Phosphodiesterase 1B (PDE1B) and PDE10A are dual-specificity PDEs that hydrolyse both cyclic adenosine monophosphate and cyclic guanosine monophosphate, and are highly expressed in the striatum. Several reports have suggested that PDE10A inhibitors may present a promising approach for the treatment of positive symptoms of schizophrenia, whereas PDE1B inhibitors may present a novel mechanism to modulate cognitive deficits. Previously, we have reported a novel dual inhibitor of PDE1B and PDE10A, compound 2 [(3-fluorophenyl)(2-methyl-2,3-dihydro-4H-benzo[b][1,4]oxazin-4-yl)methanone] which has shown inhibitory activity for human recombinant PDE1B and PDE10A in vitro. In the present study, the safety profile of compound 2 has been evaluated in rats in the acute oral toxicity study, as well as; the antipsychotic-like effects in the rat model of schizophrenia. Compound 2 was tolerated up to 1 g/kg when administered at a single oral dose. Additionally, compound 2 has strongly suppressed ketamine-induced hyperlocomotion, which presented a model for the positive symptoms of schizophrenia. It has also shown an ability to attenuate social isolation induced by chronic administration of ketamine and enhanced recognition memory of rats in the novel object recognition test. Altogether, our results suggest that compound 2 represents a promising therapy for the treatment of the three symptomatic domains of schizophrenia.
Matched MeSH terms: Phosphodiesterase Inhibitors/pharmacology; Phosphodiesterase Inhibitors/therapeutic use
Dipyridamole is a platelet inhibitor indicated for the secondary prevention of transient ischemic attack. It inhibits the enzyme phosphodiesterase, elevates cAMP and cGMP levels and prevents platelet aggregation. Dipyridamole inhibits the cellular uptake of adenosine into red blood cells, platelets and endothelial cells that results in increased extracellular availability of adenosine, leading to modulation of cardiovascular function. The antiplatelet action of dipyridamole might offer therapeutic benefits in secondary stroke prevention in combination with aspirin. Inflammation and oxidative stress play an important role in atherosclerosis and thrombosis development, leading to stroke progression. Studies demonstrated anti-inflammatory, anti-oxidant and anti-proliferative actions of dipyridamole. These pleiotropic potentials of dipyridamole might contribute to improved therapeutic outcomes when used with aspirin in preventing secondary stroke. Dipyridamole was documented as a coronary vasodilator 5 decades ago. The therapeutic failure of dipyridamole as a coronary vasodilator is linked with induction of 'coronary steal' phenomenon in which by dilating resistance vessels in non-ischemic zone, dipyridamole diverts the already reduced blood flow away from the area of ischemic myocardium. Dipyridamole at high-dose could cause a marked 'coronary steal' effect. Dipyridamole, however, at low-dose could have a minimal hemodynamic effect. Low-dose dipyridamole treatment has a therapeutic potential in partially preventing diabetes mellitus-induced experimental vascular endothelial and renal abnormalities by enhancing endothelial nitric oxide signals and inducing renovascular reduction of oxidative stress. In spite of plenteous research on dipyridamole's use in clinics, its precise clinical application is still obscure. This review sheds lights on pleiotropic pharmacological actions and therapeutic potentials of dipyridamole.
Matched MeSH terms: Phosphodiesterase Inhibitors/pharmacology; Phosphodiesterase Inhibitors/therapeutic use
The quest for improving and maintaining sexual function has been going on since time immemorial. The advent of an effective oral drug, sildenafil, has brought about unprecedented open discussion on male erectile dysfunction, and gas accelerated the pace of development of new therapies for erectile dysfunction. New knowledge in the physiology of sexual function has enabled researchers to target drug treatment at the whole network of the central nervous system and the numerous cascadic enzymatic reactions leading to relaxation of the corporal smooth muscle. One of the brightest potential applications of future molecular technology in the study of erectile dysfuction is in the utilization of gene therapy.
Matched MeSH terms: Phosphodiesterase Inhibitors/pharmacology; Phosphodiesterase Inhibitors/therapeutic use
To evaluate the efficacy and tolerability of vardenafil, a phosphodiesterase type-5 (PDE-5) inhibitor, in men of Asian ethnicity with erectile dysfunction (ED).
Sildenafil citrate (Viagra), a selective inhibitor of cGMP-specific phosphodiesterase type-5, has been used as an oral therapeutic drug for erectile dysfunction. The present paper is a clinical study of the success rate and side-effects of the use of sildenafil in a multi-racial population in Singapore.
Aim: To explore the barriers faced by general practitioners (GPs) in the management of patients with erectile dysfunction (ED).
Methods: This was a qualitative analysis of focus group discussions and in-depth interviews involving 28 Malaysian GPs.
Results: GPs' perception of ED being not a serious condition was a major determinant of their prescribing practice. Doctor's age (younger), gender (female), short consultation time and lack of experience were cited as barriers. The GPs' prescribing habits were heavily influenced by the feedback from the first few patients under treatment, the uncertainty of etiology of ED without proper assessment and the profit margin with bulk purchase. Other barriers include Patients' coexisting medical conditions, older age, lower socio-economic status, unrealistic expectations and inappropriate use of the anti-impotent drugs. Cardiovascular side effects and cost were two most important drug barriers.
Conclusion: The factors influencing the management of ED among the general practitioners were multiple and complex. An adequate understanding of how these factors (doctors, patients and drugs) interact can assist in the formulation and implementation of strategies that encourage GPs to identify and manage ED patients.
