Sumatriptan for migraine attacks in children: a randomized placebo-controlled study. Do children with migraine respond to oral sumatriptan differently from adults?

Oral sumatriptan is an effective acute treatment for migraine in adults, but its efficacy in children is still undetermined. Twenty-three children, aged 8.3 to 16.4 years, took both sumatriptan and placebo in a randomized, double-blind, placebo-controlled, crossover trial. The primary endpoint was a > or = 50% decrease in pain intensity on a 100-mm visual analogue scale at 2 hours. Other endpoints of efficacy were pain intensity difference (PID), showing pain relief at each time point; summed pain intensity differences (SPIDs), estimating overall pain relief; and preference. Two hours after sumatriptan, 7 of 23 reached the primary endpoint, and after placebo, 5 of 23 (difference 9%, 95% CI for difference, -21 to 38%; p = ns). Within 2 hours, the headache disappeared completely in 5 of 23 children after sumatriptan and in 2 of 23 children after placebo (p = ns). Median PIDs were slightly better for sumatriptan between 0.5 and 4 hours (p = ns). Median SPIDs increased almost identically up to 2 hours. Thereafter, median SPIDs for placebo remained practically constant, whereas for sumatriptan, the improvement continued. At 4 hours, the median SPID for sumatriptan was 2.4 times as high as for placebo. However, the maximum differences between median SPIDs at 4 hours (38.5, 95% CI, -75.8 to 57.5; Wilcoxon signed rank test, p = 0.4) or at any other point were not statistically significant. Of the 23 children, 13 preferred sumatriptan and 2 placebo (sign test, p = 0.004). The failure of this and previous controlled studies suggests that the response of children to sumatriptan may be different from adults.     

Subcutaneous sumatriptan in the acute treatment of migraine in patients using dihydroergotamine as prophylaxis. French Migraine Network Bordeaux-Lyon-Grenoble

The efficacy of sumatriptan, a 5-HT1 receptor agonist, in patients with migraine attacks occurring despite prophylactic treatment with oral dihydroergotamine, was assessed in a double-blind placebo-controlled study involving 76 patients. Thirty-seven patients were treated with a subcutaneous injection of 6 mg sumatriptan self-administered with an auto-injector and 39 with placebo given by the same route. Patients having inadequate relief were allowed to use a second injection of test medication 1 hour later and rescue treatment between 2 hours and 24 hours after the first dose. Headache relief was achieved within 2 hours after sumatriptan in 26 patients (70%) compared to 8 patients (21%) in the placebo group (P < 0.0001). Of these patients, 19 (51%) and 3 (8%) were, respectively, pain free at this time. A second injection of sumatriptan was used by 8 (22%) patients compared to 30 (77%) patients in the placebo group (P < 0.0001), whereas rescue medication was used respectively by 13 (35%) and 22 (58%) patients (P < 0.024). The adverse event profile of sumatriptan was not affected by the concomitant use of dihydroergotamine and side-effects were all minor and transient. Patient satisfaction was significantly higher in the sumatriptan group (75%) compared to patient satisfaction with placebo (16%). These results show that the high efficacy rate of subcutaneous sumatriptan and its safety profile remain unchanged in migraine patients receiving oral dihydroergotamine as prophylaxis.     

Differential effects of 7-OH-DPAT on amphetamine-induced stereotypy and conditioned place preference

