Farzad Ashrafi

Safety and possible outcome assessment of autologous Schwann cell and bone marrow mesenchymal stromal cell co-transplantation for treatment of patients with chronic spinal cord injury

BACKGROUND AIMS Cell replacement therapy has become a promising issue that has raised much hope in the regeneration of central nervous system injury. Evidence indicates that successful functional recovery in patients with spinal cord injury will not simply emphasize a single therapeutic strategy. Therefore, many recent studies have used combination strategies for spinal cord regeneration. METHODS We assessed the safety and feasibility of a bone marrow mesenchymal stromal cell and Schwann cell combination for the treatment of patients with chronic spinal cord injury. Eight subjects who received a complete traumatic spinal cord injury (American Spinal Injury Association [ASIA] classification A) enrolled in this study. The patients received this autologous combination of cells directly into the injury site. The mean duration of follow-up was approximately 24 months. RESULTS No magnetic resonance imaging evidence of neoplastic tissue overgrowth, syringomyelia or psuedomeningocele in any of the patients was seen during the study. There was no deterioration in sensory or motor function in any of the patients during the course of the study. Three patients had negligible improvement in ASIA sensory scale. No motor score improvement and no change in ASIA classification was seen. The patients had widely subjective changes in the course of the study such as urination and defecation sensation and more stability and trunk equilibrium in the sitting position. CONCLUSIONS There were no adverse findings at least 2 years after autologous transplantation of Schwann cell and mesenchymal stromal cell combination into the injured spinal cord. It appears that the use of this combination of cells is safe for clinical application to spinal cord regeneration.

Comparison of the acute physiology and chronic health evaluation score (APACHE) II with GCS in predicting hospital mortality of neurosurgical intensive care unit patients.

Background: The Glasgow Coma Scale (GCS) is popular, simple, and reliable, and provides information about the level of consciousness in trauma patients. However, a systemic evaluation scale especially in patients with multiple traumas is so important. The revised Acute Physiology and Chronic Health Evaluation system type 2 (APACHE II) is a physiologically based system including physiological variables. This study compares the efficacy of the predicting power for mortality and functional outcome of GCS and APACHEII in patients with multiple traumas in intensive care unit. Methods: This study included the patients with head injury associated with systemic trauma admitted in the ICU of Shahid Rajaee Hospital in 2007 and 2008. Sensitivity, specificity and correct prediction of outcome by GCS and APACHE II were assessed and compared. Results: This study included 93 patients (79 males, 14 females; mean age 60.5; range 14 to 87 years) with head injury associated with systemic trauma in 2007 and 2008. Mortality increased in the elderly group. The mean survival score using APACHE II was 36.5 and death score was 67.4. These values using GCS were 10.3 and 6.8, respectively. Conclusion: For the assessment of mortality, the GCS score still provides simple, rapid and effective assessment in head injury patients, however, for the prediction of mortality in patients with multiple trauma APACHE II is superior to GCS since it includes multiple systemic parameters in these patients.

Effectiveness and Safety of MLC601 in the Treatment of Mild to Moderate Alzheimer's Disease: A Multicenter, Randomized Controlled Trial

Background: MLC601 is a possible modulator of amyloid precursor protein processing, and in a clinical trial study MLC601 showed some effectiveness in cognitive function in Alzheimers disease (AD) patients. We aimed to evaluate the effectiveness and safety of MLC601 in the treatment of mild to moderate AD as compared to 3 approved cholinesterase inhibitors (ChEIs) including donepezil, rivastigmine and galantamine. Methods: In a multicenter, nonblinded, randomized controlled trial, 264 volunteers with AD were randomly divided into 4 groups of 66; groups 1, 2, 3 and 4 received donepezil, rivastigmine, MLC601 and galantamine, respectively. Subjects underwent a clinical diagnostic interview and a cognitive/functional battery including the Mini-Mental State Examination (MMSE) and Alzheimers Disease Assessment Scale - Cognitive subscale (ADAS-Cog). Patients were visited every 4 months, and the score of cognition was recorded by the neurologists. Results: There were no significant differences in age, sex, marital status and baseline score of cognition among the 4 groups. In total, 39 patients (14.7%) left the study. Trend of cognition changes based on the modifications over the time for MMSE and ADAS-cog scores did not differ significantly among groups (p = 0.92 for MMSE and p = 0.87 for ADAS-Cog). Conclusion: MLC601 showed a promising safety profile and also efficacy compared to 3 FDA-approved ChEIs.

Efficacy and Tolerability of MlC601 in Patients with Mild to Moderate Alzheimer Disease who were Unable to Tolerate or Failed to Benefit from Treatment with Rivastigmine.

