Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation

CONTEXT: In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. OBJECTIVE: To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. DESIGN AND SETTING: Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. PARTICIPANTS AND INTERVENTION: Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. OUTCOME MEASURES: Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. RESULTS: In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. CONCLUSIONS: We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo.     

Daily doses of 20 mg of elemental iron compensate for iron loss in regular blood donors: a randomized, double-blind, placebo-controlled study

BACKGROUND: A considerable number of regular blood donors develops an iron deficiency, and the exact amount of iron required to compensate for the iron loss from whole-blood donation in males and females is still unknown. STUDY DESIGN AND METHODS: A total of 526 regular blood donors (289 male and 237 female) were randomly assigned to treatment with either 40 mg, 20 mg, or 0 mg per day of elemental iron as ferrous gluconate for a period of 6 months, during which one unit of whole blood was collected on four occasions (males) or three occasions (females). Hemoglobin level, serum ferritin, and soluble transferrin receptor levels were measured before each donation. RESULTS: Daily doses of either 40 mg or 20 mg of elemental iron adequately compensated for iron loss in males, who gave blood at 2-month intervals, but did not result in a positive iron balance or an increase in storage iron as reflected by the logarithm of the ratio of transferrin receptor to ferritin concentration. In females, who donated at 3-month intervals, the same daily doses not only restored the iron balance but also led to an increase in storage iron. The number of gastrointestinal side effects due to iron supplementation (12%) was only slightly higher in both iron groups than in the placebo group. CONCLUSION: The results of this study indicate that 20 mg of elemental iron per day can adequately compensate for iron loss in males and females who donate whole blood up to four (females) or six times per year (males).     

Amitriptyline in the prophylactic treatment of migraine and chronic daily headache

(Headache 2011;51:33‐51) Objective and Background.— Amitriptyline is one of the most commonly used medications in migraine prophylaxis. There have been relatively few placebo‐controlled studies of amitriptyline in migraine prophylaxis or in treatment of chronic daily headache (CDH). This report deals with a large placebo‐controlled trial of amitriptyline vs placebo of 20 weeks duration that included subjects with intermittent migraine (IM) as well as CDH. The study was carried out between 1976 and 1979; however, results have never been fully reported. Methods.— Patients with a history of migraine as defined by the 1962 Ad Hoc Committee report were recruited for this study. Subjects had at least 2 headaches per month, and no limit was placed on the number of headaches per month that could be experienced. The study format included a 4‐week baseline period (Period A) in which all subjects received placebo in a dose of 2 pills per day for one week, 3 pills per day for one week and then 4 pills per day for 2 weeks. Subjects with at least 2 migraine headaches in this period were then entered into Period B and randomized into either amitriptyline or placebo tracks. Medication consisted of identical tablets containing either 25 mg amitriptyline or placebo. Period B was 4 weeks in duration with dose titration identical to Period A. The dose could be reduced if necessary to reduce side effects. The minimum dose was one pill per day. Period C was a 12‐week maintenance or stabilization period in which the patient continued the dose established by week 8 with visits at weeks 12, 16, and 20. Patients kept a headache calendar that was used for data collection. Headache frequency (per month), severity, and duration (hours) were the primary measurement parameters employed for data analysis. Results.— For the entire group, 391 subjects were entered into Period A, 338 were randomized into Period B, 317 (81%) subjects completed the first post‐randomization visit (8 weeks), 255 (65%) completed week 12, 210 (54%) completed week 16, and 186 (48%) completed week 20. Using headache frequency and evaluating parameters of (a) improvement, (b) no change, or (c) worsening relative to baseline, there was a significant improvement in headache frequency for amitriptyline over placebo at 8 weeks (P = .018) but not at 12, 16, or 20 weeks. When amitriptyline and placebo patients were compared for headache frequency at 8, 12, 16, and 20 weeks to their own placebo stabilization period at 4 weeks, statistically significant improvement vs worsening was seen in headache frequency at each evaluation point for both amitriptyline and placebo groups (P ≤ .01) reaching 50% reporting a decrease in frequency in each group and approximately 10% reporting worsening by week 20. There were no significant differences in headache severity or duration between amitriptyline and placebo groups at anytime during the study. Within the study sample, there were 36 amitriptyline and 22 placebo subjects who had headaches ≥17 days/month that fit the current definition of CDH by the Silberstein‐Lipton criteria. These were analyzed separately as a subgroup for comparison of amitriptyline vs placebo using a metric of (1) no change or worsening; (2) up to a 50% improvement; and (3) ≥50% improvement in headache frequency. Amitriptyline was superior to placebo in number with improvement in frequency of ≥50% at 8 weeks (25% vs 5% [P = .031]) and at 16 weeks (46% vs 9% [P = .043]). There was a trend for amitriptyline to be superior to placebo at 12 and 20 weeks but this did not reach significance. Conclusions.— In this study, using headache frequency as the primary metric, for the entire group, amitriptyline was superior to placebo in migraine prophylaxis at 8 weeks but, because of a robust placebo response, not at subsequent time points. For the subgroup with CDH, amitriptyline was statistically significantly superior to placebo at 8 weeks and 16 weeks with a similar but nonsignificant trend at 12 and 20 weeks. Compared with placebo amitriptyline is effective in CDH. Amitriptyline was also significantly effective in IM compared intragroup to its own baseline; however, placebo was equally effective in the same analysis. The reason for the robust placebo response in the IM group is not clear, but has been occasionally reported.     

