Inhalation pharmacokinetics based on gas uptake studies

On the basis of previous determinations of pharmacokinetic parameters for inhaled vinyl chloride in men, rhesus monkeys, and rats, and on improved pharmacokinetic models a pharmacokinetic treatment of the problem of peak concentrations of vinyl chloride, as occuring in industrial practice, became possible. For the calculations, metabolic elimination kinetics of vinyl chloride was assumed to be first order as experiments in different species including rhesus monkeys showed linear pharmacokinetics up to atmospheric exposures of 200–300 ppm. The distribution of vinyl chloride between atmosphere and organism under different conditions was evaluated using steady-state-kinetics. After treating the processes of influx, efflux, and metabolism, the numerical values for the parameters derived from a human kinetic experiment were used to theoretically calculate the time courses of concentration of vinyl chloride in the organism and of the cumulative amount of vinyl chloride metabolized, under the conditions of (a) a 2 h constant exposure to 5 ppm vinyl chloride and (b) two subsequent peaks of 50 ppm with a duration of 5 min each. This model calculation suggested that, regardless of the exposure profile, the amount of (reactive) metabolites formed from vinyl chloride would soleley be a function of the mean atmospheric vinyl chloride concentration over time. The general validity of this suggested rule could subsequently be demonstrated. As the concentration of the reactive metabolite of vinyl chloride responsible for the carcinogenic effect at the target site must be a resultant of both formation and inactivation, an evaluation of the differential risk of different exposure profiles can reasonably be based on biochemical examinations of the detoxifying pathways. This points out the relevance of studies of the patterns of different metabolites of vinyl chloride in man under varying exposure profiles.     

A comparison of the effects of TMB-8 and nifedipine on pressor responses to α1- and α2-adrenoceptor agonists in pithed rats

TMB-8 has been characterized as an inhibitor of the release of Ca⁺ from intracellular pools. We have studied the modification of the pressor responses to selective _l-adrenoceptor agonists (methoxamine and phenylephrine), and to selective ₂-adrenoceptor agonists (B-HT 920 and B-HT 933) in pithed rats, produced by TMB-8. We have compared this modification with that produced by the calcium antagonist nifedipine. Nifedipine (100 g/kg, 300 g/kg, and 1000 g/kg) inhibited in a dose-dependent manner the pressor responses to the ₁- and ₂-adrenoceptor agonists, the dose-response curves to the ₂-adrenoceptor agonists being shifted further to the right. TMB-8 at a dose of 3000 g/kg did not modify the pressor effects of the _l-adrenoceptor agonists, and neither did it reinforce the inhibition of such responses produced by nifedipine. By contrast, TMB-8 pretreatment (0.03 g/kg, 0.3 g/kg, 3 g/kg, 30 g/kg, 300 g/kg and 3000 g/kg) inhibited the responses to both ₂-adrenoceptor agonists, the inhibition being more pronounced with B-HT 920. A similar effect was obtained with 0.03 g/kg TMB-8 and 0.3 g/kg TMB-8, particularly in the case of B-HT 920. It was stronger with higher doses, but similar for all doses over 3 g/kg. The inhibition of the pressor responses mediated by the stimulation of ₂-adrenoceptors by TMB-8 was less in rats treated with the Ca²⁺ entry promoter BAY K 8644 (300 g/kg), and could also be reduced by the continuous infusion of CaCl₂ (0.25 g/min). These results suggest that in pithed rats TMB-8 may also behave as an inhibitor of the Ca⁺ influx into vascular smooth muscle.     

Pharmacoepidemiology and the “Impact Factor”

The field of Pharmacoepidemiology/Drug Utilization research has been analysed by studying published research articles under the medical subject headings (MeSH terms) Pharmacoepidemiology, Drug Utilization and Drug Utilization Review. There were 1822 articles published, and stored in Medline, during the 32-month period between 1 January 2001 and 31 August 2003; these papers might represent a field of research, due to the similarity of MeSH terms used for coding and the set of journals in which the articles were published. A total of 457 articles, representing 25% of all articles in the field, were published in 14 different journals, and 50% of all articles (948) were collected in only 64 different journals. The two main journals publishing research in Pharmacoepidemiology/Drug Utilization are Pharmacoepidemiol Drug Saf and the Eur J Clin Pharmacol. These two publications are the official journals of the three main societies in the field and are at least partially focused on this subject, with 45.7% of all articles in Pharmacoepidemiol Drug Saf and 11.1% of all articles in Eur J Clin Pharmacol included under the studied MeSH terms; other journals only occasionally publish papers in this line of research. These two journals are the leaders in pharmacoepidemiology and drug utilization research, having impact factors (IFs) in 2002/2003 above (1.955/1.972 for EJCP) and a bit below (1.092/1.257 for PDS) the middle of the ranking of publications, according to the IF, in the Pharmacology and Pharmacy list of the Science Citation Index (SCI).     

