bluuebunny/crossref_metadata_2025 huggingface dataset:
Effects of tobacco smoking and oral contraceptive use on theophylline disposition.
Authors: Gardner MJ , Tornatore KM , Jusko WJ , Kanarkowski R
Published: July 2012

The independent as well as interactive effects of chronic (greater than 6 months) oral contraceptive (OC) use and cigarette smoking on single‐ dose (4 mg/kg) theophylline disposition were assessed in 49 young, healthy women. Significant elevations (40%) in theophylline plasma clearance were found in women who smoked. OC use resulted in decreases in clearance of a similar magnitude (28%). These factors do not appear to interact with respect to theophylline disposition. The combination of main effects tended to cancel one another (clearance of 49.1 ml h‐1 kg‐1 ideal body weight for OC non‐user, non‐smoker, vs 49.7 ml h‐1 kg‐1 for OC user‐smoker). Single dose exposure to OC in non‐users did not significantly alter theophylline pharmacokinetics for the group as a whole. However, in the subgroup of smoking subjects, significant decreases in clearance were evident (P less than 0.05). Analogous results were found for half‐life. Volume of distribution was slightly diminished in smokers, but was unaffected in OC users. Areas under the serum concentration‐time (AUC) profiles of norgestrel and ethinyloestradiol were examined in 27 women as indices of OC exposure. The smallest values of theophylline clearance were found in the subjects with largest AUC of both OC steroids. Appropriate statistical analyses of data which are influenced by multiple factors are discussed. Special concern is needed when the factor partitioning process yields subgroups of unequal sizes.
The effective plasma concentrations of sulmazol (AR‐L 115 BS) on haemodynamics in chronic heart failure.
Authors: Renard M , Jacobs P , Mols P , Melot C , Dresse A , Bernard R
Published: July 2012

Sulmazol (AR‐L 115 BS) is a new inotropic drug which has arterial and venous vasodilating properties. We used it in seven patients with severe refractory heart failure to determine the effective plasma concentration levels and the most effective bolus dose on haemodynamics. The haemodynamic monitoring included a Swan‐Ganz catheter in the pulmonary artery and a radial catheter. Haemodynamic measurements and plasma concentration determinations were performed before sulmazol injection and at 5, 10 and 30 min after a bolus 0.25, 0.50, 0.75 mg/kg. We observed a gradual increase in cardiac index and decrease in pulmonary wedge pressure when plasma concentration levels rose but the beneficial effects were mainly observed for sulmazol plasma concentrations above 1 microgram/ml. A bolus injection of 0.75 mg/kg was effective in all cases: a significant increase of cardiac index (1.9 to 2.5 1 min‐1 m‐2; P less than 0.001) and a significant decrease in pulmonary wedge pressure (30 to 25 mm Hg; P less than 0.005) and right atrial pressure (13 to 10 mm Hg, P less than 0.01) were observed. In these patients sulmazol improved the severely deteriorated left ventricular function without affecting heart rate and blood pressure.
Pharmacokinetic and pharmacodynamic characteristics of trazodone in the elderly.
Authors: Bayer AJ , Pathy MS , Ankier SI
Published: July 2012

The pharmacokinetic and some pharmacodynamic characteristics of a single oral dose of 100 mg trazodone were compared in young and elderly volunteers. The maximum plasma concentration of trazodone was similar in both age groups. The time to maximum concentration was apparently prolonged in four subjects who swallowed the capsule with a minimal volume of fluid. This may have been due to the capsule being retained in the oesophagus. The terminal phase half‐life of trazodone was significantly prolonged (P less than 0.05) and area under the plasma concentration‐time curve was significantly larger (P less than 0.01) in the elderly. Apparent oral clearance was significantly reduced (P less than 0.01) in the elderly. Measurement of critical flicker fusion threshold and subjective assessment of alertness using a visual analogue scale, confirmed the sedative effect of trazodone in both age groups. The elderly subjects were less alert for a longer period following drug administration than the young. The differing pharmacokinetic and pharmacodynamic characteristics of trazodone in the young and elderly may be due to an age‐related reduction in hepatic drug‐metabolising activity, a difference in regional distribution or a change in CNS sensitivity to the drug.
Interaction of bemetizide and indomethacin in the kidney.
Authors: Dusing R , Nicolas V , Glatte B , Glanzer K , Kipnowski J , Kramer HJ
Published: July 2012

The effect of a single oral dose of 25 mg bemetizide on renal function without and with concomitant administration of the prostaglandin synthesis inhibitor indomethacin was investigated in ten healthy volunteers during sustained water diuresis. Bemetizide induced a significant increase in urinary sodium and chloride excretion from 196 +/‐ 30 and 163 +/‐ 28 mumol/min to 690 +/‐ 54 and 537 +/‐ 51 mumol/min (P less than 0.01). This effect occurred in the absence of changes in glomerular filtration rate, urinary excretion of phosphate or the delivery of chloride beyond the proximal nephron to the distal tubules (distal delivery) [(CH2O + CCl)/GFR . 100], but was associated with a significant decrease in distal fractional chloride absorption (DFACl) [CH2O/(CH2O + CCl)] from 0.84 +/‐ 0.02 to 0.63 +/‐ 0.02 (P less than 0.01). Bemetizide also increased urinary excretion of prostaglandin (PG) E2. Concomitant indomethacin administration significantly suppressed urinary excretion of PGE2 and markedly decreased urinary excretion of sodium and chloride during control and following bemetizide administration. Indomethacin had no effect on glomerular filtration rate, urinary excretion of phosphate, distal delivery or the urinary excretion of bemetizide but significantly increased DFACl both during control and after bemetizide administration. Our results show that bemetizide as a thiazide‐diuretic acts in the diluting segments of the nephron. Indomethacin administration induces retention of sodium and chloride and blunts the renal effects of bemetizide via increased absorption in the diluting segments. The interaction of both drugs most likely represents a pharmacodynamic interaction.
Steady state pharmacokinetic haemodynamic studies of intravenous nitroglycerin in congestive cardiac failure.
Authors: Armstrong PW , Watts DG , Moffat JA
Published: July 2012

