Safety of L-proline as a stabilizer for immunoglobulin products.

Privigen(®) (immune globulin intravenous [human], 10% liquid) and Hizentra(®) (immune globulin subcutaneous [human], 20% liquid) are stabilized by proline. The clinical implications of administering proline-containing immunoglobulin products to patients with defects of proline metabolism have not been addressed; Privigen and Hizentra are contraindicated in these patients. Some patients with chromosome 22q11.2 deletion syndrome have elevated proline levels; however, only 3-4% of patients also have an immunodeficiency that requires IgG therapy. This review summarizes the evidence related to the safety and pharmacokinetics of proline assessed in Privigen and Hizentra preclinical and clinical studies, and subsequent implications for patients with defects in proline metabolism. Clinical data indicate that proline does not accumulate after Privigen or Hizentra treatment and is not associated with adverse events. There is no evidence to suggest that patients with defects of proline metabolism would be affected by transient elevations in plasma proline following Privigen and/or Hizentra treatment.

IBS patients show frequent fluctuations between loose/watery and hard/lumpy stools: implications for treatment.

OBJECTIVES: The objectives of this study were to determine how variable stool consistency is in patients with irritable bowel syndrome (IBS) and to assess the relationship between stool consistency and gastrointestinal symptoms. METHODS: Individuals with a physician diagnosis of IBS were recruited by advertisement. Enrollment questionnaires included the Rome III Diagnostic Questionnaire and IBS Symptom Severity Scale. Then, 185 patients meeting the Rome criteria for IBS rated the consistency (using the Bristol Stool Scale) of each bowel movement (BM) for 90 days and whether the BM was accompanied by pain, urgency, or soiling. Each night, they transferred BM ratings from a paper diary to an internet form and also reported the average daily intensity of abdominal pain, bloating, bowel habit dissatisfaction, and life interference of bowel symptoms. Only the longest sequence of consecutive days of diary data was used in the analysis (average of 73 days). RESULTS: Patients were 89% females with average age 36.6 years. Among the patients, 78% had both loose/watery and hard/lumpy stools; the average was three fluctuations between these extremes per month. The proportion of loose/watery stools correlated r=0.78 between the first and second months and the proportion of hard/lumpy stools correlated r=0.85 between months. Loose/watery stools were associated with more BM-related pain, urgency, and soiling than hard/lumpy or normal stools; however, IBS-C patients had significantly more BM-unrelated abdominal pain, bloating, dissatisfaction with bowel habits, and life interference than IBS-D patients. Questionnaires overestimated the frequency of abnormal stool consistency and gastrointestinal symptoms compared with diaries. CONCLUSIONS: Stool consistency varies greatly within individuals. However, stool patterns are stable within an individual from month to month. The paradoxical findings of greater symptom severity after individual loose/watery BMs vs. greater overall symptom severity in IBS-C implies different physiological mechanisms for symptoms in constipation compared with diarrhea. Daily symptom monitoring is more sensitive and reliable than a questionnaire.

Higher doses of subcutaneous IgG reduce resource utilization in patients with primary immunodeficiency.

The recommended dose of IgG in primary immunodeficiency (PID) has been increasing since its first use. This study aimed to determine if higher subcutaneous IgG doses resulted in improved patient outcomes by comparing results from two parallel clinical studies with similar design. One patient cohort received subcutaneous IgG doses that were 1.5 times higher than their previous intravenous doses (mean 213 mg/kg/week), whereas the other cohort received doses identical to previous subcutaneous or intravenous doses (mean 120 mg/kg/week). While neither cohort had any serious infections, the cohort maintained on higher mean IgG dose had significantly lower rates of non-serious infections (2.76 vs. 5.18 episodes/year, P < 0.0001), hospitalization (0.20 vs. 3.48 days/year, P < 0.0001), antibiotic use (48.50 vs. 72.75 days/year, P < 0.001), and missed work/school activity (2.10 vs. 8.00 days/year, P < 0.001). The higher-dose cohort had lower health care utilization and improved indices of well being compared to the cohort treated with traditional IgG doses.

Retrospective analysis of transient elevations in alanine aminotransferase during long-term treatment with acetaminophen in osteoarthritis clinical trials.