Prevention and treatment of experimental influenza A virus infection in volunteers with a new antiviral ICI 130,685

The initial prophylactic and therapeutic trials of ICI 130,685 against influenza A virus infection are reported. Prophylaxis with either 200 mg/day (38 volunteers received drug and 40 received placebo) or 100 mg/day (28 volunteers received drug and 28 received placebo) for seven days significantly reduced illness, mean clinical score and nasal secretion weight when volunteers were challenged with 10(4.1) EID50 of influenza virus A/Eng/40/83 (H3N2). Overall, prophylaxis with 200 mg/day and 100 mg/day gave 91% and 72% protection against illness relative to placebo, respectively. In addition, prophylaxis with both regimens for seven days also significantly reduced the number of volunteers who excreted virus. In a therapeutic study, volunteers were inoculated with the same dose of virus and those who developed symptoms which persisted for 6-15 h were treated with 200 mg/day of drug (20 volunteers) or placebo (19 volunteers) for four days. Generally, treatment reduced both the amount of virus excreted and the mean daily clinical score. However, these reductions were only statistically significant (P less than 0.05) on the third day of medication for the amount of virus excreted and on the fourth day of treatment for the mean clinical score. It was concluded that ICI 130,685 is effective in the prevention and treatment of influenza virus infection. An initial tolerance study in 16 volunteers who received either drug (200 mg/day) (8 volunteers) or placebo (8 volunteers) for seven days, indicated that the drug was generally well tolerated. Combining data from all studies, 43% of volunteers who received the drug at the 200 mg/day dosage and 21% who received placebo complained of one or more symptoms. However, symptoms were generally minor and of short duration. At the lower dosage (100 mg/day) the symptoms were qualitatively similar to those reported with placebo.     

European Multicenter Trial of Nimodipine in the Prophylaxis of Classic Migraine (Migraine With Aura)

SYNOPSIS
This double-blind, randomized study of the Nimodipine 40 mg t.i.d. vs placebo in the prophylaxis of classic migraine (migraine with aura) included 89 patients. Required migraine frequency was 2–8 migraine days/4 weeks and at least two of the attacks within the last 6 months had to be with aura. The study was carried out at 11 European centers. After a 4 week run-in period, patients were randomly allocated to nimodipine or placebo for 12 weeks (parallel groups). There were 7 dropouts, 3 on Nimodipine, and 4 on placebo. A gradual and verymarked improvement was seen both with Nimodipine and placebo amounting to between 60 and 90 per cent during the last 4 weeks. Statistical analysis on all included patients (intention to treat) revealed no difference between Nimodipine and placebo for migraine days or migraine index. In patients "valid for analysis of efficacy" there were also no significant difference. Due to a very marked placebo effect and use of the parallel groups design, the present trial is relatively weak despite a fairly large sample size. It cannot rule out the possibility of an important effect of Nimodipine in classic migraine with a high degree of certainty.     

