bluuebunny/crossref_metadata_2025 huggingface dataset:
COMPARISON OF THE BRONCHODILATOR EFFECTS OF SALBUTAMOL INHALED AS A DRY POWDER AND BY CONVENTIONAL PRESSURISED AEROSOL
Authors: DUNCAN D. , PATERSON I.C. , HARRIS D. , CROMPTON G.K.
Published: July 2012

A double‐blind placebo controlled comparison of the bronchodilator effects of salbutamol inhaled as a dry powder and by conventional pressurized aerosol was carried out in 20 patients with chronic bronchial asthma.

No significant difference in the bronchodilator response between 400 μg and 600 μg of dry powder and 200 μg from the aerosol was detected.

Even with the highest dose of 600 μg dry powder salbutamol no subjective or objective side‐effects were observed and the inhalation of salbutamol in a lactose base was well tolerated by all the patients.
Immunological investigations of Candida albicans in respiratory disease.
Authors: Edge G , Longbottom JL , Tee RD , Pepys J
Published: July 2012

1. Tests against rabbit antiserum to Candida albicans showed about 40 protein antigens in cytoplasmic extract compared with two in a commercial test extract, which contained mainly polysaccharide (mannan) antigens. 2. Positive precipitin tests to the mannan preparation were recorded in 40% of 56 asthmatics on systemic corticosteroids and 37% of 56 rhinitis patients not so treated. The titres were slightly higher in the corticosteroid group. There was no increase in precipitins over 0‐9 months in asthmatics treated with beclomethasone dipropionate aerosol (BDA) by inhalation, or over 0‐12 months in rhinitis patients treated with BDA nasal spray. No positive reactions to the purified protein fraction were recorded. 3. Radioallergosorbent tests for specific IgE antibody showed a higher incidence of positive results with whole C. albicans yeast cells than with purified cytoplasmic protein. There was a higher incidence of positive results to protein in patients on systemic corticosteroids than in the other patients. No change in incidence occurred in asthmatics on BDA. The number of positive results in 56 rhinitis patients increased on BDA from 28 to 37 for yeast cells, and from 7 to 16 for cytoplasmic protein. This was attributed to C. albicans challenge tests. 4. Specific IgA antibodies to yeast cells were detected in 48/56 asthmatics on systemic corticosteroids, and there were no significant changes over 0‐9 months on BDA. The corresponding figures for rhinitis patients were 25/56, and again there were no significant changes over 0‐12 months on BDA.
Kinetic interaction of nomifensine with a 1, 5‐benzodiazepine (clobazam).
Authors: Rupp W. , Heptner W. , Uihlein M. , Bender R. , Taeuber K.
Published: July 2012

1. Among the numerous possibilities of drug interactions, pharmacokinetic interactions may cause mutual changes in absorption, distribution, metabolism and elimination of either drug. In the present study this approach was used to investigate pertinent effects of nomifensine and clobazam. 2. Ten normal subjects participated in an intra‐individual comparison of nomifensin 75 mg alone and in combination with clobazam 15 and 30 mg. The study design was carried out according to a Latin square in double‐blind conditions. One‐week wash‐out periods were used between the trial days. Serum levels of nomifensine were measured by radioimmunoassay (RIA) and of original clobazam by gas chromatography (GC). Classical criteria for bioavailability (peak serum levels, time of peak, area under the serum level time curve) and the half‐life of elimination from the serum were used for retrieval of pharmacokinetic information. 3. Results showed no relevant differences in the criteria mentioned above, after administration of each drug alone or in combination. Therefore, extrapolations were made to multiple dose kinetics based on assumptions derived from practical therapy. They showed comprehensive agreement with therapeutic results in depressed patients. 4. The use of the classical criteria for bioavailability, in addition to the calculation of the half‐time of elimination from serum, provides sufficient information for the decision whether pharmacokinetic drug interaction is present or absent. There was no such interaction after single doses of nomifensine or clobazam.
Repeated dose comparison of nomifensine, imipramine and placebo on subjective assessments of sleep and objective measures of psychomotor performance.
Authors: Hindmarch I. , Parrott AC
Published: July 2012

1. Nine normal subjects volunteered to participate in a randomized single‐blind crossover study of nomifensine 75 mg and two comparators, imipramine 75 mg and placebo. 2. Each volunteer received placebo for 3 d, then the first test drug for 4 days. This sequence was repeated twice more, so that each subject received each comparator. All medication was taken three times daily. 3. Assessments were made on days 3, 5 and 7 of each sequence, and consisted of a Sleep Evaluation Questionnaire, a test of Critical Flicker Fusion and a measure of Complex Reaction Time (CRT). 4. There were no significant differences in the CRT. There was a significant increase in critical flicker fusion with nomifensine. 5. Although both nomifensine and imipramine disturbed the quality of sleep, only imipramine produced a hangover.
Nomifensine in Parkinson's disease.
Authors: Bedard P. , Parkes JD , Marsden CD
Published: July 2012

1. Eight patients who failed or ceased to respond to levodopa, or who had developed the “on‐off” phenomenon were treated additionally with nomifensine. 2. The dosage of nomifensine started at 50 mg, was increased to 150 mg daily, and other medication was continued unchanged. The duration of treatment was from 2‐5 months. Assessments were carried out at 2‐week intervals using a validated rating scale. 4. Loss of dopaminergic nigrostriatal neurones characterizes Parkinson's disease, and it is probably for this reason that indirect dopamine (DA) agonists, whose actions depend on intact presynaptic mechanisms, are less active. 3. Nomifensine was not shown to be of antiparkinsonian value in these patients but may be of value as an antidepressant in patients with Parkinson's disease.
Controlled randomized group comparison of nomifensine and imipramine in depressive illness.
Authors: Forrest A. , Hewett A. , Nicholson P.
Published: July 2012

