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At least 235 records · Page 13Linked to original sources
PubMed2001

High-performance liquid chromatographic analysis for a non-chromophore-containing phosphatidyl inositol analog, 1-((1-O-octadecyl-2-O-methyl-sn-glycero)phospho)-1D-3-deoxy-myo-inositol, using indirect UV detection.

Phosphatidylinositide-3-kinase (PI3 kinase) is an important constituent of growth factor regulation. It is also involved in oncogene signaling pathways. An ether-containing phosphatidyl inositol(PI) analog, OMDPI, 1-[(1-O-octadecyl-2-O-methyl-sn-glycero)-phospho]-1D-3-deoxy-myo-inositol, is a potent inhibitor of this pathway and may be clinically useful in the treatment of a variety of neoplasms. OMDPI is currently being investigated as an anti-tumor agent by the National Cancer Institute, NIH. OMDPI, a non-chromophore-containing PI analog, is not directly adaptable to the commonly used UV detection of HPLC. This paper reports the development and validation of an HPLC assay for OMDPI based on indirect UV detection, in which a UV-absorbing ion-pair reagent (the probe), protriptyline, is added to the mobile phase to induce a signal for the compound. The method is sensitive (limit of detection <5 microl of 1 microg/ml or 5 ng), precise (R.S.D.<2.5%), linear (r2=0.9995) and accurate (error<0.7%). It is superior to refractive index detection and evaporative light scattering detection in either sensitivity or linearity and does not require special equipment.

Chromatography, High Pressure Liquid↗
PubMed1999

Effects of antidepressants in rats trained to discriminate the beta-2 adrenergic agonist clenbuterol.

The ability of indirectly acting agonists such as norepinephrine uptake inhibitors, serotonin reuptake inhibitors, and atypical antidepressants to substitute for clenbuterol, a beta-2 adrenergic agonist, was examined in rats trained to discriminate 0.03 mg/kg clenbuterol and saline using a fixed-ratio 10 (FR 10) schedule with water reinforcement. The beta-2 selective adrenergic agonist clenbuterol produced an orderly dose-response relationship, and its discriminative stimulus effects were antagonized by the beta-adrenergic antagonist propranolol. It was found that the effects of tricyclic antidepressants and selective norepinephrine uptake inhibitors did not generalize to the discriminative stimulus effects of clenbuterol, with the exception of high doses of protriptyline. Moreover, compounds from other drug classes, including fluoxetine and phenelzine, did not substitute for clenbuterol. Atypical antidepressants, such as trazodone, rolipram, and bupropion also did not engender drug-appropriate responding. Prenalterol and dobutamine, both purported to be beta-1 adrenergic receptor agonists, partially substituted for clenbuterol, but at relatively high doses. The present results show that the antidepressants tested do not share discriminative stimulus effects with clenbuterol, a beta-2 adrenergic agonist.

Adrenergic beta-Agonists↗
PubMed2003

Behavioral and pharmacologic therapy of obstructive sleep apnea.

Previous attempts at using pharmacologic agents in the treatment of OSA have been disappointing. Medroxyprogesterone has not been found to be useful in the treatment of OSA. Use of protriptyline is limited by frequent side effects, but its role in mild and REM-related OSA must be clarified. SSRIs seem to be ineffective in treatment of severe OSA. Further studies are needed to determine their effect in persons with mild disease. This is important because patients with mild OSA (AHI < 15 hours) are most likely to be noncompliant with CPAP therapy [91]. A recent systematic review of drug treatments for OSA concluded that the current data do not support the use of any drug as an alternative to CPAP [92]. Of 56 studies identified, only 9 studies met methodologic criteria. Clearly, basic research and adequately powered clinical trials are needed to identify an effective medication for OSA.

Behavior Control↗
PubMed1997

Use of identical assay conditions for cocaine analog binding and dopamine uptake to identify potential cocaine antagonists.

