Bimodal administration of entacapone in Parkinson's disease patients improves motor control.

Catechol-O-methyl transferase (COMT) inhibition by entacapone enhances levodopa absorption and reduces 'off' time in Parkinson's disease (PD). We hypothesized that the administration of entacapone in a bimodal fashion (two doses 1 h apart) would enhance levodopa absorption and improve the motor symptoms of PD. Patients with PD (n = 17) were given immediate (IR)- or controlled (CR)-release levodopa each with either one or two doses of entacapone. Bimodal entacapone produced a significant increase in IR and CR levodopa half-life, 'area under the curve' (AUC), and C(max) with levodopa CR. For both IR and CR levodopa, bimodal entacapone resulted in a significant improvement in the Unified Parkinson's Disease Rating Scale part III (motor). Bimodal entacapone increased COMT inhibition, improved the pharmacokinetics of levodopa and improved motor scores for 6 to 8 h. Bimodal use of entacapone may be useful in selected patients to improve motor control and implies that controlled release COMT inhibition would be beneficial in PD patients.

Determination of 5-chloro-7-iodo-8-quinolinol (clioquinol) in plasma and tissues of hamsters by high-performance liquid chromatography and electrochemical detection.

This paper describes a method of determining clioquinol levels in hamster plasma and tissue by means of HPLC and electrochemical detection. Clioquinol was separated on a Nucleosil C18 300 mm x 3.9 mm i.d. 7 microm column at 1 ml/min using a phosphate/citrate buffer 0.1M (400 ml) with 600 ml of a methanol:acetonitrile (1:1, v/v) mobile phase. The retention times of clioquinol and the IS were, respectively, 11.6 and 8.1 min; the quantitation limit (CV>8%) was 5 ng/ml in plasma and 10 ng/ml in tissues. The intra- and inter-assay accuracies of the method were more than 95%, with coefficients of variation between 3.0 and 7.7%, and plasma and tissue recovery rates of 72-77%. There was a linear response to clioquinol 5-2000 ng/ml in plasma, and 10-1000 ng/g in tissues. The method is highly sensitive and selective, makes it possible to study the pharmacokinetics of plasma clioquinol after oral administration and the distribution of clioquinol in tissues, and could be used to monitor plasma clioquinol levels in humans.

Effect of acute intravenous clomipramine and antiobsessional response to proserotonergic drugs: is gender a predictive variable?

BACKGROUND: Previous studies on serotonergic responsivity in obsessive-compulsive disorder (OCD) showed about 50% of patients experiencing an acute worsening of OC symptoms when administered meta-chlorophenylpiperazine or i.v. clomipramine. The aim of this study was to determine what variables influence the response to acute i.v. clomipramine. Could this response be predictive of the response to chronic treatment with two serotonergic drugs with differing selectivity profiles: clomipramine and fluvoxamine? METHODS: Fifty OC patients were consecutively recruited. All underwent a challenge with 25 mg i.v. clomipramine and placebo and were administered 10-week oral clomipramine or fluvoxamine according to a double-blind design. The efficacy of the antiobsessional treatment was evaluated by Yale-Brown Obsessive-Compulsive Scale and Clinical Global Impression scale scores. RESULTS: Obsessions worsened in 42% patients as rated by change values in 100-mm visual analogue scale scores for the clomipramine vs. placebo infusion. There was a significant difference in gender distribution between "worsened" and "unchanged" patients, since female subjects were more frequently "unchanged." Thirty-one patients completed the 10-week treatment. According to both qualitative and quantitative evaluations, female subjects showed a better antiobsessional response, and this difference was enhanced in the clomipramine-treated group. CONCLUSIONS: Results suggest a role for reproductive hormones in the pathophysiology or treatment of OC patients.

Decreased CSF concentrations of homovanillic acid and gamma-aminobutyric acid in Alzheimer's disease. Age- or disease-related modifications?

Fifteen patients, 48 to 72 years old, with Alzheimer's disease were studied. Clinical status was assessed by neurologic and neuropsychologic examinations and psychometric testing. Patients were divided into two groups on the basis of clinical assessment: group 1, little mental deterioration, and group 2, serious mental deterioration. Nineteen subjects, 27 to 72 years old, without neurologic disease served as controls. Levels of homovanillic acid (HVA), 5-hydroxyindoleacetic acid (5-HIAA), and gamma-aminobutyric acid (GABA) were determined in lumbar CSF by fluorimetric or radioreceptor binding (GABA) methods. The HVA concentrations increased with age in the controls, whereas the GABA levels decreased with age and 5-HIAA levels were not modified. When compared with the age-matched controls, the patients with Alzheimer's disease showed low concentrations of HVA but not of 5-HIAA or GABA. The decrease in HVA level was more pronounced in patients with severe mental deterioration and therefore appeared to be disease related.

