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PubMed1980

The effect of dibenzazepines (tricyclic antidepressants) on cerebral capillary permeability in the rat in vivo.

The degree of equilibration of [3H]water across the cerebral capillary was evaluated by measuring its cerebral extraction fraction (Ew) by using a dual label radioactive tracer technique. All tricyclic antidepressants (125 mumol/kg i.p. at 5 min) increased Ew as compared to base line. The rank order of the drugs in producing this response was doxepin greater than amitriptyline greater than imipramine greater than nortriptyline greater than desmethylimipramine greater than protriptyline. The effect of amitriptyline, the prototype tricyclic for this study, was rapid in onset (maximal effect within 5 min), reversible (duration 15 min), dose-dependent and generalized throughout the brain. Amitriptyline also induced a marked increase in the cerebral extraction fraction of [3H]ethanol. A difference in the time course of the drug effect on these two tracers indicated that the elevation in E was due to the increase in cerebral capillary permeability to both polar and lipid soluble substances. This work demonstrates that tricyclic antidepressants have important central effects on non-neuronal tissue.

Amitriptyline↗
PubMed1994

Automated HPLC assay of fluoxetine and norfluoxetine in serum.

This automated assay determines the concentration of the antidepressant fluoxetine (Prozac) and its active metabolite norfluoxetine in serum by reversed-phase HPLC with spectrophotometric detection. Extraction, injection, and quantification are performed by the Gilson Aspec automated sample handler. The patient's specimen, with added protriptyline as internal standard, is extracted with solid-phase and liquid-liquid methods. Separation is conducted isocratically on a 5-microns (particle size) Supelcosil LC-8-DB reversed-phase column with a triethylamine acetate:acetonitrile mobile phase. The detection limit is 10 micrograms/L and absorbance varies linearly with concentration between 20 and 1,000 micrograms/L for both compounds. Mean recovery was 62% for fluoxetine and 70% for norfluoxetine over linear limits. Within-run and day-to-day imprecision (CV), evaluated at three concentrations (50, 200, and 500 micrograms/L), ranged from 2% to 7%. An extensive interference study of 108 drugs was conducted. Results (n = 58) by the automated method (y) correlated well with those by a manual HPLC method (x): y = 0.96x + 10.20 (r = 0.951, Sylx = 42.9) for fluoxetine, and y = 0.95x - 1.37 (r = 0.917, Sylx = 47.2) for norfluoxetine.

Autoanalysis↗
PubMed1977

Simultaneous measurement of secondary and tertiary tricyclic antidepressants by GC/MS chemical ionization mass fragmentography.

We present a method for measuring seven commonly used tricyclic antidepressants in plasma. This method is suitable for monitoring therapeutic concentrations and for screening drug overdoses in cases where the identity of the abused tricyclic antidepressant may not be known. Drugs from alkalinized plasma are extracted into hexane in one step; two injections into the gas chromatograph/mass spectrometer follow. The tertiary amines (amitriptyline, doxepin, and imipramine) are analyzed by direct injection; the secondary amines (nortriptyline, desmethyldoxepin, desipramine, and protriptyline) are analyzed after derivitization with trifluoroacetic anhydride. Clomipramine and desmethyltrimipramine are suitable internal standards. Chemical ionization mass fragmentography, with methane as the reactant gas, is used. While maintaining specificity for these drugs, concentrations in human plasma ranging from 5 to 500 microng/liter can be measured. The coefficients of variation are about 4 to 11%.

Antidepressive Agents, Tricyclic↗
PubMed1995

[Treatment of obstructive sleep apnea syndrome with a mandibular positioning device and other nonsurgical modalities].

