Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Peripheral vascular disease (PVD) is generally accepted to result in the failure of skeletal muscle blood flow to increase adequately at the onset of muscular work. There are currently no routine pharmacological interventions towards the treatment of PVD, however, recent Phase III trials in the USA have demonstrated the clinical potential of the phosphodiesterase III inhibitor Cilostazol for pain-free and maximal walking distances in patients with intermittent claudication. PVD is characterized by a marked reliance on oxygen-independent routes of ATP regeneration (phosphocreatine hydrolysis and glycolysis) in skeletal muscle during contraction and the rapid onset of muscular pain and fatigue. The accumulation of metabolic by-products of oxygen-independent ATP production (hydrogen and lactate ions and inorganic phosphate) has long been associated with an inhibition in contractile function in both healthy volunteers and PVD patients. Therefore, any strategy that could reduce the reliance upon ATP re-synthesis from oxygen-independent routes, and increase the contribution of oxygen-dependent (mitochondrial) ATP re-synthesis, particularly at the onset of exercise, might be expected to improve functional capacity and be of considerable therapeutic value. Historically, the increased contribution of oxygen-independent ATP re-synthesis to total ATP generation at the onset of exercise has been attributed to a lag in muscle blood flow limiting oxygen delivery during this period. However, recent evidence suggests that limited inertia is present at the level of oxygen delivery, whilst considerable inertia exists at the level of mitochondrial enzyme activation and substrate supply. In support of this latter hypothesis, we have reported on a number of occasions that activation of the pyruvate dehydrogenase complex, using pharmacological interventions, can markedly reduce the dependence on ATP re-synthesis from oxygen-independent routes at the onset of muscle contraction. This review will focus on these findings and will highlight the pyruvate dehydrogenase complex as a novel therapeutic target towards the treatment of peripheral vascular disease, or any other disease state where premature muscular fatigue is prevalent due to metabolite accumulation.
 ...
PMID:Metabolic inertia in contracting skeletal muscle: a novel approach for pharmacological intervention in peripheral vascular disease. 1499 19

Erectile Dysfunction (ED) is common in men with diabetes. Diabetic men are three times as likely to develop ED as non-diabetic men. The cause is multifactorial, but most commonly reflects endothelial dysfunction and autonomic neuropathy. Diabetes and vascular disease often coexist and ED may be a marker for silent occlusive arterial disease, for which the patient should be screened. Many men still do not volunteer their problem, hence, routine questioning by health care professionals is an important part of the overall management because of the deleterious effect of ED on relationships, self-esteem and quality of life. Treatment is effective in the majority and all options should be considered, beginning with the much preferred oral phosphodiesterase type 5 inhibitors (sildenafil, tadalafil, vardenafil). Female Sexual Dysfunction or Disorder (FSD) is more difficult to define and specific studies in diabetics are limited. Problems with arousal, lubrication and orgasmic dysfunction occur, but the fatigue of diabetes may be influencing these complaints, and in general, psychological issues appear to predominate.
 ...
PMID:Sexual dysfunction and diabetes. 1516 Nov 20

Erectile dysfunction (ED) increases in prevalence and severity because of aging processes and related organic, iatrogenic and social problems. Decline of testosterone (T) levels is observed with age and also in illnesses with a common basis of endothelial damage. The T deficiency may lead to decreased energy, mood depression, reduction of sexual desire, but no correlation has been reported between T level and severity of ED, which is mainly a neurovascular disease. In facts, inhibition of phosphodiesterase type 5 (PDE5) isoenzyme with sildenafil, tadalafil and vardenafil enhances vasodilatation in the corpus cavernosum and subsequent penile erection. Absolute pharmacological potency of PDE5 inhibitors is similar and non-selectivity defines the side-effects profile, while their elimination half-life explains not only the different duration of action, but also short and long-term tolerability. Efficacy of PDE5 inhibitors in younger patients is greater in respect to older subjects because of associated pathologies and the decline in hypothalamic-pituitary-gonadal function. T is essential in erectile function, controlling the expression and activity of PDE5 and therefore, androgen supplementation improves therapeutic response to PDE5 inhibitors in hypogonadal subjects. Since sexual behavior is a complex interplay of physical, psychological, and social factors, the possible effect of these drugs on androgen levels and brain function need to be deeply investigated. The ubiquitarious distribution of PDE5 and the availability of selective inhibitory molecules foster newer studies in the treatment of heart failure, pulmonary hypertension, inflammation, and depression. This new progress is certainly contributing to a better medical approach to sexuality and quality of life in aging people.
 ...
PMID:New achievement and novel therapeutic applications of PDE5 inhibithors in older males. 1604 60

