bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystal structure of Bombyx mori nucleopolyhedrovirus ORF75 reveals a pseudo-dimer of thiol oxidase domains with a putative substrate-binding pocket
Authors: Hou Yong , Xia Qingyou , Yuan Y. Adam
Published: July 2012

Bombyx mori nucleopolyhedrovirus (BmNPV) triggers the global shutdown of host silkworm gene expression and protein synthesis approximately 12–18 h post-infection. Genome sequence analysis suggests that BmNPV ORF75 could be a flavin adenine dinucleotide (FAD)-linked thiol oxidase essential for virion assembly and virus propagation. Here, we report the crystal structure of BmNPV ORF75 at 2.1 Å (0.21 nm). The structure of BmNPV ORF75 resembles that of the thiol oxidase domain of human quiescin thiol oxidase (QSOX), displaying a pseudo-dimer of canonical and non-canonical thiol oxidase domains. However, BmNPV ORF75 is further dimerized by its C-terminal canonical thiol oxidase domain. Within the unique quaternary structural arrangement, the FAD-binding pocket and the characteristic CXXC motif from each monomer is 35 Å (3.5 nm) away from that of its corresponding molecule, which suggests that BmNPV ORF75 might adopt a deviant mechanism from that of QSOX to catalyse disulfide bond formation. Our thiol oxidase activity assay on the point mutations of the conserved residues participating in FAD recognition reveals an aromatic cage next to the FAD isoalloxazine moiety for substrate binding. These data suggest that the thiol oxidase activity of BmNPV ORF75 could be critical to catalyse the formation of the disulfide bonds of certain BmNPV proteins essential for BmNPV virion assembly.
Isolation and characterization of a bacteriophage F20 virulent to Enterobacter aerogenes
Authors: Mishra Charitra Kumar , Choi Tae Jin , Kang Sun Chul
Published: July 2012

An aquatic phage, designated F20, was characterized and its physico-chemical characteristics studied. F20 was specifically virulent to only two strains of Enterobacter
aerogenes (ATCC 13048 and the multi-drug-resistant strain K113) among other species tested (n = 15). It was classified in the family Siphoviridae of T1-like viruses and contained a linear dsDNA genome estimated to be 51.5 kbp enclosed by an isometric capsid of 50±2 nm in diameter and a tail of 150±3 nm in length. F20 was able to survive in a broad pH range between 4 and 11, showed potential for future animal trials using oral solution and resisted chloroform and ethanol. It exhibited remarkable stability between room temperature and 70 °C for up to 150 min, and even up to 6 months at room temperature. Knowledge of this phage belonging to the widespread T1-like viruses might be helpful for adopting therapeutic strategies against E. aerogenes.
Redetermination of tetramethyl tetrathiafulvalene-2,3,6,7-tetracarboxylate
Authors: Katzsch Felix , Weber Edwin
Published: July 2012

An improved crystal structure of the title compound, C14H12O8S4, is reported. The structure, previously solved using the heavy-atom method (R= 7.1%), has now been solved using direct methods. Due to the improved quality of the data set anRvalue of 2.06% could be achieved. In the crystal, C—H...S and C—H...O contacts link the molecules.
2,2-Diethyl 3,4-dimethyl 5-(4-cyanophenyl)pyrrolidine-2,2,3,4-tetracarboxylate
Authors: He Long
Published: July 2012

The title compound, C21H24N2O8, was synthesized by a 1,3-dipolar cycloaddition reaction of dimethyl fumarate, diethyl 2-aminomalonate and 4-cyanobenzaldehyde. Both methyl ester groups display atransconfiguration and the pyrrolidine ring possesses an envelope conformation, with the C atom in the 3-position as the flap. In the crystal, N—H...N hydrogen bonds and weak C—H...O interactions occur.
N-[(2Z,4Z)-4-Benzylidene-6-chloro-1,4-dihydropyrido[2,3-d][1,3]thiazin-2-ylidene]benzamide
Authors: Fernandes Manuel A. , Levendis Demetrius C. , Reid David H.
Published: July 2012

In the crystal structure of the title compound, C21H14ClN3OS, molecules assemble into inversion dimersviapairs of N—H...N hydrogen bonds involving the N—H hydrogen of the thiazine ring and the N atom of the pyridine ring. There is a close intramolecular contact [2.570 (2) Å] between the carbonyl O atom of the benzamide and the S atom of the puckered thiazine ring. The title compound can exist in two tautomeric forms,viz.amino or imino. The observed structure is compatible with the imino form on the basis of observed residual electron density and the two C—N bond lengths of 1.308 (2) and 1.353 (2) Å.
(Ethylenediamine-κ2N,N′)bis(perchlorato-κO)bis(pyridine-κN)copper(II)
Authors: Ourari Ali , Bounab Nawel , Bouacida Sofiane , Aggoun Djouhra
Published: July 2012

In the title compound, [Cu(ClO4)2(C2H8N2)(C5H5N)2], the CuIIcation is located on a twofold rotation axis and is coordinated by four N and two O atoms in a tetragonally distorted octahedral geometry. The crystal packing can be described as ClO4tetrahedra and CuN4O2octahedra alternating in a zigzag fashion along thecaxis. The structure is stabilized by intermolecular N—H...O and C—H...O hydrogen bonds, as well as π–π interactions [centroid–centroid distance = 3.7179 (15) Å].
(S,E)-3-[(2-Hydroxybenzylidene)amino]-2-(2-hydroxyphenyl)-2,3-dihydroquinazolin-4(1H)-one
Authors: Tinguiano Daniel , Sy Adama , Thiam Ibrahima Elhadj , Gaye Mohamed , Retailleau Pascal
Published: July 2012

