bluuebunny/crossref_metadata_2025 huggingface dataset:
Steady‐state pharmacokinetics of lithium carbonate in healthy subjects.
Authors: Hunter R
Published: July 2012

1. The pharmacokinetics of lithium in six healthy volunteers stabilised on lithium were investigated and appropriate pharmacokinetic parameters calculated. 2. The results illustrate important differences in single and multiple dose lithium pharmacokinetics; the implications for minimising lithium‐induced renal damage are discussed.
Pharmaceutical innovation by the seven UK‐owned pharmaceutical companies (1964‐1985).
Authors: Prentis RA , Lis Y , Walker SR
Published: July 2012

1 A total of three hundred and nineteen new chemical entities (NCEs) were investigated in man for the first time between 1964 and 1985 by seven UK‐owned pharmaceutical companies. The majority (96.2%), were self‐originated by the UK company or one of its overseas subsidiaries. 2 There was an increase in the number of NCEs investigated each year in man, doubling from an average of 12 per year up to 1980, to over 20 per year between 1981 and 1985. The majority of first drug evaluations in human volunteers were carried out in the UK (92.2%), in contrast to evaluation of new medicines in patients, where 42.9% were first tested outside the UK. 3 The majority of NCEs evaluated in man (78%), were in four therapeutic classes: anti‐infectives (32%), anti‐allergics (22%), drugs acting on the central nervous system (13%) and cardiovascular system agents (11%). 4 By the end of 1985, 49 (15.4%) of these NCEs had been marketed in the UK and 198 (62.0%) discontinued from further development. The main reasons for termination were inappropriate pharmacokinetics in man (39.4%), and lack of clinical efficacy (29.3%). 5 Average development times increased from less than 2 years between 1964 and 1965, to around 8 years in the 1980s with a consequent reduction in the effective patent life.
In vitro immunological degranulation of human basophils is modulated by lung histamine and Apis mellifica.
Authors: Poitevin B , Davenas E , Benveniste J
Published: July 2012

1. The effect of high dilutions of two homeopathic drugs Lung histamine (Lung his) and Apis mellifica (Apis mel) used for the treatment of allergic diseases has been assessed on in vitro human basophil degranulation. Experiments were conducted blind. 2. Basophil degranulation induced by 1.66 × 10(‐9) M anti‐IgE antibody was significantly inhibited in the presence of 5 Lung his (5th centesimal dilution of Lung his) and 15 Lung his (15th centesimal dilution of Lung his) by 28.8% and 28.6% respectively and by 65.8% in the presence of 9 Apis mel (9th centesimal dilution of Apis mel). Basophil degranulation induced by 1.66 × 10(‐16) to 1.66 × 10(‐18) M anti‐IgE antibody was also inhibited by high dilutions of Lung his and Apis mel with an inhibition of nearly 100% with 18 Lung his (18th centesimal dilution of Lung his) and 10 Apis mel (10th centesimal dilution of Apis mel). An alternance of inhibition, inactivity and stimulation was observed when basophils were incubated in the presence of serial dilutions of Lung his and Apis mel. 3. The investigation of the clinical efficacy of high dilutions of Lung his and Apis mel should be envisaged in allergic diseases in parallel with in vitro and ex vivo biological assays.
Pharmacokinetics of midazolam and alpha‐hydroxy‐midazolam following rectal and intravenous administration.
Authors: Clausen TG , Wolff J , Hansen PB , Larsen F , Rasmussen SN , Dixon JS , Crevoisier C
Published: July 2012

1. In an open cross‐over trial, plasma concentrations of midazolam were measured in eight healthy male volunteers following administration of 0.3 mg kg‐1 body weight given by the rectal and intravenous routes. 2. Maximum plasma concentrations of 92‐156 ng ml‐1 (mean 118 ng ml‐1) were recorded from 20 to 50 min (mean 31 min) after rectal application. The rectal bioavailability was 40‐65% (mean 52%) and the terminal half‐life was 114‐305 min (mean 161 min). 3. A substantial first‐pass hepatic effect was observed following rectal administration. 4. No systemic or local intolerance was noted. 5. In conclusion, the rectal route of administration provides a rapid and reliable absorption of midazolam.
Pharmacokinetics of chloroquine in Thais: plasma and red‐cell concentrations following an intravenous infusion to healthy subjects and patients with Plasmodium vivax malaria.
Authors: Edwards G , Looareesuwan S , Davies AJ , Wattanagoon Y , Phillips RE , Warrell DA
Published: July 2012

1. Chloroquine diphosphate (15 mg base kg‐1) was given by constant rate intravenous infusion to two groups of Thai subjects. Eleven were patients with malaria (10 with Plasmodium vivax and one case with Plasmodium malariae) and 10 were healthy normal volunteers. 2. Plasma and packed red‐cell concentrations of chloroquine, electrocardiographic intervals, arterial blood pressure and pulse were measured at frequent intervals. 3. Peak plasma concentrations at the end of the infusion ranged from 979 to 2,900 ng ml‐1 in the malaria patients. In the group of healthy subjects the range was 550‐2,200 ng ml‐1. Values for terminal elimination rate constant, (lambda z) plasma clearance (CL), initial volume of distribution (V1) and volume of distribution at steady state (Vss) were calculated. For the healthy subjects, mean estimates of these parameters were lambda z = 0.062 +/‐ 0.030 day‐1, CL = 597 +/‐ 238 ml min‐1, V1 = 0.66 +/‐ 0.71 l kg‐1 and Vss = 132 +/‐ 50 l.kg‐1 For the group of malaria patients, the corresponding values were lambda z = 0.055 +/‐ 0.032 day‐1, CL = 535 +/‐ 246 ml min‐1, V1 = 0.74 +/‐ 0.75 l kg‐1 and Vss = 136 +/‐ 64 l kg‐1 There was no statistically significant difference in the estimates for any parameter between groups (P less than or equal to 0.05). 4. Chloroquine concentrations in packed red blood cells consistently exceeded those in plasma and showed no consistent change with time throughout the period of study in either group. The median value for the red cell to plasma ratio was between 3 and 4 in each group.(ABSTRACT TRUNCATED AT 250 WORDS)
Prediction of drug concentrations in human skim milk from plasma protein binding and acid‐base characteristics.
Authors: Atkinson HC , Begg EJ
Published: July 2012

