Radioiodinated derivatives of beta adrenoceptor blockers for myocardial imaging.

Four new beta-adrenoceptor blocking agents carrying tyramine as the amino moiety were synthesized and the distribution of their I-125-tagged derivatives evaluated in rats. This distribution was compared with the distribution of various agonists and antagonists labeled with H-3 and C-14, and with the in vitro binding affinity of the new derivatives. A radioiodinated derivative of a cardioselective blocker, alprenolol, showed poor blood clearance and no cardiac selectivity. A derivative of another cardioselective blocker, practolol, showed a promising heart-to-blood ratio (ca. 19) and cardioselectivity with a heart-to-lung ratio of ca. 2. Two additional practolol analogs showed no improvement over the practolol derivative; because of the increased lipophilicity of these derivatives, blood clearance and cardioselectivity were diminished. An inverse correlation is suggested between the dissociation constant for the beta adrenoceptor in the lung and the heart-to-blood and heart-to-lung values. We conclude that polarity plays an important role in the blood clearance and cardioselectivity of these beta-adrenoceptor derivatives.     

11 November 1979--a day to remember: the Mississauga disaster

The derailment of a train carrying potentially lethal chlorine, accompanied by exploding tank cars of propane, set into motion the evacuation of the Mississauga Hospital, Queensway General Hospital (Etoblcoke), and Oakville-Trafalgar Memorial Hospital, near Toronto. The method in which the three hospitals, along with the 220,000 residents of Mississauga, were evacuated was so highly efficient and orderly that many now question the necessity of the action. But absence of panic should not be interpreted as an absence of danger. The Economist (17 - 23 November, 1979, volume 273, number 7107) extrapolated data from a British study to show there was enough chlorine in the tank to kill 24,000 people, given the population density in the area of the derailment. The purpose of this article is to describe the involvement of hospital pharmacy in the "Mississauga Saga", and to draw some conclusions from this experience.     

Effect of postextrasystolic potentiation on amplitude and timing of regional left ventricular wall motion in ischaemic heart disease

In order to investigate the effects of postextrasystolic potentiation on left ventricular wall motion, the left ventriculograms of 30 patients were digitised frame by frame and regional movement demonstrated by contour displays. Postextrasystolic potentiation caused significant increases in end-diastolic volume, ejection fraction, and peak ejection and filling rates. The amplitude of normally moving segments increased by 5.7 +/- 2.3 mm, regardless of initial amplitude. Hypokinetic segments moved normally if the initial amplitude was greater than 5 mm, and there was a reduced or absent response if 4 mm or less. Four specific abnormalities of timing of motion were studied during isovolumic contraction, early ejection, and isovolumic relaxation. Their timing and extent were all unaffected in postextrasystolic beats. These results thus give no evidence for the entity "reversible asynergy". Rather, they suggest that the response of local wall motion to postextrasystolic potentiation depends only on basal amplitude and increased volume change in postextrasystolic beats.     

Studies on the stability of trimelamol, a carbinolamine-containing antitumor drug

The stability of trimelamol (N2,N4,N6-trimethylol-N2,N4,N6-trimethylmelamine) a synthetic carbinolamine-containing antitumor drug, has been studied. Two major degradation pathways have been characterized and a unified mechanism proposed to rationalize the chemistry involved. One degradation pathway involves the consecutive loss of hydroxymethylene units by elimination of formaldehyde until the parent trimethylmelamine (4) results. An HPLC method was used to obtain kinetic data for the loss of trimelamol and to monitor the order of appearance of three degradation products. This pathway was shown to follow first-order kinetics at all pH values studied at both 18 and 37 degrees C. The second pathway involves the coupling of two trimelamol molecules via a methylene bridge to form bis(trimelamol) (6) which had been previously referred to in the literature as a "polymer". This reaction is acid catalyzed and temperature dependent. Bis(trimelamol) is virtually water insoluble and adheres strongly to glass surfaces. Finally, t1/2 values have been determined for trimelamol in aqueous solution at different temperatures, and the kinetics of formation of degradation products has been studied over a period of 30 h under a variety of conditions of pH and temperature. The data reported here are relevant to both the formulation and clinical administration of trimelamol, and may contribute to an understanding of mechanism of action and future analogue development studies.     

DNA damage and differential cytotoxicity produced in human carcinoma cells by CC-1065 analogues, U-73,975 and U-77,779.

U-73,975 (U-73) and U-77,779 (U-77), two analogues of the cyclopropylpyrroloindole antitumor antibiotic CC-1065, are promising novel chemotherapeutic agents which are known to alkylate the N3 position of adenine in a sequence-selective manner. The concentration of U-73 required to produce a 1 log cell kill in 6 human tumor cell lines varied from 20-60 pM. U-77 was more cytotoxic than U-73, with the concentrations required for a 1 log cell kill ranging from 1-20 pM. The cytotoxicity of U-73 and U-77 was found to be independent of the guanine O6-alkyltransferase phenotype. The sensitivity of the BE and HT-29 human colon carcinoma cells was increased when the time of drug exposure was increased from 2 to 6 h. DNA interstrand cross-links, as measured by the technique of alkaline elution, could only be detected when HT-29 or BE cells were exposed to extremely high concentrations of U-77 for 6 h. No other forms of DNA damage were detected in genomic DNA with either compound. U-77 was also found to induce DNA interstrand cross-links in naked DNA, as measured by an agarose gel method. The rate of interstrand cross-linking was extremely rapid with the "second-arm" of the cross-link being completed within 2 h. The mechanism by which these cyclopropylpyrroloindole compounds elicit their cytotoxicity, however, remains to be elucidated.     

The cellular basis of delirium and its relevance to age-related disorders including Alzheimer's disease.

A wide variety of conditions lead to delirium (i.e., metabolic encephalopathies) in human beings and animals. Despite the varied etiology the clinical consequences are relatively stereotyped which suggests that the diverse insults that cause delirium may act by common metabolic and cellular "final pathways." Related molecular and cellular mechanisms may be involved in aging and Alzheimer's disease, conditions that predispose to the development of delirium. Animal models of delirium better reflect age-related disorders such as Alzheimer's disease than those that impair a single neurotransmitter system such as the cholinergic system; the metabolic encephalopathies produce global cognitive disturbance, which is more typical of these disorders. Thus, research related to delirium has far-reaching implications for normal and abnormal brain function.