bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma lipid fractions during long‐term monotherapy with the ISA‐ containing beta‐adrenoceptor blocker bopindolol in hypertensive patients.
Authors: Van Brummelen P. , Bolli P. , Koolen MI , Staehelin HB , Buhler FR
Published: July 2012

The influence of bopindolol monotherapy on blood pressure and plasma lipid fractions was investigated in 24 hypertensive patients. Bopindolol lowered blood pressure and heart rate significantly. When compared with placebo no changes were found in the plasma concentrations of total cholesterol, LDL cholesterol and HDL cholesterol. Plasma triglycerides were significantly increased after 4 and 8 weeks but not after 12 weeks of bopindolol. It is concluded that bopindolol is an effective and well tolerated beta‐adrenoceptor blocker in hypertensive patients. The fact that it does not lower HDL cholesterol could be a potential advantage.
Should we routinely measure free plasma phenytoin concentration?
Authors: Rimmer EM , Buss DC , Routledge PA , Richens A.
Published: July 2012

The plasma protein binding of phenytoin was investigated in 56 epileptic patients attending the outpatient clinic. The free phenytoin fraction was measured by equilibrium dialysis at 37 degrees C and the total concentration by a homogenous enzyme immunoassay technique. The free fraction ranged from 0.123 to 0.177 (median 0.144, mean +/‐ s.d. = 0.145 +/‐ 0.12). Distribution was consistent with normality. Four of the patients were also taking sodium valproate. The median free fraction of phenytoin in these patients was 0.174, 21% higher than that of the total group (P less than 0.05). The total concentration of phenytoin varied from 0.3 to 29.4 micrograms/ml (median 12 micrograms/ml, mean +/‐ s.d. = 13.31 +/‐ 6.13 micrograms/ml) and the free fraction was not related to the total drug concentration. There was a highly significant relationship between free phenytoin concentration and total phenytoin concentration (r = 0.986, P less than 0.001). There appears to be very little variability in protein binding of phenytoin in epileptic patients and thus total plasma phenytoin concentration closely reflects the free (unbound) drug concentration. Routine estimation of free plasma phenytoin concentration is therefore unnecessary and should be reserved for those patients where alteration in binding is likely, e.g. renal or hepatic disease or where adverse effects occur at unexpectedly low total phenytoin concentrations.
Pharmacodynamic correlates of modified absorption: studies with lormetazepam.
Authors: Pierce DM , Franklin RA , Harry TV , Nicholson AN
Published: July 2012

The bioavailability, pharmacokinetics, and effects on performance of lormetazepam (1 mg) have been compared using soft gelatin capsule and tablet formulations. Lormetazepam was more rapidly absorbed from the soft gelatin capsule (tmax = 1.0 +/‐ 0.2 h) than from the tablet (tmax = 2.4 +/‐ 0.4 h), and the plasma concentration‐time curve for the capsule was shifted to the left. Bioavailability and elimination kinetics did not differ between the formulations. The number of substitutions in the digit symbol test was reduced between 0.5 and 1.5 h for both formulations (P less than 0.001), but the degree of impairment at 0.5 h was greater after the capsule than after the tablet (P less than 0.01). Visuo‐motor co‐ordination was impaired from 0.5 to 1.5 h after the tablet and the capsule (P less than 0.01), and extended to 5.5 h after the tablet (P less than 0.05). These observations reflect the differences in the plasma concentration‐time curves.
Comparison of pseudoephedrine and triprolidine, alone and in combination in preventing nasal congestion in subjects with allergic rhinitis using nasal histamine challenge.
Authors: Empey DW , Frosolono MF , Hughes DT , Perkins JG
Published: July 2012

The abilities of triprolidine 2.5 mg and pseudoephedrine 60 mg, alone and in combination, to protect against an increase in nasal airway resistance (NAR) after histamine challenge were determined in eighteen individuals with grass pollen allergy. The study was conducted outside the pollen season using a double‐blind, placebo controlled crossover design. The prior administration of pseudoephedrine 60 mg and triprolidine 2.5 mg alone or in combination was superior to placebo in reducing the increase in NAR after challenge with 1.0% histamine. However, such NAR measurements did not differentiate between pseudoephedrine 60 mg and triprolidine 2.5 mg administered alone or in combination. Challenge with 0.1% histamine failed to discriminate between any of the test medications.
Acetylator phenotyping: the effect of ethanol on the dapsone test.
Authors: Hutchings A. , Monie RD , Spragg B. , Routledge PA
Published: July 2012

In twelve healthy drug‐free subjects (six slow acetylators), administration of alcohol (to achieve an ethanol concentration between 650 and 1180 mg 1(‐1)) did not significantly affect the ratio of monoacetyl dapsone (MADS) to dapsone (DDS) 3 h after oral dapsone (100 mg). We conclude that moderate acute ethanol consumption is unlikely to alter the acetylator phenotype measured by the dapsone test.
Effect of angiotensin II and captopril on renal tubular function in man.
Authors: Dusing R , Moritz J , Glanzer K , Kramer HJ
Published: July 2012