Aim: To evaluate the efficacy and tolerability of MLC601 in patients with mild to moderate Alzheimer disease (AD). Study Design: This is an open-label pilot study. Place and Duration of Study: It was conducted at three university referral centres in Iran from September 2009 until November 2011. Methodology: One-hundred and twenty four outpatients with mild to moderate AD who had previously failed to tolerate or benefit from treatment with Rivastigmine for 6 months at a dose of 2 to 12 mg per day were switched to a MLC601 regimen of one capsule three times per day for up to 18 months. Outcome measures included adverse events (AEs), withdrawal rate, and changes in the Mini-Mental State Examination (MMSE) and the cognitive subscale of the AD Assessment Scale (ADAS-cog) relative to baseline measurements. Research Article British Journal of Medicine & Medical Research, 3(2): 341-350, 2013 342 Results: Two patients were lost to follow up, and 122 patients completed the 18-month trial. The mean age of the participants was 65.3±6.4 years (range 54-82), and 77 (63.1%) of the participants were female. Improved cognitive function was observed in the first 6 months of the regimen (ADAS-cog=-3.1±10.1; MMSE=1.2±3.0), and the stabilisation of cognitive decline was observed over the remaining 12 months (ADAScog=-1.6±7.6; MMSE=0.8±4.2). AEs were predominantly gastrointestinal and occurred in 7.3% of patients. Conclusions: MLC601 showed good tolerability and promising effects on cognitive function in AD patients during 18 months of treatment.

Health-related quality of life in patients with relapsing-remitting multiple sclerosis treated with subcutaneous interferon β-1a in Iran

Purpose: Multiple sclerosis (MS) requires long-term therapy and can affect many aspects of a patients life, including quality of life. MS patients score lower on health-related quality of life (HRQoL) measures. The efficacy of subcutaneous interferon (IFN) β-1a has been extensively evaluated by using objective measures but its impact on HRQoL is currently unclear. In this observational study, we evaluated HRQoL of Iranian patients with relapsing-remitting MS (RRMS) treated with IFN β-1a by using short-form 36 (SF-36) and multiple sclerosis international quality of life (MusiQoL) questionnaires. Methods: Four hundred recruited RRMS patients were treated with human serum album free IFN β-1a for 1 year. Patients were required to fill in SF-36 and MusiQoL questionnaires at the first visit and at each follow-up visit. Expanded disability status scale (EDSS) evaluation was performed at baseline and at each visit. Comparisons in HRQoL between visits were calculated using Cohens d effect size. The relationship between change in EDSS score and the score of each questionnaire was calculated using Pearson correlation coefficients. Results: Three-hundred and eighty three completed the study. Two-hundred and thirty nine were female. Mean (SD) age was 28.75 (±5.49). After 1 year, overall MusiQoL Index score effect size was −0.16 and SF-36 physical component and mental component showed overall effect sizes of −0.28 and −0.53, respectively. Mean (range) EDSS change was 1 (1–4). Three-hundred and seventy four were clinically stable with mean (range) EDSS change of 0.1 (−2–0.5). Increase in EDSS was linked to a decrease in both MusiQoL and SF-36. Conclusion: We found that, HRQoL did not change significantly over the first year of therapy. Furthermore, decreases in HRQoL were inversely correlated with increases in EDSS score.

Efficacy and Safety of MLC601 in the Treatment of Mild Cognitive Impairment: A Pilot, Randomized, Double-Blind, Placebo-Controlled Study

Background and Aim: Mild cognitive impairment (MCI) is characterized by declined cognitive function greater than that expected for a person’s age. The clinical significance of this condition is its possible progression to dementia. MLC601 is a natural neuroprotective medication that has shown promising effects in Alzheimer disease. Accordingly, we conducted this randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of MLC601 in MCI patients. Methods: Seventy-two patients with a diagnosis of MCI were recruited. The included participants were randomly assigned to groups to receive either MLC601 or placebo. An evaluation of global cognitive function was performed at baseline as well as at 3-month and 6-month follow-up visits. Global cognitive function was assessed by Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) scores. Efficacy was evaluated by comparing global function scores between the 2 groups during the study period. Safety assessment included adverse events (AEs) and abnormal laboratory results. Results: Seventy patients completed the study, 34 in the MLC601 group and 36 in the placebo group. The mean changes (±SD) in cognition scores over 6 months in the MLC601 group were –2.26 (±3.42) for the MMSE and 3.82 (±6.16) for the ADAS-cog; in the placebo group, they were –2.66 (±3.43) for the MMSE and 4.41 (±6.66) for the ADAS-cog. The cognition changes based on both MMSE and ADAS-cog scores were statistically significant between the placebo and the MLC601 group (p < 0.001). Only 5 patients (14.7%) reported minor AEs in the MLC601 group, the most commonly reported of which were gastrointestinal, none of them leading to patient withdrawal. Conclusion: MLC601 has shown promising efficacy and acceptable AEs in MCI patients.


Does Histologic Subtype Influence the Post-Operative Outcome in Spinal Meningioma?

