A Phase I study to assess the safety, tolerability, and pharmacokinetics of AZD4877, an intravenous Eg5 inhibitor in patients with advanced solid tumors.

PURPOSE: Inhibition of kinesin spindle protein or Eg5 causes the formation of monoastral mitotic spindles, which leads to cell death. AZD4877 is a specific, potent inhibitor of Eg5. METHODS: This was a Phase I, open-label, two-part study to evaluate the maximum tolerated dose (MTD) and safety and tolerability of AZD4877 in patients with advanced solid malignancies. In part A, the MTD of AZD4877, administered as three weekly 1-h intravenous (iv) infusions in a 28-day schedule, was determined by evaluating dose-limiting toxicity (DLT). In part B, the safety, tolerability, and pharmacokinetic profile of AZD4877 at the MTD were evaluated. RESULTS: In part A, 29 patients received at least one dose of AZD4877 (5 mg, n = 4; 7.5 mg, n = 4; 10 mg, n = 3; 15 mg, n = 3; 20 mg, n = 3; 30 mg, n = 6; 36 mg, n = 3; 45 mg, n = 3). The MTD was defined as 30 mg, with the primary DLT being neutropenia. Although exposures appeared to be similar at the AZD4877 20 and 30 mg doses, dose reductions and omissions were higher in the 30-mg cohort; therefore, an intermediate dose, 25 mg, was evaluated in part B (n = 14). In part B, neutropenia remained the most commonly reported causally related adverse event. Exposure to AZD4877 was approximately dose proportional. Severity of neutropenia was related to exposure. CONCLUSION: The MTD of AZD4877 given as a 1-h iv infusion on days 1, 8, and 15 of a 28-day cycle was 30 mg. At the selected 25 mg dose, AZD4877 had an acceptable safety profile.

Triage: techniques and applications in decision making.

Correct decision making may have far-reaching consequences. Triage is an area in which decision-makers must know what they are doing, why they are doing it, and which actions to take to achieve a satisfactory outcome. Triage has its origins in military history and today is used in a variety of medical settings. In this article we focus on the role of triage in disaster situations, its application in military settings, and its use in disaster medicine. Useful concepts enabling correct decision making by the triage officer include the application of computer technology and a review of methods of patient categorization. The dynamic nature of triage and the role of the triage officer as part of a team approach to disaster patient management are highlighted. We explore techniques for the successful training and education of triage officers and investigate a model of the emergency physician as the triage officer.

Management of unique clinical entities in disaster medicine.

This article discusses the management of clinical problems encountered particularly in disasters. These include the principles of multiple-casualty triage, and field and hospital management of blast injury, crush syndrome, compartment syndrome, particulate inhalation, and traumatic asphyxiation. The indications for extraordinary measures, such as field amputation, are detailed. A brief review of the causes and epidemiology of these entities is provided, with emphasis on the clinical management in the disaster setting.

Disasters within hospitals.

Hospital disaster planning should encompass events that affect the safety of the hospital environment and address those measures that ensure the availability of necessary services. Although most of the emphasis has been placed on general disaster planning, there is little written about disasters occurring within a hospital. In recent years, several incidents at our medical center involving fire, flood, and power failure resulted in a reevaluation of our preparedness to handle such situations. These experiences prompted this discussion and literature review of internal disaster plan because it is likely that at some time an internal emergency may occur.

Reactivation of latent herpes simplex virus by excimer laser photokeratectomy.

We tested whether excimer laser photorefractive and phototherapeutic keratectomy may reactivate latent herpes simplex and cause recurrent keratitis in mice. Two of ten latently infected mice that were treated with ten excimer laser pulses to the corneal epithelium shed herpes simplex virus type 1, as did four of ten mice that were treated with 50 excimer laser pulses. Ocular shedding of herpes simplex virus was detected in four of ten mice that were treated with ethylenediamine-tetraacetic acid (EDTA) scraping of the corneal epithelium without laser keratectomy, and in six of ten mice on which combined EDTA-facilitated epithelial removal was performed followed by the application of ten excimer laser pulses. In both EDTA-treated groups, viral shedding was prolonged and 18 of 20 mice developed marked corneal opacification or neovascularization, or both. Corneal photoablation with the excimer laser may induce reactivation of latent herpes simplex virus, even in mice with clear and smooth-appearing corneas, and should be considered in the differential diagnosis of humans with persistent corneal epithelial defects after refractive or therapeutic excimer procedures.

Estrogen and progesterone receptors and human conjunctiva.

