bluuebunny/crossref_metadata_2025 huggingface dataset:
Use of narcotic antagonists in anaesthesia.
Authors: De Castro J
Published: July 2012

1 The introduction of morphine antagonists into anaesthesiology has aroused great scientific interest, increased our knowledge of analgesia, and opened new frontiers for therapeutics. 2 The advantages and disadvantages of these compounds are described and assessed. 3 The best choices for treatment of pain are the most potent and long‐acting drugs of this group with a wide safety margin. As an antidote to narcotic agonists, naloxone seems to be the most suitable drug in the majority of cases, although in certain conditions drugs having less rapid onset of action and of longer duration may be more desirable. 4 In all cases of treatment after anaesthesia when antagonists to narcotic analgesics are used, drug administration must depend on careful control, which necessitates specific and prolonged patient care by specifically trained and competent staff.
Side‐effects of mixed agonist‐antagonist analgesics used in sequential anaesthesia.
Authors: Devaux C , Schoepffler P , Gauthier‐Lafaye JP
Published: July 2012

1 Mixed agonist‐antagonist analgesics have analgesic action but also possess a range of side‐effects. 2 Narcotic antagonists do not reverse the non‐specific effects of opiates. 3 Under certain circumstances the effects of agonists and mixed agonist‐antagonists can be additive. 4 Chronic dosage of mixed agonist‐antagonists leads to a lower level of dependence than that observed with the standard narcotics. 5 Mixed agonist‐antagonists may not antagonize the respiratory effects of narcotics and may result in potentiation of such depression.
Finger tremor and cigarette smoking.
Authors: Lippold OC , Williams EJ , Wilson CG
Published: July 2012

1 Finger tremor was recorded with a strain gauge and an accelerometer. 2 Records were subjected to frequency analysis and the amplitude or power at frequencies up to 25 Hz were computed. 3 Comparison was made between the tremor during a control period, during sham smoking and during smoking a cigarette. 4 Smoking significantly increases tremor amplitude by at least twofold over all frequencies from 1 Hz to 25 Hz.
Investigation of a combined arteriolar dilator and beta‐adrenoceptor antagonist (SK & F 92657) in the peripheral vessels of man.
Authors: Collier JG , Pitcher DW
Published: July 2012

1 SK & F 92657 is a new compound which in animals has both precapillary vasodilator and beta‐adrenoceptor blocking activity. The effects of the drug on forearm blood flow and dorsal hand vein distensibility have been studied in healthy volunteers. 2 Forearm blood flow was measured by venous occlusion plethysmography. The drug was infused directly into a brachial artery. The effects of SK & F 92657 on resting flow and on the dose‐response relationship for intra‐arterial isoprenaline were studied. 3 Venous distensibility was measured in the large veins on the back of the hand. The drug was infused directly into a selected vein and its effects on resting tone and on the responses to noradrenaline and to isoprenaline were investigated. 4 Intra‐arterial infusion of SK & F 92657 over 2 min caused a dose‐dependent increase in forearm blood flow which developed gradually to reach a maximum after approximately 40 min. Infusion into dorsal hand veins at 100 ng/min and 500 ng/min had no dilator effect in veins preconstricted with noradrenaline. At higher doses SK & F 92657 potentiated the constrictor effect of noradrenaline. 5 In both veins and arteries SK & F 92657 attenuated the dilator effects of isoprenaline. The drug had no effect on the venodilator effects of bradykinin, histamine or sodium nitroprusside. 6 The pattern of response of these vessels to locally infused SK & F 92657 is exactly that expected of a drug combining the properties of hydralazine‐like vasodilatation and beta‐adrenoceptor blockade. Furthermore, in the arterioles, both properties were manifest at the same dose.
Azatadine maleate in perennial allergic rhinitis: effects on clinical symptoms and choice reaction time.
Authors: Hillas JL , Somerfield SD , Wilson JD , Aman MG
Published: July 2012

1 The efficacy of the antihistamine azatadine maleate at maximum recommended dosage (4 mg/day) for 1 week was assessed relative to placebo in a double‐blind crossover study of twenty patients with perennial allergic rhinitis. 2 Sixteen patients reported significant improvement in their clinical symptoms while taking the active drug. 3 The size of skin test weals for both histamine provocation and common inhalant allergens (prick test) diminished significantly after the azatadine treatment. There was no correlation between inhibition of skin reactions and symptom improvement. 4 Eight subjects reported sedative effects attributable to azatadine maleate. Their performance on a choice reaction to placebo occurred in the non‐sedated group.
Metabolism of an oral tryptophan load. II: Effect of pretreatment with the putative tryptophan pyrrolase inhibitors nicotinamide or allopurinol.
Authors: Green AR , Aronson JK , Curzon G , Woods HF
Published: July 2012

1 The effect of seven days administration of either allopurinol (300 mg daily) or nicotinamide (500 mg twice daily) on the metabolism of an oral L‐tryptophan load (50 mg/kg) has been investigated. 2 Administration of either drug failed to alter the plasma total or free tryptophan or plasma kynurenine curve. Nor was the urinary excretion of tryptophan, kynurenine, 5‐hydroxyindoleacetic acid or indole acetic acid influenced. 3 Allopurinol pretreatment did increase the volume of distribution of tryptophan. 4 These data suggest that allopurinol and nicotinamide are unlikely to be of value as tryptophan pyrrolase inhibitors in vivo and therefore would not increase the therapeutic effect of L‐tryptophan when it is given to treat depressive illness.
Induction of delta‐aminolaevulinic acid synthase in leucocytes of patients on phenytoin therapy‐comparison with changes in rat hepatic tissue.
Authors: McColl KE , Moore MR , Thompson GG , Goldberg A
Published: July 2012