1. Protein binding in human skim milk of a series of seven drugs with diverse plasma protein binding and acid‐base characteristics, was measured by ultrafiltration. 2. A mathematical relationship between plasma and skim milk unbound fractions was established using measured values from this study along with values from the literature. 3. The relationship enables prediction of unknown protein binding values of drugs in skim milk from known plasma protein binding values. 4. Knowledge of milk protein binding enables a more accurate assessment of total milk concentrations than is available from existing theory which is limited to prediction of unbound drug.
The influence of haematocrit on blood cyclosporin measurements in vivo.
Authors: Johnston A , Marsden JT , Holt DW
Published: July 2012

The influence of haematocrit on blood cyclosporin measurements has been studied in 276 paired blood and plasma samples from 21 renal transplant patients. A highly significant correlation was found between blood and plasma cyclosporin concentrations, r = 0.8744, but the correlation between blood or plasma cyclosporin and haematocrit was not significant. The ratio of blood/plasma cyclosporin did not significantly increase with increasing haematocrit. It was concluded that in vivo the influence of haematocrit on the measurement of blood cyclosporin concentrations was negligible.
Cimetidine does not increase alpha 1‐acid glycoprotein serum concentrations.
Authors: Parish RC , Gotz VP , Mehta JL
Published: July 2012

Serum concentrations of alpha 1‐acid glycoprotein (AAG) were studied in six healthy, male volunteers before and after administration of cimetidine, 300 mg by mouth every 6 h for 2 days. Serum AAG concentrations were measured at three different times during the first day, i.e. before cimetidine administration, and on the fourth and sixth days, after commencing cimetidine administration. Neither cimetidine treatment nor time of day contributed significantly to differences in serum AAG concentration, and no interaction of these factors was observed. It is concluded that altered drug‐AAG binding as a result of cimetidine therapy is not likely to be an important mechanism contributing to cimetidine drug interactions.
Effects of nifedipine, verapamil and diltiazem on renal function.
Authors: Chellingsworth MC , Kendall MJ
Published: July 2012

Eight healthy female volunteers were given single doses of nifedipine 10 mg, verapamil 80 mg, diltiazem 120 mg or placebo on 4 different study days. Urine and sodium output increased after all four drugs, but the increase after nifedipine was significantly greater than after verapamil or placebo. Nifedipine caused a significant increase in heart rate; none of the drugs caused any change in blood pressure. Potassium excretion, creatinine clearance, free water clearance and plasma renin activity did not change with any drug. The mechanism of the natriuresis and diuresis has still to be elucidated.
Factors affecting the clinical response to treatment with digoxin and two calcium antagonists in patients with atrial fibrillation.
Authors: Lewis RV , McDevitt DG
Published: July 2012

It has been suggested that patients in whom atrial fibrillation (AF) is associated with poor exercise tolerance respond better to treatment with xamoterol plus digoxin than to digoxin alone; this may be attributable to better control of exercise induced tachycardia. We have examined data obtained during studies comparing digoxin and two calcium antagonists in the treatment of AF to see whether subgroups of patients with particularly poor exercise tolerance, rheumatic heart disease or rapid post‐exercise heart rates might derive particular benefit from one modality of treatment as opposed to another. The results do not indicate that calcium antagonists improve exercise tolerance compared with digoxin in any of these subgroups despite achieving consistently better control of exercise induced tachycardia.
A comparative study of the formation of chemically reactive drug metabolites by human liver microsomes.
Authors: Kitteringham NR , Lambert C , Maggs JL , Colbert J , Park BK
Published: July 2012

1. The metabolism of amodiaquine (A), ethinyloestradiol (E), mianserin (M), phenytoin (Ph), sulphanilamide (S) and paracetamol (Pa) to both stable and chemically reactive, i.e. irreversibly protein bound, metabolites was investigated using microsomes prepared from histologically normal human liver obtained from eight kidney donors. 2. All drugs, except amodiaquine, were metabolized by NADPH‐dependent microsomal enzymes to chemically reactive metabolites. The degree of NADPH‐dependent binding varied between drugs (E, 11.5 +/‐ 5.8% incubated drug; M, 3.0 +/‐ 1.9%; Ph, 0.10 +/‐ 0.09%; S, 0.57 +/‐ 0.38%; Pa, 1.2 +/‐ 1.2%; mean of eight livers +/‐ s.d.). 3. Inclusion of glutathione (1 mM) or ascorbic acid (1 mM) in the incubation reduced the NADPH‐dependent binding for all substrates, indicating the involvement of electrophilic oxidation products. 4. Binding of M and Pa correlated with each other (Spearman's r = 0.86) and with total cytochrome P‐450 content (r = 0.76 and 0.78 respectively). E binding also correlated with the binding of M (r = 0.79) and Pa (r = 0.81) but not with cytochrome P‐450. Binding of Ph and S did not correlate with any of the other measured metabolic parameters.
In vitro inhibition studies of tolbutamide hydroxylase activity of human liver microsomes by azoles, sulphonamides and quinolines.
Authors: Back DJ , Tjia JF , Karbwang J , Colbert J
Published: July 2012

