Diminished susceptibility to daptomycin accompanied by clinical failure in a patient with methicillin-resistant Staphylococcus aureus bacteremia.

We cared for a patient with methicillin-resistant Staphylococcus aureus bacteremia who experienced clinical failure with daptomycin. The failure was accompanied by progressive elevation of the daptomycin minimum inhibitory concentration during treatment. DNA fingerprinting confirmed that the minimum inhibitory concentration elevation occurred within the same strain of methicillin-resistant Staphylococcus aureus. This observation provides important new information to clinicians who adopt this promising drug for treatment of serious infections caused by methicillin-resistant Staphylococcus aureus.     

A chimeric tyrosine/tryptophan hydroxylase

The neurotransmitter biosynthetic enzymes, tyrosine hydroxylase (TH), and tryptophan hydroxylase (TPH) are each composed of an amino-terminal regulatory domain and a carboxylterminal catalytic domain. A chimeric hydroxylase was generated by coupling the regulatory domain of TH (TH-R) to the catalytic domain of TPH (TPH-C) and expressing the recombinant enzyme in bacteria. The chimeric junction was created at proline 165 in TH and proline 106 in TPH because this residue is within a conserved five amino-acid span (ValProTrpPhePro) that defines the beginning of the highly homologous catalytic domains of TH and TPH. Radioenzymatic activity assays demonstrated that the TH-R/TPH-C chimera hydroxylates tryptophan, but not tyrosine. Therefore, the regulatory domain does not confer substrate specificity. Although the TH-R/TPH-C enzyme did serve as a substrate for protein kinase (PKA), activation was not observed following phosphorylation. Phosphorylation studies in combination with kinetic data provided evidence that TH-R does not exert a dominant influence on TPH-C. Stability assays revealed that, whereas TH exhibited a t_1/2 of 84 min at 37°C, TPH was much less stable (t _1/2=28.3 min). The stability profile of TH-R/TPH-C, however, was superimposable on that of TH. Removal of the regulatory domain (a deletion of 165 amino acids from the N-terminus) of TH rendered the catalytic domain highly unstable, as demonstrated by at _1/2 of 14 min. The authors conclude that the regulatory domain of TH functions as a stabilizer of enzyme activity. As a corollary, the well-characterized instability of TPH may be attributed to the inability of its regulatory domain to stabilize the catalytic domain.     

Uninformed Decisionmaking The Case of Surrogate Research Consent

A New York court recently struck down state Office of Mental Health regulations governing research involving subjects with impaired decisionmaking capacity. The court held that neither incapacitated adults nor minors could participate in any research protocol that contained a nontherapeutic element, irrespective of possible benefits to the subject or the importance of the knowledge to be gained. Although the decision rested on a technical point of law and dealt only with psychiatric research, the court's holding has significantly broader implications.     

The Role of the Clinical Research Coordinator in Multicenter Clinical Trials

The clinical research coordinator plays a crucial role in organizing a site's participation in the expanding arena of multicenter medical and pharmacologic clinical trials. This summary clarifies the role of the clinical research coordinator for inexperienced staff members assuming these responsibilities and outlines planning procedures leading to successful implementation. Emphasis is placed on establishing an interdependent relationship with the principal investigator, careful protocol assessment, team building, and staff feedback. Useful tools such as study manuals and physicians' study orders are described.     

Phase I and pharmacologie study of liposomal daunorubicin (DaunoXome)

Summary We have completed a phase I and pharmacology study of liposomally-encapsulated daunorubicin (DaunoXome). Of 32 patients entered, 30 were evaluable. No toxicity was encountered at the initial doseescalation steps from 10 to 60 mg/m². At 80 mg/m², two patients manifested grade 2 neutropenia. At least grade 3 neutropenia occurred in all patients receiving 120 mg/m². Alopecia and subjective intolerance were mild. Cardiotoxicity was not observed except for an episode of arrhythmia in a patient with lung cancer and prior radiation. Only one minor objective response was observed in this population of refractory solid tumors. Pharmacokinetics differed from those of the free drug with no detection of daunorubicinol. We recommend future phase II studies with a dose of 100 mg/m² in previously treated and 120 mg/m² of DaunoXome in previously untreated patients with solid tumors.EDW is supported in part by ACS award 92-14-1     

Systematic review of the treatment of cancer-associated anorexia and weight loss.

PURPOSE: We systematically assessed the efficacy and safety of appetite stimulants in the management of cancer-related anorexia. Literature databases were searched for randomized controlled trials of appetite stimulants in the treatment of cancer anorexia. MATERIALS AND METHODS: Studies were graded according to quality. Fifty-five studies met inclusion criteria. RESULTS: Only two drugs have evidence to support their use for anorexia (progestins and corticosteroids). There is strong evidence against the use of hydrazine sulfate. The outcomes of these trials have been mixed and patient population heterogeneous. CONCLUSION: The optimal dose, time to start, and duration of treatment for many appetite stimulants for cancer anorexia is still unknown. A more systematic approach to research methodology with universal outcome measure and prospective randomized studies are need. Combination regimens are needed but this cannot at the present time be supported by the data presented.