Sex differences in the medication choice for hypertension in general practice. A study with written case simulations

The objective of this study was to explore explanations for the preference of physicians to prescribe blockers to hypertensive men and diuretics to hypertensive women.A qualitative study among 12 family physicians was conducted with a combination of written case simulations, semistructured interviews and statements on attitudes of physicians towards antihypertensive drug choice.Among the male hypertensive cases the most frequently prescribed drugs were blockers, whereas among the female hypertensive cases diuretics were more often prescribed. Physician characteristics associated with a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were: older age (no residency in family medicine), the believe that blockers are more effective in men with regard to lowering blood pressure and that diuretics are more effective in women, a nonevidence based attitude and a sexrelated attitude towards the choice of blockers and diuretics in general, and in particular towards the prescribing of blockers to hypertensive men because men have a higher absolute risk of coronary heart disease than women. An additional explanation for these findings may be the higher prevalence of ankle oedema among women. Patient characteristics associated with more prescribing of blockers to hypertensive men and diuretics to hypertensive women were: current employment and a "highrisk" profile in terms of blood pressure level and additional cardiovascular risk factors.Although, most considerations underlying a preferred prescribing of blockers to hypertensive men and diuretics to hypertensive women were not evidencebased, the actual choice of antihypertensive drug (diuretic or blocker) was evidencebased. These considerations may also play a role in the sex difference in the choice of calcium antagonists and angiotensin converting enzyme inhibitors and require further investigation.     

δ9-Tetrahydrocannabinol,ethanol, and amphetamine as discriminative stimuli-generalization tests with other drugs

Three groups of rats (A, B, C) were trained in a T-maze to discriminate between drug- and control solution-induced internal discriminative stimuli. The drugs used to induce discriminative stimuli were: ⁹-THC, 5.0 mg/kg (Group A); ethanol, 1.2 g/kg (Group B), and amphetamine, 1.0 mg/kg (Group C). After discrimination acquisition several drugs were tested for generalization in each group. Group A was tested with ⁸-THC, CBD, CBN, ethanol, pentobarbital, chlorpromazine, amphetamine, and apomorphine; only ⁸-THC and CBN induced ⁹-THC-like responses. Group B was tested with ⁹-THC, ⁸-THC, CBD, CBN, pentobarbital, and amphetamine; pentobarbital induced ethanol-like response. Group C was tested with ⁹-THC, apomorphine, and ethanol; ⁹-THC and apomorphine elicited amphetamine-like responses.This work is part of the Thesis of Doctor of Sciences presented by O.F.A. Bueno at Escola Paulista de Medicina.With a fellowship from FundaÇÃo de Amparo à Pesquisa do Estado de SÃo Paulo (FAPESP).     

European drug information centres ‐ survey of activities

A questionnaire survey of European drug information centres (DICs) was conducted. DICs mentioned in the ESCP directories and other sources were identified and contacted. Information on basic characteristics was obtained: affiliation, the scope of activities, employees, questionanswer service characteristics, information sources and the economic aspects of the DICs' work. Information from 84 DICs was analysed (return rate = 71.3%). DICs are mainly affiliated to hospitals (68%), rather rarely with faculties of pharmacy (6%) or with faculties of medicine (8.3%). Activities of DICs mainly include: questionanswer service (98%), issue of bulletins (68%), participation in P&T committees (63%), tuition (61%) and druguse evaluation (52%). Pharmacists, 12 full or parttime, are the most frequent employees working in the DICs. When the questionanswer service was analysed, it was found that 56% of the DICs are open only to the healthcare professionals and 43% provide a service to the lay public. Questions are mainly concerned with the side effects, indication/therapeutic use and the dosage of the drugs. The majority of DICs (91%) document their activities, very often on a computer database. Quality assurance is provided by almost 75% of DICs, usually by a review (58 %) or a feedback questionnaire (32%). Information sources listed as most frequently used include Martindale The Extrapharmacopeia, journals such as Lancet, Medline and Micromedex databases. DICs are usually financially supported by the organizations to whom they are affiliated. Fees are charged, for special activities, by 9.5% of DICs.     