1. A number of compounds have been examined for their ability to inhibit tolbutamide hydroxylase activity in human liver microsomes (control value at a substrate concentration of 150 microM being 0.27 +/‐ 0.12 nmol min‐1 mg‐1 protein; mean +/‐ s.d.; n = 7). 2. IC50 (concentration of inhibitor producing 50% inhibition) values were determined for a range of sulphonamides, imidazoles and aminoquinoline compounds. The most potent inhibition was evident with the 1‐ substituted imidazole antimycotic drugs ketoconazole, clotrimazole and miconazole and the sulphonamide sulphaphenazole (IC50 values of 16.5, 2.5, 0.85 and 0.5 microM respectively). A number of compounds showed little or no inhibition of tolbutamide hydroxylase as judged by an IC50 of greater than or equal to 500 microM. 3. The Km value for tolbutamide hydroxylase was 125 microM and Vmax, 0.44 nmol min‐1 mg‐1 protein. All the substituted imidazoles examined in kinetic studies 1v vs 1s, Line‐ weaver‐Burk plots) produced either non‐competitive or mixed inhibition. The sulphonamides exhibited competitive inhibition, the Ki for sulphaphenazole being 0.22 microM. Primaquine showed mixed inhibition. Dixon plots confirmed the type of inhibition produced. 4. Although the competitive inhibition between some sulphonamides and tolbutamide is consistent with metabolism by the same isozyme of cytochrome P‐450 it does not prove it and further studies with purified enzymes will be necessary to confirm this.
Central effects of beta‐adrenoceptor antagonists. I‐Performance and subjective assessments of mood.
Authors: Currie D , Lewis RV , McDevitt DG , Nicholson AN , Wright NA
Published: July 2012

1. Central effects of the beta‐adrenoceptor antagonists, propranolol (40, 80 and 160 mg) and atenolol (50 and 100 mg) were studied in 12 healthy male subjects. Two placebo ingestions and an active control (oxazepam 15 mg) were included. Single doses were administered double‐ blind at 11.00 h, and assessments of performance and subjective feelings were made before, 2 h and 4 h after ingestion. 2. Performance was measured using letter cancellation, digit symbol substitution, continuous attention, choice reaction time, finger tapping, short term and immediate memory, critical flicker fusion and two flash fusion. Subjective feelings were assessed using twelve visual‐analogue scales. 3. Oxazepam impaired performance at letter cancellation (P less than 0.001), digit symbol substitution (P less than 0.05), continuous attention (P less than 0.001), immediate recall (P less than 0.05) and finger tapping (P less than 0.05), but neither of the beta‐adrenoceptor antagonists affected these measures. Propranolol (40 and 160 mg) also impaired short term memory (P less than 0.05), though it was not possible to establish this effect with atenolol. 4. Subjective alertness was reduced by oxazepam (P less than 0.01) and atenolol (P less than 0.05), while propranolol (40 mg) reduced anxiety (P less than 0.01) and propranolol (80 mg) impaired ability to concentrate (P less than 0.05). 5. The results suggest that both lipophilic and hydrophilic antagonists modify the central nervous system, though impairment may be difficult to establish with conventional tests. The observations on memory and alertness suggest that the central effect of beta‐ adrenoceptor antagonists may be subtle.
Acute and long‐term renal and metabolic effects of piretanide in congestive cardiac failure.
Authors: McNabb WR , Noormohamed FH , Lant AF
Published: July 2012

1. The renal and metabolic effects of the sulphamoylbenzoic acid diuretic, piretanide, have been studied, under controlled dietary conditions, in 39 patients with congestive cardiac failure. 2. In acute studies, peak saluresis occurred within 4 h of oral piretanide administration; saluresis was complete within 6 h, after which a significant antidiuretic effect was observed. Addition of triamterene, 50 mg, blunted the 0‐6 h kaliuretic effect of piretanide. Over 24 h, piretanide, alone, caused insignificant urinary losses of potassium when compared with control. 3. In comparative studies, the piretanide dose‐response curve was found to be parallel to that of frusemide over the dose range studied. The 0‐6 h saluretic responses of piretanide, 6, 12 and 18 mg, were found to be equivalent to frusemide, 40, 80 and 120 mg respectively. The collective mean ratios of all the saluretic responses to each dose of piretanide with the corresponding dose of frusemide was observed to be 0.99 +/‐ 0.12, over 0‐6 h period, and 0.86 +/‐ 0.09 over the 24 h period. The relative potency of piretanide, when compared with frusemide was found to be 6.18 (95% confidence limits 4.87‐8.33), over the 0‐6 h period, and 4.73 (95% confidence limits 3.65‐ 6.14), over 24 h period. 4. In 15 patients in severe cardiac failure, urinary recovery of piretanide, over first 6 h, at the start of treatment was 21.2 +/‐ 2.1% while efficiency of the diuretic (mmol Na/mg drug) was 47.3 +/‐ 4.1. Long‐term piretanide therapy was continued in the same group for up to and in some cases over 3 years. No other diuretics or potassium supplements were given. Piretanide dosage ranged from 6 to 24 mg day‐1 according to clinical need. Plasma potassium fell significantly at 12 and 24 months, though remaining within the normal range. At these same times, significant elevations in both plasma urate and total fasting cholesterol were observed. Two patients developed overt gout on high dose piretanide therapy (24 mg day‐1). Piretanide was well tolerated, and effective in the management of congestive cardiac failure without any other recognized metabolic or electrolyte changes.
Effect in man of aspirin, standard indomethacin, and sustained release indomethacin preparations on gastric bleeding.
Authors: Prichard PJ , Poniatowska TJ , Willars JE , Ravenscroft AT , Hawkey CJ
Published: July 2012