We conducted pharmacokinetic haemodynamic studies in 10 patients with congestive cardiac failure to determine both the time to steady state concentration after commencement of a standard infusion rate of 21 micrograms/min i.v. GTN and the haemodynamic response once steady state plasma concentration ws achieved. Nitroglycerin was detected in plasma 2 min after commencement of the infusion, the concentration rose to a peak of approximately 4 ng/ml at 30 min and was maintained throughout the balance of the infusion period. During GTN infusion heart rate, systolic blood pressure and cardiac index were unchanged; there was significant declines (P less than 0.01) in pulmonary systolic pressure (SPA) (52 to 42 mm Hg), pulmonary capillary wedge pressure (PCWP) (26 to 20 mm Hg), and right atrial pressure (RAP) (12 to 8 mm Hg). These pressure changes were first evident within 5 min, approached maximum by 10 min and were maintained throughout the remainder of the infusion period. A one compartment model fitted to haemodynamic and GTN data revealed time constants (+/‐ approximate standard error) for SPA, PCWP, RAP and GTN of 8.2 (3.4), 9.7 (3.0), 8.1 (3.8) and 8.1 (1.9 respectively. Clearance for GTN was 6.2 +/‐ 2.7 (s.d.) 1 min. These data demonstrate steady state concentration of GTN is approached asymptotically with a time constant of 8.1 min during i.v. infusion of 21 micrograms/min. The time constants for haemodynamic measurement most sensitive to GTN's effect, i.e. SPA, PCW and RAP were remarkably similar to the time constant found for GTN concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Dipyridamole increases red cell deformability.
Authors: Sowemimo‐Coker SO , Kovacs IB , Pickles H , Hedges A , Turner P
Published: July 2012

The effects of dipyridamole on red cell filterability both in vitro and ex vivo were measured. In a balanced, randomised and double‐blind trial, six healthy male and female volunteers (22‐37 years) were given dipyridamole 400 mg/day or matching placebo in four divided doses for 3 days, and heparinised venous blood samples were taken 1 h after the ingestion of the last dose. Filterability of red cells was increased significantly (P less than 0.05 paired t‐test) when the subjects were on dipyridamole compared with placebo. In separate experiments, 15 min incubation with 2 or 20 micrograms/ml dipyridamole in vitro was found to have no effect on the filterability of freshly prepared red cell suspensions. After 24 h storage at 4 degrees C, the filterability of red cells was significantly decreased (P less than 0.01) and this could be partially prevented by adding dipyridamole to the stored cells (P less than 0.05). These results suggest that dipyridamole has an effect on the behaviour of the red cell membrane to increase the deformability of the cells. This may contribute to its therapeutic effect.
Ranitidine does not affect gonadal function in man.
Authors: Wang C , Wong KL , Lam KC , Lai CL
Published: July 2012

We studied the effect of ranitidine on gonadal function in 20 male subjects with chronic duodenal ulcer. Eleven were treated with ranitidine 150 mg twice daily for 3 months and 150 mg at night for 9 months, nine with placebo for 3 months. Similar to placebo, treatment with ranitidine did not influence basal serum concentrations of testosterone (T), luteinizing hormone (LH), follicle stimulating hormone (FSH) and prolactin (PRL). No significant changes were found in sperm concentration, motility or morphology. Ranitidine does not affect gonadal function in man.
The effect of cimetidine on tolbutamide kinetics.
Authors: Dey NG , Castleden CM , Ward J , Cornhill J , McBurney A
Published: July 2012

Although possible on theoretical grounds, no interaction between cimetidine and tolbutamide could be demonstrated in ten healthy volunteers. The plasma tolbutamide concentrations over 12 h following 0.5 g orally were essentially the same before and after 1 and 7 days cimetidine (400 mg twice daily).
A prospective randomised controlled trial of diazepam (valium) vs emulsified diazepam (diazemuls) as a premedication for upper gastrointestinal endoscopy.
Authors: Gleeson D , Rose JD , Smith PM
Published: July 2012

Two hundred and forty four patients were randomised to receive either diazepam or emulsified diazepam (diazemuls) intravenously prior to routine upper gastrointestinal endoscopy. The groups were comparable with regard to age, sex, medical condition, vein size, and amount of drug administered. A quantitative assessment of symptoms at the injection site during the ensuing week was made by analysing questionnaires on pain and tenderness, which the patients graded each day, on a scale 0‐3. Twenty‐one out of 82 patients who received diazepam (25.6%) and 22 out of 84 who received diazemuls (26.2%) had local symptoms. Although the mean symptom scores over 7 days for the two groups were not different (5.95 +/‐ 5.19 and 7.27 +/‐ 6.30 respectively), more patients who received diazepam reported induration (P = 0.033). In 112 patients, signs of thrombosis in the injected veins were looked for 3‐7 weeks later without knowledge of the preparation given. Thrombosis was present in 13 (25%) patients who had received diazepam and two (3.6%) who had received diazemuls (P less than 0.002). Only eight (53%) patients with thrombosed veins had symptoms. Thrombosis after intravenous injection of diazepam or diazemuls may be symptomless, and is significantly less likely following diazemuls.
Active metabolites of acenocoumarol: do they contribute to the therapeutic effect?
Authors: Thijssen HH , Baars LG
Published: July 2012

