Clinical Neuropharmacology

Published by Lippincott, Williams & Wilkins
Online ISSN: 0362-5664
Publications
Article
In a series of earlier studies, an oral dose of 0.5 mg/kg d-amphetamine was administered to 81 patients with schizophrenia and eight normal control subjects. Seven more subjects with schizophrenia received placebo. Blood pressure and pulse rate were monitored before and 3 hours after drug administration. Blood pressure increased in both amphetamine groups, whereas placebo had no effect. However, pulse rate did not change in the schizophrenic group and only increased after 3 hours in normal control subjects as blood pressure began to decrease. Significant negative correlations between systolic blood pressure and pulse rate occurred at 2 and 3 hours, suggesting that the early cardiovascular response to amphetamine is an increase in blood pressure that recruits reflex control of heart rate. Eighteen of these subjects had hypertensive responses. Six subjects received 5 mg haloperidol intramuscularly, and 12 others had their blood pressure monitored until normalization. Haloperidol led to a more rapid decline of some but not all indices of blood pressure, suggesting that amphetamine-induced hypertension may have a dopaminergic component.
 
Article
We assessed the antiparkinsonian response in MPTP-treated monkeys after acute or repeated treatment with oral L-Dopa, subcutaneous administration of L-Dopa methyl ester (LDME) or apomorphine, alone and in combination with D1 antagonists SCH 23390 (SCH) or NNC 01-0112 (NNC). When given alone, the L-Dopa effect occurred within the first hour after treatment. Coadministration of SCH or NNC with L-Dopa significantly delayed the onset of action. The response duration remained unchanged, as did the extent of the antiparkinsonian effect, after SCH, whereas the former became shorter at the higher doses of NNC tested. Bypass of the gastrointestinal tract using parenteral injections of LDME and apomorphine allowed the rapid turning "on" of the animals. Both D1 antagonists administered with LDME delayed the onset and shortened the duration of the therapeutic effect as the dose increased. Pretreatment with SCH failed to block the antiparkinsonian effect induced by apomorphine, but reduced the response duration markedly in a dose-related fashion. Repeated treatment of one monkey with SCH combined with the same dopaminergic drugs produced results similar to those obtained after acute treatment in four animals. The results obtained with parenteral administration of LDME and apomorphine most probably involve pharmacodynamic actions resulting in increased threshold of response. The delay observed with L-Dopa suggests pharmacokinetic interference possibly mediated via dopamine receptors located at the level of the gut.
 
Voiding Diary 
Article
Parkinson disease (PD) patients present urinary symptoms during the course of the disease, very often suggestive of overactive bladder and sustained by neurogenic detrusor overactivity. These symptoms cause a severe lowering of quality of life determining social withdrawal and they need to be early diagnosed to restore social interaction and prevent urinary tract complications. Today overactive bladder diagnosis is easier, thanks to the availability of new investigative tools, particularly voiding questionnaires. The aim of the present study was to evaluate the reliability of the Overactive Bladder screener (OAB screener/OAB-questionnaire), a new voiding questionnaire specifically developed for the overactive bladder diagnosis in PD subjects suffering from overactive bladder symptoms. Clinical data obtained by the questionnaire were compared with urodynamic outcomes, at basal conditions and after antimuscarinic treatment, to better explorate the questionnaire reliability. Forty PD patients have been enrolled in the protocol, and submitted to the OAB screener, voiding diary and urodynamic investigation before and after antimuscarinic treatment. OAB-score and urodynamic parameters were statistically analyzed and compared. The OAB-q well correlated with voiding diary and urodynamic data of Parkinson subjects either at baseline or after the antimuscarinic treatment. The study suggests that this clinical tool might be used for neurogenic overactive bladder diagnosis and that it seems to be a useful outcome measure for treatments of neurogenic OAB.
 
Article
Objective: Ponezumab (PF-04360365) is a humanized anti-amyloid beta (Aβ) monoclonal antibody designed for treatment of Alzheimer disease (AD). A single 2-hour intravenous infusion of 0.1 to 10 mg/kg was previously shown to be safe and well tolerated in subjects with mild to moderate AD, with measurable effects on plasma and cerebrospinal fluid Aβ. This phase I, dose-escalation, open-label study evaluated the safety, pharmacokinetics, and pharmacodynamics of a single 10-minute intravenous infusion. Methods: Subjects with mild to moderate AD received ponezumab 1 mg/kg (n = 3), 3 mg/kg (n = 3), 5 mg/kg (n = 4), or 10 mg/kg (n = 5). They were followed up as outpatients for 6 months. Results: All subjects completed the trial. Ponezumab was safe and well tolerated with no deaths, withdrawals, or drug-related moderate, severe, or serious adverse events. Mild drug-related adverse events included headache (3 patients) and lethargy and hypoesthesia (both in 1 patient). No infusion reactions, clinically meaningful laboratory abnormalities, vital sign changes, electrocardiographic changes, or antidrug antibodies were detected. There was no evidence of brain microhemorrhage, vasogenic edema, encephalitis, or other imaging abnormality. Cognitive function showed no treatment-related trends. Ponezumab displayed approximately dose-proportional increases in plasma exposure. Steady-state volume of distribution was 113 to 172 mL/kg, clearance was 2.7 to 3.0 mL/d/kg, and terminal half-life was 35 to 52 days. Plasma maximum observed concentration and the area under the plasma concentration-time profile from time 0 extrapolated to infinite time of Aβ(1-x) and Aβ(1-40) increased dose-dependently. Conclusions: Administration of ponezumab as a 10-minute infusion was safe and well tolerated and produced effects on plasma Aβ species comparable with a 2-hour infusion. Shorter infusions may provide more flexibility, comfort, and convenience for patients and caregivers.
 