The addictive and euphorogenic properties of cocaine are thought to result from inhibition of the dopamine transporter (DAT). Recent evidence suggests that dopamine and cocaine bind to distinct sites on the transporter protein. Therefore it should be possible to design drugs which specifically inhibit cocaine recognition by the DAT while permitting the transporter to maintain its function of accumulating dopamine. One way to monitor such activity is to compare the inhibition constants of test agents for inhibition of radiolabelled dopamine uptake (Kiuptake) and inhibition of the binding of a cocaine ligand such as [3H]2 beta-carbomethoxy-3 beta-3 beta-(fluorophenyl)tropane (CFT; Kibind) and select for compounds with Kiuptake/Kibind ratios greater than unity. Because others have shown that compounds can exhibit Kiuptake/Kibind ratios greater than unity when the assays are performed under non-identical conditions, we have established these assays under identical conditions of time, temperature and buffer using a Chinese hamster ovary (CHO) cell line which stably expresses the human DAT. Kinetic and saturation analyses were performed on both assay and over 200 structurally diverse compounds were screened. Using identical assay parameters, several series of compounds having Kiuptake/Kibind ratios significantly greater than unity were identified. Such compounds include local anesthetics (procaine, dibucaine, tolperisone, dyclonine, diperodone), antipsychotic agents (10-(diethylaminopropionyl)phenothiazine), antidepressants (desipramine, imipramine, protriptyline), a diuretic (5-N-methyl-N-isobutyl-amilioride), an anticholinergic agent (prindinol), a PKC inhibitor (H-8), a calcium channel antagonist (loperamide) and an antimalarial compound (chloroquine). To our knowledge, even though these compounds exhibit low binding affinities (3-24 microM), they represent some of the most cocaine site-selective compounds identified to date using identical assay parameters.

Animals↗
PubMed1977

Quantitative analysis of tricyclic antidepressants in serum from psychiatric patients.

A method for the quantitative analysis of tricyclic antidepressants in the serum of psychiatric patients is described. The method can be used for determining amitriptyline, nortriptyline, imipramine, demethyllimipramine, clomipramine, demethylclomipramine, trimipramine and protriptyline. The method consists in a series of extraction steps followed by gas chromatography with flame-ionization detector. The drugs are determined in their native state. The internal standard method is used for the quantitation.

Antidepressive Agents, Tricyclic↗
PubMed1997

Determination of a new non-narcotic analgesic, DA-5018, in plasma, urine and bile by high-performance liquid chromatography.

A high-performance liquid chromatographic method was developed for the determination of a new non-narcotic analgesic, DA-5018 (I), in rat plasma, urine and bile samples, using propranolol for plasma samples and protriptyline for urine and bile samples as internal standards. The method involved extraction followed by injection of 100 microliters of the aqueous layer onto a C18 reversed-phase column. The mobile phases were 5 mM methanesulfonic acid with 10 mM NaH2PO4 (pH 2.5)-acetonitrile, 70:30 (v/v) for plasma samples and 75:25 (v/v) for urine and bile samples. The flow-rates were 1.0 ml/min for plasma samples and 1.2 ml/min for urine and bile samples. The column effluent was monitored by a fluorescence detector with an excitation wavelength of 270 nm and an emission wavelength of 330 nm. The retention time for I was 4.8 min in plasma samples and 10.0 min in urine and bile samples. The detection limits for I in rat plasma, urine and bile were 20, 100 and 100 ng/ml, respectively. There was no interference from endogenous substances.

Analgesics, Non-Narcotic↗
PubMed1999

Simultaneous determination of citalopram, fluoxetine, paroxetine and their metabolites in plasma and whole blood by high-performance liquid chromatography with ultraviolet and fluorescence detection.

