bluuebunny/crossref_metadata_2025 huggingface dataset:
Hormonal regulation of Gi alpha level and adenylyl cyclase responsiveness.
Authors: Reithmann C. , Gierschik P. , Werdan K. , Jakobs KH
Published: July 2012

Prolonged exposure of cells to adenylyl cyclase stimulatory hormonal factors can cause an increase in the level of membrane inhibitory G protein (Gi) alpha‐subunits, while inhibitory receptor agonists have been reported to induce the opposite response. As studied in cultured rat cardiomyocytes, the beta‐adrenoceptor‐induced increase in the level of Gi alpha proteins is protein synthesis‐dependent, is apparently not accompanied by an increase in G protein beta‐subunits and results in a decreased adenylyl cyclase responsiveness. On the other hand, a decrease in Gi alpha level apparently results in sensitization of adenylyl cyclase stimulation. These data suggest that the up‐ or down‐ regulation of the level and activity of Gi protein alpha‐subunits is a rather general cellular response, providing an intracellular negative feedback control against prolonged receptor activation.
Different desensitization mechanisms of two alpha 1‐adrenoceptor subtypes in the contraction of rabbit aorta.
Authors: Suzuki E. , Tsujimoto G. , Hashimoto K.
Published: July 2012

Using alpha 1‐adrenoceptor selective antagonists chlorethylclonidine (CEC) and WB4101, both functional and radioligand binding studies showed that rabbit aorta contains at least two pharmacologically distinct alpha 1‐adrenoceptor subtypes of approximately 10% alpha 1a and 90% alpha 1b receptors, and that each receptor subtype has a distinct role in the alpha 1‐adrenoceptor‐mediated vasoconstrictive response through different biochemical mechanisms for increasing intracellular Ca2+; alpha 1a receptors cause tonic response predominantly dependent on the influx of extracellular Ca2+, while alpha 1b receptors stimulate phosphoinositides (PI) hydrolysis/intracellular Ca2+ mobilization and cause phasic response mainly independent of extracellular Ca2+. Incubation of rabbit aorta with 10 microM noradrenaline (NA) for 2 h resulted in a reduction in the phasic response and PI hydrolysis to NA with no change in the tonic response. Similar to the NA incubation, the protein kinase C stimulator PMA (1 microM) selectively attenuated alpha 1b‐receptor mediated PI hydrolysis and phasic contraction but had little effect on alpha 1a‐ receptor‐mediated tonic response. The protein kinase C inhibitor H‐7 (10 microM) blocked these inhibitory effects of PMA. Treatment with H‐7 (10 microM) prevented the NA‐induced alpha 1b receptor desensitization in inositol monophosphate (IP) formation and phasic response. The results suggest that activation of C kinase may be involved in the development of selective desensitization of alpha 1b receptors by a short‐time in vitro incubation of NA.
Desensitization and down‐regulation of brain alpha 2‐adrenoceptors by centrally acting antihypertensive drugs.
Authors: Hamilton CA , Yakubu MA , Howie CA , Jardine E. , Reid JL
Published: July 2012

Rabbits were treated with intravenous clonidine (8 mumol kg‐1 day‐1), guanabenz (20 mumol kg‐1 day‐1), rilmenidine (80 mumol kg‐1 day‐1) or vehicle via osmotic minipumps. After 6 days treatment mean arterial pressure (MAP), pressor responses to intravenous alpha‐methyl noradrenaline and depressor responses to intracisternal clonidine were studied, and [3H]‐yohimbine binding to forebrain and hindbrain examined in vitro. Clonidine, guanabenz and rilmenidine had similar effects on MAP and caused a similar attenuation of the depressor response to intracisternal clonidine, but only guanabenz attenuated pressor responses to intravenous alpha‐methyl noradrenaline. Rilmenidine had no effect on [3H]‐yohimbine binding to brain membranes. Clonidine treatment decreased binding in hindbrain while guanabenz treatment decreased binding in both fore‐ and hindbrain. Thus, the depressor effects of chronic treatment did not correlate with the effects on [3H]‐ yohimbine binding sites in rabbit brain suggesting that the blood pressure lowering effects of many centrally acting antihypertensive drugs are not necessarily dependent on binding to the alpha 2‐ adrenoceptor site labelled by [3H]‐yohimbine.
Effects of insulin on human beta‐adrenoceptors.
Authors: Sager G.
Published: July 2012

The effect of insulin on beta‐adrenoceptor stimulation and binding in mononuclear leucocytes from healthy subjects was studied. After 1 min exposure to insulin, the sensitivity and maximum response to (−)− isoprenaline and the number of beta‐adrenoceptors increased. After 35 min exposure to insulin, the sensitivity and maximal response to (−)− isoprenaline stimulation were lower than the pretreatment values. The beta‐adrenoceptor density was similar to the control value after 35 min exposure to insulin. The present observations may account for some of the cardiovascular effects of insulin.
Beta 2‐adrenoceptor up‐regulation in relation to cAMP production in human lymphocytes after physical exercise.
Authors: Graafsma SJ , van Tits LJ , Willems PH , Hectors MP , Rodrigues de Miranda JF , De Pont JJ , Thien T.
Published: July 2012

The effect of isotonic bicycle exercise on beta 2‐adrenoceptors and cAMP production in lymphocytes was studied. The origin of the newly exposed receptors was studied by measuring radioligand binding in the presence of hydrophylic or lipophylic 'cold' ligands. During exercise beta 2‐adrenoceptor density increased from 1207 +/‐ 144 to 1776 +/‐ 152 sites/cell (56 +/‐ 14%). Isoprenaline induced an increase in cAMP synthesis, which was 68 +/‐ 15% higher than those values measured before the test. Forskolin did not induce a higher increase in cAMP production after exercise. The increase in receptor density seems not to be due to a transfer of internalized receptors to the membrane surface. We conclude that physical exercise induces an up‐regulation of beta 2‐adrenoceptors on lymphocytes and that these adrenoceptors are functional.
The relationship between adrenaline and beta 2‐adrenoceptors on human lymphocytes.
Authors: Graafsma SJ , Hectors MP , van Tits LJ , Rodrigues de Miranda JF , Thien T.
Published: July 2012

