Assessing the pharmaceutical care needs of asthmatic patients

Objectives: To measure patients perceptions of their care needs, by developing a tool to assess these needs and evaluate its utility in community pharmacy practice.Method: A survey tool comprising 37 items was developed to assess asthmatic patients perceptions of their health-related needs, using data from literature reviews and expert opinions. The tool was piloted on 25 patients to ensure the content of the questionnaire was valid. Changes were made following piloting and the modified tool was then tested in the main study, on 101 patients from thirteen community pharmacies in Portugal. Data from this phase were subjected to factor analysis and reliability testing.Results: 118 asthmatic patients were recruited, of which 101 questionnaires were eligible for analysis. From these, 40 were male (39.6%) and 61 were female (60.4%). The mean age of respondents was 41 years (sd=19.02). The first changes made to the survey tool included the adding of items relevant to patients recruited in the pilot and the simplification of the scaling used. The survey tool was then subjected to factor analysis and reliability testing. Six scales emerged, which described the need for GP support, specialist support, pharmacist support, nurse support, other carers support and written support. Internal consistency was good (Cronbachs coefficient alpha ranged from 0.81 to 0.93). Although there were no significant associations between educational level and other factors, other attributes influenced the communication between pharmacist and physician (²=6.972; P=0.031). Patients with a lower level of education (up to six years) valued communication between these two professionals more than among patients with higher education. The patients age group was associated with an expressed need for explanation of inhaler technique (²=6.494; P=0.039). There was extended need in both oldest and youngest patients. There was a significant difference between high and low scorers to the factor pharmacists role in asthma (F1) and patients treated by either specialist or GP (²=4.935; P=0.026). There were differences between those who were bothered by their asthma or not and their perceptions of Pharmacists ideal role in asthma (F1 & 3) (²=5.967; P=0.051).Conclusion: The tool needs further development to ensure its validity and utility in practice. This will provide greater insight into patients perceptions of their healthcare needs, which can allow health professionals to target their interventions. Such a tool may then be used in pharmacies that intend to change their current practice, to raise pharmacists awareness ofpatients demands. Developing ways to meet those needs will ultimately lead to an increased quality service and therefore client satisfaction.     

Antifungal Activity of a New Triterpenoid Glycoside from Pithecellobium racemosum (M.)

Purpose. In a continuation of our search for novel antifungal compounds from higher plants, the standard extract of the bark of Pithecellobium racemosum was found to have good activity against important AIDS-related opportunistic yeasts. Methods. The extract was subjected to bioguided fractionation using silica gel column chromatography which led to purification of triterpene glycosides. The structures of these compounds were determined by a combination of spectroscopic (IR, NMR, HRMS) and chemical methods. Results. Compound 1 is a new glycoside, 3-O[-L-arabinopyranosyl (1 -2)][-L arabinopyranosyl (1 -6)]2-acetoamido-2-deoxy--D-gluco-pyranosyl oleanolic acid and Compound 2 was identified as the known compound 3-O-[-L-arabinopyranosyl (l-2)]-L-arabinopyranosyl (1-6)] 2-acetamido-2-deoxy--D-glucopyranosyl echinocystic acid. Conclusions. Compound 1 is a new glycoside, 3-O-[-L-arabinopyranosyl (1-2)]-L-arabinopyranosyl (l-6)]-2-acetoamido-2-deoxy--D-glucopyranosyl oleanolic acid and exhibits moderate antifungal activity against T. mentogrophytes, C. albicans and S. cerevisiae with MIC values of 6.25, 12.5 and 12.5 g/ml respectively.     

A comparison of the analgetic potency of some analgesics as measured by the “flinch-jump” procedure

Summary The effects of various doses of morphine, dl-methadone, nalorphine, codeine, meperidine and saline on the flinch-jump thresholds of rats were measured by a procedure described previously. While none of the drugs influenced the flinch threshold, the group slopes of elevation of jump thresholds were significant for all drugs studied. In order of potency as revealed by this method, nalorphine ranked with morphine and methadone, while codeine and meperidine were less potent, suggesting that the procedure may be useful as a screening test for analgesic drugs.     

