Repositioning FDA-Approved Drug Against Chagas Disease and Cutaneous Leishmaniosis by Structure-Based Virtual Screening.

BACKGROUND: Chagas disease and cutaneous leishmaniasis, two parasitic diseases caused by Trypanosoma cruzi (T. cruzi) and Leishmania mexicana (L. mexicana), respectively, have a major global impact. Current pharmacological treatments for these diseases are limited and can cause severe side effects; thus, there is a need for new antiprotozoal drugs. METHODS: Using molecular docking, this work describes a structure-based virtual screening of an FDA-approved drug library against Trypanosoma cruzi and Leishmania mexicana glycolytic enzyme triosephosphate isomerase (TIM), which is highly conserved in these parasites. The selected compounds with potential dual inhibitory activity were tested in vitro to confirm their biological activity. RESULTS: The study showed that five compounds: nilotinib, chlorhexidine, protriptyline, cyproheptadine, and montelukast, were more active against T. cruzi, than the reference drugs, nifurtimox and benznidazole while chlorhexidine and protriptyline were the most active against L. mexicana. CONCLUSIONS: The analysis of these compounds and their structural characteristics may provide the basis for the development of new antiprotozoal agents.

Protriptyline improves spatial memory and reduces oxidative damage by regulating NFκB-BDNF/CREB signaling axis in streptozotocin-induced rat model of Alzheimer's disease.

Antidepressants are well known to exert their role via upregulation of brain derived neurotrophic factor (BDNF). BDNF has been reported to exerts its neuroprotective effect in rodent and primate models as well as in patients of Alzheimer's disease (AD). The aim of our study was to evaluate the effect of protriptyline (PRT), a tricyclic antidepressant, in streptozotocin (STZ)- induced rat model of AD. Total 10 µl of STZ was injected into each ventricle (1 mg/kg). PRT (10 mg/kg, i.p.) treatment was started 3-day post STZ administration and continued till 21 days. We found that STZ treatment significantly increased pTau, Aß42 and BACE-1 expression, oxidative stress and neurodegeneration in hippocampus and cortex of adult rats. STZ induced impairment in spatial learning and retention memory was associated with increased NFκB and reduced CREB and BDNF expression in cortex and hippocampus. Interestingly, PRT treatment significantly reduced pTau, Aß42 and BACE-1 levels, neurodegeneration, oxidative stress and glial activation, contributing to the improved spatial learning and retention memory in STZ treated rats. Moreover, PRT treatment significantly improved p-ERK/ERK ratio and enhanced BDNF and CREB levels by reducing NFκB and GFAP expression in STZ treated rats. Our data suggest that impaired NFκB and CREB signaling potentially contribute in AD pathogenesis by elevating oxidative stress and neuroinflammation mediated neurodegeneration. Our study has established protriptyline as a multi target molecule in pre-clinical model of AD and further investigations on PRT like molecules could pave way for further development of effective new treatments in neurodegenerative disorders.

Protriptyline, a tricyclic antidepressant, inhibits voltage-dependent K+ channels in rabbit coronary arterial smooth muscle cells.

In this study, we explore the inhibitory effects of protriptyline, a tricyclic antidepressant drug, on voltage-dependent K+ (Kv) channels of rabbit coronary arterial smooth muscle cells using a whole-cell patch clamp technique. Protriptyline inhibited the vascular Kv current in a concentration-dependent manner, with an IC50 value of 5.05 ± 0.97 µM and a Hill coefficient of 0.73 ± 0.04. Protriptyline did not affect the steady-state activation kinetics. However, the drug shifted the steady-state inactivation curve to the left, suggesting that protriptyline inhibited the Kv channels by changing their voltage sensitivity. Application of 20 repetitive train pulses (1 or 2 Hz) progressively increased the protriptyline-induced inhibition of the Kv current, suggesting that protriptyline inhibited Kv channels in a use (state)-dependent manner. The extent of Kv current inhibition by protriptyline was similar during the first, second, and third step pulses. These results suggest that protriptyline-induced inhibition of the Kv current mainly occurs principally in the closed state. The increase in the inactivation recovery time constant in the presence of protriptyline also supported use (state)-dependent inhibition of Kv channels by the drug. In the presence of the Kv1.5 inhibitor, protriptyline did not induce further inhibition of the Kv channels. However, pretreatment with a Kv2.1 or Kv7 inhibitor induced further inhibition of Kv current to a similar extent to that observed with protriptyline alone. Thus, we conclude that protriptyline inhibits the vascular Kv channels in a concentration- and use-dependent manner by changing their gating properties. Furthermore, protriptyline-induced inhibition of Kv channels mainly involves the Kv1.5.

