The clinical pharmacology of the adenosine deaminase inhibitor 2′-deoxycoformycin

Summary 2-deoxycoformycin (2-dCF; Pentostatin), a stoichiometric inhibitor of mammalian adenosine deaminase (ado deaminase), exhibits immunosuppressive and antilymphocytic activity in animal test systems. A clinical pharmacology/phase I study of 2-dCF administered as a single agent has been completed (18 patients). Dose levels ranged from 0.1 mg/kgx1 to 0.25 mg/kg/dayx5; ado deaminase and 2-dCF were measured spectrophotometrically. Plasma decay curves were bi-exponential ( and t_1/2 values about 1 and 10 h respectively). Recovery of unchanged 2-dCF from urine (48 h) was 32%–48% of the administered drug. Major toxic manifestations were lymphocytopenia (all patients) and urate nephropathy (1 patient, with subsequent patients in the series receiving allopurinol, 300 mg/day). Three partial responses were seen in seven patients with acute lymphocytic leukaemia receiving 0.25 mg 2-dCF/kg/dayx5.     

The development of a medication reminder card for elderly persons

This paper describes the development and testing of a medication reminder card specifically designed for elderly persons on complex drug regimens. The need for such a system was confirmed by a survey of approximately 100 Canadian hospital pharmacy departments where no system provided at discharge by respondents met with our criteria for the "ideal" card. The new medication reminder card was tested in 29 ambulatory and 16 institutionalized elderly persons. Over 75 percent of patients continued to use the card two weeks post enrollment and a majority of ambulatory elderly were still using the card at six weeks. In addition to organizing medications and providing a reminder for patients to take drugs, the card facilitated communication with the pharmacist (a mean of 20 minutes) and with other health care professionals. Patients found the card easy to read and the system easy to understand. Despite time constraints, eight of nine participating community pharmacists indicated they would continue to use the system for select patients. A major obstacle to the use of the card was patient reluctance, for a variety of reasons. Although the card will require further modification in design, it provides a useful alternative as a compliance aid for ambulatory and hospitalized patients on chronic, complex drug regimens.     

Detailed monitoring of the effects of mannitol following experimental head injury.

The experimental model of a cerebral missile injury developed by Crockard was used in three groups of Rhesus monkeys treated with mannitol. One group received mannitol 15 minutes after being injured with a BB pellet at 90 m/sec impact. Another group was wounded identically, but mannitol treatment was delayed until 1 hour after injury. The last group was wounded with the missile traveling at 180 m/sec, and mannitol was started 15 minutes after trauma. The data were contrasted with the results from the original model. After receiving mannitol, all groups showed marked improvement in mean blood pressure, cerebral perfusion pressure, cerebral blood flow, and cerebral metabolic rate of oxygen consumption out of proportion to the degree of reduction in intracranial pressure (ICP). The authors conclude that the therapeutic value of mannitol may, in some injuries, be directly related to its effects on blood flow and metabolism, as well as to its better known effects upon ICP.     

Economic impact analysis: a theoretical approach

Where the traditional focus of local planning has been on access to health services, recent legislation and policy reflect an equally prominent concern for costs. Appropriate methodologies for collection and analysis of financial and economic data have been lacking. A particularly difficult problem, both theoretically and practically, is the economic impact of a capital investment by one provider on the rest of the local service system. In order to focus the attention of health service planners, economists and others on this issue, a preliminary theory of "economic impact analysis" is outlined here. Scope of concern and conditions of application ("ripple" and "spigot" models) are defined. Existing analytical tools are reviewed, and related philosophical issues raised.     

Treatment of human tumor xenografts with monoclonal antibody 806 in combination with a prototypical epidermal growth factor receptor-specific antibody generates enhanced antitumor activity.

Monoclonal antibody (mAb) 806 is a novel epidermal growth factor receptor (EGFR) antibody with significant antitumor activity that recognizes a mutant EGFR commonly expressed in glioma known as delta2-7 EGFR (de2-7 EGFR or EGFRvIII) and a subset of the wild-type (wt) EGFR found in cells that overexpress the receptor. We have used two human xenograft mouse models to examine the efficacy of mAb 806 in combination with mAb 528, a prototypical anti-EGFR antibody with similar specificity to cetuximab. Treatment of nude mice, bearing s.c. or i.c. tumor human xenografts expressing the wt or de2-7 EGFR, with mAbs 806 and 528 in combination resulted in additive and in some cases synergistic, antitumor activity. Interestingly, mAb 528 was also effective against xenografts expressing the ligand independent de2-7 EGFR when used as a single agent, showing that its antitumor activity is not merely mediated through inhibition of ligand binding. When used as single agents, neither mAbs 806 or 528 induced down-regulation of the de2-7 EGFR either in vitro or in vivo. In contrast, the combination of antibodies produced a rapid and dramatic decrease in the total cell surface de2-7 EGFR both in vitro and in xenografts. Consistent with this decrease in total cell surface de2-7 EGFR, we observed up-regulation of the cell cycle inhibitor p27(KIP1) and a decrease in tumor cell proliferation as measured by Ki-67 immunostaining when the antibodies were used in combination in vivo. Thus, mAb 806 can synergize with other EGFR-specific antibodies thereby providing a rationale for its translation into the clinic.     

Scintigraphic evaluation of colonic transit in two patients with idiopathic chronic constipation

Bowel transit in two women with protracted constipation was evaluated after oral administration of In-111 DTPA in water. Serial abdominal images were obtained for as long as 96 hours to assess transit through the stomach, small bowel, and colon. In both patients, large bowel transit was delayed. A pattern of colonic inertia was observed in one patient, whereas retention in the distal colon was seen in the other patient. Both patients underwent total colectomy with marked symptomatic relief. Colonic transit studies of these patients are presented, and the literature is reviewed.     

Journeying with Peter and Sam: reflections on a healing attitude

Reflection enables the practitioner to learn through everyday experiences towards realising desirable practice however it is articulated. In this paper I share my story in journeying with Peter and Sam in a hospice setting with the intention to ease suffering. In considering what is significant within this story, I pay particular attention to the idea of a healing attitude for deeper reflection in order to develop my appreciation of the nature and significance of a healing attitude.