The pharmacokinetics and pharmacodynamics of racemic acenocoumarol (AC), the amino (AM) and acetamido (AA) derivative were investigated in healthy volunteers after administration of a single oral (10 mg) dose. All three coumarins were rapidly absorbed from the gastrointestinal tract. The elimination half‐lives were 10.9, 10.4, and 4.1 h, for AC, AM and AA, respectively. After the oral administration of AC, no AM and AA was detected in the plasma, and less than 1% of the dose was recovered in the urine (0‐24 h) as AM. Renal clearance was the main route of elimination of AM and AA; the former by glomerular filtration, the latter by active excretion. Binding to serum proteins was the highest for AC (1.52% free). AM and AA were less tightly bound (about 3% free). AM or AA did not interfere with the AC plasma protein binding. The oral administration of AC resulted in a rise in prothrombin time with a maximum effect at 24 to 30 h. No anticoagulant activity was observed upon the administration of AM and AA. The results indicate that the compounds AM and AA, if they are formed out of AC at all, do not contribute to the anticoagulant activity of AC.
Effect of chloroquine and primaquine on antipyrine metabolism.
Authors: Back DJ , Purba HS , Park BK , Ward SA , Orme ML
Published: July 2012

The effects of two antimalarial drugs, chloroquine and primaquine on antipyrine kinetics and metabolism have been studied in volunteers. Chloroquine (250 mg) given 2 h before antipyrine (600 mg orally) had no effect on salivary kinetics of antipyrine or on the urinary recovery of metabolites. Primaquine (45 mg) given 2 h before antipyrine (300 mg orally), increased antipyrine half‐life (calculated from 0‐24 h) from 12.7 +/‐ 3.2 (mean +/‐ s.d.) to 25.3 +/‐ 3.9 h and decreased clearance from 3.01 +/‐ 0.67 to 1.32 +/‐ 0.32 1 h‐1. There was no change in the apparent volume of distribution. Antipyrine half life changed with time in the presence of primaquine and when calculated between 24 and 48 h had returned to control. After primaquine, the metabolic clearance (calculated from 0‐24 h) of antipyrine to its three main metabolites, 3‐ hydroxymethylantipyrine, 4‐hydroxyantipyrine and norantipyrine was significantly reduced. There was no selective effect on a particular metabolic pathway. There was no change in 6 beta‐hydroxycortisol excretion (expressed as a ratio of total 17‐hydroxy‐corticosteroids) in the period 0‐48 h following primaquine administration. The inhibition of hepatic metabolism by primaquine but not the structurally related chloroquine may be an example of a structure activity phenomenon and could be of clinical significance.
Clinical pharmacological studies with prazosin during pregnancy complicated by hypertension.
Authors: Rubin PC , Butters L , Low RA , Reid JL
Published: July 2012

The disposition and effect of orally administered prazosin have been studied in eight women with hypertension which was uncontrolled by beta‐ adrenoceptor blockade during the last trimester of pregnancy. Results were compared with healthy men of similar age. The median time to peak concentration was 165 min during pregnancy and 120 min in the men (P less than 0.04). Area under the concentration vs time curve was 3914 ng l‐1 min in pregnancy and 2439 ng l‐1 min in the men (P less than 0.06). Mean elimination half‐life was 171 min in the pregnant women and 130 min in the men (P less than 0.01). Blood pressure was lowered by prazosin in both supine and standing positions. Blood pressure control remained satisfactory in six of the eight women and the median prolongation of pregnancy was 22 days. Neonatal outcome was satisfactory and all babies are developing normally. We conclude that prazosin is more slowly, but apparently more completely, absorbed during pregnancy and that its half‐life is slightly prolonged. Prazosin appears to be both effective and safe when used during the last trimester to control blood pressure.
Effects of beta 1‐adrenoceptor agonism on plasma renin activity in normal men.
Authors: Staessen J , Cattaert A , De Schaepdryver A , Fagard R , Lijnen P , Moerman E , Amery A
Published: July 2012

The contribution of beta 1‐adrenoceptors to the regulation of plasma renin activity was investigated in nine healthy sodium‐replete volunteers: seven subjects received a cumulative intravenous dose of 75 micrograms/kg prenalterol, a predominant beta 1‐adrenoceptor agonist, and two subjects only vehiculum. In the seven actively treated subjects beta 1‐adrenoceptor agonism increased (P less than 0.001) systolic intra‐arterial pressure by an average of 16 +/‐ 4 mm Hg and heart rate by 19 +/‐ 3 beats min. These increases were significantly (P less than 0.04) different from the changes observed in the two control subjects (+ 3 +/‐ 4 mm Hg and ‐1 +/‐ 4 beats/min, respectively). Plasma renin activity, however, tended to decrease in both the actively (‐38%) and saline (‐28%) treated subjects. Predominant beta 1‐adrenoceptor agonism, powerful enough to increase systolic pressure and heart rate does not increase plasma renin activity in supine sodium‐replete normal man.
A comparison of a combination of penbutolol and frusemide with the two compounds individually in the treatment of hypertension.
Authors: Chadha DR , Houtzagers JJ
Published: July 2012

Forty‐one patients completed a randomized, double‐blind, between‐group comparison of a combination of penbutolol and frusemide, with penbutolol alone, and frusemide alone in the management of mild to moderate essential hypertension. The results suggest that the combination caused a superior reduction in systolic and diastolic pressure compared with penbutolol and a superior reduction in systolic blood pressure compared with frusemide.
Effect of ICI 118551 on bronchial beta‐adrenoceptor function and exercise heart rate in normal man.
Authors: Tattersfield AE , Cragg DJ
Published: July 2012

