Multiple Sclerosis and Use of Medical Cannabis: A Retrospective Review of a Neurology Outpatient Population.

BACKGROUND: Patients diagnosed as having multiple sclerosis (MS) experience a wide range of symptoms requiring pharmacologic management, and many do not achieve adequate symptom control. The purpose of this study was to evaluate the role of medical cannabis (MC) as part of a comprehensive treatment plan for patients with MS. METHODS: A retrospective medical record review of 141 patients with MS receiving MC for symptom management was conducted. Data were collected for up to 4 follow-up appointments after initiation of MC. Outcomes included changes in MS symptoms, medication changes, adverse events, and changes in cognition and mobility. RESULTS: Patients experienced extensive MS symptom improvement after initiation of MC, with alleviation of pain (72% of patients) and spasticity (48% of patients) and improvement in sleep (40% of patients) the most common. There was a significant reduction in concomitant opioid use after initiating MC as evidenced by a significant decrease in daily morphine milligram equivalents among patients prescribed opioid analgesics (P = .01). Decreases in muscle relaxant use and benzodiazepine use did not reach significance (P > .05). The most common adverse reaction to MC was fatigue (11% of patients). CONCLUSIONS: In many patients with MS, MC was well tolerated, eased pain and spasticity, improved sleep and other symptoms, and reduced use of concomitant opioid analgesics. Prospective studies are needed to further investigate the role of MC in the treatment of patients with MS.

Medical Cannabis in the Treatment of Parkinson's Disease.

OBJECTIVES: Medical cannabis (MC) has recently garnered interest as a potential treatment for neurologic diseases, including Parkinson's disease (PD). A retrospective chart review was conducted to explore the impact of MC on the symptomatic treatment of patients with PD. METHODS: Patients with PD treated with MC in the normal course of clinical practice were included (n = 69). Data collected from patient charts included MC ratio/formulation changes, PD symptom changes after initiation of MC, and adverse events (AEs) from MC use. Information regarding changes in concomitant medications after MC initiation, including opioids, benzodiazepines, muscle relaxants, and PD medications, was also collected. RESULTS: Most patients were initially certified for a 1:1 (∆ 9 -tetrahydrocannabinol:cannabidiol) tincture. Eight-seven percent of patients (n = 60) were noted to exhibit an improvement in any PD symptom after starting MC. Symptoms with the highest incidence of improvement included cramping/dystonia, pain, spasticity, lack of appetite, dyskinesia, and tremor. After starting MC, 56% of opioid users (n = 14) were able to decrease or discontinue opioid use with an average daily morphine milligram equivalent change from 31 at baseline to 22 at the last follow-up visit. The MC was well-tolerated with no severe AEs reported and low rate of MC discontinuation due to AEs (n = 4). CONCLUSIONS: The MC may improve motor and nonmotor symptoms in patients with PD and may allow for reduction of concomitant opioid medication use. Large, placebo-controlled, randomized studies of MC use in patients with PD are required.

Gabapentin to treat acute alcohol withdrawal in hospitalized patients: A systematic review and meta-analysis.

BACKGROUND: Gabapentin is an antiepileptic medication with evidence of benefit in alcohol use disorder patients. The mechanism of action of gabapentin may also benefit patients suffering from acute alcohol withdrawal syndrome (AWS). METHODS: A systematic review and meta-analysis were conducted to examine if gabapentin can effectively replace/reduce the use of benzodiazepines for the treatment of acute alcohol withdrawal symptoms in hospitalized patients. Time to alcohol withdrawal symptom resolution, amount of benzodiazepines administered, rate of resolution of alcohol withdrawal symptoms, serious withdrawal-related complications, and hospital length of stay (LOS) were examined. RESULTS: Eight retrospective studies (n = 2030) were included in this meta-analysis. There were no studies that examined study outcomes for patients who received only gabapentin and no benzodiazepines; in all studies, gabapentin-treated patients may have received benzodiazepines prior to gabapentin. There were no significant differences between gabapentin-treated and benzodiazepine-treated groups in time to symptom resolution, amount benzodiazepines administered, withdrawal-related complications, or LOS. There was a significant difference in the rate of symptom resolution favoring gabapentin-treated patients (p = 0.05); however, this analysis included only one study. Subgroup analyses of severe AWS patients revealed a significant decrease in LOS (p = 0.04) and a decrease in amount of benzodiazepines administered (p = 0.02) in gabapentin-treated patients, but these analyses included only one study. Subgroup analysis of patients receiving only gabapentin without benzodiazepines found a significantly decreased LOS in the gabapentin group compared to the benzodiazepine group (p < 0.001), but this analysis included only two studies. CONCLUSIONS: There is insufficient evidence to support the widespread use of gabapentin to treat inpatients suffering AWS. All studies included in this meta-analysis are retrospective with high risk of confounding. Well-designed, randomized, controlled studies of gabapentin to treat patients with AWS are required.

