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)

Sirolimus is a new immunosuppressive drug that has been evaluated in animal experiments. The current study was conducted on humans with reformulated sirolimus in doses from 3 mg/m2 to 15 mg/m2. Sixteen renal transplant recipients were included in this phase I study to determine the safety, tolerance, and preliminary pharmacokinetics of increasing single doses of orally administered sirolimus. All 16 patients had stable renal graft function after a renal transplant at least 6 months before the study. Basal immunosuppression consisted of cyclosporine and prednisolone (n = 10) or cyclosporine, azathioprine, and prednisolone (n = 6). Four groups (I, 3 mg/m2; II, 5 mg/m2; III, 10 mg/m2; IV, 15 mg/m2) of four patients were assigned randomly to receive sirolimus (n = 3) or placebo (n = 1). Among the 12 patients who received sirolimus, five had mild transient study events such as headache, nausea, mild dizziness, hypoglycemia, epistaxis, and decrease in platelets. No serious adverse events occurred and no nephrotoxic effects could be related to the single dose administration of sirolimus. The only study event that was judged as probably related to sirolimus was the single case of thrombocytopenia. The other events were evaluated as possibly related. Thrombocytopenia occurred at the highest dose level (15 mg/m2 sirolimus). In two of the patients in the placebo group, slight elevations of liver enzymes and serum amylase were seen. Blood and plasma sirolimus concentrations were analyzed by an electrospray-high performance liquid/mass spectrophotometric (ESP-HPLC/MS) method Sirolimus showed an extensive red blood cell distribution with a mean blood/ plasma ratio of 49.1. The elimination half-life ranged from 43.8 to 86.5 hours (mean 56.9 hours). The Cmax and the area under the concentration versus time curves (AUC) correlated reasonably with doses from 3 to 15 mg/m2. The oral dose clearance ranged from 42 to 339 ml/h.kg. No clinically significant differences were seen in the trough concentrations of cyclosporine or the AUCs before and after the administration of sirolimus. Administration of single oral doses of sirolimus from 3 to 15 mg/m2 was safe and well tolerated in stable renal transplant recipients. Thrombocytopenia may be the dose-limiting toxicity. Additional phase II and phase III clinical trials will define the immunosuppressive efficacy of sirolimus.
Ther Drug Monit 1997 Aug
PMID:Kinetics and dynamics of single oral doses of sirolimus in sixteen renal transplant recipients. 926 80

The effect of extended-release isosorbide mononitrate (ER-ISMN) on exercise tolerance 1 hour after dosing was compared with that of placebo in a multicenter, randomized, double-blind study of 151 patients with stable effort-induced angina. During a 9- to 24-day placebo run-in, patients underwent Bruce protocol baseline exercise tolerance tests, after which they received ER-ISMN or placebo for 5 days. ER-ISMN patients took 60 mg each morning for the first 4 days and 120 mg on the morning of the fifth day. One hour after dosing, ER-ISMN patients had a significantly greater increase in total exercise time (days 1 to 4: 5 +/- 53 seconds; day 5: 53 +/- 58 seconds) than the placebo-treated patients (days 1 to 4: 14 +/- 37 seconds; day 5: 21 +/- 48) (p <0.001). The times to development of angina and 1-mm ST-segment depression were significantly longer in the ER-ISMN group than in the placebo group. The difference between the groups in mean time to onset of angina was 34 seconds after the 60-mg dose (p = 0.004) and 49 seconds after the 120-mg dose (p <0.001). The mean time to development of a 1-mm ST-segment depression was 51 and 61 seconds longer after the 60-mg and 120-mg ER-ISMN doses, respectively, than after placebo (p <0.001). Treatment-related adverse events were reported in 37% (28 of 75) and 7% (5 of 76) of patients in the ER-ISMN and placebo groups, respectively. As expected, headache was more frequent in the ER-ISMN group than in the placebo group (28% and 1%, respectively). The effects of ER-ISMN (60 mg and 120 mg) are clinically evident 1 hour after dosing, resulting in better exercise tolerance in patients with angina pectoris.
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PMID:Effect of extended-release isosorbide mononitrate one hour after dosing in patients with stable angina pectoris. IMDUR Study Group. 941 33