Ca2+ Signaling and Cell Death Induced by Protriptyline in HepG2 Human Hepatoma Cells.

The effect of protriptyline on Ca2+ physiology in human hepatoma is unclear. This study explored the effect of protriptyline on [Ca2+ ]i and cytotoxicity in HepG2 human hepatoma cells. Protriptyline (50-150 µM) evoked [Ca2+ ]i rises. The Ca2+ entry was inhibited by removal of Ca2+ . Protriptyline-induced Ca2+ entry was confirmed by Mn2+ -induced quench of fura-2 fluorescence. Except nifedipine, econazole, SKF96365, GF109203X, and phorbol 12-myristate 13 acetate did not inhibit Ca2+ entry. Treatment with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) inhibited 40% of protriptyline-induced response. Treatment with protriptyline abolished BHQ-induced response. Inhibition of phospholipase C (PLC) suppressed protriptyline-evoked response by 70%. At 20-40 µM, protriptyline killed cells which was not reversed by the Ca2+ chelator 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid-acetoxymethyl ester (BAPTA/AM). Together, in HepG2 cells, protriptyline induced [Ca2+ ]i rises that involved Ca2+ entry through nifedipine-sensitive Ca2+ channels and PLC-dependent Ca2+ release from endoplasmic reticulum. Protriptyline induced Ca2+ -independent cell death.

Molecular investigations of protriptyline as a multi-target directed ligand in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disorder involving multiple cellular and molecular processes. The discovery of drug molecules capable of targeting multiple factors involved in AD pathogenesis would greatly facilitate in improving therapeutic strategies. The repositioning of existing non-toxic drugs could dramatically reduce the time and costs involved in developmental and clinical trial stages. In this study, preliminary screening of 140 FDA approved nervous system drugs by docking suggested the viability of the tricyclic group of antidepressants against three major AD targets, viz. Acetylcholinesterase (AChE), ß-secretase (BACE-1), and amyloid ß (Aß) aggregation, with one member, protriptyline, showing highest inhibitory activity. Detailed biophysical assays, together with isothermal calorimetry, fluorescence quenching experiments, kinetic studies and atomic force microscopy established the strong inhibitory activity of protriptyline against all three major targets. The molecular basis of inhibition was supported with comprehensive molecular dynamics simulations. Further, the drug inhibited glycation induced amyloid aggregation, another important causal factor in AD progression. This study has led to the discovery of protriptyline as a potent multi target directed ligand and established its viability as a promising candidate for AD treatment.

Pharmacological approaches to the treatment of obstructive sleep apnoea.

BACKGROUND: Currently the treatment of choice for symptomatic obstructive sleep apnoea (OSA) is continuous positive airway pressure (CPAP). Some patients with OSA do not tolerate CPAP or have insufficiently severe symptoms to justify its use; for these patients, drug therapy would be a desirable potential therapeutic alternative. OBJECTIVE: To summarize the current evidence on the effectiveness of drug therapy in patients with OSA. METHODS: A systematic review of randomized controlled trials was performed to investigate the effects of drug therapy on OSA. RESULTS/CONCLUSIONS: Searches of bibliographical databases revealed 33 trials investigating the effects of 27 different drugs on OSA severity and/or symptoms. The mechanisms by which these drugs are supposed to improve OSA include, amongst others, an increase in tone of the upper airways, an increase in ventilatory drive, a reduction in airway resistance, and alterations in surface tension forces in the upper airway. In most of these studies there was no significant effect on OSA observed. However, there is evidence from a few small trials that some drugs, especially those thought to increase upper airway muscle tone, have the potential to reduce OSA severity; but further data from larger studies of adequate duration are needed.

