Disposition of the Aromatase Inhibitor LY56110 and Associated Induction and Inhibition Studies in Rats, Dogs, and Monkeys

Disposition of the Aromatase Inhibitor LY56110 and AssociatedInduction and Inhibition Studies in Rats, Dogs, and Monkeys.LINDSTROM, T. D., AND WHITAKER, G. W. (1987). Fundam. Appl.Toxicol. 8, 595–604. Compound LY56110 was well absorbedbut slowly excreted in the rat, dog, and monkey. Oral administrationof 5 mg/kg of [¹⁴C]LY56110 (5-bis(4-chlorophe-nyl)methylpyrimidine)to the rat, monkey, and dog resulted in a total excretion of68, 65, and 30% of the radioactivity within 5 days, respectively.Very low urinary excretion was observed in the rat and dog (2%),with fecal excretion being the predominant mode of eliminationin all three species. The plasma radioactivity half-life was49, 41, and greater than 100 hr in the rat, monkey, and dog,respectively. The plasma half-life of parent compound was 18hr in the rat and 10 hr in the dog. LY56110 accounted for only25, 12, and 1% of the plasma radioactivity area under the curvein the rat, dog, and monkey, respectively. High levels of radioactivitywere observed in the target tissues of fat, adrenals, and ovariesof rats. LY56110 induced hepatic cytochromes b₅ and P-450 andcytochrome c reductase in rats after 14 days of oral dosingat 10 mg/kg but not in monkeys after 10 days of oral dosingat 10 mg/kg. The compound was more potent than aminoglutethimideor cimetidine in inhibiting hepatic ethylmorphine and p-nitro-anisoledemethylase activity in vitro. LY56110 also inhibited ethinamate-inducedsleeping time in rats in vivo. The compound induced a reversetype I binding spectrum with rat ovarian microsomes.     

Cremation of Leadless Pacemaker

Cremation of implanted cardiac electronic devices can be associated with explosion from rapid gas formation causing potential hazard to the crematoria staffs and facilities. We present four patients who had undergone cremation with a leadless pacemaker (Micra^TM, Medtronic Inc., Minneapolis, MN, USA) left inside their bodies. There was neither reported explosion nor damage to the cremation chamber during the cremation process. In this small series, cremation of Micra^TM is not associated with noticeable explosion.     

Leukocyte antibodies in human sera and in immune rabbit sera

A study of leukocyte antibodies is presented using (1) the sera of rabbits immunized with human leukocytes, and (2) the sera of three patients screened forthe presence of such antibodies from among 36 patients with hematologic disease,31 of whom (including the 3 studied in detail) had received multiple transfusions.The following technics are described and were employed: Leukoagglutination,leukoprecipitation including tube and agar-plate methods, agglutination ofantigen-coated tanned and untanned sheep erythrocytes, the effect of antiseraupon phagocytosis of heat-killed staphylococci by leukocytes, and upon ameboidmotility of leukocytes.

The leukoagglutinin test gives reliable clearcut results providing that appropriate controls are included and certain criteria adhered to, in order to facilitatethe recognition of clumping due to other factors than true antigen-antibodyunion.

No leukoprecipitins were detected in human sera with the technics used inthis study. Immune rabbit sera, on the other hand, gave two reaction-lines inagar media, when set up against leukocyte extract.

Immune rabbit sera reacted strongly with antigen-coated tanned sheep redblood cells. Human sera did not so react. One of the three selected human serareacted with antigen-coated untanned erythrocytes, suggesting the presence of apolysaccharide antigen extractable from human leukocytes and capable of stimulating antibody formation in the human. Immune rabbit sera, and otherhuman sera, did not react in this test.

A suggestive but perhaps not a conclusive effect upon phagocytosis of bacteriaby leukocytes exposed to human leukocyte antibody for 1 hour could be demonstrated.

By means of ameboid motility studies, a cytotoxic effect of the human antiseraupon human leukocytes could be demonstrated after 18 hours of incubation, butnot after 3 hours. This was interpreted as evidence of a delayed reaction.

