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PubMed1983

Amitriptyline and ethanol: pharmacokinetic and pharmacodynamic interaction.

Amitriptyline has clinically important interactions with ethanol. Five healthy volunteers received 25 mg of amitriptyline orally, preceded by one hour and followed for eight hours by oral ethanol (or juice), dosed to achieve and maintain blood ethanol concentrations of 800 mg/l. In the presence of ethanol, amitriptyline free plasma concentrations were increased by a logarithmic mean of 204%, 186% and 127% at 1.5, 2, and 2.5 h, respectively, and amitriptyline free AUC0-8h was increased by 48% +/- 13% (means +/- SEM) (t = 5.21, p less than 0.01). Nortriptyline total AUC0-8h was increased by 26.6% +/- 12% (means +/- SEM) (t = 2.21, p less than 0.09). At the time of peak amitriptyline plasma concentrations, mean postural sway was increased over baseline by 92% with, and 2% without ethanol; likewise, mean short term memory (word recall) was decreased over baseline by 71% with, and 37% without ethanol. Ethanol increases free amitriptyline plasma concentrations most dramatically during the period of drug absorption; this is due to a decrease in amitriptyline hepatic clearance, resulting in decreased first-pass extraction. Together with the pharmacodynamic interaction, the kinetic changes provide a rationale for the toxicity of this combination and its deleterious effects on psychomotor skills.

Adult↗

PubMed1979

Reevaluation of the indoleamine hypothesis of depression. Evidence for a reduction of functional activity of central 5-HT systems by antidepressant drugs.

The effects of antidepressant drugs on central 5-HT receptor activity were studied in rats and mice. Antidepressant drugs were evaluated for their ability to displace 3H-5-HT and 3H-d-LSD from membrane binding sites in the dorsal neocortex of rats in vitro and for their ability to block 5-HTP and d-LSD induced behavioral effects in mice. The degree of blockade of head-twitches in mice produced by the antidepressants was highly correlated with their affinity for 3H-d-LSD binding sites. A number of antidepressant drugs such as amitriptyline, nortriptyline, mianserine, doxepine, nomifensine and dibenzepine appear to possess marked 5-HT receptor blocking activity at some type of 5-HT receptors in brain. New antidepressant drugs such as zimelidine, which specifically inhibit 5-HT reuptake and do not block 5-HT receptor sites, may after chronic treatment also reduce the functional activity of 5-HT systems by producing adaptive changes in postsynaptic 5-HT mechanisms. Thus, a new indoleamine hypothesis of depression is presented: the therapeutic action of antidepressant drugs may in part be due to a reduced functional acitivity of some central 5-HT systems.

Animals↗

PubMed1992

Pharmacologic manipulation of graft versus host induced splenomegaly.

A murine graft versus host (GVH) model was developed as a tool for drug discovery. A pharmacological survey revealed that as a class the anti-rheumatics (e.g., auranofin, azathioprine, and methotrexate) were the most potent inhibitors of GVH induced splenomegaly. The immunosuppressants, cyclophosphamide and cyclosporine A, and the glucocorticoids (e.g., dexamethasone, hydrocortisone, and corticosterone) were all able to suppress the GVH response. Anti-inflammatory agents (e.g., indomethacin and piroxicam), and a series of central nervous system affecting drugs, including serotonin agonists (e.g., trifluromethylphenylpiperazine (tfMPP), 1-(3-chlorophenyl)piperazine (mCPP), and quipazine), and tricyclic antidepressants (e.g., amitriptyline, desipramine, imipramine, and nortriptyline) typically were ineffective at doses up to 10 mg/kg. However, at high dose levels (30 mg/kg) piroxicam enhanced while amitriptyline and cyproheptadine (a mixed serotonin and histamine antagonist) suppressed GVH induced splenomegaly. These data provide a pharmacological profile for a series of immunomodulator, anti-inflammatory, and central nervous system active compounds in a classic immunologic model.

Animals↗

PubMed1990

Behavioral evidence implicating dopamine in sensorimotor arousal and norepinephrine in the sedative effects of antidepressant drugs.