Cost-effectiveness and cost per successful treatment has been evaluated in 186 outpatients randomised to treat moderate to severe migraine attacks either with subcutaneous sumatriptan 6 mg (n = 97) or with their current therapy (n = 89) during an open, multicentre study of 3 months. Within 2 hours, headache severity decreased to none/mild in 86% of all attacks in the sumatriptan group (STG) compared to 25% in the customary group (CTG). Migraine was alleviated earlier in the STG than in the CTG (median 3.78 vs. 13.39 hours, p < 0.0001). The direct and total cost of treatment was 133 and 2012 BF, respectively, in the CTG and 1400 and 2522 BF, respectively, in the STG. Measuring the effectiveness of earlier pain relief with sumatriptan, the incremental cost-effective ratios for direct and total cost were 132 and 53 BF per hour of relieved pain, respectively. For this price, significantly more sumatriptan patients improved their quality of life by more than 20% (61.6 vs. 20.6% patients, p < 0.001) and less sumatriptan patient consulted a medical professional (11.3 vs. 29.2% patients, p < 0.01), used less medication for adverse events (6.2 vs. 22.5%, p < 0.001) and suffered less from associated migraine symptoms. The median number of hours of diminished work-efficiency (3 vs. 7 hours, p < 0.01) or of suspension of non-professional activity (10 vs. 24 hours, p < 0.001) was also significantly lower in the STG. The total cost per successfully treated patient was lower in the STG. Sumatriptan is more effective, provides a better quality of life, reduces health care resource utilisation, and improves work productivity as compared to the CTG, thereby resulting in a favourable cost-effectiveness ratio.     

Sumatriptan. An updated review of its use in migraine

Sumatriptan is a selective agonist at serotonin 5-HT1-like receptors, including 5-HT1B/1D subtypes. It is an effective treatment for acute migraine attacks and the injectable form has also shown efficacy in the treatment of cluster headaches. In placebo-controlled clinical trials, sumatriptan, administered subcutaneously, orally, intranasally or rectally was significantly more effective than placebo in relieving migraine headache and in producing resolution or reduction of other symptoms associated with migraine, including nausea, photophobia and phonophobia. Improvements in clinical disability were also significantly greater after sumatriptan than after placebo. Headache recurred in 21 to 57% of patients who received oral or subcutaneous sumatriptan, but most patients responded to a second dose of the drug. Results of comparative trials showed that subcutaneous sumatriptan 6 mg was significantly more effective than either patients' usual antimigraine treatments or intranasal dihydroergotamine mesylate 1 mg in relieving migraine headache. Subcutaneous sumatriptan 6 mg and subcutaneous dihydroergotamine mesylate 1 mg provided similarly effective migraine relief, but the headache recurrence rate was significantly higher after sumatriptan than after this formulation of dihydroergotamine mesylate. Response rates achieved after oral sumatriptan were similar to those reported after treatment with oral naratriptan, rizatriptan or lysine acetylsalicylate plus metoclopramide. Treatment of acute migraine attacks with oral or subcutaneous sumatriptan leads to less loss of workplace productivity than other antimigraine therapies. Several pharmacoeconomic analyses showed that gains in workplace productivity in sumatriptan recipients ranged from 12.1 to 89.8 hours per patient per year. Significant improvements from baseline in overall health-related quality-of-life scores were also experienced by sumatriptan recipients. Sumatriptan is generally well tolerated. Nausea, vomiting, malaise and fatigue are the most common adverse events with oral sumatriptan. Injection site reactions occur in 10 to 40% of patients receiving the drug subcutaneously. A bitter taste at the back of the mouth occurs frequently after intranasal administration. Serious adverse events occur in about 0.14% of patients with migraine treated with sumatriptan. As the drug is associated with the rare development of cardiovascular effects, it is contraindicated in patients with a history of cardiovascular disease. CONCLUSIONS: Despite its relatively high acquisition cost, reductions in lost workplace productivity experienced by patients treated with sumatriptan may result in savings in the overall cost of migraine to society. Thus, sumatriptan is a useful first- or second-line treatment option for patients with moderate or severe migraine.     

Cardiovascular responses of conscious rats to carotid body chemoreceptor stimulation by intravenous KCN

This multicentre, double-blind, randomised, crossover study compared the efficacy, safety and tolerability of subcutaneous sumatriptan (6 mg and 12 mg) with placebo in 134 in-patients with cluster headache. Headache improvement to mild or no pain at 5, 10 and 15 min after treatment was recorded. At 10 min, headache relief was reported by 25% (placebo), 49% (6 mg) and 63% (12 mg) of patients and at 15 min the results were 35% (placebo), 75% (6 mg) and 80% (12 mg) (p < 0.001 for all comparisons with placebo). The 12 mg dose was not significantly better than the 6 mg dose and was associated with more adverse events. The 6 mg dose is therefore recommended for the acute treatment of cluster headache.     

