SUMMARYPurpose: To assess the pharmacology of perampanel and its antiseizure activity in preclinical models. Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl) benzonitrile] is a novel, orally active, prospective antiepileptic agent currently in development for refractory partial-onset seizures. ]Perampanel binding to rat forebrain membranes was not significantly displaced by glutamate or AMPA but was displaced by the noncompetitive AMPA receptor antagonists CP465022 (K i 11.2 ± 0.8 nM) and GYKI52466 (K i 12.4 ± 1 lM). In mice, perampanel showed protective effects against audiogenic, MES-induced, and PTZ-induced seizures (ED 50 s 0.47, 1.6, and 0.94 mg/kg, respectively). Perampanel also inhibited 6 Hz electroshock-induced seizures when administered alone or in combination with other antiepileptic drugs (AEDs). In amygdala-kindled rats, perampanel significantly increased afterdischarge threshold (p < 0.05 vs. vehicle), and significantly reduced motor seizure duration, afterdischarge duration, and seizure severity recorded at 50% higher intensity than afterdischarge threshold current (p < 0.05 for all measures vs. vehicle). Perampanel caused dosedependent motor impairment in both mice (TD 50 1.8 mg/ kg) and rats (TD 50 9.14 mg/kg), as determined by rotarod tests. In mice, the protective index (TD 50 in rotarod test/ ED 50 in seizure test) was 1.1, 3.8, and 1.9 for MES-induced, audiogenic, and PTZ-induced seizures, respectively. In rat, dog, and monkey, perampanel had a half-life of 1.67, 5.34, and 7.55 h and bioavailability of 46.1%, 53.5%, and 74.5%, respectively. Significance: These data suggest that perampanel is an orally active, noncompetitive, selective AMPA receptor antagonist with potential as a broad spectrum antiepileptic agent.

The effect of cyclophosphamide (CY) on ovarian function was studied in patients with breast cancer receiving prolonged daily administration of this agent (100 mg/day) after radical surgery. Out of 18 premenopausal patients that received 8.4-39.9 g CY, 15 developed permanent amenorrhea. The average dose given before the onset of amenorrhea was 5.2 g in patients in their 40s and 9.3 in their 30s. Urinary estrogens and serum progesterone were measured weekly for approximately 6 months postoperatively in six patients receiving CY. After the onset of amenorrhea, the levels of both hormones ceased to show their normal cyclic changes and remained low persistently, meanwhile serum FSH and LH were markedly elevated. No ovarian follicle was histologically found in three amenorrheic patients who underwent therapeutic oophorectomy after CY therapy. These findings indicate that CY induced primary ovarian failure.

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Background. Epidemiologic and experimental studies suggest that dietary fish oil and vegetable oil high in ω‐3 polyunsaturated fatty acids (PUFAs) suppress the risk of colon cancer. The optimal amount to prevent colon carcinogenesis with perilla oil high in ω‐3 PUFA α‐linolenic acid in a 12% medium‐fat diet was investigated in female F344 rats. For comparison, safflower oil high in ω‐6 PUFA linoleic acid was used. Methods. Thirty or 25 rats at 7 weeks of age in each group received an intrarectal dose of 2 mg N‐methyl‐N‐nitrosourea 3 times weekly in weeks 1 and 2 and were fed the diets with various levels of perilla oil and safflower oil throughout the experiment. Results. The incidence of colon cancer at the termination of the experiment at week 35 was 40%, 48%, and 32% in the rats fed the diets with 3% perilla oil plus 9% safflower oil, 6% perilla oil plus 6% safflower oil, and 12% perilla oil plus 0% safflower oil, respectively, whereas it was 67% in the rats fed the control diet with 0% perilla oil plus 12% safflower oil. The amount of diet consumed and the body weight gain were identical in all of the dietary groups. The ratios of ω‐3 PUFA to ω‐6 PUFA in the serum and the colonic mucosa at week 35 were increased in parallel to the increased intake of perilla oil. Conclusions. The results suggest that a relatively small fraction of perilla oil, 25% of total dietary fat, may provide an appreciable beneficial effect in lowering the risk of colon cancer.

Nine patients with solitary sternal metastasis of breast carcinoma were treated aggressively, with partial (n = 8) or total (n = 1) resection of the sternum. Parasternal and mediastinal lymph node dissection also was performed concomitantly for every patient. Chest wall defects were reconstructed with acrylic resin plate (n = 3) or rectus abdominus myocutaneous flap (n = 6). All patients received chemoendocrine therapy postoperatively. The median survival of these nine patients was 30 months. The prognosis of the patients (n = 4) with the mediastinal or parasternal lymph node metastasis were poor and all of them died of second relapse within 30 months. The prognosis of those (n = 5) without the lymph node metastasis, however, was quite favorable; three survived more than 6 years. These results suggest that sternectomy should be indicated for the solitary sternal metastasis when no evidence of systemic spread is noted since it can improve the quality of life and occasionally may result in long-term survival. Cancer 621397-1401, 1988. REAST CANCER has tendency toward frequent relapse B in bone; the incidence of bone metastasis is reported 56% on autopsy,' the most frequent sites of bone metas-tasis being the thoracic and lumbosacral spine. The bone metastasis usually appears to be multicentric and, even in case of solitary metastasis at initial presentation, should be considered multiple in nature. Therefore surgery, as a curative treatment, is not indicated for bone metastasis but as a palliative treatment for pathologic fractures and compression of the spinal cord. We believe, however, that sternal metastasis should be considered as a different category from vertebral bone metastasis since the sternum lacks communication to the paravertebral venous plexus,* through which cancer cells spread easily to other bones. Sternal metastasis seems more likely to remain solitary for a longer time. Therefore, we believe that surgery can be indicated for sternal me-tastasis as an effective treatment when no evidence of sys-temic spread is found. For the reasons mentioned above, we have treated ster-nal metastasis aggressively, with partial or total resection of the sternum. Unfortunately, reports are rare regarding surgical treatment for sternal metastasis of breast cancer. The current article reports results of surgical treatment of nine patients with first relapse in the sternum. Patients From 1964 to 1986, 1570 patients with operable breast cancer underwent mastectomy in the Center for Adult Diseases, Osaka, Japan. Bone lesion as the first manifestation of relapse was found in 88 patients, comprising 27% of the 326 patients having relapse postoperatively. Although the most frequent sites of bone relapse were the cervical, thoracic, and lumbosacral spine (67%), five patients developed sternal metastasis. Another four patients with sternal metastasis were referred to our hospital. In all, nine patients with sternal metastasis were analyzed in this report. The clinical and histologic characteristics of the primary breast can...