Long-term low-dose ketoconazole treatment in bilateral macronodular adrenal hyperplasia (BMAH)

Le traitement médicamenteux du syndrome de Cushing secondaire à une hyperplasie surrénalienne macro-nodulaire bilatérale (bilateral macronodular adrenal hyperplasia, (BMAH)) est généralement administré pour une période limitée avant de procéder à l'exérèse chirurgicale des surrénales. Les antagonistes des récepteurs surrênaïïens aberrants se sont révélés inefficaces à long terme pour empêcher la surrénalectomie. Nous reportons le cas d'une patiente avec BMAH traitée durant 10 ans par des petites doses de kétoconazole, afin de contrôler la sécrétion de Cortisol. A l'âge de 48 ans, elle a présenté des céphalées et une hypertension artérielle. Les investigations ont donné les résultats suivants: absence de signes cliniques de syndrome de Cushing ; hyperplasie nodulaire des surrénales ; valeurs normales de la creatinine, le potassium et l'aldostérone plasmatiques ; valeurs normales des métanéphrines et de l'aldostérone urinaires ; élévation du Cortisol libre et des métabolites stéroïdiens urinaires ; et suppression de l'ACTH et de l'activité de la rénine plasmatiques. Un protocole de dépistage des récepteurs surrénaliens aberrants n'a pas montré de dépendance hormonale illégitime. Le kétoconazole a permis une normalisation rapide du Cortisol et de l'ACTH avec un effet qui persiste après 10 ans de traitement, tandis que l'imagerie surrénalienne ne montre pas de changement de taille et d'aspect de celles-ci. La sécrétion stéroidienne chez les patients présentant une BMAH est moins importante que celle de surrénales normales ou de tumeurs secrétrices et peut être contrôlée avec de petites doses de kétoconazole. Ce traitement, bien toléré, constitue une alternative au traitement chirurgical.

Enhancement of viability of radiosensitive (PBMC) and resistant (MDA-MB-231) clones in low-dose-rate cobalt-60 radiation therapy

AbstractObjective:In the present study, the authors investigated the in vitrobehavior of radio-resistant breast adenocarcinoma (MDA-MB-231) cells line and radiosensitive peripheral blood mononuclear cells (PBMC), as a function of different radiation doses, dose rates and postirradiation time kinetics, with a view to the interest of clinical radiotherapy.Materials and Methods:The cells were irradiated with Co-60, at 2 and 10 Gy and two different exposure rates, 339.56 cGy.min–1 and the other corresponding to one fourth of the standard dose rates, present over a 10-year period of cobalt therapy. Post-irradiation sampling was performed at pre-established kinetics of 24, 48 and 72 hours. The optical density response in viability assay was evaluated and a morphological analysis was performed.Results:Radiosensitive PBMC showed decrease in viability at 2 Gy, and a more significant decrease at 10 Gy for both dose rates. MDAMB- 231 cells presented viability decrease only at higher dose and dose rate. The results showed MDA-MB-231 clone expansion at low dose rate after 48–72 hours post-radiation.Conclusion:Low dose rate shows a possible potential clinical impact involving decrease in management of radio-resistant and radiosensitive tumor cell lines in cobalt therapy for breast cancer.

Effects of low-level laser therapy on wound healing

OBJECTIVE: To gather and clarify the actual effects of low-level laser therapy on wound healing and its most effective ways of application in human and veterinary medicine.METHODS: We searched original articles published in journals between the years 2000 and 2011, in Spanish, English, French and Portuguese languages, belonging to the following databases: Lilacs, Medline, PubMed and Bireme; Tey should contain the methodological description of the experimental design and parameters used.RESULTS: doses ranging from 3 to 6 J/cm2 appear to be more effective and doses 10 above J/cm2 are associated with deleterious effects. The wavelengths ranging from 632.8 to 1000 nm remain as those that provide more satisfactory results in the wound healing process.CONCLUSION: Low-level laser can be safely applied to accelerate the resolution of cutaneous wounds, although this fact is closely related to the election of parameters such as dose, time of exposure and wavelength.