Risk factors for the development of adverse drug events in hospitalized patients

Adverse drug events in hospitalized patients lead to increased morbidity, mortality and costs. Early detection of adverse drug events could aid in the prevention of these adverse outcomes. A costeffective system for the early detection of adverse drug events should focus on high risk patients. A study was set up with the primary aim to identify characteristics that are associated with the development of adverse drug events (ADEs) in hospitalized patients.ADE reports were gathered from physicians and nurses (spontaneous reports) and from patients after intensive ward interviews by hospital pharmacists. All patients admitted to the internal medicine wards of two Dutch hospitals, during a two month period, were included.The following characteristics were analyzed for their potential relationship to the occurence of ADEs: age (categorized), gender, number of drugs prescribed during hospital stay, types of drugs used and changes in drug use on admission.Age was found to be inversely associated with the development of ADEs (OR 0.36, CI 0.210.61 for age category > 80 years; OR 0.56; CI 0.311.02 for age category 7580 years and OR 0.69; CI 0.421.11 for age category 6074 years). Furthermore, statistically significant associations were found for the number of drugs prescribed per hospitalized patient (for the class of 46 drugs per patient OR 2.61, CI 1.325.18), for newly prescribed drugs (OR 6.65, CI 2.6316.81) and for the cessation of drugs on hospital admission (OR 1.50, CI 1.022.20). The use of gastrointestinal drugs (OR 2.13, CI 1.323.45), central nervous system drugs (OR 1.66, CI 1.072.57) and antibiotics (OR 2.44, CI 1.653.60) were associated with the development of ADEs, when compared to all other drugs taken by the patients.In this study, the most important risk factors are the number of drugs used per patient and the starting of a new drug during hospitalization. As most hospitalized patients start new drug therapies while in hospital, this seems an inappropriate focus. However, careful monitoring of patients using more than 7 drugs at a time may be possible in a costeffective system for the early detection of ADEs.     

Liposomes Containing Interferon-Gamma as Adjuvant in Tumor Cell Vaccines

Purpose. Liposomal systems may be useful as a cytokine supplementin tumor cell vaccines by providing a cytokine reservoir at the antigenpresentation site. Here, we examined the effect of liposomeincorporation of mIFN on its potency as adjuvant in an established tumor cellvaccination protocol in the murine B16 melanoma model. Adjuvanticityof the mIFN-liposomes was compared to that achieved bymIFN-gene transfection of the B16 tumor cells. Furthermore, we studiedwhether liposomal incorporation of mIFN indeed increases theresidence time of the cytokine at the vaccination site. Methods. C57B1/6 mice were immunized with i) irradiated IFN-genetransfected B16 melanoma cells or ii) irradiated wild type B16 cellssupplemented with (liposomal) mIFN, followed by a challenge withviable B16 cells. The residence time of the (liposomal) cytokine at thesubcutaneous (s.c.) vaccination site was monitored using radiolabeledmIFN and liposomes. Results. Immunization with irradiated tumor cells admixed withliposomal mIFN generated comparable protection against B16 challenge asimmunization with mIFN-gene modified tumor cells. Irradiated tumorcells admixed with soluble mIFN did not generate any protectiveresponses. Radiolabeling studies indicated that free mIFN rapidlycleared from the s.c. injection site. Association of [¹²⁵I]-mIFNwith liposomes increased the local residence time substantially: liposomalassociation of mIFN resulted in a prolonged local residence time ofthe cytokine as reflected by a 4-fold increase of the area under thecurve. The amount of released cytokine in the optimal dose rangecorresponds to the amount released by the gene-transfected cells. Moderate but significant CTL-activity against B16 cells was found for miceimmunized with irradiated cells supplemented with mIFN-liposomescompared to untreated control animals. Conclusions. Prolonged presence of mIFN at the site of antigenpresentation is crucial for the generation of systemic immune responsesin the B16 melanoma model. These studies show that liposomalencapsulation of cytokines is an attractive strategy for paracrine cytokinedelivery in tumor vaccine development.     

