Association of Naturalistic Administration of Cannabis Flower and Concentrates With Intoxication and Impairment.

Importance: The rapidly growing legal cannabis market includes new and highly potent products, the effects of which, to our knowledge, have not previously been examined in biobehavioral research studies because of federal restrictions on cannabis research. Objective: To use federally compatible, observational methods to study high-∆9-tetrahydrocannabinol (THC) legal market forms of cannabis. Design, Setting, and Participants: In this cohort study with a between-groups design that was conducted in a community and university setting, cannabis flower users and concentrate users were randomly assigned to higher- vs lower-THC products within user groups. Participants completed a baseline and an experimental mobile laboratory assessment that included 3 points: before, immediately after, and 1 hour after ad libitum legal market flower and concentrate use. Of the 133 individuals enrolled and assessed, 55 regular flower cannabis users (41.4%) and 66 regular concentrate cannabis users (49.6%) complied with the study's cannabis use instructions and had complete data across primary outcomes. Exposures: Flower users were randomly assigned to use either 16% or 24% THC flower and concentrate users were randomly assigned to use either 70% or 90% THC concentrate that they purchased from a dispensary. Main Outcomes and Measures: Primary outcome measures included plasma cannabinoids, subjective drug intoxication, and neurobehavioral tasks testing attention, memory, inhibitory control, and balance. Results: A total of 121 participants completed the study for analysis: 55 flower users (mean [SD] age, 28.8 [8.1] years; 25 women [46%]) and 66 concentrate users (mean [SD] age, 28.3 [10.4] years; 30 women [45%]). Concentrate users compared with flower users exhibited higher plasma THC levels and 11-hydroxyΔ9-THC (THC's active metabolite) across all points. After ad libitum cannabis administration, mean plasma THC levels were 0.32 (SE = 0.43) µg/mL in concentrate users (to convert to millimoles per liter, multiply by 3.18) and 0.14 (SE = 0.16) µg/mL in flower users. Most neurobehavioral measures were not altered by short-term cannabis consumption. However, delayed verbal memory (F1,203 = 32.31; P < .001) and balance function (F1,203 = 18.88; P < .001) were impaired after use. Differing outcomes for the type of product (flower vs concentrate) or potency within products were not observed. Conclusions and Relevance: This study provides information about the association of pharmacological and neurobehavioral outcomes with legal market cannabis. Short-term use of concentrates was associated with higher levels of THC exposure. Across forms of cannabis and potencies, users' domains of verbal memory and proprioception-focused postural stability were primarily associated with THC administration.

[Influence of diagnostic pathway on clinical and non-conventional therapies use in women with breast cancer of the cohort DAMA]. / Influencia de la vía diagnóstica en la clínica y el uso de terapias no convencionales en mujeres con cáncer de mama de la cohorte DAMA.

OBJECTIVE: To describe and analyze the characteristics of breast cancer tumours according to the diagnostic pathway. We analyse the adverse effects of the treatments and the use of unconventional therapies in order to alleviate them. METHOD: Descriptive design nested in a mixed cohort (Cohort DAMA). The dependent variable was the route to diagnosis of breast cancer. The independent variables were age, body mass index, social class, disposable family income, type of tumour, histological degree, tumour stage, recurrences, treatment, adverse effects derived from treatments and unconventional therapies. Bivariate descriptive analyses were performed and univariate and multivariate regression models were adjusted; and graphic representations of the unconventional therapies. RESULTS: There are differences in the characteristics of the tumours, and the impact of the adverse effects derived from the treatments. The patients diagnosed by screening were older, from a high social class, had a higher percentage of tumours of grade I differentiation, initial stages, fewer recurrences and fewer adverse effects due to treatment, although this was not different in the screening group compared to the rest. There was also less use of unconventional therapies. CONCLUSIONS: The results indicate that the implementation of screening programmes increases the possibility of detecting tumours in initial stages and with therapies with fewer adverse effects. As a result, there is less need to resort to unconventional therapies.

Association Between Psychotropic Medication Polypharmacy and an Objective Measure of Balance Impairment Among Middle-Aged Adults: Results from the US National Health and Nutrition Examination Survey.