1 In rats daily phenytoin (DPH) administration resulted in an increase in hepatic cytochrome P450 content. The rise in cytochrome P450 was associated with a temporary increase in the acitvity of hepatic delta‐ aminolaevulinic acid (ALA) synthase. 2 In patients newly commenced on DPH anticonvulsant therapy the activity of ALA synthase in peripheral leucocytes showed a marked temporary increase during the first 10 days of therapy. 3 These findings suggest that DPH induces a haem‐requiring eenzyme system in peripheral leucocytes as well as in hepatic tissue.
Diazepam and N‐desmethyldiazepam concentrations in saliva, plasma and CSF.
Authors: Hallstrom C , Lader MH
Published: July 2012

1 Salivary and plasma diazepam and nordiazepam concentrations were measured in 51 paired samples from four experimental situations. In seven of the patients CSF samples were estimated. 2 Correlation of 0.89 (P less than 0.001) was observed between salivary and plasma diazepam and 0.81 (P less than 0.001) between salivary and plasma nordiazepam. 3 Mean salivary diazepam was 1.6% (+/‐ 0.3%) of the plasma diazepam. It was found to vary markedly in an acute dosage study. Mean salivary nordiazepam was 2.9% (+/‐ 1%) of the plasma measure and was dependent on salivary flow rate. 4 CSF diazepam was in equilibrium with unbound plasma diazepam and salivary diazepam. 5 Mean protein binding of diazepam in vitro was 99.3% with no variations as a function of concentration. 6 The results suggest salivary diazepam and nordiazepam measures to be of value in epidemiological studies. However, they do not predict accurately the plasma total or unbound drug concentration from a salivary sample in an individual.
Dose‐response study of the nasal decongestant and cardiovascular effects of pseudoephedrine.
Authors: Empey DW , Young GA , Letley E , John GC , Smith P , McDonnell KA , Bagg LR , Hughes DT
Published: July 2012

1 The effects of different doses of orally administered pseudoephedrine on nasal airway resistance (NAR) were studied in a group of eighteen healthy subjects using double‐blind conditions with drugs administered in a series of cross‐over experiments according to a Latin‐square design. 2 Challenge with 1% histamine diphosphate to one nostril 1 h after administration of the drugs produced increases in NAR. 3 The effects of pre‐treatment with both placebo and increasing doses of pseudoephedrine on this histamine‐induced increase in NAR were examined. Pseudoephedrine 60 mg, 120 mg and 180 mg significantly (P less than 0.05) reduced the effect of histamine on NAR compared with the placebo, and the protective effects of these doses did not differ significantly from each other. Pseudoephedrine 15 mg and 30 mg did not differ from placebo in their effects on NAR. 4 Small, but statistically significant increases in pulse and systolic blood pressure occurred after pseudoephedrine 120 mg and 180 mg, but not after pseudoephedrine 60 mg, 30 mg or 15 mg. No significant effects were produced by any of the doses of pseudephedrine with regard to diastolic blood pressure. Similarly no dose of pseudoephedrine altered mood or produced any excess of unwanted effects compared with placebo. 5 We conclude that pseudoephedrine 60 mg is the optimal single adult dose since this achieves maximal nasal decongestion without cardiovascular or other unwanted effects.
Naloxone pharmacokinetics in the newborn.
Authors: Moreland TA , Brice JE , Walker CH , Parija AC
Published: July 2012

1 Plasma naloxone levels were determined by RIA over a period of 6–36 h in three groups of neonates, (1) those given 35 microgram i.v. (n = 6), (2) those given 70 microgram i.v. (n = 6) and (3) those given 200 microgram i.m. (n = 17) naloxone HCl within 1 min of birth. 2 After intravenous administration of 35 and 70 microgram of naloxone peak levels of 4–15 ng/ml and 9–20 ng/ml respectively were reached in 5‐ 40 min and the mean plasma half‐life after both doses was 3.1 +/‐ 0.5 h. 3 Peak levels of 7–35 ng/ml were reached 0.5 to 2 h after intramuscular administration of 200 microgram. The fall in concentration after this was consistently biphasic with the levels declining rapidly between one and four hours and then slowly from four hours onwards. 4 Plasma levels at 24–36 h after i.m. administration were as high as they were 4 h after i.v. administration of 35 microgram and this may account for the prolonged duration of action when this route is used.
Theophylline kinetics in relation to age: the importance of smoking.
Authors: Cusack B , Kelly JG , Lavan J , Noel J , O'Malley K
Published: July 2012

1 Single dose studies of theophylline kinetics were compared in groups of young and elderly smokers and non‐smokers to assess the effect of age on theophylline absorption and the effect of smoking on drug metabolising enzyme activity in old age. 2 The rate and extent of absorption was not affected by age. Distribution and elimination kinetics were similar in young and elderly non‐smokers. 3 In young subjects the elimination half‐life of theophylline was shorter and clearance was significantly greater in smokers than in non‐smokers. 4 In the elderly mean elimination half‐life was significantly shorter in smokers and their plasma clearance was 40% higher than in non‐smokers. The statistical difference for clearance was at the 7% level of significance. 5 These data indicate that ageing per se does not affect theophylline elimination and also that induction of theophylline metabolism due to smoking occurs in old age. Smoking is a variable that should be taken account of when assessing drug metabolism in elderly patients.
Drug metabolism and liver function after methyldopa withdrawal.
Authors: Ylikallio A , Sotaniemi EA
Published: July 2012