Effect of a cholecystokinin antagonist on some effects of diazepam.

Dose responses were evaluated for the effects of diazepam alone or together with the cholecystokinin receptor antagonist CR 1409 on pentetrazole-induced convulsions, motor performance and spontaneous motor activity. The results obtained showed that the cholecytokinin antagonist potentiated the effects of diazepam on motor performance and the anticonvulsant activity of diazepam, while it did not affect spontaneous motor activity. The data presented are consistent with a role for cholecystokinin in some effects of diazepam.

Short and long-term effects of reserpine on the concentration of 1-(4-hydroxy-3-methoxyphenyl)-ethane-1,2-diol (MOPEG-SO4) in the brain of the rat.

1 Reserpine (1.25 mg/kg i.p.) induced an increase (172% of controls) in the concentration of 1-(4-hydroxy-3-methoxyphenyl)-ethane-1,2-diol sulphate (MOPEG-SO(4)) in rat brain and a decrease in the noradrenaline (NA) concentration to 50% of controls 2 h after injection. At this time the MOPEG-SO(4)/NA ratio was 0.28. Thereafter the MOPEG-SO(4) concentration declined and the NA concentration decreased further to 28% of control.2 Higher doses of reserpine (2.5 and 5 mg/kg i.p.) did not induce a larger increase in the concentration of MOPEG-SO(4).3 While a second dose of reserpine (1.25 mg/kg i.p.) given 24 h after the first did not increase the MOPEG-SO(4) concentration, amphetamine (5.0 mg/kg i.p.) administration or electrical stimulation significantly increased the concentration of MOPEG-SO(4).4 NA and MOPEG-SO(4) concentrations were examined during 5 days after a single dose of reserpine (1.25 mg/kg i.p.). While the concentration of NA started to return towards normal after 24 h, that of MOPEG-SO(4) remained at approximately 70% of controls during the entire period.5 The probenecid-induced accumulation rate of MOPEG-SO(4) was significantly lower 3 and 4 days after reserpine and returned to the control value on the fifth day. At this time the concentration of NA had reached 50% of the control value.6 These experiments indicate that MOPEG-SO(4) is not the major metabolite of NA during the initial phase of reserpine-induced NA release. Reserpine acts on the storage pool while amphetamine (like electrical stimulation) acts on the functional pool. During the first phase of post-drug recovery, there is a clear decrease in NA output which appears to be regulated by the concentration of NA in the storage pool.

Correlation between desipramine levels and (-)-noradrenaline uptake and chronotropic effect in isolated atria of rats.

1. The uptake of unlabelled and [(14)C]-desipramine was studied in rat isolated atria incubated in a medium containing concentrations of desipramine ranging from 200 pg/ml to 2 mug/ml. The uptake was found to be dose- and time-dependent. Equilibrium was not reached after 2-3 h of incubation unless concentrations of desipramine higher than 1 mug/ml were used.2. The washout curves of atria previously loaded with desipramine showed that the drug is slowly released and that this release is not influenced by its initial tissue concentration.3. The binding appeared to be at non-specific sites and not at sites where noradrenaline is stored since atria taken from rats treated with 6-hydroxydopamine accumulated the drug at the same rate as control atria.4. The inhibition of (-)-noradrenaline uptake and the potentiation of the chronotropic response to (-)-noradrenaline is correlated with the concentration of desipramine in atria for tissue levels of the drug ranging from 0.01 to 1 mug/g. Higher tissue levels show less potentiation of the effect of (-)-noradrenaline or even inhibition of the maximal response to (-)-noradrenaline. These concentrations of desipramine (> 7 mug/g) markedly depressed the atrial rate.5. The results show that despite the accumulation of desipramine by unspecific sites, concentrations of desipramine in the tissue are correlated with the pharmacological response. Furthermore a gradual shift from potentiation to inhibition of noradrenaline response can be obtained with the same bath concentrations of desipramine by increasing the time of incubation.

Stereotyped behavior and hyperthermia in dogs: correlation with the levels of amphetamine and p-hydroxyamphetamine in plasma and CSF.