Freshly frozen conjunctival tissue from premenopausal and postmenopausal women and male subjects were processed for estrogen and progesterone receptors by using monoclonal antibodies and a peroxidase-antiperoxidase technique. No immunocytochemical staining was localized in the nuclei of the cells treated with the monoclonal antibodies to human estrogen receptor or human progesterone receptor in any of the conjunctival specimens, in contrast to the strongly positive staining in breast adenocarcinoma controls. Immunocytochemical staining disclosed no evidence for estrogen or progesterone receptors on cells of the ocular surface.

Culture and 'compliance' among leprosy patients in Pakistan.

In Pakistan approx. 30% of the 18,000 known leprosy patients have dropped out of their treatment programs. To investigate reasons for such widespread noncompliance, 128 diagnosed leprosy patients--59 outpatients and 69 inpatients--were interviewed in Karachi. More than half of the 'noncompliant' outpatients denied having the disease. Denial was found to be an understandable coping mechanism in view of the severe stigma associated with leprosy. The presence of close-knit extended families, in which joint decision-making was the norm and in which such a dread diagnosis could spell the end of job and marriage prospects for even distant relatives, contributed to the likelihood of denial. In such a setting, the very term 'noncompliant' appeared to be an oversimplification since it covered so many different types of culturally-constrained behavior. In addition, many of the patients who initially seemed most 'compliant' by virtue of being long-term hospital inpatients in fact owed their hospitalization to the fact that they had been markedly noncompliant in the past. Thus the usual view that adherence to a biomedical treatment regimen constitutes 'compliance' and that nonadherence to such a regimen constitutes 'noncompliance' proved inadequate for understanding the health behavior of these Third World leprosy victims. The study also showed that many patients had initially consulted traditional healers, inadequately-trained physicians, and/or untrained medical practitioners for treatment of their symptoms, which resulted in lengthy delays before they were correctly diagnosed. Further, even after the diagnosis was made and appropriate medications were prescribed by trained personnel, most patients were not told what had caused their leprosy and how the drug regimen worked to combat it: when questioned, only 4% of the 128 respondents attributed the disease to infectious organisms. In addition, patients were usually not warned in advance of the possibility of undesirable side effects from their leprosy medications, which led to further 'compliance' problems. The findings of this study emphasize the need for better training of physicians and other health care providers in early diagnosis of leprosy and better health education of diagnosed patients. To be truly effective, the treatment of leprosy must include counseling of extended families and education of the public at large as well as enhanced communication with the patients themselves.

Eye lesions of epidermolysis bullosa. Clinical features, management, and prognosis.

Blepharitis, bullous lesions of the eyelids, and corneal erosions occur in patients with some, but not all, forms of epidermolysis bullosa. This preliminary report documents the ophthalmologic lesions observed in a series of 78 patients of varying ages.

Astrocytoma of the ciliary body.

A healthy 24-year-old man was noted to have rubeosis iridis and a ciliary body mass. Iridocyclectomy successfully removed the lesion with preservation of vision and resolution of rubeosis. Histologic and immunocytochemical examinations revealed a glial tumor of the ciliary epithelium.

Contrasting patterns of blood pressure and related factors within a Maori and European population in New Zealand.

Contrasting patterns of blood pressure are found for contiguous populations of Maori and Europeans living in New Zealand. Among the 511 participants in this study, approximately one-fifth manifested elevated levels of blood pressure. The Maori adults were found to have generally higher pressure levels compared with the Europeans; however, the opposite relationship appears when Maori and European youth are compared. Consistently lower blood pressure levels are found in the Maori youth. An examination of the trends by age shows a distinct crossover in early adulthood when the Maori begin to manifest blood pressure elevations at a sharply increased rate compared with the Europeans. Differences in body mass are found between the youthful segments of the populations. Body mass index is found to be significantly higher among the Maori youth; nonetheless, the European youth demonstrate higher levels of blood pressure. The study examines possible interactions between blood pressure and possible stress-related factors such as career aspirations in the presence of varying social and academic pressures. For both ethnic groups we find that, relative to the group means, those with the highest academically-related ambitions, demonstrate the highest levels of blood pressure.

Stressful life events and marital dysfunction.

The relationship between stress and marital dysfunction was examined in 1979-80 through a study of two demographically matched groups of married couples. The study group consisted of couples who had been referred for therapy for marital problems while the control group had never been referred for psychiatric treatment of any kind. The authors compared the incidence, magnitude, and source of stressful life events. The two groups of couples differed in their reports of the incidence and sources of stress, but not in the magnitude of stress. Study couples reported almost twice the frequency of stressful events over the three-year period before referral and a significant increase in stress in the year immediatly before referral. Changes in family structure, family interaction, or both were the major sources of stress for both groups but especially so far the referred couples. The authors concluded that a significant association exists between stressful life events and marital dysfunction, and that the clincal assessment of life events can play a meaningful role in evaluation and treatment planning.