Ralph P. Miech

Purine metabolism in Schistosoma mansoni

Abstract Schistosoma mansoni has been found to have a spectrum of purine nucleotides which is similar, but not identical to mammalian cells. The principal component of this system is ATP, which is present at a level of about 5·5 × 10 −9 moles/mg worm pairs. The ATP concentration falls if worms are incubated in a defined medium containing no purines. When worms are incubated in the presence of adenine or adenosine, ATP levels rise sharply and may be maintained at higher than normal levels. Schistosomes were found not to incorporate labelled glycine or glucose into purine nucleotide bases. In contrast, 14 C-8-adenine is taken up from the medium and can be detected in nucleotides, principally as ATP. In comparison with various mammalian cell systems, schistosomes show a much higher rate of uptake of free adenine. These findings suggest that schistosomes do not utilize the de novo pathway for the synthesis of nucleotides. It is postulated that the salvage mechanism is required to fulfil the worms purine requirements. A new rational chemotherapeutic approach for schistosomiasis, based on interference with their specific nucleotide pathways, may thus become possible.

Pathophysiology of Mifepristone-Induced Septic Shock Due to Clostridium sordellii

OBJECTIVE: To explain the role of mifepristone in medical abortions that results in fulminant and lethal septic shock due to Clostridium sordellii. DATA SOURCES: MEDLINE, PubMed, and Google Scholar databases were searched (1984–March 2005%). Key search terms were mifepristone, RU38486, RU486, Mifeprex, medical abortion, septic shock, innate immune system, cytokines, and Clostridium sordellii. STUDY SELECTION AND DATA EXTRACTION: All articles identified from the data sources were evaluated and all information deemed relevant was included for the information related to the development of the understanding of the pathophysiology of mifepristone-induced septic shock due to C. sordellii. DATA SYNTHESIS: The mechanisms of action of mifepristone were incorporated into the pathophysiology of septic shock due to C. sordellii. Mifepristone, by blocking both progesterone and glucocorticoid receptors, interferes with the controlled release and functioning of cortisol and cytokines. Failure of physiologically controlled cortisol and cytokine responses results in an impaired innate immune system that results in disintegration of the bodys defense system necessary to prevent the endometrial spread of C. sordellii infection. The abnormal cortisol and cytokine responses due to mifepristone coupled to the release of potent exotoxins and an endotoxin from C. sordellii are the major contributors to the rapid development of lethal septic shock. CONCLUSIONS: Theoretically, it appears that the mechanisms of mifepristone action favor the development of infection that leads to septic shock and intensifies the actions of multiple inflammatory cytokines, resulting in fulminant, lethal septic shock.

Effects of isoproterenol, theophylline and carbachol on cyclic nucleotide levels and relaxation of bovine tracheal smooth muscle.

Abstract The effect of theophylline and isoproterenol on bovine tracheal smooth muscle tension and cyclic AMP levels was investigated. Concentrations of isoproterenol (4 × 10 −6 M) and theophylline (10 mM) that relaxed carbachol-contracted tracheal muscle by 85–95% did not significantly elevate control levels of cyclic AMP. In the absence of carbachol, several-fold increases in cyclic AMP were caused by isoproterenol although no elevations by theophylline were measurable. However, when isoproterenol and theophylline were administered together, theophylline potentiated the rise in cyclic AMP caused by isoproterenol. Phosphodiesterase studies in tracheal muscle showed the presence of a high and a low K m enzyme which were inhibited by theophylline. Cyclic GMP levels were elevated in muscles contracted by carbachol as well as in carbachol-contracted muscles that had been relaxed by theophylline. In non-tension studies, in which the tracheal muscle was not under isometric tension, carbachol or theophylline alone increased cyclic GMP and together they synergistically elevated cyclic GMP. Atropine blocked the elevation caused by carbachol but not that caused by theophylline. In contrast to theophylline, isoproterenol did not elevate cyclic GMP, and in carbachol-contracted muscles that had been relaxed by isoproterenol, cyclic GMP levels were no different from control. Also, in non-tension studies, isoproterenol decreased basal cyclic GMP and antagonized the increase in cyclic GMP due to carbachol. The results indicate that whole-tissue levels of cyclic AMP and cyclic GMP do not correlate with the state of tracheal smooth muscle tension. Cyclic GMP levels do not clearly correlate with either contraction or relaxation. The inhibition by carbachol of increases in cyclic AMP due to isoproterenol and the inhibition by isoproterenol of increases in cyclic GMP due to carbachol provide evidence for a reciprocal cholinergic-adrenergic antagonism of cyclic AMP and cyclic GMP levels. The antagonism did not appear to be due to either cyclic nucleotide affecting the elevation of the other since the levels of both cyclic nucleotides were depressed.

