Cerebral hemodynamic changes during the trigeminocardiac reflex: description of a new animal model protocol.

The trigeminocardiac reflex (TCR) is a well-known brainstem reflex, first described in skull base and neurosurgery by the senior author in 1999, leading to reflex apnea, bradycardia, and changes of mean arterial pressure. There seem to be differences between peripheral and central stimulation of the TCR, and there is a lack of clear data about the cerebral hemodynamic changes during the TCR. However, the research of this reflex principally focused on clinical cases for peripheral and central stimulation during the last years, and on rabbits for peripheral stimulation several decades ago, so there was a need for an animal model that allows us to use the current state-of-the-art imaging methods. The new animal model protocol as introduced by the authors gives, for the first time, deep insights into the cerebral hemodynamic changes during the TCR and gives substantial evidence whether the TCR represents an oxygen-conserving reflex or not.

Difference in functional outcome of ipsilateral tinnitus after intraoperative occurrence of the trigemino-cardiac reflex in surgery for vestibular schwannomas.

OBJECT: Surgical manipulation of the fifth cranial nerve in its intra- or extracranial course may lead to bradycardia or even asystole as well as arterial hypotension, a phenomenon described as the trigemino-cardiac reflex (TCR), first described by the authors previously [11]. The authors report here the impact of this reflex on post-operative ipsilateral tinnitus in patients undergoing vestibular schwannoma surgery. METHODS: Thirty six patients scheduled for vestibular schwannoma surgery were studied retrospectively for parameters influencing the post-operative ipsilateral tinnitus function. According to the occurrence of intra- operative TCR the patients were divided into a TCR-subgroup and a non-TCR subgroup. There was no difference in tumour size between these subgroups. RESULTS: The TCR occurred in 17% of the patients during vestibular schwannoma surgery and influenced the occurrence of post-operative ipsilateral tinnitus: the overall incidence of post-operative ipsilateral tinnitus was 22%. Sixty (60) percent of the patients in the TCR subgroup and 17% of those in the non-TCR subgroup experienced ipsilateral tinnitus postoperatively. There was no correlation between tinnitus and pre- or post-operative hearing function. CONCLUSION: Hypotension after intra-operative TCR is not only a negative prognostic factor for hearing preservation but also for ipsilateral tinnitus in patients undergoing vestibular schwannoma surgery. In combination with worse hearing function after intra-operative TCR, the present finding underlines the importance of the TCR during skull base surgery in relation to improved functional outcome.

Disappearance of organochlorine residues from abdominal and egg fats of chickens, Ontario, Canada, 1969-1982.

Abdominal fats were collected from 8-week old broilers slaughtered at provincially inspected abattoirs across Ontario between 1969 and 1982. Domestically produced hen eggs were collected from either egg grading stations or producers over the same period. Composite samples were analyzed for organochlorine insecticides and industrial chemicals. Between 1979 and 1982, organophosphorus insecticides were routinely included in these analyses. Sigma DDT and PCB residues declined rapidly between 1969 and 1982 in extractable lipids of both abdominal and egg fats, while dieldrin declined less markedly over the same period. Declines in residues followed first order logarithmic regression equations. Chlordane and heptachlor epoxide were rarely observed above the detection limit of 1 microgram/kg in egg fat; however, the incidence of these residues in abdominal fat increased after 1973 following the removal of aldrin, dieldrin, and heptachlor in 1969 and the subsequent increased use of chlordane for soil insect control until 1977. Lindane residues were rarely observed above the detection limit. In 1979, when the detection limit was reduced, both alpha-BHC and lindane were identified, but at levels below 1 microgram/kg. Endosulfan, methoxychlor, and fenthion were identified on one or 2 occasions over the 13-year period.

[Comparative study of the bioavailability and the pharmacodynamic effect of five allopurinol preparations (author's transl)]. / Vergleichende Prüfung der Bioverfügbarkeit und des pharmakodynamischen Effektes von fünf Allopurinol-Zubereitungen.

