Methamphetamine and Designer Stimulants Modulate Tonic Human Cerebrovascular Smooth Muscle Contractility: Relevance to Drug-Induced Neurovascular Stress.

To avoid criminal prosecution, clandestine chemists produce designer stimulants that mimic the pharmacological and psychoactive effects of conventional stimulants, such as methamphetamine. Following persistent or high-dose exposure, both acute vasoconstriction and loss of vascular homeostasis are reported dangers of conventional stimulants, and designer stimulants may pose even greater dangers. To compare the effects of a conventional stimulant and two designer stimulants on vascular contraction, this study examined the direct effects of 1,3-benzodioxolylbutanamine (BDB) and N-butylpentylone in comparison to methamphetamine on the function of human brain vascular smooth muscle cells (HBVSMCs). HBVSMCs suspended in collagen gels were exposed to varying concentrations of each drug, and the degree of constriction was assessed over one week. The MTT assay was used to measure the impact of the three drugs on the cellular metabolic activity as a marker of cellular toxicity. The highest concentration tested of either methamphetamine or N-butylpentylone produced a loss of HBVSMC contractility and impaired cellular metabolism. BDB showed a similar pattern of effects, but, uniquely, it also induced vasoconstrictive effects at substantially lower concentrations. Each drug produced direct effects on HBVSMC contraction that may be a mechanism by which the cardiovascular system is damaged following high-dose or persistent exposure, and this could be exacerbated by any sympathomimetic effects of these compounds in whole organisms. BDB appears to impact HBVSMC function in ways distinct from methamphetamine and N-butylpentylone, which may present unique dangers.

Chronic Cannabis Intoxication and Propofol-Induced Salivation: Causes and Considerations.

Legalization/decriminalization of cannabis will increase the numbers of patients who have had recent exposure to recreational or medical cannabis. Currently, little has been reported about potential interactions between cannabis use and Propofol anesthesia e.g., for oropharyngeal procedures. We describe three cases of 'cannabis-induced hypersalivation after propofol' (CHAP) and present our institutions' experience with this unique pharmacological combination. Increased hypersalivation may complicate procedures and represent a procedural risk of suffocation. We evaluate possible pharmacological interactions that might underlie this phenomenon and consider management options going forward.

Interferon-gamma depresses human intestinal smooth muscle cell contractility: Relevance to inflammatory gut motility disturbances.

AIM/BACKGROUND: In addition to absorptive disturbances, inflammatory bowel diseases (IBD) perturb normal contractility of intestinal smooth muscle. Such motility disturbances may reflect both nervous alterations and increased abundance of cytokines (e.g. IL-1ß, TNF-α, and IFN-γ), which impair normal intestinal smooth muscle structure and function. In a previous study, we reported that IL-1ß decreased mesenteric muscular contractility, consistent with cytokine-mediated changes in contraction present in IBD. Here, we considered the impact of pro-inflammatory cytokines on human intestinal smooth muscle cell (HISMC) contractility in vitro, which might provide a method for evaluating treatments for IBD. MATERIALS AND METHODS: We used an in vitro tonic contraction assay to study how HISMC contractility was affected by cell density, serum, and cytokines (IL-1ß, TNF-α, and IFN-γ). MTT (3-(4, 5-dimethyl thiazolyl-2)-2, 5-diphenyltetrazolium bromide) and wound healing analyses were also used to measure cell proliferation and migration in HISMC in response to IFN-γ. KEY FINDINGS: We found that IFN-γ (but not IL-1ß or TNF-α) significantly depressed HISMC tonic contractility over six days. IFN-γ also decreased HISMC proliferation, migration, and smooth muscle F-actin expression in a dose-dependent manner (studied at 4 days). SIGNIFICANCE: Our studies indicate that IFN-γ dose and time-dependently reduces normal HISMC contractility, motility and proliferation which may contribute to dysmotility observed in GI inflammatory disorders and that IFN-γ therapeutics might restore normal HISMC contractility impaired in IBD.

Postoperative delirium in elderly patients after elective hip or knee arthroplasty performed under regional anesthesia.

Delirium is a major adverse postoperative event in elderly patients. Incidence rates of postoperative delirium are difficult to determine. Because of the accuracy, brevity, and ease of use by clinical interviewers, the Confusion Assessment Method (CAM) has become widely used. This study used the CAM to determine the rate of postoperative delirium in patients undergoing total hip arthroplasty (THA) and total knee arthroplasty (TKA) procedures under regional anesthesia. Following Institutional Review Board approval, a prospective study of 20 patients per group ages 70 and above undergoing unilateral THA or TKA was initiated. Both groups received a combined spinal-epidural, postoperative patient-controlled epidural anesthesia, and postoperative oral opioids. Patient interviews occurred five times: once preoperatively and two times each on postoperative days 1 and 2. Only two patients were assessed as delirious according to the CAM method (one in each group; 5%). Patient assessment by other clinicians indicated that five additional patients experienced acute change in mental status; however, these patients were not delirious at the times of the study interviews. The rate of delirium in the elderly after arthroplasty performed under regional anesthesia is very low. Reasons for this include patient selection criteria and anesthesia type. The study excluded patients with several proposed risk factors for postoperative delirium: prior history of dementia, history of mental illness, and use of benzodiazepines. The use of regional anesthesia may have also reduced the occurrence of postoperative delirium.