Modulation of human platelet aggregation by the phosphodiesterase type 5 inhibitor sildenafil.

The aim of this study was to investigate if the phospodiesterase type 5 inhibitor sildenafil inhibits collagen- or ADP-induced human platelet aggregation and bleeding time. To investigate this, two studies were designed. In the first, a single oral dose of sildenafil, 100 mg, was administered to healthy men. Bleeding time was determined and agonist (ADP and collagen)-induced platelet aggregation (ex vivo in platelet rich plasma) was measured 0, 1, and 4 h after application. In the second, a single oral dose of sildenafil, 50 mg, was administered and, in addition to the parameters in the first study, we also determined the platelet aggregation after 24 h and measured the effect of a nitric oxide donor (S-nitroso-N-acetylpenicillamine [SNAP]) in combination to mimic a physiologic nitric oxide release from the endothelium. The bleeding time of 1 h after sildenafil medication (100 mg) was significantly prolonged but recovered toward control values after 4 h, whereas application of sildenafil at a lower dose (50 mg) did not alter the bleeding time. Sildenafil (100 and 50 mg) did not inhibit the ADP-induced aggregation, whereas the collagen-induced aggregation (100 mg) was markedly reduced after 1 h and significantly inhibited 4 h after application. This inhibitory effect was overcome by higher concentrations of collagen. SNAP (0.5 microM) induced an inhibition of platelet aggregation that was potentiated after taking sildenafil (50 mg, 1 and 4 h afterward) and abrogated after 24 h. These data indicates that sildenafil may inhibit collagen-induced platelet aggregation ex vivo. After co-administration of nitric oxide, collagen- and ADP-induced platelet aggregation was significantly inhibited, which may reflect physiologic conditions of an in vivo system.

[Poisoning by perazine--organ distribution and interpretation]. / Intoxikation mit Perazin--Organverteilung und Interpretation.

A fatal intoxication of a 22-year-old woman after intake of the phenothiazine perazine is described. In all of investigated organs e.g. in liver, lungs and kidneys high concentrations of the active agent could be found. The analytical results lead to the assumption that at least 14, most likely 30 tablets of Taxilan 100 have been taken. An unintended overdosage seems to be excluded just as an administration by another person.

Comparison of nonradioactive microtiter plate enzyme immunoassays for the sensitive detection of fentanyl.

Fentanyl is a very strong opioid with analgesic properties that are approximately 80 times stronger than those of morphine and therefore is used in major surgery and treatment of pain in tumor patients. Cases of fentanyl abuse by intravenous injection, inhalation, oral or nasal application have been reported especially in the USA. Therapeutic levels of fentanyl are as low as 1 ng/ml of serum and therefore a screening test must have a detection limit below that concentration. Recently three non-radioactive enzyme immunoassays (EIAs) have become commercially available from COZART, STC and DIAGNOSTIX, all of them supplied by MAHSAN Diagnostika for evaluation with serum samples from forensic and clinical cases. A calibration curve is obtained with samples that contain 0, 0.1, 0.5, 1 and 5 ng fentanyl per ml of negative serum. The calibration curve of COZART is especially in the low range, steeper than those of STC and DIAGNOSTIX. The cut-off for all these EIAs, however, can be set at 0.5 ng/ml. After the administration of therapeutic doses, fentanyl concentrations were between 3 and more than 5 ng/ml as determined with the EIAs. The presence of the typical drugs of abuse, e.g. heroin, methadone, cocaine, cannabinoids and amphetamines including the derivatives of methylenedioxyamphetamine, don't generate false-positive results. No cross-reactivity was also observed at toxic levels of benzodiazepines and paracetamol and therapeutic levels of barbiturates, phenothiazines, antidepressants and analgesics. The EIAs tested so far appear to be suitable for the detection of fentanyl at therapeutic levels. False-positive results or cross-reactivity towards other compounds have not been observed.

Detection of psilocin in body fluids.

