Rodica TALMACI, PhD Hematology Department – “Fundeni” Clinical Institute University of Medicine and Pharmacy “Carol Davila” BIRTH DATE and PLACE: 1973 September 9th, Chisinau, Moldova CITIZENSHIP: Romanian AREA OF INTEREST: Management of development and research activity in Molecular Biology Molecular investigation of haematological malignancies Molecular
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Effect of methylphenidate andor levodopa coupled with physiotherapy on functional and motor recovery after stroke a randomized, doubleblind, placebocontrolled trialActa Neurol Scand 2011: 123: 266–273 DOI: 10.1111/j.1600-0404.2010.01395.x Eﬀect of methylphenidate and⁄or levodopacoupled with physiotherapy on functionaland motor recovery after stroke – arandomized, double-blind,placebo-controlled trial Lokk J, Salman Roghani R, Delbari A. Effect of methylphenidate and ⁄ or levodopa coupled with physiotherapy on functional and motor recovery after stroke – a randomized, double-blind, placebo-controlled trial.
1Department of Neurobiology, Care Sciences and Acta Neurol Scand: 2011: 123: 266–273.
Society, Karolinska Institute, Stockholm, Sweden; 2Department of Clinical Sciences, University of SocialWelfare & Rehabilitation, Tehran, Iran; 3Iranian Objective – Amphetamine-like drugs are reported to enhance motor Research Center on Aging, University of Social Welfare recovery and activities of daily living (ADL) in stroke rehabilitation, but results from trials with humans are inconclusive. This study isaimed at investigating whether levodopa (LD) and ⁄ or methylphenidate(MPH) in combination with physiotherapy could improve functionalmotor recovery and ADL in patients with stroke. Material andmethods – A randomized, double-blind, placebo-controlled trial withischemic stroke patients randomly allocated to one of four treatmentgroups of either MPH, LD or MPH+LD or placebo combined withphysiotherapy was performed. Motor function, ADL, and strokeseverity were assessed by Fugl-Meyer (FM), Barthel index (BI), and Key words: functional recovery; levodopa;methylphenidate; motor recovery; physiotherapy; National Institute of Health Stroke Scale (NIHSS) at baseline, 15, 90, and 180 days respectively. Results – All participants showed recoveryof motor function and ADL during treatment and at 6-month follow- Ahmad Delbari, Department of Neurobiology, CareSciences and Society, Division of Clinical Geriatrics, up. There were slightly but signiﬁcant diﬀerences in BI and NIHSS Huddinge Hospital 14183, B 62 Karolinska Institute, compared to placebo at the 6-month follow-up. Conclusion – Ischemic chronic stroke patients having MPH and ⁄ or LD in combination with physiotherapy showed a slight ADL and stroke severity improvement over time. Future studies should address the issue of the optimal therapeutic window and dosage of medications to identify thosepatients who would beneﬁt most.
been hypothesized that pharmacological inter- ventions administered to stroke patients may have The burden of stroke-related disability is enormous the potential to modulate neuronal and synaptic and expected to increase with our aging population plasticity (4). In human clinical trials, there were (1). Following stroke, 40–67% of patients may inconsistent results regarding the effect of D-amphet- have a persisting motor deﬁcit which may not amine (5), selective serotonin reuptake inhibitors improve despite ongoing physiotherapy (2).
(6), donepezil (7), or levodopa (LD) (8) on post-stroke Many novel therapeutic treatments in stroke recovery. Previous investigations into the effective- rehabilitation have recently been identiﬁed and are ness of methylphenidate (MPH) during early post currently being investigated in clinical trials (3). An stroke rehabilitation have shown it be a safe area of promise in stroke rehabilitation is that of medication with the potential of advancing recovery Ôrehabilitation pharmacologyÕ. The potential may (9). However, the result of a study by Restemeyera exist for these new pharmacological interventions to et al. (10) suggested that a single dose of LD is not expedite and improve the recovery process. It has sufﬁcient for improvement in motor function after chronic stroke. There is a dose-response effect and Qom, Iran, when being referred to outpatient associated with the drug (11), and its effectiveness rehabilitation treatment at the Neurorehabilitation is improved after administration of multiple doses Clinic of Rofeydeh Hospital aﬃliated to the on an intermittent schedule (12). Although signi- University of Social Welfare & Rehabilitation, ﬁcant advances have been made in development of Tehran, Iran from March 2006 to September potential pharmacotherapies for stroke rehabili- tation, deﬁnitive scientiﬁc evidence of the clinical In the beginning, a trained physician assessed all effectiveness of such therapies is still lacking (13).