In the title compound, C21H17N3O3, the dihydroquinazoline ring adopts a screw-boat conformation and its stereogenic C atom has anSconfiguration. The dihedral angle between the mean planes of the two hydroxyphenyl rings is 86.61 (12)°. The amino H atom forms an intramolecular hydrogen bond with a phenol O atom, while the hydrazine N atom acts as an acceptor for the H atom of the other phenol group. In the crystal, O—H...N and O—H...O hydrogen bonds and weak C—H...centroid(π-ring) intermolecular interactions are observed, forming chains along [1-10] and [110].
5-Iodo-2-methyl-3-(4-methylphenylsulfinyl)-1-benzofuran
Authors: Choi Hong Dae , Seo Pil Ja , Lee Uk
Published: July 2012

In the title compound, C16H13IO2S, the 4-methylphenyl ring makes a dihedral angle of 88.36 (7)° with the mean plane [r.m.s. deviation = 0.006 (2) Å] of the benzofuran fragment. In the crystal, molecules are linked by weak C—H...O hydrogen bonds and an I...O contact [3.103 (2) Å]. The crystal structure also exhibits slipped π–π interactions between the benzene and furan rings of neighbouring molecules [centroid–centroid distance = 3.659 (2) Å].
2,2′-(Piperazine-1,4-diyl)diethanaminium bis(2-hydroxybenzoate)
Authors: Cukrowski Ignacy , Adeyinka Adedapo S. , Liles David C.
Published: July 2012

The asymmetric unit of the title salt, C8H22N42+·2C7H5O3−, comprises half a 2,2′-(piperazine-1,4-diyl)diethanaminium dication plus a 2-hydroxybenzoate anion. In the crystal, the anions and cations are linked by N—H...O and O—H...O hydrogen bonds to form infinite two-dimensional networks parallel with theaunit-cell face. The conformation adopted by the cation in the crystal is very similar to that adopted by the same cation in the structures of the nitrate and tetrahydrogen pentaborate salts.
3-Acetyl-1-(2,3-dichlorophenyl)thiourea
Authors: Gowda B. Thimme , Foro Sabine , Kumar Sharatha
Published: July 2012

In the crystal structure of the title compound, C9H8Cl2N2OS, there are two molecules in the asymmetric unit which are connected by a pair of N—H...S hydrogen bonds. An intramolecular N—H...O hydrogen bond stabilizes the molecular conformation of each molecule.
Methyl 2,6-diphenyl-1-p-tolyl-4-(p-tolylamino)-1,2,5,6-tetrahydropyridine-3-carboxylate
Authors: Venugopala K. N. , Nayak Susanta K. , Odhav Bharti
Published: July 2012

In the title compound, C33H32N2O2, the tetrahydropyridine ring adopts a boat conformation with the carbonyl group in ans-cisconformation with respect to the C=C bond of the six-membered tetrahydropyridine ring. The molecular conformation is stabilized by intramolecular N—H...O, C—H...O and C—H...π interactions. Formation of centrosymmetric head-to-head dimers is observed through pairwise intermolecular N—H...O hydrogen bonds. Additional weak C—H...O and C—H...π interactions stabilize the three-dimensional molecular assembly.
The distribution of quinidine in human blood.
Authors: Hughes IE , Ilett KF , Jellett LB
Published: July 2012

The uptake of quinidine by washed human red blood cells from isotonic buffer solution (pH 7.4) occurred rapidly and was proportional to the concentration of drug in buffer. A constant red cell/buffer partition ratio of 4.16+/‐0.15 s.e. mean was found. 2. Uptake from buffer solution was not affected by temperature or ouabain or by gassing with nitrogen or carbon monoxide and there was no evidence of saturability. Drug in red blood cells was associated largely with the cell contents (94.4+/‐1.5% s.e. mean) following partition. 3 Plasma reduced the uptake of quinidine so that a red cell/plasma partition ratio of 0.82+/‐ 0.09 s.e. mean was found. 4 Alteration of plasma binding by dilution of plasma with buffer showed that uptake was proportional to free drug concentration. 5 The possibility of red cell uptake of drug should be included in any considerations concerning pharmacokinetic aspects of drug action in the body.
The effect of age on plasma levels of propranolol and practolol in man.
Authors: Castleden CM , Kaye CM , Parsons RL
Published: July 2012

1. Plasma levels of propranolol and practolol were measured in groups of elderly and young subjects, after the oral administration of propranolol (40 mg) and practolol (200 mg) on separate occasions. 2. At all sampling times the mean plasma propranolol level in the group of elderly subjects was substantially greater than the corresponding level in the group of young subjects, there being a significant difference between the two, and a fourfold difference in the mean peak levels. 3. After practolol, there was no significant difference between the mean plasma concentrations of the drug in the two groups for the first 2 hours. Subsequently, the mean plasma levels in the group of elderly subjects were somewhat higher than the corresponding levels in the young group, the differences between the two reaching significance. 4. It is suggested that there is a need to substantially reduce the dose of propranolol given to elderly patients. With practolol, however, no reduction is necessary providing renal function is normal for the patient's age.
Isoprenaline antagonism of cardioselective beta‐adrenergic receptor blocking agents on human and rat adipocytes.
Authors: Harms HH , Van der Meer J
Published: July 2012

1. The beta‐adrenergic blocking potencies of practolol, ICI 66082, tolamolol, acebutolol, H 93/26, H 87/07, pindolol and Ro 3‐4787 were compared with that of propranolol, on human and rat adipocytes. 2. A good correlation was found between the potencies on adipocytes of the two species but not between our results and literature data on antagonism of isopernaline tachycardia in the anaesthetized cat. 3. The results indicate that differences between adrenergic beta‐receptors in heart and adipose tissue may be detected using cardioselective beta‐ adrenergic receptor blocking agents.
Pralidoxime mesylate absorption and heart rate response to atropine sulphate following intramuscular administration of solution mixtures.
Authors: Holland P , Parkes DC , White RG
Published: July 2012

