[Antidotes in clinical toxicology]. / Antidote in der klinischen Toxikologie.

This overview describes antidotes, and their clinical pharmacology, that have an established significance in the currently practiced clinical toxicology because of their proven effectiveness in the treatment of serious poisonings. For the proper, efficient, and targeted use of an antidote, pharmacological knowledge is required, which is a central subject of this article. Current data from the literature are used as reference along with the accumulated experiences about possible adverse effects in order to include them in therapeutic considerations. The dosage of antidotes is the subject of several other review articles and is therefore not included in this synopsis.

[Comparison of the cost of treatment of premature labor with atosiban or beta-sympathomimetics from the perspective of the health care payer--a pharmacoeconomic model]. / Srovnání nákladu na lécbu predcasného porodu atosibanem nebo beta-sympatomimetiky z perspektivy plátce zdravotní péce--farmakoekonomický model.

OBJECTIVE: To evaluate the cost of treating premature delivery with atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) from the perspective of health care payer--the medical insurance company. DESIGN: A pharmaco-economic model based on the results of randomized, controlled clinical study. SETTING: Hospital Pharmacy at Vitkovice Hospital of Blessed Mary Antonia, Ostrava. METHODS: The study is based on the application of clinical decision-making analysis, which includes results of a randomized controlled clinical study as well as data on the cost of clinical interventions and cost of drug therapy. The pharmaco-economic model was created from the perspective of the payer of health care--the insurance company. This model presumes the administration of atosiban or beta-sympatomimetic drugs (fenoterol and hexoprenalin) for the period of 18 and 48 h and the therapy of possible untoward effects for the next 72 h after the administration of the drugs. The analysis of sensitivity of pharmacokinetic model also employs so called low and high estimate of supplementary cost for the treatment of untoward effects. RESULTS: After the administration of the drugs for the period of 18 h the total cost of the payer of medical care was in the range of 21,914.5-21,974.4 CKr in atosiban, 19,878.7-22,661.4 CKr in fenoterol and 19,942.9-21,974.4 CKr in hexoprenalin. In the administration of the drugs for 48 h, the overall cost of the payer of medical care was in the range of 43,082.5-43,142.4 CKr in atosiban, 19,960.3-23,150.7 CKr in fenoterol and 20,131.3-23,574.0 in hexoprenalin. CONCLUSIONS: This study compared overall cost associated with hospitalization of a premature delivery from the perspective of the medical care payer, i.e. the health insurance company. The authors applied a pharmaco-economic model evaluating hospitalization for the period of 48 h and subsequent therapy of possible untoward effects for the period of up to 72 h. In case of a shorter administration of atosiban (up to 18 h) the overall cost of hospitalization for premature delivery for the period of 48 h from the point of view of medical insurance company is basically comparable with the administration of beta-sympatomimetic drugs. If atosiban is administered for more than 18 h, the overall cost of hospitalization is higher than with beta-sympatomimetic drugs, and the cost increases in relation to the duration of atosiban administration.

[Availability of antidotes in hospital pharmacies in the Czech Republic]. / Dostupnost antidot v nemocnicních lékárnách Ceské republiky.