1. We have compared acute gastric bleeding caused by a new slow release preparation of indomethacin (indomethacin Continus) with that caused by aspirin and other indomethacin preparations. 2. In a randomized crossover study, blood loss into timed gastric aspirates was determined in 20 healthy volunteers after receiving, over 96 h, either placebo, aspirin (600 mg four times daily; 17 doses) indomethacin BP (50 mg three times daily; 13 doses), Indocid‐R (75 mg twice daily; 9 doses) or indomethacin Continus (75 mg twice daily; 9 doses). A venous blood sample was also taken during each treatment period for subsequent determination of alpha 1‐glycoprotein, and for drug assay. 3. Gastric bleeding on placebo was 1.4 (0.7‐2.8) microliters 10 min‐1 (mean, 95% confidence interval). Both aspirin and the indomethacin preparations caused significantly more bleeding (P less than 0.05). Rates of bleeding after aspirin, indomethacin BP, Indocid‐R, and indomethacin Continus were respectively 22.0 (10.7‐47.2) microliters 10 min‐1, 4.4 (2.2‐9.1) microliters 10 min‐1, 10.8 (5.3‐22.3) microliters 10 min‐1, and 5.1 (3.0‐10.6) microliters 10 min‐1. 4. Rates of bleeding after indomethacin BP and indomethacin Continus, but not Indocid‐R, were significantly less than after aspirin (P less than 0.01). 5. Salicylate or indomethacin was detectable in the plasma of all subjects after the active treatment periods, except for one instance involving a subject allocated indomethacin BP. Indomethacin levels were significantly higher 2 h after Indocid‐R than with indomethacin BP or indomethacin Continus. 6. alpha 1‐acid glycoprotein levels were not significantly affected by prior treatment with aspirin or indomethacin.
Passage of chloroquine into semen.
Authors: Ette EI , Ogonor JI , Essien EE
Published: July 2012

The passage of chloroquine into semen was investigated in four healthy men following the oral administration of four chloroquine sulphate tablets (600 mg base) to each subject. Chloroquine was found to be excreted into semen with a slow transfer rate constant of 0.0002 min‐1, and the semen/plasma ratio based on regression analysis was 0.40 +/‐ 0.06 (mean +/‐ s.d.). It is concluded that the passage of chloroquine from plasma to semen occurs by passive diffusion.
Extended blood collection period required to define distribution and elimination kinetics of propofol.
Authors: Campbell GA , Morgan DJ , Kumar K , Crankshaw DP
Published: July 2012

The pharmacokinetics of propofol were investigated following bolus intravenous administration of 2‐3 mg kg‐1 of drug to eight surgical patients. Apparent elimination half‐life, volume of distribution and systemic blood clearance of propofol correlated strongly with the sampling period, which ranged from 8 to 52 h, depending on the time taken for the propofol concentration to reach the detection limit of the assay. In the three patients in whom the sampling period exceeded 42 h, apparent elimination half‐life (55.6 h) and apparent volume of distribution (1370 l) greatly exceeded previously published estimates and systemic blood clearance (1020 ml min‐1) was much less than previous estimates. This suggests that previous estimates were biased by the relatively short duration of blood collection in those studies (8 to 12 h).
How can we design trials to detect clinically important changes in disease severity?
Authors: Saintonge Chaput de DM , Kirwan JR , Evans SJ , Crane GJ
Published: July 2012

1. Forty‐eight British rheumatologists judged the change in disease activity in 50 sets of patient data drawn from life and presented as ‘paper patients”. Each set comprised two values, recorded a year apart, for 10 commonly measured clinical variables. Doctors recorded the size of improvement or deterioration on a visual analogue scale (VAS) and whether the change was clinically important or not. 2. Clinical judgement policies were modelled using linear regression of the clinical variables on the VAS score. 3. Doctors showed little agreement over which patients had improved and which had not. Possible reasons could be discovered by inspecting their judgement policies. 4. The weights attributed to the clinical variables differed considerably between doctors. Furthermore weights the doctors believed they attached to the variables frequently differed from the weights in the regression models. 5. These models could be used to calculate the smallest change required in any clinical variable before it would be considered clinically important. However, the size of such changes was often outside the observed clinical range suggesting that the use of single outcome variables is unrealistic. 6. The modelling procedure described can be applied during the planning stage of the trial to participating physicians, patients, health economists or any other group having an interest in the results. The models themselves can then be used to reach a consensus policy for judging what is a successful outcome. This may be expressed as a linear combination of specific outcome measures. Its use may improve the power of clinical trials and the relevance of their results.
The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine.
Authors: Wooding‐Scott RA , Smalley J , Visco J , Slaughter RL
Published: July 2012

1. The pharmacokinetics and pharmacodynamics of quinidine and 3‐ hydroxyquinidine based upon measurements of total and unbound serum concentrations were determined after a single dose (400 mg) and at steady state (200 mg every 6 h). 2. The oral clearance (7.6 +/‐ 1.9 vs 4.8 +/‐ 2.0 ml min‐1 kg‐1; P less than 0.05) and renal clearance (1.2 +/‐ 0.3 vs 0.63 +/‐ 0.25 ml min‐1 kg‐1; P less than 0.005) or quinidine were lower during steady state than after the single dose. 3. The area under the serum concentration vs time curve (AUC) of 3‐hydroxyquinidine was greater at steady state than after the single dose (2.0 +/‐ 0.7 vs 3.0 +/‐ 0.6 mg l‐1 h; P less than 0.05) and its renal clearance was less (3.0 +/‐ 1.1 vs 1.54 +/‐ 0.38 ml min‐1 kg‐1; P less than 0.05). 4. The slope of the relationship between quinidine concentration and change in QTc interval was greater at steady state (40.1 +/‐ 21.7 vs 72.2 +/‐ 41.7 ms/(mg l‐1); P less than 0.05).
Relationship between the rate of appearance of oxprenolol in the systemic circulation and the location of an oxprenolol Oros 16/260 drug delivery system within the gastrointestinal tract as determined by scintigraphy.
Authors: Davis SS , Washington N , Parr GD , Short AH , John VA , Lloyd P , Walker SM
Published: July 2012

