Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Zardaverine is a newly developed selective phosphodiesterase III and IV inhibitor. This study investigates the bronchodilatory properties of zardaverine, administered by inhalation. Twelve patients with reversible bronchial obstruction (increase in forced expiratory volume in one second (change FEV1 % predicted) at least 15% after 200 micrograms salbutamol, median age 31 yrs, range 21-54 years) entered the double-blind, crossover study. Four puffs of either zardaverine (total dose 6 mg) or placebo were inhaled at 15 min intervals. Pulmonary function (specific airway conductance (sGaw) and FEV1 was measured by body plethysmography at regular intervals (5 and 12 min after each puff and, in addition, 30, 60, 120, 180 and 240 min after the last puff). Compared to placebo, sGaw and FEV1 increased significantly during the first hour of repeated inhalations, but not during the entire observation period of almost 5 h. The maximum mean difference between zardaverine and placebo for FEV1 was 0.3 l or 12% and occurred approximately 1 h after inhalation of the first puff. In seven patients FEV1 increased by > 15%. The duration of action varied considerably between patients. Three patients complained of side-effects (headache, drowsiness, vertigo, nausea), and one of these dropped out of the study due to vomiting. We conclude that inhalational administration of zardaverine has a modest and short-lasting bronchodilating activity.
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PMID:Bronchodilatory effect of inhaled zardaverine, a phosphodiesterase III and IV inhibitor, in patients with asthma. 142 7

A review of the clinical efficacy of four structurally distinct antidepressant drugs is presented. Their antidepressant activity can be rationalised within current pharmacological hypotheses of drug action, despite markedly different effects on "in vitro" testing. Fluoxetine, a specific serotonin re-uptake inhibitor, has proven safe, effective treatment for depressive illness and may have a role to play in the treatment of obsessive-compulsive disorder and panic attacks. While it has few of the anticholinergic side effects of the tricyclic antidepressants, nausea, tremor, headache, weight loss, nervousness and sweating are side effects most frequently reported. Minaprine, a compound with weak MAO inhibiting properties and effects on serotonergic receptors, has clinical efficacy in the treatment of depression based on several comparative studies. It is claimed that minaprine lacks anticholinergic and sedative properties. Moclobemide, a specific, reversible inhibitor of MAO-A, has been extensively evaluated in depressive illness. The major advantage of this agent over other irreversible, non-specific MAO inhibitors, is the significant attenuation of the so-called "cheese effect" with doses of tyramine likely to be encountered in foodstuffs. Rolipram, a phosphodiesterase inhibitor, represents a new approach to antidepressant treatment. Limited clinical data suggest that the drug may be an effective antidepressant with few side effects. The place of these agents in therapy is yet to be established.
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PMID:New pharmacological approaches to the management of depression: from theory to clinical practice. 158 Aug 88

Enoximone, a new phosphodiesterase-inhibitor with positive inotropic and vasodilating activities is available for intravenous use in patients with severe heart failure. A review of the current knowledge regarding the adverse effects of this substance reveals that they are characterized by cardiovascular, central nervous, and gastrointestinal side effects. Adverse effects occurred in 20% of patients and were mostly due to the pharmacological properties of enoximone. Cardiovascular side effects (10%) were the most frequent; ventricular and supraventricular arrhythmias were most common. Two to three percent of the patients experienced hypotension due to the vasodilator activity of enoximone. Headache, insomnia, and anxiety were the most frequent adverse effects on the central nervous system. Three percent of the patients treated experienced vomiting, nausea, abdominal pain, and diarrhea. An increase of liver enzymes and serum glucose could be observed, mostly in patients with previous liver disease or diabetes. Pharmacokinetic drug interactions are not known; possible pharmacodynamic interactions result from the pharmacological properties of the drugs. Intravenous therapy with enoximone causes a few serious side effects that can only be controlled by careful observation of the patients treated.
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PMID:[Tolerance of enoximone in patients with heart failure]. 183 4