1 The effects of methyldopa withdrawal on liver function and drug metabolism were investigated in ten elderly females suffering from the drug‐induced orthostatic reaction and resistant hypertension. 2 There was a significant increase in serum albumin level, antipyrine metabolism and urinary excretion of D‐glucaric acid 6 months after the methyldopa withdrawal. 3 The results suggest that patients treated with methyldopa might show a reduced metabolizing ability in spite of normal liver function tests.
Pharmacokinetics, beta‐adrenoceptor blockade and anti‐hypertensive action of labetalol during chronic oral treatment
Authors: Sanders GL , Davies GM , Rawlins MD
Published: July 2012

Br J Clin Pharmacol 1980 Aug;10(2):121‐6

1 beta‐Adrenoceptor blockade, plasma labetalol concentrations and anti‐ hypertensive actions were investigated at 2 hourly intervals during the interdose period of chronic oral therapy in six hypertensive patients. 2 beta‐adrenoceptor blockade varied during the inter‐dose period and was maximal 2 and 4 h after the oral dose (P > 0.05). 3 Systolic pressure rose during the interdose period (P > 0.05). A significant correlation was found between the degree of beta‐adrenoceptor blockade and the change in systolic pressure at 2 h after the oral dose. 4 Efficacy of labetalol as a beta‐adrenoceptor antagonist and anti‐ hypertensive drug was assessed 2 h after an oral dose during chronic eight hourly dosage in sixteen hypertensive patients. Pharmacokinetics of labetalol were studied in the same patients. 5 Peak plasma labetalol concentration occurred 2 h after the oral dose and subsequently the plasma concentration declined monoexponentially. 6 The steady state concentration (CSS) of labetalol was correlated significantly with the daily oral dose in mg kg‐1, the mid point labetalol concentration (Cmax+Cmin) divided by 2 and the isoprenaline dose ratio‐1 at 2 h after the oral dose. 7 No correlation was found between the antihypertensive effect and the CSS ng ml‐1 labetalol or between the isoprenaline dose ratio‐1 and the CSS labetalol ng ml‐1.
Comparative pharmacokinetics and pharmacodynamics of cardiac glycosides.
Authors: Kelman AW , Sumner DJ , Lonsdale M , Lawrence JR , Whiting B
Published: July 2012

1 The pharmacokinetics and pharmacodynamics of ouabain, digoxinn and beta‐methyl digoxin (medigoxin) have been investigated in a crossover study in four normal healthy volunteers. 2 Pharmacokinetics were studied using [3H]‐labelled glycosides and the shortening of the left ventricular ejection time (LVET) was used as a measure of the effect of the drugs. A graded exercise protocol was used to correct for the effects of heart rate on LVET. 3 In three of the four subjects, both digoxin and beta‐methyl digoxin produced a shortening in the LVET, but no such change could be detected with ouabain in any of the four subjects. 4 There was a good linear correlation between the shortening of the LVET and the amounts of digoxin or beta‐methyl digoxin present in the body tissues. 5 One subject who showed no drug‐related LVET shortening had greatly enhanced clearances of all three drugs studied.
Failure of alkaline diuresis to enhance diflunisal elimination.
Authors: Balali‐Mood M , Prescott LF
Published: July 2012

1 The effects of alkaline diuresis on the elimination of a single oral dose of 750 mg diflunisal were studied in six healthy male volunteers. 2 The plasma concentrations and half‐life of diflunisal were not reduced by alkaline diuresis. 3 The 72 h urinary recovery of unchanged diflunisal was more than doubled with alkaline diuresis, but even so, only 5‐7% of the administered dose was excreted unchanged. 4 With alkaline diuresis there was a significant increase in the mean renal clearance of diflunisal from 0.27 to 0.46 ml/min, but there was no significant correlation between the renal clearance of diflunisal and urine flow or pH. 5 However, there was a significant increase in the overall mean renal clearance of diflunisal from 0.22 ml/min over the period 0‐24 h to 0.73 ml/min from 48‐72 h. 6 Forced alkaline diuresis is unlikely to be of value in diflunisal poisoning.
Urinary primaquine excretion and red cell methaemoglobin levels in man following a primaquine:chloroquine regimen.
Authors: Greaves J , Evans DA , Fletcher KA
Published: July 2012

1 Red cell methaemoglobin levels were found to be significantly raised in healthy subjects given a 14‐day course of primaquine with chloroquine on the first 3 days. 2 The methaemoglobin levels were not related to the quantity of primaquine excreted. 3 No primaquine could be detected in the plasma at 24 h following the last three daily doses.
Oxyfederine and propranolol—a controlled trial in angina pectoris.
Authors: Whittington J , Raftery EB
Published: July 2012

1 A double‐blind‐crossover randomised trial was performed to compare the effects of oxyfedrine (maximum dose 32 mg three times daily), propranolol (maximum dose 120 mg three times daily) and placebo in 30 patients with chronic stable angina pectoris. Assessment was by means of symptom level, ECG responses to graded exercise and haematological and biochemical investigation. 2 Oxyfedrine and propranolol resulted in similar significant improvements in symptom level (P < 0.05 in both cases), and ST index (propranolol P < 0.02; oxyfedrine P < 0.05). Neither drug produced any significant changes in haematologaical or biochemical investigations and only infrequent minor side effects were noted. 3 These results indicate that oxyfedrine is a safe and well‐ tolerated drug with an efficacy comparable with that of propranolol in the treatment of patients with angina pectoris.
Time course changes in levels of arachidonic acid and prostaglandins D2, E2, F2 alpha in human skin following ultraviolet B irradiation.
Authors: Black AK , Fincham N , Greaves MW , Hensby CN
Published: July 2012