Article
The long-term effects of mesulergine, a new drug with dopamine agonistic properties, were studied in 28 patients with Parkinson's disease. In 18 patients with late side effects of levodopa, the addition of mesulergine (10.9 mg/day) induced significant decreases in the global (-48%), rigidity (-62%), and akinesia (-37%) scores. The drug was found to be very effective on tremor (-71%). Mesulergine was useful in cases of inefficacy of levodopa alone or persistent intolerable side effects. The decrease in levodopa dose and the addition of mesulergine permitted a significant reduction in dyskinesia. Used as sole therapeutic agent (10.9 mg/day), mesulergine was found to be active on tremor and rigidity scores but not on akinesia or global scores. Mesulergine induced few side effects. These results show the antiparkinsonian properties of mesulergine that seem to be of significant therapeutic value in patients with tremor or in combination with levodopa.
 
Article
Several authors have suggested that catecholamine depletion may affect attentional processes in human subjects and could be implicated in the frontal lobe syndrome that has been described in Parkinson's disease (PD). The present study reports the effects of a placebo and naphtoxazine (SDZ-NVI-085), a selective noradrenergic alpha 1 agonist. These substances were administered to nine parkinsonian patients who were assessed on measures of attention, including neuropsychological tests and evoked potentials. The results indicate that naphtoxazine may improve performance on some tests of "frontal functions," including the Stroop and the Odd-Man-Out tests, which have been previously found to be affected in PD. However, the results of some other neuropsychological tests of frontal function were not affected by naphtoxazine. Specific evoked potentials such as the Nd1 and Nd2 curves--which are thought to reflect attentional processes and which have been found to be affected in PD--were improved by naphtoxazine. Finally, naphtoxazine reduced the percentage of errors and restored the lateralization of N100 during the Shifting Reaction Time Task, suggesting that this substance may act on the processes underlying the shifting deficit in these patients. The results are discussed in terms of the specific cognitive processes that may be affected by naphtoxazine and in terms of the role of the noradrenaline in attentional deficits found in PD.
 
Article
To assess the efficacy, tolerance, and safety of amineptine in ambulant treatment of depressive states, an open multicenter trial was performed by 135 general practitioners in a large number of depressed patients (1,229) with different nosologies and living in all areas of Portugal. The protocol included criteria of inclusion and exclusion and the full methodology was discussed with the practitioners in previous meetings coordinated by a psychiatrist. Daily dosage was 200 mg (two tablets); other psychotropic drugs were associated rarely and only when strictly necessary. Assessments were made at day 0, 7, 28, and 56, using the Clinical Global Impressions (CGI), Hamilton Depression Rating Scale (HDRS), diagram HARD, and a list of side effects. Results were analyzed statistically with calculation of statistical significance. The calculation of the correlation coefficients between the different measurement instruments was also made. There were 84 dropouts mainly due to missed appointments and intolerance of the medication. It is worth noting that 50% of the patients were treated with monotherapy, and that other psychotropics used were almost always anxiolytic drugs. Efficacy of amineptine was very good and rapid since there was a statistically significant difference in all observations with the different instruments of measurement used. Results were good in all types of depression, mainly in the neurotic and reactive ones. Moderate or severe side effects were seldom observed and transient. The acceptability was good or very good in 97.1% of the cases.
 
Article
The effect of carbamazepine and its -10,11-epoxide on the development of amygdala-kindled seizures and on completed kindled seizures in the rat was evaluated. Neither carbamazepine (15 mg/kg) nor the -10,11-epoxide (15 mg/kg) was capable of preventing the development of amygdala-kindled seizures, although both drugs, at these doses, exerted marked anticonvulsant effects on completed kindled seizures. These data suggest that different phases of kindling are differentially responsive to pharmacological intervention. They also support the conclusion that different mechanisms underlie the acquisition and maintenance of kindled seizures.
 
Article
Various drugs, when used during acute stroke, may affect stroke outcome. Some advise against the use of certain drugs that may be potentially harmful when used in acute stroke. However, for many of such drugs, the evidence is scarce. Therefore, we studied the use of various drugs at stroke onset as independent predictors of outcome at 3 months. In an observational study of 1013 acute ischemic stroke patients, medication on admission was registered and divided in 10 categories. Functional outcome at 3 months was rated using the modified Rankin scale as functional independent (Rankin 0, 1, and 2) or as functional dependent or dead (Rankin 3, 4, and 5, or 6). Independent predictive values of medication use on outcome were analyzed using multivariate regression modeling. Vasodilator use was independently associated with less favorable functional outcome at 3 months (odds ratio [OR], 0.37 [95% confidence interval {CI}, 0.16-0.89]; P = 0.025) in lacunar stroke, as was the use of diuretics (OR, 0.43 [95% CI, 0.22-0.82]; P = 0.010) in atherothrombotic stroke. Calcium antagonists were independently associated with better outcome at 3 months (OR, 2.64 [95% CI, 1.04-6.69]; P = 0.042) in cardioembolic stroke. Our study does not yield strong evidence in favor of testing various commonly used drugs as potential neuroprotectives in acute stroke.
 