The effects of acute and chronic antidepressant treatment on acoustic startle were evaluated in three experiments. Administration of 2.5-10.0 mg/kg desipramine, amitriptyline, and nortriptyline depressed acoustic startle responding after repeated sensory stimulation. In contrast to the tricyclic drugs, the serotonin reuptake inhibitor zimelidine increased acoustic startle, and inhibition of dopamine reuptake following acute nomifensine and bupropion administration did not influence startle reactivity in the doses examined. The response reducing effects of desipramine and amitriptyline persisted following chronic exposure to these drugs, and these findings were discussed in relation to the inhibitory actions of the tricyclics on locus coeruleus neurons. A second major finding in this study was that animals challenged with d-amphetamine during desipramine and amitriptyline withdrawal showed a facilitated startle response. Enhanced startle reactivity to amphetamine was also observed following long-term exposure to iprindole, and a withdrawal hyperactivity of acoustic startle was evident after chronic treatment with amoxapine, bupropion, and nomifensine. These results agree with evidence that repeated administration of antidepressants increases dopamine neurotransmission which modulates sensorimotor arousal.

Acoustic Stimulation↗

PubMed1991

Biphasic effect of tricyclic antidepressants on the release of norepinephrine from the adrenergic nerves of the rabbit heart.

The release of norepinephrine (NE) from the right atrium of the rabbit heart was used as a model to investigate biphasic effects due to tricyclic antidepressants, similar to those clinically observed in the treatment of depression and known as "therapeutic window". Strips of the atrium were loaded with 3H-NE, and then superfused by Krebs solution. The basal release and the electrical stimulation evoked release of 3H-NE were measured in the presence and absence of four clinically used tricyclic antidepressants: imipramine, amitriptyline, desipramine and nortriptyline. In addition, guanethidine, an adrenergic neuron blocker, was also studied. At lower concentrations (0.5-10 microM) tricyclic antidepressants increased, whereas higher concentrations (50-100 microM), inhibited the evoked release of NE. This inhibition was not prevented by the alpha2 adrenoceptor antagonist yohimbine, excluding the possibility of alpha 2 adrenoceptor-mediated inhibition of NE release. In higher concentrations the tricyclic antidepressants increased the basal release of NE in a Ca-independent way. Secondary amine derivatives were more potent inhibitors of the evoked release, and enhance the resting basal release of NE to a greater extent than the tertiary ones. Similarly, guanethidine (1-50 microM) also decreased the evoked release and increased the basal release of NE in a concentration dependent manner. Yohimbine failed to counteract the inhibition caused by guanethidine and the increment of the basal release was Ca-independent. It is concluded that the effect of tricyclic antidepressants in potentiating the release of NE is masked by their adrenergic neuron blocking properties, i.e. they inhibit the release of NE.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Canine cataplexy is preferentially controlled by adrenergic mechanisms: evidence using monoamine selective uptake inhibitors and release enhancers.

Narcolepsy is currently treated with anti-depressants to control REM-related symptoms such as cataplexy and with amphetamine-like stimulants for the management of sleepiness. Both stimulant and antidepressant drugs presynaptically enhance monoaminergic transmission but both classes of compounds lack pharmacological specificity. In order to determine which monoamine is selectively involved in the therapeutic effect of these compounds, we examined the effects of selective monoamine uptake inhibitors and release enhancers on cataplexy using a canine model of the human disorder. A total of 14 compounds acting on the adrenergic (desipramine, nisoxetine, nortriptyline, tomoxetine, viloxazine), serotoninergic (fenfluramine, fluoxetine, indalpine, paroxetine, zimelidine) and dopaminergic (amfonelic acid, amineptine, bupropion, GBR 12909) systems were tested. Some additional compounds interesting clinically but with less pharmacological selectivity, i.e., cocaine, dextroamphetamine, methylphenidate, nomifensine and pemoline, were also included in the study. All compounds affecting noradrenergic transmission completely suppressed canine cataplexy at low doses in all dogs tested, whereas compounds which predominantly modified serotoninergic and dopaminergic transmission were either inactive or partially active at high doses. Our results demonstrate the preferential involvement of adrenergic systems in the control of cataplexy and, presumably, REM sleep atonia. Our findings also demonstrate that canine narcolepsy is a useful tool in assessing the pharmacological specificity of antidepressant drugs.