To study the relation between plasma adrenaline (AD) and noradrenaline (NA) and the beta 2‐adrenoceptor number (Bmax) on lymphocytes these variables were measured in the following three groups: a) In 67 normotensive volunteers after a rest period of at least 15 min. b) In 10 essential hypertensive (HT) and 10 age and sex matched normotensive (NT) subjects before and after a standardized bicycle exercise test (BE). c) In 10 bilaterally adrenalectomized females (AF) and 10 healthy age matched females (NF) before and after a mental arithmetic test (MA). Significant correlations were found between AD and Bmax in NT (r = 0.30, P = 0.015) and between the proportional increase in AD and the proportional increase in Bmax after BE (r = 0.60, P less than 0.005). The MA induced elevation of Bmax was blunted after adrenalectomy. All these findings point to a relation between AD and beta 2‐adrenoceptor regulation.
Cyclic AMP antagonizes mitogen‐induced accumulation of inositol phosphates in human peripheral mononuclear leucocytes in vitro.
Authors: van Tits LJ , Daul A. , Grosse‐Wilde H. , Brodde OE
Published: July 2012

The effect of intracellular increases of cyclic adenosine monophosphate (cAMP) on the accumulation of inositol phosphates (IPs) in response to various mitogens in vitro in human peripheral mononuclear leucocytes (MNL) was investigated. The beta‐adrenoceptor agonists inhibited mitogen‐induced IPs‐accumulation by about 30‐50% with a rank order of potency isoprenaline greater than adrenaline much greater than noradrenaline. This rank order corresponded with the order of potency of the beta‐adrenoceptor agonists to generate cAMP. The beta‐ adrenoceptor agonist‐induced inhibition of IPs‐accumulation in response to mitogen could be completely prevented by the beta 2‐adrenoceptor selective antagonist ICI 118,551, but not by the beta 1‐adrenoceptor selective antagonist CGP 20712A. Furthermore, the isoprenaline‐induced inhibition of IPs‐accumulation in response to mitogen could be enhanced by the phosphodiesterase inhibitor IBMX. We conclude that cAMP antagonizes mitogen‐induced IPs‐accumulation in human peripheral MNL in vitro.
Effect of lymphokines on beta‐adrenoceptor function of human peripheral blood mononuclear cells.
Authors: van Oosterhout AJ , Nijkamp FP
Published: July 2012

Pathological induced changes in beta‐adrenoceptor function occur in diseases such as asthma and hypertension. The mechanism(s) of this dysfunction is at present unclear. In the present study, the effect of lymphokines on beta‐adrenoceptor agonist induced cAMP production in peripheral blood mononuclear cells (PBMC) is investigated. Pre‐ incubation of PBMC during 20 h with interleukin‐2 (IL‐2, 100 u ml‐1) and granulocyte/macrophage‐colony stimulating factor (GM‐CSF, 100 u ml‐ 1) significantly decreases beta‐adrenoceptor agonist induced cAMP production by 35 +/‐ 8% and 37 +/‐ 11% respectively. IL‐3 and IL‐4 do not affect beta‐adrenoceptor agonist induced cAMP production in PBMC. It can be concluded that IL‐2 and GM‐CSF, mediators derived from T‐ lymphocytes, can induce beta‐adrenoceptor dysfunction in PBMC.
T cell mediated induction of bronchial hyperreactivity.
Authors: Garssen J. , van Loveren H. , van der Vliet H. , Nijkamp FP
Published: July 2012

Inadequate reactions of the immune system, i.e. allergic or hypersensitivity reactions, can lead to lung tissue injury. We investigated the relationship of type IV hypersensitivity, as an example of IgE independent hypersensitivity, with the induction of airway hyperreactivity. After antigen challenge (picrylsulphonic acid (PSA] in picrylchloride (PCl) sensitized mice, peribronchial and perivascular accumulation of mononuclear cells was found that was maximal 48 h after challenge. At several time points after challenge, changes in smooth muscle tone of mouse isolated tracheas were measured isometrically. In sensitized mice the response to carbachol was increased, reaching a maximum 48 h after challenge. This hyperreactivity was not found in athymic (nude) mice. We concluded from these data that airway hyperreactivity can be immunologically induced other than by IgE.
Neutrophils increase histamine contractions in pig coronary artery: a role for lipoxygenase products.
Authors: van Heuven‐Nolsen D. , Ten Have GA , Nijkamp FP
Published: July 2012

The possible role of neutrophils and the endothelium in the induction of hyperreactivity of the pig coronary artery to histamine was studied. In pig isolated coronary arteries histamine caused a concentration‐ dependent contraction; maximal contraction to histamine, however, was reduced in endothelium‐denuded arteries. Pre‐incubation of intact coronary arteries with isolated neutrophils did not affect the contractile response to histamine, while pre‐incubation of endothelium‐ denuded arteries induced a hyperreactivity to histamine. This induction of hyperreactivity to histamine by neutrophils in pig coronary arteries seems to be mediated by lipoxygenase products, since it could be prevented by pre‐incubation of the preparations with lipoxygenase inhibitors, but not with inhibitors of cyclo‐oxygenase or with scavengers.
Parainfluenza‐3 induced hyperreactivity of the guinea pig trachea coincides with an increased number of bronchoalveolar cells.
Authors: Folkerts G. , Janssen M. , Nijkamp FP
Published: July 2012