Article
BL-1020, a novel gamma aminobutyric acid (GABA) ester of perphenazine, is a new oral antipsychotic with a strong affinity for dopamine and serotonin receptors. Unlike first- and second-generation antipsychotics, it has agonist activity at GABA(A). This is the first study to examine tolerability and safety of BL-1020 in schizophrenia. This was a phase-II, open-label, multicenter, 6-week study treating patients (n = 36) with chronic schizophrenia. Dosing started at 20 mg/d and increased over 7 days to 40 mg/d. Weekly assessments were conducted. All but 1 patient was titrated to 30 mg/d at day 4; on day 7, 30 were titrated to 40 mg/d. Four patients discontinued the study prematurely. There was no clinically relevant increase in vital signs, sedation, dizziness, or other central nervous system effects or electrocardiogram or laboratory abnormalities and a small increase in weight. Ten patients experienced extrapyramidal symptoms (EPS) requiring treatment with an anticholinergic; 4 patients were unable to reach maximum dose because of EPS. Extrapyramidal Symptom Rating Scale did not indicate clinically significant changes in EPS. The most common adverse event was insomnia (6 patients); other frequent adverse effects (all n = 3) were extrapyramidal disorder, headache, parkinsonism, tremor, and hyperprolactinemia. There was improvement on Positive and Negative Syndrome Scale and Clinical Global Impression of Change with 22 patients showing at least 20% decrease by end point on Positive and Negative Syndrome Scale and 31 patients showing at least minimal improvement on Clinical Global Impression of Change. These data suggest that 20 to 40 mg/d of BL-1020 is associated with clinically relevant improvement of psychosis with no worsening of EPS and support further testing in randomized controlled trials.
 
Article
This study examines the response to treatment in 17 patients with kleptomania who were treated with naltrexone as monotherapy for up to 3 years. Patients were treated with naltrexone (range, 50-200 mg/day) and were assessed at each clinic visit for stealing behavior, urges to steal, and for overall symptom severity. Liver function tests were examined regularly during treatment. Comparison of baseline symptoms with the most recent follow-up visit showed that 13 patients (76.5%) reported reduction in their urges to steal, and 7 (41.1%) reported no stealing behavior. In addition, 9 (52.9%) were rated as being either "not ill at all" or having "very mild" kleptomania symptoms at the most recent clinic visit. The mean effective dose of naltrexone was 135.3 +/- 38.6 mg/day. Monthly liver function tests revealed no elevations or abnormalities. These findings from a clinical setting suggest that a substantial percentage of patients report clinically significant improvement in kleptomania symptoms when treated with naltrexone.
 
Article
The effect of a single dose (60 mg p.o.) of the serotonin agonistic agent fenfluramine (FNF) on plasma cortisol, prolactin (PRL), growth hormone (GH), and immunoreactive beta-endorphin (ir-beta-EP) levels was assessed in eight major depressed patients and eight controls. The hormones were monitored at basal level (0') and hourly during 5 h following FNF administration. The pharmacological challenge caused an elevation of 80% in PRL secretion in the healthy controls and only 42% in the depressed patients. However, the actual prolactin response (delta max) failed to discriminate depressed patients from controls. A blunted response followed by a decrease (33%) in serum cortisol levels was observed in depressed patients 5 h after drug administration while an increase of 94% was obtained in controls after 3 h. FNF provocation did not affect GH and ir-beta-EP plasma levels. The blunted cortisol responsiveness to FNF administration in depressed patients may reflect functional hypoactivity of central serotonergic system at least during the acute phase of major depression. It is not clear why the cortisol hyporesponsivity in depressed patients is not accompanied by a similar reduced PRL response to FNF challenge.
 
Article
Blockade of the N-methyl D-aspartate (NMDA) receptor by the ion-channel-blocking drug aptiganel hydrochloride (CNS 1102, Cerestat) is neuroprotective in focal cerebral ischemia. Short intravenous infusions of up to 30 microg/kg have been well tolerated by healthy male volunteers. We undertook a randomized, double-blind, placebo-controlled study in 20 male volunteers to examine the safety, tolerability, and cardiovascular and psychomotor effects of a dosing paradigm similar to that envisaged for therapeutic use. Aptiganel HCl was infused over 4 h in total doses of 15, 32, 50, or 73 microg kg. Mean arterial pressure increased significantly with dose group (p < 0.01, analysis of covariance). Motor reaction time was related to maximal plasma concentration (r2 = 0.21, p < 0.001). Transient symptoms and signs of peripheral paresthesiae, light-headedness, and euphoria were seen at total doses of 32 microg/ kg. Higher doses were associated with motor retardation, perceptual disturbances, and hallucinations (one case). Clearance was 125 +/- 55 L/h, and volume of distribution was 537 +/- 1,261. Total doses of up to 32 microg/kg of aptiganel HCl infused over 4 h are well tolerated by healthy males. Aptiganel HCl causes elevation of blood pressure and is associated with central nervous system symptoms and signs similar to other noncompetitive NMDA antagonists.
 
Article
BAM-1110 [(5R,8R,10R)-6-methyl-8-(1,2,4-triazol-l-ylmethyl) ergoline maleate] is a newly synthesized dopamine agonist that produces little anorexic side effects (nausea and vomiting). The current study examines the effects of BAM-1110 on parkinsonian symptoms in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated monkeys, an animal model of Parkinson's disease. First, a significant antiparkinsonian effect of apomorphine hydrochloride (0.3 mg/kg given subcutaneously) was confirmed in these animals. BAM-1110 (0.1, 0.3, and 1 mg/kg subcutaneously) relieved parkinsonian symptoms in a dose-dependent manner. Significant effects were observed at doses of 0.3 and 1 mg/kg and lasted for at least 3 h. BAM-1110, at a dose of 0.3 mg/kg that produced the submaximal antiparkinsonian effect, did not induce significant abnormal behaviors such as hyperactivity and stereotyped behaviors. Significant stereotyped behaviors were observed at 1 mg/kg of BAM-1110. Apomorphine induced hyperactive and stereotyped behaviors in parallel with its antiparkinsonian effect. BAM-1110 appears to be a potentially useful dopamine agonist to treat Parkinson's disease because of its relatively weak drug-induced hyperactive disturbances and anorexic side effects.
 