Active compounds of some mushrooms e.g. Psilocybe cubensis, Paneolus subalteatus or Stropharia coronilla, the psychotropic agents psilocybin and psilocin, have hallucinogenic effects. In one case of 'magic mushroom' intake, we had to analyse blood and urine. Psilocin was detected in the urine with REMEDi HS. Most of the psilocin was excreted as the glucuronide. Therefore an enzymatic hydrolysis should be the first step in analysis. Free psilocin was determined at a concentration of 0.23 mg/l while the total amount was 1.76 mg/l urine. The concentration of psilocin in serum was too low for detection with REMEDi HS. We proved a GC-MS-method with d(3)-morphine as internal standard and silylation with MSTFA. Similarly to urine, most of the psilocin in serum was found in the conjugated form. The concentration of free psilocin was 0.018 mg/l, that of total psilocin, 0.052 mg/l serum.

Effects of prepulses and d-amphetamine on performance and event-related potential measures on an auditory discrimination task.

RATIONALE: Prepulse inhibition (PPI) of the startle reflex is a measure of sensorimotor gating, that is the processing of the startle stimulus (S2) is inhibited by the interfering processing of a closely preceding prepulse (S1). It has been demonstrated that PPI is disrupted in a variety of mental disorders and that several neurotransmitter systems, including dopamine, participate in the modulation of sensorimotor gating. Previous studies have also shown that a task-relevant S1 enhances PPI in healthy subjects but not in schizophrenic patients. These findings indicate an influence of attentional processes on sensorimotor gating and an impairment of this modulation in schizophrenia. OBJECTIVE: Assuming a dopamine-mediated suppression of S1 processing as a mechanism of resource management and selective attention, which might be impaired in certain mental disorders, the present study investigated the effects of the indirect dopaminergic agonist d-amphetamine on prepulse-altered S2 discrimination and event related potentials (ERPs). METHODS: Twelve healthy volunteers were tested in a double-blind, placebo-controlled experimental design. Here, S2 is the target in a difficult Go/NoGo auditory discrimination task. RESULTS: Confirming our previous results, S2 processing is "accentuated" by a weak acoustic prepulse in healthy subjects, thus leading to a lower rate of errors of omission but also to more false alarms (i.e. a liberal response bias). This performance change correlated with a prepulse-induced increase in the amplitude of the P3 ERP towards non-targets ("prepulse-induced non-target positivity"; PINTP). In addition, the results of the present study show that under prepulse conditions amphetamine disrupts "S2 accentuation" associated with a dose-related reduction of the P2 component of the S1 response and a plasma level related reduction of PINTP. CONCLUSIONS: These data suggest an involuntary attentional shift towards S1 processing with increasing dopamine-release similar to that observed in patients with schizophrenia or OCD. It is concluded that sensory gating alters selective attention via dopaminergic modulation.

[Techno-festival mit fatal outcome]. / Techno-Festival mit tödlichem Ausgang.

The authors report on a 21-year old female who died suddenly during a techno-festival. The autopsy findings and the results of chemical-toxicological analyses were not able to clear up the cause of death. Pathophysiological and toxicological considerations demonstrate that only a combination of facts are sufficient to explain the sudden death of this young woman.

[Routine case of "auto-erotic accident"--surprising turn in evaluation of cause of death after chemical-toxicologic analysis]. / Routinefall "autoerotischer Unfall"--überraschende Wendung in der Bewertung der Todesursache nach chem.-tox. Analyse.

A man with indications of autoerotic manipulations was found dead in his flat and a homicide had to be excluded. Diverse material found in the flat suggested that the man was a consumer of cocaine. But the analyses of blood, urine and organs showed high concentrations of amphetamine and it was thought about an unintentionally mix-up with cocaine. A hair analysis was made and only amphetamine was detected. Therefore the utensils (mirror, razor-blade and sniff-pipe) belong to a rare nasal consumption of amphetamine.