Neonatal exposure to zearalenone causes persistent anovulatory estrus in the rat

The effect of neonatal administration of zearalenone on the female reproductive system was studied in the rat. A single subcutaneous injection of 1.0 mg zearalenone to 3- or 5-day-old rats caused persistent vaginal estrus in adulthood. Ovaries in these animals contained many large follicles but no newly formed corpora lutea. The same effects were observed in rats which had received 100 g estradiol-17 in the neonatal period. Most rats which had received 100 g zearalenone or 10 g estradiol-17 showed regular 4-day estrous cycles and had newly formed corpora lutea in their ovaries. These results demonstrate that neonatal exposure to zearalenone produces persistent anovulatory estrus in the rat, the potency being about one tenth that of estradiol-17.     

Effect of the phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711) on gastric secretion and gastric mucosal cyclic AMP

Summary The effect of the phosphodiesterase inhibitor 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone (ZK 62711) on gastric secretion and the cyclic AMP system of the gastric mucosa was studied in rats and guinea pigs. In rats, 0.03–0.3 moles/kg ZK 62711 i.v. stimulated acid and pepsin secretion in a dose-dependent manner and 0.03 moles/kg i.v. enhanced the effect of histamine. In guinea pigs no reproducible stimulation was found after intravenous injections of ZK 62711. The stimulation of gastric secretion in the rat by 0.3 moles/kg ZK 62711 i.v. was not affected by vagotomy but was totally inhibited by 10 moles/kg cimetidine i.v. The structurally related phosphodiesterase inhibitor, 4-(3-butoxy-4-methoxybenzyl)-2-imidazolidine (Ro 20-1724), at the dose of 3.3 moles/kg i.v. stimulated gastric secretion in anaesthetised rats to a similar extent as 0.3 moles/kg ZK 62711 i.v. The content of cyclic AMP in the rat gastric mucosa in vivo was slightly increased by 10 moles/kg ZK 62711 i.v, whereas lower doses did not change it. Accumulation of cyclic AMP in the rat gastric mucosa by 50 moles/kg histamine i.v. was enhanced by simultaneous injections of 3.3 moles/kg ZK 62711 i.v. In rat gastric tissue slices in vitro 1–50 M ZK 62711 increased the level of cyclic AMP but 100 M histamine had no effect in the absence or presence of ZK 62711. In gastric mucosal slices of the guinea pig 10 and 50 M ZK 62711 increased the cyclic AMP content which effect was inhibited by 100 M cimetidine and enhanced the stimulatory effect of 100 M histamine on cyclic AMP. The activity of soluble cyclic AMP phosphodiesterase was inhibited by ZK 62711 in the rat (IC₅₀=18 M) and guinea pig gastric mucosa (IC₅₀=1.5 M). Adenylate cyclase was not affected in the homogenate of the guinea pig gastric mucosa. The results indicate that the phosphodiesterase inhibitor ZK 62711 which increases cyclic AMP levels in the gastric mucosa in vivo and in vitro, is a potent stimulator of gastric acid secretion.     

Regulation of adenylate cyclase activity in hamster adipocytes

Summary In ghosts of hamster adipocytes, the regulation of adenylate cyclase (ATP: pyrophosphate lyase, cyclizing; EC 4.6.1.1) activity by prostaglandins, -adrenergic agonists and nicotinic acid was studied. These three classes of antilipolytic agents caused adenylate cyclase inhibition without an apparent lag phase. Maximal inhibitions observed ranged between about 45% (by -adrenergic agonists) and 60% (by prostaglandins and nicotinic acid). The order of potency for the inhibitory prostaglandins (PG) was PGE₁ PGE₂>PGF₂PGI₂>PGD₂>6-keto PGF₁. The IC₅₀ values obtained were about 0.007, 0.06, 0.3 and 1 M for PGE₁, PGF₂, PGD₂ and 6-keto PGF₁, respectively. -Adrenergic agonists, studied in the presence of the -adrenergic blocking agent, propranolol (30 M), inhibited the fat cell enzyme with the order of potency (1)-adrenaline > (1)--methylnoradrenaline (1)-noradrenaline > clonidine tetryzoline > (1)-phenylephrine. The IC₅₀ values obtained for (1)-adrenaline and (1)-noradrenaline were about 3 and 10 M, respectively. The inhibitory effect of (1)-adrenaline was blocked by the -adrenergic antagonists with the potency order yohimbine phentolamine > prazosin. These findings suggest that an ₂ of receptors is involved in this catecholamine-induced inhibition. Nicotinic acid (10 M) reduced adenylate cyclase activity by about 60% with half-maximal effectiveness at about 0.6 M. The nicotinic acid derivatives, nicotinamide, -pyridylcarbinol and NAD (up to 100 M), had no effect on enzyme activity.Inhibition of the hamster adipocyte adenylate cyclase by the antilipolytic agents required the presence of both GTP, which reduced basal activity by about 80% at 10 M, and sodium ions, which specifically activated the GTP-affected from of the enzyme. Inhibition was also observed in the presence of ACTH, which in a GTP-dependent manner increased adenylate cyclase activity. Pretreatment of the enzyme preparation with NaF (10 mM) partially reduced the inhibitory effect, and preactivation with the stable GTP analogue, guanylyl 5-imidodiphosphate (100 M), abolished the adenylate cyclase inhibition by the antilipolytic agents.Abbreviations PG prostaglandin - GMP-P(NH)P guanylyl 5-imidodiphosphate Some of the data were presented in abstract form (Aktories et al., 1979a)     