In a randomised, double-blind, four-way crossover study, 24 healthy volunteers received 240 mg/d pentaerithritol tetranitrate (PETN, CAS 78-11-5), 150 mg/d PETN, 60 mg/d isosorbide mononitrate slow release (ISMN, CAS 16051-77-7) or placebo in each study period for two days. Headache and disability to work were self-rated six times per day; individual measurements were combined to total scores. ISMN caused headaches more frequently (in approx. 90% of volunteers) and more severe (average total score 15.2) and a greater disability (average total score 6.0) than the high or low PETN-dosage (both in approx. 50%, headache score 4.9 or 6.4, disability score 1.1 or 2.1, resp.) and placebo (in approx. 10%, headache 0.8, disability 0), all these differences were statistically significant (p < 0.01, Wilcoxon). The high PETN-dosage showed a non-significant trend to produce fewer systemic side effects than the low PETN-dosage (not vice versa). With ISMN six volunteers prematurely terminated the study period and one volunteer who was replaced withdrew from the entire study due to side effects; all volunteers completed the study periods with the other medications.
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PMID:[Actions of pentaerithritol tetranitrate, isosorbide mononitrate and placebo on headache and ability to work of healthy subjects]. 968 21

Recent studies suggest that nitric oxide (NO) plays an important role in nitrate-induced headache and in spontaneous migraine attacks. Organic nitrates act as prodrugs for NO and headache is a predominant adverse effect of nitrates but often disappears during continuous treatment. Insight into tolerance to headache could lead to insight into vascular headache mechanisms in general. The specific aim of the present study was therefore to characterize the headache and accompanying symptoms during continuous nitrate administration until a state of tolerance to headache had developed. 5-isosorbide-mononitrate (5-ISMN) 30 mg three times daily was administered orally for 7 days in 11 healthy subjects in a double-blind, randomized placebo controlled cross-over design. Wash-out between periods was 14 days or more. Haemodynamic data from the present study were compared to the observed changes of headache over time. Headache during 5-ISMN was longer lasting and more severe compared to placebo (P<0.004). In 10 subjects the headache fulfilled the pain sub-criteria for migraine and in five subjects all diagnostic criteria for migraine without aura were fulfilled. Conversely, 20 min of intravenous infusion of glyceryl trinitrate caused a milder headache and no migraine. The present results therefore suggest that NO may elicit a migraine attack in many healthy subjects if a high enough dose is given for several hours. A close temporal association between the disappearance of headache and the attenuation of the 5-ISMN induced dilatation of the superficial temporal artery was observed. In contrast, tolerance in the middle cerebral artery already appeared after 24 h, which was earlier than the development of tolerance to headache. If vasodilatation is the cause of headache the results point to extracerebral arteries. However, cytotoxic and pain modulating central nervous system effects of NO, the time courses of which are unknown, may also play a role, involving both intra- and extracranial arteries.
Cephalalgia 2000 Jun
PMID:Headache characteristics during the development of tolerance to nitrates: pathophysiological implications. 1103 39

1. The differential responsiveness of various sections and regions in the vascular system to the vasodilator activity of organic nitrates is important for the beneficial antiischaemic effects of these drugs. In this study we examined the vasodilator activity of organic nitrates in cerebral arteries, where vasodilation causes substantial nitrate induced headache. 2. Isolated porcine basilar and coronary arteries were subjected to increasing concentrations of glyceryl trinitrate (GTN), isosorbide-5-nitrate (ISMN) and pentaerythritol tetranitrate (PETN). S-nitroso-N-acetyl-D,L-penicillamine (SNAP) and endothelium-dependent vasodilation was investigated for comparison purpose. 3. The vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.33+/-0.1, n=8), ISMN (1.61+/-0.07, n=7) and PETN (>10 microM, n=7) in basilar arteries was more than 100 fold lower than that of GTN (6.52+/-0.06, n=12), ISMN (3.66+/-0.08, n=10) and PETN (6.3+/-0.13, n=8) observed in coronary arteries. 4. In striking contrast, the vasodilator potency of SNAP (halfmaximal effective concentration in -logM) was almost similar in basilar (7.76+/-0.05, n=7) and coronary arteries (7.59+/-0.05, n=9). Likewise, no difference in endothelium dependent relaxation was observed. 5. Denudation of the endothelium resulted in a small increase of the vasodilator potency (halfmaximal effective concentration in -logM) of GTN (4.84+/-0.09, n=7, P<0.03) in basilar arteries and similar results were obtained in the presence of the NO-synthase inhibitor N(omega)-nitro-L-arginine (4.59+/-0.05, n=9, P<0.03). 6. These results suggest that cerebral conductance blood vessels such as porcine basilar arteries seems to have a reduced expression and/or activity of certain cellular enzymatic electron transport systems such as cytochrome P450 enzymes, which are necessary to bioconvert organic nitrates to NO.
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PMID:Impaired vasodilator response to organic nitrates in isolated basilar arteries. 1115 58