Hypogonadism (low serum testosterone) is commonly associated with erectile dysfunction (ED). However, many urologists may lack appreciation of the relative merits of treating hypogonadism compared with oral phosphodiesterase inhibitors for sexual dysfunction. Testosterone-replacement therapy (TRT) may be the best treatment for men with ED when the presentation includes diminished libido or other sexual symptoms or when non-sexual symptoms such as depressed mood, decreased sense of vitality, and increased fatigue also exist. The health benefits of TRT also include improvements in body composition, bone density, cognition, and sense of well-being. Thus, there may be good reasons to use TRT as first-line therapy for the man with ED. Concerns regarding prostatic and cardiovascular risks of TRT have not been supported by the literature. Nevertheless, men receiving TRT must be monitored at regular intervals with digital rectal examination and blood testing for prostate-specific antigen. Hematocrit or hemoglobin also should be obtained regularly due to the risk of erythrocytosis. Awareness of the benefits of TRT in the man with ED may improve clinical outcomes.
 ...
PMID:Hypogonadism in the man with erectile dysfunction: what to look for and when to treat. 1623 23

Erectile dysfunction in men with multiple sclerosis (MS) is a very common symptom that often leads to a reduced quality of life. It is related to neurological dysfunction, psychological factors, side effects of medication or generalized MS symptoms, such as fatigue or micturition problems, usually in combination. The question of sexual dysfunction should always be broached during routine follow-up, regardless of age and social status. The possibility that erection problems can be a side-effect of drugs commonly used in MS must also be remembered. There are several effective pharmacological treatments, such as phosphodiesterase inhibitors and prostaglandin E(1) (alprostadil). The contraindications and side effects should be familiar to the MS doctor. Dose titration in the initial stages is recommended to avoid priapism. In the future, combinations of impotence drugs may be tested.
 ...
PMID:Treatment of erectile dysfunction in multiple sclerosis. 1678 15

Sildenafil, a phosphodiesterase-5 inhibitor is widely used for the treatment of erectile dysfunction. Recently, the FDA approved the use of sildenafil in the therapeutic treatment of pulmonary arterial hypertension. Sildenafil crosses the blood-brain barrier and has been shown to enhance memory. Tremor, rigidity and akinesia are the most common symptoms seen in Parkinson's disease. Fatigue and sexual dysfunction are the other prominent features seen in Parkinson's disease. Interestingly, sildenafil is used therapeutically to treat sexual dysfunction in Parkinson's disease patients. Currently research on Parkinson's disease focuses on developing novel drug therapies for retarding the nigral dopaminergic neurodegeneration. Hence, we investigated the anti-fatigue and neuroprotective effects of sildenafil. In this study, the effect of sildenafil on fatigue was evaluated using forced swim test in mice. Sildenafil had no effect on fatigue as seen by the swim time. With regard to neuroprotective effects, we investigated the effects of sildenafil using two animal models of Parkinson's disease. In this study, 6-hydroxydopamine-lesioned (unilateral) rats and MPTP-treated mice were used as the animal models of Parkinson's disease. 6-Hydroxydopamine-lesioned rats were used to determine the effect of sildenafil on rotational behavior. Ipsilateral or contralateral rotational behavior can indicate the amphetamine-like activity or apomorphine-like activity of sildenafil. Sildenafil did not induce contralateral or ipsilateral rotations in 6-hydroxydopamine-lesioned rats. Sildenafil did not protect against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopamine depletion in the striatum.
 ...
PMID:Evaluation of neuroprotective and anti-fatigue effects of sildenafil. 1782 48

Pulmonary hypertension (PH) is a hemodynamic state characterized by elevation in the mean pulmonary arterial pressure and pulmonary vascular resistance leading to right ventricular failure and premature death. PH can be the result of a variety of diseases of different etiologies. Pulmonary arterial hypertension (PAH) should be distinctly differentiated from pulmonary venous hypertension (PVH) as a result of left heart disease. PAH is commonly caused by or associated with an underlying pulmonary, cardiac, or systemic disease (APAH). In the absence of an identifiable etiology or associated underlying disease, PAH is referred to as idiopathic (IPAH). IPAH, formerly known as primary pulmonary hypertension (PPH), is a rare disease most commonly seen in women of childbearing age. Presenting symptoms and signs are nonspecific and include dyspnea on exertion, fatigue, and a loud pulmonary component of the second heart sound. Transthoracic Doppler echocardiography is an excellent noninvasive test to detect the presence of pulmonary hypertension, although every patient should receive a right heart catheterization to confirm the diagnosis. A detailed work up, including laboratory tests and imaging studies, is also indicated to rule out known causes of pulmonary hypertension. Several targeted treatment options have become available in recent years and include parenteral and inhaled prostanoids, oral endothelin receptor antagonists, and oral phosphodiesterase type-5 inhibitors. As a result of their complex care, patients should be referred to centers with expertise in pulmonary hypertension.
 ...
PMID:Pulmonary hypertension: evaluation and management. 1800 30