The effect of gamma-butyrolactone on locomotor activity in the rat

The effect of -butyrolactone (GBL) on locomotor activity in the rat was studied. Low doses of GBL (100 and 200 mg/kg) had a biphasic effect on activity. Initially, the activity of the rats was reduced, and this reduction was then followed by a period of hyperactivity. The effect of -flupenthixol (50 g/kg -FPT), atropine (10 mg/kg), benztropine (25 mg/kg), protriptyline (15 mg/kg), and clomipramine (25 mg/kg) was investigated on this biphasic effect. -FPT reduced the hyperactivity while benztropine potentiated it; atropine, clomipramine, and protriptyline had little effect. It is concluded that the increase in activity could be due to a release of dopamine.     

Pharmacokinetics and pharmacodynamics of nitroglycerin and its dinitrate metabolites in conscious dogs: Intravenous infusion studies

Intravenous infusions of nitroglycerin (GTN), 1,2-glyceryl dinitrate (1,2-GDN), and 1,3-glyceryl dinitrate (1,3-GDN) were given to four conscious dogs at 10 g/min, 30 g/min, 50 g/min, and 70 g/min of GTN and 20 g/min and 100 g/min of GDNs. The steady state plasma concentrations (Css)of GTN were reached after about 60 min whereas for 1,2-GDN and 1,3-GDN the Csswere reached at about 150 min after the infusion began. Except for one dog, the Cssof GTN were not proportional to infusion rate, however, all dogs together showed a good linear relationship between Cssof GTN and infusion rates with an average correlation coefficient of 0.917±0.102. Large variability in GTN clearance after various infusion rates was observed in all dogs. The Cssratios of 1,2-GDN/GTN and 1,3-GDN/GTN yield overall averages of 31.5 ±17.2 and 5.47 ±3.19,respectively. Average Cssratios of metabolites 1,2-GDN/1,3-GDN were 5.78±1.23. This ratio is different from those obtained after iv bolus and oral dosing indicating that the biotransformation of GTN to 1,2-GDN and 1,3-GDN differs for each dosing route. The clearances for 1,2-GDN and 1,3-GDN were not changed over the dose range of 20 g/min to 100 g/min. Terminal half-lives of 1,2-GDN and 1,3-GDN postinfusion were similar to those values obtained after a single bolus dose (45 min). It appears that all the GTN dose at steady state can be accounted for by the formation of measurable 1,2-GDN and 1,3-GDN. Large intra- and interdog variations in systolic blood pressure decrease (SPD) following infusions of GTN were observed, however, all dogs showed a clear systolic blood pressure decrease when the highest infusion rate (70 g/min) was given. No significant systolic blood pressure drop was detected following 20 g/min infusions of 1,2-GDN or 1,3-GDN. It was clear that systolic blood pressure in all dogs decreased following 100 g/min infusions of 1,2-GDN or 1,3-GDN. When SPD values were plotted vs. log GTN concentrations following the infusion of 70 g/min of GTN in all four dogs, a counterclockwise hysteresis was observed indicating the significant contribution of the active dinitrate metabolites to GTN pharmacodynamics.This work was supported in part by NIH grant HL32243.     