Ever since xanthines were introduced into asthma therapy, more than 125 years ago, their therapeutic effectiveness has been explained as being due to extrapulmonary rather than, or in addition to, pulmonary drug actions. This article emphasizes that theophylline may have several potentially important effects in the lung. Theophylline relaxes the smooth muscle of large and small airways in humans and animals. Its relaxant effect is relatively independent of the type of mediator that constricts the airway. This suggests that functional antagonism, rather than specific pharmacologic mediator antagonism (e.g., adenosine antagonism), explains its bronchodilator effect. The consistent relaxant property of such xanthines as theophylline distinguishes these compounds from many other classes of established and experimental bronchodilator agents. Furthermore, many anti-inflammatory effects have been noted, suggesting that xanthines might be considered as prophylactic agents. Theophylline may not only attenuate the activity of stationary and blood-borne pulmonary inflammatory cells; it may also exert an anti-inflammatory action by directly affecting targets such as the epithelial lining (increasing the mucociliary transport rate) and the microvasculature (possibly reducing plasma exudation). The experimental anti-inflammatory pharmacology of theophylline is compatible with the observation that theophylline inhibits late pulmonary reactions in patients with atopic asthma and in sensitized animals challenged with allergen. The mechanism(s) of action behind the pulmonary actions of theophylline has not been assessed (neither phosphodiesterase inhibition nor adenosine antagonism may be involved). Central nervous system, gastroesophageal, renal, and metabolic actions of theophylline are briefly reviewed. Headache, nausea, and the relaxation of the lower esophageal sphincter can perhaps be classified as nonexcitatory and inhibitory effects in which the mechanism(s) of action is unknown.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Overview of effects of theophylline. 287 16

The effects of 9 beta-methyl carbacyclin, a chemically stable analogue of epoprostenol (prostacyclin, PGI2) were studied, in comparison with epoprostenol, both in vitro and in vivo in man. In vitro 9 beta-methyl carbacyclin and epoprostenol inhibited platelet aggregation induced by ADP, collagen, the endoperoxide analogue U46619 and arachidonic acid. The potency of 9 beta-methyl carbacyclin relative to epoprostenol was comparable in ADP and collagen-aggregated platelet rich plasma (PRP), 9 beta-methyl carbacyclin being 0.01 times as active as epoprostenol. The anti-aggregatory potencies of the two compounds were comparable in PRP and whole blood. The phosphodiesterase inhibitor isobutyl methyl xanthine enhanced the anti-aggregatory activity of both compounds in vitro. 9 beta-methyl carbacyclin and epoprostenol elevated platelet cyclic AMP, 9 beta-methyl carbacyclin being 0.04 times as active as epoprostenol. In a placebo controlled trial both drugs produces significant headache and facial flushing when compared with placebo. Nasal stuffiness, abdominal discomfort and nausea were reported on all three treatments. Both drugs caused significant and comparable increase in heart rate and decrease in pre-ejection (PEP) and PEP/left ventricular ejection time (LVET) ratio compared with placebo. Systolic and diastolic blood pressure, LVET and QS2 index were unchanged. Platelet aggregation responses to ADP were significantly inhibited by all three doses of both drugs compared with placebo. Bleeding time was significantly longer during epoprostenol infusion than either placebo or 9 beta-methyl carbacyclin infusion. Neither drug had significant effect, compared with placebo, on kaolin activated clotting time in PPP, PRP or in PRP in the presence of heparin, prothrombin time, partial thromboplastin time, thrombin clotting time, fibrinogen, fibrinogen degradation products or euglobulin clot lysis time. The pharmacodynamic effects and duration of action of 9 beta-methyl carbacyclin and of epoprostenol are similar; 9 beta-methyl carbacyclin is approximately 100 times less potent than epoprostenol in man.
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PMID:A chemically stable analogue, 9 beta-methyl carbacyclin, with similar effects to epoprostenol (prostacyclin, PGI2) in man. 608 4