A gas-chromatographic method for simultaneously measuring p-hydroxyamphetamine (pOA) against amphetamine (A) in plasma and CSF is presented. The time course of body temperature (Tb), stereotyped behavior (St), and A and pOA levels in plasma and CSF were studied after administration of 0.6 and 1.5 mg/kg p.o. of A to dogs. Stereotyped behavior reached maximal value 2.5 h after A, as did levels of A in CSF. The A levels in CSF decreased steadily in the following hours and simultaneously with the levels of A in plasma. St remained elevated and began to decrease after 6.5 h. The relationship between St and amounts of A was not linear but exponential. This suggest that both A and its metabolite contributed to this effect. In fact, a linear relationship was found between St and the amounts of pOA in CSF. Body temperature had a time course similar to A plasma levels, reaching peak value after 1.5 h and declining thereafter simultaneously with A. A linear relationship was found between Tb and the amounts of A in plasma. Thus Tb seems to be a peripheral A effect related to the presence of the drug in plasma.

Paradoxical effect of amphetamine in an endogenous model of the hyperkinetic syndrome in a hybrid dog: correlation with amphetamine and p-hydroxyamphetamine blood levels.

A telomian-beagle hybrid has been studied as a possible model for the hyperkinetic syndrome in children. Behavior tests showed that hybrids, like children, exhibit hyperactivity, impulsiveness, and impaired learning. Two groups of hybrid could be differentiated; the behaviour of one improved after amphetamine (responders) while that of the other did not (nonresponders). Moreover hybrids were less responsive than beagles to other effects of amphetamine such as stereotyped behaviour and hyperthermia. Measurement of blood levels of amphetamine and its active metabolite p-hydroxyamphetamine (pOA) showed that hybrids form less pOA. We propose that the lesser response of hybrids to toxic effects of amphetamine is due to this difference in amphetamine metabolism. Responders showed higher peak blood levels of amphetamine than nonresponders and their improvement on amphetamine correlated with blood levels of amphetamine. Therefore high levels of amphetamine appear to be necessary for its 'paradoxical' effect in this model. This suggests that amphetamine acts by activating both noradrenergic and dopaminergic neuronal systems in the CNS.

Impairment of memory and plasma flunitrazepam levels.

Flunitrazepam was administered to volunteers in three different oral doses. The effects on psychomotor sedation, attention, working memory and explicit memory were then assessed at various intervals after dosing and compared with levels of the drug in the plasma. Three groups of 12 healthy males with similar levels of education were given placebo or flunitrazepam (1, 2 or 4 mg) in a double-blind, random-sequence study. Volunteers completed a battery of tests at night, 3.5 h after taking the drug and in the morning, 10 h afterward. Blood samples were collected for drug analysis before and after the nocturnal tests and before morning tests. At night, only the highest dose of flunitrazepam (4 mg) induced significant changes in psychomotor sedation, attention, working memory, and prose immediate recall. Doses of 2 and 4 mg flunitrazepam significantly reduced the mean scores of explicit memory (morning tests). Z-scores, calculated from differences between flunitrazepam and placebo, revealed that 2 mg flunitrazepam impaired memory but not alertness or attention. Linear regression analysis of the relationship between plasma levels of flunitrazepam and its effects (Z-scores) indicated that there was a significant positive correlation between peak levels of flunitrazepam at night and impairment of night attention and explicit memory, i.e. delayed recall of prose (r = 0.59, P < 0.01) and trigrams (r = 0.55, P < 0.01). However, memory and attention Z-scores as a function of plasma levels fitted with nonlinear regression analysis to the Emax model had higher correlation coefficients. To produce an effect equal to 50% of the maximum effect for memory impairment, concentrations (EC50) were 6.1 and 6.4 ng/ml for prose and trigrams delayed recall; but for attention they were much higher, at 13.2 ng/ml. The overall results indicate that higher concentrations were needed to impair attention than were required to impair memory.

Effects of flunitrazepam on cognitive functions.

The effects of various oral doses (1, 2, 4 mg) of flunitrazepam on vigilance, attention, immediate memory, short-term memory, learning, non-consolidated and consolidated long-term memory were determined. Twelve healthy young male volunteers were given placebo or flunitrazepam in a double-blind, random latin-square sequence, crossing over every 2 weeks. Volunteers completed a battery of tests at night, 3.5 h after drug administration, and in the morning, 10 h after drug administration. Flunitrazepam 1 mg did not significantly impair any of the functions tested at night, while 4 mg impaired vigilance, attention, immediate memory, short-term verbal memory and learning. The impairments of immediate and short-term memory seem to be related and proportional to reductions in vigilance and attention. Doses of 2 mg and 4 mg impaired the speed of learning but did not decrease the amount of material learned. Flunitrazepam caused dose-related impairment of long-term memory, both consolidated and not. This reduction of long-term memory does not seem to be related to the impairments of vigilance, attention or learning. The lowest dose did not modify vigilance and learning in any subject, improved attention in half of the subjects but reduced long-term memory in a similar number of subjects. Therefore, our results indicate selective impairment of long-term memory. Since there were no differences between the effects on consolidated and non-consolidated memory, the amnesic effect of flunitrazepam seems to be due to a decrease in the storage of memory traces. There were no clear generalized residual effects in the morning after administration.

