The pharmacology of fever

The ability to minimise, if not prevent, large variations in deep body temperature that would otherwise result from some environmental conditions is a homeostatic function of unquestioned benefit that is demonstrated only by the more highly evolved animals. Nevertheless, body temperature is raised above normal values in many pathological conditions. This increase in temperature or fever is an active and co-ordinated response, which indicates the involvement of the CNS. Central injection and lesion studies have shown that the brain, in particular the PO/AH, is the site of action of fever-inducing agents, termed pyrogens. Electrophysiological data show that pyrogens modify the activity of central thermosensitive neurones as if to increase heat gain and decrease heat loss. The common response of fever to pyrogens of diverse origins is attributable to fever being mediated by an endogenous pyrogen released by phagocytic cells in the host. The mechanism by which central neuronal function is disturbed by pyrogens present in the periphery is not known. Tracer studies have yet to demonstrate the passage of a pyrogen across the blood-brain barrier. The possible involvement of several putative neuro- transmitters and modulators in fever has been reviewed here, but most compounds have not been studied sufficiently to allow firm conclusions to be drawn. Much of the data is limited to the effects of the putative mediators on normal thermoregulation but, even when the effect is hyperthermia, such observations do not necessarily indicate a role for the endogenous material in fever. Dose-response curves for agonists and the effects of antagonists are often undetermined. This shortfall in data is due to some extent to the nature of fever; a central response in vivo over several hours. Although fever may enhance other host reactions to combat infection and inflammation, neither this benefit nor the undesirability of antipyretic therapy has been demonstrated unequivocally in either homeothermic laboratory animals or humans. Consequently, antipyretic drugs continue to be used clinically to alleviate the fever, malaise and/or pain commonly associated with disease. The drugs in common usage are the nonsteroidal antipyretic analgesics, many of which also have an anti-flammatory effect. The primary mode of action of these drugs as antipyretics appears at present to be the inhibition of cyclo-oxygenase and a consequent reduction of prostanoid material in pyrogen-sensitive areas of the brain. PGEs in the PO/AH have received most study to date, but other mediators in other parts of the CNS, where the density of pyrogen receptors may be sparse, cannot be discounted and await further investigation.     

Changes in the biochemical and biophysical parameters of cholinergic synaptic vesicles on transmitter release and during a subsequent period of rest

Synaptic vesicles were isolated on sucrose density gradients from perfused blocks of Torpedo electric organ under varying experimental conditions. Newly synthesized acetylcholine was labelled with [³H]acetate in order to distinguish synaptic vesicles which had been recycled during stimulation-induced transmitter release and, in consequence, had become smaller and denser from the larger, lighter vesicles characteristic of unstimulated tissue. After 1800 pulses at 0.1 Hz, the density of these smaller vesicles increased from a pre-stimulation value of 1.056 g.ml^?1 to 1.067 g.ml^?1, whereas their water space (measured as the space occupied by the permeant solute glycerol), decreased by 34% from 65% to 43% of vesicle volume. During a subsequent 12 h rest period, these changes were partially reversed; water space returned to 52% of control and this change was highly correlated with a decrease in vesicle density and an increase in vesicular acetylcholine. The diameter of vesicles in whole tissue sections showed corresponding changes. An additional 12 h rest period did not lead to further significant recovery, suggesting that the preparation had a limited suitability for following long term processes depending on normal energy metabolism.The results can be explained on the assumption that when vesicles reform after releasing transmitter their core has a lower osmotic pressure than that of fully loaded vesicles. Reloading is accompanied by osmotically induced rehydration.     

Gibberellin biosynthesis in Gibberella fujikuroi: cloning and characterization of the copalyl diphosphate synthase gene

