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.

Multiple hamartoma syndrome (Cowden's disease).

The four male patients with multiple hamartoma syndrome (Cowden's disease) in this report, have most of the previously reported findings associated with this syndrome and several important unreported findings that include multiple cutaneous trichilemmomas, cafe-au-lait spots, cutaneous squamous cell carcinoma, pathologic fracture, craniomegaly, probable malignant lung tumor, retinal glioma, drusens of the optic disk and retina, pseudotumor cerebri, mediastinal mass, and multiple small papillomatous lesions of the esophagus, stomach, and duodenum.

Grade animals in Canadian dairy cattle improvement.

Grade dairy animals in Canada are an important resource in genetic evaluations of the populations. A program was established in 1972 to provide accurate identification of grade animals. This paper describes Canada's National Identification Program, its acceptance, and its procedures and use in Canada. National Identification Program has proven to be an excellent program to identify grade animals on milk recording programs in Canada.

Evaluation of a subcutaneously implanted chamber for antibody production in rabbits.

Polyclonal antibody production in subcutaneous chambers was compared to traditional antibody production methods in rabbits. The chamber, a sterilized plastic wiffle golf ball that had been surgically implanted in the subcutis of the thoracic region, was immunized via a percutaneous injection of antigen into the core of the ball through one of the perforations in the chamber wall. Rabbits bearing chambers were immunized on the same schedule and with the same concentrations of antigens as were provided the adjuvant injected rabbits. Fluid volumes of 12 to 22 ml could be removed from each chamber at weekly intervals. Chamber antibody to specific microbial antigens was equal to or better than serum antibody produced to the same antigens with Freund's or acrylamide adjuvants. The comfort of the rabbit, the ease in chamber immunization, and the recovery of high titer antibody in large volumes make the subcutaneous chamber an attractive method for polyclonal antibody production.

Morphophysiologic characterization of peripheral neuropathy in zinc-deficient guinea pigs.

Zinc-deficient guinea pigs develop a peripheral neuropathy characterized by abnormal posture and gait, hyperesthesia, slowed motor nerve conduction velocity (MNCV), and decreased sciatic nerve Na,K-ATPase activity. This study was designed to further investigate longitudinally the morphophysiologic features of the neuropathy. Weanling guinea pigs were fed a low-zinc (<1 mg/kg) diet ad libitum (-ZnAL), an adequate-zinc (100 mg/kg) diet ad libitum (+ZnAL), or the adequate diet restricted in intake ((+ZnRF). Electrophysiologic, morphologic, and biochemical parameters of peripheral nerves were examined at 2.5, 4.0, and 5.5 weeks. Serum zinc was significantly lower by 2.5 weeks and growth rate reduced by 4 weeks in -ZnAL animals. Postural abnormalities were first obvious at 4 weeks, although MNCVs were significantly slower in zinc-deficient animals at all time intervals. The conduction of sensory impulses, as measured by spinal cord somatosensory evoked potentials (sSSEP), was significantly slower in the -ZnAL animals at 5.5 weeks. Examination of teased preparations and histologic sections of sciatic nerves at 5.5 weeks revealed no degenerative lesions or differences in density of myelinated fibers (MF). The size frequency distribution of MF in all groups was unimodal, with a trend toward smaller myelinated nerve fibers in -ZnAL and +ZnRF animals. Sciatic nerve Na,K-ATPase activity in the -ZnAL animals was significantly reduced after 4 weeks of zinc deprivation. At 5.5 weeks, nerve concentrations of myo-inositol, glucose, fructose, and sorbitol were significantly decreased in -ZnAL animals compared with the +ZnRF and +ZnAL controls. The peripheral neuropathy associated with acute zinc deficiency is a parenchymatous axonal disorder characterized by slowed motor and sensory nerve impulse conduction and reduction in nerve Na,K-ATPase activity and nerve concentrations of simple sugars and their metabolites.

Cutaneous angiolipoleiomyoma.

We describe eight cases of cutaneous angiolipoleiomyoma, a rare tumor previously reported only once under the term cutaneous angiomyolipoma. Clinically, the tumors were acquired, solitary, asymptomatic nodules that were always acral in location. Patients' ages ranged from 33 to 77 years (median 52.6 years); the male/female ratio was 7:1. Signs of tuberous sclerosis or renal angiomyolipoma were absent in all cases. Histologically, the tumors were subcutaneous, well circumscribed, and composed of smooth muscle, vascular spaces, connective tissue, and mature fat. In some tumors the fat was the predominant component, and in others smooth muscle predominated. Elastic tissue stains revealed that some blood vessels had developed an elastic lamina whereas other blood vessels lacked it. Additional histologic features occasionally observed included vascular thrombi, glomus bodies, and focal mucin deposition.