referred patients for inclusion and exclusion crite- Much eﬀort has been made to identify medica- ria. Non-eligible patients were oﬀered the standard tions that could increase the capacity of CNS rehabilitation care. All therapists were trained to regeneration and maximize the gains of rehabili- provide a standardized rehabilitation program to tating motor and ⁄ or cognitive functions in inca- all patients. Two trained physicians evaluated the pacitated patients. The results of published studies patients completely, initially, for medical history to date, however, are not convincing.
and general, neurologic and outcome-speciﬁc phys-ical examination. These two physicians were fol-lowing up patients at all sessions, ensuring that all patients received standard rehabilitation and the We hypothesized that psychostimulant drugs com- evaluation was performed adequately. The reha- bined with physiotherapy would improve recovery bilitation program was usually scheduled to be from stroke. To investigate this hypothesis, a administered in the morning. Blood pressure and placebo-controlled comparative drug study with heart rate were monitored immediately before LD and ⁄ or MPH in combination with physiother- Ischemic patients with a paretic arm and ⁄ or legfollowing a stroke that had occurred 15–180 days previously and being able to follow the instructions An interventional, randomized, double-blind, pla- cebo-controlled trial on patients with chronic As MPH is a potentially hypertensive agent, ischemic stroke in a 2 · 2 factorial design with comorbidities which could be negatively aﬀected patients being given four diﬀerent treatments. With by the drug implicated exclusion. The exclusion an 80% power to detect a 20% diﬀerence from criteria were hemorrhagic stroke, myocardial baseline to 3 and ⁄ or 6 months a signiﬁcance level infarction or angina pectoris within the last of 0.05, one hundred patients were needed.
A computerized randomization was performed unstable metabolic disease, sequelae of earlier by a person not involved in the research process.
cerebral lesion, non-controlled hypertension (sys- Full written informed consent was obtained from tolic blood pressure ‡170 mm Hg, diastolic blood the patients before randomization or an assent was pressure ‡110 mm Hg), tachycardia (‡100 bpm), taken from a relative ⁄ caregiver if the participant major cognitive deﬁcit (aphasia, apraxia, neglect, was incapable of giving his ⁄ her consent. Each concentration, and memory deﬁcits) or psychiatric patientÕs treatment status was kept unavailable disease that hindered adequate participation in the from the patients themselves, the caregivers, the study, glaucoma, uncontrolled epilepsy, hypersen- study physicians, and the physiotherapists. The sitivity to MPH or LD, prominent agitation, or patientsÕ demographic data including age, gender, current antidepressant treatment. Patients receiv- established stroke risk factors, paretic side, stroke ing alfa-adrenergic antagonists or agonists, neuro- duration, and any history of stroke were collected.
leptics, benzodiazepines, or a MAO inhibitor were The Ministry of Health in Iran and University of Social Welfare and Rehabilitation Ethics Commit-tee approved the study, and it was performed according to the Declaration of Helsinki (14).
The MPH ⁄ LD ⁄ placebo drugs were randomly dis-tributed in boxes labeled 1–100. A computerized random-number generator was used by a person Participants were consecutively enrolled from not involved in the study, to generate the random eight acute care hospitals in the cities of Tehran allocation sequence list with four groups.