Treatment of low-risk gestational trophoblastic neoplasia comparing biweekly eight-day Methotrexate with folinic acid versus bolus-dose Actinomycin-D, among Brazilian women

PURPOSE: To compare two single-agent chemotherapy (ChT) regimens evaluating, in first-line treatment, response and side effects and, in final single-agent treatment, the outcomes, among Brazilian patients with low-risk gestational trophoblastic neoplasia (GTN), according to International Federation of Gynecology and Obstetrics (FIGO) 2002. METHODS: Retrospective analysis of two concurrent cohorts with 194 low-risk GTN patients: from 1992 to 2012, as first-line treatment, 115 patients received 4 intramuscular doses of methotrexate alternated with 4 oral doses of folinic acid (MTX/FA) repetead every 14 days and, since 1996, 79 patients received an endovenous bolus-dose of actinomycin D (Act-D), biweekly. At GTN diagnosis, patient opinion was taken into consideration when defining the initial single-agent ChT regimen, and when there was resistance or toxicity to one regimen, the other drug was used preferentially. This study was approved by the Irmandade da Santa Casa de Misericórdia de Porto Alegre Ethical Committee. RESULTS: Both groups were clinically similar (p>0.05). In first-line treatments, frequency of complete response was similar (75.7% with MTX/FA and 67.1% with bolus Act-D); the number of ChT courses -median 3 (range: 1-10) with MTX/FA and 2 (range: 1-6) with bolus Act-D - and the time to remission -median 9 weeks (range: 2-16) with MTX/FA and 10 weeks (range: 2-16) with bolus Act-D) - were not different between the groups. In both groups, first-line side effects frequency were high but intensity was low; stomatitis was higher with MTX/FA (p<0.01) and nausea and vomit with Act-D (p<0.01). Final single-agent ChT responses were high in both groups (94.8% with MTX/FA and 83.5% with bolus Act-D; p<0.01) and 13% higher in the group initially treated with MTX/FA. Rates of hysterectomy and of GTN recurrence were low and similar. No patient died due to GTN. CONCLUSION: The two regimens had similar first-line ChT response. Final single-agent response rates were high and similar in both groups but the final single-agent remission rate was higher in the MTX/FA group.

Low level resistance of goosegrass (Eleusine indica) to glyphosate in Rio Grande do Sul-Brazil

In the last growing seasons, goosegrass (Eleusine spp.) control failures have been observed following application of glyphosate on Roundup Ready® soybean in Rio Grande do Sul (RS) - Brazil, suggesting this species' resistance to the herbicide. Thus, the objectives of this study were to identify the occurrence of goosegrass resistance to the herbicide glyphosate in RS; and to determine the predominant species of the genus Eleusine, as well as the LD50 and GR50 of the suspected resistant biotypes. Two experiments were conducted under greenhouse conditions: one to identify the biotypes resistant to glyphosate, and the other, a dose-response curve experiment, as well as a study of the botanical characteristics of the species. In the first experiment, 39 biotypes were tested, mainly Eleusine indica, collected with suspected resistance to glyphosate. The glyphosate dose was 2,160 g e.a. ha-1, and the control was evaluated at 28 days after treatment. All biotypes were effectively controlled,with the biotypes from the municipality of Boa Vista do Incra showing greater tolerance. Two biotypes suspected of resistance (12.1 and 12.3) and a susceptible biotype in a dose-response experiment were tested at the following doses: 0, 135, 270, 540, 1,080, 1,620, and 2,160 g e.a. ha-1. The results of this experiment showed that biotype 12.1 does not present resistance to glyphosate and biotype 12.3 has a low level resistance since it is effectively controlled by the herbicide at the maximum dose.

Low-dose doxycycline prevents inflammatory bone resorption in rats

Matrix metalloproteinases (MMP) are considered to be key initiators of collagen degradation, thus contributing to bone resorption in inflammatory diseases. We determined whether subantimicrobial doses of doxycycline (DX) (<=10 mg kg-1 day-1), a known MMP inhibitor, could inhibit bone resorption in an experimental periodontitis model. Thirty male Wistar rats (180-200 g) were subjected to placement of a nylon thread ligature around the maxillary molars and sacrificed after 7 days. Alveolar bone loss (ABL) was measured macroscopically in one hemiarcade and the contralateral hemiarcade was processed for histopathologic analysis. Groups of six animals each were treated with DX (2.5, 5 or 10 mg kg-1 day-1, sc, 7 days) and compared to nontreated (NT) rats. NT rats displayed significant ABL, severe mononuclear cell influx and increase in osteoclast numbers, which were significantly reduced by 5 or 10 mg kg-1 day-1 DX. These data show that DX inhibits inflammatory bone resorption in a manner that is independent of its antimicrobial properties.