Metabolism,Distribution, and Transdermal Permeation of a Soft Corticosteroid,Loteprednol Etabonate

The soft corticosteroid, loteprednol etabonate (chloromethyl 17-ethoxycarbonyloxy-11-hydroxy-3-oxoandrosta-1,4-diene-17-carboxylate), I, was designed based on the inactive metabolite approach. Accordingly, I should be metabolized by hydrolysis to the corresponding inactive cortienic acid derivative, II. The in vitro and in vivo metabolism of I indeed yielded mainly this inactive metabolite, which is more hydrophilic and thus readily eliminated from the body. Relatively high levels of I were found in tissues after intravenous administration of the drug in rats. The permeability of I through hairless mouse skin was comparable to what has been found for related hard steroids, without significant metabolism taking place in the skin.     

Different effects of vinblastine on the polymerization of isotypically purified tubulins from bovine brain

Vinblastine, a highly successful antitumor drug, targets the tubulin molecule. Tubulin, the subunit protein of microtubules, consists of an - and a -subunit, both of which consist of isotypes encoded by different genes. We have purified three isotypes of bovine brain tubulin, namely, _II, _III and _IV. Microtubule associated protein-2 (MAP2) and Tau-induced assembly of these isotypes were compared in the presence and absence of vinblastine. MAP2-induced assembly of unfractionated tubulin and all the isotypes except _II tubulin was resistant to 1M vinblastine. Vinblastine at low concentrations (<10M) progressively inhibited the assembly of all of the isotypes but the vinblastine concentration required for inhibition of MAP2-induced microtubule assembly was minimal for _II. The tau-induced assembly of unfractionated tubulin and _III were equally sensitive to 1M vinblastine whereas _II and _IV were much more sensitive to vinblastine. The microtubules obtained in the presence of tau from unfractionated tubulin, _II and _IV could be easily aggregated by 20M vinblastine whereas such as aggregation of microtubules obtained from _III and tau required approximatedly 40M vinblastine. Our results suggest that among the tubulin isotypes, _II is the most sensitive to vinblastine in the presence of MAPs while _III is the most resistant and this intrinsic resistance of _III dimers persists in the polymeric form of _III tubulin as well. These results may be relevant to the therapeutic and toxic actions of vinblastine.     

Cocaine-sensitive O-methylation of noradrenaline in dental pulp of the rabbit: Comparison with the rabbit ear artery

Summary Incisor pulp from the rabbit metabolises exogenous noradrenaline in concentrations between 0.12 and 1.2 mol/l mainly to NMN.Effects of chronic sympathetic denervation indicated that in incisor pulp the NMN is extraneuronal in origin, and that DOPEG and DOMA formation, as well as a major part of the noradrenaline which accumulates in the tissue, are associated with the sympathetic nerves.NMN formation was unaffected by hydrocortisone 210 mol/l, but was strongly inhibited by cocaine 30 mol/l. These effects contrasted with those in the rabbit ear artery, where NMN formation was increased by cocaine 30 mol/l and decreased by hydrocortisone 210 mol/l.In COMT-inhibited denervated pulp, cocaine inhibited the accumulation of noradrenaline.Monoamine fluorescence histochemistry of pulp exposed to noradrenaline 50 mol/l indicated that cocaine-sensitive uptake occurred in fibroblasts.It is concluded that O-methylation of noradrenaline in dental pulp involves prior uptake of the amine by a process resembling uptake, but which is distinguished from uptake₁ by its extraneuronal location.Abbreviations DOMA 3,4-dihydroxy mandelic acid - DOPEG 3,4-dihydroxyphenylethyleneglycol - NMN normetanephrine - OMDA O-methyl deaminated metabolite fraction, comprising vanillyl-mandelic acid (VMA) plus the 3-methoxy derivative of DOPEG (MOPEG) - MAO monoamine oxidase - COMT catecholO-methyl transferase Send offprint requests to I. S. de la Lande at the above address     