1. Nomifensine, an isoquinoline dopaminergic agonist, was investigated in a randomized double‐blind group comparison with imipramine, in 40 out‐patients with depression. 2. Assessments were made at weekly intervals for 4 weeks using the Hamilton Depression Scale and the Beck Depression Inventory. Blood, kidney and liver function were also monitored weekly. 3. Nomifensine was shown to be at least as effective as imipramine in relieving depression and to relieve tha anxiety component of the disease significantly more rapidly. Neither drug produced serious unwanted effects.
Dopaminergic agonist nomifensine compared with amitriptyline: a double‐ blind clinical trial in acute primary depressions.
Authors: Grof P. , Saxena B. , Daigle L. , Mahutte G.
Published: July 2012

1. Nomifensine (8‐amino‐2‐methyl‐4‐phenyl‐1,2,3,4,‐ tetrahydroisoquinoline) is a new antidepressant which displays an interesting pharmacological profile and acts as a potent dopaminergic agonist. 2. In a double‐blind clinical trialnomifensine was compared with a standard and widely tested antidepressant amitriptyline. A total of 24 patients with primary acute depressions, defined by research criteria, were treated for 8 weeks and their clinical condition and laboratory values monitored at regular intervals. The dosage schedule was a flexible one, with a daily dose range from 50‐200 mg for nomifensine and 50‐225 mg for amitriptyline. 3. Nomifensine and amitriptyline were found to be equivalent in their antidepressant efficacy. Nomifensine, however, showed a trend towards more rapid effect and was relatively free of side‐effects. 4. As nomifensine combined antidepressant activity with low frequency of adverse effects, it would seem to be suitable for wider use in the treatment of primary depressions. The results of our study have to be generalized with caution because of the limited sample size.
A profile of nomifensine.
Authors: Hanks GW
Published: July 2012

1. Nomifensine is a new antidepressant of novel chemical structure (a tetrahydroisoquinoline) with a pharmacological and therapeutic profile which differentiates it from any existing group of psychotropic agents. 2. The basic animal pharmacological profile is similar to that of the tricyclic antidepressants, imipramine and desmethylimipramine, but with a comparative lack of peripheral anticholinergic and cardiotoxic effects. 3. The pattern of effects on monoamine neurotransmitters is unique amongst antidepressants in that nomifensine is a potent dopamine agonist, has a powerful inhibitory effect on noradrenaline uptake and a weaker inhibitory effect on serotonin uptake. These pharmacological differences are reflected in the behavioural activity of the drug. 4. Clinically nomifensine has been shown to be an effective non‐sedative antidepressant; its relative lack of anticholinergic and other somatic side‐effects (particularly on the cardiovascular system) have been confirmed in patients.
The second Lilly Prize Lecture, University of Newcastle, July 1977. beta‐Adrenergic receptor blockade in hypertension, past, present and future.
Authors: Prichard BN
Published: July 2012

All beta‐adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta‐adrenoceptor blocking drugs have been reported which also possess alpha‐adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta‐adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta‐adrenoceptor blocking drugs. The non‐selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I‐IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta‐adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub‐divided into groups I‐IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta‐adrenergic receptor blocking drugs which in addition have alpha‐ adrenergic receptor blocking properties (Division III).
A comparison of four beta‐adrenoceptor antagonists in patients with asthma.
Authors: Benson MK , Berrill WT , Cruickshank JM , Sterling GS
Published: July 2012

1 Cardiovascular and airways response to two non‐cardioselective beta‐ adrenoceptor blocking drugs, propranolol and pindolol (with partial agonist activity) and two cardioselective beta‐adrenoceptor blocking drugs, acebutolol (with partial agonist activity) and atenolol, were compared in twelve patients with asthma. 2 All four drugs produced a significant reduction in resting pulse rate and prevented the increase in heart rate following inhaled isoprenaline (1,500 microgram). 3 Seven patients in clinical remission showed no significant bronchoconstrictor response to any of the drugs. In the remaining five patients, bronchoconstriction was greatest following propranolol (mean reduction in FEV1 26.6%) and least following atenolol (mean reduction in FEV1 6.5%). 4 The bronchodilator response to inhaled isoprenaline was blocked by propranolol and pindolol but not by acebutolol and atenolol. 5 Partial agonist activity did not appear to be clinically useful.
Continued use of non‐steroidal anti‐inflammatory drugs: an index of clinical efficacy.
Authors: Rooney PJ , Capell HA , Paterson S , Buchanan WW , Dick WC
Published: July 2012

1 A double‐blind entry to a trial of an active non‐steroidal anti‐ inflammatory drug, flurbiprofen against placebo was undertaken until 100 patients with classical rheumatoid arthritis had been allocated to each treatment. 2 Each patient was given a long‐term supply of drug and was asked to vary their own dosage within simple limits, according to the severity of their symptoms. They were instructed to return immediately they felt dissatisfied with their medication either on account of side‐effect or of lack of effect. 3 The length of time that patients remained satisfied with their drug was used as the sole measure of efficacy of the drug. At 2 weeks there were only 30% remaining on placebo and by 4 months no patients remained satisfied with the inactive drug. Forty‐three per cent were satisfied with flurbiprofen at the end of 1 year. 4 Clearly compliance with anti‐ rheumatic drugs is better if the drugs are effective and there is no long‐term placebo response in rheumatoid arthritis.
RESPONSES OF HUMAN SKIN BLOOD VESSELS TO SYNTHETIC HISTAMINE ANALOGUES
Authors: ROBERTSON I. , GREAVES M.W.
Published: July 2012

The vascular responses of human skin to two synthetic analogues of histamine, 2‐methyl histamine (an H1‐receptor agonist) and 4‐methyl histamine (an H2‐receptor agonist) have been studied in vivo.

