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.

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.

Medical therapy for obstructive sleep apnea: a review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine.

A significant number of patients with obstructive sleep apnea neither tolerate positive airway pressure (PAP) therapy nor achieve successful outcomes from either upper airway surgeries or use of an oral appliance. The purpose of this paper, therefore, was to systematically evaluate available peer-reviewed data on the effectiveness of adjunctive medical therapies and summarize findings from these studies. A review from 1985 to 2005 of the English literature reveals several practical findings. Weight loss has additional health benefits and should be routinely recommended to most overweight patients. Presently, there are no widely effective pharmacotherapies for individuals with sleep apnea, with the important exceptions of individuals with hypothyroidism or with acromegaly. Treating the underlying medical condition can have pronounced effects on the apnea/hypopnea index. Stimulant therapy leads to a small but statistically significant improvement in objective sleepiness. Nonetheless, residual sleepiness remains a significant health concern. Supplemental oxygen and positional therapy may benefit subsets of patients, but whether these therapies reduce morbidities as PAP therapy does will require rigorous randomized trials. PAP therapy has set the bar high for successful treatment of sleep apnea and its associated morbidities. Nonetheless, we should strive towards the development of universally effective pharmacotherapies for sleep apnea. To accomplish this, we require a greater knowledge of the neurochemical mechanisms underlying sleep apnea, and we must use this infrastructure of knowledge to design well-controlled, adequately powered studies that examine, not only effects on the apnea/hypopnea index, but also the effects of pharmacotherapies on all health related outcomes shown beneficial with PAP therapy.

In pursuit of drugs for American trypanosomiasis: evaluation of some "standards" in a mouse model.

Forty-nine "standard" compounds known to be useful in the treatment of other diseases were tested for their suppressive activity against the trypomastigotes of Trypanosoma cruzi-infected mice. The most active was the antidepressant protriptyline, which was almost three times as effective as the reference drug, nifurtimox. A major value of the present data is to demonstrate the refractoriness of the T. cruzi parasite against many of the drug standards that have known biological activity.

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.

Nocturnal respiratory failure as an indication of noninvasive ventilation in the patient with neuromuscular disease.

Patients with neuromuscular disease may suffer from nocturnal respiratory failure despite normal daytime respiratory function. The physiological reduction in muscle tone during sleep may be life-threatening in a patient with impaired muscle strength. Nocturnal respiratory failure may occur in patients with the postpolio syndrome, amyotrophic lateral sclerosis, myasthenia gravis, myotonic dystrophy, and muscular dystrophy. Diagnosis of obstructive, central and mixed apneas, hypopneas, and hypoventilation is best made using polysomnography. Therapeutic options include noninvasive ventilation such as continuous positive airway pressure, bilevel positive airway pressure, intermittent positive pressure ventilation and, rarely, tracheostomy, oxygen, or protriptyline. Evaluation by a sleep specialist should be initiated in any neuromuscular patient with nocturnal symptoms such as air hunger, intermittent snoring or breathing, orthopnea, cyanosis, restlessness, and insomnia. Daytime symptoms may include morning drowsiness, headaches and excessive daytime sleepiness. Polycythemia, hypertension, and signs of heart failure may also be seen. Effective treatment is available, and may improve the quality of life, and possibly increase survival.

Management of simple snoring, upper airway resistance syndrome, and moderate sleep apnea syndrome.

The spectrum of respiratory sleep disorders has been extended in the last years to include conditions that are less well defined than severe obstructive sleep apnea (OSA). Moderate OSA, snoring, and upper airway resistance syndrome (UARS) represent three conditions in which there are still unresolved pathophysiological, epidemiological, and clinical questions. Therefore, the therapeutic approach remains unclear. We have tried to define these entities and to review the respective indications and efficacy of pharmacological treatment, weight loss, sleep posture, oral appliances, upper airway surgery, and finally, continuous positive airway pressure (CPAP). From these data, we also aim to define strategies of treatment for moderate OSA, snoring, and UARS. However, these conditions are likely to be particularly appropriate for randomized trials comparing different modalities of treatment that may be the only way to validate these treatment strategies.

A naturalistic assessment of protriptyline for attention-deficit hyperactivity disorder.