Guinea pigs were inoculated intra‐tracheally with bovine parainfluenza type 3 virus (PI‐3) to investigate whether airway hyperreactivity was associated with an increase in the number of broncho‐alveolar cells. Two days after saline or PI‐3 inoculation no difference in histamine reactivity of the isolated tracheal spirals was observed. The number of broncho‐alveolar cells was also not changed. However, 4 days after PI‐3 inoculation the histamine‐induced contraction of the tracheal spirals was increased by 45% and the number of inflammatory cells in the airways by 150% as compared with the control group. In conclusion, PI‐3 infection of the guinea pig respiratory airways induces tracheal hyperreactivity which is associated with an increase in broncho‐ alveolar cells.
Alterations of neuroreceptors in nasal hyperreactivity.
Authors: van Megen YJ , Rodrigues de Miranda JF , Klaassen AB
Published: July 2012

Cholinergic and adrenergic abnormalities have been observed in nasal allergy and may be due to changes in pharmacological characteristics of neuroreceptors. Radioligand receptor binding studies demonstrated no significant changes in affinities or densities of alpha‐adrenoceptors, a decreased number of beta‐adrenoceptors and a decreased affinity combined with a decreased number of muscarinic acetylcholine receptors.
Receptor modification in the brains of spontaneously hypertensive and Wistar‐Kyoto rats: regionally specific and selective increase in cerebellar beta 2‐adrenoceptors.
Authors: Jones CR , Palacios JM , Hoyer D. , Buhler FR
Published: July 2012

Quantitative in vitro autoradiography was used to study beta‐adrenergic and benzodiazepine receptor density in discrete regions from sagittal brain sections of 20 week old hypertensive (SHR) and normotensive (WKY) rats. The density of beta‐adrenoceptors was increased by 68% in the granule cell layer of the cerebellum of the SHR without a change in receptor affinity; this increase was specific for receptors of the beta 2‐subtype. On the other hand, benzodiazepine receptor density was unchanged in the cerebella of SHR. These results indicate that brain beta‐adrenoceptors are differentially modulated by the hypertensive state which may be either a cause or a consequence of alterations in adrenergic nervous system activity found in the SHR.
Differing calcium sensitivities of human cerebral and digital arteries, human metatarsal veins, and rat aorta.
Authors: Iwanov V , Moulds RF
Published: July 2012

1. The effects of the voltage dependent calcium channel blocking agent nifedipine, and of a calcium free bathing medium, on the responses of human blood vessels obtained postmortem to various agonists have been compared with those of the rat aorta. The human vessels studied were digital arteries, basilar arteries and metatarsal veins. 2. Responses to potassium chloride (5‐80 mM), noradrenaline (10(‐9)‐10(‐4) M), 5‐ hydroxytryptamine (10(‐8)‐10(‐4) M) and U46619 (10(‐11)‐10(‐6) M), in the presence and absence of nifedipine (1, 10, and 100 nM) or in a calcium‐free bathing medium, were assessed using an area‐under‐curve analysis. 3. In general, the order of sensitivity of the vessels to inhibition of agonist induced contractures by nifedipine was basilar arteries greater than metatarsal veins = digital arteries = rat aorta. 4. For all the vessels, the order of sensitivity for antagonism of responses to the agonists by nifedipine was potassium chloride greater than 5‐hydroxytryptamine = noradrenaline greater than U46619. 5. A calcium free bath inhibited responses of digital arteries to potassium chloride more than noradrenaline, 5‐hydroxytryptamine or U46619, and responses of rat aorta to a greater extent than responses of the digital arteries. 6. In the rat aorta, a calcium‐free bath inhibited responses to all agonists (except KCl) to a greater degree than did nifedipine. 7. We conclude that inhibition of extracellular calcium entry through voltage dependent calcium channels affects contractile responses of different blood vessels to different extents, and, within the same blood vessel, responses to different contractile agonists to different extents.
Lack of enzyme induction with oxcarbazepine (600 mg daily) in healthy subjects.
Authors: Larkin JG , McKee PJ , Forrest G , Beastall GH , Park BK , Lowrie JI , Lloyd P , Brodie MJ
Published: July 2012

1. Oxcarbazepine (OXC), the 10‐keto analogue of carbamazepine (CBZ), has similar anticonvulsant efficacy and possibly improved patient tolerability. Unlike CBZ, it is metabolised by reduction and may not induce hepatic monooxygenase enzymes. 2. Serum concentrations of OXC and its active metabolite 10‐OH‐carbazepine (10‐OH‐CZ) were followed after a single 300 mg dose and during and after 300 mg OXC twice daily for 29 doses in eight healthy male volunteers. 3. Antipyrine metabolism, urinary 6‐beta‐hydroxycortisol excretion, sex hormone binding globulin (SHBG) levels and circulating androgens were measured as indices of hepatic enzyme induction before, during and after treatment with OXC. 4. Elimination half‐lives (mean +/− s.e. mean) of 10‐OH‐CZ were unaltered by 2 weeks' therapy with OXC (before 11.3 +/− 1.1 h; after 13.9 +/− 3 h). Trough plasma concentrations of 10‐OH‐CZ at steady‐state (31 +/− 2.2 mumol l‐1) were higher than predicted (16.5 +/− 4 mumol l‐1). 5. Antipyrine metabolism, urinary 6‐beta‐hydroxycortisol excretion, SHBG levels and circulating androgens were unaltered by treatment with OXC. 6. OXC (600 mg daily) does not induce hepatic monooxygenase enzymes and so is likely to have more predictable dose‐ concentration relationships and to produce fewer physiological and pharmacological interactions than CBZ.
Inter‐ and intraindividual variability in the concentration‐effect (sedation) relationship of flunitrazepam.
Authors: Grahnen A , Wennerlund P , Dahlstrom B , Eckernas SA
Published: July 2012