1. The position in the gastrointestinal tract of an orally administered oxprenolol Oros drug delivery system labelled with technetium‐99m DTPA was followed by gamma scintigraphy, and the corresponding plasma drug concentration‐time profiles after oral and i.v. administration were used to relate pharmacokinetic and transit data. 2. Gastric emptying time (0.8 +/‐ 0.4 h, mean +/‐ s.d.), and the time to arrival in the colon (3.8 +/‐ 0.7 h) were reasonably consistent after administration of the Oros system to fasted subjects, as were the calculated small intestine transit times (3.0 +/‐ 0.7 h). As expected there were wide individual variations in colonic transit, so that recorded values for total transit ranged from 6 to 32 h (median, 24.7 h). 3. Absorption of oxprenolol occurred throughout the GI tract including the colon. Plasma drug concentration‐time profiles and input functions (calculated by deconvolution) could be related to transit behaviour and in vitro release. Inflexions in the calculated rate of drug input when the Oros system was located in the colon corresponded with periods of stagnation at the hepatic and splenic flexures in two subjects and the ileocaecal junction in two others. The mechanism of these changes is unclear.
Pharmacokinetics of pholcodine in healthy volunteers: single and chronic dosing studies.
Authors: Chen ZR , Bochner F , Somogyi A
Published: July 2012

1. The pharmacokinetics of pholcodine after two single doses and after chronic administration were studied in healthy human volunteers. 2. Six subjects received single oral doses of 20 and 60 mg of pholcodine according to a balanced cross‐over design with an interval of 3 weeks between the two treatments. Blood and saliva samples and all urine were collected over 168 h after each dosage administration. Subsequently, the same subjects received 20 mg pholcodine 8 hourly orally for 10 days. Blood and saliva samples and all urine were collected during an 8 h dosing interval after the last dose on day 11. 3. Plasma, saliva and urine concentrations of pholcodine were determined by a high performance liquid chromatographic assay. 4. After the single doses, pholcodine was absorbed rapidly (tmax = 1.6 +/‐ 1.2 h) and eliminated slowly with a mean half‐life of 50.1 +/‐ 4.1 h. The renal clearance of pholcodine was 137 +/‐ 34 ml min‐1 and was inversely correlated with urine pH (r = 0.60) but not with urine flow rate. 26.2 +/‐ 3.3% of the dose was excreted as unchanged pholcodine after both doses. The concentration of pholcodine in saliva was 3.6 times higher than in plasma. 5. After chronic administration, the pharmacokinetics of pholcodine were not statistically different from the single dose parameters. 6. Pholcodine did not appear to undergo conjugation. The plasma protein binding was 23.5%. Morphine, in unconjugated or conjugated form, was not detected in the urine of any subject after pholcodine administration.
The effect of concurrent aspirin upon plasma concentrations of tenoxicam.
Authors: Day RO , Paull PD , Lam S , Swanson BR , Williams KM , Wade DN
Published: July 2012

1. The effect of chronic, high‐dose aspirin therapy upon the disposition of a single dose and multiple doses of tenoxicam was examined in normal volunteers. 2. Aspirin caused a 24% drop in the t1/2 (P less than 0.005), a 49% rise in the volume of distribution (P less than 0.0003) and a 98% increase in the clearance (P less than 0.0001) of tenoxicam after a single dose of the tenoxicam. 3. Steady‐state concentrations of tenoxicam decreased significantly from 10.4 +/‐ 1.5 to 4.5 +/‐ 1.6 micrograms ml‐1 in the presence of chronic, high‐dose aspirin treatment. 4. Tenoxicam percentage free measured in plasma from a normal volunteer was 0.56 +/‐ 0.05% over the tenoxicam concentration range 1‐20 micrograms ml‐1 and rose to 1.24 +/‐ 0.07% in the presence of aspirin 150 micrograms ml‐1. 5. The effect of aspirin upon the disposition of tenoxicam was consistent with a competitive protein binding interaction.
Simplified approaches to the determination of antipyrine pharmacokinetic parameters.
Authors: Scavone JM , Greenblatt DJ , Blyden GT , Harmatz JS , Graziano PJ
Published: July 2012

1. The pharmacokinetics of single intravenous doses of antipyrine were determined in 96 volunteers using multiple (12 or more) plasma antipyrine concentrations measured by high‐pressure liquid chromatography during 24‐48 h after dosage. These kinetic estimates were compared with those based on: A, the 4 h and 12 h points only; B, the 4 h through 12 h points; C, the 8 h and 24 h points only. 2. Mean clearance values for the complete study (48.0 ml min‐1) were nearly identical to abbreviated approaches A, B, and C (49.1, 49.3, and 46.4 ml min‐1), and were highly correlated (r = 0.99). 3. Coefficients of variation (CV) between individual clearance values for complete vs abbreviated studies averaged 5.5%, 5.8% and 2.9%, and CVs were less than 15% in 95.8%, 93.7% and 98.9% of subjects, respectively, for methods A, B, and C. 4. Overall mean values of elimination half‐life (11.9, 12.1, 12.0 and 12.5 h) and volume of distribution (43.7, 45.1, 45.2, and 44.71) were likewise very similar for complete A, B and C analyses respectively. 5. The best correlation with the complete study was observed for the 8 and 24 h sampling scheme, for which clearance values were within 5% of the reference method in 84% of subjects, and within 10% in 97% of subjects. 6. Antipyrine pharmacokinetic parameters can be estimated with reasonable precision using a simplified two‐point blood sampling procedure following a single intravenous dose. Estimates of elimination half‐life, volume of distribution and clearance based on 8 h and 24 h data points correlated best with complete pharmacokinetic studies.
Alpha 1‐acid glycoprotein concentration and molecular heterogeneity: relationship to oxprenolol binding in serum from healthy volunteers and patients with lung carcinoma or cirrhosis.
Authors: Fraeyman NF , Dello CD , Belpaire FM
Published: July 2012