Article
Cognitive deficits affecting executive (frontal) functions have been widely described in Parkinson's disease (PD). However, dopa therapies are generally ineffective at reversing these deficits, except for tasks involving a sharing of attention such as working memory or simultaneous processing tasks. The aim of this study was to assess the relation between the nigrostriatal dopaminergic denervation in PD, as measured by SPECT with (123)Iodine-beta-CIT and the cognitive deficits, as measured by a simultaneous processing task, which had already been shown to be sensitive to dopa treatment. Ten patients with PD and ten control subjects were selected and matched for age, sex, and education. All subjects were assessed using computed visuo-auditory tasks which allow for the measurement of three cognitive processing conditions: 1) a Selective Processing Time; 2) a Competitive Processing Time; and 3) a Simultaneous Processing Time. Patients with PD were assessed both with (ON) and without (OFF) their usual dopaminergic treatment. The simultaneous processing condition but not the selective or the competitive conditions took significantly more time for patients with PD OFF than for either the control subjects or the patients with PD ON. In addition, when patients with PD were OFF, the simultaneous processing condition was correlated with the (123)Iodine-beta-CIT binding, but not when they were ON. These results suggest that nigrostriatal DA denervation may be involved in the specific impairment that patients with PD experience with simultaneous cognitive processing.
 
Article
Cabergoline is an ergotic dopamine agonist with D2 receptor activity and a very long half-life. This pharmacological profile may result in clinically different effects. Small clinical trials indicate that overnight switching from 1 agonist to another can be performed safely. To determine safety and efficacy of overnight switching from dopamine agonists to cabergoline in patients with advanced Parkinson disease (PD). Patients with advanced PD and motor complications not optimally controlled by levodopa and a stable dose of bromocriptine, pergolide, pramipexole, and ropinirole were converted to cabergoline overnight. Patients were assessed by using an on-off diary, Unified Parkinson Disease Rating Scale (subscales I-IV), Parkinson's Disease Quality of Life 8 (PDQ-8), an ad hoc sleep questionnaire and an ad hoc off-period severity questionnaire. All rating scales were administered just before conversion and after 2, 6, and 12 weeks of treatment, when patients were on an optimal dose of cabergoline. Adverse effects were assessed at every visit following a check list. One hundred twenty-eight patients were included in the trial. Forty were on pergolide (mean dose, 2.8 mg/d), 38 on pramipexole (mean dose, 2.1 mg/d), and 32 on ropinirole (mean dose, 8.1 mg/d). Patients on bromocriptine (n = 18) were excluded from the analysis because of the small sample size. Three patients reported serious side effects (respiratory arrest, dyskinesias, and face edema and abdominal pain). Twenty-eight patients reported 41 adverse events. Twelve patients were withdrawn due to adverse effects (hallucinations [n = 5], dyspnea [n = 1], dizziness [n = 4], and vascular problems [n = 2]). A significant improvement in assessed parameters was obtained (P < 0.0001). Mean levodopa dose remained unchanged. After 12 weeks, the mean dose of cabergoline was 3.2 mg, and 25% of patients were taking the drug twice a day. Switching from pergolide, ropinirole, and pramipexole to cabergoline in an overnight schedule is safe. The observed clinical improvement may be related to a placebo effect, to the use of low doses of dopamine agonists, or to a direct effect of cabergoline.
 
Article
BW 1370U87 is unique among potent inhibitors of monoamine oxidase-A (MAO-A) in that it contains no nitrogen. Like other MAO-A inhibitors, BW 1370U87 elevates neurotransmitter amines in the brain over the same dose range at which it exhibits positive activities in animal models of depressive illness. However, BW 1370U87 differs from most other MAO inhibitors in that its mechanism of action follows simple competitive kinetics, so that an unusually high concentration of tyramine in peripheral tissues may displace the inhibitor from MAO-A sites in the intestine and liver. In addition, BW 1370U87 concentrations in brains of rats appear much higher than in plasma, whereas extensive metabolism of the parent compound in the liver produces weaker MAO-A inhibitors with the same type of competitive mechanism. Early phase-I safety trials at acute doses up to 2,000 mg of BW 1370U87 showed no adverse reactions, whereas MHPG in urine was decreased, indicating that in vivo inhibition of MAO-A was achieved in humans. Thus BW 1370U87 represents a new agent with potential therapeutic application in depression and other CNS illnesses.
 
Article
Two patients with spinocerebellar ataxia (types 3 and 14) experienced marked improvement in their cerebellar symptoms shortly after taking varenicline (Chantix).
 
Article
To assess the potency of a formulated drug product containing 150-kd botulinum toxin type A (BoNT/A) as the active pharmaceutical ingredient. Potencies of 3 unexpired lots of a commercially available BoNT/A drug product, reportedly devoid of complexing proteins (Xeomin), were determined using an approved in-house potency bioassay by injecting mice intraperitoneally and recording percent-mortality across dilutions. For each test session, duplicate sets of dilutions were performed for each lot alongside a 900-kd BoNT/A (BOTOX) potency reference standard. A relative potency for each 150-kd BoNT/A preparation was determined using this potency reference standard. A standard normalized potency estimate for each lot of 150-kd BoNT/A was calculated by multiplying the relative potency by the nominal value for the reference standard. The average potency for each 150-kd BoNT/A lot was calculated using a weighted combination of assay results and compared against the labeled potency of 100 U per vial. Similar follow-on testing was performed 1 year later to assess stability. The average potencies for the 3 lots of 150-kd BoNT/A product were 69 (95% confidence interval [CI], 65-73), 75 (95% CI, 70-80), and 78 (95% CI, 70-87) U per vial. Follow-on testing produced even lower potency results for all 3 lots. The potency of the drug product containing 150-kd BoNT/A (Xeomin) measured substantially lower than the labeled 100 U per vial when tested in a potency assay approved for release testing of an established drug product containing 900-kd BoNT/A (BOTOX).
 