1. The relationship between plasma flunitrazepam concentrations and the degree of sedation was evaluated in 20 healthy subjects receiving two single oral doses of 1 mg flunitrazepam on two different occasions (1 week apart). The degree of sedation was rated blindly during the two treatment sessions in parallel with blood sampling (48 h). 2. A strong correlation between the concentrations of flunitrazepam in plasma and the degree of sedation was found according to the sigmoid Emax model. The plasma drug concentration producing 50% of maximal effect (EC50) was found to be 7.0 and 6.5 ng ml‐1 on the two occasions, respectively. The variability in EC50 between subjects was larger (C.V. 39%) than the variability within subjects (C.V. 27%). 3. The steepness of the concentration‐response curve as reflected in the slope factor(s) showed a virtual ‘all or none’ response to flunitrazepam with s values ranging from 3 to 30 with a mean of about 14. 4. The results in young healthy subjects suggest that the present dosage recommendations for temporary insomnia (1‐2 mg) may be inappropriate; the dose can probably be reduced to 0.5 mg in some patients to achieve moderate sedation.
Effects of granisetron and lorazepam, alone and in combination, on the EEG of human volunteers.
Authors: Link CG , Leigh TJ , Fell GL
Published: July 2012

1. The EEG effects of granisetron, a potent and selective 5‐HT3 receptor antagonist (160 micrograms kg‐1), and lorazepam (2.5 mg) were examined in 12 healthy male volunteers. 2. The results indicated that lorazepam had a marked effect on the CNS, significantly increasing power in the slow (1‐7 Hz) and fast (13‐20 Hz; 21‐30 Hz) wavebands whilst reducing power in the mid range (8‐12 Hz). 3. In contrast there was no demonstrable effect of granisetron on the EEG at the dose tested, and no evidence of a pharmacodynamic interaction between the two compounds.
Effects of clonidine and yohimbine on the pupillary light reflex and carbachol‐evoked sweating in healthy volunteers.
Authors: Morley MJ , Bradshaw CM , Szabadi E
Published: July 2012

The effects of single doses of clonidine hydrochloride (200 micrograms), yohimbine hydrochloride (22 mg), a combination of the two treatments, and placebo, on some autonomic functions were studied in healthy volunteers using a double‐blind crossover design. Clonidine prolonged the recovery time of the light reflex, lowered systolic blood pressure and reduced subjectively rated alertness; these effects were reversed by yohimbine. Responsiveness of sweat glands to carbachol was not affected by the treatments.
A study of adjunctive copper sulphate treatment in patients with rheumatoid arthritis who have relapsed while taking D‐penicillamine.
Authors: Pullar T , Wrigley H , Newton K , Toothill C , Wright V
Published: July 2012

Formation of a D‐penicillamine‐copper complex may be necessary for the anti‐rheumatic effect of D‐penicillamine. Thus, depletion of copper stores by D‐penicillamine may eventually lead to relapse in D‐ penicillamine treated patients. Twenty‐one patients who relapsed on D‐ penicillamine were randomised to copper sulphate 20 mg daily (n = 13) or matched placebo (n = 8) in addition to penicillamine daily for 16 weeks. Urinary copper was increased in the copper treated patients but no statistically significant or clinically important improvement occurred in either group.
Prednisolone concentrations in cerebrospinal fluid after different prednisolone prodrugs.
Authors: Buhrer M , Frey FJ , Frey BM
Published: July 2012

The concentration‐time curves of prednisolone in cerebrospinal fluid (CSF) and plasma were measured following an equimolar i.v. bolus dose of prednisolone phosphate (five patients) and prednisolone phthalate (four patients). Independent of the prodrug administered, the value of the AUC (0.360 min) in CSF was more than three times lower than the corresponding value in plasma. The AUCs of unbound prednisolone in plasma were higher after prednisolone phosphate, than after prednisolone phthalate (68.1 +/− 15.7 vs 19.0 +/− 5.2 micrograms ml‐1 min, P less than 0.001). Similarly, the AUCs of prednisolone were higher in the CSF after prednisolone phosphate, than after prednisolone phthalate (17.6 +/− 2.8 vs 3.3 +/− 1.0 micrograms ml‐1 min, P less than 0.0001). The results indicate that the concentrations of prednisolone in CSF are much lower than the unbound concentrations in plasma and that therapeutic inequivalence should be expected when the two prodrugs are given in equimolar doses.
A method of studying pharmacokinetics in man at picomolar drug concentrations.
Authors: Cunningham VJ , Pike VW , Bailey D , Freemantle CA , Page BC , Jones AK , Kensett MJ , Bateman D , Luthra SK , Jones T
Published: July 2012

1. We describe a new method that enables the tissue kinetics of picomolar concentrations of drugs to be measured in man. The method is based on the administration of a drug, labelled with a short‐lived positron‐emitting radioisotope, such as carbon‐11 (t1/2 = 20.4 min, beta + = 99.8%) or fluorine‐18 (t1/2 = 109.8 min, beta + = 96.9%), which is then detected in vivo by an array of 10 large uncollimated sodium iodide scintillation detectors, arranged as five opposing pairs, with each pair collecting data over one major organ or region of the body. 2. To illustrate the scope of the new method we report the results of administering [O‐methyl‐11C]‐diprenorphine, an established radioligand for central opiate (mu, kappa, and delta) receptors and L‐6‐ [18F]‐fluoro‐DOPA, a marker for dopaminergic neurons. 3. Only 2‐10 muCi (74‐370 kBq) of radioactivity are used and, as a consequence of the high specific activities with which carbon‐11 and fluorine‐18 labelled compounds can be prepared, the method requires less than a nanomole of drug to be administered. In many cases, this amount of drug might be considered low enough to avoid any adverse biological effect. Furthermore repeat studies are possible in many without delivering unacceptable radiation burdens. 4. The high sensitivity realised for both radioactivity and mass suggests a mean for determining the human biodistribution of a new drug at a very early stage in its development. This has potential benefit to drug discovery programmes and to ensuing drug therapies.
The effects of magnesium hydroxide on the absorption and efficacy of two glibenclamide preparations.
Authors: Neuvonen PJ , Kivisto KT
Published: July 2012

