[Trends in Abuse of Biogenic Drugs in Parts of Germany 2007-2013]. / Entwicklung des Missbrauchs psychotroper Pflanzen und Pilze in Deutschland ­ Interpretation der Zahlen aus 3 Giftinformationszentren für die Jahre 2007­2013.

AIM OF THE STUDY: Based on an abundance of information on the internet, psychotropic plants and mushrooms are of increasing relevance as legal and cheap alternatives to other illicit drugs. Due to the lack of a German database, the abuse of selected biogenic drugs using reported exposures to 3 German Poison Information Centres (PICs) was examined. METHODS: Information on abuse of biogenic drugs was collected from the German PICs in Berlin, Erfurt and Fribourg (2007-2013). RESULTS: 602 drug abuses were reported to the selected PICs. 52% reported consumption of tropane alkaloid-containing plants (Angel's trumpet, Thorn apple, Belladonna), 25% of psilocybin-containing mushrooms and 10% of nutmeg. Angel's trumpet was identified as the most abused plant. Consumers of tropane alkaloid-containing plants were mainly adolescents, whereas the majority of the abusers of psilocybin-containing mushrooms and nutmeg were rather young grown-ups and school children, respectively. A preponderance of moderate and severe effects (55%) could be noticed for exposures to tropane alkaloid-containing plants. More than 90% of suspected cases of tropane alkaloid-containing as well as psilocybin-containing plants abuse resulted in the treatment recommendation 'surveillance in hospital'. Mydriasis, hallucinations, tachycardia and agitation were the main symptoms after the abuse of biogenic drugs. CONCLUSIONS: The data from the PICs suggest abuse of biogenic drugs in parts of Germany. A decreasing trend is observed, probably caused by the competition with new synthetic designer drugs. The results underline the dominance of Angel's trumpet in the abuse of biogenic drugs and emphasize the importance of easy accessibility for the abuse of biogenic drugs. Unexpectedly, the number of nutmeg abuse cases increased during the investigated period.

A method for evaluating cocaine-induced social preference in rats.

Drug addicts are extremely sensitive to cues that predict drug availability and exposure to these cues can facilitate drug relapse. Cues vary in their nature but can include drug-associated paraphernalia, environmental contexts, and discrete conditioned stimuli (e.g., advertisements). One cue that has recently been heavily investigated is that of social interaction. To date, it has been demonstrated that when cocaine is conditioned with social interaction, place preference for cocaine significantly increases, suggesting that the presence of social interaction during a drug-associated "high" enhances the magnitude of drug reward. When social interaction is provided in a mutually exclusive, non-drug environment though, it can serve as a preventative stimulus towards cocaine seeking. What remains unknown is whether contact with rats associated with drug experience facilitates preferential social interactions for those rats. The first step in answering this question is to determine if rats can behaviorally discriminate between drug-associated and non-drug-associated conspecifics, much like humans can differentiate their "drug-friends" from their non-drug-using friends. Using a custom social interaction chamber, in which rats were able to interact with two distinct conspecifics via holes in a boundary wall, we demonstrate that rats exhibit more interactive and investigative behavior towards a partner that was consistently present during the drug-state, than a partner that was present when the rat was "sober". It is our hope that this protocol will contribute to the development of models designed to study social cue-induced reinstatement, and related neural substrates, and will ultimately contribute to the treatment of substance use disorders.

[Development and Periodicity of Human Exposures in Suicidal Intention Reported to the Centre Erfurt from 2004-2013]. / Entwicklung und Periodizität humaner Expositionen in suizidaler Absicht im Einzugsbereich des Giftnotrufs Erfurt von 2004­2013.

Aim of the Study: Exposures in suicide attempts are demanding for hospitals and poisons information centres (PICs). Therefore, the time characteristics of their frequency were studied. Methods: A retrospective analysis was undertaken of all human exposures reported to Centre Erfurt from the beginning of 2004 to the end of 2013 according to their frequency in the respective year, season, month, weekday, time of the weekday, circumstances of exposure, age and gender. Results: 59.7% of all exposures (n=137 104) were accidental, 23.4% occurred in suicide attempts and 3.3% in substance abuse. 0.3% of the suicide attempts resulted in death. Their number continuously increased from n=2 422 in 2004 to n=3 458 in 2013, but their relative frequency remained almost constant at 23.4%. Their highest numbers were reached in the spring and summer with maxima in July and August and minima in February and September. During the week, the most suicide attempts were observed between Sunday and Tuesday and the least on Friday. Highest rate of suicide attempts was seen at 10 pm and lowest at 6 am. The median of age was 39 years (first quartile 24 years, third quartile 50 years). The female proportion was almost twice as high as the male. Conclusions: Hospitals the Centre Erfurt is serving should be particularly prepared for exposures in suicide attempts in the spring and summer (especially in July and August), at the beginning of the week and shortly before midnight.

