A Placebo-Controlled Trial of Dextromethorphan as an Adjunct in Opioid-Dependent Patients Undergoing Methadone Maintenance Treatment

Background:

Low-dose dextromethorphan (DM) might have anti-inflammatory and neurotrophic effects mechanistically remote from an NMDA receptor. In a randomized, double-blind, controlled 12 week study, we investigated whether add-on dextromethorphan reduced cytokine levels and benefitted opioid-dependent patients undergoing methadone maintenance therapy (MMT).

Methods:

Patients were randomly assigned to a group: DM60 (60mg/day dextromethorphan; n = 65), DM120 (120mg/day dextromethorphan; n = 65), or placebo (n = 66). Primary outcomes were the methadone dose required, plasma morphine level, and retention in treatment. Plasma tumor necrosis factor (TNF)-α, C-reactive protein, interleukin (IL)-6, IL-8, transforming growth factor–β1, and brain-derived neurotrophic factor (BDNF) levels were examined during weeks 0, 1, 4, 8, and 12. Multiple linear regressions with generalized estimating equation methods were used to examine the therapeutic effect.

Results:

After 12 weeks, the DM60 group had significantly longer treatment retention and lower plasma morphine levels than did the placebo group. Plasma TNF-α was significantly decreased in the DM60 group compared to the placebo group. However, changes in plasma cytokine levels, BDNF levels, and the methadone dose required in the three groups were not significantly different.

Conclusions:

We provide evidence—decreased concomitant heroin use—of low-dose add-on DM’s efficacy for treating opioid-dependent patients undergoing MMT.     

Non-invasive evaluation of therapeutic response in keloid scar using diffuse reflectance spectroscopy

The pathogenesis and ideal treatment of keloid are still largely unknown, and it is essential to develop an objective assessment of keloid severity to evaluate the therapeutic response. We previously reported that our diffuse reflectance spectroscopy (DRS) system could assist clinicians in understanding the functional and structural condition of keloid scars. The purpose of this study was to understand clinical applicability of our DRS system on evaluating the scar severity and therapeutic response of keloid. We analyzed 228 spectral data from 71 subjects with keloid scars. The scars were classified into mild (0-3), moderate (4-7) and severe (8-11) according to the Vancouver scar scale. We found that as the severity of the scar increased, collagen concentration and water content increased, and the reduced scattering coefficient at 800 nm and oxygen saturation (SaO₂) decreased. Using the DRS system, we found that collagen bundles aligned in a specific direction in keloid scars, but not in normal scars. Water content and SaO₂ may be utilized as reliable parameters for evaluating the therapeutic response of keloid. In conclusion, the results obtained here suggest that the DRS has potential as an objective technique with which to evaluate keloid scar severity. In addition, it may be useful as a tool with which to track longitudinal response of scars in response to various therapeutic interventions.OCIS codes: (170.5280) Photon migration, (170.4580) Optical diagnostics for medicine, (170.6510) Spectroscopy, tissue diagnostics, (290.1990) Diffusion     

Assessment of the pharmacokinetics,removal rate of hemodialysis,and safety of lactulose in hemodialysis patients

Lactulose is often used to treat hepatic encephalopathy or constipation, and also exhibits benefits to chronic renal insufficiency due to reduce nitrogen-related products in serum. The present study investigated the pharmacokinetics of lactulose, its removal rate through dialysis, and safety by administering lactulose 6.5 g (Lagnos Jelly Divided Pack 16.05 g) orally to six hemodialysis patients who resided in Taiwan. As a result, the means of maximum plasma concentrations (C_max) and Time to reach C_max (Tmax) were 3090 ± 970 ng/mL and 6.5 ± 2.3 hours, respectively. The mean plasma concentration was 2220 ± 986 ng/mL after administration for 24 hours. Sequentially, the mean plasma concentration reduced to 307 ± 117 ng/mL after the application of 4-hour dialysis. Area under the plasma concentration-time curve from zero to 24 h post-dose (AUC_0–24h) were 56,200 ± 21,300 ng h/mL and the AUC_0–28h was 61,200 ± 23,300 ng h/mL. The rate of lactulose removal by dialysis was 83.6 ± 8.9%. In addition, the multiple doses of lactulose using a simulated model suggested that no plasma accumulation would be expected while coordinating with dialysis. Good tolerability was confirmed, while the mild adverse effect of diarrhea was observed in one case during the study period. No death or serious adverse effect was reported. Based on the present study, we demonstrated the pharmacokinetic transition with respect to plasma levels of lactulose in patients with impaired renal excretion treated with hemodialysis.     