Pathways of nucleotide metabolism in schistosoma mansoni—VI adenosine phosphorylase

Abstract Schistosoma mansoni worms have been found to have an adenosine phosphorylase enzyme which requires inorganic phosphate during cleavage and α-ribose-1-phosphate for synthesis of adenosine from adenine. Kinetics of the reaction show a K m of 5.6 × 10 −5 M for adenosine and a broad pH activity range from 6.0 to 8.0. The adenosine phosphorylase activity can be distinguished from purine nucleoside phosphorylase by substrate specificity and by product inhibition studies.

Immunopharmacology of ulipristal as an emergency contraceptive.

A new progesterone antagonist, ulipristal has been made available as an emergency contraceptive. Ulipristal’s major mechanism of action as an emergency contraceptive has been ascribed to its ability to delay ovulation beyond the life span of the sperm. This paper analyzes the potential action of ulipristal (1) when unprotected intercourse and administration of ulipristal occur outside the fertility window and (2) when unprotected intercourse and administration of ulipristal occur at or within 24 hours of ovulation. When unprotected intercourse and the use of a single low dose of ulipristal occur outside of the fertility window, ulipristal behaves like a placebo. When unprotected intercourse and the use of a single low dose of ulipristal occur within the fertility window but before ovulation, ulipristal behaves like an emergency contraceptive by delaying ovulation and thereby preventing fertilization. When unprotected intercourse and the administration of ulipristal occur at or within 24 hours of ovulation, then ulipristal has an abortifacient action. It is proposed that the abortifacient mechanism of a low dose of ulipristal taken after fertilization but before implantation is due to the ability of ulipristal to block the maternal innate immune system to become immunotolerant to the paternal allogenic embryo. Progesterone’s critical immunotolerant actions involving early pregnancy factor, progesterone-induced blocking factor, and uterine natural killer cells are compromised by ulipristal.

Pathopharmacology of Excessive Hemorrhage in Mifepristone Abortions

Objective: To explain a pathopharmacologic mechanism that initiates an increase in hemorrhage following medical abortions with mifepristone. Data Sources: MEDLINE, PubMed, and Google Scholar databases were searched (1990–July 2007). Key search terms were mifepristone, RU486, medical abortion hemorrhage, bleeding, inflammation, innate immune system, phagocytes, macrocytes, cytokines, interleukins, and nitric oxide. Study Selection and Data Extraction: All articles identified from the data sources were evaluated and all information deemed relevant was included for the information related to the development of the understanding of the pathopharmacology of mifepristone as the initiating cause of increased hemorrhage in medical abortions. Mifepristones blockade of glucocorticoid receptors, prolonged generation of nitric oxide (NO), and postabortion vasodilatation of uterine vasculature by NO that favors excessive hemontiage were the criteria used to determine whether information was relevant for inclusion. Data Synthesis: Inescapable bacterial contamination of the decidua accompanies spontaneous, surgical, and mifepristone abortions and is routinely overcome by activation of the innate immune system. The combination of the induction of NO synthase (NOS) and local production of NO is one of the key features of the activation of the innate immune systems phagocytes. NO is a potent vasodilator and is associated with menstrual menorrhagia. Glucocorticoids prevent the overproduction of NOS and NO and thereby contribute to the control of hemorrhage in the postabortion phase. Conclusions: Blockade of the glucocorticoid receptors by mifepristone can result in an excess of NO that is theorized to be the cause of excessive hemorrhage seen in mifepristone abortions.

Disruption of the innate immune system by mifepristone and lethal toxin of Clostridium sordellii

The innate immune system is an immediate host response system for combating invading bacteria by initiating a protective local tissue inflammatory response. Pattern recognition molecules that are uniquely expressed in bacteria activate the hosts Toll-like receptors to produce cytokines in the form of the pro-inflammatory chemokines and interleukins. If the synthesis of pro-inflammatory cytokines is not properly controlled by cortisol, pro-inflammatory cytokines gain access to the systemic circulation and result in a systemic cytokine storm that is responsible for initiating septic shock and multiple organ dysfunctions. Cortisol-activated glucocorticoid receptors result in the synthesis and release of the anti-inflammatory cytokine interleukin-10, which prevents the further synthesis of pro-inflammatory cytokines. During a mifepristone-induced abortion, the blockade of glucocorticoid receptors by mifepristone results in the disruption of the innate immune system. The combination of ischemic decidua, necro...