To determine whether the beta 2‐selectivity of ICI 118551 extended to human airways, we measured bronchial beta‐adrenoceptor blockade and the reduction in exercise heart rate in six normal subjects on different occasions after ingestion of ICI 118551 20 or 50 mg, propranolol 40 mg or placebo in random order. Bronchial beta‐adrenoceptor blockade after each active drug was measured as the displacement of the airway dose‐ response curve to salbutamol and expressed as a dose ratio. Exercise heart rate was measured during the fifth minute of steady state exercise at 70% of the subject's maximum work load. The mean dose ratios for the salbutamol airway dose‐response curves following ICI 118551 20 and 50 mg and propranolol 40 mg were 11, 55 and 48 respectively. The mean reductions in exercise heart rate for the three drugs were 0.6, 6.6 and 16.6% respectively. These results confirm that the beta 2‐selectivity of ICI 118551 includes airway beta 2‐ adrenoceptors in man.
Cardiovascular effects of AQ‐A 39 in healthy volunteers.
Authors: Hilaire J , Broustet JP , Colle JP , Theron M
Published: July 2012

Ten healthy male volunteers performed maximal exercise tests on a bicycle ergometer. A control reading was obtained; at a second session propranolol 80 mg was given, and then placebo, 100 mg or 200 mg AQ‐A 39 were administered in a randomised double‐blind manner. At peak exercise, the heart rate averaged 191.6 beats/min during the control test, 185.8 beats/min after placebo, 172.4 beats/min with 100 mg of AQ‐ A 39 (‐10%), 166.0 (beats/min) with 200 mg of AQ‐A 39 (‐13.4%); with 80 mg of propranolol, the heart rate averaged 132.8 beats/min and the workload accomplished was substantially lower than that accomplished with AQ‐A 39 and placebo which remained the same as in the control test. No effect on blood pressure was observed. The rate pressure product was significantly reduced with AQ‐A 39.
Dose tolerance to lorazepam develop with once weekly dosing?
Authors: File SE , Lister RG
Published: July 2012

The effect of once weekly administration of lorazepam (2.5 mg) to benzodiazepine‐naive student volunteers was assessed in a number of performance tests and on self‐ratings. Tolerance developed to the effects of lorazepam on finger‐tapping and on self‐ratings of dizziness. No tolerance was observed to the drug‐induced impairment in a nonsense‐syllable paired associate learning test or to the effects on self‐ratings of sedation or on heart rate. It is suggested that the reduced impairment in the digit‐symbol substitution test observed in weeks 2 and 3 of lorazepam treatment was due to a ‘masked’ practice effect rather than to tolerance. Test‐retest correlation coefficients were calculated for all the tests used. The effect of lorazepam in each test was also correlated with its effect in the other tests. There were significant correlations in performance on placebo in the finger‐ tapping (r = 0.66), digit‐symbol substitution (r = 0.94), symbol copying (r = 0.96) and nonsense‐syllable learning (r = 0.74) tests. It is suggested that benzodiazepine experience should be given to drug‐ naive subjects before they are used in cross‐over experiments that involve this class of compound, since the major change in impairment occurred between the first and second exposure to lorazepam.
The effect of intravenous epoprostenol (prostacyclin, PGI2) on cerebral blood flow and cardiac output in man.
Authors: Cook PJ , Maidment CG , Dandona P , Hutton RA , James IM
Published: July 2012

Epoprostenol (prostacyclin, PGI2) was given intravenously to seven healthy volunteers in a dose of 4 ng kg‐1 min‐1 over a 30 min period. Diastolic blood pressure fell but there was no change in cardiac output. The mean PGI2 concentration at the end of the infusion was 0.43 ng/ml (1.1 nM) and a significant inhibition of ADP‐induced platelet aggregation occurred. Although obvious facial flushing occurred in all subjects and some subjects complained of headache, cerebral blood flow tended to fall. The results do not support the hypothesis that PGI2 acts as a physiological vasodilator involved in the homeostasis of normal cerebral blood flow.
Arachidonic acid and prostaglandin levels in dithranol erythema: time course study.
Authors: Barr RM , Misch KJ , Hensby CN , Mallet AI , Greaves MW
Published: July 2012

Arachidonic acid and prostaglandins were measured in uninvolved psoriatic skin before and after treatment for up to 24 h with dithranol. Prior to treatment, skin exudate contained 2744 ng ml‐1 arachidonic acid and 26.4 ng ml‐1 PGE2. After treatment with dithranol, the arachidonic acid concentration increased to a maximum of 5556 ng ml‐ 1 at 48 h whilst PGE2 increased to 93.4 ng ml‐1 at 12 h and then declined. The erythemal response was apparent at 6‐12 h and maximal at 72 h. These results suggest that PGE2 mediates the early development of dithranol erythema.
The effect of selective and non‐selective beta‐adrenoceptor blockade, and of naloxone infusion, on the hormonal mechanisms of recovery from insulin‐induced hypoglycaemia in man.
Authors: Armitstead JG , Lightman SL , Brown MJ , Causon RC , Vaughan NJ
Published: July 2012

The rise in plasma adenosine‐3′,5′‐monophosphate occurring in response to insulin induced hypoglycaemia in normal human subjects, was abolished by non‐selective beta‐adrenoceptor blockade but unaffected by selective beta 1‐adrenoceptor blockade. This implies that the rise is secondary to beta 2‐adrenoceptor stimulation. The abolition of this rise by non‐selective beta‐adrenoceptor blockade had no pronounced effect on the recovery from hypoglycaemia. Endogenous opiate receptor blockade with naloxone had no significant effect on the recovery from insulin induced hypoglycaemia, or the hormonal mechanisms involved.
Metabolism of digoxin after oral and intrajejunal administration.
Authors: Magnusson JO
Published: July 2012