Fluoxetine differentially alters alcohol intake and other consummatory behaviors in problem drinkers

The effects of fluoxetine, a relatively selective long-acting serotonin uptake inhibitor, on the consumption of alcoholic and nonalcoholic drinks, cigarette smoking, and body weight were assessed in 29 men who were early stage problem drinkers. After a 2-week baseline, subjects were randomly assigned to receive 40 mg/day fluoxetine (n = 8), 60 mg/day fluoxetine (n = 11), or placebo (n = 10) for 4 weeks. Fluoxetine 60 mg/day decreased mean daily alcoholic drinks from (X +/- SEM) 8.3 +/- 0.7 during baseline to 6.9 +/- 0.7 and decreased total drinks per 14 days from 115.8 +/- 9.3 to 96.5 +/- 9.5 (p less than 0.01; 17.3% decrease from baseline), with no significant increase in days of abstinence. Neither 40 mg/day fluoxetine nor placebo had effects on intake of alcohol. Fluoxetine 60 mg/day decreased total and mean daily alcoholic drinks compared with 40 mg/day fluoxetine (ANCOVA, both p less than 0.02), but neither dose of fluoxetine was different from placebo. Compared with placebo, both 40 mg/day fluoxetine and 60 mg/day fluoxetine no differences were detected between treatment groups, 60 mg/day fluoxetine increased mean daily nonalcoholic beverages from baseline (5.0 +/- 0.4 to 5.6 +/- 0.3, p less than 0.01) and increased daily cigarettes smoked (from 25.1 +/- 4.6 to 26.9 +/- 4.5, p less than 0.05), whereas no significant changes from baseline were observed with 40 mg/day fluoxetine or placebo.(ABSTRACT TRUNCATED AT 250 WORDS)     

Oestriol in the prophylactic treatment of recurrent urinary tract infections in postmenopausal women.

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66-91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p less than 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.     

gamma-Tocopherol Accelerated Sodium Excretion in a Dose-Dependent Manner in Rats with a High Sodium Intake

We have previously reported that gamma-tocopherol (gamma-Toc) displays a natriuretic potency in rats fed a NaCl diet and administered 20 mg gamma-Toc. In this study, we investigated whether gamma-Toc has natriuretic potency at a dose lower or higher than 20 mg in rats given a NaCl diet. Male rats were fed a control diet or a NaCl diet and administered either placebo or 10, 20 or 40 mg of gamma-Toc. The rat urine was collected for 24 hours (divided into 6 hour periods) and the 2,7,8-trimethyl-2-(2'-carboxyethyl)-6-hydroxychroman (gamma-CEHC) level, the sodium excretion content, and the urine volume were determined. The 24-hour gamma-CEHC and sodium levels in the urine of the NaCl groups given 20 mg or 40 mg gamma-Toc were significantly higher than those in the placebo group. The peak levels of urine sodium and gamma-CEHC in the NaCl group given 40 mg gamma-Toc appeared at 0-6 h, which was a more rapid increase than that seen in the group given 20 mg gamma-Toc. The 24-hour urine volumes of the NaCl groups given 10 and 20 mg gamma-Toc were significantly higher than the urine volume of the placebo group. Our findings suggested that gamma-Toc increased sodium excretion in a dose-dependent manner in rats fed a NaCl diet. Moreover, a high dose of gamma-Toc may accelerate its metabolism and cause an increase in the rate of sodium excretion.     

Efficacy and Tolerability of Famotidine in Preventing Heartburn and Related Symptoms of Upper Gastrointestinal Discomfort

This randomized, double-blind, placebo-controlled, four-way crossover trial was designed to compare the efficacy of famotidine and placebo in preventing meal-provoked upper gastrointestinal symptoms. One hundred twenty-one subjects (58 men and 63 women), aged 20--61 years, were randomly assigned to one of four treatment sequences which included single oral doses of placebo, famotidine 5 mg, famotidine 10 mg, and famotidine 20 mg, spaced approximately 7 days apart. To be eligible for randomization, subjects had to have at least a 2-month history of heartburn and acid/sour stomach occurring at least three times per week. Treatment was administered 1 h prior to ingestion of test meals (chili and wine). Rescue antacid medication (Maalox((R))) was available for subjects who required additional relief. Heartburn severity. acid/sour stomach, and overall discomfort were evaluated on a six-point scale immediately prior to each test meal and every 15 min thereafter for 5 h. A global evaluation of the test medication, using a five-point scale, was performed prior to rescue medication use or at the end of each treatment session. Heartburn and peak acid/sour stomach were rated as significantly milder following prophylactic treatment with famotidine 5, 10, and 20 mg compared to placebo. Treatment with all three doses of famotidine was rated as "good" or "excellent" by significantly more subjects (58--63%) than following treatment with placebo (38%). In addition, rescue medication was used by significantly fewer subjects following famotidine (17--18%) compared to placebo (37%). Famotidine was generally well tolerated in this trial, with type and frequency of reported adverse experiences similar to that observed following placebo. These results indicated that famotidine doses of 5, 10, and 20 mg were significantly more effective than placebo in preventing symptoms of upper gastrointestinal distress when administered 1 h in advance of meal provocation.     

