bluuebunny/crossref_metadata_2025 huggingface dataset:
The effect of acute and chronic captopril therapy on baroreflex function in man.
Authors: Kondowe GB , Deering AH , Riddell JG , Johnston GD , Harron DW
Published: July 2012

1. The effect of captopril 12.5 mg three times daily for 14 days on baroreflex sensitivity was investigated in six normotensive salt‐ replete male subjects. 2. Baroreflex sensitivity [delta R‐R interval ms/mmHg systolic blood pressure (SBP)] was assessed following decreases and increases in SBP with glyceryl trinitrate and phenylephrine respectively and during Valsalva's manoeuvre. 3. Captopril had no effect on supine intra‐arterial SBP or R‐R interval on days 1 and 15 compared with placebo. However decreases (P less than 0.05) which occurred in plasma angiotensin II on day 1 (12.3 +/‐ 0.8 to 7.6 +/‐ 1.5 pg ml‐1) and on day 15 (14.5 +/‐ 1.5 to 6.3 +/‐ 0.5 pg ml‐1) and increases (P less than 0.02) in plasma renin activity on day 1 (1.2 +/‐ 0.7 to 4.8 +/‐ 0.8 ng A I ml‐1 h‐1) and on day 15 (1.1 +/‐ 0.2 to 5.4 +/‐ 0.9 ng A I ml‐1 h‐1) compared with placebo, indicated angiotensin‐ converting enzyme inhibition. 4. Baroreflex sensitivity was unchanged by captopril on day 1 and day 15 compared with placebo following the use of glyceryl trinitrate and phenylephrine to deactivate and activate respectively the baroreceptors, and during the strain and release phases of Valsalva's manoeuvre.
Time course of the effects of epoprostenol on effective pulmonary blood flow in normal volunteers.
Authors: Bush A , Busst CM , Millar A , Syrett N
Published: July 2012

1. Epoprostenol (prostacyclin) has been widely used as a vasodilator, but its effects on cardiac output are controversial and the time course of its effects little studied. 2. We report its cardiovascular effects in doses of 5 and 10 ng kg‐1 min‐1 in six healthy volunteers. 3. Each of the two doses caused a mean 20% rise in effective pulmonary blood flow and a 15% rise in heart rate. These effects appeared to reach a maximum within 10 min of starting or increasing the rate of infusion, with no evidence of a rebound effect. 4. When the dose was reduced, heart rate and effective pulmonary blood flow appeared to reach a new steady state within 5 min of reducing or stopping the infusion. Only minor side‐effects were encountered, and they were rapidly reversed on stopping the drug. 5. These results should be applied to the therapeutic use of epoprostenol as a vasodilator, particularly when titrating the optimum dose for a given individual.
Atenolol‐nifedipine combinations compared to atenolol alone in hypertension: efficacy and tolerability.
Authors: Maclean D , Mitchell ET , Coulson RR , Fitzsimons TJ , McDevitt DG
Published: July 2012

1. In a double‐blind, randomised, three‐way‐crossover study, 25 patients with sitting diastolic blood pressure between 95 and 120 mm Hg (Phase V) after 4 weeks' run‐in on atenolol 50 mg twice daily, received atenolol 50 mg twice daily alone, atenolol 50 mg plus nifedipine 20 mg each twice daily and atenolol 50 mg plus nifedipine 40 mg each twice daily in three treatment periods each lasting 4 weeks. ‘Washout’ periods were not included. 2. The two combination treatment regimes lowered the 12 h post‐dose blood pressure more effectively than did atenolol alone, but the high dose nifedipine combination was no more effective than the low dose nifedipine combination. Sitting systolic BP (+/‐ s.e. mean) at the end of each period was 174 +/‐ 5 mm Hg after the atenolol run‐in, 170 +/‐ 5 mm Hg with atenolol alone, 156 +/‐ 5 mm Hg with the low dose combination and 158 +/‐ 4 mm Hg with the high dose combination. Corresponding diastolic BP readings were 106 +/‐ 2 mm Hg, 106 +/‐ 2 mm Hg, 97 +/‐ 2 mm Hg and 99 +/‐ 2 mm Hg respectively. 3. Side‐effects tended to occur less commonly with the low dose of the fixed combination than with atenolol alone. An increased number of side‐ effects occurred with the 40 mg twice daily doses of nifedipine, particularly flushing/erythema, oedema of the ankles/feet, and a hot feeling in the legs. These differences did not reach significance. 4. Overall compliance was good (98 +/‐ 0.7 s.e. mean %) and was similar within the different treatment regimes.(ABSTRACT TRUNCATED AT 250 WORDS)
Effectiveness and tolerability of CV‐3988, a selective PAF antagonist, after intravenous administration to man.
Authors: Arnout J , Van Hecken A , de Lepeleire I , Miyamoto Y , Holmes I , de Schepper P , Vermylen J
Published: July 2012

1. The efficacy and tolerability of CV‐3988, a selective PAF antagonist with structural analogies with PAF, were studied after intravenous infusion in man. 2. The compound, in doses from 750 to 2,000 micrograms kg‐1, significantly reduced platelet sensitivity for PAF. The threshold aggregating concentration (TAC) of PAF, expressed in % of the mean predosing value, increased in a dose dependent manner reaching 356 +/‐ 162% of the basal TAC at the end and 266 +/‐ 123% of the basal TAC 4 h after infusion of the highest dose. The TAC of PAF returned to the basal value within 24 h after the end of the infusion. 3. CV‐3988 did not cause major side effects nor changes in blood pressure, pulse and respiratory rate. However, small but clinically insignificant changes in plasma haemoglobin and serum haptoglobin were seen at the end and 4 h after the end of the infusion, indicating a slight haemolysis. 4. Our results indicate that, when adequate infusion volumes and infusion rates are used, CV‐3988 can safely be administered to man and should be useful in elucidating the role of PAF in disease.
Enantioselectivity of 4‐hydroxylation in extensive and poor metabolizers of debrisoquine.
Authors: Eichelbaum M , Bertilsson L , Kupfer A , Steiner E , Meese CO
Published: July 2012