To study the influence of administration site on metabolism of digoxin in the gut, urinary excretion of digoxin and its metabolites was compared after oral and intrajejunal administration of [3H]‐digoxin solution to eight healthy volunteers, using liquid chromatography for the drug analysis. Dihydrodigoxin was not excreted in higher amounts after the more distal administration. The excretions of hydrolytic and non‐extractable metabolites were significantly greater after the oral administration.
Chemical structure and properties of midazolam compared with other benzodiazepines.
Authors: Gerecke M
Published: July 2012

A short review is given of the basic chemical development in the field of ‘classical’ and ‘annelated’ benzodiazepines, distinguishing between pro‐drugs and directly acting compounds. Some properties of midazolam that are of special interest for its practical use are discussed, such as: the basicity of its imidazole ring nitrogen, which allows water‐ soluble salts and well‐tolerated aqueous injectable solutions to be prepared; its stability to hydrolytic degradation; its rapid metabolic inactivation, which is mainly determined by the methyl group on the imidazole ring, and which is much faster than that of classical benzodiazepines.
Preclinical pharmacology of midazolam.
Authors: Pieri L
Published: July 2012

Midazolam, a new imidazobenzodiazepine, forms salts that are stable in water solution, and has an overall pharmacological potency similar to that of diazepam but a much shorter duration of action. It produces all the characteristic effects of the benzodiazepine class. Its metabolites account for only a negligible part, if any, of its pharmacological effects observed in the mouse. The time course of its anticonvulsant activity, studied with different experimental protocols and by different routes of administration, revealed an almost immediate onset of action. Midazolam was slightly more potent, and its duration of action was shorter than diazepam, in enhancing presynaptic inhibition in the spinal cord of cats and in depressing spontaneous activity of cerebellar Purkinje cells in the rat. Midazolam decreased spontaneous multiunit activity (MUA) in different nuclei of the brain in ‘encephale isole’ rats. This depression was reversed by Ro 15‐1788, a recently discovered selective benzodiazepine antagonist. Midazolam and diazepam decreased the cyclic GMP level in the cerebellum of rats with about the same potency; the effect of midazolam was of much shorter duration than that of diazepam. Midazolam had one‐third the potency of diazepam in displacing 3H‐flunitrazepam in mouse brain in vivo, and also in this case the effect of midazolam was of brief duration, as compared with diazepam. Midazolam in therapeutic doses was virtually ineffective in the cardiovascular system of conscious dogs after p.o. or i.v. administration. No direct effects of the drug on autonomic functions were found. The animal data suggest the usefulness of midazolam as an oral sleep‐inducer, as an agent for i.v. induction of anaesthesia and as an i.v. or i.m. anticonvulsant in status epilepticus or tetanus, because of its rapid onset of action and its excellent local tolerance as water‐soluble injection form.
Safety aspects of midazolam.
Authors: Schlappi B
Published: July 2012

The LD50 in the rat and the mouse is about 1600 mg/kg (oral administration) and 75 mg/kg (rat) and 50 mg/kg (mouse) on intravenous administration. Subchronic oral studies over 13 weeks in doses of 5, 15 and 45 mg/kg/day in the dog and 50, 100 and 200 mg/kg/day in the rat have demonstrated minimal toxicity for midazolam, as for other benzodiazepines. High doses produced increased liver weight in the rat and the expected increases in alkaline phosphatase in the dog (species‐ specific reaction). Detailed blood and urine analyses as well as histological examination of organs produced no indication of changes relevant for man. Subchronic parenteral studies (i.v. and i.m. for five weeks) using up to 6 mg/kg/day in dogs and rats showed the compound to be not only systemically, but also locally, extremely well tolerated. Reproduction toxicology studies have shown that midazolam is neither embryotoxic nor teratogenic and that it has no effect on the fertility and post‐natal development of animals. In the AMES test and the fluctuation test, midazolam had no mutagenic effect.
Effect of midazolam on sleep.
Authors: Ziegler G , Ludwig L , Klotz U
Published: July 2012

Midazolam (15 mg p.o.) was compared with placebo and oxazepam (15 mg) in 12 healthy volunteers and in seven patients suffering from sleep disorders in a single‐blind cross‐over study. Each treatment period lasted for seven days. The last two nights were spent in a sleep laboratory to evaluate the efficacy of the three compounds. The drugs were given to the patients every day and to the volunteers only on the recorded nights immediately before going to bed. The subjects rated their quality of sleep every morning after administration. Midazolam shortened (P = 0.025) the sleep latency to first stage 2 (t2 = 29 min) compared with placebo (t2 = 58.7) min and oxazepam (t2 = 55.4 min) in the group of patients; in the group of volunteers t2 was shortened (P = 0.05) only by midazolam (t2 = 17.2 min) compared with placebo (t2 = 24.6 min). REM suppression was not found in the group of patients, while sleep stages 3 + 4 were slightly reduced. However, a suppression of REM by midazolam (P = 0.025) and oxazepam (P = 0.01) was observed in the volunteers compared with placebo. The effects of midazolam seemed to be related to its pharmacokinetics. The drug increased the amount of stage 3 + 4 (P = 0.01) and suppressed REM (P = 0.005) compared with oxazepam and placebo, only during the first 3 h, when it was measurable in plasma. Midazolam was rated by the patients more favourably than oxazepam (P = 0.025) and placebo (P = 0.05). The volunteers noted no difference amongst the three treatments, but reported hangover effects after oxazepam.
Automatic scoring of polygraphic sleep recordings: midazolam in insomniacs.
Authors: Gath I , Bar‐On E , Rogowski Z , Bental E
Published: July 2012