Availability of antidotes in the Czech Republic (CR) is insufficient. Many antidotes are not approved in CR, so their obtaining is problematic. The purpose of this study is to examine the real availability of antidotes in Czech hospital pharmacies and to assess the influence of hospital size, hospital localisation, antidote cost, and the fact of antidote approval in CR on antidote availability. Finally, some proposals for the solution of the situation are mentioned. A structured questionnaire was constructed and mailed to 85 hospital pharmacies. A total of 46 hospital pharmacies sent back completely answered questionnaires and they were statistically assessed. The questionnaire included a summary of poisonings and usable antidotes. The recommended quantity of each antidote was included. Availability of antidotes (D) and sufficient availability of antidotes (DD) were calculated for each answering hospital pharmacy as a ratio of poisonings for which the antidote was available or available in a sufficient quantity, to all poisonings mentioned in the questionnaire. The other calculated parameter was the availability of an individual antidote (d) and the sufficient availability of an individual antidote (dd)--they were calculated as a ratio of pharmacies stocking the antidote, or stocking the antidote in a sufficient quantity, to evaluated pharmacies. Availability of 23 different antidotes for 20 poisonings was assessed. Antidotes for roughly one half of assessed poisonings are available (D 55.69 +/- 12.42%) and for about one third of poisonings the antidotes are available in a sufficient quantity (DD--37.23 +/- 14.10%). The D and DD have been dependent on hospital size (measured as the number of beds). D and DD have not been dependent on the localisation of the hospital (measured as a period of transport time to the hospital of higher type of care), d and dd ranged between 0-100% and were dependent on the antidote cost. There were significant differences between d and dd of antidotes approved (R) and unapproved (NR) in CR (d(R)--70.51 +/- 33.26%, d(NR)--10.19 +/- 9.26%, p < 0.001; dd(R)--47.55 +/- 29.94%, dd(NR)--6.93 +/- 7.76%, p < 0.001). The results of the study confirm a very unsatisfactory situation in antidote availability in Czech hospital pharmacies. Hospital stocks of many antidotes are inadequate. Often, the antidotes are available, but their quantity is insufficient. The worst situation is in small hospitals, in the very costly antidotes, and in the antidotes not registered in CR.

Presence and activity of cytochrome P450 isoforms in minipig liver microsomes. Comparison with human liver samples.

Cytochrome P450 (CYP) of the 3A family (CYP3A) has been detected in minipig liver microsomes by immunochemical screening (Western blotting), revealing bands that co-migrate with human CYP3A4 and 3A5. The nifedipine oxidase activity and testosterone 6beta-hydroxylating activity (specific markers for CYP3A enzymes) of the human liver microsomal and minipig liver microsomal samples were comparable, as were the results of specific inhibition of this activity by triacetyloleandomycin. The presence of CYP1A, 2A, 2C, 2D, and 2E1 marker activities in minipig liver microsomes was found by testing with the respective specific substrates (7-ethoxyresorufin, coumarin, tolbutamide, bufuralol, and chlorzoxazone). 7-Pentoxyresorufin O-depentylase activity (indicative of CYP2B) was absent from minipig as well as human liver microsomal samples. The results indicate that minipigs might be, in many cases, the most suitable experimental animals to predict biotransformation pathways in humans, because the activity of the most important CYP isoform in humans (CYP3A, metabolizing the majority of known drug substrates) is present in minipigs, with comparable levels and activities. Moreover, there is no need to induce CYP enzyme levels.

[Cytochrome P450--its significance in the biotransformation of xenobiotics and interspecies comparisons]. / Cytochrom P450--význam v biotransformaci xenobiotik a mezidruhové srovnání.

Enzyme system of cytochrome is the most important system of the oxidative biotransformation of xenobiotics. It was formerly assumed to be mainly a system of detoxication, however, it was recognized to be involved in many reactions leading to biological activation of compounds. This activation may give rise to unwanted products with rather detrimental effects. Isoforms of cytochrome are classified according to the similarity in primary structures into families and subfamilies. The great variability observed in enzymatic activities and in levels of particular isoforms is based on the known genetic polymorphism and on the enzyme induction or inhibition. However, this may be reflected in different pharmacologic responses to many drugs. Due to existence of interspecies differences in the presence of cytochrome P450 isoforms as well as due to differences in the substrate specificity it is difficult to extrapolate results obtained in experiments on animals to the human cases. A survey of isoforms, important for biotransformation of xenobiotics and of their properties is presented.

Potential cancerostatic benfluron is metabolized by peroxidase: in vitro biotransformation of benfluron by horseradish peroxidase.

Horseradish peroxidase (HRP) was used to investigate whether benfluron (a potential cytostatic drug) can be biotransformed extra-hepatically by systems other than flavin-containing monooxygenase and cytochromes P450. Three types of incubation mixtures differing in buffers (Na-phosphate buffer 50 mmol/l, pH 6.8 and 8.4 and Tris-HCl buffer 25 mmol/l, pH 7.5) were tested. The amount of N-demethylated benfluron (demB) formed was significantly higher (up to 4 times in the Na-phosphate buffer, pH 8.4, and 5 times in the Na-phosphate buffer, pH 6.8, and in the Tris-HCl buffer, pH 7.5) compared to control experiments. The highest yields of demB were obtained with the moderately alkaline Na-phosphate buffer (50 mmol/l, pH 8.4). The concentration of demB increased during thirty minutes of incubation, and then remained constant through the end of two-hour incubation. The results support the hypothesis that benfluron can be metabolized extra-hepatically by N-demethylation reaction catalyzed by peroxidases.