A method for the simultaneous determination of the three selective serotonin reuptake inhibitors (SSRIs) citalopram, fluoxetine, paroxetine and their metabolites in whole blood and plasma was developed. Sample clean-up and separation were achieved using a solid-phase extraction method with C8 non-endcapped columns followed by reversed-phase high-performance liquid chromatography with fluorescence and ultraviolet detection. The robustness of the solid-phase extraction method was tested for citalopram, fluoxetine, paroxetine, Cl-citalopram and the internal standard, protriptyline, using a fractional factorial design with nine factors at two levels. The fractional factorial design showed two significant effects for paroxetine in whole blood. The robustness testing for citalopram, fluoxetine, Cl-citalopram and the internal standard revealed no significant main effects in whole blood and plasma. The optimization and the robustness of the high-performance liquid chromatographic separation were investigated with regard to pH and relative amount of acetonitrile in the mobile phase by a central composite design circumscribed. No alteration in the elution order and no significant change in resolution for a deviation of +/-1% acetonitrile and +/-0.3 pH units from the specified conditions were observed. The method was validated for the concentration range 0.050-5.0 micromol/l with fluorescence detection and 0.12-5.0 micromol/l with ultraviolet detection. The limits of quantitation were 0.025 micromol/l for citalopram and paroxetine, 0.050 micromol/l for desmethyl citalopram, di-desmethyl citalopram and citalopram-N-oxide, 0.12 micromol/l for the paroxetine metabolites by fluorescence detection, and 0.10 micromol/l for fluoxetine and norfluoxetine by ultraviolet detection. Relative standard deviations for the within-day and between-day precision were in the ranges 1.4-10.6% and 3.1-20.3%, respectively. Recoveries were in the 63-114% range for citalopram, fluoxetine and paroxetine, and in the 38-95% range for the metabolites. The method has been used for the analysis of whole blood and plasma samples from SSRI-exposed patients and forensic cases.

Acetonitriles↗
PubMed2000

The high performance liquid chromatography electrospray ionization mass spectrometry analysis of diverse basic pharmaceuticals on cyanopropyl and pentafluorophenylpropyl stationary phases.

Cyanopropyl (CN) and pentafluorophenylpropyl (PFPP) modified silica columns give good retention and good peak shape for the high performance liquid chromatography/electrospray ionization/mass spectrometry (HPLC/ESI/MS) analysis of several classes of basic drugs. These phases enhance the ESI-MS signal by providing good retention of basic drugs with a mobile phase containing 90% acetonitrile. With C18 columns, in order to achieve good retention of basic drugs, only a mobile phase containing less than 40% acetonitrile can be used. Higher concentrations of acetonitrile produce a larger MS signal in the ESI process; the MS signal was a factor of 9 and 12 times greater on the CN and PFPP phases when compared with the C18 phase for the analysis of codeine. The C18 phase required only 4.0-6.0% acetonitrile to obtain the same retention time for codeine. The CN and PFPP stationary phases can be used for the analysis of a range of basic drugs, including many compounds which are poorly retained on the popular C18 and C8 stationary phases. Applications of CN and PFPP columns in the HPLC/ESI/MS of basic drugs include the analysis of antimalarials, such as quinine, bronchodilators, such as salbutamol and tulobuterol, cardioactive drugs, such as procainamide and beta-blockers, tricyclic antidepressants (TCAs), such as protriptyline and trimipramine and alkaloids, such as morphine and codeine. The CN and PFPP phases are also useful for the analysis of bufuralol and its metabolite, hydroxy-bufuralol. All the above analyses were performed using the same mobile phase, 90% acetonitrile; thus the HPLC method development process was expedited. The CN and PFPP phases also gave reproducible retention times and peak shape after more than 8 h of analyses.

Chromatography, High Pressure Liquid↗
PubMed2002

Painful ejaculation and urinary hesitancy in association with antidepressant therapy: relief with tamsulosin.

Painful ejaculation has been reported in association with a variety of antidepressants such as the tricyclic antidepressants (TCAs, e.g. clomipramine, imipramine, desipramine, protriptyline, amoxapine), the selective serotonin reuptake inhibitors (SSRIs, e.g. fluoxetine), venlafaxine and the MAOIs. Apart from lowering the dose and changing the antidepressant, no strategies are available to treat this side effect. In this paper, painful ejaculation following the administration of reboxetine is described in two patients. Both patients were treated concomitantly with the selective alpha(1A)-adrenoceptor antagonist, tamsulosin. A re-challenge was performed in one patient. The Hamilton Depression Rating Scale (HAM-D), the American Urological Association symptom index, a (dis)satisfaction item score and the Udvalg for Kliniske Undersoegelser (UKU-side effect rating scale) were used to assess the treatment. Tamsulosin rapidly and completely resolved the painful ejaculation and urinary hesitancy in both patients. A re-challenge in one patient resulted in a prompt reappearance of both side effects. Tamsulosin resolved the problem of painful ejaculation in these patients; however, larger studies are needed to confirm these results.