Both compounds evoked dose‐related erythema, 2‐methyl histamine but not 4‐methyl histamine causing erythema mediated by an axon reflex, thus suggesting that the axon reflex and direct vasodilator action of histamine are due to H1 and H2 actions respectively.

The H1‐receptor antagonist chlorpheniramine inhibited erythema due to 2‐methyl histamine. Cimetidine, an H2‐receptor antagonist, had no effect on the reaction to 2‐methyl histamine. In contrast, the erythema reaction to 4‐methyl histamine was suppressed by both cimetidine and chlorpheniramine.

Although both histamine analogues caused wealing, this was not dose‐related within the dose range used, and neither chlorpheniramine nor cimetidine caused detectable suppression of wealing responses to either histamine analogue.

These results lend further support to the view that human skin blood vessels possess H2 as well as H1 receptors.
THE EFFECT OF LITHIUM TREATMENT ON ERYTHROCYTE MEMBRANE ATPase ACTIVITIES AND ERYTHROCYTE ION CONTENT
Authors: HESKETH J.E. , LOUDON J.B. , READING H.W. , GLEN A.I.M.
Published: July 2012

ATPase activities were studied in erythrocyte membranes prepared from blood of patients suffering from affective disorders.

Long‐term (9–12 months) administration of lithium led to an increase in the erythrocyte membrane Na/K ATPase activity (54%) when studied on an age and sex matched basis or when the patients were studied before and after treatment. The Mg ATPase activity was also increased (38%) but there was no consistent effect of lithium treatment on Ca stimulated ATPase activity in the membranes. It is suggested that the effect of lithium treatment on Na/K ATPase was due to recovery of the patients rather than an effect of the drug.

MgATPase activity increased regardless of clinical condition. Short‐term lithium treatment (2–4 weeks) led to increased Mg ATPase activity (43%). These results suggest that lithium treatment itself causes an increase in Mg ATPase activity and that this effect is not dependent on changes in protein synthesis.

Lithium treatment (long‐term) increased the erythrocyte sodium content by 15%. No effect on plasma sodium, magnesium, potassium or erythrocyte magnesium and potassium was observed.
PLASMA, BONE, HIP CAPSULE, AND DRAIN FLUID CONCENTRATIONS OF CEPHAZOLIN DURING TOTAL HIP REPLACEMENT
Authors: PARSONS R.L. , BEAVIS J.P. , DAVID JILL A. , PADDOCK GILLIAN M. , TROUNCE J.R.
Published: July 2012

A rapid intravenous bolus injection of cephazolin (4.0 g) was administered immediately before induction of anaesthesia to seven patients having total hip replacement.

The plasma, bone, hip capsule and drain fluid concentrations of cephazolin following rapid intravenous injection of cephazolin were all well above the minimum bactericidal concentration of this antibiotic against a wide range of organisms, in particular, the penicillin resistant Staph. aureus, most Gram negative rods and Bacteroides species that cause postoperative infections in these patients.

These results suggest that an intravenous bolus injection of cephazolin (4.0 g) given during induction of general anaesthesia should provide safe, effective prophylactic cover against all the organisms that cause postoperative wound infections in patients who undergo total hip replacement. This pharmacokinetic finding needs to be confirmed in a larger clinical trial of cephazolin.

The optimum empirical prophylactic mode of administration of cephazolin that provides high plasma and tissue concentrations during this procedure appears to be a rapid intravenous bolus injection before induction of anaesthesia.

The intravenous injections of cephazolin were well tolerated in every patient. No cases of thrombophlebitis occurred and no other side or toxic effects were reported.
PHARMACOKINETICS AND METABOLISM OF VARIOUS BENZODIAZEPINES USED AS HYPNOTICS
Authors: BREIMER D.D.
Published: July 2012

In the management of insomnia with drugs, any action should be restricted to the duration of the night and residual effects should be absent during the day‐time. The intermittent type of drug action desired is fundamentally different from drug treatment where a constant effect is sought.

Duration of drug action is dependent on the kinetics of distribution and elimination of the parent drug and its effective metabolites. In addition biopharmaceutical factors, such as those which promote a rapid rate of absorption, are important.

These considerations serve as a guide for a review of the kinetics and metabolism of various benzodiazepines.
PHARMACOKINETICS OF CLOSELY RELATED BENZODIAZEPINES
Authors: CURRY S.H. , WHELPTON R.
Published: July 2012

It is commonplace for drugs to vary by only minor chemical differences. This is particularly so for those seven benzodiazepines discussed in this paper which are related both as precursors and as metabolites. However, minor chemical differences may cause major differences in physicochemical and pharmacodynamic properties.

