Complexity of Translating Analytics to Recent Cannabis Use and Impairment.

While current analytical methodologies can readily identify cannabis use, definitively establishing recent use within the impairment window has proven to be far more complex, requiring a new approach. Recent studies have shown no direct relationship between impairment and Δ9-tetra-hydrocannabinol (Δ9-THC) concentrations in blood or saliva, making legal "per se" Δ9-THC limits scientifically unjustified. Current methods that focus on Δ9-THC and/or metabolite concentrations in blood, saliva, urine, or exhaled breath can lead to false-positive results for recent use due to the persistence of Δ9-THC well outside of the typical 3-4 h window of potential impairment following cannabis inhalation.

Examining impairment and kinetic patterns associated with recent use of hemp-derived Δ-tetrahydrocannabinol: case studies.

Background: As a result of the legalization of U.S. industrial hemp production in late 2018, products containing hemp-derived Δ-tetrahydrocannabinol (Δ-THC) are increasing in popularity.

Indeterminacy of cannabis impairment and ∆-tetrahydrocannabinol (∆-THC) levels in blood and breath.

Previous investigators have found no clear relationship between specific blood concentrations of ∆-tetrahydrocannabinol (∆-THC) and impairment, and thus no scientific justification for use of legal "per se" ∆-THC blood concentration limits. Analyzing blood from 30 subjects showed ∆-THC concentrations that exceeded 5 ng/mL in 16 of the 30 subjects following a 12-h period of abstinence in the absence of any impairment. In blood and exhaled breath samples collected from a group of 34 subjects at baseline prior to smoking, increasing breath ∆-THC levels were correlated with increasing blood levels (P < 0.

A comprehensive breath test that confirms recent use of inhaled cannabis within the impairment window.

Legalization of cannabis for medicinal and/or recreational use is expanding globally. Although cannabis is being regulated country by country, an accurate recent use test with indisputable results correlated with impairment has yet to be discovered. In the present study, a new approach for determining recent cannabis use within the impairment window after smoking was developed by studying 74 subjects with a mean age of 25 years and average use history of 9 years.

Development and Validation of a Liquid Chromatography High-Resolution Mass Spectrometry (LC-HRMS) Bioanalytical Method for Quantifying Cannabinoids in Whole Blood: Application for Determining Recent Cannabis Use.

Background: Cannabis legalization is expanding rapidly throughout the United States, but there is no reliable means of establishing recent use.

Objective: To develop and validate a bioanalytical method for determination of Δ9-tetrahydrocannabinol (Δ9-THC), cannabinol, 11-hydroxy-Δ9-THC, 11-nor-9-carboxy-Δ9-THC, and 8β,11-dihydroxy-Δ9-THC in whole blood microsamples by liquid chromatography high-resolution mass spectrometry (LC-HRMS).

Methods: Cannabinoid extraction from whole blood was performed using a mixture of n-hexane/ethyl acetate (90:10, v/v).

Repurposing ospemifene for potentiating an antigen-specific immune response.

Objective: Ospemifene, an estrogen receptor agonist/antagonist approved for the treatment of dyspareunia and vaginal dryness in postmenopausal women, has potential new indications as an immune modulator. The overall objective of the present series of preclinical studies was to evaluate the immunomodulatory activity of ospemifene in combination with a peptide cancer vaccine.

Methods: Immune regulating effects, mechanism of action and structure activity relationships of ospemifene and related compounds were evaluated by examining expression of T-cell activating cytokines in vitro, and antigen-specific immune response and cytotoxic T-lymphocyte activity in vivo.

Novel cancer antigens for personalized immunotherapies: latest evidence and clinical potential.

The clinical success of monoclonal antibody immune checkpoint modulators such as ipilimumab, which targets cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), and the recently approved agents nivolumab and pembrolizumab, which target programmed cell death receptor 1 (PD-1), has stimulated renewed enthusiasm for anticancer immunotherapy, which was heralded by Science as 'Breakthrough of the Year' in 2013. As the potential of cancer immunotherapy has been recognized since the 1890s when William Coley showed that bacterial products could be beneficial in cancer patients, leveraging the immune system in the treatment of cancer is certainly not a new concept; however, earlier attempts to develop effective therapeutic vaccines and antibodies against solid tumors, for example, melanoma, frequently met with failure due in part to self-tolerance and the development of an immunosuppressive tumor microenvironment. Increased knowledge of the mechanisms through which cancer evades the immune system and the identification of tumor-associated antigens (TAAs) and negative immune checkpoint regulators have led to the development of vaccines and monoclonal antibodies targeting specific tumor antigens and immune checkpoints such as CTLA-4 and PD-1.

Assessing the Effects of Concurrent versus Sequential Cisplatin/Radiotherapy on Immune Status in Lung Tumor-Bearing C57BL/6 Mice.