OBJECTIVE: Psychotropic medications (e.g., antidepressants, anxiolytics, and neuroleptics) are increasingly prescribed with two or more taken concurrently (polypharmacy), and have been associated with an increased risk of falling. The aim of this study was to examine the association between psychotropic medication use and balance impairment using an objective balance measure. METHODS: We derived data from participants aged 40 years and older in the US National Health and Nutrition Examination Survey (1999/00-2003/04) who completed the Modified Clinical Trial of Sensory Interaction and Balance and indicated current medications (n = 3090). Balance impairment was defined as failing the Modified Clinical Trial of Sensory Interaction and Balance condition 4 (standing on foam surface, eyes closed). Medication use included specific psychotropic classes, a count of psychotropic medications, and a count of non-psychotropic medications taken concurrently. Nested multiple logistic regression assessed relationships between medication use and balance impairment, adjusting for covariates and complex sampling. RESULTS: One third of participants had balance impairment. After accounting for medical comorbidities, there was no relationship between individual classes of psychotropic medications and balance impairment. After adjusting for all covariates, there was a dose-response relationship between the number of psychotropic medications taken and balance impairment, with every additional medication associated with a 35% higher odds (odds ratio = 1.35; 95% confidence interval 1.07-1.70). In comparison, there was no increase in the odds of balance impairment associated with each additional medication taken for participants only taking non-psychotropic medications. CONCLUSIONS: Psychotropic medication polypharmacy is associated with an increased odds of balance impairment. Clinicians should exercise caution when prescribing combinations of psychotropic medications, and refer to physical therapy for assessment and treatment if balance impairment is detected.

Chemotherapy-Induced Peripheral Neuropathy in Long-term Survivors of Childhood Cancer: Clinical, Neurophysiological, Functional, and Patient-Reported Outcomes.

Importance: In light of the excellent long-term survival of childhood cancer patients, it is imperative to screen for factors affecting health, function, and quality of life in long-term survivors. Objective: To comprehensively assess chemotherapy-induced peripheral neuropathy in childhood cancer survivors to define disease burden and functional effect and to inform screening recommendations. Design, Setting, and Participants: In this cross-sectional observational study, cancer survivors who were treated with chemotherapy for extracranial malignancy before age 17 years were recruited consecutively between April 2015 and December 2016 from a single tertiary hospital-based comprehensive cancer survivorship clinic and compared with healthy age-matched controls. Investigators were blinded to the type of chemotherapy. A total of 169 patients met inclusion criteria, of whom 48 (28.4%) were unable to be contacted or declined participation. Exposures: Chemotherapy agents known to be toxic to peripheral nerves. Main Outcomes and Measures: The clinical peripheral neurological assessment using the Total Neuropathy Score was compared between recipients of different neurotoxic chemotherapy agents and control participants and was correlated with neurophysiological, functional, and patient-reported outcome measures. Results: Of the 121 childhood cancer survivors included in this study, 65 (53.7%) were male, and the cohort underwent neurotoxicity assessments at a median (range) age of 16 (7-47) years, a median (range) 8.5 (1.5-29) years after treatment completion. Vinca alkaloids and platinum compounds were the main neurotoxic agents. Clinical abnormalities consistent with peripheral neuropathy were common, seen in 53 of 100 participants (53.0%) treated with neurotoxic chemotherapy (mean Total Neuropathy Score increase, 2.1; 95% CI, 1.4-2.9; P < .001), and were associated with lower limb predominant sensory axonal neuropathy (mean amplitude reduction, 5.8 µV; 95% CI, 2.8-8.8; P < .001). Functional deficits were seen in manual dexterity, distal sensation, and balance. Patient-reported outcomes demonstrating reduction in global quality of life and physical functioning were associated with the Total Neuropathy Score. Cisplatin produced long-term neurotoxicity more frequently than vinca alkaloids. Conclusions and Relevance: Clinical abnormalities attributable to peripheral neuropathy were common in childhood cancer survivors and persisted long term, with concurrent deficits in patient-reported outcomes. Both the type of neurotoxic agent and a targeted clinical neurological assessment are important considerations when screening survivors for long-term neuropathy. Further development of peripheral neuropathy-specific pediatric assessment tools will aid research into neuroprotective and rehabilitative strategies.

Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: a single-centre, open-label, dose-escalation, phase 1 trial.