[Human Single Drug Exposures to Non-opioid Analgesics Reported to the Poisons Information Centre Erfurt from 2003 to 2012]. / Humane nichtopioide Analgetika-Monoexpositionen im Einzugsbereich des Giftnotrufes Erfurt von 2003-2012.

AIM OF THE STUDY: Because of their frequency, non-opioid analgesics (NOA) single drug exposures registered by Poisons Information Centre (PIC) Erfurt have been studied over a decade. METHODS: A retrospective analysis of frequencies, circumstances of exposure, symptom severity, and age groups in NOA single drug exposures received by the PIC Erfurt from the beginning of 2003 to the end of 2012 was undertaken. RESULTS: Of all 4749 NOA single drug exposures, the 10 most frequent were caused by paracetamol (n=1 686), ibuprofen (n=1 439), acetylsalicylic acid (n=456), dipyrone (n=274), diclofenac (n=267), flupirtine (n=138), naproxen (n=41), etoricoxib (n=36), indomethacin (n=24), and dexketoprofen (n=19). Paracetamol single drug exposures increased from 158 in 2003 to 216 in 2007 and fell afterwards to 133 in 2012. Ibuprofen single drug exposures continously rose from 57 in 2003 to 258 in 2012. Adults were more often involved in NOA (53.8%) and all single drug exposures (54.1%) than children (45.9% and 45.6%, respectively). Suicidal attempts were more frequent in NOA (43.1%) than in all single drug exposures (34.2%), whereas accidental exposures or exposures in abuse were less often (33.4 and 0.2%, 46.0 and 0.9% respectively). NOA single drug exposures resulted mostly in none to minor symptoms (77.0%) and rarely in moderate (2.1%) or severe symptoms (1.0%). One adult was found dead after probable ingestion of 32 g of acetylsalicylic acid in suicidal intention. CONCLUSIONS: Because many NOA are over-the-counter drugs, it is difficult to obtain data on their use. PIC data could provide information on the NOA use in the population.

[Human exposures to veterinary medicines reported to the Poisons Information Centre Erfurt from 2003 to 2012]. / Humane Tierarzneimittelexpositionen im Einzugsbereich des Giftnotrufes Erfurt 2003-2012.

AIM OF THE STUDY: The purpose of this study was to get information on all human exposures to veterinary medicines (HEVM) reported to the Poisons Information Centre (PIC) over a 10-year period. METHODS: A retrospective analysis of all HEVM was undertaken and a comparison was made to all human exposures (HE) registered by the PIC from the beginning of 2003 to the end of 2012 according to frequencies, circumstances of exposure, symptom severity, age groups, and substances involved in HEVM. RESULTS: In total, 389 cases of HEVM with 409 veterinary medicines were registered (0.30% of all HE, 360 monoexposures). The relative frequency of children and adults in HEVM (children: 52.4%, adults: 46.0%) and all HE (children: 48.7%, adults 48.7%) was the same with significant (p<0.05) differences in some age subgroups. The portion of accidental exposures was significantly (p<0.05) higher in HEVM (83.3%) than in all exposures (59.3%), whereas the portion of suicidal exposures was significantly (p<0.05) lower (HEVM: 6.4%, all exposures: 23.6%). Most frequent veterinary medicines (ATCvet) in HEVM were antiparasitic substances, insecticides and repellents (n=185), substances for the nervous system (n=48), substances for the cardiovascular system (n=35), and immunologicals (n=35). HEVM mostly resulted in no or mild symptoms (83.8%) and rarely in moderate (10/389, 2.6%) or even severe symptoms (5/389, 1.3%). In 4 of 5 cases of HEVM with severe symptoms, veterinary surgeons used products for animal euthanasia (n=3) or methadone (n=1). Once, self-medication with anthelmintics for several days by a goatherd resulted in transient blindness. CONCLUSIONS: In comparison to other HE, HEVM are rare. Most accidental HEVM in laymen result only in none to mild symptoms. If veterinary surgeons, however, swallow or inject products for animal euthanasia or opioids in suicidal intention, severe symptoms can be expected.