Concurrent and sequential cisplatin-based chemoradiotherapy regimens are standard therapeutic approaches in cancer treatment. Recent clinical data suggest that these different dosing schedules may adversely affect antigen-specific immunotherapy. The goal of the present preclinical study was to explore the effects of concurrent and sequential cisplatin/radiotherapy on immune status in a lung cancer mouse model.

Tecemotide: an antigen-specific cancer immunotherapy.

The identification of tumor-associated antigens (TAA) has made possible the development of antigen-specific cancer immunotherapies such as tecemotide. One of those is mucin 1 (MUC1), a cell membrane glycoprotein expressed on some epithelial tissues such as breast and lung. In cancer, MUC1 becomes overexpressed and aberrantly glycosylated, exposing the immunogenic tandem repeat units in the extracellular domain of MUC1.

Safety and efficacy of ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy due to menopause.

During the menopausal transition, women experience a number of symptoms due to declining estrogen levels, including vasomotor symptoms and vulvar and vaginal atrophy (VVA). Unlike vasomotor symptoms, vaginal dryness and dyspareunia, the main symptoms of VVA, typically worsen without treatment and can significantly impact the quality of life. Up to 60% of postmenopausal women may be affected by VVA, but many women unfortunately do not seek treatment due to embarrassment or other factors.

Ospemifene: a first-in-class, non-hormonal selective estrogen receptor modulator approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy.

Ospemifene is a selective estrogen receptor modulator (SERM) approved for the treatment of dyspareunia associated with vulvar and vaginal atrophy (VVA) due to menopause. As the first non-hormonal treatment for this indication, the approval of ospemifene represents a significant milestone in postmenopausal women's health. Ospemifene is a triphenylethylene similar in chemical structure to tamoxifen and toremifene.

Antitumor effects of cisplatin combined with tecemotide immunotherapy in a human MUC1 transgenic lung cancer mouse model.

The goals of the present study were to define the effects of simultaneous cisplatin/tecemotide therapy on tumor development in a human mucin 1 (MUC1) transgenic lung cancer mouse model and to examine the effects of radiotherapy (RTX) on splenocytes, serum cytokines, and immune response to tecemotide. Two hundred twenty-six human MUC1 transgenic C57BL/6 mice were used in five studies designed to assess (i) serum cytokine and immune responses following four weekly 10-μg doses of tecemotide; (ii) the effects of simultaneous administration of cisplatin (2.5 mg/kg × 2 doses/cycle × 4 cycles) and tecemotide (2 cycles × 8 weekly 10-μg doses/cycle) therapy on tumor development, serum cytokines, and immune response; (iii) the dose-response effects of RTX on lymphocyte counts 16 hours following doses of 2 to 8 Gy; (iv) the time course of lymphocyte recovery from 16 hours to 20 days following 8-Gy RTX; and (v) the effects of simultaneous administration of RTX (8 Gy) and tecemotide on the immune response to tecemotide (four weekly 10-μg doses).

Activating adaptive cellular mechanisms of resistance following sublethal cytotoxic chemotherapy: implications for diagnostic microdosing.

As Phase 0 studies have proven to be reasonably predictive of therapeutic dose pharmacokinetics, the application of microdosing has expanded into metabolism, drug-drug interactions and now diagnostics. One potentially serious issue with this application of microdosing that has not been previously discussed is the possibility of activating cellular mechanisms of drug resistance. Here, we provide an overview of Phase 0 microdosing and drug resistance, with an emphasis on cisplatin resistance, followed by a discussion of the potential for inducing acquired resistance to platinum-based or other types of chemotherapy in cancer patients participating in Phase 0 diagnostic microdosing studies.

Clarifying the pharmacodynamics of tecemotide (L-BLP25)-based combination therapy.

The results of a recently completed Phase III clinical trial suggest that concurrent chemoradiotherapy followed by tecemotide provides superior benefits to Stage IIIa and IIIb non-small cell lung carcinoma patients as compared with sequential chemoradiotherapy followed by tecemotide. These clinical observations will be dissected in a transgenic model of lung cancer that we have recently established (hMUC1.Tg C57BL/6 mice).

Induction of invasive transitional cell bladder carcinoma in immune intact human MUC1 transgenic mice: a model for immunotherapy development.

A preclinical model of invasive bladder cancer was developed in human mucin 1 (MUC1) transgenic (MUC1.Tg) mice for the purpose of evaluating immunotherapy and/or cytotoxic chemotherapy. To induce bladder cancer, C57BL/6 mice (MUC1.

Ospemifene for the treatment of dyspareunia associated with vulvar and vaginal atrophy: potential benefits in bone and breast.