The aim of this study was to determine the relative bioavailability of five oral allopurinol preparations and evaluation of the pharmacodynamic effect. Included were two slow-release formulations. The study was performed as complete five-way randomized steady-state cross-over trial in 10 healthy volunteers. Each day 300 mg of 1H-pyrazolo-(3,4-d) pyrimidin-4-ol (allopurinol) were orally administered for 7 days, followed by a wash-out phase of 14 days. The minimal serum levels of allopurinol and its major metabolite oxypurinol were determined by HPLC. In parallel the concentrations of uric acid in blood and in 24-h urine were measured. The two slow-release formulations had a significantly lower relative bioavailability compared to the normal formulations and, moreover, a slow-release effect could not be demonstrated. In all cases the clinical effect of the test preparations could be demonstrated, and a correlation between bioavailability and pharmacodynamic effect could be calculated. A correlation between published in vitro data and the present in vivo data could not be found.

[Comparative study of the bioavailability and pharmacokinetics of isosorbide dinitrate formulations in retard form and in standard preparations by determination of isosorbide-5-mononitrate]. / Vergleichende Prüfung der Bioverfügbarkeit und Pharmakokinetik von Isosorbiddinitrat-Formulierungen in Retardform gegen Standardpräparate mit Bestimmung des Isosorbid-5-Mononitrats.

The aim of the study was to determine the relative bioavailability and the pharmacokinetic parameters following administration of a slow-release formulation of isosorbide dinitrate (ISDN, Isdin) capsules (20, 40 and 60 mg). A gas chromatographic method was used to determine the plasma concentrations of ISDN and isosorbide-5-mononitrate (IS-5-MN). All of the required pharmacokinetic parameters were ascertained. The study was performed on 12 healthy volunteers in a steady-state crossover design. A comparison of the areas under the plasma concentration/time curves of the test preparations and the commercial preparations showed higher values for the test preparations in all of the investigations. However, these values were only statistically significant for the 40 and 60 mg formulations ISDN and the 60 mg formulation IS-5-MN.

Organochlorine and Organophosphorus Insecticides and Industrial Pollutants in the Milk Supplies of Ontario - 1983.

During the spring of 1983, fluid milk samples were collected from 359 bulk transporters representing 16 counties, municipalities and districts of Ontario, and were analyzed for organochlorine and organophosphorus insecticides plus selected halogenated industrial pollutants. Dieldrin, p,p'-DDE, heptachlor epoxide, and α-BHC were found in over 90% of samples, but none exceeded the accepted maximum residue limits. Polychlorinated biphenyls (PCB), lindane and pentachlorophenol (PCP) were found in 83, 68 and 57% of samples, respectively, with four samples exceeding the permissable PCB limit and one sample exceeding the permissable PCP limit. Residues of chlordane, endosulfan, p,p'-TDE, and p,p'-DDT were identified in only 1.9 to 4.7% of samples, and were present at levels only slightly above the detection limits. Hexachlorobenzene (HCB) was found at low levels in 40% of samples. Mean residues of organochlorines found were as follows (µg/kg butterfat): ∑DDT - 12; α-BHC - 5.3; lindane - 4.0; heptachlor epoxide - 3.9; dieldrin - 6.2; HCB - 0.67; PCB - 24; and PCP - 29. No residues of six organophosphorus insecticides, endrin, methoxychlor or mirex were detected in any samples. This survey was the sixth in a series beginning in 1967. Half-residue disappearance rates were calculated at 3.5, 5.4, 5.6 and 3.0 years for ∑DDT, dieldrin, PCB and HCB, respectively. A case history is included involving the misapplication of fenthion to a dairy herd which revealed a half-residue elimination from milk in approximately 3 d.

[Comparative studies on the in vitro dissolution and bioavailability of various acetylsalicylic acid preparations]. / Vergleichende Untersuchungen zur In-vitro-Freisetzung und Bioverfügbarkeit von verschiedenen Acetylsalicylsäure-Fertigarzneimitteln.