Thymidine transport in hepatocytes

Thymidine transport and phosphorylation were investigated in isolated rat hepatocytes and AS 30 D hepatoma cells. In contrast to hepatoma cells, hepatocytes exhibited a minimum of thymidine phosphorylation due to a 100-fold smaller thymidine kinase activity. In hepatocytes thymidine is transported by two transport systems: a specific concentrative high affinity system and an unspecific non-concentrative low affinity system. In hepatoma cells only the low affinity system could be detected. A single dose of 20 or 50 mg diethylnitrosamine/kg body weight induced in hepatocytes a remarkable increase of thymidine kinase activity and a decrease of the transport by the high affinity system. Thymidine transport and phosphorylation by hepatocytes are considered to be sensitive markers for early recognition of toxin-induced liver regeneration.

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Zusammenfassung Thymidintransport und -phosphorylierung wurden in isolierten Rattenhepatozyten und AS 30 D-Hepatomzellen untersucht. Hepatozyten wiesen im Gegensatz zu Hepatomzellen aufgrund einer 100fach niedrigeren Thymidinkinaseaktivität eine äußerst niedrige Thymidinphosphorylierungsrate auf. In Hepatozyten wurde Thymidin durch zwei Transportsysteme aufgenommen: ein spezifisches, konzentratives high affinity System und ein unspezifisches, nichtkonzentratives low affinity System. In ATP-freien Hepatomzellen konnte nur das low affinity System nachgewiesen werden. Eine einmalige Dosis von 20 bzw. 50 mg Diäthylnitrosamin/kg Körpergewicht bewirkte in Hepatozyten einen Anstieg der Thymidinkinaseaktivität und eine Verminderung des Thymidintransports über das high affinity System. Thymidintransport und -phosphorylierung in Hepatozyten erwiesen sich als sensitives System zur frühen Erkennung beginnender Leberregeneration nach toxischer Vorschädigung.

     

Inhibitory adenosine A1-receptors on rat locus coeruleus neurones

Summary Intracellular recordings were performed in ₁-pontine slice preparation of the rat brain containing the locus coeruleus (LC). Adenosine (100, 300 mol/l) and its structural analogues, namely (–)-N⁶-(R-phenyliso-propyl)-adenosine (R-PIA; 3 – 30 mol/l) and S-PIA (10, 30 mol/l), as well as 5-N-ethylcarboxamido-adenosine (NECA; 3–30 mol/l) inhibited the firing rate of spontaneous action potentials and produced hyperpolarization; their rank order of potency was RPIA - NECA > S-PIA > adenosine. When applied by superfusion, all agonists strongly desensitized the LC cells; the hyperpolarization never surmounted 6 mV. Upon pressure ejection of adenosine 10 mmol/l from ₁- micropipette positioned close to an LC neurone, the membrane potential was raised by 14 mV and the apparent input resistance decreased by 20%. When the membrane potential was hyperpolarized by current injection to ₁- similar extent as adenosine did, the fall in input resistance was only 7%. The adenosine uptake inhibitor S-(p-nitrobenzyl)-6-thioguanosine (NBTG) 30 mol/l decreased the frequency of action potentials alone; on simultaneous bath-application with adenosine 300 mol/l it potentiated the hyperpolarization caused by the purine derivative. 8-Cyclopentyl-1,3-dipropylxanthine (CPDPX) 0.1 mol/l had no effect on its own, but it antagonized both R-PIA 30 mol/l and NBTG 30 mol/l. A higher concentration of CPDPX (1 mol/l) facilitated the spontaneous firing. In conclusion, both exogenous and endogenous adenosine activates somatic and/or dendritic A₁-receptors of LC neurones leading to an enhancement of potassium conductance and thereby to ₁- decreased firing rate and ₁- hyperpolarization. Send offprint requests to P. Illes at the above address     

Cysts in rabbit foetal brains

Reports have appeared in the literature on brain cysts in rabbit foetuses. This paper reports on investigations carried out to assess whether cystic dilatation is a malformation or an artefact. The results show that cystic dilatation arises by splitting of the pia-arachnoid membrane leading to a space between the skull and the neural tissue which is lined by the pial layer on its interior aspect and the arachnoid on its exterior aspect. The evidence presented indicates that cystic dilatation is a fixation-induced artefact. In addition, the presence of several artificial tissue clefts and spaces in preserved rabbit foetal brains is reported.     