1. The effect of magnesium hydroxide on the absorption and efficacy of two glibenclamide preparations was investigated in healthy volunteers in two separate studies, using a randomized cross‐over design with two phases. 2. A single dose of magnesium hydroxide (850 mg) or water only (150 ml) was given immediately after the ingestion of a micronised (1.75 mg, seven subjects) or a non‐micronised (2.5 mg, six subjects) preparation of glibenclamide. Plasma concentrations of glibenclamide, insulin and glucose were measured. 3. Magnesium hydroxide accelerated (P less than 0.05) the absorption of glibenclamide from the micronised preparation to a small extent but the extent of absorption and the insulin and glucose responses were unaltered. 4. Coadministration of magnesium hydroxide with the non‐micronised glibenclamide preparation increased the area under the plasma glibenclamide concentration‐time curve from 0 to 3 h, five‐fold (P less than 0.05), the total area three‐ fold (P less than 0.05) and the peak drug concentration three‐fold (P less than 0.05). The incremental insulin area from 0 to 3 h was increased 35‐fold (P less than 0.05) and the maximum insulin response 10‐fold (P less than 0.05) by magnesium hydroxide. 5. Concomitant ingestion of magnesium hydroxide and non‐micronised glibenclamide may greatly enhance the absorption and efficacy of glibenclamide. The absorption of micronised glibenclamide appears to be only slightly influenced by magnesium hydroxide.
Polymorphisms in oxidative drug metabolism: relationship to food preference.
Authors: Britto MR , McKean HE , Bruckner GG , Wedlund PJ
Published: July 2012

To determine whether a correlation exists between polymorphisms of oxidative drug metabolism and dietary preference, 29 poor metabolizers of dextromethorphan, 18 poor metabolizers of mephenytoin and 134 extensive metabolizers of both drugs were screened for their preferences for various food items. Poor metabolizers of dextromethorphan showed a diminished stated preference for cauliflower and coconut, and poor metabolizers of mephenytoin showed a diminished stated preference for spinach and cabbage.
1‐Methylxanthine derived from theophylline as an in vivo biochemical probe of allopurinol effect.
Authors: Birkett DJ , Miners JO , Day RO
Published: July 2012

The urinary 1‐methyluric acid (1MU) to 1‐methylxanthine (1MX) ratio has been assessed as a biochemical index of oxipurinol effect in vivo in man. Dosing with theophylline was used to produce 1MX as an intermediate metabolite in six healthy volunteers. A sigmoid Emax model was fitted to the data and gave a mean plasma oxipurinol IC50 of 3.0 +/‐ 1.1 mg l‐1, a mean exponent n of 3.4 +/‐ 2.1 and a mean IC90 of 8.5 +/‐ 5.9 mg l‐1. There was marked interindividual variability in the steepness of the plasma oxipurinol concentration response relationship, and in the plasma oxipurinol IC90 values. The study has confirmed the feasibility of using single doses of allopurinol to construct individual plasma oxipurinol concentration‐response curves.
The relative bioavailability of diclofenac with respect to time of administration.
Authors: Mustofa M , Suryawati S , Dwiprahasto I , Santoso B
Published: July 2012

The pharmacokinetics of diclofenac after a single oral dose (50 mg) were studied in 10 healthy adults on two occasions separated by 2 weeks, once in the morning (dose administered at 07.00 h) and once in the evening (dose at 19.00 h). Peak serum drug concentrations as well as the area under the drug concentration‐time curve were significantly less during the night compared with the day (Cmax: 1886 +/‐ s.d 901 vs 2791 +/‐ 1565 ng ml‐1 and AUC: 2807 +/‐ 1376 vs 3681 +/‐ 1986 ng ml‐1 h). However, the time to reach peak concentration (tmax) and the half‐ life of diclofenac (t1/2) were not significantly different on the two occasions. We suggest that the extent of diclofenac absorption is slightly lower following administration in the evening compared with administration in the morning.
Mesalazine release from coated tablets: effect of dietary fibre.
Authors: Riley SA , Tavares IA , Bishai PM , Bennett A , Mani V
Published: July 2012

Delayed‐release mesalazine formulations relay on pH‐dependent coat dissolution to ensure delivery of 5‐aminosalicylic acid (5‐ASA) to the colon. As dietary fibre acidifies the colonic lumen we have studied the effect of fibre supplementation in 10 patients with quiescent colitis. Greater intake of dietary fibre was associated with a decrease in stool pH and an increase in stool frequency and faecal mass. However, the 24 h faecal and urinary excretion of 5‐ASA and N‐acetyl‐5‐ASA was unchanged. The percentage of total faecal ASA excreted as N‐acetyl‐5‐ ASA correlated with whole‐gut transit time, suggesting that prolonged transit may be disadvantageous to patients with colitis as N‐acetyl‐5‐ ASA appears to be inactive.
The drug treatment of atrial fibrillation.
Authors: Channer KS
Published: July 2012

1. Atrial fibrillation is an inefficient cardiac rhythm associated with impaired exercise tolerance, exertional dyspnoea, palpitation and a substantial risk of thromboembolism. 2. The first decision in management is to consider cardioversion which can be achieved in suitable cases electrically, or pharmacologically with a class Ic antiarrhythmic drug like flecainide or propafenone. 3. Prophylaxis in paroxysmal atrial fibrillation is best achieved with a class Ic drug or a class III drug such as sotalol or amiodarone. 4. Control of ventricular rate in chronic atrial fibrillation can be achieved by pharmacological manipulation of the atrioventricular node by digoxin alone, or in combination with the calcium channel blockers verapamil or diltiazem, or beta‐adrenoceptor blockers with intrinsic sympathomimetic activity like pindolol or xamoterol. 5. In view of the considerable risk of thromboembolism in patients with chronic atrial fibrillation anticoagulation or at least treatment with aspirin should be considered.
Phenotypic debrisoquine 4‐hydroxylase activity among extensive metabolizers is unrelated to genotype as determined by the Xba‐I restriction fragment length polymorphism.
Authors: Turgeon J , Evans WE , Relling MV , Wilkinson GR , Roden DM
Published: July 2012

