Comprehensive insight into the neurotoxic mechanisms of low dose Pb exposure in Wistar rats: Benchmark dose analysis.

Lead (Pb) is a toxic metal that affects almost all human's system and organs, with the nervous system as the most sensitive. Better understanding of the Pb neurobehavioral effects and neurotoxicity requires realistic study scenarios based on low level exposure. The aim of this study was to determine neurotoxic effects and mechanisms of Pb in six low doses and to establish dose-response relationship for these effects and related Benchmark dose (BMD). Forty-two, male albino Wistar rats were randomized into seven groups, control and Pb-exposed: 0.1, 0.5, 1, 3, 7 and 15 mg Pb/kg body weight/day (oral gavage) for 28 days. Behavioural tests (Elevated plus maze test, Spontaneous locomotor activity test and Novel object recognition test) were conducted in the last week of experiment, in the control, lower (0.5 mg Pb/kg), middle (3 mg Pb/kg) and higher (15 mg Pb/kg) dose groups. The acetylcholinesterase activity, oxidative status and essential elements levels (Cu, Zn, Mn and Fe) were measured in brain tissue along with histological analyses. External and internal dose-response analyses were performed using PROASTweb 70.1 software. The results have shown that subacute exposure to very low doses of Pb resulted in memory deficits in rats that was accompanied with acetylcholinesterase enzyme activity decrease. The observed hyperactive behaviour was accompanied by dose-dependent induction of brain oxidative stress and Zn elevation. The histological alterations in Purkinje cells were only detected in the group treated with the highest Pb dose. The lowest BMD considering entire oxidative status was calculated based on total oxidative status (4.5e-06 mg Pb/kg b.w./day). The findings reported in our study may be beneficial in further evaluating the health consequences and human health risk assessment of low-level Pb exposure.

Low-lead doses induce oxidative damage in cardiac tissue: Subacute toxicity study in Wistar rats and Benchmark dose modelling.

Exposure to toxic metals, including lead (Pb), were found as important risk factor for cardiovascular diseases. The aim of the study was to simulate low-level subacute Pb exposure scenario and to determine redox status, redox scores (OXY-score, damage score and protective score) and copper (Cu), zinc (Zn), iron (Fe) and manganese (Mn) levels in cardiac tissue of Wistar rats. Based on the obtained results we have established dose-toxic response relationship and derived Benchmark dose. The male Wistar rats were divided in seven groups (n = 6), six threated groups that received 0.1; 0.5; 1; 3; 7; 15 mg Pb/kg body weight/day for 28 days, by oral gavage and control group. The results of the presented study demonstrated that Pb affect cardiac tissue by inducing production of superoxide anion radical (O2.-) and consequently raising malondialdehyde (MDA) levels. The positive trend in OXY-score and damage score were determined. Effect size analysis showed that the main toxic effects were oxidative damage and elevation of MDA. The lowest BMD was calculated for MDA (2.2e-0.6 mg Pb/kg b.w./day). Obtained BMD may be useful in further assessing point of departure in the human health risks assessment of low-level Pb exposure scenario.

The burden of productivity loss of U.S. commercially insured patients diagnosed with Dupuytren's disease undergoing collagenase versus fasciectomy treatment.

Background: We conducted a comparative assessment of the productivity loss associated with the two different treatment options for Dupuytren's disease: collagenase and fasciectomy. Methods: The retrospective claims analysis was performed using the data from IBM MarketScan® Commercial (CD) and Health and Productivity Management (HPM) Databases over five years (2012-2016). We identified two cohorts of patients who underwent either collagenase or fasciectomy in the CD. Propensity-score matched patients were linked to their productivity loss claims in the HPM database. Productivity loss measures were assessed over a 12-month follow-up period. Results: Out of 702 collagenase and 999 fasciectomy propensity score-matched patients in the CD, there were 147 collagenase and 273 fasciectomy patients in the HPM database. Over the follow-up period, collagenase-treated patients were significantly less likely to use short-term disability (STD) leave (9.7% vs. 20.2%; P = 0.009), reflecting in the lower average number of absent STD days (mean, 2.8 vs. 8.1; P = 0.002) in comparison to fasciectomy-treated. The mean indirect STD cost was considerably lower in the collagenase vs. fasciectomy group ($375 vs. $1,108; P = 0.002). Conclusion: This study indicates that collagenase vs. fasciectomy treatment may be related to a lower rate of workplace absence and lower indirect cost in a year following the treatment.