[Poisonings due to Substance Abuse Reported to the Poisons Information Centre Erfurt from 2002 to 2011]. / Substanzmissbrauch - Entwicklung des Vergiftungsgeschehens im Einzugsbereich des Giftnotrufes Erfurt 2002-2011.

AIM OF THE STUDY: Because of their importance for clinical toxicology, developments of sub-stance abuse reported to the Poisons Information Centre (PIC) Erfurt were investigated and compared to other reasons of human exposures. METHODS: A retrospective analysis of all human exposures (exposures of humans to substances in abuse, accidental and unknown circumstances, and suicide attempts) (n=125,130) from the beginning of 2002 to the end of 2011 was undertaken according to substance classes, reasons of exposures, symptom severity, age groups, and gender. RESULTS: Cases of substance abuse (3,760, 3.0% of all exposures) continuously increased from 252 (92 with one and 160 with multiple substances) in 2002 to 507 in 2011 (239 with one and 268 with multiple substances). In relation to all exposures, only the abuse of multiple substances rose significantly (p<0.001). In comparison to all substances of exposure, ethanol, amphetamine-type stimulants, benzodiazepines/analogues, and liquid ecstasy abuse significantly (p<0.005) increased while cannabis and Brugmansia/Datura species abuse significantly (p<0.05) decreased. Substance abuse significantly (p<0.001) more often caused moderate (23.7%) and severe symptoms (6.1%) than in suicide attempts (9.6%; 4.4%). First legal highs exposures were registered in 2010 and led significantly (p<0.001) more often to moderate symptoms (50%) than cannabis exposures (19.4%). CONCLUSIONS: The clinical significance of substance abuse is shown by the fact that it resulted more often in moderate and severe symptoms than suicide attempts. Data on substance abuse from PICs could supplement official annual drug reports in aspects of clinical toxicology.

Synergistic immunosuppressive effects of the mTOR inhibitor sirolimus and the phytochemical curcumin.

The immunosuppressant sirolimus and curcumin, the main principle of the turmeric spice, have shown antiproliferative effects on many human and not-human cell lines. Whereas the antiproliferative effect of sirolimus is mainly mediated by inhibition of mTOR, curcumin is described to affect many molecular targets which makes it unpredictable to appraise if the effects of these both substances on cell proliferation and especially on immunosuppression are additive or synergistic. To answer this question we investigated the interaction of both these substances on OKT3-induced human peripheral blood mononuclear cell (PBMC) proliferation. OKT3-induced human PBMC proliferation was determined by measuring (3)H-thymidine incorporation. Influence of curcumin on interleukin-2 (IL-2) release and IκB-phosphorylation in PBMC was determined by ELISA and western blot, respectively. Curcumin-induced apoptosis and necrosis was analyzed by FACS analysis. Whereas curcumin completely inhibited OKT3-induced PBMC proliferation in a dose-dependent manner with an IC(50) of 2.8 µM, sirolimus could reduce PBMC proliferation dose-dependently only to a minimum of 28% at a concentration of 5 ng/ml (IC(50) 1.1 ng/ml). When curcumin was combined at concentrations of 1.25-2.5 µM with sirolimus at concentrations from 0.63 to 1.25 ng/ml the effects were synergistic. Combination of curcumin (1.25-2.5 µM) with sirolimus (5 ng/ml) showed additive effects. The effects after combination of curcumin at 5 µM with each sirolimus concentration and sirolimus at 10 ng/ml with each curcumin concentration were presumably antagonistic. We conclude that the immunosuppressive effects of curcumin and sirolimus in low concentrations are synergistic in OKT3-activated PBMC. Whether curcumin and sirolimus have also synergistic antiproliferative effects in tumor cells has to be shown in further experiments including animal models.

Calcium channel antagonist exposures reported to the Poisons Information Center Erfurt.