Adrenergic Agents↗

PubMed1992

Urinary metabolites of amitriptylinoxide and amitriptyline in single-dose experiments and during continuous therapy.

In a cross-over design, six healthy volunteers received 50 mg amitriptylinoxide (AT-NO) IV and orally and 50 mg amitriptyline (AT) IV. Urine was collected completely for 8 h and occasionally up to 48 h. In addition, five patients each under treatment with AT-NO or AT for tension headache collected 24-h urine samples. The following compounds were analysed by HPLC: AT-NO, E- and Z-10-hydroxy-AT-NO (E- and Z-10-OH-AT-NO), free and conjugated AT, E- and Z-10-OH-AT and their mono- and didemethylated analogues, and 2-OH-nortriptyline (2-OH-NT). Unchanged AT-NO in urine accounted for an average of 34% and 22% of the single IV and oral doses, respectively, and for 28% in continuous therapy, with a further 8-9% being excreted as E- and Z-10-OH-AT-NO. The remaining part was converted to the same metabolites as was AT. In the steady state the measured compounds accounted for 74% and 77% of the daily AT-NO and AT doses, respectively. The renal plasma clearance of AT-NO varied between 75 and 265 ml/min in the six volunteers. Tubular secretion must play an important part in the renal excretion of AT-NO.

Adult↗

PubMed1992

Diffusion as a mechanism of postmortem drug redistribution: an experimental study in rats.

In some cases of drug overdose there is a reservoir of unabsorbed drug in the stomach and gut. Furthermore, agonal aspiration might establish a second reservoir in the lungs. Two experimental rat models were used to study if diffusion from these reservoirs could contribute to the phenomenon of postmortem drug redistribution. Overnight fasted rats were sacrificed by CO2 and 75 mg of amitriptyline (AMI) was administered by a gastric tube. In the first series (n = 19), the tubes were removed after AMI administration. In the second series (n = 17), the trachea was ligated and cut prior to drug administration to prevent airways contamination. The rats were left at room temperature on their back for a period of 5, 10, 24, 48, 96 up to 192 h and samples of heart blood, blood from the inferior vena cava, tissue samples from heart, lungs, different liver lobes, kidney and psoas muscle were taken. In both series of rats we observed that as early as 5 h postmortem increasing concentrations of amitriptyline were found in the liver lobes lying closest to the stomach. In rats where the trachea was not ligated, drug contamination of the lungs also resulted in an increase in drug concentration within 5 h in heart blood and heart muscle. In rats where the trachea had been ligated, amitriptyline was found in the lungs after 96 h postmortem. The main metabolite nortriptyline was also detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Amitriptyline↗

PubMedDate not supplied

Antidepressant use in elderly medical inpatients: lessons from an attempted clinical trial.

The authors conducted a clinical trial to examine the efficacy and safety of nortriptyline in the treatment of major depression in elderly medical inpatients. The diagnosis of major depression was made by a psychiatrist in 41 of 680 patients 65 years of age or older. The study was balted at the midpoint because of inadequate patient recruitment, primarily a consequence of medical illnesses that prevented more than 80% of eligible patients from participating in or completing the clinical trial. Major or minor medical contraindications to the use of antidepressants were present in over 90% of depressed patients. Short-term follow-up was conducted on untreated depressed patients, those receiving antidepressants at the time of assessment, and those in whom antidepressant treatment was initiated after assessment. Non-randomized exposure to antidepressants did not predict remission of depression at follow-up due to spontaneous remission in the untreated group. Given the prevalence of medical contraindications to antidepressant use among depressed elderly patients and the problems with side effects in treated patients, there were few depressed, elderly hospitalized patients who were candidates for antidepressant therapy.

Aged↗

PubMedDate not supplied

In vitro forecasting of drugs that may interfere with codeine bioactivation.