Association of changes in norepinephrine and serotonin transporter expression with the long-term behavioral effects of antidepressant drugs.

Previous work has shown that repeated desipramine treatment causes downregulation of the norepinephrine transporter (NET) and persistent antidepressant-like effects on behavior, ie effects observed 2 days after discontinuation of drug treatment when acute effects are minimized. The present study examined whether this mechanism generalizes to other antidepressants and also is evident for the serotonin transporter (SERT). Treatment of rats for 14 days with 20 mg/kg per day protriptyline or 7.5 mg/kg per day sertraline reduced NET and SERT expression, respectively, in cerebral cortex and hippocampus; these treatments also induced a persistent antidepressant-like effect on forced-swim behavior. Increased serotonergic neurotransmission likely mediated the behavioral effect of sertraline, as it was blocked by inhibition of serotonin synthesis with p-chlorophenylalanine; a parallel effect was observed previously for desipramine and noradrenergic neurotransmission. Treatment with 20 mg/kg per day reboxetine for 42, but not 14, days reduced NET expression; antidepressant-like effects on behavior were observed for both treatment durations. Treatment for 14 days with 70 mg/kg per day venlafaxine, which inhibits both the NET and SERT, or 10 mg/kg per day phenelzine, a monoamine oxidase inhibitor, produced antidepressant-like effects on behavior without altering NET or SERT expression. For all drugs tested, reductions of NET and SERT protein were not accompanied by reduced NET or SERT mRNA in locus coeruleus or dorsal raphe nucleus, respectively. Overall, the present results suggest an important, though not universal, role for NET and SERT regulation in the long-term behavioral effects of antidepressants. Understanding the mechanisms underlying transporter regulation in vivo may suggest novel targets for the development of antidepressant drugs.

Protriptyline block of the human ether-à-go-go-related gene (HERG) K+ channel.

Protriptyline, a tricyclic antidepressant for psychiatric disorders, can induce prolonged QT, torsades de pointes, and sudden death. We studied the effects of protriptyline on human ether-à-go-go-related gene (HERG) channels expressed in Xenopus oocytes and HEK293 cells. Protriptyline induced a concentration-dependent decrease in current amplitudes at the end of the voltage steps and HERG tail currents. The IC(50) for protriptyline block of HERG current in Xenopus oocytes progressively decreased relative to the degree of depolarization, from 142.0 microM at -40 mV to 91.7 microM at 0 mV to 52.9 microM at +40 mV. The voltage dependence of the block could be fit with a monoexponential function, and the fractional electrical distance was estimated to be delta=0.93. The IC(50) for the protriptyline-induced blockade of HERG currents in HEK293 cells at 36 degrees C was 1.18 microM at +20 mV. Protriptyline affected channels in the activated and inactivated states, but not in the closed states. HERG blockade by protriptyline was use-dependent, exhibiting a more rapid onset and a greater steady-state block at higher frequencies of activation. Our findings suggest that inhibition of HERG currents may contribute to the arrhythmogenic side effects of protriptyline.

Activation and desensitization by cyclic antidepressant drugs of alpha2-autoreceptors, alpha2-heteroreceptors and 5-HT1A-autoreceptors regulating monamine synthesis in the rat brain in vivo.