BACKGROUND: We investigated the toxicity profile of the three main groups of calcium channel antagonists (CCA) and compared mixed CCA exposures (CCA plus another drug) with mono CCA exposures. METHODS: All CCA exposures reported to the PIC Erfurt from 2000 to 2009 were analyzed retrospectively. RESULTS: In total, 727 (230 mono and 497 mixed) CCA exposures were registered. Although CCA exposures increased almost twofold from 56 in 2000 to 108 in 2009 their relative frequency to all exposures remained constant. The five CCAs most frequently involved in exposures were the five most frequently prescribed ones in Germany over the same period. In mono and mixed CCA exposures, none or minor symptoms were most often seen with dihydropyridines (mono: 84.7%; mixed: 68.0%) followed by diltiazem (mono: 71.4%; mixed: 62.5%) and verapamil (mono: 57.1%; mixed: 50.0%). Highest rates of moderate (mono: 8.6%: mixed: 20.2%) and severe symptoms (mono: 18.6%; mixed: 23.7%) were observed after verapamil ingestions. Death most frequently occurred with diltiazem (mono: 28.6%; mixed: 12.5%). Rates of moderate symptoms were higher in mixed (13.3%) than in mono CCA exposures (4.8%). No distinct differences were seen regarding the relative frequency of none or minor symptoms, severe symptoms, and death between mono and mixed CCA exposures. CONCLUSION: Exposures to verapamil more often resulted in moderate and severe symptoms than with dihydropyridines. Death mainly occurred with diltiazem. Moderate symptoms were more frequent in mixed than in mono CCA exposures. The frequency of CCAs involved in exposure was related to their prescription.

Comparative study analyzing effects of sirolimus-cyclosporin and sirolimus-tacrolimus combinations on bile flow in the rat.

The new immunosuppressive agent sirolimus is combined in transplant patients with the cholestatic substances cyclosporin and tacrolimus. Nothing is known about possible cholestatic effects of these combinations. Therefore, we compared their effects on bile flow and on important bile parameters in an acute bile fistula model in rats. Cyclosporin reduced bile flow, biliary excretion of bile salts, cholesterol, and GSH to 20-40% of basal values. Sirolimus decreased bile flow to 50% and excretion of GSH to 30% of the initial conditions but had no effect on cholesterol and bile salt excretion. In contrast, tacrolimus increased bile flow to 120% and GSH excretion to 220% of the basal levels. Sirolimus/cyclosporin decreased bile flow and bile parameters to the same extent as cyclosporin alone. Sirolimus/tacrolimus reversed sirolimus-induced reduction of bile flow and GSH excretion and resulted in a normal bile salt and cholesterol excretion, thus it may be the better alternative in cholestatic patients.

Influence of curcumin on cyclosporin-induced reduction of biliary bilirubin and cholesterol excretion and on biliary excretion of cyclosporin and its metabolites.

We investigated the ability of curcumin, which can be extracted from different Curcuma species, to prevent cyclosporin-induced reduction of biliary bilirubin and cholesterol excretion, and its influence on biliary excretion of cyclosporin (CS) and its metabolites in the bile fistula model in rats. I.v. injection of curcumin (25 and 50 mg/kg) after 30 min increased dose-dependently basal bile flow (30 microliters/kg/min) up to 200%, biliary bilirubin excretion (3000 pmol/kg/min) up to 150%, and biliary cholesterol excretion (22 nmol/kg/min) up to 113%. CS (30 mg/kg) reduced bile flow to 66% and biliary excretion of bilirubin and of cholesterol to 33% of the basal value 30 min after i.v. injection. I.v. administration of curcumin (25 and 50 mg/kg) 30 min after CS increased bile flow dose dependently again to 130% for 1 hour and biliary excretion of cholesterol and of bilirubin to 100% of the basal value for 30 and 150 min, respectively. Injection of curcumin 15 min before CS prevented the CS-induced drop of bile flow at 50 mg/kg and reduction of biliary bilirubin excretion already at 25 mg/kg until the end of the experiment (180 min). The CS-induced reduction of biliary cholesterol excretion, however, was not prevented by curcumin. Finally, the biliary excretions of CS (1200 ng/kg/min) and its metabolites (1200 ng/kg/min) were slightly reduced by curcumin at a dose of 50 mg/kg (to 83% of the initial values). The clinical importance of these controversial effects remains to be shown.

Choleretic effects of curcuminoids on an acute cyclosporin-induced cholestasis in the rat.