Study of the biotransformation of a potential benzo[c]fluorene antineoplastic using high-performance liquid chromatography with high-speed-scanning ultraviolet detection.

As the sum of benfluron metabolites found was only a part of the total amount applied, a search for undiscovered metabolites was undertaken in the extracts from isolated rat hepatocytes and in the bile and perfusate in the experiments with an isolated perfused rat liver. To identify the metabolites, high-performance liquid chromatography with UV spectral analysis was used, as benfluron derivatives exhibit characteristic absorption spectra. Administration of known metabolites to experimental animals and selective induction of certain metabolic pathways led to the finding of new metabolites and of the respective conjugates. Fast atom bombardment-mass spectrometry analysis was used to identify the newly found metabolites and conjugates.

[Dangerous intoxication from extreme serum concentrations of methaqualone metabolites. Detection and quantification of biosynthesis with gas chromatography-mass spectrometry]. / Lebensbedrohliche Intoxikation durch extreme Serum-konzentration eines Methaqualonmetaboliten. Nachweis und Quantifizierung mittels Biosynthese und Gaschromatographie-Massenspektrometrie.

CLINICAL COURSE: We present a potentially fatal case of acute methaqualone (M) poisoning with very low serum concentrations of M but extremely high levels of its metabolite, 2-methyl-3-(2-hydroxymethyl-phenyl)-4 (3H)-chinazoline (Met-1). A 23-year-old man was admitted to the intensive care unit 2 days after ingestion of 4-5 g M in an suicidal attempt. On admission he was somnolent and poorly responsive to painful stimuli. Physical examination revealed a heart rate of 95 bpm, a blood pressure of 125/65 mmHg, and a normal body temperature. His chest was clear to auscultation, respirations were shallow, and the skin was cyanotic. The electrocardiogram was unremarkable. The chest radiograph showed a normal heart size without pulmonary infiltrates or venous congestion. The pupils were dilated but reactive to light. The neurologic examination was further remarkable for increased limb reflexes, myoclonia, and positive pyramidal signs. During the next 2 days the patient became comatose and developed respiratory insufficiency due to non-cardiogenic pulmonary oedema, which was confirmed by chest radiograph and haemodynamic investigations by means of right heart catheterisation. He required mechanical ventilation for 6 days. Finally, he recovered completely and was discharged in good condition. DIAGNOSTICS: A lumbar puncture revealed neither blood nor pleocytosis in the cerebrospinal fluid. Cranial computed tomography was carried out on an emergency basis, but no abnormality was disclosed. An electroencephalogram did not exhibit any significant pathological findings. Testing for infectious diseases or porphyria gave negative results. Toxicological screening based on enzyme immunoassays (ELISA) was negative for alcohol, tricyclic antidepressants, benzodiazepines, barbiturates, and morphine, but gave a positive result for M. From the moment of admission daily blood samples were taken and analysed by combined gas chromatography and mass spectrometry. These showed very low levels of M but extremely high levels of Met-1. THERAPY: After gastric lavage, continuous enteric lavage with activated charcoal and mannitol was initiated to minimise intestinal absorption. Since M was hardly detectable in the serum, haemoperfusion was not regarded as indicated for drug elimination and treatment was restricted to general supportive measures. To rule out a central anticholinergic syndrome, an anticholinesterase drug (physostigmine) was administered but remained without therapeutic effect. CONCLUSIONS: The presented case is the first report of a life-threatening intoxication after M ingestion primarily caused by Met-1. It supports the significance of this metabolite for the toxic effects of the drug. A toxicological screening test based on ELISA proved helpful due to its cross-reactivity with metabolites. In cases similar to ours, resin haemoperfusion may be indicated to remove the metabolites despite low detectable concentrations of the parent substance in the serum.

Upregulation of a lymphoid serine protease in kidney allograft recipients.

