Application of Akaike's information criterion (AIC) in the evaluation of linear pharmacokinetic equations

According to linear pharmacokinetics, the time course of plasma concentration of a drug, C_p,is expressed by a sum of exponential functions, C_p= _i=1 ⁿ a_i .This article describes a statistical technique to estimate the number of exponential terms, n,for the time course of drug by the application of Akaike's information criterion (AIC). Plasma concentrations of ethoxybenzamide, sulfisoxazole, bishydroxycoumarin, and diazepam measured following bolus intravenous injection were used as clinical examples for this method. Selection of models is compared between the AIC method and an Ftest method at significance levels of 5% and 1%.     

Pharmacokinetics of methotrexate in leukemia cells: Effect of dose and mode of injection

A lumped compartmental model has been derived to predict methotrexate concentration as a function of time for L1210 cells in BD2F ₁ female mice at doses ranging from 3 mg/kg to 400 mg/kg. Using standard methods of parameter estimation as well as experimental determinations, an integrated approach was derived to account for the differences between the subcutaneous (s.c.) and intraperitoneal (i.p.) modes of injection. It was found that a single generalized forcing function can be used to fit plasma concentration after s.c. injection for all doses. Adequate fits (average error<20% while the standard deviation of experimental determinations was±22%) of L1210 cell data after s.c. injection were obtained. The best results were for a maximum facilitated influx constant V_max of 0.424 g/min/ml, a Michaelis influx constant K_m of 1,42 g/ml, and a first-order efflux constant of 0.047 min^–1.The model simulations were not sensitive to V_max, K_m,and so long as the ratio V_max/was approximately 9g/ml. The values of V _max ,K _m ,and which were obtained from our analysis of the in vivodata can be explained on the basis of previously performed in vitroexperiments. The parameters obtained from modeling the s.c. data were then applied for i.p. injection data. The resulting fits were adequate (average error<20% while the standard deviation of experimental determinations was±22%). A single generalized forcing function for drug concentration in the peritoneal cavity after i.p. injection for all doses was derived. The application of these results enables the prediction of methotrexate concentration in neoplastic cells at other doses after either s.c. or i.p. injection.     

Blutverteilungsmuster in der Lunge beim plötzlichen Säuglingstod

Zusammenfassung Bei 67 Fällen von plötzlichem Säuglingstod (SIDS) wurde die Blutverteilung in den Lungen mit Hilfe der Benzidin-Färbung an 50 dicken histologischen Schnitten untersucht. Es besteht ein fokales, akutes Emphysem und häufig ein diffuses, alveoläres und auch interstitielles Emphysem. In allen Lungenabschnitten finden sich z.T. ausgedehnte Atelektasen und Dystelektasen. Die Atelektasen und Dystelektasen zeigen eine hochgradige Hyperämie bei weitgestellten Alveolarkapillaren, während der Blutgehalt in den von Emphysem betroffenen Bezirken vermindert ist. Die mögliche funktionelle Bedeutung der gestörten Blutverteilung in der Lunge für eine zunehmende Hypoxie und den Todesmechanismus wird diskutiert.Als Vortrag auf der 56. Tagung der Deutschen Gesellschaft für Rechtsmedizin gehalten. Graz 17.–20.9.1977     

Tetrahydronorharmane (Tetrahydro-β-carboline), a physiologically occurring compound of indole metabolism

Summary In the present paper a sensitive method is described to measure tetrahydronorharmane (THN) in the urine of man and rats as well as in the forebrain of rats. The compound is extracted into diethyl ether, separated by thin layer chromatography (TLC), acetylated with radiolabelled acetic anhydride and further isolated by two-dimensional TLC development. The existence of THN in urine of man was proven by using chromatography with different solvent systems, cocristallisation, isotope dilution technique as well as mass-spectrometry. The amount of THN in the urine varied over a wide range.With the same method it was demonstrated that THN occurs also in the forebrain of rats. The concentration increases after loading with tryptamine.The findings are discussed in view of the hypothesis that THN acts as a compound modulating neuronal mechanism.     

6. Die Chirurgie in der Entscheidung — 20 Jahre Berufsverband der Deutschen Chirurgen

Zusammenfasung 1. Chirurgische Arbeit erfordert Wissen und Können, aber auch Reife und Verantwortungs-Fähigkeit. Gewährleisten die derzeitigen Aus- und Weiterbildungsgänge und unsere Haltung dem Nachwuchs gegenüber dieses Erziehungs-Ziel? 2. Die Bewältigung zentrifugaler Kräfte und die Integration autonomer Teile in der Chirurgie gelingt nur mit Hilfe der Teilgebiets-Idee, die Abwehr von Tendenzen, die Chirurgie wieder zum operierenden Werkzeugo zu degradieren, nur durch verstärkte Interaktion mit den Nachbardisziplinen. 3. Die Überwindung der vielfältigen auf die Arbeit des Chirurgen ausgeübten Pressionen ist nur durch Bewahrung einer sich selbst verptlichteten Freiheit als Grundlage aller chirurgischen Berufstätigkeit erreichbar.     