Although the physicochemical differences are difficult to relate to effect, the influence of structure on absorption, distribution and elimination is of considerable importance in governing duration of effect, as shown by studies in monkeys and in man. This in turn dictates the suitability of a particular drug as a day or night sedative, as an anticonvulsant, or as an anxiolytic.

Structure affects the relative potency of the compounds as anticonvulsants, anxiolytics or sedatives so that judicious choice of a particular compound for a particular patient and condition will lead to improved therapy. It is fallacious to consider all benzodiazepines as similar.
BIOAVAILABILITY OF TEMAZEPAM IN SOFT GELATIN CAPSULES
Authors: FUCCELLA L.M.
Published: July 2012

Healthy volunteers received single doses of temazepam 30 mg in conventional gelatin capsules, suppositories or in solution. They experienced marked sedation and sleepiness. The onset of sleepiness was prompt after the administration of the solution; this latter showed the fastest absorption and gave the highest peak plasma levels. This observation led to the development of the soft gelatin capsule.

To assess bioavailability of the formulation, plasma levels of temazepam were determined in healthy volunteers after single oral administration of soft and hard capsules, and after seven consecutive night‐time doses of the soft capsule. Absorption from the soft gelatin capsule was faster and produced earlier and higher peak plasma levels. There were no differences in relative availability.

The apparent half‐life of temazepam after night‐time administration was shorter than after morning administration, but no change was observed between the first and seventh night‐time doses.
EFFECTS OF HYPNOTIC AND SLEEP‐INDUCING DRUGS ON OBJECTIVE ASSESSMENTS OF HUMAN PSYCHOMOTOR PERFORMANCE AND SUBJECTIVE APPRAISALS OF SLEEP AND EARLY MORNING BEHAVIOUR
Authors: HINDMARCH I.
Published: July 2012

An acute dose comparison against placebo of the effects of nitrazepam 5 mg and temazepam 15 and 30 mg on measures of arousal and performance and on subjective assessment of sleep was carried out in 20 subjects with a history of using night‐time medication for insomnia.

Amylobarbitone (100 mg) was included as an active control and each drug was given in hard gelatin capsules. Subjects reported improved sleep with nitrazepam 5 mg and temazepam 30 mg, but there was evidence of impaired performance the next day with temazepam 30 mg.

The effect of temazepam 20 mg prepared in the Scherer formulation was compared against placebo in a further ten subjects. The subjects reported improved sleep without evidence of impaired performance the next day.
DIAZEPAM AND ITS HYDROXYLATED METABOLITES: STUDIES ON SLEEP IN HEALTHY MAN
Authors: BARBARA M. STONE
Published: July 2012

The effects of diazepam 5, 10 and 15 mg and its hydroxylated metabolites, 3‐hydroxydiazepam (temazepam) 10, 20 and 30 mg and 3‐hydroxy, N‐desmethyldiazepam (oxazepam) 15, 30 and 45 mg on sleep in healthy man were studied in young adulthood and in middle age. The effectiveness of the drugs for sleep during the day was also investigated.

In young adults diazepam and temazepam reduced sleep onset latencies and awake activity and increased total sleep time, and temazepam also reduced drowsy sleep. The activity of oxazepam was similar to that of temazepam except that it had no effect on sleep onset latencies. In middle age the effects of diazepam and temazepam were less pronounced than would be expected from studies in young adulthood. Essentially they reduced awake activity.

During the day diazepam increased total sleep time and reduced drowsy sleep in young adults, but temazepam and oxazepam had less activity than would be expected from their effect on night‐time sleep. With temazepam there was no increase in total sleep time, although there was reduced awake activity and drowsy sleep, and with oxazepam total sleep time was increased without changes in awake activity and drowsy sleep.

It is considered that these hypnotics provide a basis for the management of sleep disturbance in persons involved in skilled activity. In limited doses each drug has hypnotic activity without residual effects on performance.
Pharmacokinetics of single and multiple doses of clobazam in humans.
Authors: Rupp W , Badian M , Christ O , Hajdu P , Kulkarni RD , Taeuber K , Uihlein M , Bender R , Vanderbeke O
Published: July 2012

1. The pharmacokinetics of clobazam and its biotransformation product N‐ desmethylclobazam were investigated after single and multiple doses in normal subjects. 2. The relevant physicochemical properties of clobazam were measured and are presented. Different assay methods (radiochemical, fluorimetric and gas chromatographic) were applied and the results correlated. 3. After single doses the pharmacokinetic profile of clobazam includes time to peak levels 1–4 h after dosing, peak levels increasing linearly with the logarithm of dose, and terminal half‐lives of about 18 hours. At least 87% of an oral dose is absorbed, as indicated by urinary recovery of labelled material. 4. In multiple‐dose studies unchanged clobazam levelled off at minimum steady‐ state concentrations within one week of dosing. During 28 d of medication N‐desmethylclobazam accumulated to near steady‐state levels about eight times higher than those of the unchanged compound. 5. No pharmacokinetic interactions were discovered between clobazam and the antidepressant nomifensine.
A clinical view of clobazam.
Authors: Wieck HH , Blaha L , Heerklotz B
Published: July 2012