The drug protocol developed for this study was based on what was prescribed and suggested inprevious studies (15). The reasons for choosing assessed quantitatively using the FM scale which suggested from animal and human experiments is developed for use in clinical rehabilitation (16–18), they had rare side effects (19), and they settings. It is a stroke-speciﬁc impairment index were readily available in Iran when compared to that is widely used for assessment of motor recovery. Its reliability and validity are well doc- MPH does not cause addiction, and doses of umented (23–25). On this scale, a score of 0 means £40 mg do not lead to insomnia or loss of no motor function (ﬂaccid hemiplegia) and a score appetite in adults (13). In this four-group inter- of 100 indicates normal motor function (divided vention model, drug treatment was given in the into 66 points for normal arm motor function and form of identical white tablets of 2 · 10 mg of 34 points for normal leg motor function). Each either MPH or placebo of identical appearance item is scored on a 3-point ordinal scale (0 cannot and a tablet with either 125 mg LD or placebo. It perform, 1 performs partially, and two performs was administrated at least 60 min before the fully). Motor function was assessed by a physio- training session to coincide with the timing of therapist at baseline, at the end of the 15th session, peak pharmacological action of drugs (20). Treat- and at follow-up (3 and 6 months after baseline).
ments continued 5 days a week for a total of 15drug therapy sessions, a frequency often used in Activities of daily living – Autonomy in ADL was evaluated using the Barthel index (BI) (26). BI was Patients received the boxes in consecutive order.
developed as a scoring technique measuring the Placebo and drugs were prepared by a hospital patientÕs performance in 10 ADL. The BI is pharmacist independent of the investigators to be considered a reliable disability scale for patients with stroke (27). The items can be divided into one The potential side eﬀects of LD, including group that is related to self-care (feeding, groom- ing, bathing, dressing, bowel and bladder care, and toilet use) and one group related to mobility Also for MPH, the possible side eﬀects were (ambulation, transfers, and stair climbing) (15).
closely monitored including insomnia, nausea, The maximal score is 100 in ﬁve-point increments.
or nervousness, over the ﬁrst 24 h after adminis- The lowest score is 0, representing a totally Stroke severity – The National Institute of Health Stroke Scale (NIHSS) is used to assess stroke Patients received daily 45-min physical therapy severity (29). It consists of 11 items and the sessions. A goal-oriented approach was used in maximum possible score is 31. A score of 0 each session to accomplish a range of activities indicates no clinically relevant neurological abnor- encompassed in a standard treatment: mobiliza- mality. The NIHSS is not time-consuming to tion, selective movements exercise, sensory-motor, administer, taking <8 min to perform (30).
Good overall interrater reliability has been shown in multicenter stroke trials (31), and the NIHSS transfer, ambulatory activities, and other activities has shown a very good sensitivity, speciﬁcity, and of daily living (21). The theoretical framework of accuracy in predicting clinical results at 3 months treatment was neurodevelopmental wherein the facilitation versus abnormal movement inhibition (22). Increasingly, complex functional activities these data were means, standard deviations, fre- were introduced over time to cause progressive quencies, and percentages used to describe age, improvements in trunk and limb muscle control gender, days since stroke onset, history of previous (22). The content, not the volume of the training, stroke, paretic side, and risk factors. Data of the varied from each patient depending of the sever- four treatment groups and the mean change from ity of his or her paresis. Individuals received baseline to 15, 90, and 180 days of BI, FM, and additional rehabilitation treatment depending on NIHSS were compared by ANOVA or Kruskal– their neurological impairments such as speech Wallis test, as appropriate. Signiﬁcant results were further investigated with post hoc test (Tukey).
One-Sample Kolmogorov–Smirnov was used to diﬀerent to the other patients with regard to check normality of distribution of variables. The demographic, motor function, stroke severity, or signiﬁcance level was established at 0.05.
ADL. Seventy-eight patients completed the treat-ment and follow-up process with data included inthe analysis (Fig. 1). Baseline characteristics of the patients of the respective group are presented inTable 1. Patients were compared regarding age, gender, risk factors, stroke duration, history of Hundred patients, diagnosed with ischemic stroke, stroke, and paretic side. The mean age of patients were recruited from March 2006 to September was 64 Æ 9.8(65.4 Æ 9.2 for men and 61.8 Æ 10.6 2008. During 6-month follow-up, 15 patients died for women), and 2.6% were younger than 45, and seven patients dropped out, data which were 46.1% were 45–64 years of age and 51.3% not included in the analysis. They were not ‡65 years. Through logistic regression analysis, Figure 1. Patients ﬂow chart, describing subjects excluded and included in treatment process; MPH, methylphenidate; LD, levodopa;MPH & LD, methylphenidate & levodopa; P, placebo.