Adrenergic alpha-Antagonists↗
PubMed2002

The role of noradrenaline and selective noradrenaline reuptake inhibition in depression.

Depression is a common disorder that impacts on all aspects of a person's life. For the past 10 years, clinicians have focused on serotonin in their treatment of depression. This is largely due to the growing acceptance of the efficacy and safety of the selective serotonin reuptake inhibitors (SSRIs) in comparison with older tricyclic antidepressants (TCAs). However, evidence for a role of noradrenaline in depression has been accumulating for some time, beginning with the discovery that drugs which either caused or alleviated depression acted to alter noradrenaline metabolism. Until recently, the role of noradrenaline in depression was predicted from clinical experience with noradrenergic TCAs (desipramine, nortriptyline and protriptyline) and selective serotonin and noradrenaline reuptake inhibitors (venlafaxine, milnacipran). The licensing of reboxetine, a selective noradrenaline reuptake inhibitor now allows the role of noradrenaline in depression to be investigated directly. This review presents key data from the literature that support a role for noradrenaline in depression taking into account neurophysiology, psychopharmacology and clinical trial data.

Adrenergic Uptake Inhibitors↗
PubMed1999

Metabolism of tricyclic antidepressants.

1. Despite the considerable advances in the treatments available for mood disorders over the past generation, tricyclic antidepressants (TCAs) remain an important option for the pharmacotherapy of depression. 2. The pharmacokinetics of TCAs are characterized by substantial presystemic first-pass metabolism, a large volume of distribution, extensive protein binding, and an elimination half-life averaging about 1 day (up to 3 days for protriptyline). 3. Clearance of tricyclics is dependent primarily on hepatic cytochrome P450 (CYP) oxidative enzymes. Although the activities of some P450 isoenzymes are largely under genetic control, they may be influenced by external factors, such as the concomitant use of other medications or substances. Patient variables, such as ethnicity and age, also affect TCA metabolism. The impact of gender and related reproductive issues is coming under increased scrutiny. 4. Metabolism of TCAs, especially their hydroxylation, results in the formation of active metabolites, which contribute to both the therapeutic and the adverse effects of these compounds. 5. Renal clearance of the polar metabolites of TCAs is reduced by normal aging, accounting for much of the increased risk of toxicity in older patients. 6. Knowledge of factors affecting the metabolism of TCAs can further the development and understanding of newer antidepressant medications.

Antidepressive Agents, Tricyclic↗
PubMed1992

Complexation studies of cyclodextrins with tricyclic antidepressants using ion-selective electrodes.

The complexation of six tricyclic antidepressant drugs [amitriptylin (AMN), nortriptylin (NRN), imipramin (IMN), doxepin (DXN), protriptylin (PTN), and maprotilin (MPN)] with alpha- and beta-cyclodextrins (CDs) using ion-selective electrodes (ISEs) as drug ion sensors is described. Binding parameters were calculated by nonlinear fitting of the model described by the Scatchard equation, to the experimental data of a titration of a CD solution with the ion of interest. One binding site (the CD cavity) was found in all cases with both CDs. The calculated association constants at 25 degrees C using CD concentrations in the range of 0.0100-0.0010 M, varied from 4.81 x 10(3) M-1 (MPN) to 23.9 x 10(3) M-1 (AMN) in the case of beta-CD and from 50 M-1 (DXN) to 123 M-1 (MPN) in the case of alpha-CD. The precision for the estimation of the binding parameters was 0.1-5.0% (within-run RSD%) and 8-10% (between-run RSD%; n = 3). The complexation of the drugs with beta-CD was also examined as a function of temperature in the range of 5-37 degrees C; it was found to decrease by increasing temperature. Van't Hoff analysis gave good correlations (r greater than or equal to 0.989) for all drug ions studied. The estimates of the thermodynamic parameters indicate that the formation of inclusion complexes is enthalpy driven. A compensation plot based on the thermodynamic parameters delta H and delta S resulted in a linear relationship, which is indicative of a common type of force involved in the complexation of drugs to beta-CD.