1. The oxime pralidoxime mesylate (P2S) and atropine sulphate, alone and mixed, have been administered intramuscularly to forty‐four human subjects. Doses of 750 mg and 500 mg P2S and 2.0 mg atropine sulphate were used. 2. The presence of P2S had no significant influence, as judged by effect on heart rate, on the absorption of atropine although there was a tendency for atropine to exert its effects more rapidly when administered mixed with P2S. 3. No significant difference in the rate of uptake of P2S as judged by plasma levels following injection, between a combined (plus atropines) and single (P2S alone) intramuscular injection was found.
Blood pressure responses to noradrenaline and dopamine infusions in Parkinson's disease and the Shy‐Drager syndrome.
Authors: Wilcox CS , Aminoff MJ
Published: July 2012

Studies of pulse rate and blood pressure responses to graded intravenous infusions of noradrenaline and dopamine were performed on five patients with Parkinson's disease, five with the Shy‐Drager syndrome and seven healthy subject. Cardiovascular reflex responses to standing and to the Valsalva manoeuvre were found to be preserved in all patients with Parkinson's disease but to be grossly defective or absent in all with the Shy‐Drager syndrome. Each subject received separate intravenous infusions of L‐noradrenaline and dopamine, delivered at increasing rates, until a 30% rise in systolic blood pressure was achieved. Heart rate decreased during pressor responses to noradrenaline in control subjects and patients with Parkinson's disease, but increased in those with the Shy‐Drager syndrome. Heart rate increased during pressor responses to dopamine in all subjects. Compared to control subjects supersensitivity to noradrenaline was observed both in patients with Parkinson's disease and, to a greater extent, in those with the Shy‐Drager syndrome. Subsensitivity to dopamine was observed in patients with Parkinson's disease, but supersensitivity in those with the Shy‐Drager syndrome.
The effect of nisoxetine (Lilly compound 94939), a potential antidepressant, on biogenic amine uptake in man.
Authors: Lemberger L , Terman S , Rowe H , Billings R
Published: July 2012

Preclinical studies with nisoxetine (Compound 94939) (3‐[o‐ Methoxyphenoxy]‐N‐methyl‐3‐phenylpropylamine HCl) had shown it to have antidepressant properties and to be almost devoid of anticholinergic activity and depressant effects on cardiac conduction (in contrast to the commonly used tricyclic antidepressants from which nisoxetine significantly differs in structure). Placebo and nisoxetine (10‐20 mg b.d. for 7 days) were administered to normal volunteers in a single‐ bind crossover study. Adverse side effects were minimal. There were no significant changes in heart rate or blood pressure seen when no other drugs were given. The effect of nisoxetine on uptake of biogenic amines was utilized to study its mechanism of action. The transient rise in blood pressure seen after an intravenous bolus of tyramine decreased by one‐half to two‐thirds while the rise in blood pressure upon continuous noradrenaline infusion was enhanced some two‐to eight‐fold. Both effects occurred after on dose and were greater with larger doses and chronic administration. In vitro, nisoxetine inhibits 5‐HT uptake into platelets. However, platelets harvested from subjects receiving chronic nisoxetine administration did accumulate 5‐HT. Plasma concentration of nisoxetine in these individuals was shown to be lower than that needed to block 5‐HT uptake. We concluded that nisoxetine, in safe doses, specifically increased the sensitivity of noradrenaline and decreased tyramine responsiveness, presumably by blocking uptake at the axonal membrane. In contrast, in these clinical doses it had virtually no effect on 5‐HT uptake into platelets.
Lithium and the antidiuretic hormone.
Authors: MacNeil S , Jennings G , Eastwood PR , Paschalis C , Jenner FA
Published: July 2012

The effect of lithium on the urine concentrating response to antidiuretic hormone (ADH) and the excretion of ADH has been studied in rats and man. The maximum urine osmolarity following 18 h dehydration and Pitressin (5 u) was decreased in three out of four patients during lithium treatment compared to their response to the same test in the absence of lithium. In a fifth patient, tested only during lithium treatment, the urine remained hypotonic to plasma throughout this test. Lithium increased the excretion of ADH in non‐polyuric patients from 9‐ 22 mu/24 h in the absence of lithium to 36‐202 mu/24 ‐ during lithium treatment. In four patients with lithium‐induced polyuria, a diuretic acting on the distal tubules, clorexolone, reduced the polyuria. Lithium increased urine volume and the excretion of ADH in four rats receiving lithium in their diet. The response to exogenous ADH was decreased during lithium administration.
Methods for collecting individual components of mixed saliva: the relevance to clinical pharmacology.
Authors: Stephen KW , Speirs CF
Published: July 2012

Methods are described for collecting constituents of mixed saliva, viz. parotid, submandibular, monor gland and sublingual saliva and gingival fluid. Literature is cited which showed that using these techniques, few antibiotics could be found in mixed saliva or its main components but all were detected in gingival fluid. Rifamicin and clindamycin were found in all components.
Factors affecting drug binding in plasma of elderly patients.
Authors: Wallace S , Whiting B
Published: July 2012

The binding of salicylate, sulphadiazine and phenylbutazone to plasma proteins has been studied in young and elderly subjects. Elderly patients had significantly reduced concentrations of plasma albumin, compared with subjects under 40 years of age. Sifnificant increases in free levels of all three drugs were found in elderly patients receiving multiple drug therapy, and a correlation obtained with the number of drugs being taken. It is suggested that because of their low albumin levels, elderly patients may be more susceptible to the effects of multiple drug therapy on drug binding. The clinical implications of these observations are discussed.
A comparison of slow release with conventional oxprenolol: plasma concentrations and clinical effects.
Authors: West MJ , Kendall MJ , Mitchard M , Faragher EB
Published: July 2012

