Safety and efficacy outcomes of long-term treatment up to 4 years with 5% lidocaine medicated plaster in patients with post-herpetic neuralgia

Abstract Objective: Prospective evaluation of the long-term efficacy and safety of the 5% lidocaine medicated plaster in patients with post-herpetic neuralgia (PHN). Research design and methods: Patients with persisting pain for ≥3 months after acute herpes zoster and a baseline pain intensity of at least 4 on an 11-point numerical rating scale (NRS 0-10) were treated with 5% lidocaine medicated plasters for up to 5 years and monitored in regular intervals. Efficacy parameters are presented for the first 4 years and include patients' recall of pain relief (6-point verbal rating scale (VRS), clinical global impression of change (CGIC), patients' global impression of change PGIC), and the global evaluations of study medication. Safety parameters (clinical examination, skin evaluation, laboratory) and adverse events (AEs) were assessed at regular visits. Clinical trial registration: KF10004/02. Results: A total of 102 patients continuing from a 1 year main study period were included in an extension phase of up to 3 years. Ten patients (9.8%) dropped out due to lack of efficacy and 9 patients (8.8%) due to treatment-related AEs; 56 patients (54.9%) left the study for non-treatment-related reasons. Twenty-seven patients (26.4%) were still under treatment after a total treatment period of 4 years. On average, a pain relief of at least 4.3 (between moderate and a lot) was achieved throughout the study. At all visits the CGIC and the PGIC were much or very much improved in about 80% of patients. At the final visit, study medication was rated at least to be good by 91% of physicians and 89% of patients. Drug-related adverse events (DRAEs) were reported in 19 of 102 patients, mainly mild to moderate localized skin reactions. There were no hints for a reduced analgesic effect or an increase of DRAEs with long-term treatment. Conclusions: This study demonstrates that long-term treatment of ≥12 months with the 5% lidocaine medicated plaster is effective and well tolerated in PHN patients. These findings support the recommendations to use the 5% lidocaine medicated plaster as baseline therapy for localized neuropathic pain after herpes zoster infection (PHN).     

Novel Imaging Method to Quantify Stratum Corneum in Dermatopharmacokinetic Studies: Proof-of-Concept with Acyclovir Formulations

Purpose

Tape-stripping the stratum corneum (SC) is used in the assessment of dermatopharmacokinetics (DPK). The amount of SC per tape can be determined gravimetrically, but a novel imaging method offers advantages in terms of sensitivity, reproducibility, precision, stability and speed. High-resolution images, acquired under controlled conditions, are analysed in terms of pixel greyscale values and distributions, and their usefulness in DPK studies is demonstrated in this study using acyclovir.

Methods

At all tape-stripped sites, the SC amount per tape was measured gravimetrically and by imaging. In a first series of experiments, untreated sites were stripped to determine total SC thickness. Subsequently, post-application of two acyclovir creams, drug-permeation profiles were constructed.

Results

The greyscale values from the imaging data can be used directly to estimate total SC thickness and DPK parameters. The results compared favourably with the traditional weighing method. The concentration of drug on each tape, as a function of the relative position within the SC, permitted diffusivity and partitioning parameters characterising the penetration of acyclovir to be derived.

Conclusion

The new imaging approach offers a sensitive, reproducible, precise, and rapid technique to quantify the relative SC amount removed on tape-strips, and facilitates the acquisition of DPK data.     

EVALUATION OF THE HEALTH RISK ASSOCIATED WITH EXPOSURE TO CHLOROFORM IN INDOOR SWIMMING POOLS

The exposure of swimmers to chloroform (CHCl₅) was investigated in indoor swimming pools of the Quebec City region along with the associated carcinogenic risk. Six training sessions involving 52 competition swimmers (11 to 20 yr old) were conducted in 3 different pools, while 12 adult leisure swimmers attended 5 sessions, each held in a different pool. For each session, water and ambient air CHCl₃ concentrations were measured and CHCl₃ levels in alveolar air samples (CHCl₃ALV) collected from swimmers prior to entering the swimming pool premises and after 15, 35, and 60 min of swimming. Mean water concentrations varied from 18 µg/L to 80 µg/L, while those in air ranged from 78 µg/m3 to 329 µg/m3. Multiple linear regression analyses revealed that CHCl₃ALV values in competition swimmers were strongly correlated to ambient air and water levels, and to a lesser degree to the intensity of training. Only ambient air concentration was positively correlated to CHCl₃ALV in the leisure group. Concentrations of CHCl₃ metabo lites bound to hepatic and renal macromolecules, estimated using a physiologically based pharmacokinetic (PBPK) model, were 1.6 and 1.9 times higher for the competition swimmers than for the leisure swimmers, respectively. The highest hepatic concentration predicted in competition swimmers, 0.22 µg CHCl equivalents/kg of tissue, was at least 10,000 times lower than the smallest no observed³effect level for liver tumors in animals. Data indicate that the safety margin is therefore very large, for competitive swimmers as well as for leisure swimmers.     