1. The major pathway for 4‐hydroxylation of debrisoquine in man is polymorphic and under genetic control. More than 90% of subjects (extensive metabolizers, EMs) have active debrisoquine 4‐hydroxylase (cytochrome P450IID6) while in the remainder (poor metabolizers, PMs), cytochrome P450IID6 activity is greatly impaired. 2. Within the EM group, cytochrome P450IID6‐mediated metabolism of a range of substrates varies widely. Some of this intra‐phenotype non‐uniformity may be explained by the presence of two subsets of subjects with different genotypes (heterozygotes and homozygotes). 3. Cytochrome P450IID6 substrates have not differentiated between these two genotypes. However, a restriction fragment length polymorphism (RFLP) which identifies mutant alleles of cytochrome P450IID6 locus has been described and can definitively assign genotype in some heterozygous EM subjects. 4. In this study, we used RFLP analysis and encainide as a model substrate to determine if non‐uniformity in cytochrome P450IID6 activity among EMs is related to genotype. We tested the hypothesis that heterozygotes exhibit intermediate metabolic activity and that homozygous dominants exhibit the highest activity. We proposed encainide as a useful substrate for this purpose since cytochrome P450IID6 catalyzes not only its biotransformation to O‐desmethyl encainide (ODE) but also the subsequent metabolism of ODE to 3‐methoxy‐ O‐desmethyl encainide (MODE). 5. A single 50 mg oral dose of encainide was administered to 139 normal volunteers and 14 PMs were identified. Urinary ratios among encainide, ODE and MODE in the remaining 125 EM subjects revealed a wide range of cytochrome P450IID6 activity. However, Southern blotting of genomic DNA digested with XbaI identified obligate heterozygotes in both extremes of all ratio distributions.(ABSTRACT TRUNCATED AT 250 WORDS)
Alpha 1‐acid glycoprotein (orosomucoid) and plasma protein binding of quinine in falciparum malaria.
Authors: Silamut K , Molunto P , Ho M , Davis TM , White NJ
Published: July 2012

1. Plasma concentrations of alpha 1‐acid glycoprotein (AAG) and plasma protein binding of quinine were measured in 97 Thai adults with acute falciparum malaria. There was a linear relationship between log AAG and percentage quinine binding (r = 0.71, P less than 0.001) in vivo, which was similar to that observed in vitro; the slopes and intercepts of the regression lines at AAG concentrations of 1 g l‐1 were −8.94 and −8.41, and 7.2% and 10.9%, respectively. 2. Hill plots from these data suggest a single high affinity quinine binding site on each molecule of AAG. 3. Plasma AAG concentrations were consistently raised in acute malaria, and were higher in patients with cerebral malaria [2.03 (0.51) g l‐1, mean (s.d.)], and conscious patients with severe malaria [1.93 (0.53) g l‐1] than in patients with uncomplicated infections [1.55 (0.58) g l‐ 1], P = 0.008. Plasma protein binding of quinine was correspondingly higher and thus the proportion of free drug was lower in the severe groups; 5.5 (2.4)% compared with 7.2 (1.9)%, P = 0.03. 4. Following recovery from malaria, plasma AAG concentrations fell by an estimated 0.05 g l‐1 day‐1 to levels that were approximately half (median 45%) the admission value at 28 days. 5. AAG is the principal binding protein for quinine in plasma. Changes in plasma concentrations of this acute phase reactant account for the increased plasma protein binding of quinine in acute malaria.
Effect of Plasmodium falciparum malaria infection on the plasma concentration of alpha 1‐acid glycoprotein and the binding of quinine in Malawian children.
Authors: Mansor SM , Molyneux ME , Taylor TE , Ward SA , Wirima JJ , Edwards G
Published: July 2012

1. We have measured plasma concentrations of alpha 1‐acid glycoprotein (AGP) in 18 healthy children and 85 children with falciparum malaria in Malawi. In addition, we determined the degree of protein binding of quinine (QN) in the plasma of 52 of the patients and each of the healthy controls. 2. The mean plasma AGP concentration was higher in patients than in controls (P less than 0.0001) and remained elevated 3 weeks after complete resolution of malaria infection. 3. The mean unbound QN fraction was significantly less (P less than 0.00001) in patients with malaria (0.128 +/‐ 0.037) than in controls (0.193 +/‐ 0.051) and significantly higher (P = 0.02) in convalescence (0.153 +/‐ 0.067) than during acute illness. 4. There were highly significant negative correlations between plasma AGP concentration and the free QN fraction in spiked plasma samples (r = −0.534, P less than 0.0001, n = 93) and in clinical samples (r = −0.484, P less than 0.00001, n = 225). There was a significant positive correlation between plasma concentrations of AGP and another acute phase reactant, C reactive protein (P less than 0.001).
The effects of captopril vs atenolol on memory, information processing and mood: a double‐blind crossover study.
Authors: Deary IJ , Capewell S , Hajducka C , Muir AL
Published: July 2012

1. Measures of memory, information processing ability, mood states and trait anxiety were estimated in a double‐blind, double‐dummy, randomised cross‐over trial which compared the effects of atenolol (50 or 100 mg once daily) and captopril (25 or 50 mg twice daily), each taken for 6 weeks. Eighteen patients with mild to moderately severe hypertension were included. 2. There were no significant differences in systolic or diastolic blood pressure reduction between the two drugs. Pulse rate was slower after atenolol treatment (P less than 0.05). 3. Patients undertook practice on the psychological test battery prior to the treatment phases of the study in order to minimise practice effects. 4. There were no significant differences between the treatments on any of the measures of memory or information processing. 5. Patients reported feeling less anxious during treatment with atenolol (P = 0.02). 6. There were no differences between the drugs in their cognitive effects. The present study has the advantages of using an extensive battery of standard tests in a group of well‐practised patients. The decreased anxiety reported with atenolol treatment may have clinical value and probably reflects the well‐known effect of beta‐ adrenoceptor antagonist drugs on the somatic symptoms of situational anxiety.
Remoxipride: pharmacokinetics and effect on plasma prolactin.
Authors: Movin‐Osswald G , Hammarlund‐Udenaes M
Published: July 2012