Article
A possible cause of motor fluctuations in patients with Parkinson disease is the erratic drug absorption. In a randomized double-blind double-dummy study of melevodopa (levodopa methyl ester), a highly soluble levodopa pro-drug plus carbidopa (CHF 1512) was compared to a standard formulation of levodopa/carbidopa (LD/CD) in 74 fluctuating Parkinson disease patients. The first afternoon, LD/CD tablet was substituted with an equimolar dose of CHF 1512. The study lasted 4 weeks and was followed by an 8-week (optional) open phase. The primary efficacy variable was latency to "on." Patients randomized to receive CHF 1512 had a significative shorter latency to "on" than those randomized to LD/CD and a similar "on" duration. The safety profile of CHF 1512 was also comparable with LD/CD.
 
Article
Recurrent microdeletions of chromosome 15q13.3 are causally associated with autism spectrum disorders (ASDs), suggesting that haploinsufficiency of CHRNA7, the gene that codes for the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit, is an etiological mechanism. Independent of these genetic data, given the location of α7 nAChRs on γ-aminobutyric acid-inhibitory neurons and their role in maintaining central inhibitory tone, a compelling pharmacological rationale exists for therapeutically targeting the α7 nAChR in persons with ASDs. Given the availability of positive allosteric modulators of nicotinic acetylcholine receptors and selective agonists for the α7 nAChR (eg, choline derived from dietary administration of cytidine 5'diphosphocholine and anabasine derivatives), it is possible to conduct "proof of concept" clinical trials, exploring the effects of α7 nAChR agonist interventional strategies on domains of psychopathology, such as attention, cognition, and memory, in persons with ASDs.
 
Article
Selective serotonin reuptake inhibitors (SSRIs) are apt to cause gastrointestinal adverse events such as nausea and dyspepsia. Gorei-san (TJ-17), which is composed of five herbs (Alismatis rhizoma, Atractylodis lanceae rhizoma, Polyporus, Hoelen, and Cinnamomi cortex), is a Japanese herbal medicine that has been used to treat nausea, dry mouth, edema, headache, and dizziness. The authors investigated the efficacy of TJ-17 for patients who experienced nausea or dyspepsia induced by SSRIs. Twenty outpatients who experienced nausea or dyspepsia induced by SSRIs were recruited for the study. Seventeen patients were female, three were male, and patient age ranged from 21 to 74 years (49.8 +/- 17.0 years). TJ-17 was added to the previous regimen. Nausea and dyspepsia disappeared completely in nine patients, decreased in four patients, decreased slightly in two patients, and did not change in five patients. No adverse events were associated with the addition of TJ-17 in any patient.
 
Article
17 beta-Hydroxysteroid dehydrogenase (E2-DH) activity was characterized on a semipurified microsomal preparation of human meningioma tissue (mean Km of 2 microM and Vmax of 500 pmol/mg protein/10 min) and then assayed in 49 meningioma specimens with high progesterone receptor and low estrogen receptor levels. Of these 49 tumors, 36% contained an E2-DH activity greater than 1,000 pmol/mg protein/10 min and similar to that of uterine myometrium. In this limited series of tumors, no correlation between E2-DH activity and progesterone receptor levels was noted.
 
Article
Akinetic mutism is a rare, complex neuropathologic disorder. The pharmaceutical treatment of akinetic mutism typically includes dopaminergic agents, but the resulting therapeutic effects are often unsatisfactory, and it remains unclear whether late treatment using these medications is effective. We present a case study of a 53-year-old male patient who developed akinetic mutism for a period of 7 months after a subarachnoid hemorrhage. The hemorrhage was caused by a ruptured aneurysm in the right anterior communicating artery, followed by a secondary infarction in the territory of the right anterior cerebral artery. Baseline brain F-18 fluorodeoxyglucose positron emission tomographic images revealed decreased glucose metabolism in both frontal lobes. Treatment with atomoxetine, a selective norepinephrine reuptake inhibitor, for a period of 8 weeks led to a clinically significant improvement in the patient's cognitive function and activities of daily living. A subtraction brain positron emission tomographic analysis after atomoxetine medication revealed increased cerebral glucose metabolism in both the premotor and visual association cortices. Thus, we suggest that atomoxetine can be a useful therapeutic option in the treatment of chronic akinetic mutism.
 
Article
Introduction: Cetirizine is a second-generation H1 histamine receptor antagonist that is commonly used for symptomatic relief of hay fever and other allergies and can be combined with pseudoephedrine hydrochloride, a decongestant. The most common adverse effects include headache, nausea, nasopharyngitis, vomiting, and coughing. Objective: To report on an adolescent 18-year-old woman who developed delusional thinking and depression after starting treatment with cetirizine. Case report: We report on an adolescent 18-year-old woman who developed delusional thinking and depression after starting treatment with cetirizine. Once cetirizine was discontinued, the patient returned to her clinical baseline. Conclusions: Physicians need to be aware of the potential psychiatric adverse effects associated with cetirizine.
 
Article
We administrated WEB 1881, 800 mg/day (400 mg twice a day), nine patients with dementia of the Alzheimer type for 8 weeks, and undertook an open study to investigate the clinical effects of the distribution into the cerebrospinal fluid (CSF) as well as the influence on the neurotransmitter-related substances in the CSF. These were outpatients living at home with caregivers. Significant clinical improvement was shown by means of the Gottfries, Bråne, and Steen Scale and by Hasegawa's dementia scale. Unchanged WEB 1881 was identified in the CSF. The mean concentration of which was 198.7 ng/ml, this corresponded to 19.0% of the plasma concentration. Of several neurotransmitter-related substances measured in the CSF, a marked rise of AChE activity was observed. Adverse effects consisted of a slight skin eruption in one case and alterations in a clinical laboratory test in another case. These were, however, not significant from a clinical viewpoint. It is suggested that the mechanisms of action of WEB 1881 are based on its transit into the CSF as well as the activation of intracerebral acetylcholinergic systems.
 