The O-demethylation of codeine (methylmorphine) into morphine is mediated by the polymorphic cytochrome P450 DB1 (P450 IID6). By means of in vitro screening in human liver microsomes we have studied the effect on codeine bioactivation of several drugs used as analgesics or as adjuvants for pain control. In microsomes from an extensive metabolizer subject, paracetamol (acetaminophen) and NSAIDs (acetylsalicylic acid, diclofenac, indomethacin, piroxicam, and pirprofen), benzodiazepines (chlordiazepoxide, clonazepam, diazepam, flunitrazepam, and midazolam), and anticonvulsants (carbamazepine and phenytoin) did not alter the reaction. There was marked inhibition of in vitro morphine production by neuroleptics (chlorpromazine, haloperidol, levomepromazine, and thioridazine), metoclopramide, and tricyclic antidepressants (amitriptyline, clomipramine, desipramine, imipramine, and nortriptyline). Enzyme kinetics showed competitive inhibition by neuroleptics (chlorpromazine Ki = 0.5 microM) and antidepressants (clomipramine Ki = 6.8 microM), which are substrates of the polymorphic monooxygenase. Due to the low affinity of codeine for P450 DB1 (Km = 100-200 microM), its bioactivation in extensive metabolizers, and thus its analgesic efficacy, is liable to vary greatly when it is combined with any drug that has a high affinity for the polymorphic isozyme.

Acetaminophen↗

PubMed2002

Differential modulation of efficiency in a food-rewarded "differential reinforcement of low-rate" 72-s schedule in rats by norepinephrine and serotonin reuptake inhibitors.

RATIONALE: The differential reinforcement of low-rate 72-s (DRL 72-s) schedule, in which rats must withhold a response for at least 72 s to obtain a reward (generally water), is an attractive procedure for the characterisation of potential antidepressant agents. Indeed, several antidepressants have been shown to improve efficiency (ratio of reinforcement rate to response rate) in this model, either by decreasing response rates and/or by increasing reinforcement rates. OBJECTIVE: Herein, we compared the actions of antidepressants known to inhibit serotonin (5-HT), norepinephrine (NE) and/or dopamine (DA) reuptake in a food-rewarded DRL 72-s schedule. METHODS: Rats trained in a food-rewarded DRL 72-s schedule and showing stable baseline performance were administered with drugs i.p. once a week. In independent experiments, the influence of drugs on food intake, spontaneous locomotor activity and extracellular levels of monoamines in the frontal cortex was evaluated. RESULTS: In confirmation of previous studies, the tricyclic agent imipramine (10.0 mg/kg) and the "atypical" agent mianserin (40.0 mg/kg) significantly increased efficiency. In analogy, the selective NE reuptake inhibitors (NARIs) desipramine (20.0 mg/kg), nortriptyline (2.5 mg/kg) and reboxetine (0.63 mg/kg) all displayed marked enhancements in efficiency. In contrast, the selective 5-HT reuptake inhibitors (SSRIs) citalopram (10.0 mg/kg), fluvoxamine (10.0 mg/kg) and paroxetine (10.0 mg/kg) all significantly decreased efficiency. The mixed 5-HT/NE reuptake inhibitors (SNRIs) venlafaxine (2.5 mg/kg, 10.0 mg/kg) and S33005 (0.16-10.0 mg/kg), likewise, did not increase efficiency. Further, the DA reuptake inhibitors (DARIs) bupropion (0.16-10.0 mg/kg) and GBR12935 (0.63-10.0 mg/kg) had no effect on DRL 72-s performance. All drug classes exerted a similar, mild inhibitory influence on food intake and locomotor behaviour. Imipramine, mianserin and NARIs markedly increased extracellular levels of NE, and SSRIs elevated levels of 5-HT, while SSRIs augmented levels of both. CONCLUSIONS: The present experimental procedure demonstrates, in analogy to imipramine and mianserin, robust and consistent increases in efficiency with NARIs. Their effects may be distinguished from a decrease in efficiency elicited by SSRIs, and a lack of activity of SNRIs and DARIs. While the reasons underlying the ineffectiveness of SSRIs (in contrast to previous studies) remain to be clarified, these data underline the importance of adrenergic mechanisms in the control of behaviour under conditions of delayed responding. Further, they support the interest of DRL 72-s procedures for the characterisation of diverse classes of antidepressant agent.

Adrenergic Uptake Inhibitors↗

PubMed2000

Effect of adjunctive paroxetine on serum levels and side-effects of tricyclic antidepressants in depressive inpatients.