Preservation of graft function in low-risk living kidney transplant recipients treated with a combination of sirolimus and cyclosporine

The use of sirolimus (SRL) in combination with full doses of cyclosporin A (CsA) results in reduced one-year kidney allograft function, which is associated with shorter long-term allograft survival. We determined the effect of reduced CsA exposure on graft function in patients receiving SRL and prednisone. Ninety recipients of living kidney transplants receiving SRL (2 mg/day, po) were compared to 35 recipients receiving azathioprine (AZA, 2 mg kg-1 day-1, po). All patients also received CsA (8-10 mg kg-1 day-1, po) and prednisone (0.5 mg kg-1 day-1). Efficacy end-point was a composite of biopsy-confirmed acute rejection, graft loss, or death at one year. Graft function was measured by creatinine, creatinine clearance, and graft function deterioration between 3 and 12 months (delta1/Cr). CsA concentrations in patients receiving SRL were 26% lower. No differences in one-year composite efficacy end-point were observed comparing SRL and AZA groups (18 vs 20%) or in the incidence of biopsy-proven acute rejection (14.4 and 14.3%). There were no differences in mean ± SD creatinine (1.65 ± 0.46 vs 1.60 ± 0.43 mg/dl, P = 0.48) or calculated creatinine clearances (61 ± 15 vs 62 ± 13 ml/min, P = 0.58) at one year. Mean ± SD delta1/Cr (-11 ± 17 vs -14 ± 15%, P = 0.7) or the percentage of patients with >20% (26 vs 31%, P = 0.6) or >30% delta1/Cr (19 vs 17%, P = 1) did not differ between the two groups. The use of 2-mg fixed oral doses of SRL and reduced CsA exposure was effective in preventing acute rejection and preserving allograft function.

Prevalence of low trauma fractures in long-term kidney transplant patients with preserved renal function

We evaluated the prevalence of low bone mineral density (BMD) and osteoporotic fractures in kidney transplantation (KT) patients and determined risk factors associated with osteoporotic fractures. The study was conducted on 191 patients (94 men and 97 women) with first KT for 3 years or more presenting stable and preserved renal function (serum creatinine levels lower than 2.5 mg/dl). KT patients were on immunosuppressive therapy and the cumulative doses of these drugs were also evaluated. BMD was determined by dual-energy X-ray absorptiometry at multiple sites (spine, femur and total body). Quantitative ultrasound of the calcaneus (broadband ultrasound attenuation, speed of sound, and stiffness index, SI) was also performed. Twenty-four percent (46) of all patients had either vertebral (29/46) or appendicular (17/46) fractures. We found osteoporosis and osteopenia in 8.5-13.4 and 30.9-35.1% of KT patients, respectively. Women had more fractures than men. In women, prevalent fractures were associated with diabetes mellitus [OR = 11.5, 95% CI (2.4-55.7)], time since menopause [OR = 3.7, 95% CI (1.2-11.9)], femoral neck BMD [OR = 1.99, 95% CI (1.4-2.8)], cumulative dose of steroids [OR = 1.1, 95% CI (1.02-1.12)] and low SI [OR = 1.1, 95% CI (1.0-1.2)]. In men, fractures were associated with lower lumbar spine BMD [OR = 1.75, 95% CI (1.1-2.7)], lower SI [OR = 1.1, 95% CI (1.03-1.13)], duration of dialysis [OR = 1.3, 95% CI (1.13-2.7)], and lower body mass index [OR = 1.24, 95% CI (1.1-1.4). Our results demonstrate high prevalence of low BMD and osteoporotic fractures in patients receiving a successful kidney transplant and indicate the need for specific intervention to prevent osteoporosis in this population.