Article
To evaluate whether lazabemide has proarrhythmic or hypotensive potency in Parkinson's disease (PD), we conducted an 8-week, double-blind, placcbo-controlled, parallel group study with use of 24-hour ambulatory electrocardiographic (ECG) monitoring. Fifty-one patients with PD who did not have clinically apparent heart disease were randomized in a double-blind fashion to receive either lazabemide (n = 25) or placebo (n = 26) treatments. Lazabemide therapy did not induce clinically significant arrhythmias. A paroxysmal atrioventricular (AV) block, which progressed from first-degree AV block, was found in one patient in the lazabemide group. This was determined not to be a new AV block. However, the causality of lazabemide in prolongation of the pause was not ruled out completely. In addition, the asymptomatic fall in systolic blood pressure seen 3 minutes after standing up was observed to be more pronounced in the lazabemide group than in the placebo group. The mean decrease of systolic blood pressure was 10 mmHg greater in the lazabemide group than in the placebo group. In conclusion, lazabemide did not induce any clinically significant arrhythmias in patients without clinically apparent heart disease. However, it may increase the asymptomatic, orthostatic drop in systolic blood pressure.
 
Article
Selfotel (CGS 19755), a competitive N-methyl-D-aspartate antagonist, is neuroprotective in experimental models of ischemic cerebral injury. We studied the safety and tolerability of a single intravenous dose (0.5 to 2.0 mg/kg) of selfotel in neurosurgery patients. Thirty-two neurosurgical patients undergoing intracranial surgery were given ascending doses of selfotel 2 to 14 h before surgery. Serum selfotel levels were measured over a period of 24 h. Cerebrospinal fluid (CSF) levels were measured 1.5 to 18 h after dosing. Frequent side effects included psychomimetic symptoms such as hallucinations, abnormal dreaming, agitation, and paranoia among 20 (66%) patients. Ataxia was seen among five (16%) and dizziness among eight (25%). Symptoms occurred 38 min to 40 h from administration and persisted 5 min to 4 days. Symptom severity worsened with increasing area under the curve measurements and doses above 1.0 mg/kg. All symptoms were reversible and easily treated with intravenous haloperidol. Modest elevations of hepatic enzymes were observed among four patients. No patient had severe adverse reactions. Maximum selfotel levels attained were 143 mumol (serum) and 4.76 mumol (CSF). Peak serum levels among six patients were within potentially neuroprotective ranges. CSF levels remained detectable up to 18 h after dosing. No obvious relationship was seen between CSF drug levels and symptoms. Selfotel in doses of 0.5 to 2.0 mg/kg can be administered safely to neurosurgical patients. Maximum serum levels attained were within the range shown to be neuroprotective in experimental studies. Side effects even at the highest levels are tolerable and reversible. Selfotel use in patients at risk for cerebral injury should be further explored.
 
Article
A review is presented of knowledge about the following issues in Turkey: prevalence of depression, suicidal attempts and suicide, clinical picture of depression, and etiological factors responsible for causing depression. Epidemiological studies of depression are reviewed and their results are discussed in detail, with special emphasis on conclusions with valid generalizations. As in almost all countries, depression, though exhibiting some differences clinically, is a major public health problem in Turkey. The point prevalence rate for depressive symptoms is nearly 20% and clinical depression has a rate of approximately 10%. Besides, about one-third of depressive patients are chronically ill. Specific risk groups for depression by various sociodemographic characteristics include women, widowed persons aged 40 years and over, close relatives of depressive persons, and members of lower socio-economic classes. An increase in the prevalence rates of depression in Turkey is expected due to changes in public attitudes, which do not consider depression a medical disorder at present; increase in life expectancy; rapid changes in socio-economic, cultural environments; and in family structures and lifestyles.
 
Article
A 71-year-old woman presented with severe akinesia, frozen gait, and compromised postural reflexes, without rigidity, tremor, or vertical gaze disturbance. With a working diagnosis of pure akinesia, we administered amantadine (150 mg/d) and L-threo-3,4-dihydroxyphenylserine (DOPS) (600 mg/d), which alleviated her symptoms. When frozen gait recurred 2 months later, we increased the dose of L-threo-DOPS to 900 mg/d and added levodopa (300 mg/d) combined with carbidopa, but this failed to improve the patient's symptoms. We then combined administration of tandospirone, a serotonin (5-HT) 1A agonist with L-threo-DOPS (600 mg/d), resulting in marked clinical improvement. Tandospirone is reported to activate noradrenergic neurons via the 5-HT 1A receptor, which could account for such striking improvement in a patient previously responsive to the noradrenergic precursor L-threo-DOPS given alone.
 
Article
The authors evaluated the relationships between clinical and pharmacologic parameters and the Th1/Th2/Th3 cytokine network in patients with relapsing-remitting multiple sclerosis treated with differing doses of interferon-beta1a (IFN-beta1a). Their results show that low doses are ineffective but that high doses restore Th1 regulation of the maturation and activation of monocytes, T cells, immature dendritic cells, dendritic cells, and T regulatory cells for central and peripheral self-tolerance. Interaction between interleukin (IL)-10, IL-12 p70, and IL-6 production appears to play an important role in the control of the maturation and activation states of dendritic cells and T regulatory cells, and is at the basis of the benefit of high doses. The results also indicate that the physiologic mechanisms involved in aging help immunologic reestablishment in IFNbeta-1a-treated patients. Finally, it would appear that the failure of IFNbeta-1a therapy to resolve multiple sclerosis completely is due to the suppression of IL-12 p70 mechanisms (responsible for the physiologic deletion of self-reactive cells) in activation conditions, probably by IFNbeta-1a itself.
 