The gene coding for copalyl diphosphate synthase (CPS), which represents the first gene of the gibberellin pathway, was isolated from the rice pathogen Gibberella fujikuroi. This fungus is used commercially for the production of gibberellic acid and related gibberellins. CPS is a terpene cyclase which catalyzes the first specific step of the gibberellin (GA) pathway as it branches off from the general isoprenoid (biosynthetic) pathway at geranylgeranyl disphosphate (GGDP). A cDNA fragment of the cps gene from the fungus G. fujikuroi was amplified by RT-PCR using oligonucleotides based on amino-acid sequences which were conserved between the plant CPSs and the bifunctional CPS/KS of the fungus Phaeosphaeria sp. L487. A 588-bp fragment obtained with nested PCR was used to isolate the corresponding genomic clone of the cps gene from the wild-type λ-library. This gene consists of three exons and two introns. The three exons are 2877 bp long and encode 959 amino-acid residues. The protein shares 48% identity with the bifunctional Phaeosphaeria sp. L487 FCPS and between 16% and 18% identity to the corresponding plant CPSs. Expression of the G. fujikuroi cps gene is strongly enhanced under conditions optimized for gibberellin biosynthesis and is reduced when high amounts of ammonium are present in the medium. Gene disruption, followed by gibberellin assays and Southern-blot analysis of the transformants, demonstrated clearly that the cloned gene has the expected function in the biosynthesis of fungal gibberellins. Received: 28 April / 1 July 1998     

Intraocular grafting of cultured brain tissue: growth, vascularization and neuron survival in locus coeruleus and cortex cerebri

Locus coeruleus and cortex cerebri from embryonic (ED 17) and newborn rats were kept 4 days in tissue culture under conditions maintaining organotypic features and then transplanted to the anterior chamber of the eye of adult rats. Vascularization from the host iris was delayed in pre-cultured grafts as compared to directly grafted material. In spite of this, several morphological parameters developed normally. Thus, pre-cultured grafts grew considerably in oculo. Falck-Hillarp histochemistry showed that grafts of cortex cerebri received an adrenergic innervation from the host iris and that locus coeruleus grafts contained central adrenergic neurons capable of innervating a sympathetically denervated host iris. The successful combination of tissue culture and intraocular transplantation should permit the selective advantages of both techniques to be applied to the same tissue pieces, generating new information unobtainable by either method alone.     

Development and loss of toluene diisocyanate reactivity: immunologic,pharmacologic, and provocative challenge studies

Toluene diisocyanate (TDI) sensitivity accompanied by nonspecific bronchial hyperresponsiveness occurs in approximately 5% of occupationally exposed workers. We report the case of a 32-yr-old worker followed longitudinally after removal from isocyanate exposure. TDI reactivity was lost 11 mo after removal from exposure and nonspecific bronchial hyperresponsiveness resolved after 17 mo. Bronchial reactivity to radishes (Raphanus sativus), which developed concurrently with TDI reactivity, was lost 2 yr later. Immunopharmacologic results show that the worker's initial decreased ability of lymphocytes to produce cyclic AMP returned to near normal after 2 yr. IgE antibodies to a human serum albumin tolyl monoisocyanate conjugate were still present at this time.     

Studies on the mammary tumor-inhibiting effects of diethylstilbestrol and its mono- and diphosphate

Summary Diethylstilbestrol (DES), diethylstilbestrol monophosphate (DES-MP) and diethylstilbestrol diphosphate (DES-DP) were tested for their estrogen receptor affinity, estrogenic potency and mammary tumor-inhibiting activity in vitro and in vivo. DES had a much higher receptor binding affinity than its mono-or diphosphate. All three compounds inhibited the growth of the hormone-dependent MCF-7 and hormone-independent MDA-MB 231 breast cancer line only at relatively high concentrations. The estrogenic potency in the immature mouse uterine weight test decreased in the order DES>DES-MPDES-DP. The hormone-dependent MXT mammary tumor of the mouse was inhibited by all three compounds at a dosage of 1.0 mg/kg per week. At a dose of 0.01 mg/kg, DES, DES-MP, and DES-DP stimulated the tumor growth. Thus, for the first time, a biphasic effect on tumor growth was demonstrated in intact mature animals. As the effects of all three compounds were similar in this assay, a cleavage of the phosphate groups is likely. A decrease in estrogenic potency concomitant with a retained antitumor effect of DES-MP and DES-DP compared to DES was not demonstrable in the mature mouse using the MXT assay, only in the uterotrophic test in the immature mouse.Dedicated to Professor Dietrich Schmähl on occasion of his 60th birthdaySupported by the Deutsche Forschungsgemeinschaft and by the Verband der Chemischen Industrie, Fonds der Chemischen Industrie. The authors thank Dr. Weigert, Asta-Werke AG, Degussa Pharma Gruppe, Bielefeld, FRG, for the analysis of DES-MP and DP     

Effects of several 5′-carboxamide derivatives of adenosine on adenosine receptors of human platelets and rat fat cells