In humans androgen decline is presented as a clinical picture which includes decreased sexual interest, diminished erectile capacity, delayed or absent orgasms and reduced sexual pleasure. Additionally, changes in mood, diminished well being, fatigue, depression and irritability are also associated with androgen insufficiency. The critical role of androgens on the development, growth, and maintenance of the penis has been widely accepted. Although, the exact effect of androgens on erectile physiology still remains undetermined, recent experimental studies have broaden our understanding about the relationship between androgens and erectile function. Preclinical studies showed that androgen deprivation leads to penile tissue atrophy and alterations in the nerve structures of the penis. Furthermore, androgen deprivation caused to accumulation of fat containing cells and decreased protein expression of endothelial and neuronal nitric oxide synthases (eNOS and nNOS), and phosphodiesterase type-5 (PDE-5), which play crucial role in normal erectile physiology. On the light of the recent literature, we aimed to present the direct effect of androgens on the structures, development and maintenance of penile tissue and erectile physiology as well. Furthermore, according to the clinical studies we conclude the aetiology, pathophysiology, prevalence, diagnosis and treatment options of hypogonadism in aging men.
 ...
PMID:Hypogonadism and erectile dysfunction: an overview. 1808 42

A large proportion of patients with congenital heart disease (CHD), in particular those with relevant systemic-to-pulmonary shunts, will develop pulmonary arterial hypertension (PAH) if left untreated. Persistent exposure of the pulmonary vasculature to increased blood flow, as well as increased pressure, may result in pulmonary obstructive arteriopathy, which leads to increased pulmonary vascular resistance that, if it approaches or exceeds systemic resistance, will result in shunt reversal. Eisenmenger's syndrome, the most advanced form of PAH associated with CHD, is defined as CHD with an initial large systemic-to-pulmonary shunt that induces severe pulmonary vascular disease and PAH, with resultant reversal of the shunt and central cyanosis. The histopathological and pathobiological changes seen in patients with PAH associated with congenital systemic-to-pulmonary shunts, such as endothelial dysfunction of the pulmonary vasculature, are considered similar to those observed in idiopathic or other associated forms of PAH. A pathological and pathophysiological classification of CHD with systemic-to-pulmonary shunt leading to PAH has been developed that includes specific characteristics, such as the type, dimensions and direction of the shunt, extracardiac abnormalities and repair status. A clinically oriented classification has also been proposed. The prevalence of PAH associated with congenital systemic-to-pulmonary shunts in Western countries has been estimated to range between 1.6 and 12.5 cases per million adults, with 25-50% of this population affected by Eisenmenger's syndrome. Clinically, Eisenmenger's syndrome presents with multiple organ involvement, with progressive deterioration of function over time. The signs and symptoms of Eisenmenger's syndrome in the advanced stages include central cyanosis, dyspnoea, fatigue, haemoptysis, syncope and right-sided heart failure. Survival of patients with Eisenmenger's syndrome is clearly less than that of the general population, but appears to be better than that of patients with idiopathic PAH in a comparable functional class. The treatment strategy for patients with PAH associated with congenital systemic-to-pulmonary shunts and, in particular, those with Eisenmenger's syndrome is based mainly on clinical experience rather than being evidence based. General measures include recommendations for physical activity, pregnancy, infections, air travel, exposure to high altitudes and elective surgery, and that psychological assistance be provided as necessary. Phlebotomies are required only when hyperviscosity of the blood is evident, usually when the haematocrit is >65%. The use of supplemental oxygen therapy is controversial and it should be used only in patients in whom it produces a consistent increase in arterial oxygen saturation. Oral anticoagulant treatment with warfarin can be initiated in patients with pulmonary artery thrombosis and absent, or only mild, haemoptysis. The following three classes of drugs targeting the correction of abnormalities in endothelial dysfunction have been approved recently for the treatment of PAH: (i) prostanoids; (ii) endothelin receptor antagonists; and (iii) phosphodiesterase-5 inhibitors. The efficacy and safety of these compounds have been confirmed in uncontrolled studies in patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts, as well as in patients with Eisenmenger's syndrome. One randomized controlled trial reported favourable short- and long-term outcomes of treatment with the orally active dual endothelin receptor antagonist bosentan in patients with Eisenmenger's syndrome. Lung transplantation with repair of the cardiac defect or combined heart-lung transplantation are options for Eisenmenger's syndrome patients with a poor prognosis. A treatment algorithm based on the one used in the treatment of PAH patients is proposed for patients with PAH associated with corrected and uncorrected congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome.
 ...
PMID:Management of pulmonary arterial hypertension associated with congenital systemic-to-pulmonary shunts and Eisenmenger's syndrome. 1848 98

SSc is complicated in approximately 10% of the patients by pulmonary arterial hypertension (PAH), a rare dyspnoea-fatigue syndrome caused by an increase in pulmonary vascular resistance. The prognosis of SSc-PAH is particularly poor, with estimated survival rates of approximately 50% at 2 yrs without pulmonary circulation-targeted therapies. Prostacyclins, endothelin receptor antagonists and phosphodiesterase-5 inhibitors have been shown to be efficacious in PAH, with persistent long-term benefit and approximate doubling of survival rate, and these encouraging results appear transposable to the SSc-PAH subcategory. However, PAH as well as SSc-PAH remain incurable, with insufficient functional improvement in many patients. More progress is needed, and this will require more effective drugs and adapted outcome measures.
 ...
PMID:Outcome measures in pulmonary arterial hypertension associated with systemic sclerosis. 1878 40


<< Previous 1 2 3 4 Next >>