1. alpha 1‐acid glycoprotein (AAG) concentration and molecular heterogeneity, and oxprenolol protein binding were studied in serum of 15 healthy volunteers, 14 patients with lung carcinoma and 17 patients with liver cirrhosis. 2. The AAG serum concentration was increased to 180.7% in patients with lung cancer and decreased to 73.4% in cirrhotic patients as compared with controls (P less than 0.05). 3. The concanavalin A (conA) dependent heterogeneity of serum AAG was very similar in controls and patients with lung cancer: a ratio of 9/9/2 was obtained for the conA nonreactive, the conA weakly reactive and the conA strongly reactive subfraction respectively; in cirrhotic patients, the ratio shifted to 11/7/1. 4. The heterogeneity in electric charge, demonstrated by isoelectric focusing, was similar in the three groups of subjects: 70‐80% of the focussed bands were found in the main three bands. 5. The binding of oxprenolol to serum proteins was increased in lung tumour patients and decreased in liver cirrhotic patients as compared with controls (P less than 0.05). There was no change in binding affinity and oxprenolol binding was significantly correlated to total AAG serum concentration and to the concentration of each of the conA dependent subtypes, in controls as well as in both patients groups.
Vasoactive responses of a human cystic artery: adrenoceptor characterization.
Authors: Wyse DG
Published: July 2012

1. The pharmacology of various agonists and antagonists was studied in the human isolated cystic artery. 2. The estimated pA2s for the alpha 1‐ adrenoceptor antagonist prazosin against the alpha‐adrenoceptor agonists phenylephrine, alpha‐methylnoradrenaline and noradrenaline were not significantly different. Similar results were seen for estimated pA2s of the alpha 2‐adrenoceptor antagonist yohimbine against these same agonists. Equivalent responses to exogenous noradrenaline and to transmural electrical stimulation were blocked to the same degree by an antagonist with alpha 1‐adrenoceptor blocking properties (prazosin). Responses to transmural electrical stimulation, however, tended to be more resistant than equivalent responses to exogenous noradrenaline to blockade by antagonists with alpha 2‐adrenoceptor blocking properties (phentolamine, yohimbine). 3. Relaxation to isoprenaline was observed in partially contracted arterial strips using isoprenaline concentrations of up to 10(‐6) M, but cumulative addition of higher concentrations of isoprenaline sometimes then evoked a contraction from the relaxation nadir. The relaxation effect of isoprenaline was antagonized by propranolol (10(‐5) M). 4. These findings suggest the human cystic artery has almost exclusively alpha 1‐ adrenoceptors postjunctionally, although prejunctional alpha 2‐ adrenoceptors may be present; and, it also has some postjunctional beta‐ adrenoceptors which mediate relaxation.
The effect of nisoldipine on whole blood platelet aggregation in patients with Raynaud's phenomenon.
Authors: Francis JL , Roath OS , Challenor VF , Waller DG
Published: July 2012

1. Whole blood platelet aggregation was measured by electrical impedance in 28 controls and 28 patients with primary Raynaud's phenomenon. 2. The patients were entered into a double‐blind, placebo‐ controlled cross‐over trial of the calcium antagonist nisoldipine, in which they received, in random order, three, 4 week treatments with placebo and nisoldipine (5 and 10 mg day‐1). 3. Platelet aggregation responses to two concentrations (5.0 and 0.5 micrograms ml‐1) of collagen were determined before treatment and at the end of each treatment phase. 4. There were no differences in aggregation response to either collagen concentration between controls and patients with primary Raynaud's phenomenon, or between placebo and active treatment phases. 5. These data do not support the suggestion that nisoldipine has a significant anti‐platelet effect.
The effect of allopurinol on the steady‐state pharmacokinetics of indomethacin.
Authors: Pullar T. , Myall O. , Haigh J.R. , Lowe J.R. , Dixon JS , Bird HA
Published: July 2012

The effect of 5 days treatment with allopurinol (300 mg) on the pharmacokinetics of indomethacin at steady‐state was investigated in eight patients. Allopurinol produced no significant effect on the indomethacin serum concentration‐time curve. Allopurinol did not alter significantly the amounts of indomethacin excreted in the urine within 8 h. However, the urinary ratio of N‐deschlorobenzoylindomethacin to indomethacin was reduced significantly by allopurinol administration (P less than 0.05).
The effect of inhaled ouabain on bronchial reactivity to histamine in man.
Authors: Knox AJ , Tattersfield AE , Britton J.R.
Published: July 2012

To determine the role of Na/K ATPase in determining bronchial reactivity in man, we studied the effect of 1 mg inhaled ouabain on histamine reactivity in six normal and 10 asthmatic subjects in a placebo controlled, crossover study. sGaw was measured before and up to 2 h after drug, followed by a histamine challenge test to estimate the dose of histamine causing a 35% reduction in sGAW (PD35). sGAW values after ouabain and placebo did not differ significantly. Ouabain did not affect bronchial reactivity, geometric mean (95% CI) PD35 histamine values following ouabain and placebo were 8.98 (3.8‐21.2) and 7.75 (3.2‐ 18.7) mumol respectively in normal subjects and 0.46 (0.18‐1.21) and 0.69 (0.22‐2.13) in asthmatic subjects. We were thus unable to demonstrate a role for Na/K ATPase in determining bronchial reactivity to histamine in man.
Blocking of histamine‐induced conjunctivitis by the oral antihistamine, astemizole.
Authors: Stokes TC , Feinberg G.
Published: July 2012