1 Clinically normal human abdominal skin was irradiated with three minimal‐erythema doses of ultraviolet B irradiation, (u.v.B). 2 Erythema was assessed visually, and exudate recovered by a suction bulla technique from normal skin, and at 10 min, 2, 6, 18, 24 and 48 h after irradiation. 3 Erythema was barely visible at 2 h, but increased to maximum at 24 h, which was maintained at 48 h. 4 Increased arachidonic acid and prostaglandin E2, F2 alpha and D2 concentrations in the exudate, measured by gas chromatography‐mass spectrometry, accompanied the developing erythema, with the maximal rise of arachidonic acid, prostaglandin E2 and D2 occurring at the height of the erythema at 24 h. 5 At 48 h, still at the height of the erythemal response, arachidonic acid and PGE2 levels had returned to near normal. 6 Concentrations of arachidonic acid and of its products from the cyclo‐ oxygenase pathway, parallel the development of i.u.B. erythema in the first 24 h.
Cardiovascular, respiratory and temperature responses to intravenous heroin (diamorphine) in dependent and non‐dependent humans.
Authors: Tress KH , El‐Sobky AA
Published: July 2012

1 Intravenous heroin (diamorphine) was administered to volunteers, in doses of 2.5 and 5 mg to non‐dependent and doses of 1/6, 1/3 and 1/2 of their prescribed daily dose of opiates to dependent subjects, and heart and respiration rates, blood pressure, body and skin temperature and skin conductance were measured before and for 2 h after injection. 2 Heart rate fell and continued to fall after injection in both groups of subjects although the time course was different in the two groups. This was thought to be a non‐specific effect of heroin. 3 Respiration rate fell after injection in both groups. The dependent group showed a faster recovery of pre‐drug respiration rate. This was interpreted as being due to tolerance in the dependent group. 4 Systolic blood pressure fell only in the dependent group and diastolic blood pressure only fell after injection of the largest dose of heroin in both groups. 5 Body temperature fell after injection of heroin in a similar way in both groups while neither skin temperature nor skin conductance changed. This was interpreted as a drug‐induced alteration in thermo‐ regulatory mechanisms. 6 Placebo had no effect on any of these measures. There were no differences between the responses of the high and low dose dependent subjects to different doses of heroin nor did prior ingestion of methadone affect any of the measures.
The clinical pharmacology of a herbal asthma cigarette.
Authors: Elliott HL , Reid JL
Published: July 2012

1 Herbal preparations containing atropine‐like alkaloids are marketed as proprietory asthma remedies, typically in the form of cigarettes. 2 This randomised, cross‐over study compares in six healthy volunteers the pharmacological effects caused by smoking a standard, medium tar, tobacco cigarette or a herbal cigarette. 3 Smoking a herbal cigarette is associated with a significant fall in heart rate consistent with the systemic response to atropine‐like alkaloids and a significant increase in peak expiratory flow rate consistent with the bronchodilator effect of reduced cholinergic activity. 4 Smoking a herbal cigarette seems analogous to the inhalation of ipratropium by aerosol for a local bronchodilator effect.
A comparative study of antipyrine and lignocaine disposition in normal subjects and in patients treated with enzyme‐inducing drugs.
Authors: Perucca E , Hedges A , Makki KA , Richens A
Published: July 2012

1 The disposition kinetics of lignocaine and antipyrine were compared in eight normal subjects and in eleven patients receiving chronic therapy with antiepileptic drugs. The urinary excretion of D‐glucaric acid (D‐GA) was measured in 16 subjects. 2 In patients treated with antiepileptic drugs antipyrine clearance and D‐GA excretion were significantly increased, whereas lignocaine biovailability was significantly reduced. 3 When all the subjects included in the study were considered, a significant positive correlation could be found between the apparent oral clearance of lignocaine (Dose/area under the blood concentration curve) and both antipyrine clearance (r = 0.73) and D‐GA excretion (r = 0.74). 4 When normal subjects and epileptic patients were considered separately, a significant positive correlation could be confirmed between the apparent oral clearance of lignocaine and both antipyrine clearance (r = 0.71) and D‐GA excretion (r = 0.76) in normal subjects, and between antipyrine clearance and D‐GA excretion (r = 0.75) in epileptic patients. 5 These results suggest that the reduction of the oral availability of lignocaine in epileptic patients is secondary to induction of first‐pass metabolism of the latter drug.
Kinetics of sulphafurazole in undernutrition.
Authors: Shastri RA
Published: July 2012

1 An oral dose of 75 mg/kg body weight was used to study the kinetics of sulphafurazole in wellnourished and undernourished adult subjects. 2 There were no differences in the half‐life, volume of distribution and total body clearance of the drug in the two groups of subjects. 3 The plasma protein binding of sulphafurazole was significantly reduced in the undernouished subjects. 4 It is concluded that alternations in the dosage schedule may not be necessary in the treatment of undernourished adults with sulphafurazole.
Pharmacokinetics of intravenous and oral prednisolone.
Authors: Al‐Habet S , Rogers HJ
Published: July 2012

