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)

Parenteral compounds present special drug delivery challenges. This open-label study evaluated a portable infusion pump as a means to deliver intravenous ciprostene, a stable prostacyclin analog. Ten patients with peripheral vascular disease and claudication received ciprostene (titrated to 120 ng/kg/min) infused over 8 hours 1 day per week for 4 consecutive weeks. Patients successfully maintained the pump strapped to the waist. The mean +/- standard deviation delivery error, with volumes of 6 to 10 mL over 8 hours, was -0.895 +/- 3.177%. Accordingly, the pump performed well with a potent drug under these clinical conditions. Headache, flushing, and infusion site irritation during infusion were the most frequent side effects. Blood pressure remained unchanged during infusion; however, heart rate increased significantly (P < .05, maximum increase was 13.9 +/- 2.1 beats per minute [mean +/- standard error of the mean]. Mean (+/- standard error of the mean) relative claudication times on treadmill remained unchanged; however, absolute claudication times increased (P < .05) from 6.6 +/- 1.8 to 10.0 +/- 2.2 minutes. Ciprostene inhibited adenosine diphosphate-induced platelet aggregation by 56.0 +/- 12.7% (mean +/- standard error of the mean). Mean template bleeding times and plasma concentrations of platelet-specific proteins (beta-thromboglobulin, platelet factor 4) did not change.
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PMID:Continuous intravenous dosing with ciprostene using a portable pump in ambulatory patients. 844 Jul 64

Although patients with COPD often have elevated pulmonary artery pressures (PAP) and pulmonary vascular resistance (PVR), it is uncertain whether treatment of this pulmonary hypertension is beneficial. We evaluated the extent of pulmonary hypertension in 16 patients with severe COPD complicated by acute respiratory failure and pulmonary hypertension. We assessed the hypothesis that the vasodilator prostacyclin (PGI2) would reduce PVR and improve systemic O2 transport. Patients with a COPD exacerbation requiring mechanical ventilation, and mean PAP greater than 30 mm Hg, were randomized to receive PGI2 or placebo, in addition to conventional therapy. Randomization to PGI2 or placebo therapy occurred 1 to 12 h after intubation, while the patient was mechanically ventilated. An optimal PGI2 dose (2 to 12 ng/kg/min, IV) was established in an initial dose-ranging study and then this dose was infused continuously for 48 h. PGI2 initially reduced PVR, but this effect dissipated within 24 h, indicating the development of tachyphylaxis. Tolerance to the adverse effects of PGI2 (tachycardia, hypotension, flushing, and headache) also developed over time. PGI2 treatment was associated with a significant fall in PaO2 but no increase in systemic oxygen transport. PGI2 proved to be a nonselective vasodilator that caused mild hypoxemia. Despite acute respiratory failure, pulmonary hypertension is mild in patients with severe COPD receiving mechanical ventilation and IV PGI2 is not beneficial in such patients.
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PMID:A placebo-controlled trial of prostacyclin in acute respiratory failure in COPD. 861 59