Midazolam in doses of 0.21‐0.46 mg/kg was given to four insomniacs for 27 days, and to a fifth insomniac for an additional 124 days, to assess its short, intermediate, long‐term and long‐standing efficacy. Automatic analysis of the polygraphic sleep recordings was carried out employing real‐time signal processing (based on linear prediction), and an off‐line sequential fuzzy clustering. Total sleep length did not vary significantly during medication, whereas other efficacy parameters such as sleep onset latency, wake time after sleep onset and number of nightly awakenings decreased significantly throughout the period of active medication. In one patient, midazolam was still effective after 151 days of administration. The ultrashort action (probably 3‐4 h) of midazolam could be demonstrated by the distribution of the efficacy parameters, dividing the night into 2‐h periods, by the unchanged total sleep length during medication compared with baseline and by the lack of any subjective clinical symptoms of hangover. The quantitative analysis of the signals showed that, although a decrease in the total amount of slow‐wave sleep during long‐term medication and withdrawal was detected, the total relative power in the delta band increased during drug administration. This was interpreted as redistribution of the delta activity during active medication. A lengthening of REM sleep was found during active medication probably attributable to intranight rebound. This was not followed by any clinical symptom of clinical REM rebound.(ABSTRACT TRUNCATED AT 250 WORDS)
Efficacy and safety of midazolam and oxazepam in insomniacs.
Authors: Lupolover R , Ballmer U , Helcl J , Escher J , Pavletic B
Published: July 2012

In a multicentre, double‐blind, parallel study performed in 78 hospitalized patients who complained of mild, moderate or severe insomnia, the efficacy and safety of 15 mg midazolam were compared with those of 15 mg oxazepam, both orally administered. The results showed statistically significant better results in the onset of sleep in the patients treated with midazolam. Other sleep parameters, such as quality and duration of sleep as well as the condition of the patients on morning awakenings, were also improved in more patients treated with midazolam. Safety (clinical and biological) was very good in both groups of patients.
The toxicology of brotizolam.
Authors: Hewett C , Kreuzer H , Kollmer H , Niggeschulze A , Stotzer H
Published: July 2012

Acute studies. Following oral or intraperitoneal administration, toxicity was very low (LD50 in rodents greater than 10,000 and greater than 900 mg/kg, respectively). Subacute and chronic studies in rodents. Signs of toxicity were seen only at doses of 400 mg/kg or more. Histopathological changes were found only in the 78‐week study. Subacute studies in dogs (intravenous) and primates (oral). In dogs, doses of 0.1 and 0.3 mg/kg produced ataxia, salivation, and diarrhoea. In monkeys doses of 7 mg/kg or higher produced ataxia, increased appetite, hyperreflexive muscular spasms, increase in liver weight, and lipid depletion of the adrenal cortex. Reproductive studies in the rat and rabbit. Repeated doses of up to 30 mg/kg were not associated with any disturbance in fertility; nor were any embryotoxic or teratogenic effects observed. When dams wer treated with 400 mg/kg, litter mortality was markedly increased. Mutagenicity studies. The four different tests performed gave no indication of any mutagenic effect. Local tolerance tests in the rabbit. Brotizolam was well tolerated when administered intramuscularly, intra‐arterially, or intravenously. Carcinogenicity studies in rodents. The mouse study showed no evidence of a tumourigenic effect. The rat study is still being evaluated. The toxicological studies demonstrate that brotizolam has an unusually wide therapeutic range. Findings of toxicological significance, most of which were reversible, were first recorded at doses of 7‐10 mg/kg, i.e. at more than 100‐times the intended human therapeutic dose.
Tolerance studies with brotizolam in hospitalized patients.
Authors: von Delbruck O , Goetzke E , Nagel C
Published: July 2012

A long‐term study of brotizolam (minimum 4 weeks: maximum 26 weeks) was carried out in hospitalized patients (29 to 95 years) who complained of sleep disturbance. 3.0% of the patients used 0.125 mg, 86.4% used 0.25 mg, and 10.0% used 0.5 mg daily. During the trial there was no evidence of tolerance. There were no symptoms of overdosage, physical and psychological dependency or withdrawal, and there were no interactions with the concurrently prescribed drugs. There were no changes in vital functions, haematology, or in the biochemical investigations of blood or urine which could be attributed to the drug.
Comparative studies on the efficacy of brotizolam and nitrazepam: a multi‐centre study.
Authors: Lohmann H , von Delbruck O , Findeisen P
Published: July 2012

Efficacy and tolerability of brotizolam (0.25 and 0.5 mg) were compared over a 6‐day period with nitrazepam (5.0 mg) in middle‐aged patients (less than 65 years) with sleep disturbances requiring medication. The study was double‐blind and randomised with a cross‐over design. Each preparation reduced sleep onset latency and frequency of awakenings, and improved quality and duration of sleep as well as subjective condition on awakening. Brotizolam 0.25 mg was found to be equally effective as 0.5 mg, and so the lower dose is recommended for the middle aged.
Brotizolam and chronic insomnia: a multi‐centre study.
Authors: Fritz‐Osner A , Arias‐Ortiz JL , Dorantes JF , Rabago‐Sanchez J , Rodriguez‐ Tenorio A , Sanchez‐Martinez J
Published: July 2012

A double‐blind, crossover study was carried out on the acceptability of three doses of brotizolam (0.125, 0.25 and 0.5 mg) in chronic insomniacs aged between 21 and 75 years (33 men: 42 women). Patients reported a shorter time to fall asleep and less nocturnal awakenings. Improvement in sleep was evident during the first week of the study when each patient received 0.25 mg. There were no dose‐related side‐ effects, and on withdrawal from the medication there was no evidence of disturbed sleep which would have suggested a rebound effect.
Studies in general practice with brotizolam.
Authors: Wheatley D
Published: July 2012