1 The results so far published in the literature, together with our own results, show that in clobazam (Frisium) we have a daytime tranquilizer which is comparable to the newest benzodiazepine derivatives. 2 It is particularly indicated in disorders of the sleeping‐waking rhythm, and sometimes also in psychovegetative disorders associated with epilepsy. 3. Its tranquillizing profile of action, the low incidence of side‐ effects and the absence of interactions with other drugs mean that its applications are varied, not only in neuropsychiatry but also in other medical disciplines. 4 The fact that therapeutic doses do not seem to impair driving ability to render patients incapable of carrying on their profession, means that it is suitable for the treatment of outpatients.
Effect of beta‐blockers on exercise double product (systolic blood pressure x heart rate).
Authors: Vukovich RA , Foley JE , Brown B , Willard DA , Buckley M , O'Kelly D , Fitzgerald D , Tormey W , Darragh A
Published: July 2012

1 The effect of single oral doses of six beta‐receptor antagonists on exercise‐induced changes in double product (systolic blood pressure x heart rate) were studied in 25 human volunteers. 2 Three doses of propranolol, nadolol, oxprenolol, pindolol, timolol and atenolol were selected for study on the basis of in vivo beta‐blocking potency. 3 Although all beta‐blockers studied reduced the double product response to exercise, the pharmacodynamics of this effect differed markedly. 4 Pharmacodynamic half‐lives, estimated for the drug tested, were 39 h for nadolol, atenolol 21 h, timolol 15 h, oxprenolol 13 h, propranolol 11 and pindolol 8 h. 5 These results suggest that the clinical choice of a beta‐blocker with the least problems of compliance can be made on the basis of pharmacodynamics as well as pharmacological profile.
Influence of various antihypertensive agents on lifespan of renal hypertensive rats.
Authors: Horovitz ZP , Antonaccio MJ , Rubin B , Panasevich RE
Published: July 2012

1 Daily treatment of two‐kidney clipped renal hypertensive rats with hydrallazine, hydrochlorothiazide (HCTZ) and a new orally active inhibitor of the angiotensin‐converting enzyme, captopril (SQ14,225), was correlated with survival rates for up to 9 months. 2 The groups of rats given captopril alone or captopril plus intermittent or chronic HCTZ had the best survival rate, whereas HCTZ alone or hydrallazine did not benefically affect survival. 3 Survival rates correlated well with control of BP in these animals.
Relationship between hypertension and angina pectoris.
Authors: Richardson PJ , Hill LS
Published: July 2012

1 Many factors are of importance in the relationship between angina pectoris and hypertensive heart disease. Vascular resistance modifies the oxygen supply, whereas the oxygen demand is influenced by the systolic and diastolic BPs, the diastolic filling time and wall tension, the duration of systole and transmural pressure and the sympathetic stimulation to the heart. 2 The treatment of angina pectoris in patients with hypertensive heart disease should aim to reduce myocardial ischaemia, and it is suggested that beta‐adrenoceptor antagonists are most suitable, as they reduce BP, heart rate and myocardial contractility and thus oxygen demand.
History and development of mixed opioid agonists, partial agonists and antagonists.
Authors: Martin WR
Published: July 2012

1 A brief history of the development of narcotic antagonists is outlined. 2 The clinical and pharmacological observations leading to the discovery of dualism of opiate receptors are reviewed. 3 An extension of this theory to a three‐receptor model (mu, kappa and sigma) is required to rationalize the pharmacology of the antagonists analgesics cyclazocine, pentazocine and nalorphine. 4 The methodologies available for the study of compounds with dual agonist‐antagonist activity are discussed in the light of the above receptor multiplicity, and data appertaining to the kappa‐partial agonist, nalorphine and the mu‐partial agonist buprenorphine are outlined.
Animal and molecular pharmacology of mixed agonist‐antagonist analgesic drugs.
Authors: Rance MJ
Published: July 2012

1 The pharmacology of analgesic drugs with mixed agonist‐antagonist action is reviewed in the light of the theory of drug action at single and multiple receptors. 2 Evidence for a heterogeneous population of opiate receptors in mammalian brain and in isolated tissue preparations is discussed. 3 The unusual pharmacological and pharmacokinetic profiles of the oripavine derivative buprenorphine are discussed in relation to the action of the drug at a molecular level.
Studies on the clinical pharmacology of prazosin. II: The influence of indomethacin and of propranolol on the action and disposition of prazosin.
Authors: Rubin P , Jackson G , Blaschke T
Published: July 2012

1 The possibility of pharmacodynamic and pharmacokinetic interactions of prazosin with indomethacin and with propranolol have been studied in healthy subjects. 2 In four out of nine individuals indomethacin considerably attenuated prazosin‐induced hypotension, but noradrenaline concentrations were unchanged from the day when blood pressure fell greatly. The effect of prazosin in the other five subjects was not influenced by indomethacin. 3 Indomethacin prevented the rise in plasma renin activity seen following administration of prazosin alone. 4 Propranolol did not prevent the syncope associated with the first dose of prazosin. 5 Propranolol affected neither the absorption nor elimination of prazosin. 6 It is concluded that in certain subjects indomethacin can largely prevent the hypotensive effect of parazosin, possible by increasing adrenergic receptor sensitivity. The theoretical possibility that propranolol could influence prazosin disposition or syncope was not substantiated.
Beta‐adrenoceptor blocking effects and pharmacokinetics of betaxolol (SL 75212) in man.
Authors: Giudicelli JF , Chauvin M , Thuillez C , Richer C , Bianchetti G , Gomeni R , Morselli PL
Published: July 2012