OBJECTIVE: To evaluate the potential benefit of the tricyclic antidepressant, protriptyline, in the treatment of children and adolescents with attention-deficit hyperactivity disorder (ADHD). METHOD: All clinic patients in an outpatient pediatric psychopharmacology unit treated with protriptyline for ADHD were monitored for response to treatment. Thirteen subjects (11 male, 2 female) were treated naturalistically with protriptyline for ADHD and were administered the ADHD Symptom Rating Scale and Clinical Global Impression of Severity (CGI-S) and improvement (CGI-I) at baseline and while taking medication. All patients had failed to respond to at least one previous medication trial, and 46% had psychiatric comorbidity. RESULTS: Patients received an average protriptyline dose of 17 mg (range 5 to 30 mg) for 11.5 +/- 6.8 weeks. Of the 11 patients who continued to take protriptyline for at least 4 weeks, there was a modest reduction in the ADHD symptom checklist (p < .004) and the CGI-S (p = .032). However, using a predefined criteria of response, only 45% of patients were considered positive responders. Adverse effects were prominent, with 46% of patients reporting clinically significant problems and 38% of patients discontinuing treatment because of intolerable side effects. CONCLUSION: These findings do not support the clinical utility of protriptyline in the routine management of complex cases of ADHD in children and adolescents. However, the usefulness in noncomorbid, medication-naive ADHD individuals remains unclear.

Symptomatic cataplexy in pontomedullary lesions.

Cataplexy is a cardinal manifestation of the narcolepsy syndrome. Although symptomatic narcolepsy is well described, isolated cataplexy is extremely rare. We reviewed clinical and radiologic data in two patients with isolated symptomatic cataplexy and associated CNS disease. In an HLA-DR2-positive patient with chronic progressive MS, we confirmed cataplexy by observation of reported spells. MRI revealed diffuse white-matter lesions involving the medial medulla, pons, and subcortical white matter; protriptyline provided symptomatic relief. A second patient with a pontomedullary pilocytic astrocytoma developed infrequent but recurrent cataplectic attacks in association with sleep fragmentation due to nocturnal cough and nausea. MRI revealed an enhancing lesion involving the dorsal pons and medulla. Genetic predisposition and sleep fragmentation may precipitate symptomatic cataplexy in patients with structural pontomedullary lesions.

A clinical picture of child and adolescent narcolepsy.

Although narcolepsy is rarely diagnosed before adulthood, symptoms often begin much earlier and can easily mimic psychiatric disorders in children and adolescents. Clinical experience from a pediatric sleep center is reviewed in 16 consecutive cases of polysomnographically proven narcolepsy with onset of symptoms by age 13 years. Only 1 of the 16 patients presented with the classic clinical tetrad of symptoms (sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis). Behavioral and emotional disturbances were present in 12 of 16 cases, with four patients appearing to have been misdiagnosed with a psychiatric disorder before recognition of the narcolepsy. Obesity appeared as an unexpected association in this case series, with 11 of the 16 narcoleptic patients found to be overweight at the time of diagnosis. The varied clinical presentations, polysomnographic findings, family history, and associated psychiatric symptoms are described. The importance of considering narcolepsy in the differential diagnosis of any child or adolescent with excessive sleepiness is emphasized.

Hyperekplexia: report of a nonfamilial adult onset case associated with obstructive sleep apnea and abnormal brain nuclear tomography.

We report the unique occurrence of hyperekplexia and obstructive sleep apnea (OSA) in a 48-year-old male. Polysomnography and multiple sleep latency testing excluded cataplexy, which can be confused with startle attacks. A new imaging finding was a nuclear tomography abnormality in the left frontal lobe. We postulate that this finding may represent a functional cortical lesion of a descending pathway that normally inhibits the startle reflex. Serious complications of pharmacotherapy with clonazepam, the drug of choice for hyperekplexia, can be avoided by first evaluating for OSA.

Protriptyline as an alternative stimulant medication in patients with brain injury: a series of case reports.

The results of a series of eight individual case reports in which protriptyline, an activating tricyclic antidepressant, was used as a 'stimulant' medication are presented. For some patients with head injury, traditional stimulants, such as methylphenidate, or dopaminergic stimulants, such as levodopa-carbidopa, amantadine, or bromocriptine, may be partially or totally ineffective or not tolerated. Protriptyline can be a very effective alternative and, for some patients, may be the most effective stimulant tried. In low to moderate doses, protriptyline should be considered for trials as an activating/stimulant medication in patients with head injury.

Effects of protriptyline on snoring characteristics.

We evaluated the effects of protriptyline on snoring characteristics in 14 nonapneic snorers (age range, 23 to 54 years; body mass index, 27.4 +/- 0.9 kg/m2, mean +/- SEM). The study design was a double-blind placebo-controlled crossover trial. Patients were evaluated during a polysomnographic study after each 2 weeks of treatment. Breathing sounds were recorded with two microphones symmetrically placed on each side of the bed, the signal being preamplified, equalized, and analyzed by using a real time analyzer. A snoring event was defined as a breathing sound with a sound pressure level (SPL) greater than 60 dB SPL. The snoring index (number/sleep hour) and the sound intensity of each event were automatically determined. Mild side effects were observed in ten subjects, but no subject interrupted the study because of them. The REM sleep time decreased with protriptyline with a parallel increase in stages 1 to 2. There was no difference in body position during sleep between the placebo and protriptyline trials. The snoring index decreased from 335 +/- 40 with placebo to 238 +/- 41 with protriptyline (p < 0.05) with important individual differences. Among the different sleep stages, the highest values of the snoring index were observed in slow-wave sleep with placebo. The snoring index decreased in each sleep stage with protriptyline, the highest decrease occurring in slow-wave sleep. The percentage of total sleep time (TST) spent above 60 dB SPL was significantly lower with protriptyline (6.1 +/- 1.2 percent TST) than with placebo (8.6 +/- 1.2 percent TST). Changes in snoring characteristics were not correlated with snoring severity, the drug blood level, the body mass index, or the drug-induced modifications in sleep architecture. We conclude that protriptyline can improve both snoring frequency and loudness in some nonapneic snorers, and that this improvement occurs mostly in the sleep stages where snoring is worst.