Healthcare Costs and Resource Use of Patients with Dupuytren Contracture Treated with Collagenase Clostridium Histolyticum or Fasciectomy: A Propensity Matching Analysis.

OBJECTIVE: Studies examining differences in US healthcare resource utilization (HCRU) and associated healthcare costs between collagenase clostridium histolyticum (CCH) and fasciectomy for Dupuytren contracture (DC) are limited. This study evaluated US HCRU and direct healthcare cost for the treatment of DC in privately insured patients using insurance claims. METHODS: This retrospective observational cohort study analyzed data from large nationwide insurance claims databases; it included individuals diagnosed with DC between July 1, 2011, and June 30, 2017, who were adults at index date (date of first treatment: CCH or fasciectomy). Participants had continuous health plan coverage 24 months pre-index and 12 months post-index date. All-cause and DC-related HCRU and healthcare costs from the payers' perspective were compared between propensity score-matched cohorts. Generalized linear models assessed factors associated with all-cause total healthcare costs. RESULTS: Of 83,983 patients diagnosed with DC, 1932 adults receiving fasciectomy and 953 adults receiving CCH were included. The mean ± standard deviation total all-cause healthcare cost was significantly lower with CCH than with fasciectomy (US$11,897 ± US$14,633 versus US$15,528 ± US$22,254, respectively; P<0.001). After propensity score matching, 702 and 999 patients remained in the CCH and fasciectomy cohorts, respectively. In this analysis, all-cause and DC-related total costs were significantly lower in the CCH cohort versus the fasciectomy cohort (all-cause: US$11,044 ± US$12,856 versus US$12,912 ± US$19,237, respectively, P=0.02; DC-specific: US$3417 ± US$3671 versus US$5800 ± US$4985, P<0.001), mainly due to the lower frequency of outpatient visits. CCH treatment and the use of a consumer-driven healthcare plan were associated with lower healthcare costs. CONCLUSION: Based on matched cohort data, adjusted 1-year healthcare costs for CCH-treated individuals were significantly lower compared with costs for fasciectomy-treated individuals.

Redox and essential metal status in the brain of Wistar rats acutely exposed to a cadmium and lead mixture.

Most Pb and Cd neurotoxicity studies investigate exposure to either of the toxic metals alone, while data on co-exposure are scarce. The aim of our study was to fill that gap by investigating acute combined effects of Pb and Cd on redox and essential metal status in the brain of Wistar rats. Animals were randomised in four groups of six to eight rats, which received 15 or 30 mg/kg of Cd, 150 mg/kg of Pb, or 150 mg/kg of Pb + 15 mg/kg of Cd by gavage. The fifth, control, group received distilled water only. Co-treatment with Pb and Cd induced significant increase in malondialdehyde (MDA) and thiobarbituric acid-reactive substances (TBARS) compared to control and groups receiving either metal alone. This is of special importance, as MDA presence in the brain has been implicated in many neurodegenerative disorders. The groups did not significantly differ in Zn, Cu, Mn, and Fe brain levels. Our findings highlight the importance of metal mixture studies. Neurotoxicity assessments of single chemicals do not provide a real insight into exposure to mixtures in real life. Further research should look into interactions between these metals to reveal complex molecular mechanisms of their neurotoxicity.

Effect of urine adulterants on commercial drug abuse screening test strip results.

Immunochromatographic strips for urine drug screening tests (UDSTs) are common and very suitable for drug abuse monitoring, but are also highly susceptible to adulterants kept in the household, which can significantly alter test results. The aim of this study was to see how some of these common adulterants affect UDST results in practice and whether they can be detected by sample validity tests with pH and URIT 11G test strips. To this end we added household chemicals (acids, alkalis, oxidizing agents, surfactants, and miscellaneous substances) to urine samples positive for amphetamine, 3,4-methylenedioxymethamphetamine (MDMA), tetrahydrocannabinol, heroin, cocaine, or benzodiazepines (diazepam or alprazolam) and tested them with one-component immunochromatographic UDST strips. The UDST for cocaine resisted adulteration the most, while the cannabis test produced the most false negative results. The most potent adulterant that barely changed the physiological properties of urine specimens and therefore escaped adulteration detection was vinegar. Besides lemon juice, it produced the most false negative test results. In conclusion, some urine adulterants, such as vinegar, could pass urine specimen validity test and remain undetected by laboratory testing. Our findings raise concern about this issue of preventing urine tampering and call for better control at sampling, privacy concerns notwithstanding, and better sample validity tests.