Prostacyclin (PGI2) is a bioactive substance produced by vascular endothelial cells, which exerts powerful vasodilative and anti-platelet actions. Patients with pulmonary hypertension have an imbalance between vasodilative PGI2 and vasoconstrictive thromboxane B2 (TXB2). Treatment with vasodilative agents is essential for such patients. Continuous intravenous infusion of PGI2 is an effective treatment of primary pulmonary hypertension in terms of exercise capacity and survival rate. We tested a new stable PGI2 analogue, beraprost sodium (Procyclin, Dornar) suitable for oral administration, in patients with primary and secondary pulmonary hypertension. A short-term study of cardiac catheterization in four patients with primary pulmonary hypertension showed a 15 +/- 12% reduction in mean pulmonary artery pressure in three of the four patients, and a 24 +/- 22% decrease in pulmonary vascular resistance in all four patients. Cardiac index increased by 27 +/- 14% in three of the four patients. Among three patients with secondary pulmonary hypertension, there was a 7% reduction in pulmonary artery pressure in one patient, and a 24 +/- 14% decrease in pulmonary vascular resistance in all three patients. In a long-term study (23 +/- 11 months), NYHA functional class improved from 3.0 +/- 0.7 to 2.4 +/- 0.5 in two of the five patients with primary pulmonary hypertension. Although the radiographic cardiothoracic ratio was not significantly improved, cardiac index increased by 78 +/- 60% in four of the five patients. Only two patients, one with primary and one with secondary pulmonary hypertension, died during the long-term follow-up period. Plasma TXB2/6-keto prostaglandin F1 alpha ratio decreased from 8.1 +/- 8.7 to 1.5 +/- 0.4. The optimal dose remains uncertain, but the initial dosage of 40-60 micrograms/day given in three to four doses for adult patients is considered to be acceptable. Side effects such as flushing face, headache, vomiting, and nausea were mild and resolved when the dose was reduced. Oral PGI2, beraprost, appears to be an effective and possibly adequate substitute for intravenous vasodilators in pulmonary hypertension for both short- and long-term management.
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PMID:[Short- and long-term effects of the new oral prostacyclin analogue, beraprost sodium, in patients with severe pulmonary hypertension]. 864 6

Twelve patients with systemic sclerosis were treated with intravenous infusions of the prostacyclin-stable analogue iloprost 0.5-2.0 ng/kg/min for 6 h from 8 to 13 days. Imminent gangrene was stopped in 2 patients and followed by healing. In 4 of 6 patients iloprost led to complete healing of ischaemic ulcers and in the remaining 2 patients to partial healing. One patient with severe Raynaud's phenomenon discontinued the study after 3 days due to severe headache. The 2 remaining patients with Raynaud's phenomenon as an indication improved, while no improvement was recorded in a patient with vasculitis of the lower leg. Side-effects such as headache, nausea and flushing were the reason that only 5 patients reached the maximum infusion rate. No statistical differences were recorded in digital bloodflow before and after the study or in plasma endothelin in the 9 patients investigated. Three of the 6 patients with healing ulcers, however, showed a pronounced decrease in plasma endothelin. Iloprost appears useful as a treatment of imminent gangrene and ischaemic ulcers in systemic sclerosis. This reparatory capacity could also be of a more general importance in therapy of this disease.
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PMID:Treatment of ischaemic digital ulcers and prevention of gangrene with intravenous iloprost in systemic sclerosis. 880 Mar 8

In an open study the clinical efficacy and tolerability of the stable prostacyclin (PGI2) analogue iloprost in the treatment of 900 patients with advanced peripheral arterial occlusive disease (Fontaine stage III and IV), enrolled by 169 centres, were investigated. Of these patients, treated with infusions over 6 h daily up to 42 days, 853 could be evaluated: four were excluded because of wrong diagnosis. The responder rates, defined as pain relief, no or reduced use of analgesics (stage III and IV), improvement of trophic lesions, i.e. complete or > or = 50% healing of ulcers, demarcation of necroses (stage IV), and global improvement, were 75.0% and 66.0% in stage III and 46.3% and 41.8% in stage IV patients in the valid case and intention-to-treat group, respectively. A complete healing of ulcers was observed in 12.3% of those patients (n = 375) presenting with ulcerations at the beginning of treatment. Diabetic and non-diabetic patients were comparable with regard to efficacy of iloprost. 71.4% and 66.2% (stage III and IV) of initial responders at 6 months follow-up were still free from rest pain and showing complete or partial healing of trophic lesions. 7.9% of stage III and 16.9% of stage IV patients underwent major amputation during the whole study period with a reduced amputation rate in responders compared to non-responders in stage IV. 7.9% stage III and 13.2% stage IV patients died. 83.2% and 86.0% of stage III and IV patients presented with adverse events at any time of treatment, mainly headache, nausea and flush as well as gastrointestinal symptoms, occurring mostly during the titration phase. The investigators' judgement, however, revealed a very good and good tolerability in 74.8% of stage III and in 73.7% of stage IV patients.
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PMID:Treatment of patients with peripheral arterial occlusive disease Fontaine stage III and IV with intravenous iloprost: an open study in 900 patients. 883 61