Debrisoquine (DQ) has no chiral centre, but hydroxylation in position 4 leads to formation of an asymmetric carbon centre with two possible enantiomers, their absolute configuration being R(‐) and S(+)‐4‐ hydroxydebrisoquine (4‐OHDQ). Since the absolute stereochemistry of the 4‐hydroxylation of DQ in man is unknown, the enantioselectivity of this process was studied in panels of extensive (EM) and poor metabolizers (PM) of DQ. In EM subjects 4‐hydroxylation of DQ leads almost exclusively to the formation of S(+)‐4‐OHDQ. In contrast, PM subjects were not only characterized by a decreased total 4‐OHDQ formation but also a marked loss of enantioselectivity in product formation. Between 5 to 36% of total 4‐OHDQ was excreted as R(‐)‐4‐OHDQ.
The effect of metoclopramide on the absorption of oral controlled release morphine.
Authors: Manara AR , Shelly MP , Quinn K , Park GR
Published: July 2012

The pharmacokinetics of oral controlled release morphine and metoclopramide were investigated in 20 patients in a double‐blind, randomly allocated study. The concurrent administration of metoclopramide and oral controlled release morphine led to a faster onset and increased level of sedation compared with the administration of oral controlled release morphine alone. Whilst the increased sedation may be advantageous in anaesthetic practice, it may be a potential problem in patients starting longer term therapy with these drugs.
Lisinopril: dose‐peak effect relationship in essential hypertension.
Authors: Cirillo VJ , Gomez HJ , Salonen J , Salonen R , Rissanen V , Bolognese JA , Nyberg R , Kristianson K
Published: July 2012

1. The dose‐peak effect relationship of lisinopril was evaluated in a double‐blind, parallel study in 83 patients with mild to moderate essential hypertension (supine diastolic blood pressure = 95‐115 mm Hg). 2. After a 4 week placebo washout, patients were randomly assigned to one of four treatments: lisinopril 2.5, 10, 20 or 80 mg day‐1 for 1 week. 3. Lisinopril 10 and 20 mg day‐1 produced similar peak antihypertensive effects which were greater than that produced by 2.5 mg day‐1, but less than that of 80 mg day‐1. If the incidence of first‐ dose symptomatic hypotension is related to the peak effect, then an initial lisinopril dose of 20 mg should not pose any greater risk than a 10 mg dose. 4. The magnitude of antihypertensive response at 24 h postdrug appeared to be dose related across the 2.5 to 80 mg day‐1 range.
Diuretic and natriuretic effects of nifedipine in healthy persons.
Authors: Wetzels JF , Wiltink PG , Hoitsma AJ , Huysmans FT , Koene RA
Published: July 2012

1. We have studied the diuretic and natriuretic effects and the tubular site of action of nifedipine using free water clearance (CH2O) and lithium clearance. 2. We have compared the effects of nifedipine (10 mg p.o.) with those of placebo and of frusemide (40 mg p.o.) in seven healthy volunteers during maximal water diuresis. 3. Compared with placebo, nifedipine caused a significant rise in urinary flow rate and CH2O, paralleled by significant increases in fractional excretion of sodium and lithium. The rise in sodium excretion was not accompanied by an increase in potassium excretion. 4. Frusemide caused increases in sodium and lithium excretion, comparable with the effects seen after nifedipine. CH2O did not change however. 5. Our study demonstrates that nifedipine has a clear diuretic and natriuretic effect in healthy volunteers, which is predominantly established by interference with proximal tubular sodium reabsorption. Lithium clearance did not allow us to differentiate between nifedipine and frusemide effects, thus questioning the reliability of lithium as a marker of proximal tubular sodium reabsorption.
Saliva and plasma concentrations of isoniazid and acetylisoniazid in man.
Authors: Hutchings AD , Monie RD , Spragg BP , Routledge PA
Published: July 2012

1. The pharmacokinetics of isoniazid and acetylisoniazid in plasma and saliva were compared following administration of oral and intravenous doses (200 mg) to healthy volunteers and patients. 2. In the 22 subjects studied after oral administration and the six subjects studied after intravenous administration there was complete phenotypic agreement for both slow (t1/2 greater than 130 min) and fast (t1/2 less than 130 min) acetylators using either saliva or plasma. 3. Acetylator phenotyping based on the t1/2 of INH determined using saliva collected at 2, 3, 4, 5 and 6 h after a 200 mg oral dose appears to be as reliable as that based on plasma. 4. Salivary isoniazid concentrations may provide a non‐invasive alternative to plasma concentrations.
Effect of maximal hydration on the renal responses to pretreatment with nonsteroidal anti‐inflammatory drugs and probenecid in man.
Authors: Dixey JJ , Noormohamed FH , Lant AF , Brewerton DA
Published: July 2012

The renal response to a challenge of maximal water diuresis has been studied in seven subjects pretreated over 48 h with either placebo, probenecid, indomethacin or piroxicam. Probenecid did not alter the excretion of water and sodium chloride when compared with placebo responses, but increased both phosphate and urate clearances. Indomethacin reduced significantly both water and sodium chloride clearances by approximately 40%. Piroxicam reduced water excretion to a similar extent but did not influence salt output. In parallel with these changes, both drugs caused significant phosphaturia. It is concluded that the renal actions of nonsteroidal anti‐inflammatory drugs (NSAIDs) are individually distinct and involve direct effects on tubular transport of ions and water to differing extents within both the proximal and distal portions of the nephron.
Naproxen kinetics in synovial fluid of patients with osteoarthritis.
Authors: Bruno R , Iliadis A , Jullien I , Guego M , Pinhas H , Cunci S , Cano JP
Published: July 2012