1 Doses of 16, 32, 48 and 64 mg prednisolone were administered intravenously to normal volunteers who also received 100 prednisolone orally. Plasma prednisolone concentrations were estimated by quantitative thin layer chromatography. 2 The bioavailability fraction was 1.063 +/‐ 0.154 (s.d.) indicating complete availability of prednisolone following oral administration. 3 The mean T 1/2 over all doses were 4.11 +/‐ 0.97 (s.d.) h and there was no evidence of a dose‐ related change in its value. 4 The mean systemic clearance over all doses was 0.104 +/‐ 0.034 (s.d) 1 h‐1 kg‐1. There was no evidence of a dose‐related change in clearance or in the apparent volume of distribution (overall mean 0.588 +/‐ 0.152 1 kg‐1). 5 The area under the plasma concentration‐time curve was linearly related to dose. 6 Plasma concentration‐time curves normalised for dose were superimposable. 7 It was concluded that over the dose range investigated, non‐linear pharmacokinetic behaviour had not been demonstrated in this group of normal volunteers.
Arachidonic acid metabolism, pain and hyperalgesia: the mode of action of non‐steroid mild analgesics.
Authors: Higgs GA
Published: July 2012

1 Cyclo‐oxygenase products such as prostaglandins of the E series and prostacyclin produce the hyperalgesia associated with inflammation. 2 These substances may cause pain and incapacity in some inflammatory conditions. 3 Prostaglandin E2 sensitizes the chemical receptors of afferent pain endings to other inflammatory mediators such as bradykinin and histamine. 4 Unstable intermediates formed in the generation of prostaglandins may also play a role in the production of pain. 5 Drugs such as indomethacin and aspirin which are potent inhibitors of prostaglandin biosynthesis may exert their analgesic effect through this mechanism.
Potential therapeutic applications of aspirin and other cyclo‐oxygenase inhibitors.
Authors: Farah AE , Rosenberg F
Published: July 2012

1 The ubiquitous actions of the cyclo‐oxygenase inhibitors are described. 2 These include the inhibitory effect on prostaglandin synthesis and the direct effect of aspirin on lymphocytes and their ability to produce lymphokines. 3 Aspirin reduces some types of platelet aggregation possibly involving inhibition of the precursors of thromboxane A2 and prostacyclin. 4 The therapeutic implications in relation to transient ischaemic attacks, coronary artery disease and reno‐allograft rejection are discussed. 5 The beneficial and adverse effects on the gastro‐intestinal tract are described. 6 The effects of aspirin‐like drugs on the genito‐urinary tract are described with particular reference to their adverse effects on labour and their therapeutic effect on dysmenorrhoea.
Clinical pharmacokinetics of salicylates: a re‐assessment.
Authors: Levy G
Published: July 2012

1 Aspirin is partly hydrolyzed to salicylic acid during absorption. Absorbed aspirin is rapidly hydrolyzed systemically. Salicylic acid elimination kinetics are dependent on drug concentration due to the limited capacity of two major biotransformation pathways: formation of salicyluric acid and of salicylphenolic glucuronide. 2 The time courses of the various pharmacological effects of single doses of aspirin are not directly coincident with the plasma concentrations of either aspirin or salicylic acid but there is reasonably good evidence that the pharmacological effects are related to the concentration of aspirin, salicylic acid, or both. 3 Steady‐state plasma salicylate concentrations increase more than proportionally with increasing daily dose; the time required to reach steady state increases with increasing daily dose. Dosage intervals of 8 or even 12 h are usually sufficient to maintain plasma salicylate concentrations in the anti‐inflammatory concentration range. Monitoring of plasma salicylate concentrations in this range is facilitated by the relatively small drug concentration fluctuations during a dosing interval at steady‐state. 4 Limited data suggest that the pharmacological activity of salicylate is produced by free (unbound) drug. As the plasma protein binding of salicylic acid is concentration‐dependent and subject to pronounced interindividual differences, it is preferable, at least in principle, to monitor free rather than total concentrations of salicylate in plasma. Although salicylate concentration in saliva reflects the free rather than total salicylate concentration in plasma or serum, use of saliva for indirect monitoring of plasma salicylate concentrations seems to be impractical for technical reasons.
Nephrotoxicity of mild analgesics in the Gunn strain of rat.
Authors: Axelsen RA
Published: July 2012

1 Homozygous members of the Gunn strain of rat, mutant Wistars jaundiced from lack of the enzyme uridine diphosphate glucuronyl transferase, are highly susceptible to analgesic‐induced renal papillary necrosis. 2 A single oral dose of aspirin, phenacetin or paracetamol will produce the lesion, a circumstance which does not occur in other strains. 3 The reasons for this susceptibility have not been determined, but the experimental model should prove useful in further studies of the nephrotoxicity of analgesic drugs.
Chronic toxicity of pyrazolones: the problem of nitrosation.
Authors: Kramer M
Published: July 2012

1 During 6‐month oral toxicity studies of dipyrone in rats and dogs, there was an increase in the number of reticulocytes and Heinz bodies at the highest dose, and a slight haemosiderosis was induced. 2 Similar results were obtained after parenteral administration (intravenously and subcutaneously). 3 These studies fail to contribute to the knowledge of the mechanism of allergic reactions in man. 4 In vitro studies in conditions imitating the physiological environment, show to what extent nitrosation of dipyrone takes place. 5 Subsequent toxicological investigations with the two reaction compounds, or the nitrosation product itself, are powerful instruments to show whether the nitrosamine or nitrosamide formed is dangerous. 6 In the case of pyrazolones, only aminopyrine forms a carcinogenic nitrosamine.
Clinical evaluation of mild analgesics.
Authors: Dundee JW
Published: July 2012

