PURPOSE: To evaluate power Doppler imaging as a possible screening examination for carotid artery stenosis. MATERIALS AND METHODS: In the principal pilot study, a prospective, blinded comparison of power Doppler imaging with duplex Doppler imaging, the reference-standard method, was conducted in 100 consecutive patients routinely referred for carotid artery imaging at a large, private multispecialty clinic. In the validation pilot study, a prospective, blinded comparison of power Doppler imaging with digital subtraction angiography, the reference-standard method, was conducted in 20 consecutive patients routinely referred at a teaching hospital. Using conservative assumptions, the authors performed cost-effectiveness analysis. RESULTS: Power Doppler imaging produced diagnostic-quality images in 89% of patients. When the images of the patients with nondiagnostic examinations were regarded as positive, power Doppler imaging had an area under the receiver operating characteristic curve, A(z), of 0.87, sensitivity of 70%, and specificity of 91%. The validation study results were very similar. The cost-effectiveness of screening and, as indicated, duplex Doppler imaging as the definitive diagnostic examination and endarterectomy was $47,000 per quality-adjusted life-year. CONCLUSION: The A(z) value for power Doppler imaging compares well with that for mammography, a generally accepted screening examination, and with most other imaging examinations. Power Doppler imaging is likely to be a reasonably accurate and cost-effective screening examination for carotid artery stenosis in asymptomatic populations.

Advances in non-nicotine pharmacotherapy for smoking cessation.

Progress in understanding the pharmacological nature of tobacco addiction, along with the modest success rates achieved by the nicotine replacement therapies, has provided the major impetus for the development of non-nicotine drugs as smoking cessation aids. This article reviews evidence from controlled trials of several non-nicotine medications for the treatment of nicotine dependence. Clonidine was the first non-nicotine medication to show efficacy for smoking cessation in multiple studies, but its effect was found to be limited at best. Positive results across several trials have been consistently demonstrated for amfebutamone (bupropion). Encouraging results have also been observed for nortriptyline and moclobemide. Studies of combined treatments using non-nicotine medications (amfebutamone, mecamylamine, oral dextrose) with nicotine replacement therapy suggest increased efficacy relative to treatments using one or the other treatment strategy alone. Thus, available evidence indicates that non-nicotine drug treatments offer a promising panoply of therapeutic strategies for the addicted smoker.

Patient knowledge and educational needs in irritable bowel syndrome.

OBJECTIVE: Educating patients with irritable bowel syndrome (IBS) about their disorder may promote a strong physician-patient interaction, is a recommended approach for treating mild IBS and may reduce healthcare use. Our aim was to identify the information needs, levels and associated factors in IBS, and to contrast this with patients with inflammatory bowel disease (IBD). DESIGN: Seventy adult IBS patients (Rome criteria) were prospectively recruited, together with 82 ulcerative colitis (UC) and 60 Crohn's disease (CD) patients. Demographic data, clinical data, and anxiety and depression scores (HAD scale) were recorded. Patients rated their perceived levels of disease knowledge and satisfaction with their knowledge level on visual analogue scales. Qualitative data on disease information needs were obtained by an open-ended question. SETTING: Gastroenterology out-patient clinic. RESULTS: The majority of IBS patients (77%; n = 54) and over half of IBD patients (56%; n = 79) required further information about their disease. The primary issues for IBS patients were bowel cancer risk and diet. Queries about medications ranked top for UC, while prognosis and cancer risk jointly ranked top for CD. In the IBS group, 27% rated their knowledge as < 25 out of 100 compared to 10% of IBD patients. The perceived level of knowledge in IBS was significantly negatively associated with length of hospital consulting (r(s) = -0.32; P = 0.04). CONCLUSION: Most IBS patients feel insufficiently informed, particularly in relation to risk of serious disease and role of diet. Educating IBS patients about their disorder may play a role in reducing healthcare use.

Bacterial supplementation in the irritable bowel syndrome. A randomised double-blind placebo-controlled crossover study.