1. The kinetics of naproxen in synovial fluid were studied in 407 osteoarthritic outpatients with knee effusion requiring aspiration, following a single 1100 mg oral dose of naproxen sodium. 2. The drug concentration‐time profiles were described by a biexponential function. Naproxen entered synovial fluid rapidly, reaching a maximum concentration of 36 mg l‐1 (Cmax) at 7.5 h. The first order input rate constant (kOs) was 0.41 +/‐ 0.15 h‐1 with a lag time (tlag) of 0.24 +/‐ 0.36 h. 3. Elimination from the fluid was slow (t1/2 = 31 +/‐ 12 h) and appreciable drug concentrations were still measurable (27 mg l‐1) after 24 h. 4. During once daily dosing of naproxen sodium, naproxen should accumulate in synovial fluid, a steady‐state being achieved within a week of treatment. The predicted accumulation ratio based on trough concentration was 2.4.
Ketanserin concentration‐effect relationships in individual hypertensive patients.
Authors: Donnelly R , Elliott HL , Meredith PA , Hughes DM , Reid JL
Published: July 2012

1. This study further investigates the relationship between ketanserin concentration and the fall in BP in individual hypertensive patients. 2. An integrated kinetic‐dynamic model was used to characterise the response to ketanserin for each individual in terms of BP reduction per unit drug concentration and to describe the temporal discrepancy for the plasma concentration‐effect relationship (keq). 3. Using the linear effect model ketanserin concentrations were well correlated with the fall in BP in individual patients. There was a significant reduction in the responsiveness to ketanserin (m) after 1 month: −0.25 mm Hg ng‐1 ml‐ 1, compared with −0.47 following the 1st dose. 4. There was a significant increase in keq from 0.49 (1st dose) to 1.86 h‐1 (1 month). 5. There was no relationship between the responsiveness to ketanserin and patient age, starting BP or peripheral alpha‐adrenoceptor blockade.
Psychomotor, respiratory and neuroendocrinological effects of nalbuphine and haloperidol, alone and in combination, in healthy subjects.
Authors: Saarialho‐Kere U
Published: July 2012

1. Actions and interactions on performance and respiration of single intramuscular doses of 0.15 mg kg‐1 nalbuphine and oral haloperidol twice daily for 2 days were studied double‐blind and cross‐over in 12 healthy volunteers. 2. Objective measurements of performance (choice reaction, tracking, attention, flicker fusion, Maddox wing, digit symbol substitution) and respiratory function (minute volume, end‐tidal carbon dioxide), and subjective assessments on visual analogue scales were done at baseline and 1 h, 2.5 h and 4 h after the injection of nalbuphine. Plasma concentrations of nalbuphine were estimated by radioreceptor ([3H]‐dihydromorphine) assay, and those of prolactin and growth hormone by radioimmunoassay. 3. Nalbuphine affected digit substitution, reaction time, extraocular muscle balance and flicker recognition, and depressed respiration most clearly 1 and 2.5 h post injection. Motor skills were impaired only briefly. Haloperidol alone proved inert on performance but enhanced the decremental effects of nalbuphine on digit substitution and exophoria at 1 h. It did not interact with nalbuphine on the ventilatory function. 4. Plasma concentrations of nalbuphine expressed as morphine equivalents ranged from 5 to 52 ng ml‐1, indicating considerable mu‐opiate affinity. Treatment with haloperidol increased plasma prolactin moderately whilst nalbuphine raised it markedly 1 and 2.5 h post injection. Nalbuphine elevated plasma growth hormone at 1 h post injection only.
The binding of drugs to major human milk whey proteins.
Authors: Atkinson HC , Begg EJ
Published: July 2012

The binding of nine drugs of diverse physicochemical characteristics to major human milk whey proteins is reported. This group included acids, bases and neutral drugs. No drug bound to alpha‐lactalbumin, which is the protein present in greatest concentrations in mature milk. Four drugs, diclofenac, phenytoin, prednisolone and warfarin, bound to albumin but to a much lesser extent than in plasma, consistent with quantitatively less albumin in milk. None of the basic drugs studied bound to albumin. Five drugs, atenolol, diclofenac, prednisolone, propranolol and warfarin, bound to lactoferrin though the extent was minimal except for diclofenac. This group included acids, bases and neutral drugs.
Excretion of tiapamil in breast milk.
Authors: Hartmann D , Lunell NO , Friedrich G , Rane A
Published: July 2012

The excretion of tiapamil in breast milk was studied in six lactating mothers (3‐7 days post partum) following a single oral 600 mg dose of the drug. The milk/plasma ratio of tiapamil derived from the areas under the plasma and milk concentration‐time curves was 0.44 +/‐ 0.10 mean +/‐ s.d.). Assuming an intake of 350 ml of milk during a dosing interval of 12 h, the newborn would be exposed at the maximum to 0.053 mg tiapamil. This small amount does not represent a risk for the baby.
The paradox of using a 7 day antibacterial course to treat urinary tract infections in the community.
Authors: Cheung R , Sullens CM , Seal D , Dickins J , Nicholson PW , Deshmukh AA , Denham MJ , Dobbs SM
Published: July 2012

1. We have studied determinants of outcome of 7 day courses of treatment in 77 middle aged and elderly patients, in whom the general practitioner's diagnosis of urinary tract infections had been confirmed microbiologically. Bacteria were sensitive to cephalexin or trimethoprim. Where there was no preference, treatments were allocated randomly. Compliance was monitored using a pill box with a concealed electronic device which recorded openings of the box. 2. Prescribing trimethoprim, 200 mg twice daily, was more effective than cephalexin, 250 mg four times daily (cure rates 93 and 67%) (P less than 0.006). Those cured and not cured were not distinguished by age, gender, genitourinary history, or infecting organism. 3. Compliance as measured by box openings was worse for cephalexin than for trimethopim (P = 0.01). However, both totality and pattern of compliance were similar in patients cured and not cured by cephalexin. Thus rigid adherence to a conventional course did not promote cure: fewer doses could have been prescribed. 4. Estimating compliance is essential to clinical trials where medication is self‐administered. Poor compliance may establish over exacting regimens. Counting box openings did overestimate compliance, but counting residual tablets overestimated it grossly: given the number of openings less than the ideal, there should have been 171 residual tablets, only 55 were found.
Comparative effects of fluoxetine and amitriptyline on cardiac function.
Authors: Upward JW , Edwards JG , Goldie A , Waller DG
Published: July 2012