Interleukin-1β and tumor necrosis factor-α inhibit the release of [3H]-noradrenaline from mice isolated atria

In the present study, we have investigated the ability of four cytokines, interleukin-1, interleukin-2, interleukin-6 and tumor necrosis factor-, to modulate the stimulation-induced outflow of radioactivity from isolated superfused mouse atria which where pre-incubated with [³H]-noradrenaline. The tissues were subjected twice to field stimulation (5 Hz frequency, 50 mA intensity, 2 ms pulses for 60 s) and the drugs were added prior to the second stimulation in order to assess their modulatory effects.The results show that mouse recombinant interleukin-1 and tumor necrosis factor- inhibited the stimulation-induced release of radioactivity from the isolated mouse atria. The effect of interleukin-1 was blocked by a human recombinant interleukin-1 receptor antagonist. The inhibitory effect of interleukin-1 was also abolished by the cyclooxygenase inhibitor, diclofenac (1 mol/1) suggesting that the action of interleukin-1 might be mediated through the formation of prostaglandins. The effect of interleukin-1 appears to be time-dependent, since a stronger inhibition of radioactivity release was observed when the incubation time was increased from 20 to 65 minutes before the second stimulation. Interleukin-2 and interleukin-6 were ineffective in modulating release under these experimental conditions.The ability of interleukin-1 and tumor necrosis factor- to inhibit noradrenaline release suggests that mediators of the immune system produced locally may modulate the activity of the sympathetic nervous system.     

Cocaine-induced cocaine craving

In nine experienced users of cocaine, we examined the urge to use cocaine or other drugs following a 40 mg dose of intravenous (IV) cocaine with and without oral pretreatment with 2.5 mg bromocriptine. The urge to use cocaine was assessed with a questionnaire constructed to assess both wanting and craving for cocaine or other drugs. Fifteen minutes after the administration of cocaine (but not after placebo), subjects' ratings for both drug wanting and drug craving were significantly increased. Our results provide a laboratory demonstration of cocaine-induced increases in the urge to use drugs in humans. The findings, stressing the role of internal stimuli associated with drug administration, suggest the possibility of distinguishing among related, but perhaps distinct, components of the fluctuating levels of motivation to reuse drugs.     

Cyclodextrins as Nasal Absorption Promoters of Insulin: Mechanistic Evaluations

The safety and effectiveness of cyclodextrins (CD) as nasal absorption promoters of peptide-like macromolecules have been investigated. The relative effectiveness of the cyclodextrins in enhancing insulin nasal absorption was found to be in the descending order of dimethyl--cyclodextrin (DMCD) > -cyclodextrin (-CD) > -cyclodextrin (-CD), hydroxypropyl--cyclodextrin (HPCD) > -cyclodextrin (-CD). A direct relationship linking absorption promotion to nasal membrane protein release is evident, which in turn correlates well with nasal membrane phospholipid release. The magnitude of the membrane damaging effects determined by the membrane protein or phospholipid release may provide an accurate, simple, and useful marker for predicting safety of the absorption enhancers. In order to estimate further the magnitude of damage and specificity of cyclodextrin derivatives in solubilizing nasal membrane components, the enzymatic activities of membrane-bound 5-nucleotidase (5-ND) and intracellular lactate dehydrogenase (LDH) in the perfusates were also measured. HPCD at a 5% concentration was found to result in only minimal removal of epithelial membrane proteins as evidenced by a slight increase in 5-ND and total absence of LDH activity. On the other hand, 5% DMCD caused extensive removal of the membrane-bound 5-ND. Moreover, intracellular LDH activity in the perfusate increased almost linearly with time. The cyclodextrins are also capable of dissociating insulin hexamers into smaller aggregates, and this dissociation depends on cyclodextrin structure and concentration. Enhancement of insulin diffusivity across nasal membrane through dissociation may provide an additional mechanism for cyclodextrin promotion of nasal insulin absorption.     

Tödliche Vergiftung mit Methyl-Parathion („Wofatox“)

Zusammenfassung Neben der Übersicht der Literatur des Methylparathions, mit anderem Namen Wofatox, geben wir den durch eine tödliche Wofatox-Vergiftung verursachten Selbstmord eines 50 Jahre alten Mannes bekannt. Die Wofatox-Vergiftung wurde durch den Obduktionsbefund und die chemische Untersuchung des Giftrestes, der Selbstmord durch die Umstände der Auffindung des Mannes bestätigt.Nach unserem Wissen ist in Ungarn dieser der erste bekanntgegebene tödliche Wofatox-Vergiftungsfall.     

