Cannabidiol and Δ8-Tetrahydrocannabinol: Cannabinoids of Rising Interest and Concern.

Although much is known about Δ9-tetrahydrocannabinol and its inactive open ring isomer, cannabidiol, far less is known about the effects, metabolism, and pharmacodynamics of Δ9-tetrahydrocannabinol's double-bond isomer, Δ8-tetrahydrocannabinol. With the passage of the so-called United States "Farm Bill," which was made law in order to allow legal hemp cultivation in the United States, more needs to be known about the effects of Δ8-tetrahydrocannabinol, a double-bond isomer of Δ9-tetrahydrocannabinol, and cannabidiol (CBD), which is an open-ring isomer of Δ8-tetrahydrocannabinol. It is the aim of the review to summarize current knowledge of Δ8-tetrahydrocannabinol and CBD, including the pharmacodynamics and pharmacokinetics of CBD. Also, plant genetics, the effect of cannabinoids on the current topic of viral entry into mammalian cells, and the current practice of vaping, dabbing, and dripping are covered.

Instability and poor recovery of cannabinoids in urine, oral fluid, and hair.

Cannabinoids including, but not limited to Δ9-tetrahydrocannabinol, 11-hydroxytetrahydrocannabinol, and (-)-11-nor-Δ9-tetrahydrocannabinol-9-carboxylic acid are known to toxicologists and synthetic chemists as difficult compounds because they are subject to numerous degradative pathways. It is the purpose of this short review article to discuss common pathways that result in the disappearance of cannabinoids - such as conjugate formation, adsorption to surfaces, chemical reactions, microbial action, thermal decomposition, chemical bonding, photosensitivity, sample handling, analytical methodology, and micelle trapping - and to point out possible ways to avoid such degradation.

Drugs in hair. Part I. Metabolisms of major drug classes.

Currently, hair can be reliably tested for the presence of drugs. However, one major drawback to the use of parent drugs is the question of potential external or environmental contamination. The analysis of metabolites to confirm the use of the parent drugs was proposed in this short review. The development of hair as a test matrix and the incorporation of xenobiotics, in general, into the hair matrix were discussed. What constitutes an appropriate metabolite for drug testing to mirror the use of a parent drug was proposed and discussed. The use of metabolites rather than parent drugs to indicate unequivocal use rather than external exposure was also discussed for amphetamines, cannabinoids, cocaine, opiates (codeine, morphine, 6-acetylmorphine, hydrocodone, hydromorphone, oxycodone, oxymorphone), phencyclidine, fentanyl, benzodiazepines, and ethanol. This, however, was discussed in terms of class and/or individual drug. In addition, selection or potential selection of appropriate metabolites was reviewed. The actual incorporation of drug metabolites into hair versus the metabolism of drugs which was incorporated into hair were also considered.

Generation and analysis of zebrafish melanoma models.

The rapid emergence of the zebrafish as a cancer model has been aided by advances in genetic, chemical, and imaging technologies. Melanoma in particular highlights both the power and challenges associated with cancer modeling in zebrafish. This chapter focuses on the lessons that have emerged from the melanoma models as paradigmatic of what will apply to nearly all cancer models in the zebrafish system. We specifically focus on methodologies related to germline and mosaic transgenic melanoma generation, and how these can be used to deeply interrogate additional cooperating oncogenes or tumor suppressors. These transgenic tumors can in turn be used to generate zebrafish-specific, stable melanoma cell lines which can be fluorescently labeled, modified by cDNA/CRISPR techniques, and used for detailed in vivo imaging of cancer progression in real time. These zebrafish melanoma models are beginning to elucidate both cell intrinsic and microenvironmental factors in melanoma that have broader implications for human disease. We envision that nearly all of the techniques described here can be applied to other zebrafish cancer models, and likely expanded beyond what we describe here.

Truth-telling and patient diagnoses.