[Comparison of the MTP immunoassay with EMIT in blood screening for drugs]. / Vergleich der MTP-Immunoassays mit EMIT beim Screening von Blut auf Drogen.

We compared the MTP immunoassay with EMIT for the screening of drugs of abuse (opiates, cannabinoids, cocaine metabolites and amphetamines) in whole blood samples. These blood samples were obtained from the German police, when driving under the influence of drugs of abuse was suspected. For screening with the MTP immunoassay 25 microliters of serum or blood (without any pretreatment) was pipetted into the wells of the microtiter plates and the procedure was followed as described. Prior to screening with a Cobas Mira and EMIT reagents, the samples were treated with acetone to precipitate serum proteins. The cutoff for all drugs of abuse was set at 10 ng per ml of serum or blood. In most cases there was a good agreement between the negative and positive results of the two screening assays. The agreement between the two assays in the detection of opiates and cocaine was 91% and 93%, respectively, and for cannabinoids and amphetamines approximately 80%. The MTP immunoassay was more sensitive than EMIT for the detection of cannabinoids--but at the same time the MTP immunoassay was less specific. Both screening assays have a sensitivity of 100% for the detection of opiates and cocaine, but the specificity of the EMIT--also for opiates--was substantially lower. The MTP immunoassay has in respect to amphetamines a very high sensitivity, whereas the sensitivity of EMIT for amphetamines is inacceptable due to losses during sample preparation. The specificity of MTP immunoassay for amphetamines is not optimal, because a relatively large amount of samples tested false-positive for amphetamines at the cutoff of 10 ng/ml. In summary the MTP immunoassay, although not automated, performs well in comparison with EMIT, especially if the sample preparation for EMIT testing ist considered.

Combination of fatal digoxin poisoning with endocardial fibroelastosis.

This is the first report in the forensic literature of a combination of fatal digoxin poisoning with endocardial fibroelastosis (EFE). Typical morphological features of EFE as the cause of clinically diagnosed cardiomyopathy were present in the autopsy of a 3-year-old girl, including cardiac hypertrophy and marked thickening of the left-sided endocardium, consisting of numerous elastic and collagenic fibres. After exclusion of cardiac and cerebral causes of death, accidental digoxin intoxication was proved. Postmortem toxicological analyses by fluorescence polarization immunoassay (FPIA) disclosed digoxin levels of 71 micrograms/kg (femoral vein blood), 77 micrograms/kg (cardiac blood), 255 and 221 micrograms/kg (cardiac muscle of the right and left chamber), 163 micrograms/kg (psoas muscle), 91 micrograms/kg (lung), 222 micrograms/kg (liver) and 520 micrograms/kg (kidney). The results are compared with the antemortem digoxin concentration of 39 ng/ml serum. The case is discussed from its unusual morphological and toxicological aspects, with special consideration of possible medical malpractice.

Pulmonary histopathology and survival period in morphine-involved deaths.

For an evaluation of the survival period in morphine-involved deaths, changes of pulmonary histopathology were investigated in a total of 90 morphine-associated fatalities. Although pulmonary histopathology proved to be heterogeneous, several distinctive histological patterns emerged. While the subgroup with short courses of intoxication ( < 1 h, n = 15) was mostly characterized by slight/moderate alveolar edema (12/15), severe hemorrhages (12/15) and marked acute emphysema (9/15), the phenomena of massive edema (8/15), missing/slight hemorrhages (8/15) and absent/slight emphysema (11/15) dominated in the group with intermediate survival times (1-24 h, n = 15). Intravascular leukocyte accumulations (shock equivalent) occurred in the first group only once, but in the group with the longer survival time in 10 of 15 cases. Delayed deaths ( > 24 h, n = 4) were mainly characterized by purulent bronchitis/pneumonia. Those fatalities (n = 56) that could not be classified by anamnestic data were assessed by histological criteria. In comparison with the evaluation of the survival period by toxicological analyses, concordance was found in 46 cases. Pulmonary histopathology is not a tool for an exact graduation of survival time, but the combination of several key parameters can provide criteria for a differentiation between short ( < 1 h) and longer courses of intoxication.