1 Plasma concentrations of oxprenolol have been compared in six healthy volunteers after 80 and 160 mg doses of a new slow release (SR) oxprenolol preparation, after an 80 ng dose of conventional oxprenolol (CO), and after the second of two 80 mg doses of conventional oxprenolol given 12 h apart. Basal pulse rates and blood pressures, and pulse rates before and after a standard exercise test have been compared after the four active treatments and after a placebo. 2 Peak plasma concentrations of oxprenolol attained after 160 mg of the slow release preparation were similar to the peak concentrations after the single 80 mg dose of conventional oxprenolol. Higher concentrations, however, persisted for much longer after the slow release preparations than after the conventional preparations. 3 Neither oxprenolol formulation had any effect on resting pulse rate or blood pressure in normotensive volunteers. 4 Comparison with placebo showed that the single dose of the conventional oxprenolol produced a significant reduction in exercise induced tachycardia for 8 h whereas the high dose of the slow release preparation produced a similar reduction which lasted for at least 14 hours.
Pharmacokinetics of indoramin in man.
Authors: Draffan GH , Lewis PJ , Firmin JL , Jordan TW , Dollery CT
Published: July 2012

1 The fate of oral and intravenous indoramin has been studied after single doses in man using the 14C labelled drug. Plasma concentrations of indoramin have been determined during chronic oral antihypertensive therapy employing a stable isotope dilution assay. 2 Following singleoral dosing the drug is well absorbed and extensively metabolised. Faecal excretion in 72 h accounts for 46% of the administered radioactivity of which approximately 4% is associated with indoramin. Less than 2% of the radioactivity in urine is accountable as the concentration of total metabolites. Peak plasma levels both of drug and metabolites occur 1‐2 h after dosing, the maximal lowering of blood pressure occurring at this time. 3 The clearance of indoramin, determined after intravenous administration is of the same order as liver blood flow. In the isolated perfused rat liver, the extraction ratio is 0.98.
Modification by diazepam or thioridazine of the psychomotor skills related to driving: a subacute trial in neurotic out‐patients.
Authors: Saario I , Linnoila M , Mattila MJ
Published: July 2012

Forty‐five out‐patients with clinically manifested anxiety were tested in order to study the effects of 2 weeks' treatment with placebo, diazepam (5‐10 mg three times daily) or thioridazine (25‐50 mg three times daily) on their psychomotor skills related to driving. When compared with placebo, diazepam increased the number of mistakes in reaction and co‐ordination tests and also decreased ability to discriminate the fusion of flickering light. When compared to other groups, reactive and co‐ordinative skills were more impaired in patients treated with thioridazine which also impaired divided attention. Aubjectively thioridazine was not experienced as effective an anxiolytic as diazepam.
The effect on blood pressure of beta‐adrenoceptor blocking drugs administered once daily and their duration of action when therapy is ceased.
Authors: Wilson M , Morgan G , Morgan T
Published: July 2012

The control of blood pressure achieved was similar whether pindolol or propranolol was given once or three times daily. When the drugs were ceased the antihypertensive effect lasted for longer than 24 h. There was no rebound hypertension. The full effect of the drug on blood pressure was seen within 24 h of its recommencement. Changes in blood pressure, pulse rate, and plasma renin activity occurred but these were not considered to be causally related. The response of plasma renin activity to posture was ablated when the patients were receiving beta‐ adrenoceptor blocking drugs.
Effect of amantadine on drug‐induced parkisonism: relationship between plasma levels and effect.
Authors: Pacifici GM , Nardini M , Ferrari P , Latini R , Fieschi C , Morselli PL
Published: July 2012

Amantadine, administered at a dose of 200 mg/day, antagonized the extapyramidal symptomatology induced by neuroleptic drugs in fifteen psychiatric patients. Steady‐state levels were reached within 4‐7 days of treatment. Individual plasma levels ranged from 200‐900 ng/ml. Apparent plasma half‐lives varied from 10‐28.5 h with an apparent VD of 200‐400 litres. A significant relationship was found between the plasma levels of amantadine and the effects on the extrapyramidal symptomatology. The data suggest a direct effect of amantadine on dopaminergic receptors.
Clinical pharmacokinetic studies of perphenazine.
Authors: Hansen Eggert C , Christensen Rosted T , Elley J , Hansen Bolvig L , Kragh‐ Sorensen P , Larsen NE , Naestoft J , Hvidberg EF
Published: July 2012

A gas‐chromatographic method was used for the study in man of the kinetics of perphenazine (PPZ) and its sulphoxide metabolite (PPZ‐SO). Various forms of PPZ administration were applied in eighteen schizophrenic patients and four healthy volunteers. Following an i.v. dose of 5 or 6 mg a considerable fluctuation in the plasma concentration was noted before the exponential elimination phase. The average terminal half‐life of PPZ was approximately 9.5 hours. PPZ‐SO showed up quickly but in low concentrations. After an oral dose of 6 mg no PPZ was detected in plasma and PPZ‐SO only as traces. During continuous oral medication, 12 mg three times daily, a low systemic availability and a high PPZ‐SO/PPZ ratio was found suggesting a marked first pass effect. PPZ‐enanthate given i.m. fortnightly resulted in PPZ‐ levels comparable to those seen after continuous oral medication, but PPZ‐SO concentration were much lower. No accumulation was observed. The systemic clearance rate (average approximately 100 1/h) was the same after PPZ‐enanthate i.m. and PPZ i.v., but varied three‐fold individually. Side effects were mostly, but not always, registered concomitant with high plasma levels of PPZ.
Effects of aspirin and prostaglandin E2 on secondary phase aggregation responses of schizophrenic patients treated with chlorpromazine.
Authors: Boullin DJ , Orr MW
Published: July 2012