BACKGROUND: Pancreatic cancer statistics are dismal, with a 5-year survival of less than 10%, and more than 50% of patients presenting with metastatic disease. Metabolic reprogramming is an emerging hallmark of pancreatic adenocarcinoma. CPI-613 is a novel anticancer agent that selectively targets the altered form of mitochondrial energy metabolism in tumour cells, causing changes in mitochondrial enzyme activities and redox status that lead to apoptosis, necrosis, and autophagy of tumour cells. We aimed to establish the maximum tolerated dose of CPI-613 when used in combination with modified FOLFIRINOX chemotherapy (comprising oxaliplatin, leucovorin, irinotecan, and fluorouracil) in patients with metastatic pancreatic cancer. METHODS: In this single-centre, open-label, dose-escalation phase 1 trial, we recruited adult patients (aged ≥18 years) with newly diagnosed metastatic pancreatic adenocarcinoma from the Comprehensive Cancer Center of Wake Forest Baptist Medical Center (Winston-Salem, NC, USA). Patients had good bone marrow, liver and kidney function, and good performance status (Eastern Cooperative Oncology Group [ECOG] performance status 0-1). We studied CPI-613 in combination with modified FOLFIRINOX (oxaliplatin at 65 mg/m2, leucovorin at 400 mg/m2, irinotecan at 140 mg/m2, and fluorouracil 400 mg/m2 bolus followed by 2400 mg/m2 over 46 h). We applied a two-stage dose-escalation scheme (single patient and traditional 3+3 design). In the single-patient stage, one patient was accrued per dose level. The starting dose of CPI-613 was 500 mg/m2 per day; the dose level was then escalated by doubling the previous dose if there were no adverse events worse than grade 2 within 4 weeks attributed as probably or definitely related to CPI-613. The traditional 3+3 dose-escalation stage was triggered if toxic effects attributed as probably or definitely related to CPI-613 were grade 2 or worse. The dose level for CPI-613 for the first cohort in the traditional dose-escalation stage was the same as that used in the last cohort of the single-patient dose-escalation stage. The primary objective was to establish the maximum tolerated dose of CPI-613 (as assessed by dose-limiting toxicities). This trial is registered with ClinicalTrials.gov, number NCT01835041, and is closed to recruitment. FINDINGS: Between April 22, 2013, and Jan 8, 2016, we enrolled 20 patients. The maximum tolerated dose of CPI-613 was 500 mg/m2. The median number of treatment cycles given at the maximum tolerated dose was 11 (IQR 4-19). Median follow-up of the 18 patients treated at the maximum tolerated dose was 378 days (IQR 250-602). Two patients enrolled at a higher dose of 1000 mg/m2, and both had a dose-limiting toxicity. Two unexpected serious adverse events occurred, both for the first patient enrolled. Expected serious adverse events were: thrombocytopenia, anaemia, and lymphopenia (all for patient number 2; anaemia and lymphopenia were dose-limiting toxicities); hyperglycaemia (in patient number 7); hypokalaemia, hypoalbuminaemia, and sepsis (patient number 11); and neutropenia (patient number 20). No deaths due to adverse events were reported. For the 18 patients given the maximum tolerated dose, the most common grade 3-4 non-haematological adverse events were hyperglycaemia (ten [55%] patients), hypokalaemia (six [33%]), peripheral sensory neuropathy (five [28%]), diarrhoea (five [28%]), and abdominal pain (four [22%]). The most common grade 3-4 haematological adverse events were neutropenia (five [28%] of 18 patients), lymphopenia (five [28%]), anaemia (four [22%], and thrombocytopenia in three [17%]). Sensory neuropathy (all grade 1-3) was recorded in 17 (94%) of the 18 patients and was managed with dose de-escalation or discontinuation per standard of care. No patients died while on active treatment; 11 study participants died, with cause of death as terminal pancreatic cancer. Of the 18 patients given the maximum tolerated dose, 11 (61%) achieved an objective (complete or partial) response. INTERPRETATION: A maximum tolerated dose of CPI-613 was established at 500 mg/m2 when used in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer. The findings of clinical activity will require validation in a phase 2 trial. FUNDING: Comprehensive Cancer Center of Wake Forest Baptist Medical Center.

Effective treatment for sensitive skin: 4-t-butylcyclohexanol and licochalcone A.

BACKGROUND: More than 50% of adults report to suffer from sensitive skin. This common condition is characterized by subjective sensations such as prickling, burning, skin tightness or pruritus, and is often accompanied by objective symptoms like inflammation and erythema. OBJECTIVE: The objective of this study was to develop an active ingredient concept for the treatment of sensitive skin. We tested compounds regarding their potential to (i) decrease the release of proinflammatory mediators, which among others induce erythema and (ii) counteract the hyperresponsiveness of nerve fibres and, thus, exert effects on cutaneous neurosensory dysfunction. METHODS: 4-t-butylcyclohexanol, licochalcone A and acetyl dipeptide-1 cetyl ester were analysed in vitro regarding their potential to (i) decrease the release of PGE2 and activation of NFκB and to (ii) inhibit TRPV1 activation or the release of neuronal CGRP. To assess subjective and objective symptoms of skin sensitivity in vivo, two controlled, single-blind, randomized studies were conducted with 4-t-butylcyclohexanol and the combination with licochalcone A. RESULTS: In vitro, 4-t-butylcyclohexanol significantly reduced TRPV1 activation, while acetyl dipeptide-1 cetyl ester had no effect on receptor activation. Licochalcone A significantly decreased NFκB signalling and PGE2 secretion, at lower concentrations than acetyl dipeptide-1 cetyl ester. A formulation containing 4-t-butylcyclohexanol showed a significant immediate anti-stinging/anti-burning effect in vivo, and a cream base containing a combination of 4-t-butylcyclohexanol and a licochalcone A-rich licorice extract reduced shaving-induced erythema. CONCLUSION: In vitro and in vivo data indicate that the combination of the TRPV1 antagonist 4-t-butylcyclohexanol and the potent anti-inflammatory licochalcone A provide an effective active ingredient concept for the treatment of sensitive skin, as the topical application resulted in an immediate relief from symptoms such as erythema and stinging.