How do physicians handle informing patients of their diagnoses and how much information do patients really want? How do registered nurses view both sides of this question? Three questionnaires were constructed and administered in a mid-size hospital in New York state. Physicians and nurses underestimate the number of patients who want detailed information. Patients who earn more than average, have a college education, and who are under age 60 are more likely to want information, and state that their physician should give it to them. Only 42% of physicians state that patients want a detailed description of their diagnosis and treatment options. Physicians educated outside the USA appeared to be more likely to change their criteria for informing patients and, along with American-educated nurses, were more willing to participate in formal discussions of the issue. Physicians should comply with the wishes of patients for information and include them in the team deciding on diagnosis and treatment.

Drug approval summaries: arsenic trioxide, tamoxifen citrate, anastrazole, paclitaxel, bexarotene.

This report summarizes information on drugs recently approved by the Food and Drug Administration, Office of Drug Evaluation I, Division of Oncology Drug Products. Five applications supporting new claims will be discussed: Trisenox (arsenic trioxide) for induction of remission and consolidation in patients with acute promyelocytic leukemia who are refractory to, or have relapsed from, retinoid and anthracycline chemotherapy, and whose disease is characterized by the presence of the t(15;17) translocation or PML/RAR-alpha gene expression; Nolvadex (tamoxifen citrate) in women with ductal carcinoma in situ, following breast surgery and radiation, to reduce the risk of invasive breast cancer; Arimidex (anastrazole) for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer; Taxol (paclitaxel), 175 mg/m(2) by 3 h infusion in combination with cisplatin for first-line treatment of advanced ovarian cancer; and Targretin gel (bexarotene) for the topical treatment of cutaneous lesions in patients with stage IA and IB cutaneous T-cell lymphoma who have not tolerated other therapies or who have refractory or persistent disease. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.

Nitric oxide-dependent and -independent mechanisms account for gender differences in vasodilation to acetylcholine.

The purpose of this study was to examine the mechanism of enhanced endothelium-dependent dilation in arteries from female rats compared with arteries from males. Isolated mesenteric resistance arteries ( approximately 250 microm) from sexually mature male and female Sprague-Dawley rats were pressurized and outer diameter was measured. Arteries from females were more sensitive to the endothelium-dependent vasodilator acetylcholine (Ach) compared with those from males (-log EC(50): male = 6.74 +/- 0.06; female = 6.96 +/- 0.06; P =.037). After incubation with N(omega)-nitro-L-arginine (100 microM) or apamin (30 nM), there was no longer a gender difference in midrange sensitivity to ACh. In contrast, at higher concentrations of ACh, N(omega)-nitro-L-arginine had a greater inhibitory effect in the males than in the females. Indomethacin (10 microM) decreased sensitivity to ACh in arteries from both males and females, but did not alter the maximal response or eliminate the gender difference. Finally, there was no gender difference in vasodilation to the nitric oxide (NO) donor spermine-NO complex, nor did apamin alter the spermine-NO complex response. In conclusion, mesenteric arteries from female rats are more sensitive to ACh than those from males. An enhanced contribution of an apamin-sensitive K(Ca) channel on the endothelium of female arteries appears to be responsible for the augmented ACh-stimulated NO production compared with that of males. In addition, ACh stimulates the production of a non-NO, noncyclooxygenase, endothelium-derived hyperpolarizing factor to a greater extent in females compared with males.

Acoustic streaming in micromachined flexural plate wave devices: numerical simulation and experimental verification.

This paper presents the numerical simulation and experimental validation of acoustic streaming in micromachined flexural plate wave (FPW) devices. Two-dimensional and three-dimensional models of two device types were considered: the classical device with parallel interdigitated electrodes and the focused device with curved electrodes. Influences of different parameters on the time-averaged velocity were investigated. Thermal transport effects of the acoustic streaming were also considered. We observed the amplifying effect of the streaming in the second type numerically and experimentally. To verify simulation results, the method of the particle image velocimetry (PIV) was applied in the experimental investigation.

Ultrasonic flexural-plate-wave sensor for detecting the concentration of settling E. coli W3110 cells.