The effects of nonpressor doses of intravenous angiotensin II and of the converting enzyme inhibitor captopril on renal excretory function were investigated in eight healthy volunteers during sustained water diuresis on a constant intake of 150 mmol sodium per day. The angiotensin II‐analogue val5‐angiotensin II‐asp1‐beta‐amide was infused i.v. at an average dose of 2.6 ng kg‐1 min‐1 which was the highest dose without a significant effect on arterial blood pressure. This subpressor dose of angiotensin II significantly decreased urine volume, urinary excretion of sodium, chloride and phosphate and distal delivery [(CH2O + CCl)/GFR X 100] in the absence of changes in GFR or distal fractional chloride absorption [CH2O/(CH2O + CCl)]. In a second series of experiments, an oral dose of 50 mg of the angiotensin I‐converting enzyme inhibitor captopril was given to the sodium replete volunteers. In this study, captopril did not affect arterial blood pressure, GFR or any of the determined parameters of renal tubular function. Our results strongly suggest that the nonpressor dose of angiotensin II induced renal retention of sodium chloride via increased absorption in the proximal tubule. Thus, they further support the concept that angiotensin II participates in the regulation of renal sodium chloride excretion by affecting proximal tubular absorptive capacity. However, in the sodium replete stage, angiotensin II is of no major importance in regulating sodium chloride excretion.
A comparison of the effects of intravenous propranolol and nadolol on the renal response to hypertonic saline infusion.
Authors: Waller DG , Mihindukulasuriya J , Warren DJ
Published: July 2012

Intravenous loading with 500 ml of 2.7% saline increased the clearance of PAH and inulin and urine sodium excretion in 14 healthy subjects. Intravenous propranolol (0.075 and 0.15 mg/kg) did not alter PAH or inulin clearance at rest but abolished the increase expected during saline infusion. There was no consistent effect on urinary sodium excretion. Intravenous nadolol (0.05 and 0.75 mg/kg) reduced resting PAH and inulin clearances by up to 25%. Both clearances fell significantly during saline infusion but natriuresis was not significantly reduced in spite of the changes in renal function. There was no evidence from these studies in normal volunteers that nadolol confers any advantages over propranolol in its effects on renal function.
Coumarin 7‐hydroxylase activity in human liver microsomes. Properties of the enzyme and interspecies comparisons.
Authors: Pelkonen O , Sotaniemi EA , Ahokas JT
Published: July 2012

Coumarin 7‐hydroxylation and other cytochrome P‐450‐associated enzyme activities were studied in human liver biopsy homogenates and compared with activities in livers of other species. Coumarin 7‐hydroxylation is extraordinarily active in human liver biopsy samples in vitro. Activity is lower in mouse, rabbit or guinea pig liver and essentially absent in rat liver. Cytochrome P‐450 content and other associated enzyme activities were higher in animals. Coumarin 7‐hydroxylation is induced by phenobarbitone in mouse liver, but no significant increase was seen in human or rat liver after exposure to inducers. Correlations amongst coumarin 7‐hydroxylase, aryl hydrocarbon hydroxylase, 7‐ethoxycoumarin O‐deethylase and cytochrome P‐450 are statistically significant (r values from 0.56 to 0.73), but do not permit the conclusion, that the same P‐450 form catalyzes all the reactions studied. The correlations between coumarin hydroxylation and antipyrine half‐life or clearance are statistically significant, but not good enough for predictive purposes. Coumarin 7‐hydroxylase in human liver is inhibited by alpha‐ naphthoflavone, SKF 525A, metyrapone and aniline.
The pharmacokinetics and bioavailability of a tracer dose of [3H]‐ mebendazole in man.
Authors: Dawson M , Braithwaite PA , Roberts MS , Watson TR
Published: July 2012

Five volunteers, whose ages ranged between 37 and 64 years, took part in a crossover study to determine the pharmacokinetics and bioavailability of mebendazole in man following intravenous and oral administration of a tracer dose of [3H]‐mebendazole. Following intravenous administration, the average distribution half‐life, elimination half‐life and rate of clearance were 0.20 h, 1.12 h, and 1.063 min respectively. After oral administration of the solution, the average elimination half‐life was 0.93 h, the apparent rate of clearance was 0.846 l/min, the average time to peak plasma concentration was 0.42 h, and the bioavailability of mebendazole was 22%. Comparison of metabolite area under the plasma concentration vs time data from each route of administration indicates that absorption of mebendazole from the gastrointestinal tract at this dose level is almost complete. The low bioavailability observed following oral administration at this dose level is postulated to be due to high first pass elimination. Approximately half of the administered dose of radioactivity following intravenous and oral administration was detected in the urine, and the major unconjugated metabolite of mebendazole was found to be 2‐amino‐5(6) [alpha‐ hydroxybenzyl]benzimidazole (IV), not 2‐amino‐5(6)benzoylbenzimidazole (II), as previously reported.
Flunitrazepam and lormetazepam do not affect the pharmacokinetics of the benzodiazepine antagonist Ro 15‐1788.
Authors: Klotz U , Duka T , Dorow R , Doenicke A
Published: July 2012

Following a single intravenous dose of 0.1 mg/kg, the pharmacokinetics of Ro 15‐1788, a specific benzodiazepine antagonist, have been investigated in 20 healthy male volunteers. In random order injection of Ro 15‐1788 has been preceded (5 min) by intravenous dosing with 0.06 mg/kg of lormetazepam (n = 6), 0.03 mg/kg of flunitrazepam (n = 8) or placebo (n = 6). The rapid elimination of the antagonist could be characterized by an elimination half‐life between 0.9 to 1.4 h and a total plasma clearance of 727 to 1440 ml/min. These single dose studies indicate that the disposition of Ro 15‐1788 was not affected by the acute coadministration of both benzodiazepines.
Is the clinical trial evidence about new drugs statistically adequate?
Authors: Bland JM , Jones DR , Bennett S , Cook DG , Haines AP , MacFarlane AJ
Published: July 2012

