A phase 1 study of tazarotene in adults with advanced cancer.

Tazarotene is an acetylenic retinoid which is metabolised to tazarotenic acid and which binds selectively to the retinoid receptors RARbeta and RARgamma. The safety, toxicity and pharmacokinetics of oral tazarotene were determined over 12 weeks of treatment in 34 patients with advanced cancer. Commonly seen toxicities were mucocutaneous symptoms, musculoskeletal pain and headache. Dose-limiting toxicities were hypercalcaemia, hypertriglyceridaemia and musculoskeletal pain. The maximum tolerated dose of tazarotene in this schedule is 25.2 mg day(-1). Plasma concentrations of tazarotenic acid were found to peak rapidly within 1-3 h of dosing and thereafter declined quickly. The C(max) and AUC values on day 0, and weeks 2 and 4 were similar indicating no drug accumulation. The dose-normalised C(max) and AUC values at different dose levels and different study days appeared to be similar indicating linear pharmacokinetics. No objective responses were seen, although stable disease was seen in six out of eight evaluable patients receiving the three highest dose levels of tazarotene (16.8, 25.2 or 33.4 mg day(-1)). We conclude that oral tazarotene is well tolerated when administered daily for 12 weeks, has a favourable toxicity profile compared with other retinoids and merits further investigation as an anticancer therapy.

Antagonists of retinoic acid receptors (RARs) are potent growth inhibitors of prostate carcinoma cells.

Novel synthetic antagonists of retinoic acid receptors (RARs) have been developed. To avoid interference by serum retinoids when testing these compounds, we established serum-free grown sub-lines (>3 years) of the prostate carcinoma lines LNCaP, PC3 and DU145. A high affinity pan-RAR antagonist (AGN194310, K(d) for binding to RARs = 2-5 nM) inhibited colony formation (by 50%) by all three lines at 16-34 nM, and led to a transient accumulation of flask-cultured cells in G1 followed by apoptosis. AGN194310 is 12-22 fold more potent than all-trans retinoic acid (ATRA) against cell lines and also more potent in inhibiting the growth of primary prostate carcinoma cells. PC3 and DU145 cells do not express RARbeta, and an antagonist with predominant activity at RARbeta and RARgamma (AGN194431) inhibited colony formation at concentrations (approximately 100 nM) commensurate with a K(d)value of 70 nM at RARgamma. An RARalpha antagonist (AGN194301) was less potent (IC(50) approximately 200 nM), but was more active than specific agonists of RARalpha and of betagamma. A component(s) of serum and of LNCaP-conditioned medium diminishes the activity of antagonists: this factor is not the most likely candidates IGF-1 and EGF. In vitro studies of RAR antagonists together with data from RAR-null mice lead to the hypothesis that RARgamma-regulated gene transcription is necessary for the survival and maintenance of prostate epithelium. The increased potencies of RAR antagonists, as compared with agonists, suggest that antagonists may be useful in the treatment of prostate carcinoma.

AIHA metrication update.

One of the major advantages of the SI is its precise nomenclature and rules of use. Close compliance with the SI nomenclature and rules of use assures that the SI are universally understood without additional parenthetical explanations. In the english system where symbols, abbreviations and other modifications are continuously changing one can never be sure what CFM, cfm, scf, acf, etc. mean unless the author first defines these abbreviations. More detailed information regarding the use of the SI are contained in the references cited at the end of this article.

Pediatrics manpower requirements.

Assessment and projection of manpower requirements are difficult and compelx undertakings for which no single methodology has proven to be entirely satisfactory. A frequently used approach to estimation of manpower requirements is the number of physicians needed per population. A numerical approach alone is inadequate for it fails to take into account the types and quality of services to be delivered. There are many factors which affect manpower estimates, several of which are not quantifiable. Factors unique to pediatrics which must be considered include the changing nature of health needs of the population in the age range from 0 to 21 years; the changes in the practice of pediatrics; the increasing emphasis on the importance of preventive health care and health maintenance; and the impact of scientific advances on the demand for services. A most important variable is the national level of cohort fertility. Fluctuations in this rate significantly affect the numbers of children and adolescents requiring care. It is concluded that there will not be an excess of pediatricians in 1980 and 1990. Indeed, it is questionable whether the health needs of the pediatric population can be adequately met in those years.

Metrication and AIHA.

AIHA supports a planned orderly national program for conversion to the metric system and will cooperate with other technical societies and organizations in implementing this voluntary conversion. The Association will use the International System of Units (SI) as modified by the Secretary of Commerce for use in the United States in all official publications, papers and documents. U.S. customary units can be presented in parentheses following the appropriate SI unit, when it is necessary for clarity.

Evaluation of charcoal sampling tubes.

The effectiveness of MSA charcoal tubes and those constructed by the USAF Environmental Health Laboratory were statistically compared. No significant differences were noted. Also, tube recovery efficiencies were determined for 10 different solvents for which there was no or limited data. The effects of moisture on gravimetric analysis are presented.