Marijuana Use by Patients with Multiple Sclerosis.

BACKGROUND: With social attitudes about marijuana changing and patients sometimes seeking nonmainstream treatment options, the main goal of this study was to investigate the prevalence of, and factors associated with, marijuana use by patients with multiple sclerosis (MS). METHODS: Adult patients with MS (n = 521) and controls (n = 279) from a study of clinical, neuroimaging, genetic, and environmental factors in MS progression were included. Patients with MS stated whether they had ever used marijuana before MS diagnosis, after MS diagnosis, and in the preceding 3 months as part of an in-person questionnaire. The control group stated whether they had ever used marijuana and in the preceding 3 months. RESULTS: The percentage of patients with MS reporting ever use of marijuana was 39.9%, compared with 32.7% of controls. Marijuana use in the preceding 3 months was significantly more prevalent among patients with MS (9.4%) compared with controls (0.4%) (P < .001). Marijuana use was most prevalent in male patients with MS (P = .004) and in patients with MS who used complementary and alternative medicine (P = .045). Cigarette smoking was associated with marijuana use in patients with MS (P < .001) and controls (P = .001). Increasing age was associated with decreasing prevalence of marijuana use in the patients with MS (P < 0.001). CONCLUSIONS: Patients with MS are more likely to report recent marijuana use than are people without MS. Owing to potential adverse effects, marijuana use by patients with MS may warrant vigilance by MS caregivers, given shifting social attitudes and the trend towards legalization of marijuana in the United States.

Serum lipid profile changes predict neurodegeneration in interferon-ß1a-treated multiple sclerosis patients.

The purpose of this work was to determine whether changes in cholesterol profiles after interferon-ß (IFN-ß)1a treatment initiation following the first demyelinating event suggestive of multiple sclerosis are associated with clinical and MRI outcomes over 4 years. A group of 131 patients (age: 27.9 ± 7.8 years, 63% female) with serial 3-monthly clinical and 12-monthly MRI follow-ups over 4 years were investigated. Serum cholesterol profiles, including total cholesterol (TC), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C) were obtained at baseline, 1 month, 3 months, and every 6 months thereafter. IFN-ß1a initiation caused rapid decreases in serum HDL-C, LDL-C, and TC within 1 month of IFN-ß1a initiation (all P < 0.001) that returned slowly toward baseline. In predictive mixed model analyses, greater percent decreases in HDL-C after 3 months of IFN-ß1a treatment initiation were associated with less brain atrophy over the 4 year time course, as assessed by percent brain volume change (P < 0.001), percent gray matter volume change (P < 0.001), and percent lateral ventricle volume change (P = 0.005). Decreases in cholesterol biomarkers following IFN-ß1a treatment are associated with brain atrophy outcomes over 4 years. Pharmacological interventions targeting lipid homeostasis may be clinically beneficial for disrupting neurodegenerative processes.

Interdependence of oxysterols with cholesterol profiles in multiple sclerosis.

PURPOSE: To investigate levels of oxysterols in healthy control (HC) and multiple sclerosis (MS) patients and their interdependence with demographic, clinical characteristics, and cholesterol biomarkers. METHODS: This study included 550 subjects (203 HC, 221 relapsing-remitting MS (RR-MS), 126 progressive MS (P-MS)). A complete lipid profile including total cholesterol (TC); high-density lipoprotein-cholesterol (HDL-C); low-density lipoprotein-cholesterol (LDL-C); apolipoproteins (Apo) A1, A2, B, and E; C-reactive protein (CRP); 24-hydroxycholesterol (HC); 25-HC; 27-HC; 7α-HC; and 7-ketocholesterol (KC) was obtained. Lipoprotein particle sizing by proton nuclear magnetic resonance (H1 NMR) was available for 432 subjects. RESULTS: The levels of 24-HC, 27-HC, and 7α-HC (all p < 0.015) were lower in MS compared to HC, and 7-KC was higher in P-MS compared to RR-MS ( p < 0.001). TC, LDL-C, and ApoB were associated with higher levels of all oxysterols (all p < 0.05) in HC. In MS, LDL-C was associated with higher levels of 24-HC, 25-HC, 7-KC, and 7α-HC (all p < 0.05), while TC and ApoB were associated with increased levels of all oxysterols (all p < 0.005). CONCLUSION: The findings of lower 24-HC, 27-HC, and 7α-HC in MS compared to HC and higher 7-KC in P-MS compared to RR-MS indicate that the oxysterol network is disrupted in MS.

Bayesian population modeling of drug dosing adherence.