The statistical adequacy of all papers published in the period 1976‐80 describing clinical trials of five non‐steroidal anti‐inflammatory and two analgesic drugs introduced into the UK market in 1978 and 1979 has been assessed using a checklist of simple criteria. Most trials were reported to be randomised and double‐blind. Trial designs were less satisfactory in other important respects; the sample size of most trials was inadequate to demonstrate superiority of the new drug compared with an active control therapy. The period of treatment assessment was short in view of the likelihood of prolonged prescription of drugs in these classes. It is suggested that licensing authorities should demand higher standards of clinical trial evidence offered in support of new drugs.
Effects of ranitidine on the disposition of metoprolol.
Authors: Kelly JG , Salem SA , Kinney CD , Shanks RG , McDevitt DG
Published: July 2012

The effects of ranitidine on the pharmacokinetics of metoprolol were examined in two studies. In the first study, pharmacokinetics of single doses of metoprolol were examined in six subjects before, during and after ranitidine administration for 1 week. Peak concentrations of metoprolol were increased on ranitidine but its half‐life and clearance were unaltered. In the second study, 12 subjects received metoprolol twice daily for 1 week; once with ranitidine and once with placebo. Ranitidine had no effects on the chronic‐dose pharmacokinetics or pharmacodynamics of metoprolol. The chronic dose study suggests no inhibition of the metabolism of metoprolol by ranitidine. The single dose study suggests, however, that some interaction of an as yet unknown nature, cannot be excluded.
The effect of secoverine hydrochloride on stimulated sigmoid motility: a double‐blind, placebo controlled cross‐over study in irritable bowel syndrome.
Authors: Ehsanullah M , Lee DA , Williams T , Pollard P , Gazzard B
Published: July 2012

The effect of oral secoverine hydrochloride on neostigmine‐stimulated sigmoid motility in 12 patients with irritable bowel syndrome was studied in a double‐blind placebo‐controlled cross‐over study. Both spontaneous and stimulated motor activity were significantly reduced by the compound in comparison with placebo. The most sensitive indices were the frequency of wave activity, maximum amplitude and motility index. Two patients reported mild dizziness after secoverine.
Pharmacokinetic interaction of propoxyphene with ethanol.
Authors: Sellers EM , Hamilton CA , Kaplan HL , Degani NC , Foltz RL
Published: July 2012

In order to study the effects of ethanol on the pharmacokinetics of propoxyphene, six healthy male volunteers were each given (1) propoxyphene 65 mg p.o. preceded by 1 h by ethanol 0.9 g/kg lean body weight and followed for 7.5 h by ethanol dosed to maintain breath ethanol at 800‐1000 mg/l; and (2) propoxyphene 65 mg p.o. with orange juice in the same volume and frequency as ethanol. Ethanol did not induce any significant changes in apparent t 1/2 or Cmax of propoxyphene or norpropoxyphene. The average norpropoxyphene/propoxyphene ratio decreased by a mean 36%.
Oral morphine in cancer patients: in vivo kinetics and in vitro hepatic glucuronidation.
Authors: Sawe J , Kager L , Svensson Eng JO , Rane A
Published: July 2012

The kinetics of morphine and formation of the main metabolite, morphine‐ 3‐glucuronide (M3G) after single and intravenous doses of morphine were studied in six cancer patients and compared with the formation rate of M3G in vitro in microsomes isolated from liver biopsies obtained from the same patients at palliative laparotomy. The results showed that high formation rates of M3G in vitro in microsomes isolated from liver biopsies were associated both with high apparent oral clearance values and high M3G/morphine AUC (area under the concentration vs time curve) ratios as measured in vivo in the same patients. In accordance with previous results marked interindividual differences were seen in the kinetics of morphine; the oral bioavailability varied between 30 and 69% and the systemic plasma clearance between 18.6 and 34.0 ml min‐1 kg‐ 1. This variation correlated with the variation in morphine metabolism as assessed in vitro. In vivo, a high M3G/morphine AUC ratio predicted a high oral clearance. Hepatic UDP‐glucuronyl transferase activity is thus an important determinant of the in vivo kinetics of orally administered morphine.
Tinidazole milk excretion and pharmacokinetics in lactating women.
Authors: Evaldson GR , Lindgren S , Nord CE , Rane AT
Published: July 2012

Five women undergoing acute Caesarean section were given an i.v. dose of 1600 mg tinidazole preoperatively as prophylaxis against anaerobic infection. Blood and breast milk samples were collected at 8 and 4 h intervals, respectively, for 120 h. Tinidazole concentrations were measured by means of high performance liquid chromatography (h.p.l.c). The concentration of tinidazole in breast milk was highly related to the concentration in serum (r = 0.969). Tinidazole concentrations in serum declined monoexponentially with an average half‐life of 11.4 h (range 8.7‐13.1). The milk/serum concentration ratio varied between 0.62 and 1.39. Seventy‐two hours after the Caesarean section the milk concentration exceeded 0.5 microgram/ml in only one woman. It may be calculated that at this time the maximum daily dose to the infant would be 0.1 mg/kg body weight (assuming 3.5 kg body weight and 400 ml milk consumed). We conclude that until tinidazole has been proven harmless to the neonate breast feeding following i.v. administration of 1600 mg should not be initiated earlier than 72 h after the dose.
Aztreonam in human serum and breast milk.
Authors: Fleiss PM , Richwald GA , Gordon J , Stern M , Frantz M , Devlin RG
Published: July 2012