We investigated the effects of oral aspirin 900 mg upon the platelet aggregation responses to 5‐hydroxytryptamine, dopamine or N‐dimethyl dopamine in schizophrenic patients chronically treated with chlorpromazine. Most subjects showed enchanced aggregation responses (that is appearance of secondary phase aggregation) to these agents prior to aspirin administration. When aggregation was re‐tested 23.5 h after aspirin the secondary phase of the enhanced aggregation responses was abolished. Addition of 0.14‐0.3 mumol/l prostaglandin E2 15 s after inducing aggregation partially restored the secondary phase. The observed secondary phase of aggregation may be due to increased prostaglandin synthesis or release.
Enzyme induction and renal function in man.
Authors: Ohnhaus EE , Martin J , Kinser J , Colombo JP
Published: July 2012

1. In a previous study in rats, an increased PAH clearance was found following chronic phenobarbitone administration. These results formed the basis for the present study in which fifteen healthy male volunteers were investigated and the parameters of liver microsomal enzyme activity and renal function were measured. 2. As parameters of liver microsomal enzyme activity, the antipyrine elimination in the plasma, the gamma‐glutamyl‐transpeptidase and the D‐glucaric excretion in the urine were measured. Endogenous creatinine clearance, 51Cr‐EDTA and 125I‐Hippuran clearance were determined as measurements of renal function. 3. No correlation was found between any of the parameters of microsomal enzyme activity and renal function. 4. Of the fifteen volunteers, seven having a mean antipyrine half‐life of 13.3 h were given antipyrine (500 mg) daily for 3 weeks. Afterwards all measurements of liver microsomal enzyme activity and renal function were repeated. The antipyrine half‐life decreased to 8.5 h, while the antipyrine clearance was increased by about 56%. gamma‐glutamyl‐ transpeptidase and D‐glucaric acid were also significantly increased, while renal function remained unchanged. 5. Therefore, an increased PAH‐ clearance, as found in the rat, is not obtained in man following induction of liver microsomal enzyme activity.
Rapid fluorimetric assay of minocycline in plasma or serum: comparison with microbiological assay.
Authors: Hall D
Published: July 2012

1. Plasma concentrations of minocycline were assayed by measuring the fluorescence emission of an aluminum‐minocycline chelate in a spectrofluorimeter. 2. The assay gives reproducible results over the concentration range 0.05‐5.0 mug ml‐1, and compared favourably with results achieved using a conventional large plate agar diffusion microbiological assay in a double‐blind comparison of the two methods. 3. Fluorimetric assay of minocycline in plasma was found to correlate closely with antibiotic activity (r = 0.95). The method is easy and economical to perform, results being obtained in 1 h.
Studies on the absorption and disposition of meptazinol following rectal administration.
Authors: Franklin RA , Southgate PJ , Coleman AJ
Published: July 2012

1 Rectal administration of the new analgesic drug, meptazinol, resulted in rapid absorption of the compound both in the monkey and in man. Peak plasma levels were observed within 0.5 h of dosing. 2 Absorption of the drug following rectal administration was extensive as shown by the recovery of 65‐90% of the dose in the urine. 3 Despite substantial inter‐individual variation in the observed maximum plasma concentrations of the drug, it was still evident that concentrations after rectal dosage were considerably higher than when the same dosage was given orally. 4 Elimination of the drug from plasma took place rapidly in an apparently mono‐exponential manner in both species. The half‐life of elimination in monkeys was 1.25 h and in man 2.0 h.
Radioimmunoassay of vinblastine and vincristine.
Authors: Teale JD , Clough JM , Marks V
Published: July 2012

1 The cytotoxic agent, vinblastine, was conjugated to albumin, using the Mannich reaction. Rabbits immunized with two conjugates, containing differing amounts of hapten, produce antibodies which bound [3H]‐ vinblastine. 2 Antisera from one rabbit cross‐reacted with both vinblastine and vincristine and were used to develop radioimmunoassays for measuring their concentration in plasma. 3 The antisera showed no cross‐reactivity with other alkaloids or cytotoxic drugs and provided assays sensitive to a concentration of 2.1 ng vinblastine or 3.8 ng vincristine/ml of plasma added direct to the assay tubes. 4 This is sufficiently sensitive to permit the measurement of plasma vinblastine levels for up to 24 h after the intravenous administration of 15 mg of the drug.
Once daily treatment of mild to moderate hypertension with xipamid: a controlled study.
Authors: Weber JC , Bird H , Cosh J , Davies PS , Dixon AS , Lister J , Petts HV , Prichard BN , Raftery EB
Published: July 2012

A double‐blind, placebo controlled, crossover trial of 20 and 40 mg of xipamid once daily in the treatment of mild to moderate hypertension is reported and some of the difficulties and pitfalls of multicentre trials of this type are described. 2 Both doses were significantly more effective in reducing the blood pressure than the placebo and neither was superior to the other. Both produced some potassium loss. Xipamid acted for at least 22 h and was effective in up to 83% of the patients. 3 Further trials are suggested to investigate the activity of a lower dose than 20 mg.
Phase 1 tolerability and searching dose studies with 4‐isothiocyanato‐ 4′‐nitrodiphenylamine (C.9333‐Go/CGP 4540), a new anthelmintic.
Authors: Vaidya AB , Sen HG , Mankodi NA , Paul T , Sheth UK
Published: July 2012