1 The pharmacological effects and the pharmacokinetics of betaxolol (SL 75212), a new beta‐adrenoceptor blocking agent, were compared with those of propranolol and a placebo in a double‐blind trial involving six healthy volunteers. 2 Heart rate (HR), myocardial contractile force (MCF), systolic blood pressure (SBP) and peak expiratory flow rate (PEFR) were measured at rest and during vigorous exercise before and at intervals up to 25 h after oral administration of the drugs. In addition, plasma renin activity (PRA) at rest and blood levels of betaxolol and propranolol were determined. 3. Betaxolol proved to be a potent and long‐lasting beta‐adrenoceptor blocking drug, devoid of intrinsic beta‐sympathomimetic activity. Its beta‐adrenoceptor blocking action was shown to four‐fold that of propranolol at the cardiac and renal levels and to last at least 25 h after drug intake. 4 The peak blood level of betaxolol was reached 2 to 4 hr after its administration, the first‐pass loss is likely to be low and the half‐ life is 12.3 h. These pharmacokinetic data are perfectly consistent with the long duration of the pharmacological effects of betaxolol in man.
A study of the effects of atenolol and propranolol on renal function in patients with essential hypertension.
Authors: Wilkinson R , Stevens IM , Pickering M , Robson V , Hawkins T , Kerr DN , Harry JD
Published: July 2012

1 The effects of propranolol and atenolol given in random order in a cross‐over study to fifteen patients with essential hypertension have been studied. 2 Both drugs were effective in lowering blood pressure and side effects were not markedly different. 3 There was no change in exchangeable sodium or potassium or in total body potassium during treatment with either drug. 4 Ambulant plasma renin activity was reduced by both drugs but the fall in blood pressure was not related to initial plasma renin. 5 Despite equal mean reduction in blood pressure with the two drugs, creatinine clearance fell significantly only during treatment with propranolol. 6 These observations suggest that intra‐ renal beta 2‐adrenoceptors may be of importance in the regulation of renal function.
Propranolol disposition in renal failure.
Authors: Wood AJ , Vestal RE , Spannuth CL , Stone WJ , Wilkinson GR , Shand DG
Published: July 2012

1 Previous studies of propranolol disposition in renal failure have been conflicting. 2 Using simultaneous administration of [3H]‐ propranolol intravenously and unlabelled propranolol orally the principal determinants of drug distribution were calculated in normals, patients with severe renal impairment (creatinine clearance 14.5 +/‐ 2.8 ml/min) but not on haemodialysis and patients on haemodialysis (creatinine clearance less than 5 ml/min). 3 The effect of haemodialysis on propranolol binding and free fraction was also examined. The percentage of propranolol unbound rose from 7.1% to 9.9%. (P less than 0.001) 20 min following heparinization and beginning haemodialysis. This was accompanied by a large rise in free fatty acids from 0.567 +/‐ 0.059 to 3.326 +/‐ 0.691 mumol/ml (P less than 0.005). 4 The blood to plasma concentration ratios of propranolol were significantly higher in patients with renal failure (P less than 0.02) and on haemodialysis (P less than 0.001) and were significantly negatively correlated (P less than 0.001) with the haematocrit. 5 Although the half‐life propranolol was significantly shortened in the patients with renal failure (P less than 0.02), there was no change in the apparent liver blood flow, extraction ratio or the principal determinants of steady‐state drug concentrations in blood namely oral and intravenous clearance from blood. 6 There is, therefore, no pharmacokinetic basis to adjust the dosage of propranolol in patients with renal failure.
Blood plasma binding of acebutolol and diacetolol in man.
Authors: Coombs TJ , Coulson CJ , Smith VJ
Published: July 2012

1 Acebutolol or diacetolol were added to fresh human plasma in varying concentrations and their extent of binding at 25 degrees C measureed by an equilibrium dialysis technique. 2 The extent of binding for both compounds was shown to be very low, being 11‐19% for acebutolol and 6‐ 9% for diacetolol. 3 Partition coefficients were measured in an n‐ octanol/phosphate buffer (0.05M, pH 7.4) solvent system. For a cebutolol, P = 0.62 and for diacetol, P = 0.08. 4 The very low plasma binding is in accord with the hydrophilic partition coefficients of these compounds.
Roles of hepatic blood flow and enzyme activity in the kinetics of propranolol and sotalol.
Authors: Pirttiaho HI , Sotaniemi EA , Pelkonen RO , Pitkanen U , Anttila M , Sundqvist H
Published: July 2012

1 The roles of the hepatic blood flow and the drug oxidizing enzyme system in eliminating oral propranolol and sotalol were studied in twelve subjects with biopsy proven liver parenchymal disease. 2 The apparent plasma clearance of propranolol was closely related both to the in vivo (antipyrine test) and in vitro (cytochrome P‐450) indices of the activity of the hepatic mixed function oxidase system. 3 Propranolol clearance had also a clear relationship to the estimated liver blood flow. Altered flow was, however, suggested to be a minor factor when compared with changes in the enzyme system. 4 The elimination rate of sotalol had no correlation to the indices of hepatic drug metabolism or to the estimated liver blood flow. 5 It is concluded that both the deteriorated sinusoidal perfusion and the decreased mass of drug metabolizing enzymes may be responsible for the impaired elimination of oral propranolol in subjects with parenchymal liver disease.
Acquired tolerance to dilator action of hydrallazine during oral administration.
Authors: Robinson BF , Collier JG , Dobbs RJ
Published: July 2012