The antiaggregation and hemodynamic effects of the new prostacyclin analogue beraprost sodium were investigated in a randomized, placebo-controlled, double-blind clinical trial of Latin-square design. Twelve healthy Caucasian males randomly received 8-day oral treatments of 20, 40, and 60 micrograms of beraprost sodium and a placebo. One-week washout periods followed each treatment. Pharmacokinetic and pharmacodynamic measurements were performed on days 1 and 8 for each period of treatment. All three doses of beraprost sodium significantly inhibited platelet aggregation on day 8 (compared with placebo) during the 1st h after drug intake. Incubation of the 60-micrograms beraprost sodium samples with ADP (2, 5, and 10 microM) and collagen (1.25 micrograms/mL) decreased platelet aggregation by 10, 19, 16, and 6 +/- 4% (mean +/- SE), respectively, compared with placebo. No significant hemodynamic effects on blood pressure, heart rate, and digital pulse were observed. The 60-micrograms dose of beraprost sodium did significantly decrease the IRZ index (which may reflect the left ventricular pre-ejection period) on days 1 and 8. Some subjects experienced headache and facial flushing, effects that were dose dependent and reversible. Beraprost sodium at 20- to 60-micrograms doses exerts platelet antiaggregation (day 8 of therapy) and slight hemodynamic (days 1 and 8 of treatment) effects in Caucasian males. Beraprost sodium hemodynamic effects and potential benefits in patients with cardiovascular disease should be explored further.
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PMID:Platelet-aggregation inhibition and hemodynamic effects of beraprost sodium, a new oral prostacyclin derivative: a study in healthy male subjects. 896 Mar 77

We review the role of several biochemical and hormonal factors in menstrual migraine pathogenesis: ovarian hormones, aldosterone circadian rhythm, nocturnal urinary melatonin excretion, sympathetic autonomic system, prolactin levels and dopaminergic function, endogenous opioid tonus, platelet activity and arachidonic acid metabolites. In particular, we focus on certain aspects of platelet function and prostaglandin metabolism, taking into consideration the different behavior of platelet sensitivity to prostacyclin, intraplatelet 5HT, peripheral plasma concentrations of 6-keto-PGF1alpha and PGE2 in menstrual migraine sufferers and in control subjects during the menstrual cycle. A comprehensive view of the data suggests that a complex impairment of PG and 5HT metabolism, and of platelet function, may play a significant role in the pathogenesis of menstrual migraine. However, it is not yet clear whether these alterations are primary or secondary to neuroendocrine disorders.
Cephalalgia 1997 Dec
PMID:Pathophysiological aspects of menstrual migraine. 949 76

Morphological and functional alterations of platelets in migraineurs may be linked to the development of migraine. We examined the eicosanoid synthesis of platelets of untreated female migraineurs in a headache-free period and compared it to that of age- and blood group-matched healthy female volunteers. In the platelets of headache-free migraineurs significantly less amounts of anti-aggregatory prostaglandin D2 and prostacyclin, as well as of 12-L-hydroxy-5,8,10-heptadecatrienoic acid (a potent endogenous inducer of endothelial prostacyclin production) were produced, while the synthesis of platelet aggregatory thromboxane did not differ when compared to that of healthy women. These results suggest that the platelet eicosanoids of migraineurs in the headache-free period might promote the development of cellular, vascular and neurological events inducing headache.
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PMID:Platelet arachidonate cascade of migraineurs in the interictal phase. 1093 1