The flexural-plate-wave (FPW) sensor, a type of ultrasonic sensor, can detect changes in E. coli W3110 concentration in solution as the cells settle onto the sensor under the influence of gravity. A model of the sensor's response to cell settling has been developed and is in good agreement with the experimental data. The FPW technique improves on conventional methods for determining cell concentrations; this technique allows for on-line data collection, is nondestructive, and requires only small sample volumes. The FPW sensor has applications as a device to measure cell concentrations and growth rates in industrial fermentors, biofilms, and wastewater treatment facilities.

Antitumor and immunotherapeutic effects of activated invasive T lymphoma cells that display short-term interleukin 1alpha expression.

Expression of cytokines in malignant cells represents a novel approach for therapeutic treatment of tumors. Previously, we demonstrated the immunostimulatory effectiveness of interleukin 1alpha (IL-1alpha) gene transfer in experimental fibrosarcoma tumors. Here, we report the antitumor and immunotherapeutic effects of short-term expression of IL-1alpha by malignant T lymphoma cells. Activation in culture of T lymphoma cells with lipopolysaccharide-stimulated macrophages induces the expression of IL-1alpha. The short-term expression of IL-1alpha persists in the malignant T cells for a few days (approximately 3-6 days) after termination of the in vitro activation procedure and, thus, has the potential to stimulate antitumor immune responses in vivo. As an experimental tumor model, we used the RO1 invasive T lymphoma cell line. Upon i.v. inoculation, these cells invade the vertebral column and compress the spinal cord, resulting in hind leg paralysis and death of the mice. Activated RO1 cells, induced to express IL-1alpha in a short-term manner, manifested reduced tumorigenicity: approximately 75% of the mice injected with activated RO1 cells remained tumor free. IL-1 was shown to be essential for the eradication of activated T lymphoma cells because injection of activated RO1 cells together with IL-1-specific inhibitors, i.e., the IL-1 receptor antagonist or the M 20 IL-1 inhibitor, reversed reduced tumorigenicity patterns and led to progressive tumor growth and death of the mice. Furthermore, activated RO1 cells could serve as a treatment by intervening in the growth of violent RO1 cells after tumor take. Thus, when activated RO1 cells were injected 6 or 9 days after the inoculation of violent cells, mortality was significantly reduced. IL-1alpha, in its unique membrane-associated form, in addition to its cytosolic and secreted forms, may represent a focused adjuvant for potentiating antitumor immune responses at low levels of expression, below those that are toxic to the host. Further assessment of the immunotherapeutic potential of short-term expression of IL-1alpha in activated tumor cells may allow its improved application in the treatment of malignancies.

Efficacy of nonfetal human RPE for photoreceptor rescue: a study in dystrophic RCS rats.

This study determines the efficacy of nonfetal human retinal pigment epithelium (RPE) for photoreceptor rescue utilizing the dystrophic RCS rat as an animal model. Eyes from 10- and 49-year-old donors were obtained through the Rochester Eye and Human Parts Bank. The RPE was isolated by enzymatic treatment of the choroid-RPE with 2% dispase for 30 min at 37 degrees C. Mechanically dissociated RPE cells were injected at the superior hemisphere into the subretinal space of dystrophic RCS rats during the fourth postnatal week. Rats receiving vehicle injection served as sham controls. The animals were immunosuppressed with daily cyclosporine injections (10 mg/kg) and sacrificed 30 days posttransplantation for histologic evaluation of the RPE graft and its effect on photoreceptor survival. Transplantation of adult human RPE promoted the survival of photoreceptors in the dystrophic RCS rat. Morphometric analysis of the grafted superior hemisphere demonstrated a threefold increase in photoreceptor cell density (149.2 +/- 50 SD) compared to sham controls (39.7 +/- 31 SD) and the untouched inferior hemisphere (52.8 +/- 28 SD). RPE from the 49-year-old donor was as effective as RPE from the 10-year-old donor in promoting photoreceptor survival. The results of this study in RCS rats suggests that RPE from adult human donors of varied ages is suitable for transplantation and retains the capability to promote survival of photoreceptor cells. This finding opens the possibility of using nonfetal RPE cells in human retinal transplantation.