1. The effects of fluoxetine and amitriptyline on the electrocardiogram (ECG) and systolic time intervals (STIs) were measured during a double‐ blind parallel‐group study in depressed patients. 2. ECGs and STIs were measured after a 1 week placebo run‐in, following 1 week's treatment with fluoxetine 40 mg daily or amitriptyline 100 mg daily, and then after 3 weeks' treatment with fluoxetine 60‐80 mg daily or amitriptyline 150‐200 mg daily. 3. Fluoxetine had no effect on the ECG or STIs at any dose. Amitriptyline 150‐200 mg daily shortened the sinus cycle length by a mean of 12%, prolonged the PR interval by 8% and the QRS duration by 10%. Amitriptyline did not significantly alter the STIs.
Lack of effect of cimetidine on the pharmacokinetics of bupivacaine in healthy subjects.
Authors: Pihlajamaki KK , Lindberg RL , Jantunen ME
Published: July 2012

1. The possibility of a pharmacokinetic interaction between the H2‐ receptor antagonist cimetidine and the long‐acting local anaesthetic agent bupivacaine was studied in seven healthy, non‐smoking volunteers. 2. The study consisted of two sessions at a minimum interval of 4 days. In a randomized, crossover fashion, the volunteers received bupivacaine HCl 1.4 mg kg‐1 by i.m. injection at two occasions, once after no premedication, and once after two oral doses of 400 mg cimetidine. The concentrations of bupivacaine and its metabolites, 4′‐ hydroxybupivacaine and desbutylbupivacaine, were assayed by h.p.l.c., in serum up to 8 h and in urine fractions up to 24 h. 3. No influence of cimetidine on the pharmacokinetics of bupivacaine or on the serum cumulation of urinary recovery of its measured metabolites was detected. 4. These data suggest that cimetidine may be used safely as a premedication before local anaesthetic procedures with bupivacaine.
Allopurinol dosage selection: relationships between dose and plasma oxipurinol and urate concentrations and urinary urate excretion.
Authors: Day RO , Miners JO , Birkett DJ , Whitehead A , Naidoo D , Hayes J , Savdie E
Published: July 2012

1. Allopurinol usage in 50 patients of a city teaching hospital was surveyed. 2. The plasma concentrations of oxipurinol and uric acid and the urinary production of uric acid were examined. 3. The daily doses of allopurinol ranged from 50 to 1200 mg but 83% of patients were taking 300 mg daily. 4. A wide range of plasma oxipurinol concentrations was observed from 2.8 to 55.8 mg l‐1 with a mean +/‐ s.d. of 15.2 +/‐ 11.7 mg l‐1. 5. The population studied included a high proportion of patients with renal impairment and creatinine clearance was a significant determinant of oxipurinol concentrations (P less than 0.005). 6. There was no significant correlation between plasma urate and plasma oxipurinol concentrations and only a few plasma urates were above the upper limit of the reference range of the laboratory. 7. It was apparent that many patients were taking unnecessarily high daily doses of allopurinol and that renal status was not always considered when deciding dosage regimens of allopurinol.
The influence of infusion rate on the pharmacokinetics and haemodynamic effects of nisoldipine in man.
Authors: van Harten J. , van Brummelen P. , Zeegers RR , Danhof M. , Breimer DD
Published: July 2012

1. The pharmacokinetics and haemodynamic effects of nisoldipine on long term i.v. infusion of 2.40 mg and 9.59 mg in 25 h were studied in six healthy subjects. Liver blood flow at 0.8 and 24 h was assessed by measuring indocyanine green (ICG) clearance. 2. After high‐dose nisoldipine, systemic clearance was 0.99 +/‐ 0.16 1 min‐1, volume of distribution was 5.8 +/‐ 1.5 1 kg‐1 and elimination half‐life was 10.7 +/‐ 2.4 h. The pharmacokinetic parameters were similar after low‐dose nisoldipine. 3. No significant changes in apparent liver blood flow were observed after either high‐dose or low‐dose nisoldipine. 4. Systolic blood pressure did not change, whereas diastolic blood pressure decreased by approximately 10% during both treatments. Maximal increase in heart rate was approximately 37% at high‐dose infusion, whereas this was one half lower during the low‐dose regimen. 5. Increased infusion rate results in an unfavourable shift in the haemodynamic effect profile of nisoldipine.
The effect of lithium on the renal response to the dopamine prodrug gludopa in normal man.
Authors: Jeffrey RF , Macdonald TM , Brown J. , Rae PW , Lee MR
Published: July 2012

1. The effect of oral lithium on the renal response to gamma‐L‐glutamyl‐ L‐dopa (gludopa, 25 micrograms kg‐1 min‐1) was investigated in seven normal males. 2. Gludopa at this dose produced an 800‐fold increase in urine dopamine excretion. It was natriuretic and suppressed plasma renin activity without altering blood pressure and pulse. 3. Lithium alone increased sodium excretion and stimulated plasma renin activity. However, it abolished the natriuresis produced by gludopa. 4. Gludopa did not significantly affect lithium clearance. 5. This study suggests that lithium interacts with dopamine at the proximal tubule and that the lithium clearance method is not suitable for investigating dopaminergic mechanisms in the kidney.
Vascular responses to local atrial natriuretic peptide infusion in man.
Authors: Webb DJ , Benjamin N. , Allen MJ , Brown J. , O'Flynn M. , Cockcroft J.R.
Published: July 2012