The effects of antidepressant drugs on the synthesis of noradrenaline and serotonin (5-HT) were assessed using the accumulation of 3,4-dihydroxyphenylalanine (dopa) and 5-hydroxytryptophan (5-HTP) after decarboxylase inhibition as a measure of the rate of tyrosine and tryptophan hydroxylation in the rat brain in vivo. Three inhibitory synthesis-modulating receptors were investigated simultaneously: the alpha2C-autoreceptor modulating dopa/noradrenaline synthesis, and the alpha2A-heteroreceptor and 5-HT1A-autoreceptor modulating 5-HTP/5-HT synthesis. Acute treatment (2 h, i.p.) with desipramine (1-10 mg/kg), protriptyline (0.3-10 mg/kg) and nisoxetine (3-10 mg/kg), selective NA reuptake blockers, dose-dependently decreased dopa synthesis in cortex (15%-40%) and hippocampus (20%-53%). Fluoxetine (1-10 mg/kg) and zimelidine (1-10 mg/kg), selective 5-HT reuptake blockers, did not alter dopa synthesis. Fluoxetine and zimelidine dose-dependently decreased 5-HTP synthesis in cortex (14%-43%) and hippocampus (27%-54%). Desipramine and protryptyline did not alter 5-HTP synthesis in cortex but in hippocampus it was decreased (36%). Repeated desipramine (10 mg/kg for 1-21 days) or fluoxetine (3 mg/kg for 3-21 days) treatment resulted in a time-dependent loss in their ability to decrease dopa or 5-HTP synthesis. Desipramine (1-21 days) did not alter 5-HTP synthesis in cortex, but in hippocampus it was decreased (21%-37%, days 1-14) followed by recovery to control values (day 21). Fluoxetine (3-21 days) did not alter brain dopa synthesis. To further assess the desensitization of alpha2C-autoreceptors, alpha2A-heteroreceptors and 5-HT1A autoreceptors regulating the synthesis of dopa/NA or 5-HTP/5-HT after chronic desipramine and fluoxetine, the effects of clonidine (agonist at alpha2-auto/heteroreceptors) and 8-OH-DPAT (agonist at 5-HT1A-autoreceptors) were tested. In saline-treated rats, clonidine (1 mg/kg, 1 h) decreased dopa and 5-HTP synthesis in cortex (58% and 54%) and hippocampus (54% and 42%). In desipramine-treated rats (10 mg/kg, 21 days), but not in fluoxetine-treated ones (3 mg/kg, 14 days), the effect of clonidine was attenuated in cortex (12% and 18%) and only for dopa synthesis in hippocampus (31%). In saline-treated rats, 8-OH-DPAT (1 mg/kg, 1 h) decreased 5-HTP synthesis in cortex (63%) and hippocampus (75%). In fluoxetine-treated rats, but not in desipramine-treated ones, this inhibitory effect was markedly attenuated in cortex (26%) and hippocampus (9%). These findings indicate that acute treatment with cyclic antidepressant drugs results in activation of inhibitory alpha2C-autoreceptors, alpha2A-heteroreceptors and/or 5-HT1A-autoreceptors regulating the synthesis of dopa/NA and/or 5-HTP/5-HT in brain, whereas chronic treatment with these drugs is followed by desensitization of these presynaptic receptors.

Protriptyline, chronic tension-type headaches, and weight loss in women.

Twenty-five women with chronic tension-type headaches were treated with protriptyline for 3 months, with attention paid to days of monthly headaches before and while taking the medication, as well as change in weight and side effects. One patient stopped the medication because of side effects and 2 did not return for follow-up, yielding 22 patients. The typical dose of protriptyline was 20 mg every morning. Eighty-six percent of patients had fewer headaches each month, with the mean dropping from 28.2 to 11.7 days. Seventy-three percent had a 50% or greater reduction in the number of headaches per month. The average weight change was a loss of slightly over 3 pounds during the study period. The advantages and disadvantages of protriptyline in the treatment of chronic tension-type headaches are discussed, as are mechanisms of action.