The presence of a putative, cytotoxicity-linked lymphoid serine esterase (SE) has been studied in 79 kidney graft recipients. Peripheral blood lymphocytes (PBL) bearing an N-alpha-benzyloxy carbonyl-L-lysine thiobenzyl ester (BLT)-specific SE were evaluated by a novel cytochemical staining method. A characteristic of post-allograft patients was an increased presence of SE containing granules in PBL. In 46 patients with stable graft function SE + PBL were 33.41 +/- 10.34% (controls: 26.30 +/- 5.22%, P less than 0.0025), SE + CD4+ 4.32 +/- 3.85% (controls 2.13 +/- 1.52%, P less than 0.0025) and SE + CD8+ T cells 47.68 +/- 18.64% (controls: 28.50 +/- 6.50%, P less than 0.0005). In those graft recipients undergoing a rejection episode a marked upregulation of SE activity could be observed when compared to the stable graft group: SE + PBL were 59.91 +/- 10.89% (P less than 0.0005), SE + CD8+ 74.30 +/- 10.79% (P less than 0.0005) and SE + CD4+ T cells 28.56 +/- 13.50% (P less than 0.0005). In 10 cases this increase of SE activity was observed with a time lag of up to 37 days prior to the onset of clinical or biopsy proven rejections, promptly decreasing in response to methylprednisolone antirejection therapy. In patients with recurrent rejection episodes and subsequent graft loss, a repeating increase of SE activity indicated a failure of therapeutic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

From a forester's boy to a university professor.

Austrian ophthalmologist, Dr. Karl B. Hruby, is well known for his present lens, which allows slit-lamp examination of the vitreous and fundus. He is also known as one of the first to use microsurgical methods for intraocular operations and scleral buckling for retinal detachments. In this memoir, Dr. Hruby shares the fascinating personal account of his experiences as a prisoner and physician during World War II, and as an outstanding teacher and clinician thereafter. The article is followed by the editorial comment of Dr. Fred Blodi, who invited Dr. Hruby to contribute this article.

Value of flumazenil in benzodiazepine self-poisoning.

The efficacy of the benzodiazepine-antagonist flumazenil (Ro 15-1788) was evaluated in 26 patients with coma due to benzodiazepine self poisoning, alone or in combination with alcohol or other psychoactive drugs. 77% of the patients responded to the administration of a mean dose of 1.73 mg (range 0.2 to 8 mg) with immediate awakening or an improvement of at least 2 coma grades. In the patients without response (n = 3) or with minor improvement (n = 3) other psychoactive drugs turned out to be predominantly responsible for their comatose state. Adverse effects of flumazenil treatment such as altered blood pressure or increased heart rate were observed, but were generally mild. An acute benzodiazepine withdrawal syndrome was seen in 2 cases. In conclusion, flumazenil proved to be effective in the treatment of severe benzodiazepine intoxication. Beyond that, in cases of mixed overdosage or initially unknown diagnosis the antidote assisted in the clarification of the clinical condition.

[Is retinitis pigmentosa absolutely incurable?]. / Ist die Retinitis pigmentosa zweifellos unheilbar?

The importance of phosphatides in the biochemistry of the retina and in visual function provided a basis for therapeutic administration of these substances in cases of senile maculopathy and retinitis pigmentosa. In cases of dry senile maculopathy, good results were only obtained by administering (n-3)-docosahexaenacid to the retina as the active component of intramuscular injections of Etaretin. So far only one report of a convincing therapeutic success in a case of retinitis pigmentosa has been published.

[Specific therapy of acute benzodiazepine poisoning using flumazenil (Ro 15-1788)]. / Spezifische Therapie der akuten Benzodiazepinintoxikation mittels Flumazenil (Ro 15-1788).

