Analgesic, antiulcer, antithrombotic drugs and organ damage: a population-based case-control study.

AIM: Oral medication is of paramount importance for pain treatment. Analgesics, antiulcer (AUDs) and antithrombotic drugs (ATDs) are often coprescribed in elderly people. Non-steroidal anti-inflammatory drugs (NSAIDs) require AUDs to lower the risk of peptic ulcer, and potentially interfere with ATDs. The aim of this study was to quantify the prevalence of NSAID use in patients with gastrointestinal, cardiac or kidney damage in the year 2013, compared to the general population. METHODS: We performed a population-based case-control study in the Republic of San Marino to evaluate the Odds-Ratios for upper gastrointestinal damage (gastroduodenal ulcers and/or erosions, GUE), ischemic heart disease (IHD), heart failure (HF), and renal function impairment (assessed using the CKD-EPI formula), in people who had taken AUDs, ATDs, or NSAIDs in the previous 90 days, versus people who had not taken such drugs in the same period of time. RESULTS: We found that AUDs decreased the OR for GUE (OR: 0.762; CI:0.598-0.972), while ATDs and NSAIDs increased the risk (OR: 1.238 and CI: 0.935-1.683; OR:1.203 and CI:0.909-1.592, respectively). NSAIDs seemed to increase the risk of IHD, although this was not statistically significant (OR=1.464; CI=0.592-3.621). AUDs and ATDs significantly increased the risk of renal function impairment (OR=1.369 and CI=1.187-1.579; OR=1.818 and CI=1.578-2.095, respectively), while this effect was not observed for NSAIDs. CONCLUSION: NSAIDs may induce gastrointestinal and cardiovascular damage, not only by themselves, but also when used concomitantly with common medications such as AUDs or ATDs, due to additive and/or synergistic effects. We performed a "pragmatic" analysis of the association of organ damage with use of NSAIDs/AUDs/ATDs, including patient age, treatment duration and dose, to allow for an immediate application of our findings to everyday clinical practice.

Intrathecal therapy with ziconotide: clinical experience and considerations on its use.

Ziconotide is a synthetic peptide equivalent of an w-conotoxin, obtained from the marine snail Conus magus, which acts by blocking N-type calcium channels in the spinal cord, reducing the perception of pain. It is a newly marketed drug, exclusively for intrathecal use, indicated for severe chronic pain. Ziconotide came to the physicians' table with both doubts and promises; to determine its safety and efficacy, one of the largest and most well-designed randomized double-blind studies in the history of intrathecal therapy was undertaken, and this drug demonstrated efficacy in relieving chronic pain in patients coming from many years of different therapies and therapy failures. However, the pain relief came with some adverse effects, which are few compared with morphine's adverse effects but in some cases could undermine the course of therapy with this conotoxin. The experience described in this paper began in June 2007 and gave us the opportunity to analyze how the conotoxin works outside of the papers. We noted differences between the well-known activity of morphine on pain and mood, and the more focused action of ziconotide on pain. In addition, it is important to consider the lack of addiction, opioid-induced hyperalgesia and other systemic effects that are common with morphine. These are the reasons why the Polyanalgesic Consensus Conference of 2007 put ziconotide in the first line of intrathecal therapy management.

Effects of dehydroepiandrosterone and carnitine treatment on rat liver.

It is well established that DHEA treatment is associated in the rat to an increase in fatty acids metabolism. This condition would require levels of L-carnitine much higher than those physiologically present in the liver. The possibility thus exist that during DHEA treatment the concentration of L-carnitine may become a limiting factor for fatty acids oxidation and therefore responsible of some of the effects observed after administration of the hormone. The present experiments were designed to test this hypothesis. The results show that the increase in the levels of peroxisomal enzymes induced in hepatocytes by DHEA, is greatly reduced by parallel administration of L-carnitine. Furthermore, L-carnitine administration counteracts the effect of DHEA on mitochondrial structure. On the contrary, carnitine has no significant effect on the reduction in weight gain observed upon short- or long-term treatment with DHEA.

[The protective effect of cyclosporine A, carnitine, and Mg(2+) with ADP during calcium(2+)-dependent permeabilization of mitochondria by fatty acids and activation of NADH oxidation by an external pathway]. / Zashchitnyi éffekt tsiklosporina A, karnitina i Mg(2+) s ADP pri Ca(2+)-zavisimoi permeabilizatsii mitokhondrii zhirnymi kislotami i aktivatsii okisleniia NADH po vneshnemy puti.

The ability of cyclosporin A, Mg2+ plus ADP and L-carnitine to enhance energy recoupling in liver mitochondria and to inhibit the induction of the external pathway of NADH oxidation during Ca(2+)-dependent oxidative phosphorylation uncoupling by palmitate has been studied. Cyclosporin A, Mg2+ plus ADP and L-carnitine plus ATP prevent with an equal efficiency the induction of the external pathway of NADH oxidation by palmitate and Ca2+ in mitochondria but differ drastically by their ability to increase the coupling in permeabilized mitochondria. The recoupling effect of cyclosporin is manifested after addition of Mg2+ plus ADP. The protective action of Mg2+ plus ADP is prevented by preincubation with carboxyatractylate. Oxidation of NADH via an external pathway results in delta psi generation, however, only in the presence of the recoupling factors. The role of the cyclosporin-sensitive pore in Ca(2+)-dependent damage of mitochondria as well as in the induction of the external pathway of NADH oxidation is discussed.