A review was made of all known published data on the use of isosorbide-5-mononitrate (5-ISMN) in chronic stable angina pectoris, and efficacy in terms of exercise testing (bicycle or treadmill) was assessed. Adequate documentation for effectiveness for 12 h with steady-state treatment (2 weeks) of 5-ISMN in immediate-release tablets is available only with a dosage of 20 mg twice daily, taken 7 h apart. For other dosage regimens, efficacy has been documented for 2 or at most 4 h duration after dose intake. Immediate-release tablets of 40 mg are effective only for 2 h in steady-state treatment. These data suggest that tolerance develops to some immediate-release tablet regimens. A satisfactory explanation for this is still lacking. The possibility that a rapid plasma level rise is conducive to tolerance development needs to be tested. Extended-release tablets in strengths from 30 to 100 mg are effective for 12 h after the first dose. In steady-state treatment of 3--6 weeks' duration, 12-h efficacy has been shown only for one brand of extended-release 5-ISMN (Imdur((R))) in doses ranging from 60 to 240 mg taken once daily in the morning. Currently, the best explanation to the maintained efficacy with long-term extended-release 5-ISMN is that the plasma level profile allows for a sufficiently low organic nitrate level for a sufficiently long uninterrupted fraction of the dosage interval, occurring during the night when tablet intake is once daily in the morning. Twice daily dosage every 12 h of extended-release 5-ISMN tablets causes tolerance development. Tolerability is similar for both types of tablets, and overall it is excellent. Headache is a common symptom at initiation of treatment but wanes quickly. No rebound effect in the nitrate-low period has been noted with either regimen. Few well-controlled studies have addressed quality of life efficacy, that is, the influence of symptoms and signs of daily life. Many trials of those reviewed were of suboptimal design, and conclusions were often overstated.
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PMID:Current Status of Isosorbide-5-Mononitrate Therapy in Chronic Stable Angina Pectoris. 1183 72

BACKGROUND: Nitrates, although important for the management of angina pectoris, cause significant headache in many patients. METHODS: In a randomized, double-blind crossover study, 89 patients with stable angina pectoris were used to compare two different dosage strategies of isosorbide-5-mononitrate (5-ISMN). Patients were randomized to either 60 mg 5-ISMN once daily (o.d.) for 2 weeks or 30 mg 5-ISMN o.d. for 1 week followed by 60 mg 5-ISMN o.d. for 1 week. A 2-week placebo wash-out ensued, after which the alternative treatment was given. We assessed the occurrence of angina pectoris and headache by diary cards while taking into account the numbers of isosorbide dinitrate sublingual puffs and paracetamole tables required. Data were assessed for carryover and time effects. RESULTS: The two dosage regimens were equally efficient for the relief of angina pectoris without development of tolerance. Thirty percent of the patients never experienced headache from the given dosages. The remainder showed a highly significant time-effect: The total numbers of headache attacks in the 1st period of active treatment were 2,380 vs 1,400 attacks is the 2nd period (p < 0.003), yet significantly fewer patients had headaches on low dosages than high ones (45 vs 57, p < 0.02). CONCLUSIONS: Starting on a low dosage was associated with reduced frequency and severity of headache and did not notably influence the beneficial effect of nitrates on angina pectoris. One in three patients never experienced headache from the given dosages. The overall number of headache attacks in the 1st period of active treatment was significantly higher than that of the 2nd period, irrespective of the dosages given.
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PMID:Nitrate-Induced Headache in Patients with Stable Angina Pectoris: Beneficial Effect of Starting on a Low Dosage. 1186 41