When histamine is applied topically to the eye it produces stinging and inflammation of the caruncle and bulbar and palpebral conjunctiva. This model has been employed in the present study to assess the ability of an oral antihistamine, astemizole, to attenuate the irritation and inflammatory signs. Astemizole 30 mg, taken orally once daily for 1 week, considerably lessened the stinging and significantly lowered the signs of inflammation caused by topically applied histamines.
Effect of the removal of individual antiepileptic drugs on antipyrine kinetics, in patients taking polytherapy.
Authors: Patsalos PN , Duncan JS , Shorvon SD
Published: July 2012

1. Antipyrine (AP) clearance, half‐life and volume of distribution were determined in 52 patients, taking one or more antiepileptic drug (AED), before and 4 weeks after the complete removal of phenytoin (PHT, n = 20), carbamazepine (CBZ, n = 15) and sodium valproate (VPA, n = 17). 2. PHT removal was associated with a mean 13% fall in AP clearance and a mean 16% increase in AP half‐life, in patients who were also taking CBZ with or without barbiturates. There was no significant difference between patients who did, and did not, take barbiturates, in addition to CBZ. 3. CBZ removal was associated with a mean 45% fall in AP clearance and a mean 69% increase in AP half‐life, if there was no inducing AED comedication, but had no effect on AP clearance and half‐ life if PHT and/or barbiturates were also being taken. 4. Removal of VPA had no effect on AP clearance or half‐life. 5. The removal of PHT, CBZ and VPA had no significant effect on AP volume of distribution. 6. PHT appears to be a more powerful inducer of hepatic enzyme activity, as measured by the AP test, than is CBZ.
The effect of prazosin on skin microcirculation as assessed by laser Doppler flowmetry.
Authors: Khan F. , Struthers AD , Spence VA
Published: July 2012

1. Laser Doppler flowmetry was used in six normal volunteers to record changes in fingertip skin blood flow after the administration of prazosin to block postsynaptic alpha 1‐adrenoceptors. 2. Prazosin (0.5 mg orally) did not alter systolic or diastolic blood pressure or heart rate. 3. Prazosin did significantly increase basal skin blood flow 2 h after its administration but this effect was no longer evident after contralateral hand warming. Prazosin markedly reduced the skin vasoconstrictor response to deep inspiration and to contralateral hand cooling. 4. This study suggests that postsynaptic alpha 1‐adrenoceptors are involved in maintaining skin vasoconstrictor tone at rest and are also involved in the rapid skin vasoconstriction seen in response to a deep inspiration and to contralateral hand cooling.
The calcium‐channel blocker, verapamil, does not improve portal pressure in patients with alcoholic cirrhosis.
Authors: Merkel C. , Gatta A. , Bolognesi M. , Padrini R. , Finucci GF , Angeli P. , Ruol A.
Published: July 2012

1. Recently the calcium‐channel blocker, verapamil, has been reported to decrease portal pressure in rats with experimental cirrhosis and in patients with liver cirrhosis. 2. In eight patients with alcoholic cirrhosis the effect of verapamil (5 mg i.v.) on systemic and splanchnic haemodynamics was investigated. 3. Mean arterial pressure, wedged hepatic venous pressure, hepatic venous pressure gradient, and verapamil plasma concentrations were measured before and at 10, 20, 30 min following 5 mg i.v. administration of verapamil. At 30‐40 min cardiac output, systemic vascular resistance and hepatic blood flow were also measured. 4. Verapamil plasma concentrations averaged 47.9 +/− 52.0, 36.5 +/− 36.3, 31.3 +/− 33.9 ng ml‐1 at 10, 20, 30 min respectively: mean arterial pressure and systemic vascular resistance decreased significantly (‐9% and −14% respectively), and cardiac index increased significantly (+8%). Wedged hepatic venous pressure and hepatic venous pressure gradient remained unchanged, variations never exceeding 0.2 kPa. Hepatic blood flow increased significantly by 12%. 5. These results show that i.v. administration of 5 mg verapamil does not decrease portal pressure in alcoholic cirrhosis. This lack of effect is probably the consequence of a balance between decrease in porto‐hepatic vascular resistance and increase in splanchnic blood inflow.
Theophylline‐terbutaline, a steady state study on possible pharmacokinetic interactions with special reference to chronopharmacokinetic aspects.
Authors: Jonkman JH , Borgstrom L. , van der Boon WJ , de Noord OE
Published: July 2012

1. The pharmacokinetic interaction of terbutaline and theophylline and chronopharmacokinetics of both drugs were studied in a three‐way crossover study with repeated administration of terbutaline (Bricanyl Depot) 7.5 mg twice daily, theophylline (Theo‐Dur) 300 mg twice daily alone or the combination of both for 7 days to 12 healthy volunteers (six male and six female). 2. After the morning dose on day 7, blood and urine were sampled for 12 h, and after the evening dose on day 7, blood and urine were sampled for 48 h. Theophylline concentrations in plasma and concentrations of unchanged drug and metabolites in urine were determined by two selective high performance liquid chromatography methods. Terbutaline concentrations in plasma and urine were measured with a gas chromatography‐mass spectrometry method. Area under the plasma concentration‐time curve, fluctuations in plasma concentration, mean residence time, elimination half‐life, renal clearance as well as maximal, minimal and average plasma concentration at steady state were evaluated. 3. The addition of terbutaline to the repeated administration of theophylline lowered the relative bioavailability of theophylline by approximately 11% during the night interval. The rate of elimination of theophylline and mean residence time were influenced accordingly. No significant changes in excretion of the theophylline metabolites were observed, but the excretion of 3‐methylxanthine was slightly reduced by the concomitant terbutaline administration. None of the observed changes should be of any clinical importance. 4. The addition of theophylline did not influence any of the calculated pharmacokinetic parameters of terbutaline. 5. It can be concluded that no dosage adjustment is necessary when terbutaline and theophylline are given together.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of ipratropium bromide and sodium cromoglycate on benzalkonium chloride‐induced bronchoconstriction in asthma.
Authors: Miszkiel KA , Beasley R. , Holgate ST
Published: July 2012