1 Mild analgesics pose particular problems in evaluation because of difficulty in getting suitable patients, the frequent use of oral administration and their long‐term use. 2 Despite their limitations it is possible to quantify both pain severity and pain relief using either ‘pain scores’ or ‘visual analogues’. 3 A trained observer can add information in addition to the patient's interpretation of pain. 4 There are particular problems using crossover studies with analgesics and the sequential method of evaluating results is not as useful with mild analgesics as with more potent drugs. 5 Opinions differ as to the importance of dummy medication in the study of analgesic drugs; difficulties may arise from ethical as well as practical reasons. 6 In the overall evaluation of mild analgesics it is important to consider their long term side effects. 7 Access to a large number of patients with a constant pain of 6‐8 h duration and a smaller number with long‐ term pain is the most important prerequisite in the evaluation of mild analgesic drugs.
Clinical evaluation of mild analgesics in post partum pain.
Authors: Sunshine A
Published: July 2012

1 The design of a clinical study evaluating mild analgesics in post partum patients is dependent on the purpose of the study. Work intended to determine whether a compound has any analgesic properties, requires a different design from a study positioning a drug in the continuum of available oral analgesics. A vital aspect of a well designed study is randomization of the treatments. The level of initial pain and the type of pain must also be stratified. The use of a cross‐over design can decrease patient variation and is therefore very valuable. However, order effects need to be measured. 2 The parameters obtained from the data extend beyond the directly elicited to statistically derived variables. We have derived a method to assign mathematically a numerical score to each patient's verbal report. 3 To reach a meaningful conclusion, one should base the evaluation of the compound on several studies. The interpretation of data from one study must be made with great caution, because of individual variation. In the magnitude of the response some experimenters have found differences between uterine cramp and episiotomy pain, but these have not been consistently reproduced by others.
Use of non‐steroidal anti‐inflammatory drugs in the treatment of pain in cancer.
Authors: Ventafridda V , Fochi C , de Conno D , Sganzerla E
Published: July 2012

1 Prostaglandins may precipitate or exacerbate pain and they may be produced by several tumours. 2 Non‐steroidal anti‐inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis and may also inhibit bone metastases and enhance immune responses. 3 NSAIDs alone or in association with narcotics or psychotropics may not only afford the best pain relief in neoplastic disease, but also modify the progress of the tumour. 4 The effect of NSAIDs on the gastrointestinal tract is generally adverse.
Mild analgesics in postoperative pain.
Authors: Tammisto T , Tigerstedt I
Published: July 2012

1 The intensity of postoperative pain is influenced by many factors, for example, individual variation, site of incision and type of operation, anaesthetic technique, and the interval from the end of operation to the appearance of pain. 2 These factors affect the efficacy of analgesics. 3 Mild analgesics provide adequate pain relief in half of our patients in the immediate postoperative phase when the pain is slight to moderate. 4 The maximum effect of mild analgesics corresponds to that produced by morphine 6‐10 mg. Adequate analgesia may not therefore be provided for the treatment of severe postoperative pain unless narcotic analgesics have been used peroperatively. 5 When mild analgesics are combined with narcotics synergism is achieved. 6 As postoperative pain decreases with time, mild analgesics usually provide adequate pain relief on the first and following postoperative days.
Clinical efficacy of mild analgesics in pain following gynaecological or dental surgery: report on multicentre studies.
Authors: Gomez‐Jimenez J , Franco‐Patino R , Chargoy‐Vera J , Olivares‐Sosa R
Published: July 2012

1 Dipyrone 1.0 g, paracetamol 1.0 g and placebo were compared in a double‐blind parallel group study in patients with episiotomy pain. 2 Patients were stratified according to severity of initial pain (severe or moderate) and the three treatments were randomized for each of these two groups. 3 Two‐hundred and sixty‐four patients entered the study: five patients were excluded from analysis; 127 patients had ‘severe’ pain, 132 ‘moderate’ pain. 4 Both drugs were more effective than placebo, and dipyrone was significantly more effective than paracetamol, particularly where initial pain was severe. 5 The efficacy of dipyrone 1.0 g was compared with paracetamol 1.0 g in relieving pain after tooth extraction. 6 Ninety patients entered the study and 87 were analyzed without stratification according to initial pain severity. 7 Dipyrone was consistently and significantly more effective than paracetamol at every assessment.
Acute intoxication and illness due to mild analgesics.
Authors: Fournier EP
Published: July 2012

1 Acute intoxication with mild analgesics is relatively uncommon in France. In fact, these drugs have accounted for only about 3.5% of acute drug intoxications seen at the Fernand Widal Hospital, Paris, over the past 10 years. 2 On the other hand, 23% of adverse reactions recorded by a drug monitoring service have been attributed to mild analgesics. 3 It is very difficult to establish the true incidence of acute toxicity and adverse reactions caused by these drugs. They are usually taken without medical supervision; it is often difficult to ascribe toxicity to a single agent when combination products are taken so frequently; and the underlying illness and the use of other drugs must also be considered. 4 The methods currently used to obtain adverse reaction and toxicity data have many disadvantages and shortcomings.
Epidemiological evaluation of rare side‐effects of mild analgesics.
Authors: Levy M
Published: July 2012

1 Major adverse reactions to mild analgesics, unless these drugs are abused or taken in high doses, are believed to be rare. 2 However, because of the massive and universal use of these drugs, quantitative measurement of the risk involved is imperative. At present, contradictory regulatory decisions about the use of mild analgesics are based on circumstantial evidence. 3 It is only by the conduct of epidemiological studies that data leading to decisions based on scientifically sound judgments may be obtained.
Gastrointestinal toxicity of minor analgesics.
Authors: Duggan JM
Published: July 2012