Effects of loprazolam on cognitive functions.

The effects of oral loprazolam (1, 2 mg) on vigilance, attention, immediate memory, short-term memory, learning, long-term non-consolidated and long-term consolidated memory were determined. Twelve healthy young male volunteers were given all the treatments, placebo or loprazolam, on three different occasions, in a double-blind, random latin-square sequence, crossing over every 2 weeks. Volunteers completed a battery of tests at night, 3.5 h after drug administration, and in the morning, 10 h after drug administration, to test recall of some of the material presented at night (long-term memory) and residual effects. Loprazolam did not significantly impair any of the functions tested at night. On the other hand, 2 mg loprazolam caused impairment of long-term memory, both consolidated and not. This reduction of long-term memory does not seem to be related to the impairments of vigilance, attention or learning. The 2 mg dose of loprazolam, which did not modify the mean scores and improved vigilance, attention and learning in some of the subjects, reduced long-term memory. Therefore, although caution in interpreting the results should be used, mainly because it is possible that differences in sensitivity of the tests cannot be overcome and because the relative small number of subjects, our results indicate that loprazolam might induce selective impairment of long-term memory. Since there were no differences between the effects on consolidated and non-consolidated memory, the amnesic effect of loprazolam seems to be due to a decrease in the storage of memory traces. There were no clear generalized residual effects in the morning after administration.

Effect of after-dinner administration on the pharmacokinetics of oral flunitrazepam and loprazolam.

The pharmacokinetics of two benzodiazepine hypnotics, flunitrazepam and loprazolam, was determined on two occasions in two groups of eight healthy volunteers. Single 2-mg oral doses of either drug were given in the fasting state at morning on one occasion and after a standard dinner at night on another. Compared with administration of drugs in the fasting state, administration of the drugs after dinner decreased peak plasma concentrations, delayed the time to reach maximum concentration, and prolonged the absorption half-life. The extent of absorption was reduced for flunitrazepam but not for loprazolam. The elimination half-life of both flunitrazepam and loprazolam was not changed in the two conditions. These changes may be of clinical significance because they can delay and reduce the effects of the drugs.

Pharmacokinetics of zidovudine in HIV-positive patients with liver disease.

The pharmacokinetics of zidovudine (ZDV) have been studied in eight AIDS patients with normal liver function, and in four AIDS patients with liver disease. Patients who were previously untreated with ZDV were given 250 mg ZDV, and plasma levels of ZDV and its glucuronic metabolite, GZDV, were determined at 0.5, 1, 1.5, 2, 3, and 4 hours after the dose. In patients with liver disease, Cmax and AUC of ZDV were higher, the oral clearance was only one-eighth that of patients without liver disease, and the elimination half-life was longer. There was a trend for concentrations of the principal metabolite, GZDV, to be lower in patients, and, therefore, the ratio of the AUC for GZDV to that for ZDV was much lower in patients with liver disease. Therefore, HIV-seropositive patients with liver disease had the same markedly altered disposition of ZDV as seronegative patients with liver disease. Although this therapy was not clearly associated with a higher incidence of toxicity, some patients with liver disease had to discontinue therapy because of intolerance; therefore, plasma levels of these patients should be monitored when such therapy is undertaken.

Neurochemical and behavioural modifications induced by scrapie infection in golden hamsters.

Scrapie-infected hamsters were tested for spontaneous motor activity and passive avoidance at various times after infection. After testing, some animals were killed and their whole brains assayed for norepinephrine, dopamine, serotonin and their metabolites. The apparent rate of turnover was estimated in terms of metabolite/amine concentrations. After 70 days, there was a decrease in passive avoidance and dopamine and serotonin. Passive avoidance correlated with the apparent rate of turnover of dopamine, whereas motor activity correlated with that of serotonin and dopamine.

A genetic taxonomy of hyperkinesis in the dog.

Among children who have difficulty inhibiting gross motor activity and focusing on learning tasks requiring them to do this, some are helped by central nervous system stimulants such as amphetamine, while others with identical symptoms are not. Similar variations in response to pharmacological agents are seen in other syndromes, suggesting that multiple biological mechanisms are involved and that these are selectively responsive to pharmacological manipulations. Diagnosis, therefore, involves not only the identification of the condition, but knowledge of the mechanisms by means of which it can be brought about, as well as some means of identify ing these. Since such variations often have a genetic basis, their identification and characterization by genetic and pharmacogenetic approaches permit the investigator to avoid confounding biological variation with statistical error and, ultimately, to suit the treatment to the mechanism when there is no final common path permitting a single intervention specific to a given syndrome. Because such researches are difficult with human patients, we have been attempting to identify animal models with analogous symptoms to human conditions and homologous mechanisms underlying these. The present paper is one in a series describing a dog model for hyperkinesis.