Among various oral antiplatelets, a combination of a novel prostacyclin analogue beraprost (BPT) and a potent phosphodiesterase inhibitor cilostazol (CLZ) may result in untoward clinical effects due to possible synergistic elevation of intracellular cAMP (cyclic adenosine 3',5'-monophosphate). Thereby, a clinical study of the combined administration of the two agents was attempted. Twelve healthy volunteers were assigned to take BPT/CLZ in the following schedule; BPT: 40 micrograms at day 1 and 120 micrograms t.i.d. from day 7 to 14, CLZ: 200 mg t.i.d. from day 3 to 14. At various time intervals, physical examination and blood collection for ex vivo platelet aggregation and determination of intraplatelet cAMP were performed. Throughout the observation period, no significant alteration in vital signs was observed. Seven out of 12 subjects experienced headache of a short duration accompanying facial flush in one and nausea in one, especially after ingestion of CLZ. All of these symptoms, probably caused by the vasodilating effect of the two agents, were of mild degree and no special treatment was required. Intraplatelet cAMP content was gradually but significantly increased to 9.84 +/- 4.59 pmol per 10(9) platelets at day 14 in comparison with the initial value (6.87 +/- 2.25 pmol). The platelet aggregability was significantly suppressed at various time intervals but no additive or synergistic inhibitory effect by the combined administration was noted. In conclusion, the combined administration of BPT/CLZ is safe at doses used in the study, though the beneficial clinical effect of the combined administration has yet to be elucidated.
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PMID:Clinical evaluation on combined administration of oral prostacyclin analogue beraprost and phosphodiesterase inhibitor cilostazol. 759 55

Cilostazol is a selective orally active phosphodiesterase (PDE) III inhibitor. This study was conducted to evaluate whether inhibition of PDE subtype III can reduce bronchial responsiveness. We examined the effects of cilostazol on bronchial responsiveness to methacholine in eight normal subjects by a single-blinded, crossover study. Each subject received 200 mg of cilostazol or placebo in random order. The subjects underwent methacholine challenge test 3 h after administration of each drug on two occasions separated by 5 d or more. The geometric mean value of provocative concentration of methacholine causing a 20% fall in FEV1 (PC20-FEV1) and the mean value (+/- SEM) of maximum expiratory flow on partial flow-volume curve at isovolume of 40% FVC above residual volume (PEF40) after administration of cilostazol were 25.3 (geometric standard error of the mean [GSEM], 1.35) mg/ml and 3.78 +/- 0.31 L/s, which were significantly (p < 0.02 and p < 0.05) greater than those after the placebo administration (6.81 [GSEM, 1.42] mg/ml and 2.71 +/- 0.39 L/s). All subjects complained of mild to severe headache when cilostazol was given. These findings suggest that PDE III inhibitors such as cilostazol have bronchodilator and bronchoprotective effects in humans. Further studies regarding smaller oral dosing of or aerosol administration of cilostazol or the other PDE III inhibitors are needed to determine clinical usefulness.
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PMID:Bronchodilator and bronchoprotective effects of cilostazol in humans in vivo. 781 59

Whether phosphodiesterase inhibitors increase the heart rate in patients with bradyarrhythmias is not known. We attempted to determine whether the oral phosphodiesterase inhibitor cilostazol exhibits beneficial chronotropic effects in patients with symptomatic bradyarrhythmias. Twenty patients comprising eight with bradycardic atrial fibrillation, eight with sick sinus syndrome, and four with Wenckebach-type atrioventricular block, whose 24-h total heart-beat count was < or =70,000 beats and whose maximal RR interval was > or =2.5 s, were enrolled. Holter recordings (24-h) were made before and 2 weeks after oral daily administration of 200 mg of cilostazol. Cilostazol increased the 24-h total heart-beat count from 77,429 +/- 11,168 to 107,981 +/- 13,536 (95% confidence interval, 24,605-36,497; p < 0.0001), the minimal heart rate from 33 +/- 9 47 +/- 13 beats/min (95% confidence interval, 9-19 beats/min; p < 0.0001), and the maximal RR interval from 3,149 +/- 1,018 to 2,087 +/- 601 ms (95% confidence interval, -1,517 to -608 ms; p = 0.0001). Only two patients had headaches as adverse effects. In conclusion, cilostazol had a beneficial positive chronotropic effect in patients with bradyarrhythmias, especially with bradycardic atrial fibrillation and sick sinus syndrome.
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PMID:Chronotropic effects of cilostazol, a new antithrombotic agent, in patients with bradyarrhythmias. 955 1