The influence of δ9-Tetrahydrocannabinol on intraocular pressure in the anaesthetized cat

⁹-Tetrahydrocannabinol (⁹-THC) was injected both intravenously and into the brain stem via the left vertebral artery. Contrary to results obtained with clonidine, neither the fall in intraocular pressure (IOP), nor the arterial hypotension induced by ⁹-THC, were enhanced after the central administration of the drug. For clonidine, a central mechanism underlying the ocular hypotensive effect has recently been proposed. This suggestion is based upon the enhanced fall in IOP after central administration of clonidine. The pontomedullary area is considered to be the main initial target of this drug. Obviously, the IOP-lavering mechanism of ⁹-THC is different from that of clonidine.     

EEG effects of hallucinogens and cannabinoids using sleep-waking behavior as baseline

Three hallucinogens (d-lysergicacid diethylamide (LSD), mescaline, psilocybin) and two cannabinoid derivatives (tetrahydrocannabinol (THC), synhexyl) were tested for their long-term effects on the EEG of the cat. The drug-induced alterations in the EEG frequency spectrum were "drug-specific" in the sense that they would be statistically unlikely to occur during sleep-waking behavior. The two classes of compounds produced distinctly different EEG effects which were remarkably similar within each class. The duration of activity and relative potencies were consistent with those obtained by other measures, both in cats and in other species including man.     

The feasibility of demonstration of GM- and InV-systems in decaying organs

Summary -globulin factors (Gm and InV-systems) were determined in 12 cadavers in blood and various organ exprimates (kidney, liver, spleen and muscle). Also checked was the time interval up to which these factors could still be demonstrated in decaying organs.For this purpose blood and portions of the organs were left to decay in plastic containers at an average temperature of 19.1°C. Examinations were done with the agglutination-inhibition-test. The exprimates were employed in dilutions 1:10 and 1:20. The serum factors Gm (1), (2), (4), (10) and InV (1) could be demonstrated for varying periods of time.In organs they could be demonstrated for between one and eight weeks. Only factors Gm(1) and Gm(2) could be demonstrated beyond this time. As a rule these serum factors were demonstrable in blood for a longer period of time than in organs. Factor Gm(4) proved to be the most stable one, as it could be demonstrated up to 11 weeks in decaying serum.In 2200 individual tests with a dilution 1:20 no false positive results were obtained, with the dilution 1:10, however, 5 false positive tests were found. No explanation can be given for the different periods of time for which these factors can be demonstrated under conditions of decay.

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Zusammenfassung Bei zwölf Leichen wurden im Blut und in verschiedenen Organpreßsäften (Niere, Leber, Milz und Muskel) die -Globulineigenschaften (Gm- und InV-Systeme) bestimmt und ihre Nachweiszeit bei Fäulnis überprüft. Blut und Organteile wurden hierbei in verschließbaren Plastikgefäßen bei einer mittleren Temperatur von 19,1°C faulen gelassen. Die Untersuchungen erfolgten mit dem Agglutinationshemmtest.Die Preß- bzw. Fäulnissäfte wurden in 1:10 und 1:20 Verdünnungen verwendet. Die Serumfaktoren Gm(1), (2), (4), (10) und Inv(1) konnten über unterschiedlich lange Zeiträume nachgewiesen werden.In den Organen betrug die Nachweiszeit zwischen einer und acht Wochen, wobei nur die Faktoren Gm(1) und Gm(2) über diese Wochen nachweisbar blieben. Die Serumeigenschaften waren im Blut allgemein länger nachweisbar als in den Organen. Am stabilsten erwies sich der Faktor Gm(4), der bis zu elf Wochen im faulenden Serum festgestellt werden konnte.Bei 2200 Einzelbestimmungen wurden mit der 1:20 Verdünnung in keinem Fall falsch positive Ergebnisse erzielt, mit der 1:10 Verdünnung hingegen fünf falsch positive Ergebnisse.Eine Erklärung für die unterschiedlich langen Nachweiszeiten unter Fäulnisbedingungen kann nicht gegeben werden.

     

Atomic absorption spectrometry in pharmaceutical analysis

A short review of the principles of atomic absorption spectrometry (AAS) — sources, atomizers, background correction, instrumentation, sample preparation, sensitivity, limit of detection, etc. — is given. The technique can be applied for impurity tests for trace metals as well as for assay of various commonly occurring elements in pharmaceuticals. The application of AAS in pharmaceutical analysis is illustrated with 17 examples.