MPH, methylphenidate; LD, levodopa; MPH & LD, methylphenidate & levodopa; P: placebo; HTN, hypertension; DM, diabetes mellitus; HLP, hyperlipidemia; HD, heart disease;SD, standard deviation.
Table 2 Mean and standard deviation of Baseline Barthel Index, Fugl-Meyer, and Table 3 Mean and standard deviation of Baseline Barthel Index, Fugl-Meyer, and NIHSS scores of three actively treated and placebo-treated groups NIHSS scores in 3 and 6 months and mean changed scores of three actively -treated and placebo-treated groups Mean changes scores: 6 months to baseline MPH, methylphenidate; LD, levodopa; MPH & LD, methylphenidate & levodopa; P: hypertension (HTN) was the most common risk factor, 73.1%, followed by diabetes mellitus, 28.2%, and smoking 23.1%. Right-side paresis Mean changes scores: 6 months to baseline Baseline data of motor function (FM), ADL (BI), and stroke severity (NIHSS) were homogeneous and well balanced in all four groups. Separate model for arm and leg motor scores in FM, self- care, and mobility in BI revealed no signiﬁcant Mean changes scores: 6 months to baseline diﬀerences in baseline data (Table 2).
All participants showed recovery of motor MPH, methylphenidate; LD, levodopa; MPH & LD, methylphenidate & levodopa; function (FM), ADL (BI), and stroke severity (NIHSS) during the observation period. Accordingto post hoc test, there were no signiﬁcant diﬀer-ences between the active drug and placebo groups signiﬁcant, and according to a secondary power between follow-ups (3 and 6 months) in BI, FM, analysis, for a 80% power with 50% higher and NIHSS scores, but there were signiﬁcant differences between groups, there would be a between-group diﬀerences in scores of mean need for at least 30 patients in each group.
changes of total BI and NIHSS on 6 monthsto baseline (F (3, 74) = 4.000, P = 0.011) and (F (3, 74) = 5.728, P = 0.001), respectively, witha greater gain in the combined MPH & LD groups.
We found a signiﬁcant recovery of the BI and Table 3 shows the scores and outcome at follow- ups for FM (total score, arm, and leg), BI scores from baseline to 6 months compared to placebo.
(total score, self-care, and mobility), and NIHSS.
This addition of LD and ⁄ or MPH in combination Mean improvement to ﬁrst follow-up (baseline to with physiotherapy was safe and well tolerated 3 months) of the FM was not signiﬁcant, 23.9, and indicated a slight but signiﬁcant ADL 19.9, 18.7, 12.3 in the LD + MPH; LD, MPH and improvement over time. However, all patients placebo group, respectively. There were no signif- improved their motor recovery and independence icant differences between the active drug groups as measured by the ADL as expected as most and placebo groups between follow-ups (3 and post-ischemic patients have a natural recovery potential over time (15, 33). The interpretation of adverse side effects were observed. Differences in this result is complicated by the fact that the gain of motor function between groups were not corresponding mean change in the FM motor score was not signiﬁcant. It could be that the drug or 120 min (35) or 60 min (37), as in this study, effect has more of a fortifying effect on the patient with ischemic stroke resulting in improved Diﬀerent drug regimes have been tested earlier; functioning rather than a speciﬁc motor effect. As the regime utilized here, and pioneered by others patients in this study were recruited on average (8, 15, 19), was driven by concern for potential 2 months after stroke, and there are large vari- adverse effects. As we did not ﬁnd any side effects, ables in motor abilities in patients, one could it is possible that higher and more frequent doses assume that the motor function prior to active are possible, as tested in experimental models by drug intake was too ÔgoodÕ to show further Scheidmann and Grade (8, 9) MPH is originally improvement in some patients. The potential of prescribed for attention deﬁcit hyperactivity disor- achieving further improvement and catching it der patients and often administrated at 0.5– through the scales could be reduced by a ceiling 0.75 mg ⁄ kg bodyweight with a maximum of effect. However, FM seems to be more sensitive 60 mg daily. Then, it would most probably be than the BI to changes in disability. It is well- safe and possibly have a more powerful effect with pronounced