Inhibitory effect of noradrenaline uptake inhibitors on contractions of rat aortic smooth muscle.

1 The effects of noradrenaline (NA) uptake inhibitors on contractions induced by NA, high K+, and 12-O-tetradecanoylphorbol-13-acetate (TPA) in rat isolated aorta were investigated. 2 Protriptyline (0.3 microM) and amitriptyline (0.3 microM) produced an approximately parallel shift to the right in the dose-response curve to NA. Protriptyline (> 0.3 microM), amitriptyline (> 0.3 microM) and xylamine (0.01-1 microM) significantly reduced the maximal contractile response to NA. The IC50 values for inhibition of the contractile response to 3 microM NA were 1.58 microM for xylamine, 1.70 microM for amitriptyline and 2.57 microM for protriptyline. 3 Protriptyline and amitriptyline dose-dependently inhibited the high K+ (60 mM)-induced contraction (IC50 = 0.69 microM for protriptyline and IC50 = 3.15 microM for amitriptyline). In contrast, xylamine did not affect the high K(+)-induced contraction. 4 Protriptyline and amitriptyline dose-dependently inhibited TPA (1 microM)-induced contraction in calcium-free solution; xylamine (up to 30 microM) was without effect. Staurosporine (10 nM) completely inhibited the TPA- and NA-induced contraction. 5. Protriptyline (3 microM) and amitriptyline (3 microM) caused about 54% and 60% inhibition, respectively, of aortic contractions caused by endothelin-1 (10 nM) in the absence of endothelium. Xylamine (10 microM) was without effect. 6 Inhibitory effects of NA uptake inhibitors on contractions were independent of the presence of endothelium and were unaffected by the K+ channel blockers, tetraethylammonium ions (up to 3 mM) and glibenclamide (up to 30 microM). 7 These results indicate that tricyclic antidepressant drugs such as protriptyline and amitriptyline could act as both postsynaptic adrenoceptor antagonists and direct inhibitors of muscle contraction; whereas, xylamine, a structurally distinct NA uptake blocker might principally exert its action only at alpha-adrenoceptors on rat aortic smooth muscle.

Potent block of potassium currents in rat isolated sympathetic neurones by the uncharged form of amitriptyline and related tricyclic compounds.

1. The block of K+ currents by amitriptyline and the related tricyclic compounds cyproheptadine and dizocilpine was studied in dissociated rat sympathetic neurones by whole-cell voltage-clamp recording. 2. Cyproheptadine (30 microM) inhibited the delayed-rectifier current (Kv) by 92% and the transient current (KA) by 43%. For inhibition of Kv, cyproheptaidine had a KD of 2.2 microM. Dizocilpine (30 microM) inhibited Kv by 26% and KA by 22%. The stereoisomers of dizocilpine were equally potent at blocking Kv and KA. 3. Amitriptyline, a weak base, was significantly more effective in blocking Kv at pH 9.4 (KD = 0.46 microM) where the ratio of charged to uncharged drug was 50:50 compared with pH 7.4 (KD = 11.9 microM) where the ratio was 99:1. 4. N-methylamitriptyline (10 microM), the permanently charged analogue of amitriptyline, inhibited Kv by only 2% whereas in the same cells amitriptyline (10 microM) inhibited Kv by 36%. 5. Neither amitriptyline nor N-methylamitriptyline had a detectable effect on Kv when added to the intracellular solution. 6. It is concluded that the uncharged form of amitriptyline is approximately one hundred times more potent in blocking Kv than the charged form. However, this does not seem to be due to uncharged amitriptyline having better access to an intracellular binding site.

[Effects of protriptyline on day and night time oxygenation in patients with chronic obstructive pulmonary disease].