On the mechanism of the decrease in cerebellar cyclic GMP content elicited by opiate receptor agonists

Summary Morphine, dextromoramide (4 mol/kg i.p.) and vimonol R₂ (17 mol/kg i.p.) in analgesic doses (28 to 112 mol/kg i.p.) decreased 3,5-cyclic guanosine monophosphate (cGMP) in rat cerebellar cortex; morphine also decreased the cGMP content in deep cerebellar nuclei. Intrastriatal but not intracerebellar injections of morphine (20 g) decreased cerebellar cGMP content. Naltrexone, an opiate receptor antagonist, but not apomorphine, a dopaminergic receptor agonist, blocked the effect of morphine on cerebellar cGMP. Pretreatment with 3-acetylpyridine (3-AP) which destroys the climbing fibers, failed to antagonize the effect of morphine on cerebellar cGMP. These results suggest that activation of opiate receptors in striatum decreases cerebellar cGMP content presumably by reducing activity in the mossy fiber excitatory input to cerebellum.     

Further aspects of the exploratory behaviour in aggressive mice

Aggressive mice can be divided in two sub-groups according to their exploratory activity. The active and the blocked aggressive mice show a different sensitivity to drugs, although they have a similar decrease of brain serotonin turnover rate.     

Toxic effects of some “mono-n-butyl-tin compounds” on white mice

The toxic effects of mono-n-butyl-tin-trichloride, mono-n-butyl-tin-tris-(2-ethyl-hexyl-mercaptoacetate), mono-n-butyl-tin acid and mono-n-butyl-thiotin acid on white mice were investigated. These compounds were administered to white mice by means of a stomach tube in a single dose of 4000 mg/ kg b.w. at the start of the experiment. All mice were sacrificed 24 hours after the administration.The clinical course as well as the macroscopic findings in all experimental groups indicated general signs of an acute intoxication. The histological findings in the mono-n-butyl-tin-trichloride group showed pronounced changes in the digestive tract, where haemorrhages in the mucous membrane and in the inner layer of the gastric and intestinal walls had been found. In the mice of the other experimental groups, steatosis of the hepatocytes and an irregular steatosis of the renal tubular epithelium were observed.     

Effects of calcitonin gene-related peptide (CGRP), neurokinin A and neurokinin A (4–10) on the mitogenic response of human peripheral blood mononuclear cells

Summary (1)We have studied the ability of some regulatory peptides to induce a mitogenic (incorporation of tritiated thymidine) response in human peripheral blood mononuclear cells (PBMC) and to modify the response produced by phytohaemagglutinin (PHA), a well known PBMC mitogen. (2) Human calcitonin gene-related peptide (hCGRP), human or salmon calcitonin (hCT, sCT), neurokinin A (NKA) and neurokinin (4–10) (up to 1 M for each peptide) did not produce per se any significant PBMC stimulation. (3) hCGRP (0.1 nM –1 M) produced a concentration dependent enhancement of the response to a submaximal concentration of PHA (1 g/ml). On the other hand, hCGRP decreased the mitogenic response to a maximal concentration of PHA (25 g/ml). (4) Neither hCT nor sCT (0.1 nM–1 M) had a significant influence on the response to PHA (1–25 g/ml). (5) Both NKA and NKA (4–10) produced a concentration-dependent (1 fM –10 pM) enhancement of the response to 1 g/ml PHA, while these compounds had no effect on the response to 25 g/ml PHA. (6) These findings suggest a potent modulatory action of CGRP and NKA, two peptides present in sensory and other nerves, on immune function which is possibly mediated via C2 receptors for CGRP and NK-2 tachykinin receptors, respectively.     