In 20 patients with coma (grade 4: n = 7, grade 3: n = 8, grade 2: n = 2, grade 1: n = 3) due to benzodiazepine intoxication, solely or combined with alcohol or other psychoactive drugs, the effect of a specific benzodiazepine antagonist, Flumazenil (Ro 15-1788), was evaluated. In terms of coma depth, 80% of the patients responded to application of 1.96 mg Flumazenil as a mean with immediate awakening or improvement of at least two steps in coma grading. In those 3 patients, who failed to respond to Flumazenil, the history revealed amitriptyline or barbiturates to be responsible for the comatose state. The observed side-effects of Flumazenil included increase (n = 4) or decrease (n = 3) of blood pressure, increase of heart rate (n = 7), cutaneous flush (n = 1) and ventricular extrasystoles (n = 1). Agitation and generalized convulsions, each observed in 1 patient, presumably were due to an acute benzodiazepine-withdrawal rather than an intrinsic side effect of the antagonist. In conclusion, Flumazenil proved to be a potent antagonist of benzodiazepines in patients with severe coma and even may serve as a valuable diagnostic in cases of suspected benzodiazepine intoxication.

[Was Dr. Carl Koller driven from Vienna in 1885?]. / Wurde Dr. Carl Koller 1885 aus Wien vertrieben?

In this article the principal reason for the emigration of Dr. Carl Koller is examined on the basis of the available literature. In fact, antisemitism did not play a crucial role. After his colleague, Dr. Fritz Zinner, called him an impudent Jew in public in the General University Hospital of Vienna, Koller reacted by hitting the man in the face. A duel with heavy sabres was the outcome; Koller was unharmed, whilst his opponent received two deep gashes. Such duels were strictly forbidden at that time already, but were nonetheless still executed. In consequence, Koller's hopes of obtaining a position in the Eye Department, for which he was very well qualified, and of an academic career in Vienna were dashed and he had to emigrate. Koller eventually settled in New York in 1888, where he received many distinctions during his life span. The Medical Association of Vienna also honoured him in 1930. Dr. Koller was proposed several times for the Nobel prize in Physiology and Medicine, since his discovery of cocaine as local anaesthetic in ophthalmology was undoubtedly worthy of this prize, but his discovery had been published too long previously, so that according to the statutes of the Nobel prize this distinction could not be granted. Hence, it can be concluded that although Dr. Koller was forced to leave Vienna in 1885, it was not principally for antisemitic reasons. There were Jewish professors in the Medical Faculty of Vienna University at the time and, indeed, when the author studied medicine in 1931 to 1936, four Jewish professors held chairs in Vienna and one of his predecessors as chief of the First Department of Ophthalmology, Isidor Schnabel, was Jewish.

[The first description of the Irvine syndrome]. / Die Erstbeschreibung des "Irvine-Syndroms".

Recently G. O. H. Naumann and W. Seibel, while reviewing the literature, stated that A. R. Irvine had not noticed the foregoing biomicroscopic observations of K. Hruby. The name Hruby-Irvine-Gass Syndrome would thus be more appropriate. The article concludes with a discussion of therapeutic problems.

[Rise and fall of the German University Eye Clinic in Prague]. / Aufstieg und Untergang der Deutschen Universitäts-Augenklinik in Prag.

The German University in Prague was founded in 1348 by the German Emperor Karl IV. However, it was not until 1808 that an eye clinic was established there, by Johann Nepomuk Fischer; the clinic was incorporated into the university in 1820. Fischer retired in 1847 and was succeeded by Ferdinand Arlt, though not as professor in ordinary. Fortunately, the chair in Prague was offered to Arlt before he had definitively accepted a call to Leipzig. During the period 1856 to 1883 Ferdinand Ritter von Arlt held the chair of ophthalmology in Vienna, an ophthalmic center of high repute. One of his most famous pupils was Albrecht von Graefe, of Berlin. Josef von Hasner directed the Prague Eye Clinic from 1856 to 1883, followed by Hubert Sattler (1886-1891). Isidor Schnabel was professor in Prague from 1891 to 1895, before going to Vienna. His successor, Wilhelm Paul Czermak, directed the Prague Eye Clinic from 1895 to 1906. He was followed by Isidor Schnabel's most outstanding pupil, Anton Elschnig, a Styrian by birth, who held the chair from 1907 to 1933. Under Elschnig's guidance the Prague University Eye Clinic reached a high international standard. Professor Elschnig retired in 1933 and died in Vienna in 1939 following a street accident. Elschnig's successor was his former assistant Jaroslav Kubik; he had to relinquish the chair after the Germans occupied Czechoslovakia because his wife was Jewish.(ABSTRACT TRUNCATED AT 250 WORDS)