The therapeutic approach to a patient with obstructive sleep apnea syndrome (OSAS) must be individualized because of the heterogeneity in the pathogenesis of the disorder. Although nasal continuous positive airway pressure (CPAP) is effective no matter what the pathogenesis, risk factors for this disorder should be identified in each patient. Nasal CPAP will be discussed by others. Weight loss is one of the best nonsurgical treatments of OSAS and it should be strongly recommended to obese patients with the disorder, even though only a few achieve satisfactory weight reduction. Sleeping in the lateral position or upright may be effective in some patients with OSAS. Acetazolamide, medroxyprogesterone, or protriptyline may also have a role in some patients, although the efficacy must be weighed against the considerable side effects. The cross-sectional area of the oropharynx measured by computed tomography in patients with OSAS was significantly lower than that in control subjects. Lateral cephalograms revealed a retarded mandible in many patients. A dental device designed to advance the mandible 2 to 7 mm and to eliminate the airway obstruction at the base of tongue was used in 20 consecutive patients (17 men and 3 women, average age 53.8 years) to treat the obstructive sleep apnea. The body mass index of the patients was 27.6 +/- 4.2 kg/m2 (mean +/- SD). The device moved the mandible forward (p = 0.038) and increased the airway space in the lower part of the oropharynx (p = 0.031) as assessed with lateral cephalograms. After nightly use of the device for 24 to 211 days, overnight polysomnography was performed for two nights: without the device for the first night and with it for the second night. The apnea index was reduced from an average of 30.7 to 18.5 events/hour (60.4% of the pretreatment value, p = 0.004). The number of desaturations (more than 5% decrease from the base line SaO2) decreased and the lowest level of SaO2 increased: from 26.5 to 14.4 events/hour (p = 0.009) and from 63.6 to 70.1% (p = 0.005), respectively. Not every patient improved sufficiently. Eleven of 20 patients were classified as good responders, because of a reduction in apnea index of at least 50% of the pretreatment value, and the remaining nine patients were classified as poor responders. Use of the device reduced the severity ratings of snoring and excessive daytime sleepiness not only in the good responders but also in the poor responders. No serious complications were observed. The mandibular positioning device is an effective treatment for some patients with OSAS. The effectiveness of the device should be predicted from polysomnographic and cephalometric data, and from CT measurements of the upper airway and other characteristics of the patients.

Adult↗
PubMed1997

Medroxyprogesterone acetate in the treatment of obstructive sleep apnea.

The use of MPA in patients with OSA is limited. Instead, patients with OSA should be encouraged to abstain from alcohol and respiratory depressive agents, and avoid sleeping in the supine position. In general, patients with OSA are most effectively treated with CPAP and/or surgery. Patients need to be encouraged to maintain ideal body weight, since this has been associated with a marked reduction in symptoms. For patients who are not surgical candidates or refuse to use CPAP, drug therapy may be beneficial. Fluoxetine has been shown to be as effective as protriptyline, and is better tolerated. However, further study is needed to determine whether selective serotonin-reuptake inhibitors are beneficial in treating OSA. Therefore, MPA therapy should be reserved for hypercapnic patients who refuse other modalities of treatment. The potential long-term adverse effects of MPA must be addressed before initiating therapy in men with OSA.

Humans↗
PubMed1997

Haloperidol-induced catalepsy: a model for screening antidepressants effective in treatment of depression with Parkinson's disease.

Incidence of severe depression is very common in Parkinson's disease (PD). Use of antidepressants in such cases is known to improve or worsen the existing PD. However, prediction of the effect of antidepressant on symptoms of PD is limited due to lack of suitable animal model. The present study examines the possibility of using haloperidol-induced catalepsy model in rats for this purpose. Antidepressants showed distinct effect on haloperidol-induced catalepsy, although most of them reduced forced-swimming induced immobility. In general, antidepressants with greater noradrenergic reuptake inhibition (desipramine, imipramine, amitriptyline, nortriptyline, protriptyline and maprotiline) reduced, whereas those with serotonergic reuptake inhibition (fluoxetine and clomipramine) increased haloperidol-induced catalepsy. Mianserin, an atypical antidepressant, and alprazolam, a benzodiazepine receptor analogue had no effect on haloperidol-induced catalepsy. The results suggest that haloperidol-induced catalepsy model in rats needs to be incorporated in the screening procedure when evaluating the utility of antidepressant drugs for the treatment of depression associated with PD.

Animals↗
PubMed1998

In vivo chronoamperometric measures of extracellular serotonin clearance in rat dorsal hippocampus: contribution of serotonin and norepinephrine transporters.