Former studies have shown that curcumin, which can be extracted from different Curcuma species, is able to stimulate bile flow in rats, whereas bisdemethoxycurcumin, which is mainly found in rhizomes of Curcuma longa, is believed to inhibit bile flow. To reevaluate this observation we investigated the influence of both curcuminoids on bile flow, bile acid concentration and excretion over a time period of 180 min in the bile fistula model in rats. Furthermore, we tested the ability of both curcuminoids to reduce cyclosporin-induced cholestasis. 30 min after intravenous injection of 25 mg/kg of curcumin and bisdemethoxycurcumin bile flow was enhanced from 500 microliters/kg/15 min (100%) to 180% and to 220%, respectively. The choleretic effect of bisdemethoxycurcumin lasted longer than that of curcumin. Following intravenous injection of 30 mg/kg of cyclosporin, which reduced bile flow, bile acid concentration (15 mmol/l) and excretion (12.5 mumol/kg/15 min) to 40% of the initial value, administration of curcumin and bisdemethoxycurcumin transiently increased bile flow to 100% and to 125% of the starting value, respectively. However, only bisdemethoxycurcumin statistically significantly attenuated cyclosporin-induced reduction of bile acid excretion. We conclude that the beneficial properties of curcuminoids for the therapy of cyclosporin-induced cholestasis still remain to be proven.

Small intestinal metabolism of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor lovastatin and comparison with pravastatin.

We compared the intestinal metabolism of the structurally related 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors lovastatin and pravastatin in vitro. Human small intestinal microsomes metabolized lovastatin to its major metabolites 6'beta-hydroxy (apparent K(m) = 11.2 +/- 3.3 microM) and 6'-exomethylene (apparent K(m) = 22.7 +/- 9.0 microM) lovastatin. The apparent K(m) values were similar for lovastatin metabolism by human liver microsomes. 6'beta-Hydroxylovastatin formation by pig small intestinal microsomes was inhibited with the following inhibition K(i) values: cyclosporine, 3.3 +/- 1.2 microM; ketoconazole, 0.4 +/- 0.1 microM; and troleandomycin, 0.8 +/- 0.9 microM. K(i) values for 6'-exomethylene lovastatin were similar. Incubation of pravastatin with human small intestinal microsomes resulted in the generation of 3'alpha,5'beta, 6'beta-trihydroxypravastatin (apparent K(m) = 4560 +/- 1410 microM) and hydroxypravastatin (apparent K(m) = 5290 +/- 1740 microM). In addition, as in the liver, pravastatin was metabolized in the small intestine by sulfation and subsequent degradation to its main metabolite 3'alpha-iso-pravastatin. It was concluded that lovastatin is metabolized by cytochrome P-450 3A enzymes in the small intestine. Compared with lovastatin, the cytochrome P-450-dependent intestinal intrinsic clearance of pravastatin was >5000-fold lower and cannot be expected to significantly affect its oral bioavailability or to be a significant site of drug interactions.

The toxic and metabolic effects of 23 aliphatic alcohols in the isolated perfused rat liver.

We investigated the acute toxic and metabolic effects of 23-aliphatic alcohols (16 saturated and 7 unsaturated) in the isolated perfused rat liver at a concentration of 65.1 mmol/l (approximately 0.3% ethanol). The capacity of the straight chain primary alcohols (methanol, ethanol, 1-propanol, 1-butanol and 1-pentanol) to release the enzymes glutamate-pyruvate transaminase (GPT), lactate dehydrogenase (LDH) and glutamate dehydrogenase (GLDH) into the perfusate was strongly correlated with their carbon chain length. The secondary alcohols were less active in this respect whereas branching of the carbon chain did not consistently change alcohol toxicity. Unsaturation in the straight chain but not in the branched chain alcohols was accompanied by an increase in toxicity. An increased enzyme release was in general accompanied by, and correlated to, reductions in oxygen consumption, bile secretion, and perfusion flow of the isolated livers. Statistically significant correlations exist between parameters of alcohol-induced hepatotoxicity and the membrane/buffer partition coefficents of the alcohols. With the exception of methanol, all alcohols tested increased the lactate/pyruvate ratio of the perfusate, although this effect was not correlated to the degree of hepatic injury. Hepatic ATP concentrations decreased in most cases in line with hepatic injury and were particularly correlated with changes in oxygen consumption. Hepatic concentrations of reduced glutathione (GSH) were only diminished by the unsaturated alcohols, whereas an increase in hepatic oxidized glutathione (GSSG) occurred only with some of the saturated alcohols. Hepatic concentrations of malondialdehyde (MDA) increased after two saturated and three unsaturated alcohols but did not correlate with other parameters of hepatotoxicity. In conclusion, alcohol-induced hepatotoxicity is primarily due to membrane damage induced by the direct solvent properties of the alcohols. The consequences and relative contributions of alcohol metabolization to the overall hepatotoxicity of higher alcohols requires further study.