To determine the effects of protriptyline, a tricyclic non-sedative antidepressant, on sleep architecture, day and night arterial oxygen saturation and pulmonary function, ten patients with stable chronic obstructive pulmonary disease were evaluated. Overnight polysomnographic measurements were made before and 2 to 4 months after Protriptyline (10-20 mg daily) therapy. The results showed that two patients could not tolerate the protriptyline. Protriptyline caused xerostomia in eight of 10 cases, dysuria in five of 10 cases. Protriptyline therapy did not alter sleep efficiency and sleep latency but shortened the REM sleep stage from 15.6% to 8.2% Even though protriptyline did not change simple spirometry comparing before and after therapy, protriptyline decreased delta SaO2 and increased lowest SaO2 and baseline PaO2. In conclusion, these results suggest that protriptyline may benefit COPD patients by improving nocturnal oxygenation and nocturnal desaturation events.

The carotid body in the motorneuron response to protriptyline.

Protriptyline (PRT) has been shown to preferentially stimulate upper airway inspiratory motorneurons relative to phrenic activity in hyperoxic hypercapnia in the decerebrate cat via a carotid body-independent mechanism. Since previous studies indicated that carotid body stimulation results in preferential activation of upper airway respiratory muscles during both hypercapnia and hypoxemia, we hypothesized that if PRT preferentially stimulated upper airway motorneurons, the mechanism of action might involve the carotid body. We investigated the effect of PRT on carotid body function by comparing the electrical activity of the hypoglossal (HYP) with that of the phrenic (PHR) nerve in carotid sinus nerve intact (CSNI) and CSN-sectioned (CSNX) anesthetized rats, before and after PRT (0.5 mg/kg i.v.), during 100% O2, 15% O2 (N2 balance), and 4% CO2 (O2 balance) administration. The moving time average (MTA) peak inspiratory electroneurogram activities of both the HYP and PHR nerves increased an equivalent amount after PRT injection during hyperoxia, in both CSNI and CSNX rats. During hypoxia, the HYP activity increased significantly more than the PHR activity only in CSNI rats after PRT injection. During hyperoxic hypercapnia, HYP MTAs increased a similar amount in the CSNI and CSNX rats. We conclude that the HYP and PHR respiratory motorneuron pool responses to PRT depend on the blood gas status at the time of drug administration.

Further characterization of reversal of signs of induced cotton effects of dicumarol derivatives-alpha 1-acid glycoprotein systems by protriptyline.

The interaction of dicumarol derivatives and protriptyline with respect to the binding to alpha 1-acid glycoprotein (AGP) has been investigated by circular dichroism (CD), equilibrium dialysis and ultrafiltration. Investigation of the induced CD spectra of dicumarol derivatives bound to AGP indicated that the conformations of these compounds were different when bound to AGP. Though all the dicumarol derivatives, protriptyline and AGP formed a ternary complex, interaction modes were different, depending upon the substituent groups at position 3 of the dicumarol molecule. On the basis of the protriptyline effect on the CD spectra of all dicumarol derivatives bound to AGP, the compounds were classified in the following way: (1) Dicumarol, ethylidenebis 4-hydroxycoumarin and propylidenebis 4-hydroxycoumarin caused reversal of the sign of ellipticity. This interaction was explained by cooperative binding. (2) Butylidenebis 4-hydroxycoumarin and pentylidenebis 4-hydroxycoumarin generated new band and disappeared ellipticity of the original Cotton effect. This interaction was also explained by the cooperative binding mode. (3) Ethylbiscoumacetate which generated the CD band similar to that of dicumarol in the absence of protriptyline, reversed the sign of the CD spectrum only at 325 nm. The interaction was anticooperative in nature. (4) Benzylidenebis 4-hydroxycoumarin represented type four which had no change in the CD spectrum by the addition of protriptyline. This interaction was explained by the two-state model accompanying the conformational change of AGP. These results suggested that all compounds, except for benzylidenebis 4-hydroxycoumarin, induced negative Cotton effects at 325 nm by taking the same asymmetrical perturbation by the addition of protriptyline and the interaction was carried out according to model 2. An attempt to study the interaction mechanism of two or more drugs with regard to the binding to protein using these models is thought to help in understanding drug-protein interactions.