Certain cardinal points from a clinical and theoretical standpoint with regardto the genesis of leukocyte antibodies in man are briefly reviewed. A possibleanalogy between leukocyte antibody formation and the homograft reaction isdiscussed. It is suggested that the rarity of leukocyte iso-antibody formationfollowing transfusion is related to the fact that the intravenous pathway may bea poor route of immunization for these antigens.

Submitted on April 4, 1957 Accepted on July 1, 1957     

Studies of Alpha-2-Adrenoceptor Function in Abstinent Alcoholics

Hormonal, haemodynamic and subjective psychological responses to the intravenous infusion of clonidine were investigated in nine male alcoholics who had been abstinent for 5 weeks, and were compared with those of nine healthy controls. The growth hormone response to clonidine was significantly blunted in the abstinent alcoholics. Both baseline cortisol levels and the clonidine-induced cortisol decrease were significantly greater in the alcoholics than in controls. Blood pressure, pulse rate and psychological responses to clonidine were similar in both groups. These results indicate that some aspects of alpha-2-adrenoceptor sensitivity are persistently abnormal in alcoholics at least 5 weeks into abstinence.     

Exteroceptive suppression of temporalis and masseter muscle activity is enhanced in offspring of hypertensives

Exteroceptive suppression of temporalis and masseter muscle activity was examined in young men with and without a parental history of hypertension. Recent clinical studies suggest that the second exteroceptive suppression period is attenuated in several chronic pain disorders and that this brainstem reflex may serve as a noninvasive index of endogenous pain control. In the present study, offspring of hypertensives exhibited a significant protraction of the late exteroceptive suppression period for both muscle sites, suggesting that the decreased pain sensitivity previously observed in individuals at risk for hypertension may be related to enhanced central pain modulation.     

Respiratory sinus arrhythmia: Autonomic origins, physiological mechanisms, and psychophysiological implications

Respiratory sinus arrhythmia (RSA) is being used increasingly in psychophysiological studies as an index of vagal control of the heart and may be among the most selective noninvasive indices of parasympathetic control of cardiac functions. A comprehensive understanding of RSA, however, requires an appreciation of its multiple autonomic and physiological origins. We review the physiological bases of RSA and show that RSA arises from multiple tonic and phasic processes of both central and peripheral origin. These underlying mechanisms are at least partially differentiated, have distinct dynamics and consequences, and may be differentially sensitive to behavioral and cognitive events. These multiple mechanisms are relevant for psychophysiological studies of RSA, and a thorough understanding of RSA can only be achieved through an appreciation of the dynamics of its underlying origins. There is a distinction between the psychophysiological and neurophysiological domains, and conceptual and empirical bridges between these domains are needed.     

Preparation of Dipeptoid Mimetics for the Tetrapeptide Cholecystokinin,CCK(30–33)

The diastereoselective synthesis of 2,3-methanophenylalanine methyl esters (5) has been achieved in 58% yield. The preparation of the dehydropeptides (1, R = Me; 2, R = H) and the cyclopropylpeptides (3, R = Me; 4, R = H) possessing good binding affinities for the CCK-A and CCK-B receptors is described. Conformational studies of the dipeptide esters 1 and 3 indicated the presence of a β-turn within the peptide backbone, although there was no preference in type. The Phe and Trp moieties, however, did prefer to be situated on the same side of the peptide turn which is favourable for receptor binding.     

新生儿B组链球菌感染的预防

B组链球菌也称为无乳链球菌,是导致新生儿患病和死亡的重要原因之一,可导致败血症、肺炎和脑膜炎。过去十年间,针对B组链球菌主要是预防早发感染,所谓早发感染是指发生于出生后1周内的新生儿感染。采取的预防措施是给感染B组链球菌的孕妇和新生儿选择性地服用抗生素,以减少或消除B组链球菌的垂直传播。目前,尚没有其他办法能完全预防新生儿B组链球菌败血症的发生,在分娩期内对母亲的预防或者结合分娩后对新生儿的预防,可分别使新生儿早发疾病的发病率减少80%和95%。1病因和危险因素已经证实,高达30%的女性阴道和直肠、肛门携带B组链球菌,…