Teaching residents screening,brief intervention,and referral to treatment (SBIRT) skills for alcohol use: Using chart-stimulated recall to assess curricular impact

ABSTRACT

Background: Screening, brief intervention, and referral to treatment (SBIRT) improves identification and intervention for patients at risk for developing an alcohol use disorder (AUD). Residency curriculum is designed to teach SBIRT skills, but resources are needed to promote skill implementation. The electronic health record (EHR) can facilitate implementation through integration of decision-support tools. The authors developed electronic tools to facilitate documentation of alcohol assessment and brief intervention and to reinforce skills from an SBIRT curriculum. This prospective cohort study assessed primary care internal medicine residents' use of SBIRT skills and EHR tools in practice using chart-stimulated recall (CSR). Methods: Postgraduate year 2 and 3 residents received a 5-hour SBIRT curriculum with skills practice and instruction on SBIRT electronic tools. Participants were then given a list of their patients seen in a 1-year period who were drinking at/above the recommended limit. Trainees selected 3 patients to review with a faculty member in a CSR. Faculty used a 24-item chart checklist to assess application of SBIRT skills and electronic tool use and met with residents to complete a CSR interview. CSR interview notes were analyzed qualitatively to understand application of SBIRT skills and EHR tool use. Results: Eighteen of 20 residents participated in the CSR, and 5 faculty reviewed 46 patient charts. Residents documented alcohol use (84.2% of charts) and assessment of quantity/frequency of use (71.0%) but were less likely to document assessment for an AUD (34%), an appropriate plan (50.0%), or follow-up (55%). Few residents used EHR tools. Residents reported barriers in addressing alcohol use, including lack of knowledge, patient barriers, and time constraints. Conclusions: More intensive training in SBIRT with opportunities for practice and feedback may be necessary for residents to consistently apply SBIRT skills in practice. EHR tools need to be better integrated into the clinic workflow in order to be useful.     

An Investigation into the Effect of Spray Drying Temperature and Atomizing Conditions on Miscibility,Physical Stability,and Performance of Naproxen–PVP K 25 Solid Dispersions

The present study investigates the effect of changing spray drying temperature (40°C–120°C) and/or atomizing airflow rate (AR; 5–15 L/min) on the phase structure, physical stability, and performance of spray-dried naproxen–polyvinylpyrrolidone (PVP) K25 amorphous solid dispersions. The modulated differential scanning calorimetry, attenuated total internal reflectance-Fourier transform infrared, and powder X-ray diffractometry (pXRD) studies revealed that higher inlet temperature (IT) or atomization airflow leads to the formation of amorphous-phase-separated dispersions with higher strongly H-bonded and free PVP fractions, whereas that prepared with the lowest IT was more homogeneous. The dispersion prepared with the lowest atomization AR showed trace crystallinity. Upon exposure to 75% relative humidity (RH) for 3 weeks, the phase-separated dispersions generated by spray drying at higher temperature or higher atomization airflow retained relatively higher amorphous drug fraction compared with those prepared at slow evaporation conditions. The humidity-controlled pXRD analysis at 98% RH showed that the dispersion prepared with highest atomization AR displayed the slowest kinetics of recrystallization. The molecular-level changes occurring during recrystallization at 98% RH was elucidated by spectroscopic monitoring at the same humidity. The rate and extent of the drug dissolution was the highest for dispersions prepared at the highest atomizing AR and the lowest for that prepared with the slowest atomizing condition.     

Sodium arsenite ± hyperthermia sensitizes p53-expressing human ovarian cancer cells to cisplatin by modulating platinum-DNA damage responses

Epithelial ovarian cancer (EOC) is the leading cause of gynecological cancer death in the United States. Cisplatin is a DNA damaging agent initially effective against EOC but limited by resistance. P53 plays a critical role in cellular response to DNA damage and has been implicated in EOC response to platinum chemotherapy. In this study, we examined the role of p53 status in EOC response to a novel combination of cisplatin, sodium arsenite, and hyperthermia. Human EOC cells were treated with cisplatin ± 20μM sodium arsenite at 37°C or 39°C for 1 h. Sodium arsenite ± hyperthermia sensitized wild-type p53-expressing (A2780, A2780/CP70, OVCA 420, OVCA 429, and OVCA 433) EOC cells to cisplatin. Hyperthermia sensitized p53-null SKOV-3 and p53-mutant (OVCA 432 and OVCAR-3) cells to cisplatin. P53 small interfering RNA (siRNA) transfection abrogated sodium arsenite sensitization effect. XPC, a critical DNA damage recognition protein in global genome repair pathway, was induced by cisplatin only in wild-type p53-expressing cells. Cotreatment with sodium arsenite ± hyperthermia attenuated cisplatin-induced XPC in wild-type p53-expressing cells. XPC siRNA transfection sensitized wild-type p53-expressing cells to cisplatin, suggesting that sodium arsenite ± hyperthermia attenuation of XPC is a mechanism by which wild-type p53-expressing cells are sensitized to cisplatin. Hyperthermia ± sodium arsenite enhanced cellular and DNA accumulation of platinum in wild-type p53-expressing cells. Only hyperthermia enhanced platinum accumulation in p53-null cells. In conclusion, sodium arsenite ± hyperthermia sensitizes wild-type p53-expressing EOC cells to cisplatin by suppressing DNA repair protein XPC and increasing cellular and DNA platinum accumulation.     