1 Phase 1 and 2 studies were carried out in thirteen volunteers and thirty patients with hookworm anaemia with a new anthelmintic, 4‐ isothiocyanato‐4′‐nitrodiphenylamine (C.9333‐Go/CGP 4540). Single and multiple doses were administered by mouth under careful supervision by the staff of the clinical pharmacology unit. 2 4‐Isothiocyanato‐4′‐ nitrodiphenylamine (C.9333‐Go/CGP 4540) was well tolerated in volunteers up to a single dose of 1750 mg and in patients up to 3000 mg in divided doses. Side effects were rare, transient and mild. One patient had moderate giddiness for 24 h after the compound. The laboratory investigations did not show any adverse effects on organ functions. Transient non‐specific changes in the T‐wave were occasionally observed in the e.c.g. 3 Multiple doses (125 mg, 250 mg or 1000 mg X 3) of the compound were highly effective in eradicating hookworm infection, as judged by almost 100% reduction in faecal egg counts and significant recovery of parasites from 24 h stool samples. The compound also showed activity against A. lumbricoides, T. trichiura and E. vermicularis. The compound appears to be promising and more studies, in a field situation, are desirable.
Cardiovascular effects of a new inotropic agent, U. K. 14275, in patients with coronary heart disease.
Authors: Hutton I , Hillis WS , Langhan CE , Conely JM , Lawrie TD
Published: July 2012

1 The chronotropic and inotropic properties of U.K. 14275, a phosphodiesterase inhibitor were assessed in patients with coronary heart disease. 2 Left ventricular function was assessed in eight patients with acute myocardial infarction using the non‐invasive measurement of systolic time intervals. 3 Twelve patients with angina pectoris were studied during diagnostic coronary arteriography. Left ventricular function was assessed using a high fidelity catheter tipped transducer in the left ventricle. 4 In both groups of patients U.K. 14275 infused intravenously in doses of 32, 64, 128 and 256 microgram kg‐1 bodyweight min‐1 enhanced the contractile state of the left ventricle without altering the heart rate.
A sensitive radioenzymatic assay for adrenaline and noradrenaline in plasma.
Authors: Hortnagl H , Benedict CR , Grahame‐Smith DG
Published: July 2012

1 An existing radioenzymatic assay for plasma catecholamines using catechol‐o‐methyl transferase and [3H]‐S‐adenosyl‐methionine has been modified resulting in a more sensitive assay for the measurement of plasma adrenaline and noradrenaline. 2 The lower limit of sensitivity for this method is 25 pg for adrenaline and 30 pg for noradrenaline/ml of plasma. 3 Resting supine (60 min) plasma adrenaline concentration was (mean +/‐ s.d.) 124 +/‐ 76 pg/ml(n=11) in males and 130 +/‐ 71 pg/ml (n=7) in females; plasma noradrenaline concentrations were respectively 444 +/‐ 129 pg/ml and 550 +/‐ 87 pg/ml. 4 The changes in plasma catecholamine concentrations in response to 40 degrees head‐up tilt have been determined in a group of healthy normal subjects and have been shown to be related to changes in blood pressure and heart rate.
Plasma prednisolone levels from enteric and non‐enteric coated tablets estimated by an original technique.
Authors: Morrison PJ , Bradbrook ID , Rogers HJ
Published: July 2012

1 A quantitative thin layer chromatographic technique for the estimation of plasma prednisolone levels has been devised with a minimum level of estimation of 10 ng/ml. 2 A comparative study of the absorption of 5 and 10 mg prednisolone from enteric and non‐enteric coated tablets (5 mg) was carried out in healthy subjects. 3 Mean plasma half‐life and peak plasma concentrations obtained from the non‐ enteric coated preparation agree well with previous studies in normal subjects reported by other investigators using competitive protein binding or radioimmunoassay techniques. Intersubject variability in bioavailability was noted. 4 Enteric coating increased the lag time before prednisolone appeared in the blood but did not alter the bioavailability of prednisolone compared to the equivalent dose of the non‐enteric coated tablet.
Comparison of intra‐arterial and indirect blood pressures at rest and during isometric exercise in hypertensive patients before and after metoprolol.
Authors: Hunyor S , Nyberg G
Published: July 2012

1. Blood pressure was measured both directly and indirectly in seven hypertensive patients before and after a single oral dose of 100 mg metoprolol, at rest and during sustained handgrip. 2. Intra‐arterially measured systolic and diastolic blood pressure increased linearly with time during sustained handgrip at 50% of maximal voluntary contraction. This linearity persisted for 60 s or more in most cases. Heart rate increased linearly for the first 30 s. 3. Indirectly measured blood pressure using an observer bias minimizing Auto‐Manometer, under‐read systolic and over‐read diastolic pressure both at rest and during handgrip. 4. By exact timing of recorded values during handgrip and linear extrapolation (or interpolation) from base‐line readings, mean values at 30 and 60 s of handgrip were calculated. The relationship between direct and indirect values remained the same at base‐line and 30 s of handgrip. At 60 s of handgrip, this was true only for diastolic pressure. For systolic pressure, indirect and direct values almost coincided. 5. After metoprolol, directly recorded pressure fell slightly (7–12 mm Hg, 0.02 less than P less than 0.10), both at rest and during handgrip, and heart rate fell by 15–18 beats/min (P less than 0.01). The systolic blood pressure and heart rate effect of metoprolol at 1 min handgrip correlated with peak plasma drug levels. Indirectly measured blood pressure did not change significantly. 6. The rate of rise in heart rate and blood pressure from base‐line to 60 s handgrip was not significantly influenced by metoprolol.
Factors determining the potency of cholinomimetic miotic drugs and their effect upon the light reflex in man.
Authors: Smith SA , Smith SE
Published: July 2012

