Synthesis and biological evaluation of novel cryptophycin analogs with modification in the beta-alanine region.

Structure modification of the beta-alanine region (fragment C) of the potent antimitotic agent cryptophycin was investigated. This includes: (1) introduction of substituents at the previously unsubstituted C7 position of the macrolide ring and (2) replacement of the (2R)-3-amino-2-methyl-propanoic acid (beta-alanine) with various (1)-amino acids to give the corresponding 15-membered unnatural cryptophycin analogs.

Metabolism and disposition of the antifolate LY231514 in mice and dogs.

The metabolism and disposition of LY231514 was studied in mice and dogs. LY231514 is a novel pyrrotopyrimidine-based multi-target antifolate (MTA) showing broad in vivo antitumor activity in mouse models and is currently in phase II human clinical trials. Doses (iv) of the compound showed high plasma levels, resulting in AUC values of 30-33 micrograms-hr/ml for mice and dogs after 20 and 7.5 mg/kg doses, respectively. The compound was eliminated rapidly. Half-life values for mice and dogs were about 7 and 2 hr, respectively. In vitro plasma binding measured 56% in mice, 46% in dogs, and 81% in humans. Fecal elimination was the major excretion pathway in mice after single iv doses of [14C]LY231514. Urine constituted the major route of excretion in dogs. Parent LY231514 accounted for the majority of urinary radiocarbon in mice (90%) and dogs (68%). Minor metabolites were found in urine, but the amounts were too small to isolate or identify. Based on an earlier observation that LY231514 photodegraded to produce reaction products having similar retention times as these minor urinary isolates, a photo-oxidation system was developed which in fact produced these metabolites. Subsequently, these photolytically-produced materials were used as standards to identify two novel in vivo metabolites formed by oxidation of the pyrrolo-pyrimidine ring system of LY231514. The oxidative transformations are similar to those observed for tryptophan and other indoles in that the pyrrole ring is oxidized to give an amide; further oxidation cleaves this ring, one ring carbon is lost, and a ketone is formed.

Tolerance to reduction of oral steroid dosage in severely asthmatic patients receiving nedocromil sodium.

We examined the efficacy of nedocromil sodium as an oral steroid sparing agent in a group of 37 severe, oral steroid-dependent asthmatics. All were receiving daily or alternate-day prednisone. These patients had taken part in an earlier, 12-week double-blind trial of nedocromil sodium 16 mg daily by inhalation or matching placebo. They continued with test treatment (26 patients on nedocromil sodium and 11 on placebo) on a double-blind basis for a further 12 weeks. During this time, patients visited the clinic every 2 weeks, when asthma severity and symptoms were assessed. On the basis of these assessments, the dose of oral steroid was either decreased, or maintained at the same level, or the patient was withdrawn if the asthma had deteriorated to a clinically unacceptable level. The nedocromil sodium group was able to achieve a greater percentage reduction in oral steroid dose (P less than 0.05). The rate of withdrawal due to worsening asthma was 31% from active and 55% from placebo treatment. Trends in other variables (time before withdrawal and numbers of patients able to withstand complete removal of oral steroids) favoured nedocromil sodium but the differences between the groups were not statistically significant.

Communication: a pound of prevention.

The SGNA members identified many concerns regarding malpractice, negligence and liability during the Roundtable Discussion, "When You Think the M.D. Is Wrong...", and in the 1988 SGA Legal Issues Survey. These concerns included: communication, documentation, patient and staff abuse, abandonment, personal liability and informed consent, to name a few. This article is the first in a series that will address those concerns. Many of the situations described by the members during the Roundtable Discussion and in the Survey centered around deficiencies in communication which led to conflict. This article discusses communication as your first line of defense to prevent conflict, and ultimately, a law suit. Resolution of disagreements or conflict can occur simply and professionally, in most instances, with everyone winning. In addition, a discussion relating to communication as a conflict management technique, which may ultimately result in the desired outcome, is also presented.

Nursing malpractice: the importance of documentation, or saved by the pen!

Documentation is an elemental to nursing as wound care and vital sign assessment. This article examines the reasons and techniques for accurate and complete documentation in a medical record. Several examples of nursing malpractice involving improper documentation are described. Abbreviations, flow sheets, incident reports, late entries, errors and content are included in the discussion presented.

The anatomy of a malpractice lawsuit.

The rules and laws that govern lawsuits can differ greatly from state to state. This is especially true in the area of medical malpractice. In the last few years there have been a multitude of new laws enacted and an equal amount of legislation is under consideration as of this writing. This article is a general description of the legal process that occurs when an individual health care provide is sued.

Syntheses and activities of sulfur and selenium isosteric substitution analogues of retinol.

The syntheses of sulfur and selenium isosteric substitution analogues of retinol, namely, retinyl phenyl thioether (2b), retinyl phenyl selenoether (2c), and retinyl thioacetate (2e) are described. These retinoid derivatives were examined for activity in terms of "chemoprevention" of cancer by measuring the reverse keratinization of epithelial cells in vitro. Retinoid analogues 2b, 2c, and 2e were found to be active in 20, 80, and 33.3% of the cultures, respectively, as compared to 72.7% activity for trans-retinol.