Effect of pretreatment with the selective β1-adrenoceptor antagonist bisoprolol on the subsequent cardiovascular actions and β-adrenoceptor subtype specific occupancy of celiprolol in healthy man

Summary The cardiovascular effects at rest and during exercise and ₁- and ₂-adrenoceptor occupancy following a single dose of 1200 mg celiprolol p. o. were investigated in 8 healthy subjects with or without pretreatment with a single dose of 20 mg bisoprolol p. o., using a place-bo-controlled, 2-way cross-over design.The ergometric responses of heart rate (HR) and systolic blood pressure (SBP) after celiprolol were reduced to a similar extent as after bisoprolol, but the cardiovascular function at rest was affected in a different way: there was a rise in HR, clear enhancement of cardiac systolic performance, and a considerable drop in the estimated total peripheral vascular resistance, associated with median ₁-RRA and ₂-RRA occupancies of 88 and 34%, respectively. The cardiovascular effects of celiprolol were not affected by pretreatment with bisoprolol. Celiprolol thus binds extensively to ₁-adrenoceptors, moderately to ₂-adrenoceptors, acts as ₁-adrenergic antagonist (exemplified by the ergometric effects) but has vasodilator, positive chronotropic and cardiac systolic performance enhancing properties, which do not involve either direct or indirect ₁-adrenergic agonism, but which might reflect ₂-adrenergic agonism.     

Cultured chick sympathetic neurons: ATP-induced noradrenaline release and its blockade by nicotinic receptor antagonists

The ATP-induced increase in tritium outflow from cultured chick sympathetic neurons prelabelled with [³H]-noradrenaline was investigated.Seven days-old dissociated cell cultures of embryonic paravertebral ganglia, loaded with [³H]-noradrenaline (0.05 M), were superfused in the presence of (+)-oxaprotiline and exposed to ATP, ATP-analogues, or 1,1-dimethyl-4-piperazinium (DMPP) for 2 min. ATP (3 LM-3 mM), 2-methylthio-ATP (3–100 M), as well as DMPP (10 and 100 M) induced a significant overflow of tritium. The EC₅₀-value of ATP was 20 M. Both the ATP-induced and the DMPP-induced tritium overflow was Ca²⁺-dependent and sensitive to tetrodotoxin (0.3 M) and -conotoxin (0.1 M); in addition, it was inhibited by the ₂-adrenoceptor agonist 5-bromo-6-(2-imidazoline-2-ylamino)-quinoxaline (UK-14,304; 1 M). The effects of ATP and DMPP were not additive. The ATP-induced as well as the DMPP-induced overflow of tritium was diminished by the P₂-purinoceptor antagonists suramin (300 M) and reactive blue 2 (3 M); in all 4 cases, the inhibition amouted to approximately 40%. The tritium overflow induced by ATP or DMPP was almost abolished by the nicotinic receptor antagonist mecamylamine (10 M) and markedly inhibited by hexamethonium (100 M). Neither ATP nor electrical stimulation caused an overflow of tritium from cultures loaded with [³H]-choline.The results suggest that ATP at molar concentrations induces noradrenaline release from cultured chick sympathetic neurons via an action on a subclass of the nicotinic cholinoceptor.     

Frequency- and train length-dependent variation in the roles of postjunctional α1- and α2-adrenoceptors for the field stimulation-induced neurogenic contraction of rat tail artery