Brotizolam (0.25 mg) was compared with placebo, and in a separate study, with nitrazepam (5.0 mg) in patients being treated for insomnia in general practice. Brotizolam (0.25 mg) and nitrazepam (5.0 mg) were equally effective and there was no evidence of residual effects the next day with either drug.
Some tetracycline drugs suppress mitogen‐stimulated lymphocyte growth but others do not.
Authors: Potts RC , MacConnachie A. , Brown RA , Gibbs JH , Robertson AJ , Hassan HA , Beck JS
Published: July 2012

Eight tetracycline drugs were tested for inhibitory effect on phytohaemagglutinin (PHA) stimulated growth (measured by [3H]‐TdR uptake) of peripheral blood mononuclear cells: at least 26 normal subjects were tested with each drug. Doxycycline reduced DNA synthesis appreciably at concentrations within and just above the therapeutic range of blood levels: it was the most potent inhibitor, but demeclocycline, methacycline and minocycline had similar, if less potent, effects. Tetracycline, oxytetracycline, chlortetracycline and clomocycline did not inhibit DNA synthesis of 3‐day cultures even at concentrations five to ten times greater than the therapeutic blood level. Volume spectroscopy measurements showed that none of the eight tetracycline drugs interfered with the recruitment of cells into G1‐ phase growth of the first cell cycle after PHA stimulation.
Effects of graded oral doses of meptazinol and pentazocine in comparison with placebo on experimentally induced pain in healthy humans.
Authors: Stacher G. , Steinringer H. , Winklehner S. , Mittelbach G. , Schneider C.
Published: July 2012

The opioid agonist/antagonist meptazinol has proven to exert significant analgesia in a series of painful conditions. This study investigated the effects of single oral doses of meptazinol 100, 200, and 400 mg in comparison with pentazocine 50 and 100 mg and with placebo on experimentally induced pain. In addition, the side effect profiles were assessed. Twenty‐four healthy subjects participated each in six experiments in which they received, in random double‐blind fashion, each of the treatments. Every experiment comprised 10 series of measurements, two before and eight after drug administration, carried out at 30 min intervals. Meptazinol produced significant dose‐ related increases of threshold and tolerance to electrically and thermally induced pain. Meptazinol 400 mg was significantly superior to placebo in all pain measures and proved as effective as pentazocine 50 and 100 mg, which yielded about equal effects. Meptazinol 200 mg was significantly weaker than pentazocine 50 mg and differed significantly from placebo only in its effects on pain tolerance. Meptazinol did not cause any severe side effects or systematic alterations of respiration, blood pressure, heart rate and central nervous functions. Pentazocine caused a higher number and more severe side effects, one subject reporting severe dysphoria after pentazocine 100 mg. The results give further evidence that meptazinol is well suited to replace other opioid analgesics compromised by a high incidence of adverse effects.
Colonic release of 5‐amino salicylic acid from an oral preparation in active ulcerative colitis.
Authors: Dew MJ , Ryder RE , Evans N. , Evans BK , Rhodes J.
Published: July 2012

5‐amino salicylic acid coated with acrylic based resin was given orally to eight patients with active ulcerative colitis. Abdominal X‐rays confirmed that the preparation released its contents in the terminal ileum and proximal colon. Differences between individuals were marked; the plasma ‘concentration‐time profile’ reflected variations in the time taken for tablets to reach the terminal ileum.
The effect of long‐term colchicine therapy in patients with recurrent polyserositis on the capacity of blood platelets to synthesize thromboxane A2.
Authors: Levy M. , Eldor A. , Zylber‐Katz E. , Eliakim M.
Published: July 2012

Thromboxane B2 (TXB) production during platelet activation was measured in 13 patients with recurrent polyserositis on long‐term colchicine therapy and 10 healthy controls. Plasma colchicine concentration in patients ranged between 0.8‐7.8 ng/ml (2.0‐19.5 X 10(‐9) M). Thromboxane production induced during aggregation by arachidonic acid or collagen and serum TXB2 levels (clotted blood, 37 degrees C, 1 h) did not differ among patients and controls. Previous studies reporting platelet function defects including anomalous TXB2 production, were performed in vitro using colchicine concentrations markedly exceeding the therapeutic range.
Dietary influences on the kinetics of antipyrine and aminopyrine in human subjects.
Authors: Krishnaswamy K , Kalamegham R , Naidu NA
Published: July 2012

The possible dietary influences on in vivo antipyrine and aminopyrine kinetics with reference to energy (1500, 1800, 3000 kcal) and protein (5, 10, 15, 20% protein energy‐PE) intake were studied in a carefully controlled metabolic experiment in young healthy adult male volunteers aged between 25‐34 years. Antipyrine and aminopyrine were used to evaluate drug metabolism. On 1500 kcal intake with 10% PE, the metabolism of both aminopyrine and antipyrine were significantly reduced whereas on 1800 kcal with 10% PE intake, only aminopyrine metabolism decreased significantly as compared to 3000 kcal with 10% PE. Antipyrine clearance on 1800 kcal with 10% PE however had not decreased to the same extent as on 1500 kcal with 10% PE. The results indicate that on low calorie intake with 10% PE, the drug metabolism is decreased. When the protein intake on 1500 kcal was doubled (20% PE) there was a significant stimulation of both aminopyrine and antipyrine metabolism. Aminopyrine and antipyrine clearances on 3000 kcal with 5% PE were significantly reduced as compared to 3000 kcal with 10% and 15% PE indicating that unlike proteins, carbohydrate and/or fat calories per se do not significantly stimulate drug metabolism. When the protein energy in the diet was increased from 5% to 10% or 15% at 3000 kcal, there was a stimulation of both antipyrine and aminopyrine metabolism. Significant differences between 10% and 15% of protein energy were not observed when the energy was adequate (3000 kcal). Therefore it is necessary to consider both proteins and energy as important variables affecting drug clearances from plasma in malnourished conditions.
Comparison of methods for estimating gentamicin clearance and retrospective analysis of changes in clearance with emphasis on patients with normal renal function.
Authors: Davey PG , Geddes AM , Gonda I , Harpur ES , Scott DK
Published: July 2012