The effects of blockade of serotonin (5-HT) and norepinephrine (NE) transporters (SERT and NET, respectively) on the removal of locally applied 5-HT from extracellular fluid (ECF) were examined using in vivo chronoamperometry. Male Sprague-Dawley rats were anesthetized with chloralose/urethane, and a Nafion-coated, carbon fiber electrode attached to a multibarrel micropipette was positioned into either the dentate gyrus or CA3 region of the dorsal hippocampus. Pressure ejection of 5-HT elicited reproducible electrochemical signals of similar peak amplitude and time course in both structures. Local application of the selective serotonin reuptake inhibitors (SSRI) fluvoxamine and citalopram prolonged the clearance of 5-HT in both brain regions and also increased signal amplitude in the CA3 region. These effects were abolished in rats pretreated with 5, 7-dihydroxytryptamine (5,7-DHT), a selective 5-HT neurotoxin. The NE uptake inhibitors desipramine (DMI) and protriptyline did not alter the 5-HT signal in the CA3 region but prolonged the clearance of 5-HT in the dentate gyrus; this effect was absent in rats pretreated with 6-hydroxydopamine (6-OHDA), a selective catecholamine neurotoxin. The prolongation of the removal of 5-HT from the ECF in the dentate gyrus caused by fluvoxamine or desipramine was of comparable magnitude and was dose dependent. Furthermore, per picomole of 5-HT applied, the signal amplitude and clearance time were significantly increased in the dentate gyrus of rats lesioned with either 5,7-DHT or 6-OHDA. Only 5,7-DHT treatment caused this effect in the CA3 region. From these data, it is inferred that in certain regions of brain (dentate gyrus), both the SERT and NET contribute to the active clearance of exogenously applied 5-HT.

5,7-Dihydroxytryptamine↗
PubMed1985

Diagnosis and management of obstructive sleep apnea. Part II.

Snoring has been shown to be the primary sign of a potentially serious medical condition, ie, obstructive sleep apnea. Traditionally, the otolaryngologist has been the primary resource for patients with snoring problems although, until recently, little was known about the now-acknowledged serious complications of this phenomenon. Among the primary treatments for this condition, the most commonly used to-date involve surgical procedures routinely performed by the otolaryngologist, ie, tracheostomy and uvulopalatopharyngoplasty. Thus, the practicing otolaryngologist has been thrust into the forefront of diagnosis and management of obstructive sleep apnea, and it behooves the modern practitioner to be cognizant of the multidisciplinary approach to the diagnosis and management of this problem. The utilization of information obtained during the sleep study determines the management of the sleep apneic patient.

Adult↗
PubMed1977

Metabolism of 5-hydroxytryptamine and levels of tricyclic antidepressant drugs in rat brain after acute and chronic treatment.

Because tricyclic antidepressants (TAD) are usually given chronically to patients, both their acute and their chronic effects on 5-hydroxytryptamine (5-HT) metabolism were studied. The probenecid method was used and, in addition to 5-hydroxy-indoleacetic acid (5-HIAA), some other indole compounds in brain were measured. Simultaneously, TAD levels in brain and plasma were determined. Dimethylated as well as monomethylated TADs were administered, both at 10 and 25 mg/kg i.p. Treatment with either 10 mg/kg during 14 days or 25 mg/kg given acutely resulted in a similar brain level of TAD, so any differences found could be attributed to differences in administration schedule. Drug levels in brain and plasma differed considerably after chronic and acute treatments but no major differences in the effect on 5-HIAA level in the brain were found, although accumulation of 5-HIAA following probenecid treatment was mostly lowered after treatment with dimethylated TAD. The TAD level in rat brain was not decisive for the effect on central 5-HT turnover. The monomethylated TAD affected the 5-HT turnover very little, not only acutely but also chronically.

Animals↗
PubMed1989

Differential effects of chronic treatment with mianserin and protryptiline on rat brain cortical alpha 1-adrenoceptors.

Chronic administration of mianserin induced an increase in the density of [3H] prazosin binding sites (23%) in membranes and in the maximal noradrenaline stimulation of phosphoinositide breakdown (81%) in slices from rat brain cortex. In contrast, a similar treatment with protryptiline did not induce any significant changes. These findings suggest that the effects of antidepressant drugs on rat brain cortical alpha 1-adrenoceptors may depend on the characteristics of the drug used.

Animals↗