ceiling effect; and therefore, should Pharmacological intervention may be beneﬁcial in be carefully utilized for distinguishing between patients who have previously failed to respond to severely affected patients and not for patients at a motor training in isolation (42). The question of whether using pharmacologic interventions com- There was no signiﬁcant beneﬁt on total motor bined with physiotherapy is of any clinical value scores compared with physiotherapy alone when remains unclear. In this study, we have investigated given for 15 treatments over 15 days. The results the effect of norepinephrine-facilitating drugs on of this investigation are in line with those reported ischemic stroke patients in motor function and ADL by Sonde et al. (15), Platz (35), Restemeyer (10), during chronic phases. LD and ⁄ or MPH were and Sprigg (36), where patients were unable to administered in the current study as amphetamine demonstrate a superiority of LD and ⁄ or MPH has documented deleterious cardiovascular side compared to placebo. Sonde et al. (15) used an effects (40). Catecholamine neurons have been identical trial design as in our study and also shown in animal models of brain injury to possibly found no beneﬁt in 36 patients on the FM motor alter motor recovery (43), and drugs that antagonize scale or the BI. In a study by Treig et al. (37), no catecholamine receptors (e.g., haloperidol (44) and signiﬁcant differences were found between the phenoxybenzamine (45) may have negative effects placebo-control and amphetamine-treated group on rehabilitation. Norepinephrine was shown to be on either the Rivermead Motor Assessment or the active chemical in clinical trials involving amphetamine (46); therefore, a combination of LD The eﬀectiveness of amphetamine-like drugs on and decarboxylase inhibitor was administered to motor recovery might depend on the stage of increase norepinephrine levels in the synapse (8).
disease. Studies that reported a beneﬁcial eﬀect of MPH acts by directly stimulating release of dopamine and norepinephrine, as well as blocking patients early after stroke, i.e. 3–30-day post- catecholamine reuptake (47) thereby having effects stroke (5, 22) while in this study patients in the on both dopaminergic and noradrenergic modula- LD and ⁄ or MPH groups entered the trial on average 9.3 weeks after stroke. Comparable inves- tigations did not speak to the optimal recruitment number of patients; we experienced similar diﬃ- period or the most effective treatment timeline (36).
culty with patient recruitment that other studies In trials that did not report an improvement in have faced because of a wide range of exclusion motor recovery after amphetamine treatment, criteria (15). Although we chose wide inclusion patient recruitment occurred commonly 3–10 days criteria of patients with stroke, the majority of post stroke (38–39). In a review by Goldstein, it screened stroke patients did not meet the initial was conﬁrmed that pharmacotherapy success eligibility criteria, and they were excluded from depends heavily on proper timing of drug admin- entering the study. However, 78 of the 100 eligible patients terminated the study. There is signiﬁcant potential of beneﬁts from an increase in regimented Furthermore, timing between medication and physical therapy (22). Fifteen 45-min sessions of exercise therapy has been similar in positive and physiotherapy may not have been sufﬁcient to negative trials, i.e. exercise therapy has been induce or support plastic brain changes. In a study provided within 3 h of drug administration (41), by Scheidtmann et al. (8) stroke patients receiving 100 mg LD per day for 3 weeks improved signif- 4. Losseff N. Neurological rehabilitation of stroke. London: icantly more than the placebo-treated control group. Furthermore, to date, no clinical study 5. Walker-Batson D, Smith P, Curtis S, Unwin H, Greenlee R.
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PRODUCTION OF DRUG NANOPARTICLES OF CONTROLLABLE SIZE USING SUPERCRITICAL FLUID ANTISOLVENT TECHNIQUE WITH ENHANCED MASS TRANSFER Gupta R.B1, and Chattopadhyay P.*2 1-Auburn University, 2-Ferro Corporation. Ferro Corporation, 7500, E. Pleasant Valley Road, Independence, OH 44133. U.S.A. Email: firstname.lastname@example.org Fax: (216) 7506915 ABSTRACT The use of supercritical