The subjects were 29 general medical and surgical patients with apparently normal renal function at the start of treatment with gentamicin. Nine methods of estimating gentamicin clearance (CL) were compared as means of calculating gentamicin dosage. In 23 of the 29 patients CL was measured twice during treatment. The first measurement was based on 10 blood samples taken around a dose early in treatment. CL calculated from the area under the serum concentration‐time curve using all 10 samples was designated a reference method for comparison with other methods. There was considerable inter‐individual variation in CL. Serum creatinine and body weight gave poor estimates of an individual's CL. A good estimate of CL was obtained from four blood samples taken immediately before and 2, 3 and 4 h after dosing. Prediction of serum levels is not a good method for checking CL estimations. A significant decrease in CL was found during treatment. This was probably due to a reduction in glomerular filtration rate.
Comparison between the effects of inhaled isoprenaline and fenoterol on plasma cyclic AMP and heart rate in normal subjects.
Authors: Fairfax AJ , Rehahn M , Jones D , O'Malley B
Published: July 2012

The time course of changes in plasma cyclic AMP, heart rate and bronchial tone after inhalation of fenoterol or isoprenaline from a dose‐metered aerosol are reported in a group of normal subjects. After isoprenaline, plasma cyclic AMP increased rapidly reaching a peak by 10 min and returned to basal levels within 60 min. A rapid, transient rise in heart rate occurred that was maximal by 5 min and returned to a basal level by 45 min. After fenoterol, the changes in cyclic AMP and heart rate were of much longer duration. The rise in plasma cyclic AMP was slower in onset and of greater magnitude than for isoprenaline, reaching a peak by 20 min and remaining above basal level for more than 6 h. The maximum increase in heart rate after fenoterol was less than that observed with isoprenaline but an elevated rate persisted for 4 h after inhalation of fenoterol. Fenoterol is known to have a longer duration of action as a bronchodilator in comparison with isoprenaline. The prolonged rise in plasma cyclic AMP in normal subjects given inhaled fenoterol may reflect this long duration of action. The concomitant rise in heart rate, however, suggests that the duration of plasma cyclic AMP response may in part be due to the systemic effect of the fraction of inhaled fenoterol known to be absorbed via the buccal and intestinal routes.
The effects of amrinone on platelet count, survival and function in patients with congestive cardiac failure.
Authors: Wilmshurst PT , Al‐Hasani SF , Semple MJ , Hamblin AS , Kioy PG , Lucas GF , Savidge GF , Webb‐Peploe MM
Published: July 2012

In a prospective trial, the immediate and long‐term haematological effects of amrinone were studied in sixteen patients with refractory cardiac failure. The platelet count was significantly and variably reduced in all patients and the reduction was related to log plasma amrinone concentration. Platelet survival was significantly reduced in those cases studied. No evidence of disseminated intravascular coagulation or intravascular platelet deposition was observed and the reduced platelet survival was not considered to be the result of an immunological process. Evidence of a marrow response to the reduced platelet count and survival was seen. Although no haemorrhagic symptoms were observed in the patients, the haematological side‐effects were considered to be of such severity as to limit the use of this drug in clinical practice.
Reduction of antipyrine clearance in psoriasis.
Authors: Marsden JR , Williams FM , Keys B , Rawlins MD , Shuster S
Published: July 2012

Antipyrine clearance was determined in 41 psoriatics and age‐sex matched controls, using sequential measurements of salivary concentration. Antipyrine clearance and elimination rate constant were less in psoriatics (P less than 0.05) and apparent volumes of distribution were similar. These differences were greater between female psoriatics and controls (P less than 0.025; P less than 0.05) and the differences between male psoriatics and controls were not significant. Correlation of simultaneous measurements of saliva and plasma antipyrine concentration in six psoriatics and age‐sex matched controls showed no differences between the two groups. We conclude that antipyrine clearance is reduced in psoriasis but the underlying mechanism is unclear.
Changes in circulating androgens during short term carbamazepine therapy.
Authors: Connell JM , Rapeport WG , Beastall GH , Brodie MJ
Published: July 2012

Serum concentrations of testosterone, androstenedione, dehydroepiandrosterone sulphate (DHAS), sex hormone binding globulin (SHBG) and luteinising hormone (LH) were measured before, during and after 21 days treatment with carbamazepine (CBZ)400 mg daily in six healthy male subjects. Induction of hepatic microsomal enzyme activity was confirmed by an increase in antipyrine clearance (P less than 0.02) and a fall in circulating CBZ concentrations from the seventh to the fourteenth CBZ dose (P less than 0.05). Within 7 days of starting CBZ there was a rise in SHBG (P less than 0.05) and a fall in testosterone, free testosterone fraction, DHAS and androstenedione (P less than 0.05). Testosterone, free testosterone fraction and androstenedione levels rose towards baseline by the end of the treatment period while DHAS concentration remained low (P less than 0.05). The rise in SHBG and increased androgen catabolism is most likely to be secondary to induction of hepatic monooxygenase activity by CBZ. These changes may be implicated in the production of sexual dysfunction encountered in some epileptic patients on chronic anticonvulsant therapy.