Effects of tricyclic drug on induced circular dichroism spectra of dicumarol bound to alpha 1-acid glycoprotein.

Effects of both tricyclic and non-tricyclic drugs on the extrinsic Cotton effects of dicumarol bound to human alpha 1-acid glycoprotein (AGP) have been investigated. Basic tricyclic drugs caused the reversal of the signs of the induced Cotton effects of the circular dichroism (CD) spectra of the dicumarol-AGP system while the basic drugs not possessing tricyclic rings and acidic drugs decreased the observed ellipticities without changing the signs of its CD spectra. There was no reversal of the CD signs of the drugs not containing two hydroxycoumarin rings bound to AGP by basic tricyclic drugs. Raising of pH and temperature, and the addition of guanidine hydrochloride decreased the observed ellipticities of the CD spectra of the dicumarol-AGP system without showing any change in the signs of the Cotton effects. The mutual displacement data showed that protriptyline increased its own binding and that of dicumarol with AGP. The results of CD titration and equilibrium dialysis experiments suggest that dicumarol-AGP and dicumarol-AGP-protriptyline form a 1:1 binary complex and a 1:1:1 ternary complex, respectively.

The use of protriptyline for respiratory failure in patients with chronic airflow limitation.

Treatment of nocturnal hypoventilation in patients with restrictive chest wall disease and respiratory failure, results in improved daytime arterial blood gas tensions, increase in functional ability and longer survival. Success has been achieved with the use of protriptyline which reduces the duration of rapid eye movement (REM) sleep during which nocturnal hypoventilation occurs. Eighteen patients with severe chronic airflow limitation (CAL), took part in a randomized, double-blind, crossover trial of protriptyline and placebo. Seventeen patients completed the study. The use of protriptyline was associated with a fall in the median percentage of total sleep time spent in REM from 16 to 8.8% (p less than 0.01). This was associated with a reduction in the median daytime arterial carbon dioxide tension from 6.4 kPa (range 5.2-8.5 kPa) to 5.8 kPa (range 5.0-8.1 kPa) (p less than 0.01); increased respiratory muscle strength (p less than 0.05), and increased six minute walking distance from a median of 258 m (range 58.5-585 m) to 275 m (range 171-598 m) (p less than 0.02). We found pharmacological treatment of REM-related nocturnal hypoventilation in patients with CAL to be effective, but anticholinergic side-effects, particularly in older male patients, might preclude long-term treatment.

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.

Effect of protriptyline on ventilatory responses to hypercapnia and asphyxia in normal subjects.

A double-blind crossover study was undertaken to assess the effect of protriptyline on ventilatory responses in normal subjects. Seven subjects received in random order placebo, 10 mg and 20 mg protriptyline daily for 2 weeks. Measurements of hypercapnic ventilatory response (HCVR) and asphyxial hypoxic ventilatory response (HVR) were made before treatment, 6-8 h after the first dose, and after 2 weeks treatment. Mean HCVR and HVR following 10 mg and 20 mg protriptyline did not differ significantly from measurements on placebo, neither for the single dose study or after 2 weeks.

Uptake of 3H-norepinephrine in different segments of the human non-pregnant and pregnant uterus.

Tissue specimens from uterine cervix and corpus of non-pregnant and pregnant women were incubated in vitro in the presence of 3H-norepinephrine. The uptake in the cervix exceeded those of the lower and upper segments of the corpus, and this difference was most pronounced at term pregnancy. The neuronal uptake in the cervix constituted approximately 80% of the total uptake and was higher than in isthmus and fundus (50 and 20%, respectively). The results favour the notion that cervical nerves remain functionally intact throughout pregnancy and support previous histochemical studies demonstrating a segmental difference in uterine innervation and a partial denervation of the myometrium at term.