1 The evidence for the risk of gastric erosions from aspirin is fragmentary. 2 Occult gastric bleeding following aspirin is poorly studied and the skewed distribution is unexplained; platelet factors may be relevant. 3 Overt gastric bleeding may follow aspirin; the risk is probably about one episode per two million doses. 4 There is epidemiological, clinical, experimental and histopathological evidence for an association between chronic aspirin use and chronic gastric ulcer. 5 An alternative to the Davenport hypothesis is proposed to explain the gastric action of aspirin and the non‐steroidal anti‐ inflammatory agents. 6 Paracetamol is probably bland in its gastric actions.
Plasma noradrenaline concentration in essential hypertension during long‐term beta‐adrenoceptor blockade with oxprenolol.
Authors: Jones DH , Daniel J , Hamilton CA , Reid JL
Published: July 2012

1. Chronic beta‐adrenoceptor blockade with oxprenolol causes elevation of plasma noradrenaline levels, as compared with placebo, despite a significant fall in blood pressure and pulse rate. 2. The plasma noradrenaline concentration is not influenced by the frequency of administration or the formulation of the drug. 3. Plasma noradrenaline levels are not correlated with the plasma concentration of the drug. 4. The changes in plasma noradrenaline concentrations support a peripheral rather than central mechanism of action of beta‐adrenoceptor blockers in man.
Cross tolerance between two dopaminergic ergot derivatives‐ bromocriptine and lergotrile.
Authors: Teychenne PF , Rosin AJ , Plotkin CN , Calne DB
Published: July 2012

1. When initially given to patients with idiopathic parkinsonism, lergotrile induced marked supine arterial hypotension. Tolerance to this hypotensive effect developed and larger doses of lergotrile were administered without this adverse effect. 2. Cross tolerance occurred between lergotrile and a structurally related ergot derivative, bromocriptine. A high dose of lergotrile given to patients who had been on long term bromocriptine therapy did not induce any significant hypotension when compared to placebo whereas hypotension still occurred when lergotrile was given after previous treatment with levodopa.
The effect of semisynthetic penicillins on the binding of bilirubin by neonatal serum.
Authors: Friedman LA , Lewis PJ
Published: July 2012

1. The effect of ampicillin, cloxacillin, flucloxacillin and sulphafurazole on bilirubin on bilirubin binding by pooled human umbilical cord serum and bovine serum albumin was studied in vitro using Sephadex gel filtration. 2. Sulphafurazole displaced bilirubin from binding; both cloxacillins displaced bilirubin from pooled cord serum but not bovine serum albumin. 4. No displacement of bilirubin by the cloxacillins from pooled cord serum could be detected at therapeutic plasma concentrations of these drugs. 5. Scatchard analysis of the interactions showed that displacement of bilirubin by these drugs occurred principally at the primary, high affinity, low capacity binding site.
Quantitative analysis of the disopyramide concentration‐effect relationship.
Authors: Whiting B , Holford NH , Sheiner LB
Published: July 2012

1. A combined pharmacokinetic‐pharmacodynamic model has been used to analyse the relationship between QT prolongation and changes in plasma concentration which occurred after disopyramide was given intravenously and orally to eight healthy subjects. 2. The pharmacokinetic models appropriate to intravenous and oral disopyramide have been extended by an ‘effect compartment’ which has no influence on the predetermined mass of drug in the body. 3. The model incorporates an adjustment for lag of effect behind any rapid changes in plasma concentration such as occur in the early distributive phase following intravenous administration. This permits calculation of the proportionality constant relating plasma concentration to effect. 4. Irrespective of the route of administration the mean (+/‐ s.d.) prolongation of the QT interval was 14.5 +/‐ 6.5 ms/micrograms ml‐1. 5. There was no evidence that metabolite produced during first pass after oral administration made any significant contribution to effect. 6. This modelling technique should be applicable to the study of the concentration‐effect relationship of a number of other drugs, both in health and in disease.
Metabolism of nomifensine (Alival, Merital): isolation and identification of the conjugates of nomifensine‐14C from human urine.
Authors: Hornke I , Fehlhaber HW , Girg M , Jantz H
Published: July 2012

1 It can be stated in regard to the metabolism of nomifensine that the metabolites and also the starting compound are present in alkaline urine almost completely in conjugated form. 2 The metabolites M I‐M III represent about 30% of the radioactivity excreted with urine. Two‐ thirds are N‐glucuronides and one‐third O‐glucuronides. 3 Nearly the entire remainder of the renally eliminated radioactivity in nomifensine which is present in conjugated form as N‐glucuronide. 4 Thus over 90% of the metabolites formed in man and excreted via urine have been identified.
Diurnal variations in plasma diazepam concentrations associated with reciprocal changes in free fraction.
Authors: Naranjo CA , Sellers EM , Giles HG , Abel JG
Published: July 2012

1 The characteristics and mechanism of fluctuations in diazepam and N‐ desmethyldiazepam concentrations and diazepam free fraction were studied in six volunteers, who received diazepam (10 mg, i.v. over 20 min) and in five chronic diazepam users. 2 Within a day total diazepam and N‐desmethyldiazepam concentrations varied significantly (P less than 0.001) and were lower than predicted between 23.00 and 08.00 h and higher by 09.00 h. In contrast, diazepam free fraction also varied significantly (P less than 0.001) and was highest between 23.00 and 08.00 h and lower by 09.00 h. Coincident increases in total diazepam concentrations (P less than 0.005) and decreases in diazepam free fraction were associated with food intake (P less than 0.05). 3 The coincident diurnal variations in diazepam and N‐desmethyldiazepam concentrations and the negative correlation between total diazepam concentration and diazepam free fraction (r = 0.73, P less than 0.001) suggest that the mechanism of the fluctuations is intravascular and tissue redistribution rather than effect on drug biotransformation. 4 These variations may introduce large between and within investigator experimental differences in the determination of kinetic parameters. Free drug concentration varies over the day, and within day variations in clinical effect may be observed.
Elimination of guanfacine in patients with normal and impaired renal function.
Authors: Kirch W , Kohler H , Braun w
Published: July 2012