1. The effect on skin and muscle blood flow of arterial infusion of atrial natriuretic peptide (ANP) directly into the forearm circulation, and on venous tone of direct infusion into a dorsal hand vein, was studied in normal subjects. 2. ANP produced a dose‐dependent increase in both skin and muscle blood flow, but at equivalent doses, produced no dilatation of noradrenaline‐preconstricted dorsal hand veins. These findings indicate that ANP acting locally, is an arterioselective dilator in the upper limb circulation in normal man. 3. Measurements of ANP in venous plasma during arterial infusion suggest marked clearance of ANP across the forearm vascular bed. Such peripheral clearance may, at least in part, account for the short plasma half‐life of this peptide. 4. The lowest dose of ANP infused was calculated to produce plasma levels similar to those found in patients with heart failure. The findings with this dose suggest that, in heart failure, circulating levels of ANP may be within a range capable of influencing peripheral vascular resistance directly.
Comparative effects of bisoprolol and acebutolol in smokers with airway obstruction.
Authors: Macquin‐Mavier I. , Roudot‐Thoraval F. , Clerici C. , George C. , Harf A.
Published: July 2012

1. The effects of single oral doses of 10 mg bisoprolol and 400 mg acebutolol on respiratory function were studied in nine smokers with airway obstruction in a double‐blind, placebo‐controlled experiment. 2. The effects of the drugs were assessed by measuring specific airway conductance (sGaw) for 3 h after their administration and by studying their interaction with the bronchodilator response to inhaled salbutamol. 3. sGaw did not change for 3 h after bisoprolol or acebutolol administration. The bronchodilator response to inhaled salbutamol was not affected by bisoprolol but significantly reduced by acebutolol (P less than 0.05 vs placebo). 4. Under these conditions, bisoprolol behaves like a selective beta 1‐adrenoceptor antagonist but acebutolol exhibits less beta 1‐adrenoceptor selectivity.
Pharmacokinetics and dynamics of famotidine in patients with renal failure.
Authors: Gladziwa U. , Klotz U. , Krishna DR , Schmitt H. , Glockner WM , Mann H.
Published: July 2012

1. Famotidine, a new histamine H2‐receptor antagonist was administered intravenously (20 mg) to 22 patients with end stage renal disease during a dialysis free interval (n = 6) and during different blood purification processes including haemodialysis (HD; n = 4), intermittent haemofiltration (HF; n = 4), continuous haemofiltration (CHF; n = 4) and continuous ambulatory peritoneal dialysis (CAPD; n = 4). The plasma, the dialysate/filtrate and the urine concentrations of famotidine were analysed by h.p.l.c. 2. In addition, intra‐gastric pH was measured by a long‐term‐pH probe in seven patients with renal failure and in six patients with normal renal function (control group) following 20 mg famotidine. 3. A 7 to 10 fold prolongation of famotidine's elimination half‐life (27.2 +/‐ 8.5 h; mean +/‐ s.d.) was observed in patients with renal failure as compared with the half‐life (2.6‐3.6 h) in subjects with normal renal function. 4. Total body clearance (CL) and volume of distribution (V) were found to be 33.5 +/‐ 10.1 ml min‐1 and 1.3 +/‐ 0.7 l kg‐1, respectively in patients with end‐ stage renal failure. 5. Blood purification processes have shown considerable variation in clearing famotidine from the body: 16.4 +/‐ 8.9 and 6.0 +/‐ 2.9% of the administered dose in HD with polysulphone and cuprophan membranes respectively, 7.7 +/‐ 5.2% in HF with a polyacrylonitrile membrane (each for 5 h), 4.5 +/‐ 1.1% in CAPD and 16.2 +/‐ 4.9% in CHF with a polysulphone membrane within 24 h.(ABSTRACT TRUNCATED AT 250 WORDS)
The relative effects of digoxin and diltiazem upon ventricular ectopic activity in patients with chronic atrial fibrillation.
Authors: Lewis RV , McDevitt DG
Published: July 2012

In eight patients with chronic atrial fibrillation, treatment with digoxin (plasma drug concentration 1.3 to 2.0 nmol l‐1) was associated with a significantly higher incidence of ventricular premature beats (VPBs) (mean 22.8 h‐1) than diltiazem 120 mg three times daily (mean 6.8 h‐1) (P less than 0.05). Seven out of the eight patients showed an increase in numbers of VPBs recorded over 24 h during treatment with digoxin when compared with diltiazem. The clinical importance of these results is unclear, but atrial fibrillation and ischaemic heart disease frequently co‐exist, and increases in ventricular ectopy may predispose to serious ventricular arrhythmias following myocardial infarction.
Interaction of salicylate and corticosteroids in man.
Authors: Day RO , Harris G. , Brown M. , Graham GG , Champion GD
Published: July 2012

Corticosteroids have been reported to decrease the plasma concentrations of salicylate when salicylates have been administered chronically at high doses. In the present study, two single, oral doses of sodium salicylate, 10 mg kg‐1 were administered to six adult subjects with a variety of inflammatory conditions both before and during treatment with daily oral doses of prednisone (12‐60 mg). Concomitant prednisone therapy did not increase the whole body clearance of single doses of salicylate in these subjects (0.0275 +/‐ 0.08 l kg‐1 h‐1 before prednisone; 0.0247 +/‐ 0.03 l kg‐1 h‐1 during prednisone therapy; P greater than 0.05). These results indicate that corticosteroids do not alter the clearance of single doses of salicylate in man.
The pharmacokinetics, antihistamine and concentration‐effect relationship of ebastine in healthy subjects.
Authors: Vincent J. , Liminana R. , Meredith PA , Reid JL
Published: July 2012