Long-term effects of protriptyline in patients with chronic obstructive pulmonary disease.

Protriptyline has been shown to improve nocturnal and diurnal hypoxemia in patients with chronic obstructive pulmonary disease in short trials. We prospectively evaluated the long-term effects of protriptyline on pulmonary functions (lung volume and expiratory flow, arterial blood gases) and sleep characteristics (sleep architecture, nocturnal desaturations) in these patients. Sixteen patients previously studied before and after 10 wk of protriptyline treatment were reevaluated after a long-term follow-up (range, 18 to 63 months); the results of those still receiving protriptyline were compared with those who stopped using the drug. Nine patients were still receiving protriptyline at the follow-up visit (10 to 20 mg/day at bedtime), and seven had stopped using the drug because of side effects. These two groups of patients did not differ in their follow-up duration, age, weight, pulmonary functions, and sleep architecture, or in their protriptyline-induced changes in diurnal arterial blood gases and nocturnal desaturation. At the follow-up visit, arterial blood gas determinations had returned to baseline values in all patients no longer receiving protriptyline. In the other group there was no difference between the baseline and follow-up PaO2 values (57.4 +/- 3.4 and 57.0 +/- 1.2 mm Hg, mean +/- SEM). There was no difference in the results of arterial blood gas determinations and pulmonary function tests obtained at the different visits between the two groups. Sleep architecture differed between these two groups, REM sleep time being shorter and the slow-wave sleep time being longer in the patients still receiving the drug. In both groups the cumulative SaO2 curves were similar to those obtained at baseline.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of obstructive sleep apnea to fluoxetine and protriptyline.

Protripyline is the pharmacologic agent most commonly used to treat obstructive sleep apnea (OSA); however, its anticholinergic side effects make it intolerable to many patients. Because serotonin may be a central respiratory stimulant and because the serotonin-uptake inhibitor, fluoxetine, is usually well tolerated, we wanted to try fluoxetine in the treatment of OSA. Therefore, we compared the effect of fluoxetine to that of protriptyline in 12 patients with OSA. Both drugs significantly decreased the proportion of REM sleep time and decreased the number of apneas or hypopneas in NREM sleep. The response to fluoxetine was equivalent to that of protriptyline; however, for the group as a whole, there was no significant improvement in the number of arterial oxygen desaturation events, the level of arterial oxygen desaturation, or the number of arousals with either agent. Although there was wide variability in the response to each medication, six of the 12 patients had good responses, including improvement in oxygenation, to either fluoxetine or protriptyline. Three patients could not complete the trial of protriptyline. We conclude that fluoxetine is beneficial to some, but not all, patients with OSA. Fluoxetine was better tolerated than protriptyline.

Relative efficacy of drugs for the treatment of sleepiness in narcolepsy.

A survey was conducted on 10 polysomnographic studies on the pharmacologic treatment of the sleepiness of narcolepsy. Three studies employed the MSLT and 7 employed the MWT as their polygraphic measure of sleep tendency. Statistically and clinically significant therapeutic changes were apparent for pemoline, modafinil, dextroamphetamine and methylphenidate. Codeine, ritanserin and protriptyline did show statistically significant effects. The common feature among the drugs that did produce clinically significant improvements seems to be facilitatory action on central catecholaminergic transmission. Within this group of drugs, only methylphenidate and dextroamphetamine brought MWT sleep latencies to approximately 70% of normal levels.

[Role of sleep apnea in essential arterial hypertension]. / Rôle des apnées du sommeil dans l'hypertension arterielle essentielle.

Because sleep apnoea syndrome is often associated with arterial hypertension, it has been suggested that sleep apnoea might be responsible for hypertension. This hypothesis is mainly based on epidemiological studies showing a statistically significant association between snoring and arterial hypertension; this association remains true even after data correction to take into account the increased frequency of snoring with age and overweight. However, this statistical link is no evidence of a cause-effect relationship, and the mechanism through which sleep apnoea syndrome could produce arterial hypertension remains unknown. Yet treatment of sleep apnoea syndrome seems to improve arterial hypertension, and this alone would justify a search for sleep apnoea syndrome in all patients presenting with arterial hypertension.