Concomitant use of benzodiazepines in chronic pain patients adherent to extended-release tapentadol or oxycodone treatment-A retrospective claims analysis.

OBJECTIVE: To compare concomitant benzodiazepine (BZDs) use among chronic pain patients adherent to extended-release tapentadol (TapER) or oxycodone (OxnER) and estimate the number of lives potentially saved by switching pa-tients to the less BZD coprescribed treatment. DESIGN: Retrospective database study. SETTING: Patients were identified using the IBM MarketScan® Commercial Database. The opioid overdose death esti-mates were obtained from the US national mortality register and were used to estimate the number of lives potentially saved by switching patients to the opioid treatment with lower rates of BZD coprescribing. PATIENTS, PARTICIPANTS: The authors identified 30,213 chronic pain patients between October 2012 and March 2016. Af-ter propensity score matching, N = 2,355 and N = 6,761 patients were adherent (proportion of days covered ≥80 percent) to TapER and OxnER, respectively. INTERVENTIONS: TapER versus OxnER, during the 180-day treatment. MAIN OUTCOME MEASURE(S): Proportions of BZD coprescribing, BZD dosing patterns in matched patients, and the esti-mated number of lives potentially saved by the opioid treatment switch. RESULTS: TapER patients were less coprescribed BZDs during the treatment period (38.9 percent versus 49.2 percent, OR = 0.659, p < 0.001), and had fewer days of BZD supply per patient (mean: 49.6 versus 70.2 days, p < 0.001) with similar BZD average daily dose. Due to less frequent coprescribing of BZDs with TapER, it is estimated that ~800 deaths may have been avoided in the U.S. as a result of switching patients from OxnER to TapER. CONCLUSIONS: Among treatment-adherent patients, TapER patients had fewer BZD coprescriptions than OxnER pa-tients had. Moreover, when BZDs were coprescribed, those BZD prescriptions were for shorter periods of time. Pro-spective studies are warranted to explore rates and consequences of BZD coprescribing among opioids.

Healthcare Costs And Resource Utilization In Chronic Pain Patients Treated With Extended-Release Formulations Of Tapentadol, Oxycodone, Or Morphine Stratified By Type Of Pain: A Retrospective Claims Analysis, 2012-2016.

PURPOSE: Chronic pain treatment imposes a substantial economic burden on US society. Treatment costs may vary across subgroups of patients with different types of pain. The aim of our study was to compare healthcare costs (HC) and resource utilization in musculoskeletal (MP), neuropathic (NP), and cancer pain (CaP) patients treated with long-acting opioids (LAO), using real-world evidence. PATIENTS AND METHODS: We compared total HC and resource utilization in subgroups of chronic pain patients (MP, NP or CaP) treated with three LAO alternatives: morphine-sulfate extended-release (MsER), oxycodone ER (OxnER) and tapentadol ER (TapER). Retrospective claims data were analyzed in the IBM Truven Health MarketScan® Commercial Claims Database (October 2012 through March 2016). All patients were continuously health plan enrolled for at least 12 months before the index date (first LAO prescription date) and during the LAO-treatment period. The cohorts were propensity-score matched. RESULTS: A total of 2824 TapER-treated patients were matched to 16,716 OxnER-treated patients, while 2827 TapER patients were matched to 16,817 MsER patients. The average monthly total HC were lower in the TapER than in the OxnER cohort ($2510 vs. $3720, p<0.001), reflecting significantly lower outpatient, inpatient and emergency department visit rates in the TapER cohort. Similarly, the TapER cohort exhibited a lower average monthly total HC ($2520 vs. $2900, p<0.05) than MsER cohort, with significantly fewer inpatient and outpatient visits in the TapER cohort. TapER demonstrated significantly lower total HC than OxnER in patients with NP and MP, and similar to OxnER in CaP patients. TapER costs were similar to MsER costs in all pain-type subpopulations. CONCLUSION: Based on real-world evidence, the TapER treatment for chronic pain was associated with significantly lower HC compared with MsER or OxnER. When categorized by type of pain, TapER remained a less costly strategy in comparison with OxnER for MP and NP.