Determination of low tetanus or diphtheria antitoxin titers in sera by a toxin neutralization assay and a modified toxin-binding inhibition test

A method for the screening of tetanus and diphtheria antibodies in serum using anatoxin (inactivated toxin) instead of toxin was developed as an alternative to the in vivo toxin neutralization assay based on the toxin-binding inhibition test (TOBI test). In this study, the serum titers (values between 1.0 and 19.5 IU) measured by a modified TOBI test (Modi-TOBI test) and toxin neutralization assays were correlated (P < 0.0001). Titers of tetanus or diphtheria antibodies were evaluated in serum samples from guinea pigs immunized with tetanus toxoid, diphtheria-tetanus or triple vaccine. For the Modi-TOBI test, after blocking the microtiter plates, standard tetanus or diphtheria antitoxin and different concentrations of guinea pig sera were incubated with the respective anatoxin. Twelve hours later, these samples were transferred to a plate previously coated with tetanus or diphtheria antitoxin to bind the remaining anatoxin. The anatoxin was then detected using a peroxidase-labeled tetanus or diphtheria antitoxin. Serum titers were calculated using a linear regression plot of the results for the corresponding standard antitoxin. For the toxin neutralization assay, L+/10/50 doses of either toxin combined with different concentrations of serum samples were inoculated into mice for anti-tetanus detection, or in guinea pigs for anti-diphtheria detection. Both assays were suitable for determining wide ranges of antitoxin levels. The linear regression plots showed high correlation coefficients for tetanus (r² = 0.95, P < 0.0001) and for diphtheria (r² = 0.93, P < 0.0001) between the in vitro and the in vivo assays. The standardized method is appropriate for evaluating titers of neutralizing antibodies, thus permitting the in vitro control of serum antitoxin levels.

Low-dose thioperamide injected into the cerebellar vermis of mice immediately after exposure to the elevated plus-maze impairs their avoidance behavior on re-exposure to the apparatus

The present study investigated the effect of thioperamide (THIO), an H3 histaminergic receptor antagonist, microinjected into the cerebellar vermis on emotional memory consolidation in male Swiss albino mice re-exposed to the elevated plus-maze (EPM). We implanted a guide cannula into the cerebellar vermis using stereotactic surgery. On the third day after surgery, we performed behavioral tests for two consecutive days. On the first day (exposure), the mice (n=10/group) were exposed to the EPM and received THIO (0.06, 0.3, or 1.5 ng/0.1 µL) immediately after the end of the session. Twenty-four hours later, the mice were re-exposed to the EPM under the same experimental conditions, but without drug injection. A reduction in the exploration of the open arms upon re-exposure to the EPM (percentage of number of entries and time spent in open arms) compared with the initial exposure was used as an indicator of learning and memory. One-way analysis of variance (ANOVA) followed by the Duncan post hoc test was used to analyze the data. Upon re-exposure, exploratory activity in the open arms was reduced in the control group, and with the two highest THIO doses: 0.3 and 1.5 ng/0.1 µL. No reduction was seen with the lowest THIO dose (0.06 ng/0.1 µL), indicating inhibition of the consolidation of emotional memory. None of the doses interfered with the animals' locomotor activity. We conclude that THIO at the lowest dose (0.06 ng/0.1 µL) microinjected into the cerebellum impaired emotional memory consolidation in mice.

Low-level red laser therapy alters effects of ultraviolet C radiation on Escherichia coli cells

Low-level lasers are used at low power densities and doses according to clinical protocols supplied with laser devices or based on professional practice. Although use of these lasers is increasing in many countries, the molecular mechanisms involved in effects of low-level lasers, mainly on DNA, are controversial. In this study, we evaluated the effects of low-level red lasers on survival, filamentation, and morphology of Escherichia colicells that were exposed to ultraviolet C (UVC) radiation. Exponential and stationary wild-type and uvrA-deficientE. coli cells were exposed to a low-level red laser and in sequence to UVC radiation. Bacterial survival was evaluated to determine the laser protection factor (ratio between the number of viable cells after exposure to the red laser and UVC and the number of viable cells after exposure to UVC). Bacterial filaments were counted to obtain the percentage of filamentation. Area-perimeter ratios were calculated for evaluation of cellular morphology. Experiments were carried out in duplicate and the results are reported as the means of three independent assays. Pre-exposure to a red laser protected wild-type and uvrA-deficient E. coli cells against the lethal effect of UVC radiation, and increased the percentage of filamentation and the area-perimeter ratio, depending on UVC fluence and physiological conditions in the cells. Therapeutic, low-level red laser radiation can induce DNA lesions at a sub-lethal level. Consequences to cells and tissues should be considered when clinical protocols based on this laser are carried out.