BACKGROUND: Symptoms of at least a subgroup of patients with irritable bowel syndrome may be associated with an alteration in gut flora. Studies on bacterial based therapy have yielded mixed results. AIMS: To determine if oral administration of the probiotic Lactobacillus casei strain GG under randomized placebo controlled conditions improves symptoms in irritable bowel syndrome patients with bloating related symptoms. PATIENTS: A total of 25 patients with clinically confirmed irritable bowel syndrome (Rome criteria) were enrolled in the study. METHODS: This was a randomised double-blind placebo-controlled crossover trial. Lactobacillus GG was administered as enterocoated tablets constituting a daily dosage of 10(10) colony forming units. Symptoms were assessed by daily symptom diaries and periodic questionnaires. RESULTS: Twenty-four patients were randomised; 19 (80%) female, mean age 40 years (range 24-60), mean duration of symptoms 4.9 years (range 0.5-18). Nineteen (80%) patients completed the study. No significant differences were found between Lactobacillus casei strain GG and placebo mean symptom scores for pain, urgency or bloating. A trend was noted, however, for a reduction in the number of unformed bowel motions on Lactobacillus casei strain GG treatment for patients with diarrhoea. CONCLUSIONS: Lactobacillus casei strain GG alone did not significantly improve symptoms in this irritable bowel syndrome subgroup. A "diarrhoea predominant" subgroup may warrant further investigation.

Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice.

A deficiency in microsomal triglyceride transfer protein (MTP) causes the human lipoprotein deficiency syndrome abetalipoproteinemia. However, the role of MTP in the assembly and secretion of VLDL in the liver is not precisely understood. It is not clear, for instance, whether MTP is required to move the bulk of triglycerides into the lumen of the endoplasmic reticulum (ER) during the assembly of VLDL particles. To define MTP's role in hepatic lipoprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfortunately, achieving our objective was thwarted by a lethal embryonic phenotype. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knockout mice. Inactivating the Mttp gene in the liver caused a striking reduction in VLDL triglycerides and large reductions in both VLDL/LDL and HDL cholesterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only approximately 20%. Histologic studies in liver-specific knockout mice revealed moderate hepatic steatosis. Ultrastructural studies of wild-type mouse livers revealed numerous VLDL-sized lipid-staining particles within membrane-bound compartments of the secretory pathway (ER and Golgi apparatus) and few cytosolic lipid droplets. In contrast, VLDL-sized lipid-staining particles were not observed in MTP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and there were numerous cytosolic fat droplets. We conclude that MTP is essential for transferring the bulk of triglycerides into the lumen of the ER for VLDL assembly and is required for the secretion of apo B-100 from the liver.

Use of segmental boost fields in the irradiation of inguinal lymphatic nodes.

En face electron fields to boost inguinal lymphatics have been used by oncologists for many years. With the introduction of multileaf collimators (MLC) and independent jaws, the practice of creating segmental fields to boost areas of interest has expanded. Typical anterior-posterior opposing field treatment of the pelvis may now be enhanced to include additional anterior segments to boost lymphatic tissue at a predetermined depth. This report illustrates the clinical implementation of one such segmental boost technique. Computer generated isodose plans utilize manual contour and CT-generated data for analysis of inguinal lymphatic depths. Potential areas of field overlap are discussed as well as the use of combined 6 and 15 MV photon energies to reduce areas of inhomogeneous dose. Technical details associated with MLC field size limits and other clinical factors are also discussed in relationship to smooth treatment delivery.

Strategic decision making on shifting sands.

Strategic decision making in today's health care marketplace is very challenging. In the past, strategic plans were written for five to ten years. With the rapidly changing environment, planning for more than two years is difficult. It is critical for organizations to set a pathway for success. However, the organization needs to be able to respond quickly to environmental changes and take advantage of opportunities. The article presents a case study on a relatively new organization that has ambitious strategic goals. It discusses the decision-making process on the ways to enter a new marketplace, including the key factors assessed by the organization and their implications.

A randomized, placebo-controlled dose-comparison trial of haloperidol for psychosis and disruptive behaviors in Alzheimer's disease.