1. Television pupillometry was used to measure the effect of six topically applied cholinomimetic drugs on the resting diameter and light reflex amplitude of the human pupil. Drug potency was obtained from dose response curves. 2. The tertiary amines arecoline, aceclidine and pilocarpine were considerably more effective miotics than the choline esters carbachol, methacholine and acetylcholine. 3. All the drugs which caused miosis also reduced light reflex amplitude proportionally. 4. The in vitro potency of these drugs was also measured on preparations of rabbit iris sphincter and guinea pig ileum. 5. Dose response relationships for pilocarpine in man and in vitro showed evidence of partial agonist activity on the rabbit iris only. 6. A comparison of the in vivo and in vitro results showed that three factors influenced the potency of topically applied miotics: accessibility to the iris; sensitivity to cholinesterase; and cholinoceptor agonist potency.
Drowsiness, impaired performance and tricyclic antidepressants drugs.
Authors: Bye C , Clubley M , Peck AW
Published: July 2012

1. The effects of amitriptyline, protriptyline, protriptyline, and a chemically related potential antidepressant, BW247, on performance tests and subjective ratings were studied. 2. Two groups of twelve healthy subjects received drugs and lactose dummy in identical capsules at weekly intervals according to a balanced design, under double‐blind conditions, and with standarized tests and environment. 3. Amitriptyline produced the most marked effects, with significant (P less than 0.05) impairment in auditory vigilance after 6.25 mg. Auditory reaction time, tapping rate, arithmetic, and digit symbol substitutions were impaired by amitriptyline 12.5 and 25 mg and all doses produced increased ratings of mental sedation. The effects began 1.5 h after drug and lasted approximately 5 h. 4. Nortriptyline produced fewer effects which were later in onset. Tapping at 1.8 h and auditory vigilance at 3.5 to 4.5 h were impaired by nortriptyline 25 mg whereas reaction time was prolonged by both doses at 5 h. No change in rating of mental sedation occurred. 5. No significant change in performance or subjective ratings followed protriptyline 10 mg or BW247, 12.5 and 25 mg. 6. The findings are discussed in relation to the presence of secondary and tertiary amines on the side chain of the compounds, and their relative abilities to block neuronal uptake of noradrenaline and 5‐hydroxytryptamine.
Comparative peripheral and coronary haemodynamic effects of rimiterol and isoprenaline.
Authors: Stephens JD , Hayward RP , Ead H , Adams L , Spurrell RA
Published: July 2012

1. Rimiterol and isoprenaline produced significant dose‐related increases in cardiac output. 2. These changes in cardiac output were accompanied by increases in heart rate and myocardial oxygen consumption which were similar for each drug and dose‐related. 3. Isoprenaline in contrast with rimiterol produced direct coronary vasodilation, i.e. coronary vasodilation in excess of that required to meet increases in myocardial oxygen demands. 4. It is suggested that the beta‐adrenergic receptors in the human coronary vasculature are mainly of the beta1 type. 5. Rimiterol, because it does not produce direct coronary vasodilation may be preferable to isoprenaline in the treatment of low‐cardiac output syndrome where there is regional myocardial ischaemia, since it would be less likely to produce a “coronary steal” effect.
Studies with primaquine in vitro: superoxide radical formation and oxidation of haemoglobin.
Authors: Summerfield M , Tudhope GR
Published: July 2012

1. The production of superoxide radicals from primaquine diphosphate in aqueous solution has been demonstrated, using as indicator the reduction of cytochrome C with inhibition of the reaction by superoxide dismutase. 2. Primaquine‐mediated oxidation of haemoglobin to methaemoglobin was reduced by the addition of catalase and increased by superoxide dismutase. Mannitol, a hydroxyl radical scavenger, abolished the increase in methaemoglobin observed in the presence of superoxide dismutase. EDTA reduced the oxidation of haemoglobin with and without superoxide dismutase. 3. Although the oxidation of haemoglobin in the presence of primaquine includes the effects of hydrogen peroxide, superoxide and hydroxyl radicals and metal ions, the results indicate that hydrogen peroxide, rather than the superoxide radical, is the main oxidizing species. The increase in haemoglobin oxidation occurring with superoxide dismutase may result from the augmented rate of hydrogen peroxide formation from superoxide radicals.
Plasma protein binding interaction between phenytoin and valproic acid in vitro.
Authors: Monks A , Boobis S , Wadsworth J , Richens A
Published: July 2012

1 Valproic acid or phenytoin were added to fresh human serum in varying concentrations and their binding characteristics determined by the method of Scatchard (1949). 2 Changes in serum albumin binding were investigated for phenytoin in the presence of 280, 560, 1050 and 2100 mumol l‐1 valproic acid, and for valproic acid in the presence of 40, 120, 280 and 480 mumol l‐1 phenytoin. 3 Phenytoin appeared to bind to a single site on the albumin molecule and could be competitively displaced from this site by concentrations of valproic acid above 280 mumol l‐1. 4 At high concentrations of valproic acid, the affinity of phenytoin for albumin was greatly decreased but the number of available binding sites was increased from one to four. 5 Valproic acid was bound to two high affinity and five low affinity binding sites but the latter were not detectable at valproic acid concentrations below 2100 mumol l‐ 1. 6 Phenytoin displaced valproic acid from its high affinity binding sites, although this was statistically significant only at a concentration of 480 mumol l‐1 phenytoin.
The role of the clinical pharmacologist in district general hospitals.
Authors: Silas JH , Lennard MS , Tucker GT , Smith AJ , Malcolm SL , Marten TR
Published: July 2012

Since its inception, the Clinical Pharmacology Section of the British Pharmacological Society has been discussing the wider role and responsibility of the clinical pharmacologist beyond the university department, in the district general hospital. The following policy statement is the product of these discussions, and is published in this international journal because, although the organization of the health service and its hospitals is peculiar to the United Kingdom, the concept of a clinical pharmacology service in general hospitals has far‐ reaching implications. The Editorial Board hopes that its publication will lead to recognition of the part that a general physician with a special interest in clinical pharmacology can play in patient care.
Assessment of combined oral theophylline and inhaled beta‐adrenoceptor agonist bronchodilator therapy.
Authors: Marlin GE , Hartnett BJ , Berend N , Hacket NB
Published: July 2012