RATIONALE: Previous studies showed that adjunctive paroxetine increases tricyclic antidepressant (TCA) serum levels by inhibiting cytochrome P4502D6. This effect has, however, been examined only in experimental studies using low doses of TCAs in healthy volunteers. OBJECTIVE: The present study investigated TCA serum level changes and side-effects after the addition of paroxetine in depressed patients treated with doses customarily used for inpatients. METHODS: 14 patients who had a moderate or severe depressive episode according to ICD-10 and who had not sufficiently responded (< or = 25% reduction of the Hamilton depression scale) to 3-week monotherapy with amitriptyline (n = 9) or imipramine (n = 5) with daily doses between 125 and 200 mg/day, received 20 mg/day paroxetine additionally under steady state conditions. RESULTS: After 2 weeks the serum levels of the metabolites nortriptyline (from 88 +/- 49 ng/ml to 176 +/- 57 ng/ml) and desipramine (from 152 +/- 78 ng/ml to 338 +/- 104 ng/ml) had risen to a significantly greater extent than those of the parent compounds amitriptyline (123 +/- 50 ng/ml to 195 +/- 128 ng/ml) and imipramine (from 75 +/- 36 ng/ml to 98 +/- 51 ng/ml). It is noteworthy that, with the exception of one case of incipient delirium, the combination therapy was well tolerated despite high TCA serum level rises. CONCLUSION: The higher increase of the metabolites as compared with the parent compounds can be explained by a paroxetine-induced inhibition of the liver enzyme cytochrome P4502D6, which catalyses the second step of the TCA metabolism, i.e. the hydroxylation of the metabolites. Blood levels should be meticulously monitored, if TCAs are combined with paroxetine.

Antidepressive Agents, Second-Generation↗

PubMed1999

Pharmacological characterization of the discriminative stimulus properties of the phencyclidine analog, N-[1-(2-benzo(b)thiophenyl)-cyclohexyl]piperidine.

RATIONALE: Although both cocaine and the phencyclidine analog, BTCP, have dopamine (DA) re-uptake blocking properties, under some conditions their behavioral effects can be differentiated. Therefore, we examined whether the discriminative stimulus (DS) effects of BTCP are different from those of cocaine. OBJECTIVES: To compare the effects of monoamine re-uptake blockers, varying in their in vitro potencies as inhibitors of DA, norepinephrine (NE), or serotonin re-uptake, in different groups of rats trained to discriminate either BTCP or cocaine from saline. Additionally, drugs from other pharmacological classes were tested in both groups. METHODS: Rats were trained to discriminate either BTCP (5 mg/kg, i.p.) or cocaine (10 mg/kg, i.p.) from saline under a two-lever FR10 drug discrimination procedure. RESULTS: BTCP and cocaine cross-substituted in BTCP- and cocaine-trained rats. The DA re-uptake blockers, mazindol, indatraline, methylphenidate, GBR12909, and GBR12935, occasioned dose-related drug-lever (DL) selection both in cocaine- and in BTCP-trained rats, with potencies that were significantly correlated. In contrast, the NE re-uptake blockers, nisoxetine, desipramine, and nortriptyline, produced higher levels of DL selection in BTCP-trained rats than in cocaine-trained rats, a profile like that reported in low-dose cocaine-trained rats. Drugs from other classes acted similarly in both discriminations. Further, the alpha1-adrenergic antagonist prazosin dose dependently blocked the DS effects of the training dose of BTCP, but not of cocaine. CONCLUSIONS: The results suggest that the DS effects of BTCP are similar to cocaine, and resemble those of a low training dose of cocaine.

Animals↗

PubMed2006

Use of tricyclic antidepressants in older patients with painful neuropathies.