Procarboxypeptidase in rat pancreas. Overall characterization and comparison of the activation processes

In a multicenter open longitudinal clinical trial where 479 patients suffering from migraine with or without aura were recruited, patients treated at home one to three migraine attacks with their customary treatment, and subsequently, over a 3-month period, one to three migraine attacks with 6 mg sumatriptan sc using an autoinjector. The headache response to customary treatment was 19% at 1 h and 30.5% at 2 h, and was not significantly different when only attacks treated "adequately" according to accepted treatment recommendations were considered: 16% at 1 h and 35% at 2 h. In contrast, 69% and 82% of patients treated with 6 mg sumatriptan sc had mild headache or no headache at 1 and 2 h respectively, regardless of migraine type or duration of symptoms prior to treatment. Other migraine symptoms (nausea, vomiting, photo- and phonophobia) were effectively treated with sumatriptan. Recurrence of migraine was observed in 31% of patients and was well controlled by a second injection of sumatriptan. It is concluded that 6 mg sumatriptan sc, self-administered using an autoinjector, is well tolerated and more effective than most currently used acute treatments for migraine in a population of severely affected patients consulting a neurologist.     

Naratriptan is effective and well tolerated in the acute treatment of migraine. Results of a double-blind, placebo-controlled, crossover study. The Naratriptan S2WA3003 Study Group

The efficacy and tolerability of naratriptan tablets (2.5 mg, 1 mg, and 0.25 mg) compared with placebo in the acute treatment of migraine were evaluated in a randomized, double-blind, four-period crossover study. Five hundred eighty-six assessable patients received naratriptan 2.5 mg, 595 received 1 mg, 591 received 0.25 mg, 602 received placebo. Headache relief (moderate or severe pain reduced to mild or none) 4 hours postdose was reported in 68% of patients after treatment with naratriptan 2.5 mg compared with 57% after 1 mg, 39% after 0.25 mg, and 33% after placebo (p < 0.001 naratriptan 2.5 mg and 1 mg versus placebo and 1 mg and 2.5 mg versus 0.25 mg). Headache relief was maintained 8, 12, and 24 hours postdose with no use of rescue medication or a second dose of study medication by significantly (p < 0.001) greater percentages of patients after treatment with naratriptan 2.5 mg or 1 mg compared with naratriptan 0.25 mg or placebo. Naratriptan was also more effective than placebo in reducing clinical disability and the incidences of nausea, photophobia, and phonophobia. The overall incidence of adverse events and the incidences of specific adverse events did not differ in the naratriptan groups compared with placebo. No clinically relevant changes in ECG, blood pressure, or laboratory findings were reported. These data demonstrate that naratriptan is effective and well tolerated for the acute treatment of migraine. The 2.5-mg dose was associated with superior efficacy, whereas its adverse event profile was similar to that of placebo.     

Sub-band deletion of 7q36.3 in a patient with ring chromosome 7: association with holoprosencephaly

MK-462 is a potent, selective 5HT1D receptor agonist which may be useful in treating acute migraine. We conducted a double-blind placebo-controlled inpatient study to assess the preliminary efficacy and safety of oral doses of MK-462 20 mg (n = 8) and 40 mg (n = 36) vs placebo (n = 21), administered to 65 male and post-menopausal female migraine patients aged 22-51 with moderate or severe migraine headache. Headache severity and functional disability were measured at 0.5, 1, 1.5, and 2 h post-dose. The 20 mg dose was well tolerated and 4/8 patients obtained relief in headache severity at the 2 h time point. The 40 mg dose was well tolerated and was significantly (p < 0.05) superior to placebo at the 1.5 and 2 h time points (with 27/36 or 75% obtaining relief at 2 h compared to 7/21 or 33% for placebo). Adverse events occurred in 50% of patients on 20 mg MK-462, 72% of those on 40 mg MK-462, and in 52% of placebo-treated subjects. The most common adverse events associated with MK-462 were drowsiness (20 mg 12%; 40 mg 44%; placebo 24%), dry mouth (40 mg 36%; placebo 19%), and lightheadedness/dizziness (40 mg 17%; placebo 10%). Based on these preliminary results, MK-462 appears worthy of continued study for the treatment of acute migraine.     