Efficacy,safety, and tolerability of oral eletriptan for treatment of acute migraine: a multicenter,double-blind,placebo-controlled study conducted in the United States

OBJECTIVE: To investigate the efficacy, consistency, safety, and tolerability of oral eletriptan in the acute treatment of three migraine attacks. BACKGROUND: Eletriptan is a selective 5-HT1B/1D agonist member of a class of agents known to be effective in the acute treatment of migraine. METHODS: Thirteen hundred thirty-four patients were randomized to 20 mg, 40 mg, or 80 mg of eletriptan, or placebo and could treat up to three attacks. The primary efficacy endpoint was 2-hour headache response for the first attack. Secondary endpoints included associated symptom relief, and pain-free, sustained pain-free, and consistency of response. RESULTS: Eletriptan 20 mg, 40 mg, and 80 mg achieved significantly (P <.0001) better headache response rates than placebo at 2 hours (47%, 62%, and 59%, respectively, versus 22%) and 4 hours (64%, 76%, and 79%, respectively, versus 25%). Headache response was observed to be rapid, showing improvement at 0.5 hour and 1 hour. Two-hour pain-free response rates for eletriptan 20 mg, 40 mg, and 80 mg were 14%, 27%, and 27%, respectively, compared with 4% for placebo. Sustained pain-free response rates were significantly (P <.001) better for eletriptan 20 mg (10%), 40 mg (20%), and 80 mg (18%) compared with placebo (3%). Eletriptan had a higher consistency of intrapatient response than placebo in two of three (68% to 82%) and three of three attacks (32% to 60%) versus 16% and 8%, respectively. All eletriptan doses yielded significant functional improvement at 2 hours. Adverse events were generally mild or moderate and transient, with eletriptan 20 mg having an adverse event profile comparable to placebo. CONCLUSIONS: Eletriptan is efficacious, displaying high consistency of response over multiple attacks, and is well tolerated for the acute treatment of migraine.     

Oestriol in the Prophylactic Treatment of Recurrent Urinary Tract Infections in Postmenopausal Women

A block randomized, double-blind, group-comparative, placebo-controlled study was conducted to assess the effect of oestriol on recurrent urinary tract infections in postmenopausal women. 40 women, median age 78 years (66–91), 20 in each group, were treated with oestriol three mg p.o. per day or corresponding placebo for four weeks, followed by one mg per day for eight weeks. The main response parameter was the number of urinary tract infections per week in the two treatment periods. Both oestriol and placebo reduced the number of infections per week significantly in both periods, compared with the pretreatment period. There was no difference between oestriol and placebo treatment in the first period. In the second period, however, oestriol treatment was significantly more effective than placebo (p = 0.05). Correspondingly, there was a significant difference between the two groups in the vaginal pH at the end of the study (p > 0.05). We conclude that oestriol reduces recurrent urinary tract infections in postmenopausal women.     

Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. RESULTS: The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. CONCLUSIONS: Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.     

Etodolac, aspirin, and gastrointestinal microbleeding

The effects of etodolac, a new nonsteroidal anti-inflammatory drug, on gastrointestinal (GI) microbleeding were quantitatively assessed in two studies in healthy adult men. The first was a two-group, open-label, parallel comparison of etodolac, 600 mg/day, aspirin, 2600 mg/day, and placebo in 20 subjects; the second was a four-group, double-blind, parallel comparison of etodolac, 600, 800, and 1200 mg/day, aspirin, 2600 mg/day, and placebo in 41 subjects. Subjects in both studies received a single-blind placebo on days 1 through 7, either etodolac or aspirin on days 8 through 14, and a single-blind placebo on days 15 through 19. GI blood loss (milliliters per day) was estimated by the radiolabeled (51Cr) erythrocyte method and was based on daily radioactivity counts of stool specimens and regression-estimated daily blood radioactivity. Etodolac, 600 mg/day, induced no significant GI blood loss at any time during the experiments, nor was there significant blood loss after 800 and 1200 mg/day in experiment 2. Blood loss was noted after aspirin in both.     