Serum and milk concentrations of aztreonam were studied in 12 lactating, healthy subjects over the 8 h period after the administration of a single intramuscular or intravenous 1 g dose. Milk concentrations of aztreonam were found to be much lower than serum concentrations at all time points after both routes of injection. Peak milk concentrations of aztreonam averaged less than 1% of peak serum concentrations. Times to peak concentrations averaged 6 and 10 times longer in milk than in serum after intramuscular and intravenous injections, respectively. The low milk levels, as well as the previously determined poor oral absorption of aztreonam, suggest a low risk of untoward effects in the nursing infant.
Stereoselective disposition of ibuprofen enantiomers in man.
Authors: Lee EJ , Williams K , Day R , Graham G , Champion D
Published: July 2012

This study has examined the stereoselective disposition of the enantiomers of ibuprofen in four healthy male subjects following separate administration of racemic ibuprofen (800 mg) and of each enantiomer (400 mg). A mean of 63 +/‐ 6% of an administered dose of R(‐) ibuprofen was stereospecifically inverted to the S(+) enantiomer. There were no measurable inversion of the S(+) to R(‐) ibuprofen. The kinetics of the individual enantiomers were altered by concurrent administration of the respective optical antipode. It is likely that this change reflects an interaction between the enantiomers at plasma protein binding sites. It was found that formation of ester glucuronide conjugates stereoselectively favoured the S(+) enantiomer. The data have demonstrated that the pharmacokinetics of ibuprofen and other alpha‐methylarylacetic acids cannot be interpreted adequately without studying the pharmacokinetics of the individual enantiomers.
Antipyrine clearance in children from single saliva samples.
Authors: Loft S , Haxholdt O , Dossing M
Published: July 2012

The saliva clearance of antipyrine was measured in 18 children from four samples taken about 9, 13, 22 and 25 h after ingestion of 20 mg kg‐ 1. Antipyrine clearance determined from each of the samples using a volume of distribution estimated from age (A) and body weight (BW) and height (BH) (V = 1.535 X A + 0.339 X BW + 0.300 X BH − 35.63 (1] correlated closely with clearance determined from the total elimination curve (r greater than 0.94). Random variation and systematic deviation were minimal when the 22 h sample was used for clearance determination (r = 0.98, P less than 0.001, regression curve slope = 1.00, intercept = 0.58 and residual variance = 4.02). The one‐sample method for determination of antipyrine saliva clearance is non‐invasive, easy to perform and acceptable to children.
A comparison of the effect of paroxetine and amitriptyline on the tyramine pressor response test.
Authors: Hassan SM , Wainscott G , Turner P
Published: July 2012

The effect of single and repeated dosing of paroxetine on the in vivo noradrenaline uptake process, as determined by tyramine pressor response tests, was evaluated in normal healthy subjects. No statistically significant inhibition of the uptake process was observed for paroxetine, nor did it produce sedation or dryness of the mouth, though effects were observed for amitriptyline.
Involvement of calcium in the caffeine stimulation of human sperm motility.
Authors: Hong CY , Chiang BN , Wu P , Wei YH , Fong JC
Published: July 2012

The shape of the concentration‐response curve and the amplitude of maximal motility increase for the stimulatory effect of caffeine on human sperm motility were similar to those of EGTA, a calcium chelator, and lanthanum chloride, a calcium entry blocker. On the other hand, the maximal motility stimulation induced by dibutyryl cyclic AMP was similar to that induced by trifluoperazine, a calmodulin antagonist. The antagonism of A23187 on the motility‐stimulating effect of EGTA and caffeine was competitive in nature, while that on cyclic AMP was non‐ competitive. We proposed that there could be two mechanisms for caffeine to stimulate sperm motility: at higher concentrations, caffeine modified calcium translocation; at lower concentrations, caffeine increased cyclic AMP level. The importance of calcium in the regulation of human sperm motility was reconfirmed in this study.
Effect of charcoal‐drug ratio on antidotal efficacy of oral activated charcoal in man.
Authors: Olkkola KT
Published: July 2012

The effect of charcoal‐drug ratio on the antidotal efficacy of oral activated charcoal was studied in six healthy volunteers in a randomized cross‐over study and compared with the adsorption capacity of activated charcoal in vitro. Aminosalicylic acid (PAS) 1 g and 5 g were ingested on an empty stomach in 30 ml of water. Immediately afterwards the subjects ingested 50 g of activated charcoal in 300 ml of water or 300 ml of water only. PAS 10 g 20 g were only given with 50 g of activated charcoal administered immediately afterwards. The plasma concentrations and the cumulative excretion of PAS into urine were measured for 48 h. Increasing the dose of PAS from 1 g to 20 g reduced the antidotal efficacy of activated charcoal: at a charcoal‐drug ratio of 50:1 under 5% of the dose was absorbed but at a ratio of 2.5:1 about 37%. These data correlated well to the saturation of adsorption capacity of charcoal in vitro. To minimize the possibility of saturation of the adsorption capacity of charcoal in acute intoxications where the amount and type of drug taken is usually unknown, large doses (50‐100 g) of activated charcoal should be used.
Pharmacological experiments in healthy volunteers with bopindolol, a long‐acting beta‐adrenoceptor blocking drug with partial agonist activity.
Authors: Aellig WH
Published: July 2012