Half-Life Extension and Biodistribution Modulation of Biotherapeutics via Red Blood Cell Hitch-Hiking with Novel Anti-Band 3 Single-Domain Antibodies.

Small therapeutic proteins are receiving increased interest as therapeutic drugs; however, their clinical success has been limited due to their rapid elimination. Here, we report a half-life extension strategy via strategy via red blood cell red blood cell (RBC) hitch-hiking. This manuscript details the development and characterization of novel anti-RBC single-domain antibodies (sdAbs), their genetic fusion to therapeutic antibody fragments (TAF) as bispecific fusion constructs, and their influence on TAF pharmacokinetics and biodistribution. Several sdAbs specific to the band 3 antigen were generated via phage-display technology. Binding affinity to RBCs was assessed via flow cytometry. Affinity maturation via random mutagenesis was carried out to improve the binding affinity of the sdAbs. Bi-specific constructs were generated by fusing the anti-RBC sdAbs with anti-tissue necrosis factor alpha (TNF-α) TAF via the use of a glycine-serine flexible linker, and assessments for binding were performed via enzyme-linked immunosorbent assay and flow cytometry. Pharmacokinetics of anti-RBC sdAbs and fusion constructs were evaluated following intravenous bolus dosing in mice at a 1 mg/kg dose. Two RBC-binding sdAbs, RB12 and RE8, were developed. These two clones showed high binding affinity to human RBC with an estimated KD of 17.7 nM and 23.6 nM and low binding affinity to mouse RBC with an estimated KD of 335 nM and 528 nM for RB12 and RE8, respectively. Two derivative sdAbs, RMA1, and RMC1, with higher affinities against mouse RBC, were generated via affinity maturation (KD of 66.9 nM and 30.3 nM, respectively). Pharmacokinetic investigations in mice demonstrated prolonged circulation half-life of an anti-RBC-TNF-α bispecific construct (75 h) compared to a non-RBC binding control (1.3 h). In summary, the developed anti-RBC sdAbs and fusion constructs have demonstrated high affinity in vitro, and sufficient half-life extension in vivo.

Sex-specific behavioral impairments produced by neonatal exposure to MK-801 are partially reversed by adolescent CDPPB treatment.

Psychomimetic behaviors manifest in adult rodents long after neonatal exposure to the noncompetitive NMDA receptor antagonist MK-801. In the present study, we used this neurodevelopmental model of schizophrenia to evaluate the therapeutic potential of positive allosteric modulation of metabotropic glutamate receptor 5 (mGluR5) during adolescence. To this end, we randomly assigned male and female C57BL6 mouse littermates to one of three treatment groups: (i) neonatal and adolescent saline, (ii) neonatal MK-801 (0.25 mg/kg) and adolescent saline, and (iii) neonatal MK-801 and adolescent CDPPB (10 mg/kg), a positive allosteric modulator of mGluR5. When animals reached adulthood, a wide range of behavioral tests were conducted including sucrose preference, anxiety assessment in the elevated plus maze, and a series of food-reinforced operant procedures meant to assess motor activity, motivation, learning, and attention. Neonatal MK-801 exposure produced profound motor hyperactivity in both sexes and attenuated sucrose preference in males, effects that were reversed by CDPPB. MK-801 produced other deficits such as impaired set shifting or response inhibition deficits that were not reversed by CDPPB. Overall, female mice were more susceptible to MK-801's behavioral effects than males. These findings further support the use of neonatal MK-801 exposure as an animal model of schizophrenia and suggest that CDPPB can reverse the neurodevelopmental progression of some schizophrenia-like behaviors.