Prostacyclin is an endothelially derived vasodilator and inhibitor of platelet aggregation. Despite its therapeutic potential for peripheral arterial disease, the short half-life and chemical instability are barriers to routine therapy. Accordingly, prostacyclin analogs are being evaluated in patients with peripheral arterial disease. State-of-the-art non-invasive ultrasonography allows for serial testing of the hemodynamic effects of vasoactive drugs. The safety, efficacy and hemodynamic effects of UT-15, a novel, long-acting prostacyclin analog, were studied in patients with severe intermittent claudication. A total of eight patients with stable severe intermittent claudication, Fontaine classes IIb-III, were admitted to the hospital for intravenous infusion of UT-15. A symptom-limited, dose-escalation protocol was instituted, beginning with placebo and then with increasing dosage at 60-min intervals, followed by a 2-h period of maintenance dose at the maximum well-tolerated infusion rate. The hemodynamic response in the lower limbs was assessed with serial ultrasonography, segmental arterial pressures and pulse volumes. Blood flow in the common femoral artery increased 29% (p = 0.003) by the end of the maintenance period and remained above baseline throughout the washout period (p = 0.044). Blood velocity in the lower limb increased in most of the peripheral arteries. These increases achieved statistical significance in the common femoral artery (p = 0.025) and anterior tibial artery (p = 0.019), and approached significance in the popliteal artery (p = 0.062). In two of four patients in whom blood flow was undetectable before the infusion, arterial blood flow at the ankle level became apparent on ultrasonography during maintenance infusion. UT-15 infusion improved the pulse volume recording (p = 0.016) but the ankle/brachial index did not change significantly. Common side effects at peak dose included headache and nausea. There were no serious adverse events attributable to UT-15 treatment. In most patients, the optimal infusion rate was 10-20 ng/kg per min. In conclusion, ultrasonography is a novel approach for assessing the hemodynamic response to vasoactive agents. UT-15 is well tolerated when given for up to 2 h and increases arterial blood flow and velocity in patients with severe intermittent claudication.
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PMID:Trial of a novel prostacyclin analog, UT-15, in patients with severe intermittent claudication. 1121 35

Despite evidence emerging from the experimental model of nitroglycerin-induced headache, the endogenous increase in nitric oxide (NO) production during migraine attacks is only speculative. It has been hypothesized that there is a close relationship between activation of the L-arginine/NO pathway and production of certain vasoactive and algogenic prostaglandins during spontaneous migraine attacks, but this suggestion also needs to be confirmed. In the present study the levels of nitrites, the stable metabolites of NO, were determined with high performance liquid chromatography (HPLC) in the internal jugular venous blood of five patients affected by migraine without aura examined ictally. These samples were taken within 30 min, 1, 2, and 4 h from the onset of the attack and at the end of the ictal period. At the same time, the plasma levels of calcitonin gene-related peptide (CGRP), neurokinin A (NKA), prostaglandin E2 (PGE2) and 6 keto PGF1alpha, the stable product of PGI2, were assessed with radioimmunoassay (RIA) kits in the same samples. The levels of the intracellular messengers, cGMP and cAMP, were also measured with the RIA method. Nitrite, cGMP, CGRP and NKA levels reached their highest values at the first hour, then they tended to decrease progressively and returned, after the end of attacks, to values similar or below those detected at the time of catheter insertion (ANOVA, statistical significance: P<0.001; P<<0.002; P<0.002; P<0.003, respectively). PGE2 and 6 keto PGF1alpha, as well as cAMP levels also significantly increased at the first hour but reached a peak at the 2nd hour and remained in the same range until the 4th and 6th hours. Then their values tended to decrease after the end of attacks, becoming lower than those measured immediately after catheter positioning for internal jugular venous blood drawing (ANOVA: P<0.002, P<0.004, P<0.001, respectively). Our results support early activation of the L-arginine/NO pathway which accompanies the release of vasoactive peptides from trigeminal endings and a late rise in the synthesis of prostanoids with algogenic and vasoactive properties which may intervene in maintaining the headache phase.
Cephalalgia 2000 Dec
PMID:Nitric oxide metabolites, prostaglandins and trigeminal vasoactive peptides in internal jugular vein blood during spontaneous migraine attacks. 1130 26


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