1. The kinetics and effects of ebastine 10 and 50 mg were studied after oral dosing in healthy subjects. 2. The parent drug was extensively metabolised during the first pass to its carboxylic acid derivative, carebastine. 3. The pharmacokinetics of carebastine were linear over the dose range studied and the terminal elimination half‐life was 10.6 +/‐ 2.6 and 12.5 +/‐ 1.9 h respectively after 10 and 50 mg of ebastine. 4. Antihistamine (H1‐receptor) activity was examined with intradermal histamine (2 micrograms). Oral ebastine reduced the histamine wheal area for up to 24 h and also reduced subjective local pain. 5. Antihistamine activity correlated well with plasma levels of carebastine in individual subjects. 6. Ebastine appears to have potential as an antihistamine for once a day dosing.
Ebastine: the effect of a new antihistamine on psychomotor performance and autonomic responses in healthy subjects.
Authors: Vincent J. , Sumner DJ , Reid JL
Published: July 2012

1. Ebastine, through its carboxylic acid metabolite has antihistamine (H1‐receptor) activity in man. 2. We have examined in a single blind placebo controlled study the effects of 10 mg and 50 mg of ebastine on cardiovascular, autonomic and psychomotor function in healthy subjects. 3. Ebastine had no effect on blood pressure or heart rate and there was no evidence of any anticholinergic activity on circulatory reflexes or salivation. 4. Ebastine did not impair psychomotor performance as assessed by critical flicker fusion at either dose. 5. Ebastine 10 mg had no effect on sedation measured by visual analogue scale or direct questioning, however ebastine 50 mg did cause a modest increase in indices of sedation. 6. Ebastine did not have detectable sedative properties at the 10 mg dose where long‐lasting antihistamine effects can be demonstrated.
Interactions between cilazapril and propranolol in man; plasma drug concentrations, hormone and enzyme responses, haemodynamics, agonist dose‐effect curves and baroreceptor reflex.
Authors: Belz GG , Essig J. , Kleinbloesem CH , Hoogkamer JF , Wiegand UW , Wellstein A.
Published: July 2012

1. The pharmacokinetics, hormonal and haemodynamic responses at rest and during challenges with angiotensin I (blood pressure), isoprenaline (heart rate), and noradrenaline (blood pressure) were investigated in six healthy male volunteers following a 1 week treatment with placebo, propranolol (120 mg day‐1), cilazapril (2, 5 mg day‐1), and a combination of both in a double‐blind cross‐over design. 2. Both drugs reduced systolic and diastolic blood pressure by about 7 mm Hg as compared with placebo. After coadministration, this drop in blood pressure was doubled and lasted longer than after the administration of the individual components. 3. Following cilazapril, a pronounced increase in plasma renin activity (PRA) was found (factor approximately 10 at drug peak concentrations). Coadministration of both drugs resulted only in a moderate increase in the PRA (factor approximately 3). Significant changes in plasma catecholamines were not observed. 4. Propranolol shifted the isoprenaline dose‐effect curve to the right, and cilazapril that of angiotensin I, irrespective of the presence of the other drug. Cilazapril tended to shift the noradrenaline dose‐ effect curve somewhat to the right. 5. The gain of the baroreceptor reflex (angiotensin‐stimulation) was not influenced by cilazapril but was lowered by propranolol, irrespective of the presence of the ACE inhibitor. 6. Except for a statistically not significant decrease in the peak concentrations of each drug during the combined therapy, a pharmacokinetic interaction between the two drugs was not found.
Effect of indomethacin on the pharmacokinetics and pharmacodynamics of felodipine.
Authors: Hardy BG , Bartle WR , Myers M. , Bailey DG , Edgar B.
Published: July 2012

1. We studied the effects of pre‐treatment with oral indomethacin (25 mg four times daily for 3 days) on the pharmacokinetics, haemodynamics and diuretic properties of oral felodipine (10 mg single dose) in 12 healthy male volunteers using a placebo controlled double‐blind four‐ way crossover protocol. 2. Felodipine with or without indomethacin pretreatment reduced standing diastolic blood pressure (P less than 0.001) at 0.5 to 3.0 h after dosing compared with placebo or indomethacin alone. Systolic blood pressures during indomethacin treatment alone were consistently higher than the other three treatment groups (P less than 0.01), presumably due to sodium and fluid retention. 3. Felodipine and felodipine plus indomethacin produced significantly greater excretion of urine and urinary sodium, but not of urinary potassium or creatinine when compared with placebo (P less than 0.01) over an 8 h period. 4. The pharmacokinetic parameters of felodipine (Cmax, tmax, t1/2 and AUC), the concentration‐response curves for blood pressure lowering effects, the reflex tachycardia, diuretic properties and side‐effects profile of felodipine were not significantly altered by indomethacin pretreatment in normal volunteers.
Effect of intra‐articular glucocorticoids on the disposition of sulphadimidine in chronic osteoarthritis patients.
Authors: Reeves PT , Hanrahan P. , Edelman J. , Ilett KF
Published: July 2012

1. The disposition of sulphadimidine (15 mg kg‐1 orally) was investigated in six chronic osteoarthritis patients (four slow and two fast acetylators) prior to and 4 days following intra‐articular administration of glucocorticoids. 2. The mean (+/‐ s.e. mean) renal clearance of sulphadimidine was increased from 0.03 +/‐ 0.01 to 0.07 +/‐ 0.02 ml min‐1 kg‐1 (P = 0.01) following the administration of intra‐ articular steroid. 3. Mean metabolic clearance and volume of distribution data were similar on the two study days. However, two of the slow acetylators showed marked increases (63% and 193%) in metabolic clearance following steroid treatment.
Drug treatment of intermittent claudication: a critical analysis of the methods and findings of published clinical trials, 1965‐1985 [see comments]
Authors: Cameron HA , Waller PC , Ramsay LE
Published: July 2012