1. Total body clearance and renal clearance after single intravenous doses of guanfacine were 360 +/‐ 262 (mean +/‐ s.d.) and 233 +/‐ 245 ml/min, respectively, in patients with normal renal function (glomerular filtration rate (GFR) > 90 ml/min), 308 +/‐ 274 and 34 +/‐ 22 ml/min, respectively, in patients with moderately impaired renal function (GFR 30‐10 ml/min), and 257 +/‐ 187 and 18 +/‐ 15 ml/min, respectively, in preuremic patients (GFR < 10 ml/min). 2. The cumulative urinary excretion up to 48 h after a single intravenous injection of guanfacine was 57.0 +/‐ 32.0% in patients with GFR > 90 ml/min, 14.0 +/‐ 9.0% in patients with GFR 30‐10 ml/min and 7.5 +/‐ 2.4% in preuremic patients. 3. In normal as well as impaired renal function the elimination rate constant of guanfacine was 0.05 h‐1, which corresponds to an elimination half‐life of 14 h, independent of renal function. 4. These results suggest that non‐renal elimination of guanfacine plays an important role in patients with renal failure. 5. Intestinal absorption of guanfacine was calculated to be 59 +/‐ 19% in patients with GFR > 90 ml/min, to 68 +/‐ 16% in patients with GFR 30‐10 ml/min, and to 73 +/‐ 36% in preuremic patients.
Effect of guanfacine on blood pressure and renin activity in hypertensive patients.
Authors: Rosenthal J.
Published: July 2012

1. The effect of treatment with guanfacine for 12 weeks on blood pressure and plasma renin activity was investigated in 24 hypertensive patients (WHO I‐III). 2. Systolic, diastolic and mean blood pressure values underwent significant reductions with a constant dose of guanfacine 3 mg daily for 1 week: from 197/115/149 (systolic/diastolic/mean) mmHg before therapy to 166/97/126 mmHg. After 4 weeks of treatment at varying doses, the blood pressure decreased to 157/91/118 mmHg, and after 12 weeks of treatment it levelled off at 147/83/109 mmHg. Heart rate remained essentially unchanged throughout the observation period. 3. During exercise, blood pressure and heart rate increased to the same extent during therapy as before treatment. Orthostatic hypotension was not seen in any of the patients. 4. Renin values decreased under therapy from 3.3 to 2.3 ng ml‐1 h‐1, but at no time during treatment did this decrease correlate with that of blood pressure. 5. Guanfacine treatment was accompanied by relatively few and mild side‐effects.
Acute action of guanfacine on peripheral circulation in hypertensive patients: measurements of arterial flow of the calf and of the forefoot, of venous capacity of the calf, of the blood pressure and of the heart rate.
Authors: Ehringer H. , Berger G. , Ingerle H. , Konecny U. , Woss A.
Published: July 2012

1. The acute action of an intravenous infusion (5 min) of guanfacine in doses of 0.01, 0.02 and 0.04 mg/kg on peripheral circulation was studied in five hypoertensive patients and compared with a placebo in a randomized study. The observations were combined for 2 h after drug administration. 2. Two phases of drug action were seen during and immediately after the administration of guanfacine; a dose‐dependent decrease in blood flow mainly of the forefoot but also in the calf was combined with an increase in systolic and diastolic blood pressures and a decrease in heart rate. Peripheral resistance was increased in this phase. Later, an increase in blood flow to the foot combined with a tendency towards a decrease in blood pressure were observed. 3. These preliminary results show that this second phase of action of guanfacine is dependent on the dose given.
Haemodynamics in hypertensive patients before and during guanfacine treatment.
Authors: Schafer N. , Rauh J. , Rosenthal J.
Published: July 2012

1. The haemodynamic mechanisms underlying the antihypertensive effect of guanfacine during chronic oral administration were studied. 2. Ten patients with essential hypertension were submitted to haemodynamic measurements at rest and during exercise, before and after 12 weeks' treatment with guanfacine alone at a daily dose of between 3 and 15 mg orally. 3. The relevant haemodynamic values were obtained by means of an arterial catheter in the aorta, a venous catheter in the right atrium, and the measurement of cardiac output using the thermodilution method. 4. The antihypertensive efficacy of guanfacine was confirmed. 5. In the seven patients with a high peripheral resistance the main effect of guanfacine was a marked decrease in total peripheral resistance. In three patients with hypertension characterized by high stroke volume and cardiac output, the main effect of guanfacine was to reduce these variables.
Effect of guanfacine on vigilance.
Authors: Heidbreder E. , Pagel G. , Roeckel A. , Heidland A.
Published: July 2012

1. In 20 patients suffering from mild hypertension (WHO classification I‐II) the effect on vigilance was studied under double‐blind conditions. Ten patients were given guanfacine 2 mg daily and ten others a placebo preparation. 2. Before the study and following 2 weeks' medication a battery of tests was applied in which the reaction time and attention were subjected to comparative analysis. The variation in blood pressure and heart rate under mental stress conditions was also tested. 3. The study shows a non‐significant reduction in blood pressure in the guanfacine group without the parameters of vigilance being affected. Under mental stress, there was no impairment of haemodynamic reactions. 4. It is concluded that guanfacine, at the selected dose of 2 mg daily, has no apparent effect on the vigilance of hypertensive patients.