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Optical threshold functions are a basic building block for all-optical signal processing, and this paper investigates a threshold function design reliant on a single active element. An optical threshold function based on nonlinear polarization rotation in a single semiconductor optical amplifier is proposed. It functions due to an induced modification of the birefringence of a semiconductor optical amplifier caused by an externally injected optical control signal. It is shown that switching from both the TE to the TM mode and vice versa is possible. The measured results are supported by simulation results based on the SOA rate equations.

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Fomocaine (4-[3-(4-phenoxymethylphenyl)-propyl]-morpholine, CAS 17692-39-6) is a highly effective local anaesthetic of low toxicity. The drug, which causes no allergic response, was introduced in the German Extrapharmacopoeia (DAC). Fourteen metabolites are formed after oral administration to rat and beagle dog. Less than 5% fomocaine are excreted unchanged. The metabolites were synthesized and their physico-chemical properties were investigated. No metabolite caused a surface or conduction anaesthesia with the exception of 2-hydroxyfomocaine (O/Se 4). After topical and parenteral administration irritation could not be observed. All metabolites except O/Se 10 and O/Se 11 showed a lower toxicity than fomocaine. In both species O/Se 10 and O/Se 11 are formed only in a small amount and are detoxified by conjugation.

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The nephrotoxicity of juniper oil (CAS 73049-62-4), a phytomedicine with diuretic resp. aquaretic activity, was evaluated in male Sprague-Dawley rats after oral administration. Two chemically slightly different oil batches were tested for 28 days with 100, 333 or 1000 mg (series 1, batch 1) resp. 100, 300 or 900 mg (series 2, batch 2) juniper oil/kg. Additionally terpinene-4-ol, a compound with postulated aquaretic activity, which can be found in essential juniper oil up to an amount of 10 mg% was tested in a dosage of 400 mg/kg. Neither of the tested substances induced changes in function or morphology of the kidneys at the tested doses, and they were revealed to be nontoxic.

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Ichthyol (Ammoniumbituminosulfonat DAB, dark sulfonated shale oil, CAS 8029-68-3) is used for the treatment of inflammatory skin diseases and rheumatic diseases and blunt traumata. The studies conducted were carried out to obtain information on the risk following dermal and oral application of dark sulfonated shale oil. Corresponding to the administration route envisaged for man the drug was applied by topical and systemic administration. Studies were conducted on the acute, subacute and chronic toxicity, local tolerance, and the teratogenic, mutagenic and carcinogenic potential. Dark sulfonated shale oil was found to be well tolerated whether administered for a short period or over a long time. There were no indications for a teratogenic, mutagenic or carcinogenic effect. The therapeutic index (ratio of the toxic dose in animals and the therapeutic human dose) for topical administration of dark sulfonated shale oil is > 7 depending on animal species, frequency of administration, dose-level employed and the toxicological question posed. The results of the toxicological studies coincide with more than 110 years of experience that the drug is well-tolerated by man.

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Ichthyol, pale, a pale sulfonated shale oil, is used for the treatment of inflammatory skin diseases. The studies conducted were carried out to obtain information on the risk following dermal application of sulfonated shale oil, pale. Corresponding to the administration route planned for man the drug was applied by topical and systemic administration. Studies were conducted on the acute, subacute and chronic toxicity, and the teratogenic, mutagenic and carcinogenic potential. Sulfonated shale oil, pale was found to be very well tolerated whether administered for a short period or over a long time. There were no indications for teratogenic, mutagenic or carcinogenic effects. The therapeutic range (ratio of the toxic dose in animals and the therapeutic human dose) for topical administration is > 30 depending on animal species, frequency of administration, dose-level employed and the toxicological question posed. The results of the toxicological studies coincide with the almost 70 years of experience that the drug is well-tolerated by man.

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An open trial was carried out in eight healthy male and female volunteers to examine the bioavailability as well as the main kinetic parameters of Migränerton (metoclopramide and paracetamol; CAS 364-64-5 and CAS 103-90-2, resp). in comparison with reliable literature data. The results reported here clearly show that the absorption of both active ingredients from the fixed combination is complete and that therapeutically relevant plasma concentrations are achieved within 30 min. Bioavailability as well as tmax, t1/2, and time-lag are comparable with data resulting from reliable and internationally acknowledged kinetic studies. The fixed combination was shown to be kinetically compatible with regard to all parameters determined for metoclopramide and paracetamol.