Bopindolol is a potent and specific beta‐adrenoceptor antagonist with partial agonist activity. In animal experiments it blocks both beta 1‐ and beta 2‐adrenoceptors and possesses a long duration of action. In the present study in healthy volunteers bopindolol was about ten times more potent than pindolol in reducing isoprenaline‐induced and exercise‐ induced tachycardia. In experiments on exercise‐induced tachycardia an oral dose of 2 mg produced a near maximum reduction of exercise heart rate, occurring within 2 to 3 h of administration. With higher doses (up to 12 mg) the maximum effect was reached earlier (between 1 and 2 h). The long duration of action of bopindolol observed in animal studies was confirmed in man. Twenty‐four hours after 4 and 10 mg bopindolol more than 2/3 of the maximum effect was still present. After 48 h 38% of the maximum effect of 4 mg and 50% of that of 12 mg remained. Even at 72 and 96 h exercise‐induced tachycardia was still significantly lowered after both doses of the drug. When bopindolol was administered once daily for 5 days there was a slight increase in the maximum reduction of exercise‐induced tachycardia during treatment with 1 mg/day but not with 4 mg/day, which produced a near maximum effect.
The effect of acute beta‐adrenoceptor blockade on examination performance.
Authors: Drew PJ , Barnes JN , Evans SJ
Published: July 2012

Simple tests of verbal reasoning and mental arithmetic, taken under mildly stressful conditions, have been shown to give a reproducible test of intellectual function within groups of normal subjects. Using these tests, in two separate examinations, a double‐blind cross‐over study was performed on 35 medical students to assess the effects of acute beta‐adrenoceptor blockade with propranolol on intellectual function. With placebo treatment, students recorded an average total score of 231.3 marks, with average scores of 108.9 marks on the mental arithmetic paper and 122.4 marks on the verbal reasoning paper. Treatment with propranolol was associated with an improvement in total score of 9.2 +/‐ 3.9 marks (P less than 0.05), an improvement in mental arithmetic score of 5.6 +/‐ 2.3 marks (P less than 0.05) and an improvement in verbal reasoning score of 3.6 +/‐ 2.4 marks (NS). Eighteen out of the 35 students said that they were mildly anxious before one examination and 13 students said they were anxious before both examinations. Those students who admitted anxiety seemed to benefit the most, in terms of improved examination performance, from treatment with propranolol.
Effects of end stage renal disease and aluminium hydroxide on triazolam pharmacokinetics.
Authors: Kroboth PD , Smith RB , Silver MR , Rault R , Sorkin MI , Puschett JB , Juhl RP
Published: July 2012

Triazolam 0.5 mg was administered to 11 dialysis patients and 11 age, weight and sex matched controls. Peak plasma concentrations (Cmax) were higher in control subjects, but there were no other differences between the groups. When dialysis patients took triazolam with 3600 mg aluminum hydroxide suspension, Cmax and AUC were increased into the range observed in control subjects. It appears that triazolam can be used at normal doses in patients with renal dysfunction, without regard to interaction with aluminum hydroxide gel, or to alterations in elimination.
The influence of cimetidine and ranitidine on the plasma lipid pattern.
Authors: Terruzzi V , Minoli G , Tadeo G , Nespoli M , Rossini A
Published: July 2012

The influence of H2‐receptor antagonist drugs on the plasma lipid pattern has been studied prospectively in 51 patients treated with cimetidine (26 patients) or ranitidine (25 patients) for gastroenterological diseases. Total and HDL cholesterol and total triglycerides have been measured. Ranitidine did not influence the investigated parameters, while cimetidine produced a significant increase in the HDL cholesterol serum concentration (P = 0.008).
Brief review of published alprazolam clinical studies.
Authors: Straw RN
Published: July 2012

The clinical efficacy of alprazolam has been evaluated in both anxiety states and depressive disorders. In anxiety neurosis, studies have been conducted vs placebo and/or other benzodiazepine tranquilizers. Reports, to date, with regard to panic/phobia disorders have been limited to open‐label studies and a single report from a placebo‐ controlled study. In depression, both open‐label and double‐blind studies (vs tricyclic antidepressants) have been published.
Osmotic delivery systems for the beta‐adrenoceptor antagonists metoprolol and oxprenolol: design and evaluation of systems for once‐ daily administration.
Authors: Theeuwes F , Swanson DR , Guittard G , Ayer A , Khanna S
Published: July 2012

The essential features and mode of action of oral osmotic drug delivery systems (Oros) for metoprolol fumarate and oxprenolol succinate are described. Critical aspects in the development of systems for once‐ daily administration of both drugs are discussed, and methods for evaluating in vitro release characteristics are presented. In vitro testing confirmed that drug delivery corresponded closely to the theoretical release behaviour predicted from the physicochemical and membrane permeability characteristics for both oxprenolol and metoprolol systems. In vitro release rates were also shown to be unaffected by pH, in vitro test procedures, dissolution media and long‐ term storage at different temperatures.
Investigation of drug absorption from the gastrointestinal tract of man. I. Metoprolol in the stomach, duodenum and jejunum.
Authors: Jobin G , Cortot A , Godbillon J , Duval M , Schoeller JP , Hirtz J , Bernier JJ
Published: July 2012

Gastrointestinal (GI) absorption of the beta‐adrenoceptor blocker metoprolol was investigated in five healthy subjects by means of an intubation method, employing a triple‐lumen tube introduced into the intestine, and a twin‐lumen tube in the stomach. Metoprolol was introduced into the stomach with a homogenized meal containing a nonabsorbable marker, [14C]‐PEG 4000, and another marker, PEG 4000, was perfused continuously into the duodenum just below the pylorus. Samples of GI contents were collected at regular intervals over 4 h in the stomach and at two different levels in the upper small intestine. Metoprolol was not absorbed from the stomach. Approximately 60% of the amount of drug emptied from the stomach was absorbed from the duodenum; about 50% of that leaving the duodenum was absorbed from the first part of the jejunum. The delivery process was the rate‐limiting factor of metoprolol absorption in these segments of the gut. Plasma concentrations reflected drug loss from the lumen and were higher in subjects exhibiting faster gastric emptying and higher absorption rates in the duodenum and jejunum. The intubation technique appeared to be a suitable method for investigating drug absorption from the GI tract in man.
Concentration‐effect relationship of oxprenolol in healthy volunteers: a retrospective analysis.
Authors: Racine‐Poon A , Moppert J
Published: July 2012

