Prospective Longitudinal Substance Use Patterns in Patients Preparing for Hepatitis C Treatment

Objectives: This study prospectively examined the independent courses of alcohol, drugs, and smoking over 18 months in 154 patients preparing for hepatitis C virus (HCV) treatment in relation to functioning, negative coping, and satisfaction with quality of life in data collected from a randomized controlled trial of multiple-family group psychoeducation for patients preparing for HCV treatment. Patients with HCV who had consistent abstinence, consistent use, or achievement of abstinence after study entry were examined for outcomes pertaining to functioning in the context of HCV, negative coping, and satisfaction with quality of life. Methods: Of 309 patients considering treatment for HCV recruited from outpatient clinics at two major university medical centers and a Veterans Affairs medical center for a randomized controlled trial of a psychoeducation intervention, 154 completed baseline, 6-month, and 18-month assessments. The assessments included structured diagnostic interviews; questionnaires examining functioning, coping, and satisfaction with quality of life; medical record review; and urine testing for substances of abuse. For these analyses, substance use patterns were determined as consistent abstinence, consistent use, and achieving abstinence after study entry for alcohol and drug use and smoking. Results: The entire sample generally improved in all of these three outcomes over the course of the study. The course of alcohol, drugs, and smoking predicted HCV-related functioning, negative coping, and satisfaction with quality-of-life outcomes over 18 months. Three specific patterns of use (consistent abstinence, consistent use, and achievement of abstinence after study entry) of these substances diverged in association with outcomes related to functioning, negative coping, and satisfaction with quality of life, not only across trajectories over time within substance types but also among types of substances. Conclusions: This study's finding that different substances were associated with distinct clinical outcomes suggests the need to conceptually unbundle different types of substances in managing HCV. Future research is needed to examine the clinical utility of further unbundling these substances and also to further investigate effects of various amounts of use of these substances.     

Blocking CTGF/CCN2 reverses neural fibrosis and sensorimotor declines in a rat model of overuse-induced median mononeuropathy

Encapsulation of median nerves is a hallmark of overuse-induced median mononeuropathy and contributes to functional declines. We tested if an antibody against CTGF/CCN2 (termed FG-3019 or Pamrevlumab) reduces established neural fibrosis and sensorimotor declines in a clinically relevant rodent model of overuse in which median mononeuropathy develops. Young adult female rats performed a high repetition high force (HRHF) lever-pulling task for 18 weeks. Rats were then euthanised at 18 weeks (HRHF untreated), or rested and systemically treated for 6 weeks with either an anti-CCN2 monoclonal antibody (HRHF-Rest/FG-3019) or IgG (HRHF-Rest/IgG), with results compared with nontask control rats. Neuropathology was evident in HRHF-untreated and HRHF-Rest/IgG rats as increased perineural collagen deposition and degraded myelin basic protein (dMBP) in median nerves, and increased substance P in lower cervical dorsal root ganglia (DRG), compared with controls. Both groups showed functional declines, specifically, decreased sensory conduction velocity in median nerves, noxious cold temperature hypersensitivity, and grip strength declines, compared with controls. There were also increases of ATF3-immunopositive nuclei in ventral horn neurons in HRHF-untreated rats, compared with controls (which showed none). FG-3019-treated rats showed no increase above control levels of perineural collagen or dMBP in median nerves, Substance P in lower cervical DRGs, or ATF3-immunopositive nuclei in ventral horns, and similar median nerve conduction velocities and thermal sensitivity, compared with controls. We hypothesize that neural fibrotic processes underpin the sensorimotor declines by compressing or impeding median nerves during movement, and that inhibiting fibrosis using an anti-CCN2 treatment reverses these effects.     

Synthesis, evaluation, and molecular docking studies of cycloalkyl/aryl-3,4,5-trimethylgallates as potent non-ulcerogenic and gastroprotective anti-inflammatory agents

In our effort to identify the effective gastric sparing and protective anti-inflammatory agents, a series of cycloalkyl/aryl-3,4,5-trimethylgallates were synthesized and characterized. The physicochemical properties were studied to assess the lipophilicity and chemical stability. Subsequently, the compounds were evaluated for their anti-inflammatory activity and effect on gastric mucosa by most active compounds. All the compounds exhibited promising anti-inflammatory activity. In particular, 4a, 4b, 4g, and 4h emerged as the most active compounds in the series. The results of gastric mucosal studies and biochemical estimations suggested that these compounds are non-ulcerogenic and gastroprotective. The molecular docking analysis was performed to understand the binding interactions of these compounds to cyclooxygenase isoenzyme (COX-1 and COX-2). The results from this investigation suggests cycloalkyl/aryl-3,4,5-trimethylgallates as potent safer gastrosparing and protective anti-inflammatory agents.     

Rapid Delivery of Diazepam from Supersaturated Solutions Prepared Using Prodrug/Enzyme Mixtures: Toward Intranasal Treatment of Seizure Emergencies