1 The effect on forearm blood flow of local intra‐arterial infusion of hydrallazine has been studied in twelve patients with essential hypertension and six normal subjects. 2 When the patients with hypertension were not taking hydrallazine by mouth, they responded to intra‐arterial infusions with a dose‐dependent increase in forearm blood flow that was not significantly different from that in normal subjects. 3 When the patients were taking hydrallazine by mouth, the increase in forearm flow in response to intra‐arterial infusions was reduced and forearm vascular resistance did not fall as low as it did in the control study (P less than 0.01). 4 In four patients, the response to intra‐arterial hydrallazine was attenuated to a major extent, and in three of these, there was little or no response to oral treatment. In eight patients, the response to intra‐arterial hydrallazine did not fall below one half of that in the control study and this minor reduction in sensitivity might be expected to impair, but not abolish, the response to oral treatment. 5 It is concluded that the resistance vessels commonly develop tolerance to the dilator action of hydrallazine during long‐term oral therapy. In some patients a high degree of tolerance develops and this is an important cause of failure to respond to oral treatment.
Effect of quinidine on plasma concentration and renal clearance of digoxin. A clinically important drug interaction.
Authors: Dahlqvist R , Ejvinsson G , Schenck‐Gustafsson K
Published: July 2012

1 Thirty patients on maintenance digoxin therapy and admitted for cardioversion of atrial fibrillation were closely monitored with regard to plasma levels of digoxin and quinidine. 2 Seventeen of these patients were kept on maintenance digoxin therapy. After an initial lag period of 6 to 18 h after the addition of quinidine their digoxin levels started to increase and had increased by between 20 and 330% after 3 days on quinidine. Side‐effects attributed to the raised digoxin concentration occurred in 6 of these patients. 3 As studied in 5 of these 17 patients the renal clearance of digoxin decreased markedly when quinidine was added to the therapy. There was also a slight but significant reduction in creatinine clearance (n = 4). 4 In 13 patients digoxin was discontinued 36 h prior to the first quinidine dose. Also in these patients digoxin plasma levels increased significantly. 5 It is concluded that quinidine causes an unpredictably large increase in plasma digoxin and that this effect is probably at least initially to a large part due to a redistribution of digoxin in the body. The relative contributions of re‐distribution and impaired renal clearance of digoxin to the increase in digoxin steady‐state levels are presently unknown. 6 It is recommended that close monitoring of digoxin concentration and appropriate reduction of the maintenance dose is undertaken when quinidine is to be given to patients on digitalis therapy.
A controlled comparison of oxyfedrine, isosorbide dinitrate and placebo in the treatment of patients suffering attacks of angina pectoris.
Authors: Whittington J , Raftery EB
Published: July 2012

1 In a group of 23 patients with documented ischaemic heart disease who experienced angina pectoris, oral oxyfedrine (24 mg three times daily) was compared with isosorbide dinitrate (10 mg three times daily) and placebo in a double‐blind double‐crossover clinical trial. 2 Isosorbide dinitrate appeared no better than placebo, either in terms of symptomatic relief or ECG responses to exercise. Thirty eight per cent of patients complained of headaches and 28% had to cease taking the drug for this reason. 3 Oxyfedrine produced statistically significant improvements in both symptom level (P < 0.01) and ECG ST‐segment responses to exercise (P < 0.01). The only side effect noted was a reversible loss of taste sensation by one patient. 4 Neither drug produced any adverse changes in any haematological or biochemical parameters. 5 Oxyfedrine is, therefore, to be preferred to isosorbide dinitrate, being both much better tolerated and more efficacious.
The pressor actions of noradrenaline and angiotension II in chronic autonomic failure treated with indomethacin.
Authors: Davies IB , Bannister R , Hensby C , Sever PS
Published: July 2012

1 Indomethacin treatment of postural hypotension in four patients with chronic autonomic failure increased their pressor supersensitivity to intravenous noradrenaline without causing fluid retention. 2 All patients were supersensitive to angiotensin II in spite of normal levels of plasma renin activity in the supine position and therefore (by inference) of angiotensin II. This suggests that in autonomic failure, the degree of angiotensin receptor occupancy by endogenous angiotensin II is not important in determining pressor sensitivity to exogenous angiotensin II. Indomethacin increased the pressor supersensitivity to angiotensin II in all patients. 3 Indomethacin treatment decreased supine plasma renin activity to 50% of the level present before indomethacin treatment. 4 Indomethacin increased the lying but not the standing blood pressure. The failure to raise the standing pressure may be the result of the additional postural stress overcoming any vasoconstriction resulting from the increased sensitivity of vascular receptors to noradrenaline. The decrease in plasma renin activity could also contribute to the failure of indomethacin to prevent a fall in blood pressure on standing. 5 In our patients the excretion of the main urinary metabolite (PGFM) of prostaglandin F2 alpha was higher than recorded previously in normal controls. During treatment with indomethacin, plasma indomethacin levels were in the range at which inhibition of prostaglandin synthesis occurs and the excretion of PGFM was decreased. 6 Indomethacin was not effective in the treatment of postural hypotension in these patients with autonomic failure.
Vascular smooth muscle response to fibrinogen degradation products and 5‐hydroxytryptamine: possible role in cerebral vasospasm in man.
Authors: Forster C , Whalley ET , Mohan J , Dutton J
Published: July 2012