Acute liver failure and haemolytic syndrome appeared quite suddenly as the first manifestations of Wilson disease (WD) in five of our patients previously regarded as healthy persons (although an interview showed that 2-4 weeks prior to the illness the patients complained of several non-specific symptoms, such as abdominal pain, headaches, fever, weakness or behavioural changes). All the patients were young women (17-23 years), none of them had any history of liver disease. They were admitted with icterus, nausea, vomiting and symptoms of increasing haemolysis. The diagnosis of WD was given as disturbed copper metabolism. After a short period of observation ascites and anasarca occurred, haemorrhagic diathesis and other symptoms of liver failure increased. Levels of clotting factors decreased rapidly. Despite treatment with D-penicillamine, plasmapheresis, and symptomatic drugs, three of the women died in irreversible liver coma, due to the unavailability of liver transplantation. The fourth woman was carried to the Transplantation Centre, due to aggravation of the symptoms of liver failure, where liver transplantation was performed. Histopathologically micronodular cirrhosis was shown in all these cases. The fifth patient survived having undergone the above treatment without liver transplantation. The main differences between the patient who survived and those who died or underwent transplantation were relatively higher activity of alkaline phosphatase (26 U/l vs. 10-20 U/l), slightly higher levels of clotting factors and prothrombin time, which never fall below 68% of the control (versus 14-44% in other patients). Only in the surviving patient was the Kayser-Fleischer ring present. In four of our patients we found family members who were carriers of WD.
Med Sci Monit 2001 May
PMID:Acute haemolytic syndrome and liver failure as the first manifestations of Wilson's disease. 1221 29

Botulinum toxin, the most potent known biological neurotoxin, holds great promise in the therapy of many diseases. It has been used effectively to treat strabismus, dystonias and other movement disorders, and spasticity. However, a number of potential new therapeutic indications have emerged and attracted a considerable amount of interest from the scientific community. These emerging indications included treatment for conditions associated with pain (e.g. headaches, myofascial pain, chronic low back pain), hypersecretion of glands (e.g. hyperhidrosis, sialorrhea, intrinsic rhinitis), and excessive or dyssynergic muscle contraction, and for cosmesis (e.g. myokymia, bruxism, anal fissure). There is a need for more controlled clinical trials, dose-ranging studies to determine optimal treatment, validated clinical scales and studies developed to assess the value of electromyographic guidance and skill of investigators on the outcome of treatment for some of these diseases. The long-term cost effectiveness of treatment and immunoresistance from repeated injections are also important clinical issues to address.
Med Sci Monit 2003 Feb
PMID:Emerging therapeutic applications of botulinum toxin. 1260 5

A new controlled-release isosorbide-5-mononitrate (CR-ISMN) preparation has been developed to meet the requirement for a low nitrate concentration interval in order to avoid nitrate tolerance. We conducted a randomized, double-blind, placebo-controlled study in 31 Japanese patients with stable effort angina pectoris to investigate the efficacy and safety of CR-ISMN. Patients were randomly assigned to either CR-ISMN (40 mg once daily) or placebo groups for 2 weeks after two consecutive symptom-limited treadmill exercise tests using the Bruce protocol to ascertain the reproducibility of exercise tolerance during the placebo run-in period. Exercise tests were repeated at 5, 12, and 24 hours after administration on the final day. No significant difference in exercise time to moderate angina was identified between the CR-ISMN and placebo groups at 5, 12, or 24 hours after administration. However, the changes in exercise were prolonged at 5 hours but not shortened at 24 hours in the CR-ISMN group. The results of subgroup analysis suggested that the concomitant use of insulin might lead to confounding results. Although headache was the most frequent adverse effect in the CR-ISMN group, all symptoms were mild and at self-limiting levels. The plasma concentrations of CR-ISMN maintained therapeutic levels at 5 and 12 hours, and gradually decreased to less than the minimum therapeutic concentration (100 ng/mL) at 24 hours after administration. This study demonstrates that CR-ISMN improves exercise tolerance during the daytime and is well-tolerated in Japanese patients with stable effort angina pectoris without increasing the number of serious adverse effects.
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PMID:Efficacy and safety of controlled-release isosorbide-5-mononitrate in Japanese patients with stable effort angina pectoris. 1710 40


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