Effects of single and multiple doses of desipramine (DMI) on endogenous levels of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rat brain.

A single administration of desipramine (DMI) (10 mg/kg, i. p.) decreased brain levels and probenecid-induced accumulation rate of 3-methoxy-4-hydroxyphenylglycol-sulfate (MOPEG-SO4) in rats. To investigate the mechanism of this action, the interaction of DMI with NA receptor blockers and its effects on electrical stimulation were evaluated. It was found that phenoxybenzamine (20 mg/kg) or chlorpromazine (10 mg/kg) completely prevented the DMI-induced decrease in MOPEG-SO4 brain levels. On the other hand, DMI did not antagonize the increase in MOPEG-SO4 induced in the cortex-hippocampus by stimulation of the locus coeruleus. These observations indicate that the effect of DMI on MOPEG-SO4 is more likely to be due to a reduction of neuronal impulse flow mediated by a negative feed-back mechanism resulting from impairment of reuptake than to a direct effect on NA catabolism. In contrast to the effect of a single dose, the repeated administration of DMI (10 mg/kg, twice a day for 3 days) did not significantly reduce the rate of probenecid-induced accumulation of MOPEG-SO4. This development of tolerance to the metabolite-decreasing effects of DMI indicates that complex adaptive changes occur in the NA system upon repeated DMI administration.

Pharmacokinetics and adverse effects of single doses of dothiepin in young and elderly subjects.

1. The pharmacokinetics and side-effects of Dothiepin (DOT) were studied for four days after administration of a single oral dose of 75 mg to young adult and elderly subjects. 2. In the elderly DOT is absorbed, distributed and eliminated with half-lives about the same as in young adults but it is cleared less efficiently. 3. This difference of clearance in the elderly, after single-dose administration, is not reflected in increased incidence of side-effects.

Reduced haloperidol/haloperidol ratio and clinical outcome in schizophrenia: preliminary evidences.

1. The possible influence of haloperidol and its metabolite plasma levels on clinical outcome in schizophrenic patients was evaluated. 2. 18 schizophrenic inpatients diagnosed according to DSM III, were treated with conventional haloperidol p.o. for four weeks. 3. Plasma levels of haloperidol and its reduced metabolite were measured by mass-spectrometry assay. Clinical outcome was evaluated by BPRS. 4. Cluster analysis only considering BPRS improvement and reduced haloperidol/haloperidol ratio was able to discriminate two groups of patients: one of non responders and the other of responders. The former group presented higher ratios than the latter. 5. Reduced haloperidol/haloperidol ratio could be considered as a good marker for prediction of the clinical outcome.

Factors affecting the clinical response to haloperidol therapy in schizophrenia.

Fifty-one patients diagnosed as schizophrenics or schizoaffective according to DSM-III criteria were treated with conventional haloperidol regimens for 4 or 6 weeks. The clinical picture and extrapyramidal side effects were assessed by means of the Brief Psychiatric Rating Scale (BPRS), and the Simpson and Angus Scale (EPSE). Evaluations were made at admission and after 4 or 6 weeks of treatment. The clinical response to treatment was reported as the percent change in BPRS scores at the end of treatment from the BPRS scores at baseline. Haloperidol (HAL) and hydroxyhaloperidol (REDHAL) were determined by high-performance liquid chromatography (HPLC) with electrochemical detection in plasma. The mean total BPRS item score at the end of the study was significantly lower than at the beginning of the study. HAL and REDHAL levels were significantly related to the dose, and REDHAL levels were also related to HAL levels. There was no correlation between plasma HAL levels and the percent change in BPRS. The percent change in BPRS at the end of the study was negatively correlated with plasma REDHAL levels and REDHAL/HAL ratios and was positively correlated with the baseline BPRS total score. There was no significant correlation between the duration of illness and improvement, but patients with good improvement had significantly shorter duration of illness. Patients who improved also had higher baseline BPRS scores, lower REDHAL levels and REDHAL to HAL ratios, but not significantly different HAL levels. Therefore, the shorter the duration of the disease, the higher the baseline BPRS and the lower the reduced levels of its ratio to haloperidol levels, the higher the percent improvement.(ABSTRACT TRUNCATED AT 250 WORDS)