Adrenergic and purinergic cotransmission in nicotine-evoked vasoconstriction in rabbit ileocolic arteries

Summary The possible involvement of ATP, in addition to noradrenaline, in nicotine-evoked vasoconstriction was studied in branches of the ileocolic artery of the rabbit. For measurement of vasoconstrictor responses, the arteries were simultaneously incubated and perfused. For measurement of the release of [³H]-noradrenaline, they were preincubated with [³H]-noradrenaline and then superfused.Prazosin (0.1 mol/l) antagonized the constrictor effect of exogenous noradrenaline but not that of exogenous ATP. Desensitization of P_2X-receptors by ,-methylene ATP markedly attenuated the effect of exogenous ATP but not that of noradrenaline. The presumed P₂-purinoceptor antagonist suramin (100 mol/l) reduced the maximal contraction obtainable with noradrenaline and shifted the concentration-response curve for the constrictor effect of ,-methylene ATP to the right, but did not change the effect of ATP. Nicotine elicited monophasic vasoconstrictions which faded while nicotine was still in the medium. The concentration-response curve was bell-shaped with an EC₅₀ of 50 mol/l and a maximal effect at 180 mol/l, and the exposure time-response curve indicated that responses were maximal after 5 s of contact of nicotine (180 mol/l) with the tissue. Neither prazosin 0.1 mol/l nor desensitization by ,-methylene ATP changed the time course of the response to nicotine, but both depressed the magnitude of the responses over the whole concentration- and exposure time-response curves. The depression was greater with prazosin than with ,-methylene ATP. Desensitization by ,-methylene ATP or addition of suramin 100 mol/l practically abolished the prazosin-resistant part of the response. The effect of nicotine was blocked by hexamethonium as well as by sympathetic denervation by 6-hydroxydopamine. Prazosin, ,-methylene ATP and suramin did not reduce the nicotine-evoked overflow of tritium from arteries preincubated with [³H]-noradrenaline.The results indicate that activation of prejunctional nicotine receptors releases both noradrenaline and ATP (or a similar compound), and that the latter also contributes to the ensuing effector cell response. The adrenergic component predominated over the purinergic component, in contrast to certain electrically evoked responses. Adrenergic and purinergic components seemed to cooperate synergistically at low degrees of postjunctional receptor activation. The effect of suramin against the purinergic component in the effect of nicotine, as opposed to the lack of an effect against exogenous ATP, raises questions concerning the identity and site of action of the purinergic transmitter. Send offprint requests to K. Starke at the above address     

Differential responses based on the physiological consequences of pharmacological agents

Summary Rats were trained to make differential escape responses based solely on the different physiological states brought about by pharmacological agents. Two groups were trained to differentiate between saline and chlorpromazine while a third group was trained to differentiate between saline and imipramine. When the responses were well established test drugs were substituted for the training drugs in an attempt to determine the degree of transfer of the learned response from the training drug to the test drug.It was found that the chlorpromazine trained response transferred to acepromazine, perphenazine and prothipendyl, whereas there was no transfer from chlorpromazine to prochlorperazine or to imipramine at the doses studied. The imipramine trained response did not transfer to either chlorpromazine or acepromazine. The findings were discussed briefly in terms of the possible features of the physiological states which might be crucial in determining the results.     

Activation of β2-adrenoceptors by isoprenaline and adrenaline enhances noradrenaline release in cortical kidney slices of young spontaneously hypertensive rats

Summary The aim of the present study was to investigate -adrenoceptor modulation of noradrenaline release from sympathetic nerves in superfused cortical kidney slices of 4-week-old spontaneously hypertensive rats (SHR) and age-matched controls (WKY). After preincubation with ³H-noradrenaline the kidney slices were electrically stimulated in superfusion chambers. The stimulation induced (S-I) outflow of radioactivity was mainly composed of unmetabolized 3H-noradrenaline in both strains and thus taken as an index of noradrenaline release. There was a frequency-dependent (1.25–20 Hz) increase in the S-1 outflow of radioactivity. At all stimulation frequencies tested S-I outflow of radioactivity was similar or even slightly lower in SHR than in WKY kidney slices in either the absence or presence of cocaine (10 mol/l). The non-selective -adrenoceptor agonists isoprenaline (0.l gmol/1) and adrenaline (0.01 and 0.1 mol/l) enhanced S-I outflow of radioactivity. The facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) were blocked by the selective ₂-adrenoceptor antagonist ICI 118551 (0.1 mol/l) but not by the selective ₁-adrenoceptor antagonist atenolol (0.3 mol/l). The cell-permeable CAMP analogue 8-bromo-cAMP (300 mol/l) enhanced S-1 outflow of radioactivity to a similar extent in both SHR and WKY kidney slices. A combination of 8-bromo-cAMP (300 mol/l) and adrenaline (0.1 mol/l) did not enhance S-1 outflow of radioactivity to a greater extent than 8-bromo cAMP (300 mol/l) alone in both strains. However, the facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) but not that of adrenaline (0.01 mol/l) were significantly greater in SHR than in WKY. The results suggest that stimulation of prejunctional ₂-adrenoceptors by adrenaline even in the absence of a-adrenoceptor blockade enhances noradrenaline release in kidney cortex of young SHR and WKY. This ₂-adrenoceptor mediated effect may possibly be dependent on cAMP formation. The greater facilitatory effects of isoprenaline (0.1 mol/l) and adrenaline (0.1 mol/l) in SHR as compared to WKY are in accord with receptor binding studies which show a higher density of ₂-adrenoceptors in SHR than in WKY kidney cortex.Abbreviations SHR Spontaneously hypertensive rats - WKY WistarKyoto rats - cAMP 3-5-cyclic adenosine monophosphate - S-I stimulation induced Send offprint requests to: L. C. Rump     