Background Postoperative outcome of spinal meningiomas is an important issue in surgery decision-making. There are limited and conflicting data in the literature about the prognostic factors influencing recovery, especially about the histopathologic subtypes. Objectives This study was carried out to evaluate the effect of some of these factors on postoperative outcome. Patients and Methods This study was performed on 39 patients operated for spinal meningioma between October 1998 and January 2012; their histopathologic subtype was determined according to WHO criteria. The follow up period ranged between 8 - 120 months. The influence of histopathologic subtype, grade, age, sex, surgical approach, local adhesion and anatomical location was assessed according to Frankel classification of neurologic deficit. Results From a total number of 39 spinal meningiomas, 34 cases were WHO grade I, from which 15 cases were psammomatous, 7 cases were meningothelial, 9 cases were transitional and 3 cases were fibroblastic. Five cases were grade II, 3 of which had clear cell appearance and the remaining 2 had chordoid appearance. The mean age was 51.6 (22 to 76) years; 25 cases were female and 14 cases were male. This study revealed that grade II meningioma cases had poor prognosis in all 5 cases and psammomatous subtype had poor postoperative outcome in 40% of cases while the other subtypes had good outcome in all cases (P = 0.026). Cervical location of the tumor was also related with poor outcome in 37.5% of the cases, while 22.5% had poor outcome in other locations (P = 0.029). Age below and above 45 years and sex had no significant influence on the outcome. Conclusions Spinal meningiomas of psammomatous type and grade II spinal meningiomas are associated with less favorable postoperative neurologic outcome. Cervical location has also a negative correlation with a good outcome.

Effects of Clonidine Premedication on Intraoperative Blood Loss in Patients With and Without Opium Addiction During Elective Femoral Fracture Surgeries

Background: Opium is an addictive agent and one of the most common narcotics With great challenges of intraoperative hemodynamic instabilities. Objectives: The current study aimed to assess the effects of clonidine on intraoperative blood loss in patients with and without opium addiction in femoral fracture surgeries. Patients and Methods: In a randomized clinical trial, 160 candidates for elective femoral fracture operations under general anesthesia were divided into four groups of 40 subjects: group 1 (placebo 1), subjects without addiction received placebo 90 minutes before the operation; group 2 (placebo 2), patients with opium addiction received placebo as group 1; group 3 (Clonidine 1), patients without addiction received clonidine 90 minutes before the operation and group 4 (Clonidine 2), patients with opium addiction received clonidine as premedication. Results: Intraoperative blood loss in clonidine recipient groups, patients with and without addiction, was less than that of the placebos (both P values < 0.01) and the difference magnitude was higher in patients with opium addiction. Conclusions: Premedication with clonidine to decrease intraoperative blood loss can be more effective in patients with opium addiction than the ones without addiction.

MLC601 in vascular dementia: an efficacy and safety pilot study

Background and aim Vascular dementia (VaD) is the second most common cause of dementia and currently there is scarcity of therapies for VaD. We aimed to investigate the efficacy and safety of MLC601 in the treatment of VaD. Methods In this multicenter, pilot, randomized, double-blind trial, 82 patients with VaD according to DSM-5 criteria received MLC601 or placebo capsules three times a day for 2 years. The primary efficacy end-point was evaluated by comparing Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-cognitive subscale (ADAS-cog) score between the two groups over 2 years of study. Safety was also assessed by recording adverse events and abnormal laboratory results. Results Eighty-one patients completed the study and were included in the analysis. One patient was lost to follow-up in the placebo group. After 2 years, mean (±SD) changes in the MMSE score were −3.71 (±4.50) for MLC601 group and −9.33 (±4.80) for placebo group. ADAS-cog score showed (±SD) changes of 7.34 (±9.55) and 19.00 (±11.28) for MLC601 and placebo group, respectively. Repeated measures analyses showed that both MMSE and ADAS-cog scores were significantly better in the treatment group at 24 months (p<0.001). Ten (24.39%) patients reported predominantly transient gastrointestinal adverse events in MLC601 group. No patient left the study due to adverse events. There were no clinically significant abnormalities on laboratory tests. Conclusion Patients treated with MLC601 over the 2 years showed dramatically better cognitive outcome compared with those treated with placebo. MLC601 was devoid of any serious adverse events and was well-tolerated.

Efficacy and Safety of MLC601 in Patients with Mild to Moderate Alzheimer Disease: An Extension 4-Year Follow-Up Study

Background and Aim: Alzheimer disease (AD) is the most common cause of dementia. Currently, there is no disease-modifying therapy for AD. We aimed to evaluate the long-term efficacy and safety of MLC601 in the treatment of AD. Methods: In this open-label extension study, patients with mild to moderate AD according to DSM-IV criteria were recruited. Patients received MLC601 capsules 3 times a day for 4 years. Cognitive function was assessed every 6 months using Mini-Mental State Examination (MMSE) and Alzheimer’s Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) scores. Safety profiles, including adverse events (AEs), and treatment-related abnormality in laboratory tests were also reported. Results: Of a total of 122 patients, 105 completed the study. The mean age was 66.8 ± 6.3 years at the beginning of the study. Sixty-five (61.9%) were female. The mean (±SD) change in MMSE and ADAS-Cog scores at the end of the study was 2.1 (±3.8) and –5.1 (±8.7), respectively. Repeated measure analysis revealed a statistically significant change in both scores (p < 0.001). No patient left the study due to an AE. No abnormality was noted in lab tests. Gastrointestinal symptoms were the most commonly reported AEs. Conclusion: The efficacy of treating AD patients with MLC601 over 4 years has been demonstrated in the present study. Overall, it seems that the safety and efficacy of MLC601 is promising compared to currently prescribed treatments.