Sumatriptan in the acute treatment of migraine without aura: efficacy of 50-mg dose

We conducted an open study on the efficacy of 50 mg of sumatriptan as an acute treatment for migraine without aura. We recruited 200 consecutive patients, with an established history of migraine without aura, presenting at a headache center. The patients were instructed to take half a 100-mg sumatriptan tablet for their next migraine attack, and to record details of their headache in a diary. The primary outcome of the study was headache relief from one migraine attack. Attacks were moderately intense (46%), moderate to severe (7%), or severe (47%). Total or partial benefit at 2 hours from the 50-mg dose was reported by 140 of 200 patients (70%). Thirty-six patients received no benefit from half a tablet, and 24 did not take sumatriptan, preferring their habitual medication. Side effects were few, mild, and short lasting. We conclude that the 50-mg oral dose is generally effective for migraine without aura attacks of both moderate and severe intensity and recommend this dose for all such patients. If, however, sumatriptan is ineffective at that dose it can be increased to a maximum of 100 mg.     

Effect of extended-release isosorbide mononitrate one hour after dosing in patients with stable angina pectoris. IMDUR Study Group

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.     

Effects of the novel antimigraine agent, frovatriptan, on coronary and cardiac function in dogs

The effects of frovatriptan (VML 251/SB-209509) on coronary artery function were investigated in isolated coronary arteries from beagle dogs. Low concentrations of frovatriptan produced contraction with -logEC50 7.55 +/- 0.08 (n = 11). The maximal observed contraction attained was 56 +/- 7% of the control 5-hydroxytryptamine (5-HT; 10 microM) response. At high concentrations of frovatriptan (>6 microM), reversal of sumatriptan (10 microM)-induced contractions was noted. In arteries precontracted with the thromboxane mimetic, U46619, frovatriptan produced a bell-shaped concentration-response relation with a maximal response at 600 nM. Concentrations of frovatriptan >2 microM produced marked reversal of tone, with full relaxation of precontracted tissues at 200 microM. In anesthetized, open-chest mongrel dogs, intravenous (n = 5) or intracoronary (n = 5) artery administration of frovatriptan (0.0001-1 mg/kg) had no consistent effect on left ventricular end-diastolic pressure, left end-systolic pressure, cardiac contractility, aortic blood flow, systemic peripheral resistance, coronary blood flow, coronary vascular resistance, mean arterial blood pressure, or heart rate when compared with vehicle (n = 3). Intravenous sumatriptan produced minor effects on blood pressure and heart rate. Intracoronary artery administration of sumatriptan (0.0003 mg/kg) produced an increase in systemic peripheral resistance to 120.5 +/- 8.2% compared with vehicle (97.8 +/- 5.4%; p < 0.05). This dose of sumatriptan also produced a significant increase in coronary blood flow and decrease in coronary vascular resistance. Intravenous administration of sumatriptan produced a dose-related reduction in left ventricular diastolic pressure with a reduction to 58.3 +/- 8.3% and 41.7 +/- 25% of control values observed at 0.3 and 1 mg/kg, respectively; however, administration of sumatriptan by an intracoronary route had no effect. In a model of myocardial infarction, comparable doses of sumatriptan (1.0 mg/kg) or frovatriptan (0.1 mg/kg), in terms of their effect on carotid vascular resistance, had no significant effect on infarct size. Frovatriptan had no effect on coronary blood flow after reperfusion; however, sumatriptan produced a significant reduction in coronary blood flow for < or =3 h. These studies show that frovatriptan has the capability of relaxing coronary arteries in vitro, has no overall effect on cardiac function at rest with no effect on coronary hemodynamics after myocardial infarction, and has a profile superior to that of sumatriptan.     