Adherence is a frequent contributing factor to variations in drug concentrations and efficacy. The purpose of this work was to develop an integrated population model to describe variation in adherence, dose-timing deviations, overdosing and persistence to dosing regimens. The hybrid Markov chain-von Mises method for modeling adherence in individual subjects was extended to the population setting using a Bayesian approach. Four integrated population models for overall adherence, the two-state Markov chain transition parameters, dose-timing deviations, overdosing and persistence were formulated and critically compared. The Markov chain-Monte Carlo algorithm was used for identifying distribution parameters and for simulations. The model was challenged with medication event monitoring system data for 207 hypertension patients. The four Bayesian models demonstrated good mixing and convergence characteristics. The distributions of adherence, dose-timing deviations, overdosing and persistence were markedly non-normal and diverse. The models varied in complexity and the method used to incorporate inter-dependence with the preceding dose in the two-state Markov chain. The model that incorporated a cooperativity term for inter-dependence and a hyperbolic parameterization of the transition matrix probabilities was identified as the preferred model over the alternatives. The simulated probability densities from the model satisfactorily fit the observed probability distributions of adherence, dose-timing deviations, overdosing and persistence parameters in the sample patients. The model also adequately described the median and observed quartiles for these parameters. The Bayesian model for adherence provides a parsimonious, yet integrated, description of adherence in populations. It may find potential applications in clinical trial simulations and pharmacokinetic-pharmacodynamic modeling.

Protective associations of HDL with blood-brain barrier injury in multiple sclerosis patients.

The purpose of this work was to investigate the associations of serum cholesterol and apolipoproteins with measures of blood-brain barrier (BBB) permeability and CNS inflammation following the first clinical demyelinating event. This study included 154 patients [67% female; age, 29.5 ± 8.2 years (mean ± SD)] enrolled in a multi-center study of interferon ß1-a treatment following the first demyelinating event. Blood and cerebrospinal fluid (CSF) were obtained at screening prior to treatment. A comprehensive serum lipid profile and multiple surrogate markers of BBB breakdown and CNS immune activity were obtained. Higher levels of serum HDL cholesterol (HDL-C) and ApoA-I were associated with lower CSF total protein level, CSF albumin level, albumin quotient, and CSF IgG level (all P ≤ 0.001 for HDL-C and all P < 0.01 for ApoA-I). HDL-C was also associated with CSF CD80+ (P < 0.001) and with CSF CD80+CD19+ (P = 0.007) cell frequencies. Higher serum HDL is associated with lower levels of BBB injury and decreased CD80+ and CD80+CD19+ cell extravasation into the CSF. HDL may potentially inhibit the initiation and/or maintenance of pathogenic BBB injury following the first demyelinating event.

A hybrid Markov chain-von Mises density model for the drug-dosing interval and drug holiday distributions.

Lack of adherence is a frequent cause of hospitalizations, but its effects on dosing patterns have not been extensively investigated. The purpose of this work was to critically evaluate a novel pharmacometric model for deriving the relationships of adherence to dosing patterns and the dosing interval distribution. The hybrid, stochastic model combines a Markov chain process with the von Mises distribution. The model was challenged with electronic medication monitoring data from 207 hypertension patients and against 5-year persistence data. The model estimates distributions of dosing runs, drug holidays, and dosing intervals. Drug holidays, which can vary between individuals with the same adherence, were characterized by the patient cooperativity index parameter. The drug holiday and dosing run distributions deviate markedly from normality. The dosing interval distribution exhibits complex patterns of multimodality and can be long-tailed. Dosing patterns are an important but under recognized covariate for explaining within-individual variance in drug concentrations.

Pharmacological inhibition of Rho-kinase signaling with Y-27632 blocks melanoma tumor growth.

Primarily through in vitro studies, the Rho-family of small GTPases and their effector proteins have been implicated in mediating oncogenic properties of cancer cells. We sought to determine if pharmacological inhibition of the RhoA effector proteins known as Rho-kinases (ROCK) with the small molecule inhibitor Y-27632 could inhibit melanoma in vitro and in vivo. We demonstrate that Y-27632 treatment of a panel of melanoma cells alters cellular morphology leading to spindly cells with decreased lamellipodia and increased filopodia formation. Y-27632 treatment decreases invasion and alters cell survival of cultured melanoma cells. IP injection of Y-27632 in tumor-bearing mice resulted in a reduction in melanoma tumor volume compared to control treated mice. These findings suggest that ROCK inhibition can reduce melanoma tumorigenicity.