Comparison of cytochrome P-450-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitors lovastatin and pravastatin in the liver.

In an in vitro study, the cytochrome P-450 3A (CYP3A)-dependent metabolism and drug interactions of the 3-hydroxy-3-methylglutaryl-Co A reductase inhibitors lovastatin and pravastatin were compared. Lovastatin was metabolized by human liver microsomes to two major metabolites: 6'beta-hydroxy [Michaelis-Menten constant (Km): 7.8 +/- 2.7 microM] and 6'-exomethylene lovastatin (Km,10.3 +/- 2.6 microM). 6'beta-Hydroxylovastatin formation in the liver was inhibited by the specific CYP3A inhibitors cyclosporine (Ki, 7.6 +/- 2.3 microM), ketoconazole (Ki, 0.25 +/- 0.2 microM), and troleandomycin (Ki, 26.6 +/- 18.5 microM). Incubation of pravastatin with human liver microsomes resulted in the generation of 3'alpha,5'beta, 6'beta-trihydroxy pravastatin (Km, 4,887 +/- 2,185 microM) and hydroxy pravastatin (Km, 20,987 +/- 9,389 microM). The formation rates of 3'alpha,5'beta,6'beta-trihydroxy pravastatin by reconstituted CYP3A enzymes were (1,000 microM pravastatin) 1.9 +/- 0.6 pmol.min-1.pmol CYP3A4 and 0.06 +/- 0.04 pmol.min-1.pmol CYP3A5, and the formation rates of hydroxy pravastatin were 0.12 +/- 0.02 pmol.min-1.pmol CYP3A4 and 0.02 +/- 0.004 pmol.min-1.pmol CYP3A5. The specific CYP3A inhibitors cyclosporine, ketoconazole, and troleandomycin significantly inhibited hydroxy pravastatin formation by human liver microsomes, but only ketoconazole inhibited 3'alpha, 5'beta,6'beta-trihydroxy pravastatin formation, suggesting that other CYP enzymes are involved in its formation. It is concluded that, compared with lovastatin [CLint formation 6'beta-hydroxylovastatin (microl.min-1.mg-1): 199 +/- 248, 6'-exomethylene lovastatin: 138 +/- 104)], CYP3A-dependent metabolism of pravastatin [CLint formation 3'alpha,5'beta, 6'beta-trihydroxy pravastatin (microl.min-1.mg-1): 0.03 +/- 0.03 and hydroxy pravastatin: 0.02 +/- 0.02] is a minor elimination pathway. In contrast to lovastatin, drug interactions with pravastatin CYP3A-catalyzed metabolism cannot be expected to have a clinically significant effect on its pharmacokinetics.

Influence of glycine on the damage induced in isolated perfused rat liver by five hepatotoxic agents.

Livers of fasted rats were perfused over 120 min in a recirculating hemoglobin-free system. Hepatotoxic injury induced by the addition of 1-butanol (130.2 mmol/l), CdCl2 (0.1 mmol/l), CuCl2 (0.03 mmol/l), Na3VO4 (2 mmol/l) or t-butylhydroperoxide (t-BuOOH, 0.5 mmol/l) to the perfusate was shown by strong increases in lactate dehydrogenase (LDH) and glutamate-pyruvate transaminase (GPT) release, decreased oxygen consumption between 50 and 60%, and a nearly complete suppression of bile flow. Hepatic adenosine triphosphate (ATP) and reduced glutathione (GSH) concentrations were reduced by between 30 and 80%, and 20 and 80% respectively. Only Na3VO4 and t-BuOOH evoked increased releases of glutamate dehydrogenase (GLDH) in the perfusate. Malondialdehyde (MDA) concentrations were enhanced by all toxicants in the perfusate and by all except 1-butanol in the liver. The MDA increase, however, was much higher after Na3VO4 and t-BuOOH than after the other toxicants. When glycine (12 mmol/l) was added 30 min before the toxicants to the perfusate it prevented the enzyme releases induced by all hepatotoxic agents by about 80%. Furthermore, glycine prevented the Na3VO4 induced increase of MDA in liver and perfusate, the hepatic ATP and GSH level reductions induced by 1-butanol and attenuated the reduction of oxygen consumption induced by CuCl2 and t-BuOOH. Glycine, however, did not reverse the reductions of oxygen consumption induced by CdCl2 and Na3VO4, the suppressions of bile flow and, with the exception of 1-butanol, the decreases of hepatic ATP levels induced by all agents.