Summary The effects of several 5-carboxamide derivatives of adenosine on stimulatory (R _a) adenosine receptors of human platelets and inhibitory (R _i) adenosine receptors of rat fat cells have been compared. 5-N-Cyclopropylcarboxamidoadenosine (CPCA) and 5-N-ethylcarboxamidoadenosine (NECA) most potently inhibited ADP-induced aggregation of human platelets as shown by IC₅₀-values of 0.24 and 0.34 mol/l. 5-N-Methylcarboxamidoadenosine (MECA; IC₅₀ 0.81 mol/l) and 5-N-carboxamidoadenosine (NCA; IC₅₀ 2.1 mol/l) were less potent, whereas adenosine, 2-chloroadenosine and (-)N⁶-phenylisopropyladenosine [(-)PIA] exhibit IC₅₀-values of about 1.5 mol/l. Nearly the same rank order of potency was obtained for stimulation of adenylate cyclase activity of platelet membranes and for inhibition of [³H]NECA binding to human platelets. In order to examine the effects of the carboxamide analogues on R _i adenosine receptors of rat fat cells inhibition of lipolysis and adenylate cyclase were studied. (-)PIA was the most potent inhibitor of lipolysis as shown by an IC₅₀ of 0.5 nmol/l, followed by CPCA (IC₅₀ 1.1 nmol/l) and NECA (IC₅₀ 1.3 nmol/l), whereas MECA (IC₅₀ 17.9 nmol/l) and NCA (IC₅₀ 20.1 nmol/l) were much less potent than NECA in inhibiting lipolysis. Similar results were obtained for inhibition of adenylate cyclase activity of fat cell membranes and for competition with [³H]PIA binding to fat cell membranes. The relative potencies of the adenosine analogues at both receptor subclasses were calculated from the ratio of the IC₅₀-values for inhibition of platelet aggregation and of lipolysis. (-)PIA showed the highest selectivity for R _i receptors as indicated by a 2,900-fold lower IC₅₀ for the antilipolytic than for the antiaggregatory effect. The R _a/R _i activity ratio for NECA was about 260, for CPCA 220, for NCA 105 and for MECA 45. These results indicate that all 5-carboxamide adenosine derivatives are more potent agonists at R _i receptors than at R _a receptors. Since MECA has a higher selectivity for R _a receptors than NECA, it may be useful for the characterization of stimulatory adenosine receptors in different tissues.     

原发性高血压患者红细胞[Ca2+]i浓度变化及影响因素

目的：观察原发性高血压患者红细胞[Ca^2 ]i,多巴胺β羟化酶及ATP含量变化并分析其结果。方法：测定35例高血压患者的红细[Ca^2 ]i、ATP、血清多巴胺β羟化酶活性,血糖及血浆胰岛素含量,并以30例健康成年人为对照。结果：高血压患者的红细胞[Ca^2 ]i、ATP、多巴胺β羟化酶均明显高于对照组（P＜0．05,P＜0．01）,但血糖与胰岛素未见明显变化。结论：高血压患者血清多巴胺β羟化酶活性增强伴随ATP与[Ca^2 ]i升高。     

Characterization of butyrate-dependent electroneutral Na-Cl absorption in the rat distal colon

Recent studies have established that mucosal butyrate stimulates electroneutral sodium-chloride (NaCl) absorption in the distal colon of the rat and a model in which Na-hydrogen (H) and Cl-butyrate exchanges are coupled has been proposed as the mechanism of butyrate-dependent electroneutral Na-Cl absorption. These studies were designed to examine butyrate-dependent electroneutral Na-Cl absorption in experimental conditions in which HCO₃-dependent electroneutral Na-Cl absorption is inhibited: in Na-depleted (aldosterone-treated) animals and in the presence of increased mucosal cyclic adenosine monophosphate (AMP). Butyrate-dependent electroneutral Na-Cl absorption was markedly reduced in Na-depleted rats. In contrast, the inhibition of both net Na and net Cl absorption by 5 mM serosal theophylline was significantly less in butyrate-containing, HCO₃-free Ringer solution than in butyrate-free-HCO₃-containing Ringer solution. These studies indicate that cyclic AMP does not inhibit butyrate-dependent electroneutral Na-Cl absorption and we propose that the mechanism of cyclic AMP inhibition of HCO₃-dependent electroneutral Na-Cl absorption may be a result of its inhibition of Cl-HCO₃, not Na-H exchange.