OBJECTIVE: To describe patterns of use of tricyclic antidepressants (TCAs) (e.g., amitriptyline, nortriptyline) in older patients with painful neuropathies. RESEARCH DESIGN AND METHODS: Using a large US health insurance claims database, we identified all persons who: (1) received a TCA between 1 January 1999 and 30 June 2001, (2) were aged > or =65 years as of the date of their first prescription for a TCA during this period, and (3) had one or more health care encounters for the treatment of a painful neuropathy in the 30-day period immediately preceding their initial receipt of a TCA. We then examined the prevalence of selected comorbidities and/or concurrent use of medications that might render the prescribing of a TCA inappropriate, based on a listing of contraindications, warnings, and precautions found in the package inserts for these agents. Patterns of TCA use also were examined, based on information on paid claims. RESULTS: A total of 1,732 patients met all inclusion and exclusion criteria for the study. Their mean age was 74.6 years; 60.3% were women. Amitriptyline was the most frequently prescribed TCA (79.4% of patients). Forty-one percent of study subjects receiving TCAs had conditions--primarily cardiovascular--that render the use of such agents potentially inappropriate. The mean daily dose of TCAs was universally low (about 23 mg). CONCLUSIONS: The high prevalence of conditions rendering the use of TCAs potentially inappropriate, along with relatively low daily dosages, suggest that many older patients with painful neuropathies who are prescribed these agents may be suboptimally treated.

Aged↗

PubMed1997

Metabolism of carteolol by cDNA-expressed human cytochrome P450.

OBJECTIVES: To determine human cytochrome P450 isoform(s) (CYPs) involved in the metabolism of carteolol, the biotransformation of the compound was investigated in vitro using ten isoforms of human cytochrome P450 expressed in human AHH-1 TK +/- cell lines. In addition, the inhibitory effects of carteolol on the activities of important CYP isoforms, namely, CYP1A2, 2C9, 2C19, 2E1, and 3A4, were examined. RESULTS: Carteolol was metabolised to 8-hydroxycarteolol by CYP 2D6 with KM and Vmax values of 183 mumoles.l-1 and 26.09 pmol.min-1.pmol-1 P450, respectively. CYP1A1, 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1 and 3A4 were not involved in the metabolism of the compound. CYPD6-mediated carteolol 8-hydroxylase activity was inhibited by quinidine, propranolol, nortriptyline, dextromethorphan, sparteine, bufuralol, and biperiden. Biperiden competitively inhibited the catalytic reaction with a Ki value of 0.45 mumoles.l-1. Carteolol did not affect the following catalytic reactions: CYP1A2-mediated (R)-warfarin 6-hydroxylation, CYP2C9-mediated tolbutamide methylhydroxylation, CYP2C19-mediated (S)-mephenytoin 4-hydroxylation, CYP2E1-mediated chlorzoxazone 6-hydroxylation, and CYP3A4-mediated testosterone 6 beta-hydroxylation. CONCLUSION: 8-Hydroxylation is the only cytochrome P450-catalyzed metabolic reaction of carteolol by its expressed microsomes, and CYP2D6 is the principal isoform of the enzyme involved in the catalytic reaction. Carteolol has neither stimulative nor inhibitory effects on CYP1A2, 2C9, 2C19, 2E1, and 3A4 activities.

Carteolol↗

PubMed2003

Sleep disturbances in Parkinsonism.

The present article is meant to suggest an approach to the guidelines for the therapy of sleep disturbances in Parkinson's Disease (PD) patients.The factors affecting the quality of life in PD patients are depression, sleep disturbances and dependence. A large review of the literature on sleep disturbances in PD patients, provided the basis for the following classification of the sleep-arousal disturbances in PD patients. We suggest a model based on 3 steps in the treatment of sleep disturbances in PD patients. This model allowing the patient, the spouse or the caregiver a quiet sleep at night, may postpone the retirement and the institutionalization of the PD patient. I. Correct diagnosis of sleep disorders based on detailed anamnesis of the patient and of the spouse or of the caregiver. One week recording on a symptom diary (log) by the patient or the caregiver. Correct diagnosis of sleep disorders co morbidities. Selection of the most appropriate sleep test among: polysomnography (PSG), multiple sleep latency test (MSLT), multiple wake latency test (MWLT), Epworth Sleepiness Scale, actigraphy or video-PSG. II. The nonspecific therapeutic approach consists in: a) Checking the sleep effect on motor performance, is it beneficial, worse or neutral. b) Psycho-physical assistance. c) Dopaminergic adjustment is necessary owing to the progression of the nigrostriatal degeneration and the increased sensitivity of the terminals, which alter the normal modulator mechanisms of the motor centers in PD patients. Among the many neurotransmitters of the nigro-striatal pathway one can distinguish two with a major influence on REM and NonREM sleep. REM sleep corresponds to an increased cholinergic receptor activity and a decreased dopaminergic activity. This is the reason why REM sleep deprivation by suppressing cholinergic receptor activity ameliorates PD motor symptoms. L-Dopa and its agonists by suppressing cholinergic receptors suppress REM sleep. The permanent adjustment according to the progression of the degenerative process of the disease will diminishe aggravation. The following types of sleep-arousal disturbances have to be considered in PD patients: - Sleep Disturbances, Light Fragmented Sleep (LFS), Abnormal Motor Activity During Sleep (AMADS), REM Behavior Disorders (RBD), Sleep Related Breathing Disorders (SRBD), Sleep Related Hallucinations (SRH), Sleep Related Psychotic Behavior (SRPB). - Arousal Disturbances, Sleep Attacks (SA), Excessive Daytime Sleepiness (EDS), Each syndrome has to receive a score according to its severity. III. The specific therapy consists in: LFS: Benzodiazepines & Nondiazepines. AMADS: Clonazepam, Opioid, Apomorphine infusion; RBD: Clonazepam and dopaminergic agonists; SRBD: CPAP, UPPP, nasal interventions, losing weight; SRH: Clozapine, Risperidone; SRPD: Nortriptyline, Clozapine, Olanzepine; SA-adjustment; EDS-arousing drugs. Each therapeutic approach must be tailored to the individual PD patient.