Comparison of skin calming effects of cosmetic products containing 4-t-butylcyclohexanol or acetyl dipeptide-1 cetyl ester on capsaicin-induced facial stinging in volunteers with sensitive skin.

OBJECTIVE: To assess and compare the skin calming effect of cosmetic products containing 4-t-butylcyclohexanol (Eucerin(®) UltraSensitive Soothing Care Dry Skin) or acetyl dipeptide-1 cetyl ester (La Roche-Posay Toleriane(®) Ultra Intense Soothing Care) on subjective symptoms of skin sensitivity, a controlled, single-blind, randomized split-face capsaicin-induced stinging test was conducted. METHODS: Thirty-one female test subjects, ranging from 19 to 65 years of age, with self-perceived sensitive to very sensitive skin were enrolled. After a 3-day preconditioning period with no application of facial products and positive reaction to stimulation with a 40 ppm capsaicin cream, the test products were randomly applied to either the right or left nasolabial fold. Burning severity was assessed immediately after capsaicin application, and 1, 2, 5, 10 and 15 min after application of the test products. RESULTS: All 31 subjects reported a stinging/burning sensation on both nasolabial folds after application of capsaicin. Treatment with the 4-t-butylcyclohexanol containing product resulted in significant lower values for burning/stinging after one, and two minutes post-application in comparison to the values for the acetyl dipeptide-1 cetyl ester containing product. No significant difference was determined between the two test products for the point in time with most intense burning sensation, the severity of burning and the duration of burning after capsaicin application and subsequent application of the test products. CONCLUSION: Both products alleviated capsaicin-induced burning during the first 15 min after application. A faster and more pronounced soothing effect in vivo was demonstrated for the 4-t-butylcyclohexanol containing cosmetic product in comparison to the acetyl dipeptide-1 cetyl ester containing cosmetic formulation.

The failure to detect drug-induced sensory loss in standard preclinical studies.

Over the years a number of drugs have been approved for human use with limited signs of toxicity noted during preclinical risk assessment study designs but then show adverse events in compliant patients taking the drugs as prescribed within the first few years on the market. Loss or impairments in sensory systems, such as hearing, vision, taste, and smell have been reported to the FDA or have been described in the literature appearing in peer-reviewed scientific journals within the first five years of widespread use. This review highlights the interactive cross-modal compensation within sensory systems that can occur that reduces the likelihood of identifying these losses in less sentient animals used in standard preclinical toxicology and safety protocols. We provide some historical and experimental evidence to substantiate these sensory effects in and highlight the critical importance of detailed training of technicians on basic ethological, species-specific behaviors of all purpose-bred laboratory animals used in these study designs. We propose that the time, effort and cost of training technicians to be better able to identify and document very subtle changes in behavior will serve to increase the likelihood of early detection of biomarkers predictive of drug-induced sensory loss within current standard regulatory preclinical research protocols.

Choline Ameliorates Deficits in Balance Caused by Acute Neonatal Ethanol Exposure.

Fetal alcohol spectrum disorder (FASD) is estimated to occur in 1 % of all live births. The developing cerebellum is vulnerable to the toxic effects of alcohol. People with FASD have cerebellar hypoplasia and developmental deficits associated with cerebellar injury. Choline is an essential nutrient, but many diets in the USA are choline deficient. In rats, choline given with or following alcohol exposure reduces many alcohol-induced neurobehavioral deficits but not those associated with cerebellar function. Our objective was to determine if choline supplementation prior to alcohol exposure would ameliorate the impact of ethanol on a cerebellar-associated behavioral test in mice. Pregnant C57Bl6/J mice were maintained on a choline-deficient diet from embryonic day 4.5. On postnatal day 1 (P1), pups were assigned to one of eight treatment groups: choline (C) or saline (S) pre-treatment from P1 to P5, ethanol (6 g/kg) or Intralipid(®) on P5, C and or S post-treatment from P6 to P20. On P30, balance and coordination were tested using the dowel crossing test. Overall, there was a significant effect of treatment and females crossed longer distances than males. Ethanol exposure significantly reduced the total distance crossed. Choline pre-treatment increased the distance crossed by males, and both pre- and post-treatment with choline significantly increased total distance crossed for females and males. There was no effect of choline on Intralipid®-exposed animals. This is the first study to show that choline ameliorates ethanol-induced effects on balance and coordination when given before ethanol exposure. Choline fortification of common foodstuffs may reduce the effects of alcohol.