Ketamine and strychnine treatment of an infant with nonketotic hyperglycinaemia.

UNLABELLED: Non-ketotic hyperglycinaemia (NKH) is a severe seizure disorder associated with high glycine levels. Glycine is a major inhibitory neurotransmitter in the CNS, but has also modulating effects at one of the glutamate receptors, the N-methyl-D-aspartate-(NMDA) receptor. Based on this knowledge we treated a female newborn suffering from severe NKH with the NMDA receptor blocker ketamine in association with strychnine and magnesium supplementation. This treatment led to cessation of seizures, reappearance of swallowing and sucking and improved the neurological status. Some pharmacokinetic data of strychnine and ketamine in the infant are given. CONCLUSION: Ketamine in combination with strychnine may be beneficial in non-ketotic hyperglycinaemia.

[Two traffic accidents after heroin consumption with fatal outcome]. / Zwei Verkehrsunfälle nach Heroin-Konsum mit tödlichem Ausgang.

We report on 2 road accidents where 4 people--drivers and front-seat passengers--were injured so badly that they consequently died. All four had consumed heroin, in addition to which both passengers had also consumed cocaine and dihydrocodeine respectively. The blood samples of one of the drivers was only taken after the onset of intensive medical treatment including infusions and transfusions. Nevertheless the result of the analysis clearly showed that the driving ability had been impaired by heroin. In the remaining cases the opiat concentrations were so high that they could have justified a fatal intoxication in themselves. This applies especially to one of the passengers who displayed an unconjugated morphine blood concentration of 0.96 m/l. However, also in this case at the time of the accident the blood circulation and heartbeat did not stop immediately.

Pharmacokinetics of vasoactive substances administered into the human corpus cavernosum.

The pharmacokinetics of vasoactive substances injected into the corpus cavernosum for the treatment of erectile dysfunction have not been investigated to date. We measured the local intracavernous and peripheral venous concentration curves of papaverine and prostaglandin E1, and its primary metabolite 15-keto-13,14-dihydro-prostaglandin E1 in an intra-individual comparison after intracavernous injection. Papaverine was measured with high performance liquid chromatography and prostaglandin E1 was measured with a specially adapted radioimmunoassay. The results demonstrate that papaverine is slowly draining into the systemic circulation, showing slightly elevated levels in the peripheral blood 30 and 60 minutes after injection. Prostaglandin E1 shows a much faster decrease in local concentrations with no measurable increase in the periphery, probably due to the short half-time after lung passage. Measurement of the primary metabolite proves a local degradation of prostaglandin E1 in the corpus cavernosum into the biologically inactive 15-keto-13,14-dihydro-prostaglandin E1, which also shows a slight increase in the peripheral circulation due to the longer half-time of approximately 8 minutes. The data provide good explanation for the clinical finding of a markedly decreased incidence of priapism with the use of prostaglandin E1, which can be shown to be locally metabolized, compared to papaverine, which is retained in the corpus cavernosum in cases of nonvenogenic impotence.

Hypoxanthine in vitreous humor and cerebrospinal fluid--a marker of postmortem interval and prolonged (vital) hypoxia? Remarks also on hypoxanthine in SIDS.