Schizophrenia is a severe mental disorder that affects more than 1% of the population worldwide. Dopamine system dysfunction and alterations in glutamatergic neurotransmission are strongly implicated in the aetiology of schizophrenia. To date, antipsychotic drugs are the only available treatment for the symptoms of schizophrenia. These medications, which act as D2-receptor antagonist, adequately address the positive symptoms of the disease, but they fail to improve the negative symptoms and cognitive impairment. In schizophrenia, cognitive impairment is a core feature of the disorder. Therefore, the treatment of cognitive impairment and the other symptoms related to schizophrenia remains a significant unmet medical need. Currently, phosphodiesterases (PDEs) are considered the best drug target for the treatment of schizophrenia since many PDE subfamilies are abundant in the brain regions that are relevant to cognition. Thus, this review aims to illustrate the mechanism of PDEs in treating the symptoms of schizophrenia and summarises the encouraging results of PDE inhibitors as anti-schizophrenic drugs in preclinical and clinical studies.
This paper highlights women's perceptions of sildenafil citrate (Viagra, Pfizer). It is based on a qualitative study on perceptions of erectile dysfunction in the Malaysian multicultural society. Six focus groups were conducted, consisting of 69 women, aged between 40 and 70 years, recruited from the general public and who had given informed consent. The findings revealed that the women were aware of erectile dysfunction and Viagra. Due to their concern about the negative aspects of Viagra, the Chinese and Malay traditional methods of treatment were commonly mentioned. The women from three ethnic groups viewed the possibility of their husband starting to take Viagra with lots of suspicion, mistrust and fear. They would prefer their husband discussing with them the issue of resorting to taking Viagra. The Chinese and Indian women perceived that if a man takes Viagra, it will boost his ego and he will feel more manly. Indian women felt that a man taking Viagra is proof of his love for his wife. The Malay women felt that a man would be ashamed and have a low self-esteem if he were to resort to taking Viagra. Although Viagra is meant for the male, understanding of women's perception of it is beneficial for a couple's sexual relationship.
Eurycoma longifolia Jack (Simaroubaceae family), known locally as 'Tongkat Ali' by the ethnic population, is popularly taken as a traditional remedy to improve the male libido, sexual prowess and fertility. Presently, many tea, coffee and carbonated beverages, pre-mixed with the root extract are available commercially for the improvement of general health and labido. Eurycomanone, the highest concentrated quassinoid in the root extract of E. longifolia improved fertility by increasing testosterone and spermatogenesis of rats through the hypothalamus-pituitary-gonadal axis, but the mechanisms underlying the effects are not totally clear.
OBJECTIVE:
Assess the effectiveness of sildenafil in Asian males with erectile dysfunction (ED) and one or more of the co-morbidities, mild-to-moderate hypertension, dyslipidemia, and diabetes.
MATERIAL AND METHOD:
A six-week, double-blind, randomized, placebo-controlled, multicenter study was carried out in Thailand, Malaysia and Singapore. One hundred and fifty five male subjects were randomized (2:1) to sildenafil (n = 104) or placebo (n = 51). Sildenafil was started at 50 mg and increased (100 mg) or decreased (25 mg) at week 2 if necessary.
RESULTS:
On the primary efficacy endpoint, sildenafil-treated subjects had significantly better scores on the International Index of Erectile Function (IIEF) questions 3 and 4 than placebo (p < 0.001, both questions). When accumulated into IIEF domains, all five domains were significant in favor of sildenafil. In addition, sildenafil-treated subjects were more satisfied with treatment and had a higher intercourse success rate. The majority of adverse events were mild in severity; the most commonly reported treatment-related events were dizziness (7.7%) and tinnitus (2.9%).
CONCLUSION:
Sildenafil (25, 50, and 100 mg) was found to be an effective, safe, and well-tolerated treatment for ED in the present study population of Thai, Malaysian, and Singaporean males who also had increased cardiovascular risk.
INTRODUCTION: Erectile dysfunction (ED) is a common medical disorder affecting the aging male. A man's perception of a disease affects his health seeking behaviour. This study aimed to explore perceptions of ED among men with ED and how these perceptions came about.
METHODS: This qualitative study utilized in-depth interviews involving 17 urban men aged between 40 and 75 years old.
RESULTS: Misconceptions existed regarding the definitions of ED. Most men perceived impotence to be more serious than ED. Although most were aware of the medical causes of ED, 'overuse of penis' and black magic were mentioned as culturally-related causes. ED was perceived as a serious problem associated with loss of manhood and it had a significant impact on relationships with their partners. However, some adopted an 'accepting' view and attributed it to aging and fate. Most men were only familiar with PDE-5 inhibitors and traditional therapies. PDE-5 inhibitors were perceived to be effective but they were concerned about side effects and costs.
CONCLUSIONS: Identifying men's perceptions of ED and its treatment would help doctors in their consultation, and inform health policy makers in planning appropriate public education and services.
Human osteoblasts induced by inflammatory stimuli express an inducible nitric oxide synthase (iNOS). The aim of the present study was to test the hypothesis that Aggregatibacter actinomycetemcomitans lipopolysaccharide stimulates the production of nitric oxide (NO) by a human osteoblast-like cell line (HOS cells).
The aim of the present study was to determine the role of cyclic adenosine monophosphate (cAMP) on arginase activity in a murine macrophage cell line (RAW264.7 cells) stimulated with lipopolysaccharide (LPS) from Actinobacillus actinomycetemcomitans.
BACKGROUND AND AIMS OF THE WORK: Nitric oxide (NO) has been reported to enhance the production of cAMP by hydroxyapatite (HA)-induced a human osteoblast cell line (HOS cells). The aim of the present study was to test the hypothesis that exogenous NO may up-regulate the proliferation of hydroxyapatite (HA)-induced HOS cells via the cyclic-AMP-protein kinase A (PKA) pathway.