1. The pharmacokinetics of remoxipride, a new neuroleptic, were investigated in 15 healthy subjects after an intravenous infusion of 50 mg, an intramuscular injection of 100 mg and after administration of two immediate release capsules (A and B), each of 100 mg, in a cross‐ over study. The effect of the different remoxipride formulations on plasma prolactin concentrations was also studied. 2. The volume of distribution of remoxipride was 0.65 +/‐ 0.11 kg‐1 (mean +/‐ s.d.). Total plasma clearance was 119 +/‐ 39 ml min‐1, of which 31 +/‐ 13 ml min‐1 was due to renal clearance. The absolute bioavailability after the i.m. and oral formulations was greater than 90%, indicating a small extent of first‐pass metabolism. The mean elimination half‐life was 4.8 +/‐ 1.4 h. The unbound fraction of remoxipride and the blood/plasma ratio were 0.19 +/‐ 0.03 and 0.64 +/‐ 0.06, respectively. 3. The transient increase in plasma prolactin was similar after all four remoxipride administrations and independent of the given dose.
The pharmacokinetics of dermatan sulphate MF701 in healthy human volunteers.
Authors: Dawes J , McLaren M , Forbes C , Belch JJ , Lane DA , Bray B , McEwen J , Houin G , Gianese F
Published: July 2012

1. The pharmacokinetics of dermatan sulphate MF701 were studied in 12 healthy males after administration of single intravenous bolus (200 mg), intramuscular (100 and 300 mg) and oral (1 g) doses. The study was conducted according to a within‐subject crossover design in two paired blocks. 2. Plasma drug concentrations were measured using a competitive binding assay and a range of biological activity assays, including a sensitive catalysed thrombin inhibition test. 3. Following intravenous administration, plasma concentrations of dermatan sulphate determined by competitive binding assay were described by a two‐compartment open model with an initial t1/2, in of 0.6 h and a t1/2,z of 7.5 h. Biological activity assays were insufficiently sensitive to detect the second phase, and therefore yielded apparent monoexponential kinetics. 4. After intramuscular injection the apparent bioavailability of dermatan sulphate was 16‐20%. Plasma drug concentrations increased in proportion to dose when measured by competitive binding assay. Low concentrations persisted for more than 24 h at the higher dose, and these may prove therapeutically relevant on chronic administration. 5. We confirm that dermatan sulphate is the only glycosaminoglycan known to generate significant plasma concentrations following oral administration. Oral bioavailability was estimated to be 7%.
Anti‐arrhythmic properties of the alpha‐adrenoceptor blocking drug indoramin.
Authors: James MA , Jones JV
Published: July 2012

1. The anti‐arrhythmic properties of the alpha‐adrenoceptor blocking drug indoramin were compared with the effect of disopyramide and placebo in a randomised, single‐blind, cross‐over study. Two doses of indoramin were tested, 25 mg and 50 mg and the dose of disopyramide was 150 mg. All treatments were administered three times daily. 2. Forty patients with benign ventricular arrhythmia were studied. 3. Assessment was by 24 h ambulatory electrocardiography at entry and at the end of each 2 week treatment period. 4. Indoramin was found to have a significant anti‐arrhythmic effect compared with placebo, but only at the higher dose tested. 5. The anti‐arrhythmic effect was less than that achieved with disopyramide. 6. The mechanism for this anti‐ arrhythmic effect is unknown but these results suggest that alpha‐ adrenoceptor blockade may merit further attention as an anti‐arrhythmic treatment.
The interactions between nisoldipine and two beta‐adrenoceptor antagonists‐atenolol and propranolol.
Authors: Elliott HL , Meredith PA , McNally C , Reid JL
Published: July 2012

1. The interactions between the dihydropyridine calcium antagonist nisoldipine and two beta‐adrenoceptor blocker drugs (atenolol and propranolol) were investigated in two groups of healthy normotensive subjects. 2. The steady state plasma concentrations of both beta‐ adrenoceptor blockers were significantly altered by the addition of nisoldipine: for propranolol there were significant increases in Cmax, by about 50%, and in AUC by about 30% and for atenolol there was a significant increase in Cmax, by about 20%. 3. The addition of nisoldipine was also associated with significant changes in apparent liver blood flow (measured by indocyanine green clearance) from 1.4 to 2.4 l min‐1 in the atenolol group and from 1.3 to 2.3 l min‐1 in the propranolol group. 4. Both nisoldipine‐beta‐adrenoceptor blocker combinations were associated with small enhanced blood pressure reductions e.g. from 104/60 with atenolol alone to 98/50 mm Hg with the combination but there was no alteration to the extent of beta‐ adrenoceptor blockade (as assessed by bicycle ergometry). 5. This pharmacodynamic profile in healthy normotensives is consistent with the known therapeutic efficacy of such combination treatments in patients with hypertension and angina. 6. It is suggested that there is a pharmacokinetic component to the efficacy of this type of combination, perhaps reflecting vasodilator‐induced changes in drug absorption and/or hepatic extraction.
Pharmacokinetics of molsidomine and its active metabolite, linsidomine, in patients with liver cirrhosis.
Authors: Spreux‐Varoquaux O , Doll J , Dutot C , Grandjean N , Cordonnier P , Pays M , Andrieu J , Advenier C
Published: July 2012