Hypoxanthine (Hx) is a degradation product of adenosine. Increased concentrations were reported in cases of hypoxia as well as with prolonged postmortem interval (PMI). Hx is recommended as an indicator of prolonged (cerebral) hypoxia, for example in vitamins of sudden infant death as well as a new biochemical method for estimation of postmortem time. The correlation of vitreous Hx values with the time since death was reported to be even higher than the vitreous potassium (K+) values. The authors' investigations on 92 bodies with known time since death gave a completely opposite result: a much higher correlation between vitreous K+ and time since death than vitreous Hx. The possible discrepancies between these different results will be discussed (disturbing of intra-ocular fluid dynamics by repeated sample-taking in the study of Rognum et al. The results published so far on vitreous Hx values in sudden infant death syndrome (SIDS) cases as an indicator for a prolonged cerebral hypoxia are also not convincing. When vitreous concentrations of newborn infants or infants of age < 6 months are compared to those of older infants or adults the vitreous diameter must be taken into consideration (diffusion gradient; Fick's law of diffusion). The discrepant results on vitreous Hx as a measure of vital hypoxia and PMI will be discussed. The authors' results on Hx determinations on cerebrospinal fluid in comparison to cerebrospinal spinal (CSF) potassium will also be briefly addressed.

[Drug fatalities with cadaver dumping]. / Drogentodesfälle mit Leichenbeseitigung.

7 cases of "dumping" of the bodies of drug addicts are reported. Circumstances of the case, findings at the scene, autopsy findings and confessions raised already the suspicion that the bodies were not found at the scene of death. In 5 cases the "dumping" of the bodies was outside, in 2 cases inside a house. Identification of the bodies was always easy, since personal papers (passport, identity card) were still present and no attempts were made to prevent identification. The prevalent motivation for "dumping" seems to be not to be identified as drug addict or dealer or to be brought in connection with the death of drug addicts.

[Plasma levomethadone level and concomitant use of sedatives in a methadone test program]. / Levomethadon-Plasmaspiegel und Beigebrauch von Sedativa im Methadon-Erprobungsprogramm.

Treatment of heroin addicts with levomethadone as an alternative to the clinically performed withdrawal gains in significance more and more. Just for that reason accompanying scientific programs guided along criterions of therapy research are essential. Results of an evaluation which is to be regarded as preliminary showed no correlation between methadone plasma levels and dosage. Additional consumption of opiates, barbiturates, and benzodiazepines was observed to a high degree. The efficiency of methadone treatment is to be valued only under consideration of criterions of admission to the program as for instance a drug abuse of many years or multiple unsuccessful treatments by withdrawal.

[Comparative studies of drug detection using recent immunologic methods]. / Vergleichende Untersuchungen zum Drogennachweis mit neueren immunologischen Methoden.

150 urine samples which we received from the criminal investigation department were measured with EMIT cannabis 20 and EMIT cannabis 50 reagents by EMIT Autolabsystem and especially with the immunoassay analyzer ETS by Syva Diagnostica. The confirming analyses were performed by GC-MS. If only cases are considered which are positive with cannabis 20 containing at least 10 ng 11-Nor-delta-9-THC-9-carboxylic acid in urine, there will be a negative result of 18.8% with EMIT 50. This appears to be unreasonably high. Some of these cases were also tested with Abuscreen ONTRAK-reagents. With this method the cut off for cannabis with 100 ng/ml urine is far too high but can be lowered essentially by taking a larger urine sample.

[Chemical-toxicologic studies of the epidemiology of drug use (1.)]. / Chemisch-toxikologische Untersuchungen zur Epidemiologie des Arzneimittelkonsums (1. Mitteilung).

During a long term program we secured when possible blood from a femoral vein of dead bodies. Until now 207 cases which were not selected have been investigated. The analyses were performed by high pressure liquid chromatography to prove extractable as well as by gas chromatography to determine volatile substances. These results are represented and correlated with the investigation of the CID or the Department of Public Prosecution respectively and with the results of autopsies if available and discussed.

Results of toxicological investigations of poisonings with atropine and scopolamine.

Lethal poisonings with alkaloids are rarely observed in the Federal Republic of Germany. We had however to investigate a case of poisoning with atropine and another with scopolamine during the last few years. The analysis was carried out with GC-MS and HPLC. Concentrations of the active substance on different organs of the body are represented. Thus the amount of alkaloid being taken is deduced. Cause of death is discussed by means of literature data.