Pre-exercise carbohydrate meal and endurance running capacity when carbohydrates are ingested during exercise

This study examined whether combining a pre-exercise carbohydrate meal with the ingestion of a carbohydrate-electrolyte solution during exercise is better in improving endurance running capacity than a carbohydrate-electrolyte solution alone. Ten men completed three treadmill runs at 70% VO2max to exhaustion. They consumed 1.) a carbohydrate meal three hours before exercise and a carbohydrate-electrolyte solution during exercise (M + C), or 2.) a liquid placebo three hours before exercise and the carbohydrate-electrolyte solution during exercise (P + C), or 3.) a placebo three hours before exercise and placebo during exercise (P + P). When the meal was consumed (M + C) serum insulin concentrations were higher at the start of exercise, and carbohydrate oxidation rates were higher during the first 60 min of exercise compared with the values found in the P + C and P + P trials (p < 0.01). Exercise time was longer in the M + C (147.4+/-9.6 min) compared with the P + C (125.3+/-7 min) (p < 0.01). Also, exercise time was longer in M + C and P + C compared with the P + P (115.1+/-7.6 min) (p < 0.01 and p < 0.05 respectively). These results indicate that the combination of a pre-exercise carbohydrate meal and a carbohydrate-electrolyte solution further improves endurance running capacity than the carbohydrate-electrolyte solution alone.     

Treatment with the oral growth hormone secretagogue MK-677 increases markers of bone formation and bone resorption in obese young males

The effect of 2 months of treatment with the oral growth hormone (GH) secretagogue MK-677 on markers of bone metabolism was determined in healthy obese male subjects. This was a randomized, double-blind, parallel, placebo-controlled study. Twenty-four healthy obese males, 19-49 years of age, with body mass index > 30 kg/m2 were treated with MK-677 (25 mg/day; n = 12) or placebo (n = 12) for 8 weeks. MK-677 increased markers of bone formation; a 23% increase in the carboxy-terminal propeptide of type I procollagen levels and a 28% increase in procollagen III peptide levels were seen with as little as 2 weeks of MK-677 treatment (p < 0.01 and p = 0.001 vs. placebo, respectively) while a 15% increase in serum levels of osteocalcin was not detected until 8 weeks of treatment (p < 0.01 vs. placebo). Markers of bone resorption were induced within 2 weeks of treatment with MK-677; serum levels of the carboxy-terminal cross-linked telopeptide of type I collagen were increased 26% at 8 weeks (p = 0.001 vs. placebo), and urine hydroxyproline/creatinine and calcium/creatinine ratios at 8 weeks were increased by 23% (p < 0.05 vs. placebo) and 46% (p < 0.05 vs placebo), respectively, MK-677 increased serum insulin-like growth factor binding protein-5 (IGFBP-5) by 43-44% after 2-8 weeks of treatment (p < 0.01 vs. placebo). Serum IGFBP-4 was increased by 25% after 2 weeks of treatment (p < 0.001 vs. placebo) but no significant change from baseline was observed after 8 weeks of treatment. Plasma interleukin-6 was not significantly changed by active treatment. In conclusion, short-term treatment of healthy obese male volunteers with the GH secretagogue MK-677 increases markers of both bone resorption and formation. Large increases in serum levels of IGF-1 and IGFBP-5 and a transient increase in serum IGFBP-4 were found. Future long-term studies are needed to investigate if prolonged treatment with MK-677 increases bone mass.     