Comparative studies of effects of dehydroepiandrosterone on rat and chicken liver.

1. An attempt to identify the cause of decrease of gain in body weight during dehydroepiandrosterone (DHEA) treatment was made comparing the effects of hormone treatment on chickens and rats. 2. Chickens treated with DHEA for 7-10 days do not change their weight gain with respect to controls although their mitochondrial respiration and peroxisomal catalase (index of peroxisomal mass) were increased. 3. Liver cytosolic malic enzyme and sn-glycerol-3-phosphate dehydrogenase were depressed in chickens treated with DHEA in comparison with activities in untreated controls. DHEA treatment did not increase the activity of mitochondrial sn-glycerol 3-phosphate dehydrogenase. 4. In contrast to rat liver cytosolic sn-glycerol-3-phosphate dehydrogenase this enzyme in chicken liver was inactive with NADPH.

Concerning the mechanism of increased thermogenesis in rats treated with dehydroepiandrosterone.

Dehydroepiandrosterone (DHEA) treatment of rats decreases gain of body weight without affecting food intake; simultaneously, the activities of liver malic enzyme and cytosolic glycerol-3-P dehydrogenase are increased. In the present study experiments were conducted to test the possibility that DHEA enhances thermogenesis and decreases metabolic efficiency via transhydrogenation of cytosolic NADPH into mitochondrial FADH2 with a consequent loss of energy as heat. The following results provide evidence which supports the proposed hypothesis: (a) the activities of cytosolic enzymes involved in NADPH production (malic enzyme, cytosolic isocitrate dehydrogenase, and aconitase) are increased after DHEA treatment; (b) cytosolic glycerol-3-P dehydrogenase may use both NAD+ and NADP+ as coenzymes; (c) activities of both cytosolic and mitochondrial forms of glycerol-3-P dehydrogenase are increased by DHEA treatment; (d) cytosol obtained from DHEA-treated rats synthesizes more glycerol-3-P during incubation with fructose-1,6-P2 (used as source of dihydroxyacetone phosphate) and NADP+; the addition of citrate in vitro further increases this difference; (e) mitochondria prepared from DHEA-treated rats more rapidly consume glycerol-3-P added exogenously or formed endogenously in the cytosol in the presence of fructose-1,6-P2 and NADP+.

Interaction of carnitine with mitochondrial cardiolipin.

The physiological role of L-carnitine is to determine the transport of acyl-CoA through the mitochondrial membrane. However, some observations may also suggest a direct effect of the molecule per se on the physical properties of the membrane, most probably at the level of the binding site. This possibility has been investigated by studying the influence of adriamycin, a drug that binds to cardiolipin, on the effect of carnitine on isolated rat liver mitochondria. It has been found that adriamycin almost abolishes the activating effect of carnitine on state 2 respiration. The effect and its inhibition is seen by using either the L-form of carnitine or the D-form or both. Cardiolipin removes the effect of adriamycin and restores the activation by carnitine. It is proposed that some effects of carnitine on mitochondrial properties may be the result of interaction of carnitine with cardiolipin at the membrane level.

Changes in liver structure and function after short-term and long-term treatment of rats with dehydroepiandrosterone.

The effects on the liver of feeding a diet containing 0.2% dehydroepiandrosterone were studied after short (7 d) and long (100 d) periods of treatment in rats. The short-term treatment caused hypertrophy of the hepatocytes that, at the ultrastructural level, seemed to be due to proliferation of peroxisomes and (to a minor extent) of mitochondria. The mitochondria seemed to have undergone transition from expanded to condensed configuration; accordingly, after isolation, their rate of coupled respiration was greater than that of control mitochondria. After long-term treatment, the structure of the hepatocytes reverted toward normal. In fact, at the ultrastructural level, the number and the size of peroxisomes was not significantly different from those of the controls, but degenerative phenomena were observed in the mitochondria. Attempts are made to explain the above ultrastructural and biochemical findings in view of the effects of dehydroepiandrosterone on the energy metabolism of liver.

Sources of intramitochondrial malate.

Liver mitochondria from rats treated with gluconeogenic hormones or subjected to vigorous exercise consume oxygen more rapidly than do mitochondria from control rats. These treatments result in elevated mitochondrial malate concentrations, which facilitate the entry of added substrate into the mitochondria. In this paper we describe experiments conducted to determine the source of the extra malate. Injections of glutamate plus alanine, two amino acids that are increased in blood after exercise and hormone treatment, caused liver mitochondrial malate to be increased. Injections of glucagon, cortisol, or both hormones elevated liver mitochondrial malate concentrations in both adrenalectomized and sham-operated rats.

Changes in mitochondrial activity caused by ammonium salts and the protective effect of carnitine.

Ammonium salts added to isolated rat liver mitochondria deviate alpha-ketoglutarate to glutamate synthesis, thus decreasing its availability as respiratory substrate. As a consequence a decrease of respiratory rate is observed which is paralleled by progressive mitochondrial swelling. It was demonstrated that L-carnitine may abolish this swelling thus improving structural and metabolic state of mitochondria.