1. The bronchodilator effects of 500 microgram rimiterol by pressurized aerosol, 375 mg oral theophylline and both drugs in combination were compared in a randomized, placebo‐controlled, double‐blind trial in eight patients with chronic, partially reversible airways obstruction. 2. The four treatments were (i) oral theophylline, placebo aerosol (TP); (ii) oral placebo, rimiterol aerosol (PR); (iii) oral theophylline, rimiterol aerosol (TR) and; (iv) oral placebo, placebo aerosol (PP). The aerosol was administered 2 h after the oral treatment. 3. Significant bronchodilatation (% FEV1 change from control) compared to PP occurred with TP from 60 to 480 min and with TR from 60 to 300 min, whereas with PR only for 45 min (P less than 0.05). 4. The mean, peak % FEV1 increases from control were 51.8% at 125 min, 31.7% at 125 min, 26.1% at 210 min and 0.9% at 30 min for TR, PR, TP and PP respectively. 5. At 125 min (5 min after aerosol inhalation) the mean % FEV1 change from control with TR (51.8%) Was significantly greater than with PR (31.7%), TP (22.2%) (P less than 0.05) and PP (− 2.4%) (P less than 0.01). 6. The mean, peak plasma theophylline levels were 10.19 microgram/ml at 120 min and 9.98 microgram/ml at 180 min with TR and TP respectively. Theophylline half‐life ranged between 4.3 and 12.5 h (mean +/‐ s.e. mean, 8.0 +/− 0.8 h). 7. Additive bronchodilatation was produced when rimiterol was administered with theophylline at a time when therapeutic plasma theophylline levels were achieved.
Clazepam: pharmacokinetics and effects on performance.
Authors: Giudicelli JF , Berdeaux A , Idrissi N , Richer C
Published: July 2012

1. The effects of clazepam, a new benzodiazepine (30 mg orally) on performance tests and the cardiovascular system have been compared to those of chlordiazepoxide (30 mg orally) and a placebo in a double‐ blind trial involving six healthy volunteers. Simultaneously, the pharmacokinetics of clazepam were investigated. 2. While clazepam itself could be detected neither in plasma nor in urine, it gave rise to two plasma metabolites, the former, an alcoholic derivative with a short half‐life, and the second, desmethyldiazepam, with a long half‐ life. These two metabolites and oxazepam were excreted in urine and, within the 24 h period following drug intake, accounted for 73% of the ingested dose. 3. Seven hours after its administration, clazepam slightly improved performance and reduced anxiety. The kinetics of these effects and the metabolic data suggest that clazepam acts mainly through the formation of desmethyldiazepam. However, owing to the low blood levels of this metabolite, the activity of clazepam was very moderate.
Evaluation of the anticholinergic actions of glycopyrronium bromide.
Authors: Mirakhur RK , Dundee JW , Jones CJ
Published: July 2012

1. Glycopyrronium was evaluated by intramuscular, intravenous and oral routes in six adult volunteers for its efficacy as an antisialogogue as also for its action on other aspects of cholinergic activity. 2. It was found to be an effective antisialogogue of long duration of action by all three routes. When given orally the effects were delayed in onset and persisted for too long. Intramuscular and intravenous routes were useful. The intramuscular absorption of the drug is rapid and consistent. 3. Sweat gland activity was affected in a similar fashion but less consistently and other parameters were mostly unaffected. 4. Glycopyrronium 0.2 mg intramuscularly was found to be the optimal dose. Larger doses produced subjective discomfort out of proportion to a further reduction in salivary secretion. 5. Intravenous administration causes no changes in cardiovascular stability.
The effect of tubocurarine and suxamethonium on directly and indirectly elicited contractions of skeletal muscle in unanaesthetized man using single and train of four impulses.
Authors: Udwadia BP , Gokhale SV , Barbhaiya HC
Published: July 2012

1 Contractions of adductor pollicis in unanaesthetized man were elicited by direct and indirect stimulation. Single twitch responses as well as those by a train of four impulses at 2 Hz for 2 s were elicited for indirect stimulation. 2 After a suitable control period, tubocurarine (0.05 mg/kg) or suxamethonium (0.08 mg/kg) was administered intravenously. 3 A stepwise diminution in the train of four impulses was noticed after tubocurarine. Indirectly elicited contractions due to single stimulus and direct muscle stimulation remained unaltered. 4 Partial blockade of transient duration occured after suxamethonium for single as well as train of four stimuli. Directly elicited contractions remained unchanged. The intensity of blockade depended on the rate of injection of suxamethonium. 5 Indirectly elicited contractions by train of four impulses is a reliable and sensitive method for testing neuromuscular blocking drugs in unanaesthetized man.
The inhibiton of adrenergically provoked renin release by salbutamol in man.
Authors: Wiggins R , Davies R , Basar I , Slater JD
Published: July 2012

1 The beta‐adrenoceptor agonist salbutamol is shown to have antagonist properties by its effect on adrenergically provoked renin release in normal people. 2 It significantly reduces the rate of renin secretion provoked by either endogenous (85 dregrees head‐up tilt) or exogenous (isoprenaline infusion) adrenergic stimulation. 3 Because renin is relatively simple to measure, and because in acute studies its release is relatively uninfluenced by the vagaries of direct and reflex cardiovascular effects, we suggest that, in the characterization of drugs which act on adrenergic beta‐receptors, an assessment of their effects on renin release would be useful.