A clinical comparison of two triphasic oral contraceptives with levonorgestrel or norethindrone: a prospective, randomized, single-blind study

Menstrual bleeding patterns were investigated in young women taking either a levonorgestrel triphasic, Triquilar, or a norethindrone triphasic, Ortho 7/7/7, two commonly prescribed low-dose oral contraceptives. The levonorgestrel triphasic contains ethinyl estradiol (EE) 30 micrograms + levonorgestrel (LNG) 50 micrograms for the first six days, EE 40 micrograms + LNG 75 micrograms for the following five days, and EE 30 micrograms + LNG 125 micrograms for the last ten days. The norethindrone triphasic contains EE 35 micrograms + norethindrone (NET) 0.5 mg for the first seven days, EE 35 micrograms + NET 0.75 mg for the following seven days and EE 35 micrograms + NET 1.0 mg for the last seven days. Three hundred women from 16 to 25 years of age were randomized to the levonorgestrel triphasic (n = 150) or the norethindrone triphasic (n = 150) groups. Assessments were made from daily diary cards and from bimonthly investigator interviews over 6 pill cycles. The results showed a higher incidence of intermenstrual bleeding (breakthrough bleeding and/or spotting) in the norethindrone triphasic group (NET group) than in the levonorgestrel triphasic group (LNG group): 44.9% of patients (66/147) randomized to the LNG group reported intermenstrual bleeding one or more times during the study compared with 61.9% (91/147) randomized to the NET group (p = 0.0036). Furthermore, in subjects who did not miss any pills, the proportion of patients with intermenstrual bleeding in each cycle was significantly greater (p < 0.02, cycles 1-4, 6; p > 0.05, cycle 5) and was experienced for more days per cycle (p < 0.05, cycle 1) and for more cycles per patient (p < 0.05, 5 cycles) in the NET group compared with the LNG group. Intermenstrual bleeding was also less frequently observed in the LNG group than in the NET group in patients who missed pills (p < 0.05, cycles 3, 5 and 6). In addition, early withdrawal bleeding occurred more often in the NET group than in the LNG group (p < 0.05, cycles 1, 3 and 4). The incidence of amenorrhea was similar in both groups. These results demonstrate a significantly lower incidence of intermenstrual bleeding and therefore better cycle control with the levonorgestrel triphasic Triquilar, compared with the norethindrone triphasic Ortho 7/7/7.     

Bipolar disorder: dominant or recessive on chromosome 5?

Rizatriptan (MK-462) is a potent 5HTID receptor agonist. This multicenter, double-blind, placebo-controlled, outpatient study investigated the clinical efficacy, safety, and tolerability of rizatriptan (2.5, 5, and 10 mg) as a function of dose for acute migraine. Patients with moderate or severe migraine (n = 417) were treated with placebo (n = 67), rizatriptan 2.5 mg (n = 75), 5 mg (n = 130), or rizatriptan 10 mg (n = 145). Headache severity, functional disability, and migraine symptoms were measured immediately before dosing (0) and at 0.5, 1, 1.5, 2, 3, and 4 h post-dose. Patients were permitted to take a second dose of test drug at 2 h if their headache pain was moderate or severe (i.e., placebo initially-->rizatriptan 10 mg as optional second dose; rizatriptan 2.5 mg, 5 mg, or 10 mg initially-->placebo as optional second dose). An upward dose-response relationship was observed among placebo, rizatriptan 2.5 mg, 5 mg, and 10 mg in the primary efficacy measure of proportion of patients reporting pain relief, i.e., a change in headache severity to "no pain or mild pain" at 2 h post-dose. The relationship was evident even at the first recorded timepoint, 30 min, and was statistically significant at 1.5 h and beyond. At the primary timepoint of 2 h after the initial dose, the proportion of patients reporting pain relief was 47.6% for rizatriptan 10 mg; 45.4% for rizatriptan 5 mg; 21.3% for rizatriptan 2.5 mg; and 17.9% for placebo. Seventy percent of patients on rizatriptan 10 mg reported pain relief at 4 h. Patients who took rizatriptan 5 mg and 10 mg were significantly less functionally disabled than those who took placebo at 1.5 and 2 h post-dose. Rizatriptan 10 mg was consistently more effective than 5 mg, although the differences were not statistically significant. The most frequent clinical adverse events were dizziness, somnolence, and asthenia/fatigue. No patients were discontinued for any adverse experiences and there were no serious adverse experiences.     