Article
Adverse effects of interferon (IFN) treatment are common, and efforts to minimize these reactions are of considerable importance. IFN-beta-1a is an established therapy for patients with relapsing-remitting multiple sclerosis (MS). Its psychiatric side effects are debated and not yet fully established. The authors report here the case of a patient on IFN-beta-1a therapy for MS who developed acute delirium, delusion, and depression that ceased with treatment discontinuation. Although he had a history of recurrent major depressive disorder, his prior psychiatric illness had followed a course that was clinically independent of other signs of MS. This observation points out psychiatric vulnerability of patients taking IFN-beta-1a therapy for MS and suggests that IFN-beta-1a may induce or exacerbate preexisting psychotic symptoms.
 
Article
We report a 38-year-old woman with relapsing-remitting multiple sclerosis, treated with subcutaneous injections of interferon beta (IFN-beta)-1b every other day. Disseminated cutaneous lesions were observed after 3 injections. These symptoms reappeared after drug readministration. The histopathological examination of the skin specimens confirmed nonspecific cutaneous lymphocytic vasculitis. The patient's outcome was favorable after corticosteroid placement and discontinuing IFN-beta therapy. Isolated lymphocytic cutaneous vasculitis linked to IFN-beta-1b therapy is suspected as a new association.
 
Article
Previously the authors noted an increase in glutamatergic tone in children with attention deficit hyperactivity disorder compared with age- and gender-matched control subjects. In this study they examine the effect of treatment on metabolite concentrations. Fourteen children with attention deficit hyperactivity disorder were investigated medication free and after treatment, using proton magnetic resonance spectroscopy. In the prefrontal cortex and striatum, metabolite peaks of N-acetyl-aspartate, glutamate/glutamine/gamma-aminobutyric acid, creatine/phosphocreatine, and choline compounds were measured, and ratios of the peaks were calculated and compared before and after treatment. The glutamate/glutamine/gamma-aminobutyric acid-to-creatine/phosphocreatine ratio decreased significantly in the striatum. No other metabolites demonstrated any change in response to medication. These findings suggest that glutamate may be involved in treatment response in attention deficit hyperactivity disorder, especially in the striatum.
 
Article
The intensity of interest in therapy for Alzheimer's disease (AD) has accelerated with each passing year. The nature of the effects of cholinesterase inhibitors has been refined with the publication of several studies that have examined long-term therapy as well as different aspects of the symptomatology of AD. Breakthroughs in the basic science of AD has led to new insights into potential therapeutic strategies targeted at the secretases involved in the metabolism of the Alzheimer precursor protein. An immunization approach in which the amyloid-beta protein itself was used as the immunizing agent was discontinued after unexpected toxicity occurred. Other areas of investigation with disappointing results such as estrogen replacement therapy and antiinflammatory approaches are discussed. Several other potential therapeutic agents are also reviewed.
 
Article
Orally administered levodopa, in combination with a decarboxylase inhibitor, is the gold standard therapy for Parkinson disease (PD). The problems in management of motor fluctuations in the advanced stages of the disorder are due to the close relationship between plasma levodopa levels and availability of dopamine at striatal receptor sites. The fluctuating levodopa concentrations are mainly explained by the fact that levodopa absorption only occurs in the proximal small intestine. The patient's motor function thus depends on gastric emptying, which is erratic and may even be delayed in PD. Oral therapy with sustained-release formulations and COMT inhibitors have not solved the problems satisfactorily. Therefore, infusions of levodopa by intravenous and enteral (duodenal/jejunal) routes of administration have been studied. In this review of the literature on clinically relevant levodopa infusion studies, it is shown that improvements regarding fluctuations in both plasma levodopa levels and motor performance have been repeatedly reported. The results acquired so far suggest that levodopa infusion is a safe and efficacious therapy. Recent drug delivery development and long-term studies have shown that infusion is a clinically feasible alternative to treat advanced PD.
 
Article
Tolcapone (Tasmar), an inhibitor of catechol-O-methyltransferase, is an effective antiparkinsonian agent when used as an adjunct to levodopa in patients with Parkinson disease who have end-of-dose motor fluctuations. In clinical trials, tolcapone significantly reduced "off" time and levodopa requirements. The drug is generally well tolerated, with the most common adverse events being dopaminergic related. However, clinical trials demonstrated dose-related increases in liver enzymes, and postmarketing surveillance noted 4 cases of acute hepatotoxicity with 3 fatalities that were attributed to tolcapone. For this reason, the drug was withdrawn from the market in some countries, and its use was severely restricted in the United States. An analysis of safety data indicates that, since the labeling restrictions in 1998, there have been more than 40,000 patient-years of tolcapone treatment worldwide, with only 3 reports of severe, but reversible, liver injury and no reports of hepatic fatality. It can be concluded that severe liver injury due to tolcapone is a rare event. Based on these data, the drug has been reintroduced to the market in several European countries, and the Food and Drug Administration in the United States has modified monitoring requirements. The new labeling recommends monitoring of liver function every 2 to 4 weeks for 6 months and at the physician's discretion thereafter. In addition, patients must be taken off the drug if blood tests show enzyme elevation of greater than twice the upper limit of normal. This article reviews the data pertaining to the safety and efficacy of tolcapone.
 