BACKGROUND: In two recent osteoarthritis trials, alanine aminotransferase (ALT) elevations were observed more frequently in patients receiving acetaminophen 3.9 g daily than in patients receiving placebo, and the rates were higher than aminotransferase values observed in some previous osteoarthritis studies with acetaminophen. OBJECTIVE: To retrospectively analyze ALT data from McNeil osteoarthritis clinical studies involving acetaminophen in order to assess the frequency and magnitude of ALT elevations and rate of ALT resolution while patients remained on acetaminophen treatment. A review of the literature revealed a few reports of isolated aminotransferase elevations occurring during acetaminophen therapy, but these reports were not included in the analysis because they did not include enough information to evaluate the frequency, magnitude, and rate of ALT elevations while patients remained on acetaminophen treatment. RESEARCH DESIGN AND METHODS: Nine controlled clinical trials were identified in which at least one of the treatments was acetaminophen alone. Studies were included if patients had ALT and aspartate aminotransferase (AST) values obtained at baseline and an ALT value at an additional visit after initiating therapy. Seven studies met these criteria and were included in this analysis. In these studies, patients received acetaminophen 1950-4000 mg/day for 4 weeks up to 12 months. Laboratory testing was performed at weeks 0 and 4 in the three 4-week studies; at weeks 0, 2, 4, 8, and 12 in the two 12-week studies; at weeks 0, 1, 2, 4, 6, 8, and 13 in the 13-week study; and at months 0, 1, 3, 6, 9, and 12 in the 12-month study. The pooled data set consisted of patient demographics, dosing records, aminotransferase and bilirubin laboratory values, and adverse events. RESULTS: There were no reports of hepatotoxicity or hepatic failure in any acetaminophen-treated patient (n = 1530). In the seven studies, 1039 patients had both baseline AST and ALT activity < or = upper limit of the reference range and an on-treatment ALT measurement. While on long-term acetaminophen treatment, 181 of 1039 (17.4%) patients had an ALT value that exceeded the upper limit of the reference range. None of the 1039 patients had an on-treatment ALT level > 3 times upper limit of the reference range in conjunction with a serum bilirubin > upper limit of the reference range, and no patient had an ALT level > 10 times upper limit of the reference range. Of the 1039 patients, 44 (4.2%) had an on-treatment ALT level > 1.5 times upper limit of the reference range, and 31 of the 44 patients had a subsequent measurement of ALT. Of these 31 patients, 29 (93.5%) had documented resolution or decreasing ALT while on treatment. An ALT level > 1.5 times upper limit of the reference range was not associated with a higher frequency of symptoms potentially related to hepatic origin. LIMITATIONS: The studies included in this analysis were limited to McNeil studies, none of which were designed to specifically evaluate the patterns of ALT activity. Thus, the incidence of ALT elevations after any specific duration of dosing, and the temporal pattern of ALT elevations, cannot be accurately determined. In addition, methodological differences existed across the studies. CONCLUSION: This analysis involving > 1000 acetaminophen-treated patients shows that low-level, transient ALT elevations usually resolve or decrease with continued acetaminophen treatment, are unaccompanied by signs or symptoms of liver injury, and, as such, appear to be clinically insignificant. Maximum recommended daily doses of acetaminophen did not cause liver failure or dysfunction.

Analysis of risk of bleeding complications after different doses of aspirin in 192,036 patients enrolled in 31 randomized controlled trials.

We sought to compare the risk of hemorrhage due to the low (<100 mg), moderate (100 to 200 mg), and high (>200 mg) doses of aspirin (acetylsalicylic acid [ASA]) in 192,036 patients enrolled in 31 clinical trials. Despite substantial differences in the reporting patterns of bleeding complications, low-dose ASA was associated with the lowest risk, and moderate doses caused a relatively high hemorrhagic event rate, especially with regard to minor, gastrointestinal, and total bleeding, and stroke. These findings should be considered when using combination antiplatelets, anticoagulant therapy, or both, with ASA, especially with the daily dose of >100 mg.

Aspirin is efficacious for the treatment of acute migraine.

BACKGROUND: More than 50% of migraine sufferers rely on over-the-counter medications for the treatment of migraine. Along with other over-the-counter products, aspirin is considered by the US Headache Consortium to be an option for first-line migraine treatment. This study assessed the efficacy and tolerability of aspirin versus placebo for the acute treatment of a single acute attack of migraine. METHODS: This prospective, randomized, double-blind, parallel-group, placebo-controlled study evaluated the efficacy of a single, 1000-mg dose of aspirin for the treatment of acute moderate to severe migraine, with or without aura. Subjects recorded all study evaluations in a diary at baseline and at .5, 1, 2, 3, 4, 5, 6, and 24 hours after treatment. Pain was rated on a 4-point ordinal scale from no pain to severe pain. The primary efficacy end point was headache response at 2 hours. Secondary efficacy parameters included reduction of nausea, photophobia and phonophobia, pain intensity difference, and headache recurrence at 24 hours. RESULTS: Of 485 subjects enrolled, 409 took study medication and 401 treated a confirmed migraine attack (201 with aspirin and 200 with placebo). Baseline demographic and migraine characteristics were not significantly different between groups. The 2-hour headache response rate was 52% with aspirin versus 34% with placebo (P<.001). Aspirin was significantly more effective than placebo for pain reduction beginning 1 hour after dosing (P<.001) and continuing throughout the 6-hour evaluation period. Significantly (P<.05), more subjects were pain free from the 1-hour evaluation through the 6-hour evaluation. Of the aspirin-treated subjects, 20% were pain free at 2 hours versus only 6% of placebo-treated subjects. At 24 hours, the headache recurrence rate was 21.8% for aspirin (23 of 105 subjects) and 27.7% for placebo (19 of 68 subjects). Only 34% of aspirin-treated subjects needed rescue medication at 24 hours compared with 52% of placebo-treated subjects (P<.001). Aspirin was well tolerated, and adverse events were not significantly different between groups. CONCLUSIONS: This study demonstrates that aspirin is safe and effective for treatment of acute migraine in appropriately selected patients.