A therapeutic trial of acupuncture in neurogenic bladder of spinal cord injured patients--a preliminary report

This randomized, double-blind, placebo-controlled, four-way crossover study was conducted on an in-clinic basis to assess forearm perfusion after subcutaneous (s.c.) naratriptan and placebo by reserve volume (hyperemic/baseline) and basal forearm blood flow (FBF) measured by strain gauge plethysmography. Nineteen male and female volunteer migraine subjects (International Headache Society criteria) received s.c. naratriptan 1 mg, 5 mg, 10 mg, and placebo on four separate study days outside a migraine attack. FBF was recorded at baseline, at 7-min intervals post-dose up to 1 h (basal) and once after sublingual glyceryl trinitrate administered at 1 h (hyperemic). Vital signs and electrocardiograms were recorded at baseline and 15, 30, 45, and 60 min post-dose. There were no statistically significant differences in reserve volume (hyperemic/baseline) between any dose of s.c. naratriptan and placebo. The naratriptan to placebo ratio was 102% (95% CI: 87-120%; p = 0.789) for 1 mg; 97% (95% CI: 83-114%, p = 0.737) for 5 mg; and 92% (95% CI: 79-108%; p = 0.325) for 10 mg. There were no statistically significant differences in basal FBF for any dose compared to placebo. The naratriptan to placebo ratio was 95% (95% CI: 87-104%; p = 0.263) for 1 mg; 94% (95% CI: 86-102%; p = 0.142) for 5 mg; and 94% (95% CI: 86-103%; p = 0.157) for 10 mg. The percentage of patients reporting adverse events was 53% with placebo, 53% with s.c. naratriptan 1 mg, 89% with 5 mg and 89% with 10 mg. In conclusion, these results suggest that s.c. naratriptan doses similar to and above the oral therapeutic dose equivalent (single oral dose 2.5 mg) have no significant effect on peripheral blood flow as measured by FBF. S.c. naratriptan doses 1 mg, 5 mg, and 10 mg were well tolerated.     

Frameshift mutation at codon 642 of the hMLH1 gene in human endometrial cancer

One hundred and fifty ASA 1 and 2 patients were randomly allocated to receive pethidine 25 mg (1 ml), lignocaine 10 mg (1 ml) or 0.9% saline (1 ml) on a double-blind basis, as pretreatment to reduce pain on injection of propofol. Both active treatments were significantly better than placebo at preventing pain (p < 0.01). Lignocaine was most effective in preventing pain in men (p < 0.05) whilst pethidine was more effective in women (p < 0.05).     

A controlled, prospective, 1-year trial of citalopram in the treatment of panic disorder

BACKGROUND: The objective of this study was to evaluate the efficacy and tolerability of citalopram in the long-term treatment of adult outpatients with panic disorder with or without agoraphobia. METHOD: Patients in this double-blind, parallel-group trial were assigned to 1 of 3 fixed dosage ranges of citalopram (10 or 15 mg/day, 20 or 30 mg/day, or 40 or 60 mg/day), 1 dosage range of clomipramine (60 or 90 mg/day), or placebo. After the completed 8-week acute treatment period, the eligible patients could continue the treatment for up to 1 year. Of the 475 patients who were randomly assigned for the short-term trial, 279 agreed to continue double-blind treatment at their assigned doses. The primary efficacy measure used was the Clinical Anxiety Scale panic attack item, and the response was defined as no panic attacks (score of 0 or 1). The other key measures used were the Physician's Global Improvement Scale, the Patient's Global Improvement Scale, and the Hamilton Rating Scale for Anxiety (HAM-A). RESULTS: In all drug-treated groups, except the group receiving the lowest citalopram dose, the treatment outcome was generally better than with placebo. As determined by a life table analysis of response, the probability of response during the 12 months was significantly greater with all treatment regimens than with placebo (p < .05), with citalopram 20 or 30 mg/day demonstrating the best response. Panic attacks tended to disappear in all patients remaining in the study until the end of follow-up. Analysis of the difference in the number of patients in different treatment groups remaining in the study (perhaps the best measure of long-term efficacy) also demonstrated that the patients treated with citalopram in dosage ranges of 20 or 30 mg/day and 40 or 60 mg/day had better response than placebo-treated patients (p < .0002 and p < .004, respectively). HAM-A and Global Improvement Scale scores also showed that patients treated with active drug showed greater improvement than placebo-treated patients. All treatment groups showed no new or exceptional adverse event clusters. CONCLUSION: Citalopram in the dosage range of 20 to 60 mg/day is effective, well tolerated, and safe in the long-term treatment of patients who have panic disorder.     