OBJECTIVE: The goal of this study was to compare the efficacy and side effects of two doses of haloperidol and placebo in the treatment of psychosis and disruptive behaviors in patients with Alzheimer's disease. METHOD: In a 6-week random-assignment, double-blind, placebo-controlled trial (phase A), haloperidol, 2-3 mg/day (standard dose), and haloperidol, 0.50-0.75 mg/day (low dose), were compared in 71 outpatients with Alzheimer's disease. For the subsequent 6-week double-blind crossover phase (phase B), patients taking standard- or low-dose haloperidol were switched to placebo, and patients taking placebo were randomly assigned to standard- or low-dose haloperidol. RESULTS: For the 60 patients who completed phase A, standard-dose haloperidol was efficacious and superior to both low-dose haloperidol and placebo for scores on the Brief Psychiatric Rating Scale psychosis factor and on psychomotor agitation. Response rates according to three sets of criteria were greater with the standard dose (55%-60%) than the low dose (25%-35%) and placebo (25%-30%). The advantage of standard dose over low dose was replicated in phase B. In phase A, extrapyramidal signs tended to be greater with the standard dose than in the other two conditions, primarily because of a subgroup (20%) who developed moderate to severe signs. Low-dose haloperidol did not differ from placebo on any measure of efficacy or side effects. CONCLUSIONS: The results indicated a favorable therapeutic profile for haloperidol in doses of 2-3 mg/day, although a subgroup developed moderate to severe extrapyramidal signs. A starting dose of 1 mg/day with gradual, upward dose titration is recommended. The narrow therapeutic window observed with haloperidol may also apply to other neuroleptics used in Alzheimer's disease patients with psychosis and disruptive behaviors.

Endothelial cell monolayers as a model system to investigate dengue shock syndrome.

Monolayers of the human endothelial cell line ECV304 were compared with those from primary endothelial cells from human umbilical cord veins (HUVEC) for potential use as an assay system to investigate vasoactive mediator levels in dengue viral infections. Permeability increases were induced in ECV304 monolayers which were more easily reproduced than in primary cells. The cell line monolayers were considerably more stable which allowed multiple consecutive assays to be undertaken on the same monolayers. Permeability responsiveness was maximal at 2 and 3 days postseeding and declined over a period of 7 days. The cell line formed monolayers which showed time- and concentration-dependent permeability increases in response to thrombin, tumour necrosis factor-alpha (TNF-alpha) or interleukin-1alpha (IL-1alpha) in a manner similar to primary endothelial cells. Permeability increases induced by TNF-alpha were reversible and increased exposure time required a longer recovery period. The cell line, like primary endothelial cells, supported dengue viral replication. Direct infection of confluent monolayers on polycarbonate membranes was not cytolytic and did not increase the permeability of the monolayers over a 15-day period.

Structural studies on an inhibitory antibody against Thermus aquaticus DNA polymerase suggest mode of inhibition.

TP7, an antibody against Thermus aquaticus DNA polymerase I (TaqP), is used as a thermolabile switch in 'hot start' variations of PCR to minimize non-specific amplification events. Earlier studies have established that TP7 binds to the polymerase domain of TaqP, competes with primer template complex for binding and is a potent inhibitor of the polymerase activity of TaqP. We report crystallographic determination of the structure of an Fab fragment of TP7 and computational docking of the structure with the known three-dimensional structure of the enzyme. Our observations strongly suggest that the origin of inhibitory ability of TP7 is its binding to enzyme residues involved in DNA binding and polymerization mechanism. Although criteria unbiased by extant biochemical data have been used in identification of a putative solution, the resulting complex offers an eminently plausible structural explanation of biochemical observations. The results presented are of general significance for interpretation of docking experiments and in design of small molecular inhibitors of TaqP, that are not structurally similar to substrates, for use in PCR. Structural and functional similarities noted among DNA polymerases, and the fact that several DNA polymerases are pharmacological targets, make discovery of non-substrate based inhibitors of additional importance.