Antidepressive Agents, Tricyclic↗
PubMed1987

Clinical neuropharmacology of sleep disorders.

Within the context of the comprehensive treatment of sleep disorders, which includes medical, neurologic, psychiatric, and social interventions, use of medication is often indicated. Among the three benzodiazepine hypnotics that are available in the United States for the treatment of insomnia, flurazepam is effective for both sleep induction and maintenance, and it retains most of its efficacy over a 4-week period of nightly administration; temazepam is effective only for sleep maintenance, and triazolam improves both sleep induction and maintenance with initial but not with continued administration. Rebound phenomena are more frequent and intense with the more rapidly eliminated drug, triazolam, and to a lesser degree with temazepam. Also, with triazolam, certain behavioral side effects, such as amnesia and psychotic-like symptoms, have been reported. With flurazepam, which is a slowly eliminated benzodiazepine, daytime sedation is more frequent than with the other two drugs. When insomnia is secondary to major depression, antidepressant medication should be administered. Methylphenidate, amphetamines, or other stimulant medications are used for the symptomatic treatment of the sleepiness and sleep attacks of narcolepsy and hypersomnia. For cataplexy and the other two auxiliary symptoms of narcolepsy, imipramine or other tricyclics are the drugs of choice. Protriptyline and medroxyprogesterone have been used in treating mild cases of obstructive sleep apnea, but their efficacy is limited. Similarly, for the treatment of central sleep apnea, medroxyprogesterone and acetazolamide have shown only limited effects. Medication for patients with sleepwalking, night terrors, or nightmares should be prescribed judiciously, and primarily when treatment of an underlying psychiatric condition is desired. The neuropharmacology of sleep should also consider drugs that may cause sleep disorders. Medications with sleep disturbing effects include various antihypertensives, bronchodilators, and the energizing antidepressants. Withdrawal of REM-suppressant drugs, such as the barbiturates, may cause nightmares in association with a REM rebound. Occasionally, a drug or a combination of drugs may produce somnambulistic-like activity in some patients.

Antidepressive Agents↗
PubMed1969

Brain norepinephrine: evidence that neuronal release is essential for sham rage behavior following brainstem transection in cat.

There is a direct relationship between the magnitude of sham rage produced by brainstem transection in cat and the decrease of brainstem norepinephrine. The attacks of rage are augmented by protriptyline and inhibited by haloperidol, drugs respectively facilitating or depressing the action of norepinephrine centrally. Release of norepinephrine by brainstem neurons appears essential for appearance of this behavior.

Animals↗
PubMed1992

Prominent eye movements during NREM sleep and REM sleep behavior disorder associated with fluoxetine treatment of depression and obsessive-compulsive disorder.

The clinical polysomnographic (PSG) reports of 2,650 consecutive adults studied during 41 months were reviewed retrospectively to identify all patients treated with fluoxetine or tricyclic antidepressants. The PSG reports of four other adult groups were also reviewed: periodic limb movement (PLM) disorder (n = 28); sleep terror/sleepwalking (ST/SW) (n = 54); rapid eye movement (REM) sleep behavior disorder (RBD) (n = 70); patients with clinically unremarkable sleep during two consecutive PSG studies (n = 30). Standard PSG recording and scoring methods were employed. A total of 1.5% (n = 41) and 2.0% (n = 52) of patients were receiving fluoxetine or tricyclics (amitriptyline or nortriptyline, n = 31; imipramine or desipramine, n = 16; protriptyline or trimipramine, n = 5). A selective association between fluoxetine and extensive, prominent eye movements in nonrapid eye movement (NREM) sleep was detected, utilizing Fisher's exact one-tailed statistic (p less than 0.00001 for each comparison). The detection rates were fluoxetine, 48.8% (20/41); tricyclics, 5.8% (3/52); RBD, 4.3% (3/70); objectively normal sleepers, 3.3% (1/30); PLM, ST/SW, 0% (0/82). These groups had similar mean ages (31.5-45.4 years) and gender distributions (50.0-60.7% male), apart from RBD. The effect of fluoxetine, a potent and specific serotonin reuptake inhibitor, on NREM eye movements is postulated to derive from potentiation of serotonergic neurons that inhibit brainstem "omnipause neurons", which, in turn, inhibit saccadic eye movements, thus resulting in disinhibited release of saccades. In addition, a 31-year-old man with obsessive-compulsive disorder developed RBD soon after starting fluoxetine therapy, which persisted at PSG study 19 months after fluoxetine discontinuation.