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Chloral hydrate (CAS 302-17-0) of greater than 99.4% purity was investigated on its mutagenic potential in a series of test systems according to the current EC guidelines. There were no indications for a mutagenic potential of chloral hydrate.

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Rats received 40, 80 and 160 mg KCN/kg body wt./24 h in the drinking water for 13 weeks. Fairly constant dose-related cyanide and thiocyanate levels were measured in blood, plasma and urine during the exposure. Blood cyanide concentrations were in the range of 16.0-25.5 nmol CN-/ml blood, thiocyanate concentrations in the range of 341-877 nmol SCN-/ml plasma following continuous administration of the maximum tolerated dose-level of 160 mg/kg body wt/24 h. The results suggest that continuous 13-week maximum tolerated cyanide exposure does not lead to saturation of cyanide detoxification pathways.

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Male and female cynomolgous monkeys were administered 0, 2, 6 or 18 mg/kg 8-methoxypsoralen (8-MOP) 3 times a week orally for 26 consecutive weeks. Dose-dependent emesis was the most sensitive indicator of 8-MOP toxicity. The lowest dose to elicit emesis was 3 x 6 mg/kg/week of 8-MOP. Among the histological findings proliferation of Kupffer cells was the only recurring observation. However, these finding as well as some hematological and serum electrolyte changes lacked a dose-response relationship. In the highest dosage group one female monkey was found in moribund condition on the 39th day of the study and was killed. Histopathological evidence indicated beginning shock as the cause of the rapidly deteriorating health of the monkey. Similar to effects in man and rats, 8-MOP displayed nonlinear pharmacokinetics in the cynomolgous monkey, saturation occurring between 3 x 2 and 3 x 6 mg/kg/week. Increased clearance of 8-MOP in the lowest dosage group after 26 test weeks was attributed to a combination of enzyme induction and saturable first pass effect. Since the plasma profile of 8-MOP at the lowest dose (3 x 2 mg/kg/week) in cynomolgous monkeys closely resembles that in humans after therapeutic doses (0.4-0.6 mg/kg) and because of other similarities (vomiting as earliest sign of toxicity, saturable first pass effect), it is reasonable to assume that chronic toxicity of 8-MOP as defined in this study is quite predictive for man.

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The German Chemicals Act requires that chemicals are tested for behavioral toxicity at stage 2 of the testing procedure, i.e. if more than 1000 annual tons are produced. For this purpose a guideline was developed according to which data on behavioral toxicity are to be collected, which are based on cageside observations during longterm exposure. The protocol covers outer appearance, as well as motor, sensory, autonomic and central nervous system functions. Data are to be reported in tabular form and should be evaluated by taking all aspects of the toxicological profile into account.

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Two sex steroid hormone combinations which have been used clinically as tests for detection of early pregnancy were examined for embryotoxic effects in macaques and baboons. Norethisterone acetate and ethinyl estradiol (NEA + EE) were orally administered to rhesus and cynomolgus monkeys and baboons at dosages ranging from one to 1,000 times the human dose equivalent (HDE) during days 20-50 of pregnancy. Progesterone and estradiol benzoate (P + EB) were delivered by two to six intramuscular injections to rhesus and cynomolgus monkeys between gestational days 20 and 35 at 0.1-25 X HDE. Fetuses were examined following cesarean section at 100 +/- 2 days (NEA + EE) or at term (P + EB). The results showed increased embryolethality over controls at 100-1,000 X HDE (NEA + EE) and at 10 and 25 X HDE (P + EB). Besides growth retardation, isolated cases of minor nongenital malformations were observed only in cynomolgus monkeys following treatment with both hormone combinations mainly at embryolethal dose levels and were considered spontaneous in nature. Virilization of female cynomolgus fetuses following NEA + EE treatment was manifested as two cases of clitoral enlargement in the 300 X HDE group and two cases of increased anogenital distance with reduced vaginal opening in the 1,000 X HDE group. The highest dose of NEA + EE was also maternally toxic, as two maternal deaths occurred at the end of the treatment period. One dead female cynomolgus fetus exposed to P + EB (10 X HDE) also exhibited masculinized external genitalia.(ABSTRACT TRUNCATED AT 250 WORDS)