Ospemifene is a selective estrogen receptor modulator (SERM), or estrogen receptor agonist/antagonist, that was recently approved by the US Food and Drug Administration for the treatment of dyspareunia associated with vulvar and vaginal atrophy, a chronic condition that affects up to 60% of postmenopausal women. Ospemifene is the first and only nonestrogen compound approved for this indication. Compared with other approved SERMs, such as tamoxifen, toremifene, bazedoxifene, and raloxifene, the estrogen-like effects of ospemifene in the vaginal epithelium are unique.

Antitumor effects of L-BLP25 antigen-specific tumor immunotherapy in a novel human MUC1 transgenic lung cancer mouse model.

Background: L-BLP25 antigen-specific cancer immunotherapeutic agent is currently in phase III clinical trials for non-small cell lung cancer. Using a novel human MUC1 transgenic (hMUC1.Tg) lung cancer mouse model, we evaluated effects of L-BLP25 combined with low-dose cyclophosphamide (CPA) pretreatment on Th1/Th2 cytokine production and antitumor activity.

Ospemifene, vulvovaginal atrophy, and breast cancer.

The incidence and severity of vulvovaginal atrophy (VVA) in postmenopausal breast cancer patients has a significant impact on quality of life. While the etiology of VVA is primarily related to low estrogen levels seen in menopause, women with breast cancer have an added risk of VVA induced by a combination of chemotherapy, hormonal therapy, and menopause. Ospemifene is a new, non-hormonal selective estrogen receptor modulator (SERM) triphenylethylene derivative that is effective in treating VVA in postmenopausal women.

Ospemifene and 4-hydroxyospemifene effectively prevent and treat breast cancer in the MTag.Tg transgenic mouse model.

Objective: Ospemifene, a new drug indicated for the treatment of vulvovaginal atrophy, has completed phase III clinical trials. A condition affecting millions of women worldwide, vulvovaginal atrophy has long been treated with estrogen therapy. Estrogen treatment carries with it risks of thromboembolism, endometrial proliferative effects, and breast cancer promotion.

Pharmacologic evaluation of ospemifene.

Importance Of The Field: Millions of women worldwide suffer from vulvovaginal atrophy (VVA) associated with menopause, and many women report that this adversely affects their quality of life. Ospemifene is a non-hormonal estrogen receptor agonist/antagonist effective in the treatment of VVA. Although similar in structure to other estrogen receptor agonists/antagonists that have antagonistic effects on the vagina, ospemifene has an estrogen-like effect on vaginal epithelium.

Pharmacologic effects of ospemifene in rhesus macaques: a pilot study.

Ospemifene (Ophena) is a new selective oestrogen receptor modulator currently in phase III clinical development for treatment of post-menopausal vulvar and vaginal atrophy. In the present study, we examined the pharmacokinetics, toxicity, and DNA adduct forming potential of ospemifene in the liver and endometrium of rhesus macaques following single and subchronic dosing schedules to better understand the potential toxicologic effects of ospemifene. During single weekly dosing, six macaques were administered 35 mg/kg/week ospemifene orally for 3 weeks.

Ineffectiveness of American ginseng in the prevention of dimethylbenzanthracene-induced mammary tumors in mice.

The potential of American ginseng (AG) ( Panax quinquefolium), a commonly used herbal remedy believed to have anticarcinogenic effects, to prevent the development of mammary tumors was evaluated in a mouse model of dimethylbenzanthracene (DMBA)-induced mammary carcinoma. Ginsenosides, believed to be the active components of ginseng and that have a chemical structure similar to estradiol, have previously been shown to possess phytoestrogen-like qualities similar to the soy isoflavone genistein. The effects of AG, administered as powdered root, were compared to the selective estrogen receptor modulators tamoxifen and ospemifene.

Selective estrogen receptor modulators inhibit growth and progression of premalignant lesions in a mouse model of ductal carcinoma in situ.

Introduction: Ductal carcinoma in situ (DCIS) is a noninvasive premalignant lesion and is considered a precursor to invasive carcinoma. DCIS accounts for nearly 20% of newly diagnosed breast cancer, but the lack of experimentally amenable in vivo DCIS models hinders the development of treatment strategies. Here, we demonstrate the utility of a mouse transplantation model of DCIS for chemoprevention studies using selective estrogen receptor modulators (SERMs).

Ospemifene inhibits the growth of dimethylbenzanthracene-induced mammary tumors in Sencar mice.

Ospemifene is a new selective estrogen receptor modulator (SERM) that is being developed for the treatment of urogenital atrophy and osteoporosis. Similarly to other SERMs, ospemifene exhibits antiestrogenic effects in breast tissue, which led to the hypothesis that it may be a potential breast cancer chemopreventive agent. We first assessed the ability of ospemifene, compared to tamoxifen and raloxifene, to prevent dimethylbenzanthracene (DMBA)-induced mammary tumors in female Sencar mice.