1. All trials of drug therapy for intermittent claudication published in English during the period 1965‐1985 were reviewed. A total of 75 trials had studied 33 different pharmacological agents. Treadmill exercise, the most reproducible method of evaluating symptoms in this condition, was used in 49% of trials. 2. Oxpentifylline was the drug that had been most frequently studied. In seven placebo‐controlled trials the average response to oxpentifylline, compared with placebo and weighted for sample‐size, was 65% improvement in claudication distance. There was, however, a significant negative relation between sample‐size and response (rs = ‐0.79, P less than 0.05), suggesting that this estimate was likely to have been biased by non‐publication of negative results. 3. One third of all trials were uncontrolled; 84% of these reported benefit from drug treatment, compared with 32% of placebo‐controlled trials (P less than 0.001). Sample‐sizes varied from seven to 227 patients; 31% of trials reported data from less than 20 patients and these were likely to have had insufficient statistical power. 4. Overall, 57 of the 75 trials (76%) had at least one of the following deficiencies: an uncontrolled design; not double‐blind; failure to use treadmill exercise; less than 20 patients included in the analysis. Thus, a priori three‐quarters of all trials were unlikely to have made a satisfactory assessment of drug efficacy. 5. The information available does not establish convincingly that any drug consistently improves exercise performance in intermittent claudication. In view of the deficiencies in previous trials, we propose guidelines for future studies with regard to trial design, sample‐size and methods of exercise testing.
Influence of menstrual cycle on antipyrine pharmacokinetics in healthy Indian female volunteers.
Authors: Nayak VK , Kshirsagar NA , Desai NK , Satoskar RS
Published: July 2012

The effect of the menstrual cycle on antipyrine pharmacokinetics was studied in 11 normal, healthy Indian female volunteers. Antipyrine half‐ life, apparent volume of distribution, clearance and AUC were calculated by standard methods. Results indicated that in females, antipyrine half‐life was significantly longer on day 5 as compared with that on days 15 and 21 of the menstrual cycle. It appears that hormonal changes during the menstrual cycle affect the pharmacokinetics of drugs in normal healthy females.
Human alpha‐calcitonin gene‐related peptide (CGRP) is a potent vasodilator in human mesenteric vasculature.
Authors: Marshall I. , Al‐Kazwini SJ , Holman JJ , Craig RK
Published: July 2012

1. The effect of human alpha‐calcitonin gene‐related peptide (CGRP) and sodium nitroprusside have been measured on human isolated mesenteric vasculature and on rings of human superior mesenteric artery and saphenous vein. 2. When noradrenaline (10(‐5) M) was used as the vasoconstrictor in preparations perfused with Krebs solution at constant flow, human alpha‐CGRP was 10 times more potent than sodium nitroprusside in evoking dose‐dependent falls in perfusion pressure. 3. Human alpha‐CGRP and sodium nitroprusside were about equipotent at relaxing rings of superior mesenteric artery contracted by noradrenaline (10(‐6) M). When the tone of saphenous vein rings was raised by noradrenaline (10(‐6) M), human alpha‐CGRP did not relax the vascular smooth muscle. 4. The results show that human alpha‐CGRP is a potent vasodilator in human arterial preparations and may act preferentially on arterioles rather than large arteries.
Comparison of the effect of cisapride and metoclopramide on morphine‐ induced delay in gastric emptying.
Authors: Rowbotham DJ , Bamber PA , Nimmo WS
Published: July 2012

1. The effects of metoclopramide or cisapride on morphine‐induced delay in gastric emptying in patients before surgery were compared. 2. Forty patients were allocated randomly to receive one of four premedications i.m.: placebo only, morphine 10 mg alone, morphine 10 mg with metoclopramide 10 mg and morphine 10 mg with cisapride 10 mg. Gastric emptying after each premedication was assessed indirectly from the rate of absorption of oral paracetamol. 3. Cisapride 10 mg reversed the delay in gastric emptying due to morphine. Its effects were significantly greater than those of metoclopramide 10 mg.
The disposition of ketoprofen enantiomers in man.
Authors: Sallustio BC , Purdie YJ , Whitehead AG , Ahern MJ , Meffin PJ
Published: July 2012

1. The disposition of ketoprofen enantiomers was studied in 21 patients taking racemic ketoprofen (Orudis SR). 2. In each patient the plasma concentrations of the R‐ and S‐enantiomers were similar at all times over a 24 h dosing interval. The mean (+/‐ s.e. mean) time‐averaged plasma ketoprofen concentrations over the dosage interval were 0.76 (+/‐ 0.06) mg l‐1 for R‐ketoprofen and 0.78 (+/‐ 0.06) mg l‐1 for S‐ ketoprofen. 3. Creatinine clearances for the 21 patients ranged from 6‐ 162 ml min‐1. There was no correlation between creatinine clearance and time‐averaged plasma concentration for either R‐ or S‐ketoprofen. 4. Approximately 30% of the dose was recovered in urine (unconjugated + glucuronide conjugate) and this was made up of 43% R‐ketoprofen and 57% S‐ketoprofen. Because of incomplete urine recoveries of ketoprofen it was not possible to determine whether inversion from the R‐ to the S‐ enantiomer takes place in man. 5. The data suggest that in terms of total (bound + unbound) ketoprofen, half the concentration value derived by a non‐enantiospecific analysis would give a reasonable approximation of the pharmacologically active S‐enantiomer concentration in plasma.
Stereoselective drug disposition: potential for misinterpretation of drug disposition data.
Authors: Evans AM , Nation RL , Sansom LN , Bochner F. , Somogyi AA
Published: July 2012

1. Although it is well recognised that the enantiomers of a chiral drug may possess different pharmacokinetic and pharmacodynamic properties, many studies dealing with chiral drugs which are administered as their racemates rely on non‐stereoselective analytical techniques. 2. We present a theoretical analysis to illustrate the potential which exists for misinterpretation of drug disposition and plasma drug concentration‐ effect data generated for a racemic drug using a non‐stereoselective assay. 3. It was shown that the use of such an analytical method can lead to the collection of data which may be both quantitatively and qualitatively inaccurate with respect to the individual enantiomers. For example, the clearance of the unresolved drug may indicate concentration‐ and time‐dependence even though this pharmacokinetic process is concentration‐ and time‐independent for each of the enantiomers. 4. The problems discussed emphasise the need to consider stereoselectivity in clinical pharmacological studies involving racemic drugs.
Evaluation of a long acting formulation of nicardipine in hypertension by clinic and home recorded blood pressures and Doppler aortovelography.
Authors: Webster J , Witte K , Rawles J , Petrie JC , Jeffers TA
Published: July 2012