Current treatments for seizure emergencies, such as status epilepticus, include intravenous or rectal administration of benzodiazepines. While intranasal delivery of these drugs is desirable, the small volume of the nasal cavity and low drug solubility pose significant difficulties. Here, we prepared supersaturated diazepam solutions under physiological conditions and without precipitation, using a prodrug/enzyme system. Avizafone, a peptide prodrug of diazepam, was delivered with—Aspergillus oryzae (A.O.) protease, an enzyme identified from a pool of hydrolytic enzymes in assay buffer, pH 7.4 at 32°C. This enzyme converted avizafone to diazepam at supersaturated concentrations. In vitro permeability studies were performed at various prodrug/enzyme ratios using Madin-Darby canine kidney II-wild type (MDCKII-wt) monolayers, a representative model of the nasal epithelium. Monolayer integrity was examined using TEER measurement and the lucifer yellow permeability assay. Prodrug/drug concentrations were measured using HPLC. Enzyme kinetics with avizafone-protease mixtures revealed K_M = 1,501 ± 232 μM and V_max = 1,369 ± 94 μM/s. Prodrug-protease mixtures, when co-delivered apically onto MDCKII-wt monolayers, showed 2–17.6-fold greater diazepam flux (S = 1.3–15.3) compared to near-saturated diazepam (S = 0.7). Data for prodrug conversion upstream (apical side) and drug permeability downstream (basolateral side) fitted reasonably well to a previously developed in vitro two compartment pharmacokinetic model. Avizafone-protease mixtures resulted in supersaturated diazepam in less than 5 min, with the rate and extent of supersaturation determined by the prodrug/enzyme ratio. Together, these results suggest that an intranasal avizafone-protease system may provide a rapid and alternative means of diazepam delivery.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9596-5) contains supplementary material, which is available to authorized users.KEY WORDS: avizafone enzyme activation, diazepam delivery, hydrophobic drugs, MDCK monolayers, rapid absorption, seizure emergencies, supersaturation     

Elevated monoclonal and polyclonal serum immunoglobulin free light chain as prognostic factors in B‐ and T‐cell non‐Hodgkin lymphoma

The serum immunoglobulin free light chain (FLC) assay quantitates free kappa (κ) and lambda (λ) light chains. FLC elevations in patients with diffuse large B‐cell lymphoma (DLBCL), Hodgkin lymphoma (HL), and chronic lymphocytic leukemia (CLL) are associated with an inferior survival. These increases in FLC can be monoclonal (as in myeloma) or polyclonal. The goal was to estimate the frequency of these elevations within distinct types of B‐cell and T‐cell non‐Hodgkin lymphoma (NHL) and whether the FLC measurements are associated with event‐free survival (EFS). We studied serum for FLC abnormalities using normal laboratory reference ranges to define an elevated κ or λ FLC. Elevations were further classified as polyclonal or monoclonal. Four hundred ninety‐two patients were studied: 453 B‐cell and 34 T‐cell NHL patients. Twenty‐nine % (142/453) of patients had an elevated FLC of which 10% were monoclonal elevations. Within B‐cell NHL, FLC abnormalities were most common in lymphoplasmacytic (79%), mantle cell (68%), and lymphomas of mucosa associated lymphoid tissue (31%); they were least common in follicular (15%). The hazard ratio (HR) for EFS in all patients was 1.41 (95% CI; 1.11–1.81); in all B‐cell NHL the HR was 1.44 (95% CI 1.11–1.96); in all T‐cell NHL the HR was 1.17 (95% CI 0.55–2.49). FLC abnormalities predicted an inferior OS (HR = 2.75, 95% CI: 1.93–3.90, P < 0.0001). The serum FLC assay is useful for prognosis in both B‐cell and T‐cell types of NHL. In B‐cell NHL further discrimination between a monoclonal and polyclonal elevation may be helpful and should be analyzed in prospective clinical trials. Am. J. Hematol. 89:1116–1120, 2014. © 2014 Wiley Periodicals, Inc.     

Community-based prevention of hepatitis-B-related liver cancer: Australian insights

Problem

Although most primary hepatocellular cancers (HCCs) are attributable to chronic viral hepatitis and largely preventable, such cancers remain a leading cause of cancer-related mortality wherever chronic hepatitis B is endemic.

Approach

Many HCCs could be prevented by increasing awareness and knowledge of hepatitis B, optimizing the monitoring of chronic hepatitis B and using antiviral treatments – but there are gaps in the implementation of such strategies.

Local setting

The “B Positive” programme, based in Sydney, Australia, is designed to improve hepatitis-B-related health outcomes among immigrants from countries with endemic hepatitis B. The programme offers information about disease screening, vaccination and treatment options, as well as optimized access to care.

Relevant changes

The B Positive programme has been informed by economic modelling. The programme offers culturally tailored education on chronic hepatitis B to target communities and their health practitioners and regular follow-up through a population-based registry of cases.

Lessons learnt

As the costs of screening for chronic hepatitis B and follow-up are relatively low and less than one in every four cases may require antiviral drugs, optimizing access to treatment seems an appropriate and cost-effective management option. The identification and accurate staging of cases and the judicious use of antiviral medications are predicated upon an informed and educated health workforce. As establishing community trust is a lengthy process, delaying the implementation of programmes against chronic hepatitis B until antiviral drugs become cheaper is unwarranted.     

Management of Odontogenic Space Infection with Microbiology Study

Introduction

Dental infection has plagued humankind for as long as our civilization has been a fight against microorganisms by man dates back to ancient civilization. The discoveries of antibiotics are encouraging trends towards conquest of the microbial infection.

Materials and Methods

This study emphasizes the detection of pathogenic microorganisms by microbiological examination and culture of specimens representative of the infection, importance of early and correct diagnosis of infections, prompt treatment and supportive care.

Results

The age group most commonly involved was in the third and fourth decades of life. Extraction followed by incision and drainage was done. The most commonly involved space was submandibular followed by buccal space. Thirty isolates were obtained. 43 % of the strains were strict anaerobes and 39 % were aerobes, with mixed growth was seen in 18.52 %. Amongst aerobes alpha hemolytic Streptococcus aureus and Peptostreptococcus as anaerobes were the most predominant followed by Bacteroides and Prevotella. Mixed aerobic and anaerobic isolates were obtained from 18.52 % of total cases. Overall resistance to Penicillin was 22 %, amongst aerobes.

Conclusion

Amoxicillin and Clavulanic acid combination performed better, as 100 % strains were sensitive to it. The results of this study saw a changing trend in terms of predominance of anaerobic bacteria over aerobic ones.