Summary The present paper examines the roles of postjunctional ₁- and ₂-adrenoceptors for the noradrenaline (NA)-induced neurogenic contractile response to field stimulation mainly with 1–100 pulses at 2 or 20 Hz, in the tail artery of adult normotensive rats. Pharmacological tools were employed to isolate and characterize the ₁- and ₂-adrenoceptor-mediated components of this response. The degree to which the drugs influenced NA release or reuptake was assessed by their effects on the electrochemically determined, stimulation-induced rise in the NA concentration at the innervated outer surface of the media. This response was unaffected by ,-methylene ATP (10 M) or suramin (500 M), added to desensitize or block P₂-purinoceptors, respectively prazosin (0.1 M) or SK&amp;F 104078 (6-chloro-9-[(3-methyl-2-butenyl)oxyl]-3-methyl-1H-2, 3, 4, 5-tetrohydro-3-benzazepine, 0.1 M), used to block postjunctional ₁- and ₂-adrenoceptors respectively, nifedipine (10 M), blocker of Ca²⁺ influx through L-type channels, and ryanodine (10 M), which blocks mobilization of Ca²⁺ from intracellular stores; it was moderately enhanced by yohimbine (0.1 M), blocker of pre- and postjunctional ₂-adrenoceptors, and strongly enhanced by cocaine (3 M) or desipramine (1 M), blockers of NA reuptake. Judging from their inhibitory effects on the contractile responses to the ₁- and ₂-adrenoceptor agonists, phenylephrine andxylazine, prazosin (0.1 M)and SK & F 104078 (0.1 M) could be used to selectively block ₁- and ₂-adrenoceptors respectively, while yohimbine (0.1 M) was less selective, strongly depressing ₂- and slightly depressing ₁-adrenoceptor-mediated responses. The ₁-adrenoceptor-mediated component of the contractile response to short trains at 20 Hz was fast in onset, brief in duration and abolished by ryanodine; that mediated by ₂-adrenoceptors was more delayed, prolonged and insensitive to ryanodine. Both components were dose-dependently depressed by nifedipine (0.1–10 M). The small contractile responses to single pulses, or up to 50 pulses at 2 Hz, or short train (< 4 pulses) at 20 Hz, were more markedly depressed by 0.1 M yohimbine or SK & F 104078 than by 0.1 M prazosin and, hence, mediated mainly by ₂-adrenoceptors. The reverse was true of the much larger response to longer trains at 20 Hz, which thus probably was mediated mainly by ₁-adrenoceptors. Cocaine or desipramine, as well as ,-methylene ATP or suramin, amplified both components of the NA induced contractile response especially that mediated via a₁-adrenoceptors and caused by single pulses or short trains.The main conclusions are (i) that the small NA-induced contractile responses of this artery to single pulses, or pulses at low frequency, or in short trains at high frequency, are mediated mainly via ₂-, and the larger responses to longer trains at high frequency increasingly via ₁-adrenoceptors, (ii) that the ₁- and ₂-adrenoceptor-mediated components interact cooperatively, probably at least in part by utilizing two different pathways to increase the intracellular Ca²⁺, (iii) that neuronal reuptake of NA strongly restricts both components of the NA-induced contraction, especially the ₁-adrenoceptor-mediated response to single pulses or short trains, and (iv) that both components of the NA-induced contraction, especially that mediated by ₁-adrenoceptors, may be depressed by ATP released by field stimulation and acting via P_2x-purinoceptors on smooth muscle. Based on these results a novel working hypothesis is proposed, in which it is assumed that the geometry of NA-mediated neuromuscular transmission in this vessel varies with the frequency and number of impulses in a stimulus train.Correspondence to J.-X. Bao at the above address     

An accelerated stability study of 5‐flucytosine in intravenous solution

The stability of the antimycotic drug flucytosine (5FC) and the extent of 5fluorouracil (5FU) formation in 5FC intravenous solution was studied in an accelerated stability experiment. 5FC intravenous solution (10 mg/ml) was heated at 40, 60, 70, 80 and 90 C for a maximum of 131 days. At appropriate time intervals samples were taken and the concentrations of 5FC and 5FU were determined using a newly developed, stability indicating HPLCUV method. Heating the 5FC intravenous solution at 40, 60, 70, 80 and 90 C lead to 5FC decomposition of respectively 0, 8.9, 14.4, 52.5 and 61.6%. The Arrhenius plot of the 5FC decomposition is described by: Lnk5-FC decomposition = 80.1892 * 1/T 0.2396 and the 5FU formation is described by Lnk5FU formation = 13087 * 1/T + 34.4028. It is concluded that 5FC is very stable in intravenous solution at regular storing temperatures and can therefore be stored at ambient temperatures for several years before the critical limit of 95% 5FC is reached. However, the toxic and teratogen degradation product 5FU may be present in considerable amounts in the product, due to both impurities in the raw material and the formation from 5FC upon sterilisation and storage.