Low-intensity red and infrared laser effects at high fluences on Escherichia coli cultures

Semiconductor laser devices are readily available and practical radiation sources providing wavelength tenability and high monochromaticity. Low-intensity red and near-infrared lasers are considered safe for use in clinical applications. However, adverse effects can occur via free radical generation, and the biological effects of these lasers from unusually high fluences or high doses have not yet been evaluated. Here, we evaluated the survival, filamentation induction and morphology of Escherichia coli cells deficient in repair of oxidative DNA lesions when exposed to low-intensity red and infrared lasers at unusually high fluences. Cultures of wild-type (AB1157), endonuclease III-deficient (JW1625-1), and endonuclease IV-deficient (JW2146-1) E. coli, in exponential and stationary growth phases, were exposed to red and infrared lasers (0, 250, 500, and 1000 J/cm2) to evaluate their survival rates, filamentation phenotype induction and cell morphologies. The results showed that low-intensity red and infrared lasers at high fluences are lethal, induce a filamentation phenotype, and alter the morphology of the E. coli cells. Low-intensity red and infrared lasers have potential to induce adverse effects on cells, whether used at unusually high fluences, or at high doses. Hence, there is a need to reinforce the importance of accurate dosimetry in therapeutic protocols.

Évaluation de la cytogénotoxicité humaine induite par l’exposition à de faibles doses de benzo-a-pyrène, à l’aide de biomarqueurs précoces

Le benzo-a-pyrène (BaP) est un hydrocarbure aromatique polycyclique (HAP) cancérogène pour l’homme, qui contamine toutes les sphères de notre environnement. Son métabolite, le BaP-7,8-diol-9,10-époxyde (BPDE) est considéré comme son cancérogène ultime. Le BPDE se lie à l’ADN, formant des adduits qui doivent être réparés et qui seraient responsables des dommages à l’ADN et de la cancérogenèse induite par le BaP. Les adduits BPDE-ADN et les dommages à l’ADN (bris simple-brin [BSB] à l’ADN, aberrations chromosomiques [AC], échanges entre chromatides-sœurs [ÉCS] et micronoyaux [MN]) ont été mesurés dans les lymphocytes humains exposés à de faibles concentrations de BaP, provenant de jeunes volontaires non-fumeurs et en santé. Suite à l’exposition au BaP, le niveau d’adduits BPDE-ADN et la fréquence des AC et des MN augmentent significativement, puis diminuent aux concentrations les plus élevées de BaP testées, suggérant une induction du métabolisme de phase II du BaP. Lors de la mesure des ÉCS, nous obtenons une courbe dose-réponse linéaire, indiquant la production d’un autre type de lésions devant être réparées par le système de réparation par recombinaison homologue. Ces lésions pourraient être des bris à l’ADN ou des bases oxydées (8-OH-dG), ce qui est suggéré par l’analyse des corrélations existant entre nos biomarqueurs. Par ailleurs, la comparaison de la courbe dose-réponse des hommes et des femmes montre que des différences existent entre les sexes. Ainsi, les ÉCS, les AC et les MN sont significativement augmentés chez les hommes à la plus faible concentration de BaP, alors que chez les femmes cette augmentation, quoique présente, est non significative. Des différences interindividuelles sont également observées et sont plus importantes pour les adduits BPDE-ADN, les MN et les AC, alors que pour les ÉCS elles sont minimes. Les analyses statistiques effectuées ont permis d’établir que quatre facteurs (niveau d’exposition au BaP, adduits BPDE-ADN, fréquence des AC et nombre de MN par cellule micronucléée) expliquent jusqu’à 59 % de la variabilité observée dans le test des ÉCS, alors qu’aucun facteur significatif n’a pu être identifié dans le test des AC et des MN. L’analyse du mécanisme de formation de nos biomarqueurs précoces permet de suggérer que les bris à l’ADN et les bases oxydées devraient être classées comme biomarqueurs de dose biologique efficace, au sein des biomarqueurs d’exposition, dans le continuum exposition-maladie du BaP, étant donné qu’ils causent la formation des biomarqueurs de génotoxicité (ÉCS, AC et MN). Par ailleurs, le test des AC et des MN ont permis de confirmer l’action clastogénique du BaP en plus de mettre en évidence des effets aneugènes affectant surtout la ségrégation des chromosomes lors de la division cellulaire. Ces effets aneugènes, reliés à l’étape de progression dans la cancérogenèse, pourraient être particulièrement importants puisque l’exposition au BaP et aux HAP est chronique et dure plusieurs années, voire des décennies. La compréhension des mécanismes régissant la formation des biomarqueurs étudiés dans cette étude, ainsi que des relations existant entre eux, peut être appliquée à de nombreux contaminants connus et émergents de notre environnement et contribuer à en évaluer le mode d’action.

Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial

Objectives: To evaluate the prophylactic efficacy of the human papillomavirus (HPV) quadrivalent vaccine in preventing low grade cervical, vulvar, and vaginal intraepithelial neoplasias and anogenital warts (condyloma acuminata). Design: Data from two international, double blind, placebo controlled, randomised efficacy trials of quadrivalent HPV vaccine (protocol 013 (FUTURE I) and protocol 015 (FUTURE II)). The trials were to be 4 years in length, and the results reported are from final study data of 42 months' follow-up. Setting: Primary care centres and university or hospital associated health centres in 24 countries and territories around the world. Participants: 17 622 women aged 16-26 years enrolled between December 2001 and May 2003. Major exclusion criteria were lifetime number of sexual partners (>4), history of abnormal cervical smear test results, and pregnancy. Intervention: Three doses of quadrivalent HPV vaccine (for serotypes 6, 11, 16, and 18) or placebo at day 1, month 2, and month 6. Main outcome measures: Vaccine efficacy against cervical, vulvar, and vaginal intraepithelial neoplasia grade I and condyloma in a per protocol susceptible population that included subjects who received all three vaccine doses, tested negative for the relevant vaccine HPV types at day 1 and remained negative through month 7, and had no major protocol violations. Intention to treat, generally HPV naive, and unrestricted susceptible populations were also studied. Results: In the per protocol susceptible population, vaccine efficacy against lesions related to the HPV types in the vaccine was 96% for cervical intraepithelial neoplasia grade I (95% confidence interval 91% to 98%), 100% for both vulvar and vaginal intraepithelial neoplasia grade I (95% CIs 74% to 100%, 64% to 100% respectively), and 99% for condyloma (96% to 100%). Vaccine efficacy against any lesion (regardless of HPV type) in the generally naive population was 30% (17% to 41%), 75% (22% to 94%), and 48% (10% to 71%) for cervical, vulvar, and vaginal intraepithelial neoplasia grade I, respectively, and 83% (74% to 89%) for condyloma. Conclusions: Quadrivalent HPV vaccine provided sustained protection against low grade lesions attributable to vaccine HPV types (6, 11, 16, and 18) and a substantial reduction in the burden of these diseases through 42 months of follow-up. Trial registrations: NCT00092521 and NCT00092534.

A low delta-9-tetrahydrocannabinol cannabis extract induces hyperphagia in rats

Appetite stimulation via partial agonism of cannabinoid type 1 receptors by Δ9tetrahydrocannabinol (Δ9THC) is well documented and can be modulated by non-Δ9THC phytocannabinoids. Δ9THC concentrations sufficient to elicit hyperphagia induce changes to both appetitive (reduced latency to feed) and consummatory (increased meal one size and duration) behaviours. Here, we show that a cannabis extract containing too little Δ9THC to stimulate appetite can induce hyperphagia solely by increasing appetitive behaviours. Twelve, male Lister hooded rats were presatiated before treatment with a low-Δ9THC cannabis extract (0.5, 1.0, 2.0 and 4.0 mg/kg). Hourly intake and meal pattern data were recorded and analyzed using one-way analyses of variance followed by Bonferroni post-hoc tests. The cannabis extract significantly increased food intake during the first hour of testing (at 4.0 mg/kg) and significantly reduced the latency to feed versus vehicle treatments (at doses ≥1.0 mg/kg). Meal size and duration were unaffected. These results show only the increase in appetitive behaviours, which could be attributed to non-Δ9THC phytocannabinoids in the extract rather than Δ9THC. Although further study is required to determine the constituents responsible for these effects, these results support the presence of non-Δ9THC cannabis constituent(s) that exert a stimulatory effect on appetite and likely lack the detrimental psychoactive effects of Δ9THC.