Safety,Virologic Efficacy,and Pharmacokinetics of CT-P59, a Neutralizing Monoclonal Antibody Against SARS-CoV-2 Spike Receptor-Binding Protein: Two Randomized,Placebo-Controlled,Phase I Studies in Healthy Individuals and Patients With Mild SARS-CoV-2 Infection

PurposeNeutralizing antibodies can reduce SARS-CoV-2 cellular entry, viral titers, and pathologic damage. CT-P59 (regdanvimab), a SARS-CoV-2 neutralizing monoclonal antibody, was examined in 2 randomized, double-blind, placebo-controlled, single ascending dose, Phase I studies.MethodsIn study 1.1, healthy adults were sequentially enrolled to receive CT-P59 10, 20, 40, or 80 mg/kg or placebo. In study 1.2, adult patients with mild SARS-CoV-2 infection were enrolled to receive CT-P59 20, 40, or 80 mg/kg or placebo. Primary objectives of both studies were safety and tolerability up to day 14 after infusion. Secondary end points included pharmacokinetic properties. Study 1.2 also measured virology and clinical efficacy.FindingsThirty-two individuals were randomized to study 1.1 (6 per CT-P59 dose cohort and 8 in the placebo cohort). By day 14 after infusion, adverse events (AEs) were reported in 2 individuals receiving CT-P59 20 mg/kg (headache and elevated C-reactive protein levels) and 1 receiving CT-P59 40 mg/kg (pyrexia) (all Common Terminology Criteria for Adverse Events grade 1). In study 1.2, 18 patients were randomized (5 per dose cohort and 3 in the placebo cohort). Sixteen AEs were reported in 10 patients receiving CT-P59. No AEs in either study led to study discontinuation. Greater reductions in viral titers were reported with CT-P59 than placebo in those with maximum titers >10⁵ copies/mL. Mean time to recovery was 3.39 versus 5.25 days.ImplicationsCT-P59 exhibited a promising safety profile in healthy individuals and patients with mild SARS-CoV-2 infection, with potential antiviral and clinical efficacy in patients with mild SARS-CoV-2 infection. ClinicalTrials.gov identifier: NCT04525079 (study 1.1) and NCT04593641 (study 1.2).     

Effectiveness of quinine in treating muscle cramps: a double-blind,placebo-controlled,parallel-group,multicentre trial

To determine the efficacy and safety of quinine in treating nocturnal muscle cramps we performed a double-blind, placebo-controlled, parallel-group, multicentre trial in 17 general practice centres in Germany. Ninety-eight patients aged 18-70 years with more than six muscle cramps in two weeks were enrolled. A two-week run-in period without treatment was followed by two weeks of treatment with 400 mg quinine or placebo per day and a wash-out period of two weeks without treatment. The primary outcome measure was the reduction in the number of muscle cramps between the run-in and treatment periods. The intensity of cramps, number of nights with cramps, sleep disturbance and intensity of pain were recorded as secondary outcome measures. At baseline the median number of cramps was 12 in two weeks in both groups. The median reduction between the run-in and therapy phases was eight (95% CI 7-10) versus six (95% CI 3-7) muscle cramps during quinine and placebo treatment; 36 (80%) participants in the quinine group and 26 (53%) in the placebo group had a reduction of at least 50% in the number of muscle cramps. Frequency, intensity and pain at night showed a statistically significant difference in favour of quinine. The improvement was more evident according to physician assessment than patient assessment; this is corroborated by the high placebo response rate. No significant differences were found between the two groups with respect to side-effects. Short term treatment with 400 mg quinine per day can effectively prevent nocturnal leg cramps in adults without relevant side-effects.     