A mathematical model describing the relationship between plasma concentrations of oxprenolol and submaximal‐exercise heart rates has been developed on the basis of data available from 34 healthy volunteers. This relationship, which is exponential in type, is consistent with the ‘law of diminishing returns’, and is independent of the pharmaceutical formulations used; it appears to be established instantaneously, and is not modified by repeated drug administration over 8 days. At oxprenolol concentrations of 190‐250 ng/ml, between half and three‐quarters of the subjects investigated reached 90% of their estimated maximum levels of beta‐adrenoceptor blockade.
In vitro and in vivo deconvolution assessment of drug release kinetics from oxprenolol Oros preparations.
Authors: Langenbucher F , Mysicka J
Published: July 2012

The relationship between in vitro and in vivo drug release from Oros systems has been examined by analysing plasma concentration data from two pharmacokinetic studies, using a numerical deconvolution technique. This method generates an input profile by comparing the response with that achieved following an instantaneous reference unit dose. The approach is conceptually simple and does not require compartmental pharmacokinetic modelling or curve fitting. In the analysis of the first study, the plasma profile following intravenous dosing was used as the reference function, allowing the combined release/absorption process to be calculated; for the second, an oral bolus was used, the result of the deconvolution therefore indicating the in vivo dissolution rate of the Oros systems. The in vivo release from Oros in most volunteers followed the same pattern as that measured in vitro; only after 6‐8 h was the decline in the in vivo release rate somewhat greater than expected. In a few individuals the cumulative absorption profile reached an early plateau level which coincided, on some but not all occasions, with the premature excretion of the Oros system from the body. The amount of drug in recovered systems agreed reasonably with the prediction of the deconvolution analysis.
Reproducibility of oxprenolol plasma concentrations in young female volunteers following oral administration of an oxprenolol Oros dosage form.
Authors: Jack DB , Kendall MJ , Laugher SJ , Smith SR
Published: July 2012

Plasma oxprenolol concentrations were measured in six young healthy female volunteers after single oral dosing with a 16/260 oxprenolol Oros system on three separate occasions. Reproducibility was assessed by comparing individual plasma profiles, areas under the curve, peak concentrations and times to peak. Plasma concentration‐time profiles were consistent with an extended duration of drug release from the Oros system. Individual and mean profiles on the three occasions were similar, and no significant differences in mean plasma levels, or derived pharmacokinetic parameters, were detected. The mean amount of drug in eight systems recovered from faeces corresponded to 11% of the dose. Individual amounts were related to the total transit time of the system through the body. The 16/260 Oros system functioned reproducibly within the gastrointestinal tract, and in vivo absorption mirrored in vitro drug release.
Oros controlled‐release formulations of metoprolol: an approach to the development of a system for once daily administration.
Authors: Good W , Leeson LJ , Zak SL , Wagner WE , Meeker JB , Arnold JD
Published: July 2012

A combined biopharmaceutical and haemodynamic approach to the development of a metoprolol Oros controlled‐release delivery system for once daily administration is reported. Two studies, each involving 18 healthy volunteers, were performed in which twice daily administration of 100 mg conventional metoprolol tartrate tablets was compared with once daily administration of Oros systems containing 190 mg metoprolol fumarate but with different drug release rates. Plasma drug concentrations and beta‐adrenoceptor blocking effects were measured over 24 h on days 1 and 5 of each treatment, and pre‐dose in the interval between the main study days. The results of the first study with a 19 mg/h Oros system indicated that this rate was too rapid to provide the required response under steady‐state dosing conditions. Theoretical calculations based on a one‐compartment pharmacokinetic model and input functions for hypothetical Oros systems were then performed to define the optimal release rate for a once daily preparation. The results of the second study confirmed that a 14 mg/h system possessed the required characteristics in that it maintained more uniform beta‐adrenoceptor blockade throughout 24 h, and produced pre‐dosing plasma concentrations and haemodynamic effects which were identical to those for the conventional tablet twice daily regimen.
Influence of food on the absorption of metoprolol administered as an Oros drug delivery system to man.
Authors: Lecaillon JB , Massias P , Schoeller JP , Abadie F
Published: July 2012

The influence of food on the release, absorption and metabolism of metoprolol has been studied after single administration of a 19/190 Oros system to eight healthy volunteers on four occasions, once after an overnight fast, and just before each of three daily meals (breakfast, lunch and dinner). The plasma concentration‐time profiles under the four test conditions were virtually identical, and no statistically significant differences in mean areas under the curves between 0 and 32 h, peak concentrations, or times to peak, were detected. The absorption of metoprolol was unaffected by food intake, with 80‐90% of the amount absorbed reaching the systemic circulation within 10 h. The ratios of areas under the curve for alpha‐ hydroxymetoprolol to its parent drug were in the same range for the four treatments, and similar to those reported after conventional tablets. The in vivo release and absorption of drug from the Oros system and its systemic availability, were not influenced by concomitant ingestion of food.
Ranitidine does not alter pethidine disposition in man.
Authors: Guay DR , Meatherall RC , Chalmers JL , Grahame GR , Hudson RJ
Published: July 2012