Über Beziehungen zwischen proteolytischer Aktivität und blutcoagulierender sowie bradykinin-freisetzender Wirkung von Schlangengiften

Summary 1. Protein fractions with a different relation of proteolytic to coagulating activity were obtained by ammonium sulphate fractionation of the venom from Bothrops jararaca. The precipitate at 40% saturation possessed only feeble coagulating, but strong proteolytic activity (Protease), whereas there was feeble proteolytic and strong coagulating activity in the precipitate at 60% saturation (Koagulin).2. A substance which stimulated the intestine, probably bradykinin, was formed on incubation of Koagulin or Protease with plasma globulins. With Koagulin the formation was optimal atph 6,5 and increased with the duration of incubation; with Protease theph optimum was 8,0 and the gut stimulating activity decreased with prolonged incubation.3. The effects of the Koagulin- and the Protease fraction of the venom — the thrombin-like activity, the activation of prothrombin and the formation and destruction of bradykinin — were ascribed to different substrate-specific proteases.

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Durchgeführt mit Unterstützung der Deutschen Forschungsgemeinschaft.     

Quantification of communication processes, is it possible?

The PAS^® system (ProblemAnalysisSolutionsystem) is developed to quantify oral communication processes during counselling in pharmacy practice. The pharmacist translates the patients' drugrelated questions into a Pcode, the analysis of the question into an Acode and finally the given solution upon the question into a Scode. The PAS^® system has been developed for two goals. First, for the registation of drugrelated questions from patients which gives the pharmacist insight in the most common issues addressed by patients. Second, it might help the pharmacist to structure the communication with the patient during the consultation. Fortyone pharmacists participated in the evaluation of the PAS^® system. The validation of the PAS^® system consisted of two phases: the external validation and the internal validation. Kappa values were calculated as a measure of agreement in the coding by the pharmacists. The kappavalue of the external validation for the P , A and Scodes for the total set of questions indicate a moderate to poor agreement. This means that pharmacists categorize drugrelated questions from patients in a different way. Therefore we conclude that the PAS system is less reliable for research purpose. The kappavalue of the internal validation for the Pcode varies from 0.42 to 0.91. For the Acode it varies from 0.07 to 0.35 and for the Scode from zero to 0.68. Internal reproducibility is good for Pcode but not for the Acode and Scode This implies that the pharmacist can use the Pcodes for registration of patients' questions in his own pharmacy. Moreover, the usage of the PAS^® system during counselling in pharmacy practice can structure the consultation.     

Influence of various corticoids on the augmentation of “Gomori-positive” granules in the median eminence of the rat following adrenalectomy

Summary In 465 female Wistar rats the influence of an i.m. injection of various natural or synthetic corticoids on the augmentation of Gomori-positive granules in the outer layer of the median eminence following bilateral adrenalectomy has been investigated. While the augmentation of the granules is not impaired by progesterone it is inhibited or completely blocked, depending on the dose and the manner of application, by 11-desoxycorticosterone, corticosterone, cortisol, 9-fluorocortisol, prednisolone, triamcinolone, dexamethasone and fluoroformylone. The doses necessary to suppress the augmentation of the granules correspond to those shown by other authors to be required for blocking ACTH-secretion. The inhibitory effect of the investigated corticoids on the augmentation of the granules is related to their antiphlogistic potency.The findings suggest that the amount of the Gomori-positive granules in the outer layer of the median eminence of the rat might be used as a parameter of the activity of the corticotropin-releasing factor.Supported by grant from the Landesamt für Forschung, NRW.