1 Experiments were performed to determine the effects of fibrin(ogen) degradation products on the following in vitro vascular preparations: rabbit aortic strip, rat aortic strip and human basilar arterial strip. 2 Citrated plasma and streptokinase were incubated at 37 degrees C to produce a crude preparation of fibrinogen degradation products and 0.1 ml aliquots were removed at various time intervals. These samples were tested for intrinsic activity and possible interactions with EC50 and threshold concentrations of 5‐hydroxytryptamine on the vascular preparations. 3 Enhancement of the responses obtained by both concentrations of 5‐hydroxytryptamine was produced by samples taken throughout the streptokinase incubation period, the maximum effect being seen at 90 min. 4 The 90 min incubate produced volume‐dependent (25‐400 microliters) potentiations of the responses developed in the three vascular preparations to the EC50 and threshold concentrations of 5‐hydroxytryptamine. 5 It is suggested that fibrin(ogen) degradation products may be involved in the intense vasoconstriction of the cerebral arteries following subarachnoid haemorrhage.
Bioavailability of naproxen sodium and its relationship to clinical analgesic effects.
Authors: Sevelius H , Runkel R , Segre E , Bloomfield SS
Published: July 2012

1 In the first of a series of trials with naproxen sodium it was shown that patients achieved significantly earlier and higher plasma levels of naproxen when naproxen sodium was administered. 2 In a second study comparing naproxen with naproxen sodium in patients with post‐partum pain, pain intensity was consistently lower for the group receiving naproxen sodium. However, statistically significant differences were not seen until 4 to 5 h after medication. 3 A final study documented that a more frequent dosage schedule of every 6 h led to clearly higher plasma levels than those achieved with an every 8 h regimen; plasma levels did not plateau. Doses up to 1,375 mg/day were well tolerated. 4 In conclusion, naproxen sodium appears to be an improved form of naproxen for use as a analgesic agent.
Serum level monitoring of a new slow release theophylline formulation in patients with chronic lung disease.
Authors: Marlin GE , Butcher MA , Klumpp JA , Thompson PJ
Published: July 2012

1 Serum theophylline levels were performed in 26 patients with chronic lung disease receiving rapid release theophylline (125 mg 6 hourly) and 28 patients receiving slow release theophylline (250 mg 12 hourly) under steady state conditions. 2 For rapid release theophylline the mean +/‐ s.d. serum theophylline levels at 0 and 2 h were 41.0 +/‐ 21.7 and 52.3 +/‐ 20.9 mumol l‐1 respectively and for slow release theophylline at 0, 4 and 6 h 43.7 +/‐ 25.5, 50.9 +/‐ 23.0 and 51.7 +/‐ 26.4 mumol l‐1 respectively. 3 Serum theophylline monitoring with slow release theophylline was performed in 70 patients with chronic lung disease. The initial dose was 250 mg administered 12 hourly. 4 The mean +/‐ s.d. steady state serum theophylline level achieved was 76.0 +/‐ 18.8 mumol l‐1 and the mean +/‐ s.d. dose to produce this level was 9.4 +/ 2.3 mg kg‐1 day‐1. There was no correlation between dosage and serum theophylline level. 5 Sixty percent of patients required a dosage change for stabilization (375 to 1000 mg/day). Seventeen patients reported unwanted effects (nausea or tremor), which either settled quickly or resolved with dosage reduction. 6 Serum theophylline levels were obtained at different dosages in 44 patients and 18 patients demonstrated dose‐dependent kinetics. 7 An initial dose of 500 mg/day is recommended and dosage increments should not exceed 125 mg/day with monitoring by serum theophylline levels.
Intersubject and dose‐related variability after intravenous administration of erythromycin.
Authors: Austin KL , Mather LE , Philpot CR , McDonald PJ
Published: July 2012

1 It is well‐known that considerable variability and unpredictability in serum concentrations results from orally administered erythromycin. 2 Disposition kinetics and their variability were studies in 24 healthy subjects after a single dose of erythromycin lactobionate and four doses were studied to evaluate dose‐related variability in five other subjects. 3 Erythromycin kinetics were adequately described by a classical two compartment open model with little intersubject variability. 4 Dose‐related variability occurred. Clearance was independent of dose but T1/2 beta and Vdss increased with dose. 5 Data are presented to show that non‐invasive sampling of urine and saliva are of limited value in studying erythromycin pharmacokinetics.
Effects of nifedipine on resistance vessels, arteries and veins in man.
Authors: Robinson BF , Dobbs RJ , Kelsey CR
Published: July 2012

1 The effect of nifedipine on peripheral blood vessels has been studied in man. 2 Nifedipine induced dilatation of the forearm resistance vessels when given either by local intra‐arterial infusion or sublingually (10 mg). 3 Local infusion of the drug did not relax hand veins preconstricted by infusion of noradrenaline and neither local infusion nor sublingual administration prevented constriction mediated by the sympathetic nervous system. Nifedipine was, however, a potent inhibitor of hand vein contractions induced by high concentrations of potassium provided that the noradrenergic component of the response was suppressed by simultaneous infusion of phentolamine. 4 Sublingual nifedipine (10 mg) did not dilate the elbow collateral arteries. 5 The effects of nifedipine on peripheral blood vessels are similar, but not identical, to those of verapamil. The pattern of action, with dilatation of resistance vessels but not capacitance, resembles that of hydralazine rather than glyceryl trinitrate and this suggest that nifedipine may prove useful in the treatment of hypertension.