The effect of concurrent ranitidine administration on the disposition of pethidine was investigated in eight healthy male volunteers (19‐33 years). The subjects received 70 mg i.v. pethidine HCl doses before and during ranitidine treatment (150 mg p.o. twice daily). Ranitidine therapy was not associated with significant alterations in pethidine elimination rate constant, volume of distribution at steady state, total body clearance, and 24 h urinary excretion. No alteration in pethidine oxidation to norpethidine was noted, as suggested by nonsignificant changes in lag time to appearance of quantifiable norpethidine in serum, time to peak concentration, peak concentration, area under the curve from time 0.24 h, and 24 h urinary excretion. It would appear that, unlike cimetidine, ranitidine does not interact pharmacokinetically with pethidine. Further studies are necessary to evaluate the potential clinical advantages of ranitidine vs cimetidine therapy in patients also receiving pethidine.
pH lability in serum during equilibrium dialysis.
Authors: Brors O , Jacobsen S
Published: July 2012

Changes in pH were determined in previously frozen normal human serum during dialysis against sodium phosphate, Krebs Ringer phosphate or Krebs Ringer bicarbonate buffers of pH 7.4. Serum was either untreated (native) or adjusted to pH 7.4 before dialysis. pH in native serum was 7.7‐7.9 before dialysis, showed a decrease after 1 h, and an increase after 3 h. pH‐adjusted serum showed a continuous pH increase during dialysis. The increase in serum pH during dialysis was larger at 37 degrees C than at 22 degrees C, larger at low than at high buffer molarity, and larger in native than in pH‐adjusted serum. The observed changes in serum pH during dialysis are associated with unacceptably large errors in unbound fraction in serum for a number of important drugs. Drug binding determination in serum by equilibrium dialysis should be performed with buffers providing appropriate and stable pH level.
Prednisolone protein binding in renal transplant patients.
Authors: Reece PA , Disney AP , Stafford I. , Shastry JC
Published: July 2012

Prednisolone pharmacokinetics and protein binding characteristics were studied in 10 renal transplant patients with various degrees of renal function (serum creatinine: 80‐380 mumol/l) who received their usual oral maintenance dose of prednisolone (0.18 +/‐ 0.04 mg/kg). Plasma was assayed for prednisolone and hydrocortisone by h.p.l.c. and free prednisolone concentrations were determined in each sample by a rapid ultrafiltration technique. Free prednisolone area under curve (AUCu) ranged from 101 to 436 ng ml‐1 h and was 6.3 to 15.0% of total prednisolone AUC. The fraction AUCu/AUC was closely related to serum albumin and creatinine concentrations determined at the time of study (multilinear regression correlation coefficient r2 = 0.830, P less than 0.0001); elevated serum creatinine and low albumin concentrations were associated with a higher % free. These results suggest that much of the variability in prednisolone protein binding could be attributed to inter‐patient variability in serum albumin and creatinine concentrations. Total prednisolone concentrations would be potentially misleading in any comparisons made between patient groups with different renal function.
Effects of single and multiple doses of ketoconazole on adrenal function in normal subjects.
Authors: Bradbrook ID , Gillies HC , Morrison PJ , Robinson J. , Rogers HJ , Spector RG
Published: July 2012

The plasma cortisol response to 0.25 mg tetracosactrin given by intramuscular injection was suppressed by nine oral doses of 200 mg ketoconazole given 12 hourly to nine normal female subjects. No effect was noted following a single 200 mg oral dose of ketoconazole. This suppressive effect was reversible within at least 5 days of discontinuation of ketoconazole.
Effects of verapamil and nisoldipine on human platelets: in vivo and in vitro studies.
Authors: Jones CR , Pasanisi F. , Elliott HL , Reid JL
Published: July 2012

Inhibition of platelet aggregation was observed after 4 days of oral dosing with the calcium antagonists, verapamil (160 mg) or nisoldipine (20 mg) but not following acute dosing. These effects were observed at plasma concentrations that had no effect on platelet aggregation when investigated in vitro. Verapamil added in vitro inhibited adrenaline‐ induced platelet aggregation at relatively low concentrations (IC50 16 microM) but only inhibited aggregation to adenosine diphosphate at very high concentrations (IC50 700 microM). Nisoldipine, a dihydropyridine, added in vitro had no effect on platelet aggregation induced by adenosine diphosphate but inhibited by 67%, the secondary phase of platelet aggregation induced by adrenaline. Verapamil but not nisoldipine displaced [3H]‐yohimbine from the specific binding sites on human platelets, suggesting an interaction with alpha 2‐adrenoceptors. Inhibition of adrenaline‐induced aggregation by verapamil in vitro may be a result of antagonism of alpha 2‐adrenoceptors but long term treatment with both verapamil and nisoldipine also inhibits platelet aggregation mechanisms other than by alpha 2‐adrenoceptor blockade.
Bronchial and cardiovascular responses to inhaled reproterol in asthmatics: a double‐blind placebo controlled dose‐response study.
Authors: Patchett P. , Patchett SM , Burge PS
Published: July 2012

Reproterol is a synthetic selective beta‐adrenoceptor agonist with a xanthine side chain. The bronchial and cardiovascular responses to inhaled reproterol were studied in 14 asthmatics. The study was placebo controlled and double‐blind, comparing doubling doses of reproterol from 500 micrograms‐8 mg. The peak improvement in FEV1 showed a non‐ linear dose‐response, with an initial plateau at the 1 mg dose producing a mean increase in FEV1 of 17%, but significant further improvement at the 8 mg dose, producing a mean improvement of 29% in FEV1. The time taken for improvement in airways obstruction to start shortened with increasing doses. The duration of bronchodilation was dose‐dependent, with the 8 mg dose showing a significantly longer duration of action than the lower doses. The time to drop below 75% of the maximum achieved bronchodilation was 125 min, and was independent of the dose. There were no significant changes in pulse or blood pressure at any dose. The study shows that reproterol is a well tolerated selective beta 2‐adrenoceptor agonist whose duration of action and peak effect can be significantly increased by increasing the dose to 8 mg, without producing more unwanted effects.
The influence of age and smoking on the elimination of disopyramide.
Authors: Bonde J. , Pedersen LE , Bodtker S. , Angelo HR , Svendsen TL , Kampmann JP
Published: July 2012

