Evaluation of avoralstat, an oral kallikrein inhibitor, in a Phase 3 hereditary angioedema prophylaxis trial: The OPuS-2 study.

BACKGROUND: Effective inhibition of plasma kallikrein may have significant benefits for patients with hereditary angioedema due to deficiency of C1 inhibitor (C1-INH-HAE) by reducing the frequency of angioedema attacks. Avoralstat is a small molecule inhibitor of plasma kallikrein. This study (OPuS-2) evaluated the efficacy and safety of prophylactic avoralstat 300 or 500 mg compared with placebo. METHODS: OPuS-2 was a Phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. Subjects were administered avoralstat 300 mg, avoralstat 500 mg, or placebo orally 3 times per day for 12 weeks. The primary efficacy endpoint was the angioedema attack rate based on adjudicator-confirmed attacks. RESULTS: A total of 110 subjects were randomized and dosed. The least squares (LS) mean attack rates per week were 0.589, 0.675, and 0.593 for subjects receiving avoralstat 500 mg, avoralstat 300 mg, and placebo, respectively. Overall, 1 subject in each of the avoralstat groups and no subjects in the placebo group were attack-free during the 84-day treatment period. The LS mean duration of all confirmed attacks was 25.4, 29.4, and 31.4 hours for the avoralstat 500 mg, avoralstat 300 mg, and placebo groups, respectively. Using the Angioedema Quality of Life Questionnaire (AE-QoL), improved QoL was observed for the avoralstat 500 mg group compared with placebo. Avoralstat was generally safe and well tolerated. CONCLUSIONS: Although this study did not demonstrate efficacy of avoralstat in preventing angioedema attacks in C1-INH-HAE, it provided evidence of shortened angioedema episodes and improved QoL in the avoralstat 500 mg treatment group compared with placebo.

Polymyalgia, hypersensitivity pneumonitis and other reactions in patients receiving HMG-CoA reductase inhibitors: a report of ten cases.

Ten patients who take hydroxy-methylglutaryl coenzyme A reductase inhibitors, or statin medications, and experience adverse reactions are described. All patients experienced various manifestations of hypersensitivity while receiving the drugs. One patient is described with hypersensitivity pneumonitis, which was graphically demonstrated by both high resolution computerized axial tomography and open lung biopsy.

Acute encephalopathy in siblings. Reye syndrome vs salicylate intoxication.

Siblings, aged 9 and 7 years, had simultaneous onset of vomiting, disorientation, ataxia, and coma. Both children had prodromal symptoms of upper respiratory tract infections, and had been treated with large doses of aspirin. Laboratory data showed evidence of hepatocellular dysfunction, with an elevated serum ammonia level in one patient; salicylate levels were 50 and 44 mg/100 ml. The child who died had autopsy evidence of cerebral edema and fatty liver. The difficulty in clinically differentiating Reye syndrome from salicylate intoxication is discussed.

Cholinesterase activity in pregnant women and newborns.

Plasma and red blood cell cholinesterase activity in blood samples from 259 pregnant women and cord blood from some of their newborn were compared with samples from 25 nonpregnant female volunteers and with laboratory norms (Ellman method). Plasma cholinesterase was significantly lower (p < 0.05) and red blood cell cholinesterase higher (p < 0.05) in pregnant women than in nonpregnant controls in a repeated measures analysis. By the sixth post-partum week, both plasma and red blood cell cholinesterase were similar to nonpregnant control activity. Fetal cord red blood cell cholinesterase activity was also lower than in nonpregnant women, but plasma levels were not significantly different. When compared with standard laboratory normal ranges, most (98-100%) plasma cholinesterase values in pregnant women and newborn were within range, whereas the majority (59-87%, depending on trimester) of red blood cell levels were above range in pregnancy and below range in 53% of newborns. A low red blood cell cholinesterase in pregnant women is more consistent with a possible overexposure to anticholinesterases than a low plasma cholinesterase. Periods of altered sensitivity to specific cholinesterase inhibiting drugs and environmental agents are suggested by these findings.

The effect of dapsone in steroid-dependent asthma.

We studied the steroid-sparing effect of dapsone in 10 subjects with chronic asthma in a preliminary open trial. Dapsone was chosen because it inhibits neutrophil function and possesses anti-inflammatory effects in a variety of disorders. The study group consisted of 10 subjects with stable, steroid-dependent asthma, aged 23 to 80 years, with normal glucose-6-phosphate dehydrogenase levels. Average daily baseline prednisone dose ranged from 5 to 60 mg. Dapsone, 100 mg, twice daily, by mouth, was started after a 1-month baseline period. Baseline steroid dose, symptom scores, and daily peak flow rates were compared to the latest available 4-week period of dapsone treatment. Average cumulative monthly prednisone dose was reduced from 428 mg to 82 mg (p less than 0.02). Five of 10 patients stopped steroids by month 6 and two additional patients by month 13. Two additional patients demonstrated a coincidental 74% reduction in steroid dose, and one patient demonstrated no response. Clinical parameters remained stable despite steroid reduction. These preliminary data suggest dapsone may have steroid-sparing effects in chronic asthma.

Hypersensitivity pneumonitis from Pezizia domiciliana. A case of El Niño lung.

A previously healthy woman developed severe dyspnea and was found to have restrictive lung disease and evidence of alveolitis. Open lung biopsy revealed extrinsic allergic alveolitis (hypersensitivity pneumonitis). The etiology was not initially apparent, but a home inspection showed an unusual mushroom growing in the patient's basement. Air sampling and serum precipitins against the fungal antigens confirmed that Pezizia domiciliana was the cause of the patient's hypersensitivity pneumonitis. This is the first described case of hypersensitivity pneumonitis cause by P. domiciliana. We speculate that unprecedented rainfall and flooding of the patient's basement as a result of El Niño rains produced ideal factors for the growth of this fungus.

Alterations of lymphocytes and of antibody content of human milk after processing.

The effects of pasteurization, lyophilization, and freezing on immunoglobulin and lymphocytes in human milk was studied. We found a significant decrease in total lymphocyte count after all three processing methods. Pasteurization and lyophilization caused a significant decrease in immunoglobulin concentration and in specific antibody titer to Escherichi coli. Freezing specimens up to four weeks resulted in no significant alteration of IgA content or in E. coli antibody titer. Since a major advantage of human milk is the transference of passive local immunity, these quantitative changes may have clinical importance.