Sildenafil citrate has been shown to be effective in a wide range of patients with erectile dysfunction and has been approved in the United States for this indication. The overall clinical safety of oral sildenafil, a potent inhibitor of phosphodiesterase type 5, in the treatment of erectile dysfunction was evaluated in more than 3700 patients (with a total of 1631 years of exposure worldwide). Safety and tolerability data were analysed from a series of double-blind, placebo-controlled studies and from 10 open-label extension studies of sildenafil in the treatment of erectile dysfunction. A total of 4274 patients (2722 sildenafil, 1552 placebo; age range 19-87 y) received double-blind treatment over a period of up to six months' duration, and 2199 received long-term, open-label sildenafil for up to 1 y. The most commonly reported adverse events (all causes) were headache (16% sildenafil, 4% placebo), flushing (10% sildenafil, 1% placebo), and dyspepsia (7% sildenafil, 2% placebo) and they were predominantly transient and mild or moderate in nature. These adverse events reflect the pharmacology of sildenafil as a phosphodiesterase type 5 inhibitor. No cases of priapism were reported. The rate of discontinuation due to adverse events (all causes) was comparable for patients treated with sildenafil (2.5%) and placebo (2.3%). In open-label extension studies, 90% of patients completed long-term sildenafil treatment, with only 2% withdrawing due to adverse events. Sildenafil is a well-tolerated oral treatment for erectile dysfunction.
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PMID:Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. 964 40

Erectile dysfunction may have psychological as well as a variety of organic causes. This necessitates in each case a careful medical evaluation. Various commonly used drugs, as well as alcohol and narcotics, may interfere with erection and should, whenever possible, be discontinued before starting treatment. Organic diseases should be identified and, if feasible, specially treated. In the remaining majority of afflicted men, psychological treatment and partner counseling may produce an improvement, but ultimately what is necessary remains an effective and safe medication. The drug, Sildenafil, introduces a new therapeutic principle. During sexual nerve stimulation, nitric oxide (NO) is released from nerves into the cells of the penile erectile bodies. NO activates in turn its "second messenger", the substance cyclic GMP, and the latter induces the vasorelaxation and blood filling of the erectile bodies. Orally administered Sildenafil competitively inhibits phosphodiesterase type 5, which physiologically inactivates cyclic GMP in the erectile bodies. Thus, Sildenafil increases in men with erectile dysfunction the NO-stimulated cyclic GMP concentration and, thereby, improves erection. This new therapy is attractive because 1. Sildenafil is the first pill (for oral use) with established efficacy that benefits most men with insufficient erection; 2. compared with previous therapeutic approaches (such as drug injections in the penis, instillations into the urinary duct, vacuum pumps or even prostheses), Sildenafil is at least as effective, is easy to take and appears well tolerated with no risk of a prolonged erection; 3. remarkably, this medication stimulates erection only during sexual arousal and, thus, has a rather "natural" effect, and 4. side effects (including headache, facial flushing and dyspepsia or epigastric discomfort) were mostly of mild degree and transient, so that only 4% of men interrupted treatment for this reason. Sildenafil does not need to be taken daily, but may be taken, when needed, 1 hour before a planned sexual activity. The new pill has the potential to enliven the boys "wunder horn" with fresh sound.
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PMID:[New principle in therapy of erectile dysfunction: sildenafil]. 965 82


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