Pain Responder Analysis: Use of Area Under the Curve to Enhance Interpretation of Clinical Trial Results

Interpretation of results on patient-reported pain outcomes from clinical trials should be meaningful to patients and healthcare providers. This study applied an area-under-the-curve (AUC) analysis to responder profiles in a clinical trial of pregabalin for the treatment of fibromyalgia (FM). Data were from a 14-week, randomized, placebo-controlled trial of pregabalin (300, 450, or 600 mg/day) for the treatment of FM in patients meeting American College of Rheumatology criteria for FM and with a baseline pain score of at least 40 mm on the 100-mm pain visual analogue scale. Pain was evaluated in a daily diary by patients using an 11-point numeric rating scale (0 = no pain, 10 = worst possible pain). Response profiles on pain improvement scores and their differences between pregabalin and placebo were assessed using the AUC (derived using the trapezoidal rule) from the responder curve (vertical axis, proportion of subjects; horizontal axis, minimum percent improvement in pain). The AUC can be interpreted as if all responders were improved by the same percentage equal to the AUC divided by 100. The AUCs (2,100 for placebo, and 2,944, 3,170, and 3,349 for pregabalin 300, 450, and 600 mg, respectively) can be considered as if every responder improved by 21, 29, 31, and 33.5% in the responder's respective treatment group. Pain improvement was significantly better with pregabalin ( P  < 0.05), with pregabalin responders improving by 8.4% (300 mg/day), 10.7% (450 mg/day), and 12.5% (600 mg/day) more than placebo responders. This novel approach demonstrates that responder profiles can provide an enhanced interpretation of pain outcomes for patient care and symptom management.     

Suppression of Leishmania donovani by oral administration of a bis(benzyl)polyamine analog.

We reported previously that intraperitoneal administration of a bis(benzyl)polyamine analog, MDL 27,695, suppressed both pentavalent antimony (Sbv)-susceptible and -resistant Leishmania donovani in vivo. The present studies were performed to optimize parasite suppression by parenteral administration and to evaluate the efficacy of oral treatment with MDL 27,695. L. donovani infections in BALB/c mice were suppressed greater than 99% after intraperitoneal dosing for 20 days with a total dose of 150 mg of MDL 27,695 per kg of body weight or 560 mg of Sbv per kg. Suppression was not increased by a total dose of 400 mg of MDL 27,695 per kg given for 20 days. In mice treated for 2, 4, or 7 days with either MDL 27,695 or Sbv (total doses of 60, 120, and 210 mg/kg, respectively), more liver parasites were killed with MDL 27,695 than with Sbv. Assessment of livers posttreatment showed that parasite killing continued for at least 3 days in MDL 27,695-treated mice but not for longer than 1 day in Sbv-treated mice. Intramuscular administration of drugs resulted in 92% parasite suppression by MDL 27,695 (15 mg/kg three times per day for 5 days) and 64% suppression by Sbv (60 mg/kg once per day for 5 days). Dosing of mice by oral gavage with 100 mg of MDL 27,695 per kg twice per day for 14 days resulted in 99.7% parasite suppression, and the 50% effective dose was approximately 11 mg of MDL 27,695 per kg. MDL 27,695 represents an effective new drug potentially useful for oral or parenteral treatment of visceral leishmaniasis.     

Controlled trial of the prolactin inhibitor bromocriptine (Parlodel) in the treatment of severe cyclical mastalgia

Fifty pre-menopausal women with severe and persistent cyclical mastalgia entered this randomised, double-blind, parallel group study comparing bromocriptine and placebo. Patients were treated for three months followed by a further three months on the same medication if treatment was satisfactory. Symptoms were assessed before treatment and after one, two and three months of treatment. For patients whose mastalgia was not controlled after three months, the treatment code was broken and either the dose of bromocriptine increased or the patient given active medication instead of placebo. Bromocriptine, compared with placebo, caused a significant (p less than 0.01) and sustained improvement in breast pain, tenderness and nodularity together with a reduction in serum prolactin levels (p less than 0.01). Adverse events were experienced by 9/23 (39 per cent) of patients taking bromocriptine and 2/22 (nine per cent) taking placebo. The majority of side effects reported were mild or moderate. This study shows that bromocriptine, at a dose of 5 mg/day for three months, effectively controls the symptoms of cyclical mastalgia with minimal side effects.