Q-TWiST analysis of panitumumab plus FOLFOX4 versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer

Introduction:

Panitumumab plus infusional 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) significantly improved overall survival versus FOLFOX4 alone in patients with previously untreated wild-type RAS metastatic colorectal cancer (mCRC). We applied a quality-adjusted time without symptoms of disease or toxicity (Q-TWiST) analysis to provide an integrated measure of clinical benefit, with the objective of comparing quality-adjusted survival between the two arms. We acknowledge that there are limitations associated with Q-TWIST methodology for crossover trials.

Methods:

For each treatment arm, the truncated mean times spent in the toxicity (TOX: grade 3 or 4 adverse events), time without symptoms of disease or toxicity (TWiST), and relapse (REL: after disease progression) states were estimated by the product-limit method, and adjusted using utility weights derived from patient-reported EuroQol 5-dimension measures. Sensitivity analyses were performed in which utility weights (varying from 0 to 1) were applied to time in the TOX and REL health states.

Results:

Quality-adjusted overall survival time was statistically significantly longer with panitumumab plus FOLFOX4 (20.5 months) than with FOLFOX4 alone (18.2 months) (P?=?0.025).

Conclusion:

In patients with previously untreated wild-type RAS mCRC, panitumumab plus FOLFOX4 significantly improved quality-adjusted survival compared with FOLFOX4 alone.     

New Perspectives for Fixed Dose Combinations of Poorly Water-Soluble Compounds: a Case Study with Ezetimibe and Lovastatin

Purpose

Aiming to improve the dissolution rate of ezetimibe (EZE) and lovastatin (LOV) in a fixed dose combination (FDC), co-amorphous systems and ternary solid dispersions were prepared by quench cooling and spray drying, respectively.

Methods

Formulations were characterized through X-ray diffraction, modulated differential scanning calorimetry, infrared spectroscopy, scanning electron microscopy and laser diffraction, and evaluated by ‘in vitro’ dissolution. Stability studies were conducted at different conditions during 30 days with the ternary solid dispersion composed of 75% of Soluplus® (ELS 1:1 75%).

Results

Single phase co-amorphous systems made up of the pure drugs were not able to increase the dissolution rate of EZE and LOV. However, ternary solid dispersions achieved high dissolution for both compounds, especially when Soluplus® was used as carrier. The dissolution efficiency increased up to 18 (EZE) and 6 (LOV) times in ternary solid dispersions, compared to the crystalline drugs. ELS 1:1 75% preserved its amorphous state during 30 days, in different stability conditions.

Conclusions

A spray dried ternary solid dispersion able to enhance the dissolution rate of two poorly soluble, therapeutically complementary drugs, is reported for the first time. These promising results open new perspectives for the development of more advanced FDCs.

     

Seroprevalence of seven high-risk HPV types in The Netherlands

Background

To obtain insight into the age-specific seroprevalence for seven high-risk human papillomavirus (hr-HPV) serotypes (HPV16, 18, 31, 33, 45, 52, and 58) among the general population in the pre-vaccination era in The Netherlands.

Methods

From a cross-sectional population-based study (ISRCTN 20164309) performed in 2006/2007 6384 sera of men, women and children were tested for seven hr-HPV specific antibodies using a fluorescent bead-based multiplex immunoassay with virus-like particles of the seven HPV serotypes.

Results

An increase in seroprevalence was observed in adolescents, especially for the most prevalent HPV type 16 (up to 11.3%). The increase was most pronounced in women, but was less clear for the other six HPV serotypes. Relatively stable seroprevalences were found in the middle aged cohorts and a slight decrease in the elderly. For the age cohorts >14 years, the seroprevalence among women (25.2%) was higher compared with men (20.3%) (p = 0.0002). We found that 10.1% of the population was seropositive for multiple HPV serotypes.

Conclusions

The HPV vaccination program is targeted at preadolescents as is justified by the results in this study in which a step-up in HPV seroprevalence is observed at ages of sexual debut. Although direct interpretation of seroprevalence data are hampered by cross-reactivity and seroconversion rate, these data are useful as baseline to evaluate long-term population effects of the HPV16/18 vaccination program.