Comparison of once-daily doses of omeprazole (40 and 20 mg) and placebo in the treatment of benign gastric ulcer: a multicenter, randomized, double-blind study

OBJECTIVE: The purpose of this multicenter, randomized, double-blind study, conducted in 520 patients, was to compare the efficacy and safety of omeprazole (40 and 20 mg once daily) with placebo in the treatment of benign gastric ulcer. METHODS: Treatment with omeprazole or placebo lasted 4 wk; those whose ulcers remained unhealed continued the same treatment regimen for an additional 4 wk. The effects of therapy were determined by endoscopy and assessment of GI symptoms. Safety and tolerability were evaluated through reported adverse events, physical examinations, and laboratory tests. RESULTS: At weeks 4 and 8, the proportion of patients with healed ulcers was significantly greater in the omeprazole 40- and 20-mg groups than in the placebo group (p < 0.01). At week 8, the healing rate was significantly greater in the 40-mg group than in the 20-mg group (82.7 vs 74.8%, p < 0.05). In patients with large ulcers (>1 cm), the 40-mg regimen was associated with a significantly higher healing rate (78.9%) than both the 20-mg regimen (61.4%) and placebo (34.6%) at week 8 (p < 0.05 vs omeprazole 20 mg; p < 0.01 vs placebo). Healing rates in patients with small ulcers were similar for the 40- and 20-mg groups. Omeprazole was well tolerated, with no significant differences versus placebo in the overall incidence of clinical or laboratory adverse events. CONCLUSIONS: Omeprazole 40 and 20 mg, administered once daily, healed a significantly greater proportion of patients than did placebo. The 40-mg regimen offered significant advantages over the 20-mg regimen in patients with large ulcers.     

Dormancy-associated gene expression in pea axillary buds. Cloning and expression of PsDRM1 and PsDRM2

OBJECTIVE: We evaluated the efficacy and safety of a twice-daily dosage regimen of cisapride 20 mg in relieving the symptoms of mild-moderate gastroesophageal reflux disease (GERD) in patients with moderate intensity heartburn and no history of erosive esophagitis. METHODS: After a 2-wk, single-blind, placebo run-in period, 398 patients who continued to experience moderate intensity heartburn were randomized to either placebo (n = 196) or cisapride 20 mg (n = 202) twice daily for 4 wk. RESULTS: Compared with placebo, cisapride significantly reduced scores for daytime and nighttime heartburn (p < 0.001), total regurgitation (p < 0.001), eructation (p = 0.04), and early satiety (p = 0.04). Cisapride 20 mg b.i.d. was also superior to placebo in reducing total use of rescue antacid medication (p < 0.001); reducing, in concordance analyses, daytime and nighttime heartburn with antacid usage (p < 0.001); increasing the percentage of heartburn-free days and antacid-free nights (p < 0.5); and increasing the percentage of patients self-rated as having minimal or better symptomatic improvement (p = 0.01). Cisapride 20 mg b.i.d. was well tolerated. The most common adverse event in the cisapride group was diarrhea, reported by 10% of patients, compared with an incidence of 4% in the placebo group. CONCLUSION: Cisapride 20 mg b.i.d. was shown to be effective and safe for the short-term treatment of daytime and nighttime heartburn and for other symptoms associated with mild-moderate GERD.