For five different brands of acetylsalicylic acid (ASA) preparations the in vitro/in vivo data were determined and tested for comparability. The in vitro dissolution rates were determined by two different methods (Paddle, rotating basket) whereas the in vivo data were obtained from 15 volunteers in a 5-fold cross-over trial. The markedly worse in vitro dissolution (rotating basket) of one preparation is in contrast to the in vivo data which showed bioequivalency of all five preparations. It is doubled that in vitro measurements alone reveal sufficient informations for any predictions of the in vivo characteristics (e.g. bioavailability) of a preparation. It was possible to determine separately ASA and salicylic acid using a highly selective HPLC-method developed by us.

[Gas chromatographic/mass spectrometric determinations of indomethacin serum levels in the course of pharmacokinetic studies in healthy volunteers]. / Die gaschromatographisch/massenspektrometrische Bestimmung der Indometacin-Serumspiegel im Verlauf pharmakokinetischer Untersuchungen an gesunden Freiwilligen.

For 4 different brands of indomethacin preparations the in vitro dissolution data as well as their relative bioavailabilities were determined. The in vitro tests were performed by the rotating basket method; the quantitative determinations of the serum-levels were determined by an gas chromatographic/mass spectrometric assay employing registration of the characteristic selected ion current profiles of the compound. Furthermore a special method for synthesis of the needed internal standard was also developed. The in-vivo-studies - with 15 volunteers in a 4 fold crossover-showed - in contrast to the worse in-vitro-dissolution of one preparation - bioequivalency of all four preparations. Our results clearly show that statements on in-vitro/in-vivo correlations have to be cautious.

[The bioavailability and pharmacokinetics of two carbocysteine preparations after single and multiple dosing]. / Untersuchungen zur Bioverfügbarkeit und Pharmakokinetik zweier Carbocistein-Zubereitungen nach Einfach- und Mehrfachdosierung.

The relative bioavailabilities and pharmacokinetic profiles of 2 carbocisteine preparations (capsules, granulate) were evaluated in a single dose and a steady state study. 10 healthy volunteers took in a randomized, 2fold cross over design 750 mg 3-(carboxymethylthio)alanine (carbocisteine, Transbronchin) (1 portion of the granulate or 2 capsules) as a single dose or for 4 days 3 times a day (every 8 h) 1 portion of the granulate or 2 capsules, respectively. During the saturation phase the pre-dose serum levels in the morning were determined and on day 5 - after a last dosing the elimination kinetics were evaluated. The same time frame of blood withdrawals was used for the evaluation of serum kinetics after single dosing. The new developed gaschromatographic method for the rapid, sensitive and reliable quantitative determination of carbocisteine in serum saves not only a lot of time but also improves the detection limit and selectivity by a factor of approx. 10. The studies revealed bioequivalency of the carbocisteine granulate and capsule preparations. After multiple dosing, no cumulation of the carbocisteine serum levels occurred. A comparison of the AUCo-infinity and AUC tau (single/multiple dosing, respectively) showed linear pharmacokinetics without enzyme induction or saturation phenomena in man.

Effect of storage in flour and of particle size on the bioavailability of elemental iron powders for rats and humans.

Elemental iron powders produced by different processes were separated by nitrogen elutriation into fractions based on particle size. The fractions containing fine particles (7-10 micrometer) of electrolytic iron, hydrogen (H2)- and carbon monoxide (CO)-reduced iron, and the whole sample of carbonyl iron (92% less than 11 micrometer) were blended into freshly milled wheat flour and stored at about 21 degrees C. Storing the enriched flour up to 9 months had no effect on the relative biological value (RBV) of iron for rats from each type of iron supplement. Baking bread with flour containing electrolytic, H2-reduced, and carbonyl iron after storage for 10 months also had no effect on the RBV of the iron powders. There was no change in the RBV of iron for rats from flour enriched with electrolytic iron (200 mg/kg) and ascorbic acid (200 and 1665 mg/kg flour) after storage for 1 week and 3 months. The decreases in RBV due to increase in size of particles (7-10 vs. 20-26 micrometer) were significant for H2-reduced iron and CO-reduced iron but not for electrolytic iron and carbonyl iron. The RBVs of elemental iron powders for rats were similar to the values obtained with humans, based on iron absorption after an overnight fast.