The pharmacokinetics of molsidomine were investigated in six healthy volunteers and in seven patients with alcoholic cirrhosis. After a 2 mg oral dose, molsidomine elimination half‐life was prolonged in cirrhotic patients (13.1 +/‐ 10.0 h vs 1.2 +/‐ 0.2 h, P less than 0.01) because of a decrease in its apparent plasma clearance (CL/F) (39.8 +/‐ 31.9 ml h‐1 kg‐1 in patients with cirrhosis vs 590 +/‐ 73 ml h‐1 kg‐1 in volunteers). The elimination half‐life of the active metabolite, linsidomine (SIN‐1) was also prolonged in cirrhotic patients (7.5 +/‐ 5.4 h vs 1.0 +/‐ 0.19 h, P less than 0.05). The AUC values of both molsidomine and linsidomine were increased in the cirrhotic group, but the increase in the former was considerably greater than in the latter as shown by the significant decrease of the ratio AUClinsidomine/AUCmolsidomine × 100 (4.5 +/‐ 6.1 in cirrhotic patients vs 23.5 +/‐ 3.4 in healthy volunteers, P less than 0.001). These results suggest that liver cirrhosis profoundly alters the pharmacokinetics and metabolism of molsidomine.
Medication compliance and serum lipid changes in the Helsinki Heart Study.
Authors: Maenpaa H , Heinonen OP , Manninen V
Published: July 2012

1. To control the bias caused by poor medication compliance in the Helsinki Heart Study three methods were used to measure medication compliance during the total 5 years follow up time: continuous capsule counting, semi‐annual urine gemfibrozil analysis and a new method, the digoxin marker at the end of the third and fifth study years. 2. The serum lipid responses to gemfibrozil treatment varied linearly with the level of medication compliance, e.g. the mean change in serum total cholesterol was −11.4% among those whose apparent capsule consumption was greater than or equal to 90% of the scheduled dosage, −11.2% among those who had greater than or equal to 90% positive gemfibrozil analyses and −11.4% among those with good compliance according to both digoxin marker measurements. In contrast the mean serum cholesterol change was only −0.02% if the mean daily capsule count was less than 50%, −1.7% with fewer than 50% positive gemfibrozil analyses and −1.1% if the result was poor in both digoxin marker measurements. 3. Combining the different method findings revealed that the cholesterol changes tended to be small in those groups who had poor compliance classification measured by any of the methods, even if the other results showed good compliance.
Effects of pravastatin and cholestyramine on gonadal and adrenal steroid production in familial hypercholesterolaemia.
Authors: Jay RH , Sturley RH , Stirling C , McGarrigle HH , Katz M , Reckless JP , Betteridge DJ
Published: July 2012

1. Adrenal and gonadal steroids are derived from cholesterol, which may be derived from plasma lipoproteins or de novo synthesis. 2. Inhibitors of 3‐hydroxy‐3‐methylglutaryl coenzyme A (HMG CoA) reductase, the rate limiting enzyme in cholesterol synthesis, may therefore affect steroidogenesis when used as lipid‐lowering agents in hypercholesterolaemia. 3. We have assessed gonadal and adrenal function in subjects with heterozygous familial hypercholesterolaemia (FH) before and after 12 weeks treatment with pravastatin, an HMG CoA reductase inhibitor, or cholestyramine as a control in maximal recommended doses. 4. No changes in measured plasma cortisol responses to tetracosactrin injection were seen in 11 patients on cholestyramine or 12 on pravastatin. 5. No changes were seen in testosterone, sex hormone binding globulin, androstenedione, dehydroepiandrosterone sulphate, oestradiol or 17 alpha‐hydroxyprogesterone. 6. Gonadotrophin levels were unaffected in 10 male subjects on cholestyramine and 7 on pravastatin. 7. Measurements on a subset of subjects continuing to 24 weeks treatment also showed no changes. 8. No adverse effect on adrenal or gonadal function could be demonstrated in patients with familial hypercholesterolaemia on maximal recommended doses of pravastatin.
The effects of a 5‐HT2 receptor antagonist (ICI 169,369) on changes in waking EEG, pupillary responses and state of arousal in human volunteers.
Authors: Millson DS , Haworth SJ , Rushton A , Wilkinson D , Hobson S , Harry J
Published: July 2012

1. ICI 169,369 (2‐(2‐dimethylamino ethylthio)‐3‐phenyl quinoline) is a potent selective competitive antagonist of the 5‐HT2 receptor in animal models. Effects of ICI 169,369 as single oral doses (80 and 120 mg) separated by 1 week, on the power spectrum of waking EEG, dark adapted pupil responses and sedation score, were studied in a double‐blind, placebo controlled, randomised cross over within subject comparison, in six healthy male volunteers. 2. Pupillary responses were measured using a portable infrared pupillometer following 15 min dark adaptation, assessing resting vertical pupil diameter (RPD), light constricted diameter (MPD) and recovered final diameter (FPD) at the end of a 3 s measurement cycle. 3. Both doses of ICI 169,369 produced a mean 36% (range 10‐54%) decrease in log 10 power of the waking EEG alpha activity with eyes closed (P less than 0.02), and mean 38% (range 2‐ 86%) increase in theta activity at 2 h compared with placebo. 4. Both 80 and 120 mg doses of ICI 169,369 reduced RPD by approximately 30% from a predose value of 6.25 mm (+/‐ 0.87; 95% CI) and from placebo values 6.41 mm (+/‐ 1.06) and 7.48 mm (+/‐ 1.49) at 3 and 5 h after dosing. MPD was reduced by 50% with the 120 mg dose at 5 h after dosing (placebo 5.2 mm; ICI 169,369 2.7 mm; P less than 0.05). FPD was significantly reduced (P less than 0.01) by both doses at 3 h after dosing.(ABSTRACT TRUNCATED AT 250 WORDS)
The effects of two anti‐vertigo drugs (betahistine and prochlorperazine) on driving skills.
Authors: Betts T , Harris D , Gadd E
Published: July 2012

1. The effects of betahistine 72 mg three times daily, prochlorperazine 5 mg three times daily and placebo taken for 3 days before testing were compared on two actual driving tasks (weaving and gap estimation) and two psychomotor tasks (reaction time and kinetic visual acuity) in normal subjects in a double‐blind prospectively randomised cross‐over study. 2. The psychomotor effects of betahistine could not be distinguished from those of placebo. 3. Prochlorperazine impaired driving performance causing increased carelessness and slowing on the weaving test. 4. There was little subjective appreciation of impairment whilst taking prochlorperazine.