1. A novel formulation of nicardipine (50% standard (short acting), 50% sustained release) was evaluated in mild hypertension in a double‐ blind, randomized, placebo‐controlled study, using clinic measurements (Hawksley) augmented by home recorded blood pressures (Copal UA 251). 2. Nicardipine 60 mg twice daily for 28 days produced a highly significant reduction in sitting blood pressure compared with placebo both pre dose (mean difference 17/8 mm Hg) and 2 h post dose (mean difference 34/26 mm Hg). 3. Home recordings confirmed the hypotensive effect and also revealed a consistent 'peak' effect between 2‐4 h after dosing (mean difference 32/22) mm Hg). 4. Doppler aortovelography at 2 h post‐dose showed a significant increase in in stroke and minute distance (linear analogues of stroke volume and cardiac output respectively) compared with placebo. The increase in stroke distance was linearly related to change in plasma concentration of nicardipine. 5. Of the 14 patients enrolled in the study, nine experienced troublesome adverse effects on nicardipine (headaches, facial flushing, palpitations, ankle oedema) and two of these were unable to complete the study as a result. 6. This formulation of nicardipine, in the fixed dosage used in this study, is characterized by an effective antihypertensive action but also by an unacceptable adverse effect profile, presumably due to an excess of its 'short acting' component.
Mephenytoin and sparteine oxidation: genetic polymorphisms in Denmark.
Authors: Drohse A , Bathum L , Brosen K , Gram LF
Published: July 2012

The oxidation of mephenytoin was polymorphic in 358 healthy Danish volunteers. The ratio between the chromatographic peak areas of (S)‐ and (R)‐mephenytoin (S/R) in 12 h urine was less than or equal to 0.48 in 349 extensive metabolizers (EM) and greater than or equal to 1 in 9 (2.5%) poor metabolizers (PM). Concomitant intake of mephenytoin and sparteine and subsequent assay by gas chromatography had no influence on the test results (mephenytoin S/R ratio or sparteine metabolic ratio). Among ten parents and seven siblings to six unrelated PM of mephenytoin only one (1/17 = 5.9%) was a PM. The pedigrees were compatible with an autosomal recessive mode of inheritance.
Effect of an inhaled mast cell stabiliser, N‐acetyl‐aspartyl‐glutamate (Zy15109) on allergen‐induced immediate bronchoconstriction.
Authors: Lai CK , Gregory J , Holgate ST
Published: July 2012

We have studied the effect of a mast cell stabiliser, the magnesium salt of N‐acetyl aspartyl glutamic acid (NAAGA) on allergen‐induced immediate bronchoconstriction in 12 atopic subjects. Inhaled NAAGA, at a dose of 60 mg thrice daily for 1 week, offered no protective effect on the airways against allergen challenge when compared with a matched placebo. The drug was well tolerated with no adverse effects observed.
Extra‐hepatic metabolism of midazolam.
Authors: Park GR , Manara AR , Dawling S
Published: July 2012

Six patients received 10 mg of midazolam intravenously during the anhepatic period of liver transplantation. Arterial blood was sampled during this time and for a similar period following revascularisation. The plasma was analysed using gas chromatography and electron capture detection (GC‐ECD) for midazolam alpha‐hydroxymidazolam and alpha‐ hydroxymidazolam glucuronide. Five of the six patients had small but significant concentrations of metabolites detected during the anhepatic period, demonstrating the presence of extra‐hepatic sites of metabolism for this drug. The remaining patient had plasma concentrations of metabolites below the lower limit of detection (2 micrograms l‐1). This may represent a pharmacogenetic abnormality or a temporary failure of midazolam metabolism secondary to the patients illness affecting the extra‐hepatic sites of metabolism.
Lack of effect of spiramycin on cyclosporin pharmacokinetics [see comments]
Authors: Vernillet L , Bertault‐Peres P , Berland Y , Barradas J , Durand A , Olmer M
Published: July 2012

1. The influence of spiramycin coadministration on cyclosporin pharmacokinetics was studied in five renal transplant patients. The plasma concentrations of cyclosporin were measured both by non‐specific radioimmunoassay (RIA) and high‐performance liquid chromatography (h.p.l.c.). 2. The kinetics of cyclosporin were followed before treatment, and after 1 day and then 2 weeks of oral treatment with spiramycin (3 X 10(6) iu, twice daily). The main pharmacokinetic parameters (the area under the plasma drug concentration‐time curve, the maximum plasma drug concentration and the time to reach it) obtained both by RIA and h.p.l.c. were not modified by spiramycin cotreatment after 1 day, nor after 2 weeks of spiramycin administration. Therefore, the pharmacokinetics of cyclosporin (parent drug and parent drug plus metabolites) are not influenced by the coadministration of spiramycin macrolide at therapeutic dosage. 3. Spiramycin may be preferable to other macrolide antibiotics known to interact with cyclosporin such as erythromycin or josamycin.
The renal and haemodynamic effects of a 10 h infusion of glutamyl‐L‐ dopa in normal man.
Authors: MacDonald TM , Jeffrey RF , Lee MR
Published: July 2012

1. gamma‐L‐glutamyl‐L‐dopa (gludopa) and placebo were given by intravenous infusion to 12 healthy salt replete men for 10 h in a single‐blind randomised fashion. 2. Gludopa caused a cumulative natriuresis of 46.5 mmol compared with placebo with a biphasic pattern and this was associated with a small reduction in body weight. 3. A small fall in arterial blood pressure and rise in pulse rate was seen with gludopa. 4. Plasma renin activity, atrial natriuretic peptide and urine kallikrein excretion were unchanged by gludopa but a small fall in urine aldosterone excretion, urine flow rate and free water clearance occurred. 5. The renal effects of gludopa are modest and last for only a few hours after the start of infusion.