1. Benzalkonium chloride, an antibacterial preservative that is added to nebuliser solutions, has been shown to cause bronchoconstriction when inhaled by asthmatic subjects. 2. To investigate the potential role of reflex and mast cell‐dependent mechanisms in the pathogenesis of bronchoconstriction produced by benzalkonium chloride we examined the effects of ipratropium bromide and sodium cromoglycate on this response in both concentration‐response and time‐course studies in nine asthmatic subjects. 3. Pretreatment with inhaled ipratropium bromide (1 mg) and sodium cromoglycate (40 mg) displaced the benzalkonium chloride concentration‐response curves to the right by a mean 2.2 fold and 3.1 fold respectively. 4. Ipratropium bromide and sodium cromoglycate markedly attenuated the airway response to benzalkonium chloride throughout the 45 min time course period, inhibiting the overall response by 56% and 78% respectively. 5. We conclude that benzalkonium chloride provokes bronchoconstriction in asthmatic subjects through a combination of mast cell activation and stimulation of peripheral and central neural pathways.
Lack of effect of erythromycin on the pharmacokinetics of single oral doses of phenytoin.
Authors: Milne RW , Coulthard K. , Nation RL , Penna AC , Roberts G. , Sansom LN
Published: July 2012

The effect of erythromycin on the pharmacokinetics of phenytoin was studied in eight healthy volunteers using a balanced randomised cross‐ over design. Volunteers received a single oral dose of 400 mg of phenytoin sodium during each phase. During the treatment phase, the phenytoin sodium dose was administered 4.5 days after the commencement of a 7 day course of erythromycin base (250 mg every 6 h). There was no significant difference between the control and treatment phases (P greater than 0.05) with respect to the area under the plasma phenytoin concentration‐time curve, the fraction of phenytoin unbound in plasma, the area under the unbound phenytoin concentration‐time curve, the elimination half‐life of phenytoin or the fraction of the dose excreted in urine as free and conjugated hydroxyphenylphenylhydantoin. This single dose study indicated that the intrinsic clearance of unbound phenytoin was unaffected by the concurrent administration of erythromycin.
Reversal of histamine‐induced bronchoconstriction by the H1‐receptor antagonist levocabastine: a potential model for efficacy in anaphylaxis.
Authors: Ferner RE , Ward C. , Kelly C. , Connolly M. , Bateman DN , Rawlins MD
Published: July 2012

1. The rate of onset and magnitude of the effect of levocabastine, a potent H1‐receptor antagonist, in reversing histamine‐induced bronchoconstriction were determined in a double‐blind cross‐over trial against saline placebo. Histamine was administered by nebuliser so that forced expiratory volume in 1 second (FEV1) was reduced to 80‐75% of baseline FEV1 in 10 men with mildly or moderately responsive airways and the effects of intravenous injection of saline or saline + 200 micrograms levocabastine were studied. 2. The maximum rate of recovery of FEV1 was 7[2‐10]% min‐1 (median [range]) in the first 5 min after levocabastine injection, but only 4[1‐7]% min‐1 after saline alone (P less than 0.05). 3. The median area under the recovery curve of FEV1 from 0 to 30 min after injection was 405 [228‐498]% basal FEV1 X min after levocabastine and 301[98‐502]% basal FEV1 X min after saline alone (P less than 0.002). 4. FEV1 returned to 90% of baseline within 30 min in all subjects after levocabastine, but not after saline alone (P less than 0.002). 5. Histamine‐induced bronchoconstriction was relieved more quickly by levocabastine than saline alone. This model may have application to the study of drugs used in the treatment of anaphylaxis.
Antihypertensive efficacy of the calcium‐antagonist felodipine in patients with persisting hypertension on beta‐adrenoceptor blocker therapy. The Canadian Felodipine Study Group.
Authors: Gould CA , Ollier S. , Aurich R. , Davies RJ
Published: July 2012

1. The antihypertensive efficacy of two different doses of the calcium antagonist felodipine was evaluated in patients with hypertension persisting despite beta‐adrenoceptor blocker therapy. Following a single‐blind placebo period of 4 weeks, patients were randomized to placebo (n = 36), felodipine 5 mg twice daily (n = 39) and felodipine 10 mg twice daily (n = 35) for another 4 weeks. beta‐adrenoceptor blocker therapy remained unchanged throughout the study. 2. Effects on blood pressure (BP) were evaluated after the first dose and after chronic dosing at 2 h after dosing and the end of the dosing interval (12 h). 3. Felodipine decreased systolic and diastolic BP by 30‐35/20‐ 25 mm Hg at 2 h. These decreases were similar after acute and chronic treatment. Twelve hours after dosing, decreases of 15‐20/10‐15 mm Hg were observed compared to 10/5 mm Hg on placebo, and half of the patients still had a controlled BP (supine diastolic BP less than 90 mm Hg). BP responses were rather similar for both doses of felodipine at 2 and 12 h. 4. Multiple regression analysis showed that both initial BP level and plasma felodipine concentrations were significant predictors of the BP response to felodipine, but age was not. 5. Adverse effects attributed to felodipine were mainly related to vascular symptoms (primarily flushing and ankle swelling); these occurred in about 30% of patients, and were pronounced in three patients (4%). 6. Felodipine is therefore highly effective in lowering BP of hypertensive patients on chronic beta‐adrenoceptor blocker therapy, with no evidence for a gradual lowering of the BP or for development of tolerance. Both initial BP level and plasma concentrations are better indicators of antihypertensive efficacy of this calcium antagonist than age.