Biological availability of iron supplements for rats, chicks and humans.

Fourteen experiments were concluded on the effect of protein and carbohydrate sources in the assay diets on the relative biological values (RBV) of food grade sodium iron pyrophosphate (NaFePP) and ferric orthophosphate (FePO4) vs. ferrous sulfate (FeSO4) for rats and chicks, using the response in blood hemoglobin to graded levels of supplemental iron as the assay criterion. Two trials were made with volunteers to estimate the RBV of NaFePP and FePO4 for humans, based on the increase in plasma iron 2 hours after ingestion of 100 mg of iron of a test dose following an overnight fast. The RBV of iron from NaFePP and FePO4 for rats were consistently lower when the basal diet contained nonfat dried milk (9 to 16 and 28, respectively, vs. FeSO4=100) than when casein was used (25 to 28 and 49, respectively). The addition of 22% beta-lactose, replacing sucrose in a diet containing casein fed to rats, significantly reduced the RBV of iron from NaFePP from 25 to 15; the addition of 22% alpha-lactose or 40% glucose in place of sucrose had no effect on the RBV of this iron source. The RBV of iron from NaFePP and FePO4 for chicks were 4 to 6 and 4, respectively, with the source of dietary protein having no effect. Very low RBV of iron from NaFePP and FePO4 (4.3 and 5.9, respectively, vs. FeSO4=100) were also obtained with human subjects.

Organochlorine and organophosphorus residues in the fat of domestic farm animal species, Ontario, Canada 1986-1988.

During the period 1986-1988 a total of 602 samples of animal products were analysed for organochlorine and organophosphorus pesticides and industrial organic pollutants. Samples of abdominal fat were collected from avian, bovine, caprine, lupine, ovine and porcine species together with hen eggs. The following six compounds were identified in animal tissues: DDE, dieldrin, lindane, PCB, pentachlorophenol and tetrachlorophenol. Pentachlorophenol was the most frequently found contaminant, being identified in 35% of samples, and DDE was the second in 21%. All other contaminants were present in less than 10% of samples. The residues of all six compounds detected were added to give a combined residue. Forty-three per cent of samples had non-detectable residues. A further 31% had combined residues adding to less than 0.01 mg/kg. The highest combined residues ranged between 0.1 and 1.0 mg/kg and were present in 2.8% of samples. One egg sample had a residue of 0.16 mg/kg that exceeded the 0.1 mg/kg maximum residue limit for pentachlorophenol. Residues of chlordane and its metabolites, heptachlor and its epoxide, endosulphan and its sulphate metabolite, dicofol, HCB and mirex were below their detection limits in all samples and no residues of the organophosphorus insecticide listed as applied to livestock were found in meat, fat or egg tissues.

Pharmacokinetic pilot study with imidazole 2-hydroxybenzoate using new analytical methods.

Imidazole 2-hydroxybenzoate is a new antiphlogistic compound with analgesic and antipyretic properties undergoing clinical investigations. The purpose of this pilot study was to evaluate new methods for the quantitation of imidazole, salicylic acid and salicyluric acid in plasma and urine. Imidazole metabolites caused considerable methodologic difficulties in plasma and urine. They were below the detectable limit. Salicylic acid metabolites were present in plasma also under the limit of detection (0.5 microgram/ml). In urine the metabolite salicyluric acid was measured in considerable quantities, whereas gentisinic acid was under the limit of detection. Three healthy volunteers were given a single p.o. dose of 750 mg imidazole 2-hydroxybenzoate in order to examine the practicability of these new methods a well as to evaluate the pharmacokinetics. The data are presented and interpreted. Further studies in this respect are advised.

Comparison of the pharmacokinetic profile of metaclazepam in old and young volunteers.

A single-centre, open, Phase I-study comparison of the pharmacokinetics of a single dose of metaclazepam 10 mg, a new 1,4-benzodiazepine has been done in 10 older and 20 younger volunteers. No important age-related effect was found on the kinetics of metaclazepam or its N-desmethyl derivative, the principal metabolite in man.