Neoadjuvant radiation therapy and its impact on complications after pancreaticoduodenectomy for pancreatic cancer: analysis of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP)

Objectives

This study investigated the impact of neoadjuvant radiation therapy (XRT) on postoperative outcomes following pancreaticoduodenectomy for pancreatic cancer.

Methods

The American College of Surgeons National Quality Improvement Program database was queried for the period 2005–2010 to assess complication rates following pancreaticoduodenectomy for pancreatic cancer. Two groups of patients were identified, comprising those who received neoadjuvant XRT and those who did not (control group).

Results

A total of 4416 patients were identified, including 200 in the XRT group and 4216 in the control group. There were differences in patient characteristics between the groups, including in age, hypertension and bilirubin level. Despite the fact that weight loss was more common, median operative time was longer (423 min versus 368 min; P < 0.001), and vascular reconstruction was more commonly required (20.5% versus 8.4%; P < 0.001) in the XRT group. In addition, the XRT group had a shorter median hospital stay than the control group (9 days versus 10 days; P = 0.005). Mortality (3.0% versus 2.7%; P = 0.818) and morbidity (40.5% versus 37.6%; P = 0.404) rates were not influenced by neoadjuvant XRT. Blood transfusion rates were increased in the XRT group (13.0% versus 7.4%; P = 0.003). Severe complications were influenced by age >70 years, American Society of Anesthesiologists (ASA) class >2, preoperative sepsis, dyspnoea, weight loss, impaired functional status, peripheral vascular disease and operative time of >8 h.

Conclusions

Neoadjuvant XRT is not associated with an increase in complications after pancreaticoduodenectomy.     

Exploiting PI3K/mTOR signaling to accelerate epithelial wound healing

The molecular circuitries controlling the process of skin wound healing have gained new significant insights in recent years. This knowledge is built on landmark studies on skin embryogenesis, maturation, and differentiation. Furthermore, the identification, characterization, and elucidation of the biological roles of adult skin epithelial stem cells and their influence in tissue homeostasis have provided the foundation for the overall understanding of the process of skin wound healing and tissue repair. Among numerous signaling pathways associated with epithelial functions, the PI3K/Akt/mTOR signaling route has gained substantial attention with the generation of animal models capable of dissecting individual components of the pathway, thereby providing a novel insight into the molecular framework underlying skin homeostasis and tissue regeneration. In this review, we focus on recent findings regarding the mechanisms involved in wound healing associated with the upregulation of the activity of the PI3K/Akt/mTOR circuitry. This review highlights critical findings on the molecular mechanisms controlling the activation of mTOR, a downstream component of the PI3K–PTEN pathway, which is directly involved in epithelial migration and proliferation. We discuss how this emerging information can be exploited for the development of novel pharmacological intervention strategies to accelerate the healing of critical size wounds.     

Optimal Future Liver Remnant in Patients Treated with Extensive Preoperative Chemotherapy for Colorectal Liver Metastases

Background

Patients with colorectal liver metastases (CLM) are increasingly treated with preoperative chemotherapy. Chemotherapy associated liver injury is associated with postoperative hepatic insufficiency (PHI) and mortality. The adequate minimum future liver remnant (FLR) volume in patients treated with extensive chemotherapy remains unknown.

Methods

All patients with standardized FLR > 20 %, who underwent extended right hepatectomy for CLM from 1993-2011, were divided into three cohorts by chemotherapy duration: no chemotherapy (NC, n = 30), short duration (SD, ≤12 weeks, n = 78), long duration (LD, >12 weeks, n = 86). PHI and mortality were compared by using uni-/multivariate analyses. Optimal FLR for LD chemotherapy was determined using a minimum p-value approach.

Results

A total of 194 patients met inclusion criteria. LD chemotherapy was significantly associated with PHI (NC + SD 3.7 vs. LD 16.3%, p = 0.006). Ninety-day mortality rates were 0 % in NC, 1.3 % in SD, and 2.3% in LD patients, respectively (p = 0.95). In patients with FLR > 30 %, PHI occurred in only two patients (both LD, 2/20, 10 %), but all patients with FLR > 30 % survived. The best cutoff of FLR for preventing PHI after chemotherapy >12 weeks was estimated as >30 %. Both LD chemotherapy (odds ratio [OR] 5.4, p = 0.004) and FLR ≤ 30 % (OR 6.3, p = 0.019) were independent predictors of PHI.

Conclusions

Preoperative chemotherapy >12 weeks increases the risk of PHI after extended right hepatectomy. In patients treated with long-duration chemotherapy, FLR > 30 % reduces the rate of PHI and may provide enough functional reserve for clinical rescue if PHI develops.