Adult↗
PubMedDate not supplied

Clinical pharmacokinetics of intravenous and oral bretylium tosylate in survivors of ventricular tachycardia or fibrillation: clinical application of a new assay for bretylium.

We studied 12 patients receiving either chronic oral (p.o.) maintenance bretylium and/or acute intravenous (i.v.) bretylium to evaluate drug efficacy and pharmacokinetics. All patients were survivors of ventricular tachycardia or fibrillation. A new assay for bretylium was applied, and it proved sensitive and reliable. After single intravenous dosing, bretylium was eliminated from serum with a mean rate constant of lambda iv1 = 0.0515 hr-1 and a corresponding elimination half-life of tiv1/2 = 13.5 hr (7 studies), similar to previous results in normals. Total body clearance averaged 428 ml/min, of which virtually all was accounted for by renal clearance. Seven patients responding to intravenous bretylium were transferred to oral drug. During chronic therapy (mean dose, 41 mg/kg/day bretylium tosylate), mean minimum steady-state concentration of bretylium was 186 ng/ml (range, 72-461) and was accurately predicted, within experimental error, by using the elimination rate constant determined for oral, but not intravenous, drug in normal subjects (lambda po1 = 0.115 hr-1). Determination of average steady-state concentration (Css) yielded similar conclusions. Mean 24 hr urinary excretion of bretylium during oral therapy was 18.3% (range, 9-13%). These results lend validity to earlier observations in normals and suggest route and concentration dependence of disposition. Transfer to oral bretylium allowed continued control of sustained ventricular tachycardia in all 7 patients and of unsustained ventricular tachycardia in 5. Orthostatic hypotension in 4 responded to protriptyline. Six were discharged on bretylium, with a mean follow-up of 12.2 months (range, 1-25.5). Four maintained a favorable response, and 2 died suddenly at 1 and 3 months. We conclude that further evaluation or oral bretylium is justified; attempts should be made to increase steady-state concentrations during oral therapy.

Administration, Oral↗
PubMed1979

An improved gas-liquid chromatographic procedure for the determination of amitriptyline and nortriptyline levels in plasma using nitrogen-sensitive detectors.

An improved gas-liquid chromatographic procedure for the plasma level determination of amitriptyline and nortriptyline using nitrogen-sensitive detectors is described. Derivatization of the secondary amines using trifluoroacetic anhydride greatly improves the response and reproducibility of the assay. Plasma samples containing as little as 5 ng/ml of amitriptyline and nortriptyline can be assayed precisely and reproducibly, using protriptyline as internal reference standard.

Amitriptyline↗
PubMed1985

Sensitive high performance liquid chromatographic analysis of ethmozin in plasma.

A sensitive high performance liquid chromatographic procedure for the quantitative determination of ethmozin is described. Following a one-step extraction of the drug and the internal standard, protriptyline, by diethylether at pH 9.0, the organic solvent is evaporated and the residue is reconstituted in the mobile phase and injected into the chromatograph. The separation is obtained using a CN-bonded column with a methanol-propanol-2-perchloric acid 1.16 M mobile phase. Ethmozin is detected at 268 nm. Under these conditions, the lower limit of detection is 11 nM, and the lower limit of quantification is 22 nM (10 ng/ml) for ethmozin. The procedure is linear between 0 and 8,620 nM.

Anti-Arrhythmia Agents↗