The influences of smoking and age on the elimination kinetics of disopyramide were studied in 27 subjects. Total elimination clearance of disopyramide was measured after an infusion to steady state. The total elimination clearance was significantly (P less than 0.05) decreased in elderly non‐smoking patients compared with young non‐ smoking subjects (1.54 +/‐ 0.33 vs 2.12 +/‐ 0.67 ml kg‐1 min‐1) (mean +/‐ s.d.). Smoking more than 20 cigarettes per day significantly (P less than 0.05) increased total elimination clearance in elderly (2.02 +/‐ 0.35 vs 1.54 +/‐ 0.33 ml kg‐1 min‐1), while no significant induction by tobacco was observed in young healthy persons. Serum concentrations of alpha 1‐acid glycoprotein, the major binding protein of disopyramide, were significantly higher (P less than 0.001) in the elderly patients. However, the volume of distribution (V) was significantly (P less than 0.001) greater in the elderly patients (2.44 +/‐ 0.64 vs 1.16 +/‐ 0.15 1 kg‐1). Steady‐state serum concentrations of the free drug were significantly (P less than 0.01) lower in the young volunteers (0.75 +/‐ 0.13 micrograms ml‐1) than in the elderly (0.90 +/‐ 0.10 micrograms ml‐1). The half‐life of disopyramide was significantly shorter (P less than 0.01) in the young volunteers than in the elderly patients. No difference was observed in the relationship between the serum concentration of disopyramide and its main dealkylated metabolite in the groups studied. The results indicate that it might be advisable to reduce the dosage of disopyramide by approximately 30% in elderly non‐smokers compared with young subjects.
Azathioprine suppresses the mixed lymphocyte reaction of patients with Lesch‐Nyhan syndrome.
Authors: Szawlowski PW , Al‐Safi SA , Dooley T. , Maddocks JL
Published: July 2012

The mixed lymphocyte reaction of Lesch‐Nyhan patients (HGPRT deficient) was used to study the immunosuppressive effects of azathioprine and 6‐ mercaptopurine (6‐MP). Mitogen stimulated lymphocytes of these patients are highly resistant to azathioprine and 6‐MP. When both stimulator and responder lymphocytes in the MLR were HGPRT deficient, azathioprine (36 microM) was much more inhibitory than 6‐MP (100 microM). Azathioprine produced inhibition of 98.2% and 78.5% compared with the values of 63.9% and 30.6% for 6‐MP. The difference in inhibitory activity between azathioprine and 6‐MP was reduced when normal stimulator lymphocytes were cultured with HGPRT deficient responder lymphocytes in the MLR. These results provide very strong evidence that the nucleotide metabolites of azathioprine and 6‐MP are unnecessary for immunosuppression. They also suggest that azathioprine and 6‐MP interfere with antigenic triggering of the MLR.
Adenosine stimulates respiration in man.
Authors: Watt AH , Routledge PA
Published: July 2012

Respiratory effects produced by a series of intravenous boluses of adenosine were studied in nine healthy human subjects. Adenosine produced a significant dose‐related increase in respiration, mostly due to increased depth of respiration. Possible mechanisms of this effect are discussed.
Double‐blind trial of flurbiprofen and phenylbutazone in acute gouty arthritis.
Authors: Butler RC , Goddard DH , Higgens CS , Hollingworth P. , Pease CT , Stodell MA , Scott JT
Published: July 2012

Flurbiprofen has been compared with phenylbutazone in a double‐blind study involving 33 patients with acute gout. Patients received either flurbiprofen 400 mg daily for 48 h followed by 200 mg daily, or phenylbutazone 800 mg daily for 48 h followed by 400 mg daily. The drugs were of comparable efficacy, while side‐effects were uncommon and relatively mild. Flurbiprofen appears to be a satisfactory alternative to phenylbutazone in the management of acute gouty arthritis.
Absorption kinetics of dihydroergotoxine following oral administration to man.
Authors: Woodcock BG , Rietbrock N. , Loh W. , Habedank WD
Published: July 2012

The absorption characteristics of dihydroergotoxine administered as an oral solution, tablet and retard capsule have been determined in a randomised cross‐over investigation in 12 healthy males. The plasma concentrations of dihydroergotoxine produced by the three preparations, measured using a specific and sensitive radioimmuno‐assay method over 24 h, exceeded 200 pg ml‐1 for approximately 5 h and decayed in a biphasic manner with a slowest measured half‐life of 12‐14 h. The retard capsule differs from the other two preparations in having a low Cmax (50% of that recorded for the solution) and a clearly defined plateau. The bioavailability of the retard capsule was similar to that for the solution indicating that first‐pass metabolism is not significantly increased following a three‐fold prolongation in the absorption rate constant. The 20‐40% greater bioavailability of dihydroergotoxine solution and retard capsule in comparison with the standard tablet may be due to a reduced contact time with gastric secretions achieved by means of rapid absorption from the stomach (solution) or delayed release at pH 1.5 (retard capsule).