Surface-based hemangioma of bone: three case studies and a review of the literature.

Three cases of surface-based hemangiomas were reviewed. The cases illustrate the plain film and magnetic resonance imaging findings of these benign tumors, which can appear quite aggressive, mimicking more aggressive neoplasms. Each of the patients underwent en bloc excision, and pathologic evaluation to determine the diagnosis. To date, there has been no evidence of recurrence.

Reevaluation of cyclosporine induced hepatotoxicity in the isolated perfused rat liver.

UNLABELLED: Livers of male rats were perfused for 120 min in a recirculating hemoglobin-free system with different concentrations of cyclosporine (CS 2, 10, 50, 150 and 200 mg/l). CS produced damage to the livers in a dose dependent manner. The first sign of hepatotoxicity was a reduction of bile flow amounting to 50% already at 50 mg/l CS. At concentrations of 150 mg/l and 200 mg/l, CS lead to a nearly complete suppression of bile flow, furthermore to a release of cytosolic (GPT, glutamate-pyruvate transaminase, LDH, lactate dehydrogenase) and mitochondrial (GLDH, glutamate dehydrogenase) enzymes into the perfusate and to a decrease in hepatic oxygen consumption (30% at 200 mg/l CS). As a consequence of the reduced aerobic energy supply, hepatic ATP concentration declined (70% at 200 mg/l CS). The hepatic concentrations of reduced glutathione (GSH) were not changed but those of oxidized glutathione (GSSG) increased up to 5-fold by CS. Malondialdehyde (MDA) concentrations in the liver and in the perfusate were not affected consistently by CS. The toxic actions of CS in the isolated rat liver were not influenced (a) by the feeding status of the rats (fed or fasted before surgery) or (b) by addition of superoxide dismutase (SOD, 20 mg/l) and catalase (20 mg/l) to the perfusate 30 min before CS. On the other hand, CS-induced hepatic injury could be attenuated or inhibited completely by addition to the perfusate of (1) 2 mmol/l GSH; (2) 12 mmol/l serine; (3) 12 mmol/l glycine; (4) 0.09 mmol/l deferoxamine (DFO). CONCLUSIONS: CS induces cholestasis at lower concentrations, probably by another mechanism(s) than the other signs of hepatotoxicity (enzyme release, ATP depletion). Several lines of evidence indicate a probable participation of reactive oxygen species in CS-induced hepatotoxicity. GSH, DFO, glycine and serine could provide therapeutic opportunities to prevent CS-induced hepatotoxicity in patients treated with high doses of CS.

Protection by glycine against hypoxia-reoxygenation induced hepatic injury.

Isolated perfused livers from rats fasted 16 h before surgery showed a strong decrease in oxygen consumption as well as hepatotoxic responses when subjected to 30 min of hypoxia (95%, N2/5% CO2) followed by 90 min of reoxygenation (95% O2/5% CO2). Toxicity was evident by a release of enzymes (LDH, GPT, GLDH) into the perfusate and by a nearly complete suppression of bile flow. Hepatic reduced gluthathione dropped to about 20% and hepatic ATP to about 50% of the initial values. Furthermore, the concentrations of thiobarbituric acid reactive (TBA) material increased eightfold in the perfusate and by 70% of the control values in the livers. Glycine added to the perfusate at concentrations of 3, 6 and 12 mmol/l prevented dose-dependently all measures of hepatotoxicity as well as the indices of lipid peroxidation induced by hypoxia/reoxygenation. A maximal and nearly complete protection was obtained with 12 mmol/l glycine. Glycine increased the bile flow of perfused livers not subjected to hypoxia and attenuated the drop of bile flow induced by hypoxia-reoxygenation. Ligation of the bile duct, however, did not influence the cytoprotective effects of glycine in hypoxia-reoxygenation induced hepatic injury. In conclusion, glycine is an effective antidote against hypoxia-regoxygenation induced injury of the isolated rat liver.