Article
To assess the impact of the new botulinum neurotoxin type A preparation NT 201 (Xeomin; Merz Pharmaceuticals GmbH, Frankfurt, Germany) on muscle tone, functional disability, and caregiver burden in patients with poststroke upper limb spasticity in a randomized, placebo-controlled, double-blind study. One hundred forty-eight patients with an Ashworth Scale score of 2 or higher for wrist and finger flexors and at least moderate disability in their principal therapeutic target of the Disability Assessment Scale were treated either with NT 201 (median, 320 U) or placebo and followed up for up to 20 weeks. Treatment of the wrist and finger muscles was mandatory. A significantly higher proportion of patients treated with NT 201 were responders (improvement of > or =1 point in the Ashworth Scale score), as observed in comparison to placebo 4 weeks after treatment in wrist flexors (odds ratio, 3.97; 95% confidence interval, 1.9-8.3; P < 0.001, intent to treat). For all treated flexor muscle groups, statistically significant odds ratios in favor of NT 201 were observed at week 4 (P < or = 0.009). Statistically significant results in favor of NT 201 were observed at all postinjection visits until week 12 in the principal therapeutic target (P < or = 0.005), in the global assessment of efficacy (P < 0.001), and in some tasks of the Carer Burden Scale (P < 0.05). Similar numbers of patients in each group experienced at least 1 adverse event (NT 201, n = 21; placebo, n = 20). Importantly, none of the patients developed neutralizing antibodies. NT 201 led to statistically significant improvements in muscle tone and disability and was well tolerated in patients with poststroke upper limb spasticity.
 
Article
This study investigated the tolerability and the pharmacokinetic and pharmacodynamic interactions between single oral administration of BIA 3-202 (50 mg, 100 mg, 200 mg, and 400 mg), a novel catechol-O-methyltransferase (COMT) inhibitor, and standard carbidopa/levodopa 25 mg/100 mg (Sinemet 25/100) in healthy adult volunteers. This was a single-center, double-blind, placebo-controlled, randomized, crossover study with 5 single-dose treatment periods with a washout period of 2 weeks between doses. During each treatment period, a different dose of BIA 3-202 or placebo was administered concomitantly with Sinemet 25/100. Tolerability was assessed by recording adverse events, vital signs, continuous EKG, and clinical laboratory parameters. Pharmacokinetic parameters of levodopa and 3-O-methyl-levodopa (3-OMD) were determined. The activity of soluble COMT in erythrocytes was also measured. Eighteen subjects (10 men and 8 women) participated in the study. The drug combination was well tolerated, with the adverse events reported being transient and generally mild in severity. Mean levodopa Cmax values were attained at 0.8 to 1.8 hours postdose. Thereafter, plasma levodopa levels declined with a mean t1/2 that increased in a manner that depended on the dose of BIA 3-202. The increase in systemic exposure to levodopa (AUC0-infinity) occurred at all doses of BIA 3-202, attaining its maximum at 200 mg BIA 3-202 (95% conficence interval, 1.43-1.73). The mean Cmax and AUC0-infinity values of 3-OMD decreased dose proportionally in BIA 3-202-treated subjects, with differences being statistically significant for all the doses tested. Maximum COMT inhibition occurred between 0.8 and 2.0 hours postdose, and ranged from 56 (50 mg) to 85% (400 mg). Time to return to baseline COMT activity ranged from 6 (50 mg) to 18 hours (400 mg), following the same dose-dependent tendency. In conclusion, the novel COMT inhibitor BIA 3-202 increased the bioavailability of levodopa and reduced the formation of 3-OMD when administered with standard levodopa/carbidopa.
 
Article
CV 205-502 (CV) is a long-acting dopamine agonist with potent D2 and weak D1 activity, which has not as yet been tested in patients with Parkinson's disease. We performed a dosage ranging and placebo crossover study in six patients to evaluate the efficacy and tolerance of CV when used as an adjunct to Sinemet in patients with Parkinson's disease. All patients had striking improvement. This effect was lost with placebo substitution and regained with reintroduction of CV. Benefits were sustained throughout the 6 month study. Single daily dosing could sustain the response in all but one patient. Adverse effects were mild and transient and resolved with dosage manipulation or a divided dosage regimen. CV is a promising drug for use in Parkinson's disease and further studies are indicated to test its long-term safety and efficacy.
 
Article
The antiparkinsonian efficacy and tolerability of CQA 206-291, a novel ergoline derivative with potent dopamine agonist properties, were studied during 2 months of treatment in 72 parkinsonian patients. In 36 de novo patients (patients who have not previously been treated with levodopa or dopamine agonists), CQA 206-291 was studied in an open design, while in 36 levodopa-treated patients, CQA 206-291 was studied in a randomized, double-blind, parallel-group, placebo-controlled design. CQA 206-291 induced in both groups a significant antiparkinsonian effect with an effective dose range of 5-30 mg/day. The spectrum of adverse events was similar to what is commonly observed with dopamine agonists. Further studies are required to assess the putative therapeutic advantages of CQA 206-291 when compared to other antiparkinsonian drugs.
 
Article
CQA 206-291, a new D2 dopamine receptor agonist with a biphasic dopaminergic profile, was given to six patients with idiopathic Parkinson's disease after overnight drug withdrawal. With incremental single oral doses of CQA, a dose-related, clinically significant, and prolonged antiparkinsonian effect was observed. Most subjects experienced drowsiness after the drug while a minority of subjects experienced nausea and/or vomiting or postural hypotension. Further study of this drug in humans is indicated.
 
Article
CQA 206-291, a mixed D1-D2 receptor agonist that also possesses dualistic dopamine antagonist-agonist properties, was investigated in a double-blind, placebo-controlled trial in individuals with Parkinson's disease of moderate severity. Significant improvement was noted in the treatment groups compared to the placebo group. Adverse effects were generally mild and transient. CQA appears to be an effective, well-tolerated agent in the treatment of Parkinson's disease. Nevertheless, because of laboratory-based toxicity concerns, CQA has been withdrawn from further human study and will not be developed clinically.
 
Top-cited authors
Abraham Weizman
  • Tel Aviv University
Olivier Rascol
  • Paul Sabatier University - Toulouse III
Jean-Louis Montastruc
  • Faculte de médecine université de Toulouse France
Joseph Jankovic
  • Baylor College of Medicine
Moshe Kotler
  • Beer-Yaakov & Ness-Ziona Mental Health Center affiliated to the Sackler Faculty of Medicine, Tel-Aviv Un.