Hallucinations↗

PubMed2006

Elevation in plasma Abeta42 in geriatric depression: a pilot study.

Elevated plasma amyloid beta 1-42 (Abeta42) level has been linked to increased risk for incident AD in cognitively-intact elderly. However, plasma Abeta levels in individuals with late-life depression (LLMD), especially those with a late age of onset of first depressive episode, who are at a particularly increased risk for Alzheimer's disease, have not been studied. We compared plasma Abeta in 47 elderly with LLMD with 35 controls and examined its relationships to age of onset of first depressive episode, antidepressant treatment (paroxetine or nortriptyline), and indices of platelet activation (platelet factor 4 and beta-thromboglobulin) and brain abnormalities. Results indicated that plasma Abeta42 levels and the Abeta42/40 ratio were elevated in the LLMD group relative to controls in the overall group analyses and in the age- and gender-matched groups. MRI data indicated that higher Abeta42/40 ratio was associated with greater severity of total white matter hyperintensity burden in LLMD. Plasma Abeta levels in LLMD were not influenced by age of onset of first depressive episode or antidepressant treatment and were not related to indices of platelet activation. Our preliminary results suggest that increased plasma Abeta42 and Abeta42/40 ratio are present in geriatric depression, and future studies should be done to confirm these findings and to determine their relationship to cognitive decline and brain abnormalities associated with LLMD.

Aged↗

PubMed2006

Substrate specificity and mechanism of the intestinal clonidine uptake by Caco-2 cells.

PURPOSE: This study was performed to characterize the substrate specificity and mechanism of the intestinal clonidine transport. METHODS: Uptake of [3H]clonidine into Caco-2 cells was investigated. Interaction with drugs was studied in competition assays. RESULTS: Uptake of [3H]clonidine was linear for up to 2 min, Na+-independent, and insensitive to changes in membrane potential, but strongly H+-dependent. The uptake rate of clonidine was saturable with kinetic parameters of 0.5+/-0.1 mM (Kt) and 16.6+/-1.8 nmol/2 min per mg of protein (Vmax) at an outside pH of 7.5. Many drugs such as clonidine, guanabenz, methamphetamine, imipramine, clomipramine, nortriptyline, quinine, xylazine, ephedrine, and diphenhydramine strongly inhibited the [3H]clonidine uptake with Ki values between 0.15 and 1 mM. CONCLUSIONS: Clonidine is transported by a carrier-mediated process. Substrate specificity and mechanism are very similar to the transport described in blood-brain barrier endothelial cells. The transport characteristics do not correspond to carriers for organic cations of the SLC22 family or the choline transporters CHT1 and CLT1. The system might be identical to the H+/tertiary amine antiporter. It interacts with a large number of both hydrophilic and lipophilic cationic drugs, and also, interestingly, with opiates.

Adrenergic alpha-Agonists↗