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Two sex steroid compounds which have been used clinically for parenteral supportive therapy of pregnancy were examined for embryotoxic effects in rhesus and cynomolgus macaques. Hydroxyprogesterone caproate (HPC) alone or in combination with estradiol valerate (EV) were administered intramuscularly (i.m.) to pregnant monkeys at 7-day intervals between 20 and 146 days of gestation and fetuses were examined following cesarean section at 150 +/- 2 days. HPC alone was tested in both species at doses ranging from 0.01 X to 10 X the human dose equivalent (HDE); only rhesus monkeys were exposed to the HPC + EV combination at 0.1 X to 10 X HDE. Total embryolethality resulted following the administration of HPC alone and combined with EV at 1 X and 10 X HDE in rhesus monkeys; the level of abortions in cynomolgus monkeys exposed to HPC (0.1 X to 1 X HDE) was comparable to controls. A small number of nonspecific malformations and developmental variations observed in cynomolgus fetuses after HPC exposure were considered to be incidental findings. No anomalies were found in surviving rhesus monkey fetuses treated with HPC + EV. The results indicate that long-term in utero exposure to the progestin, HPC, alone or in combination with EV in rhesus and cynomolgus monkeys, is embryolethal but not teratogenic at doses up to ten times the human therapeutic dose.

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Thymostimulin (Tp-1 Serono) was tested toxicological in rats and monkeys during 6 weeks of repeated administration. Corresponding to the therapeutic use intended in man the substance was given to rats and monkeys intramuscularly in dosages of 10 or 100 mg/kg b.w. and due to technical reasons subcutaneously in a dosage of 1000 mg/kg b.w. No substance-related effects, either systemic or local, were observed in the monkeys. After treatment with the high dose level (1000 mg/kg b.w. s.c.) the rats exhibited inflammatory changes in the region of the injection sites.

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The 90-day inhalation studies, conducted in 1975, showed that for dichloromethane the highest concentration without side effects can be expected just below 5,000 ppm by volume of air (0.5% by vol.) when administered to Beagle dogs. With rats the lowest toxic concentration was just below 10,000 ppm by volume (local tolerance) or above 10,000 ppm by volume (systemic tolerance). Administration took place on 90 consecutive days for 6 h per day.

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The aim of this study was to examine the pharmacokinetical behaviour of metoclopramide of Gastronetron retard capsules after a single administration to 8 healthy male volunteers. Determinations of the concentration of metoclopramide in the serum were made up to 24 h p.a. The calculation of the serum concentration curves was based on an open 2-compartment model. It has been proved that already 30 min after oral administration effective serum concentrations could be reached, which are maintained over about 24 h. An approximate value of 71% was obtained for the bioavailability of metoclopramide of Gastronerton retard capsules. The action achieved by the administration of 1 capsule Gastronerton retard per day can be considered equal to that of 3 single administrations of the conventional oral pharmaceutical form.

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The 90-day inhalation studies, conducted in 1975, showed that for the fluorocarbons the lowest toxic concentrations could be regarded above 5,000 ppm by volume of air (0.5% by vol.) when administered to Beagle dogs. With rats the lowest toxic concentrations were above 10,000 ppm by volume. Administration took place on 90 consecutive days for 6 h per day.

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An intraindividual comparative study of the pharmacokinetic properties of metoclopramide, the active principle of Gastronerton, and metoclopramide of a reference drug after one single administration was carried out on 6 male healthy volunteers. Gastronerton was available as ampoules, tablets, solution and capsules; the reference drug as ampoules, tablets and solution (all of them as commercial products). The concentrations of metoclopramide in the serum were determined until 24 h after administration. As one of the persons dropped out another volunteer was included. There were 6 cases for the intraindividual comparison of the parenteral/enteral form except for the comparison of the tablets/ampoules of the reference drug. An open 2-compartment model was taken as a basis for the calculation of the serum concentration curves and the pharmacokinetic parameters. With regard to the maximum serum concentrations, the preparations differed only insignificantly. The bioavailability results were as follows: metoclopramide of Gastronerton tablets 80.3%, metoclopramide of the tablets of the reference drug 57.6%, Gastronerton solution 76.7%, solution of the reference drug 49.7%. The bioavailability of metoclopramide of Gastronerton capsules was 54.8%. The half-life values were between 2.8 and 8.3 h with a mean value of 5 h.

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