bluuebunny/crossref_metadata_2025 huggingface dataset:
A review of the preclinical cardiovascular pharmacology of cilazapril, a new angiotensin converting enzyme inhibitor.
Authors: Waterfall JF
Published: July 2012

1. Cilazapril is the monoethyl ester prodrug form of the di‐acid cilazaprilat, a new angiotensin converting enzyme (ACE) inhibitor. Cilazaprilat has an IC50 of 1.9 nM as an inhibitor of rabbit lung ACE in vitro making it one of the most potent ACE inhibitors currently available. Studies on a wide range of other enzymes show that the inhibition is highly specific. 2. An oral dose of 0.1 mg kg‐1 cilazapril evoked the same maximum degree of plasma ACE inhibition (approximately 76%) in the rat as 0.25 mg kg‐1 enalapril. Cilazapril (0.25 mg kg‐1 p.o.) inhibited plasma ACE by greater than 95%. The rate of recovery of ACE activity was slower with cilazapril (5‐6% h‐1) than with enalapril (10% h‐1). 3. In anaesthetised rats cilazaprilat was equipotent with ramiprilat and slightly more potent (1.5x) than enalaprilat as an inhibitor of the angiotensin I pressor response. 4. Following oral administration to conscious rats and intravenous administration to anaesthetised dogs, cilazapril was 2‐4.5x more potent than enalapril as an ACE inhibitor. 5. In cats cilazapril (0.1 and 0.3 mg kg‐1 p.o.) dose dependently decreased plasma ACE activity and the angiotensin pressor response. Peak effects occurred at 2 h after dosing and plasma ACE inhibition was maintained at greater than or equal to 50% for up to 18 h. Mean arterial pressure was also decreased dose dependently with a peak effect at 3‐4 h. 6. Daily oral dosing of cilazapril (30 mg kg‐1 p.o.) to spontaneously hypertensive rats evoked a progressive and prolonged (24 h) antihypertensive response with a maximum decrease in systolic blood pressure of 110 mm Hg. 7. Cilazapril (10 mg kg‐1 p.o. twice daily for 3.5 days) progressively decreased blood pressure in volume depleted renal hypertensive dogs. The maximum fall in systolic pressure was 39 +/‐ 6 mm Hg. 8. Haemodynamic studies in open chest anaesthetised dogs showed that the hypotensive response to intravenous cilazapril was accompanied by a reduction in total peripheral resistance. Small decreases in cardiac output and myocardial contractile force were seen at high doses. 9. Cilazapril had no adverse effect on cardiovascular reflexes. There was no impairment of the baroreflex in rats. Exercise‐induced tachycardia and pressor responses in conscious cats were unchanged. 10. Cilazapril is exceptionally well absorbed by the oral route (98% in rats).
The pharmacokinetics and bioavailability of cilazapril in normal man.
Authors: Williams PE , Brown AN , Rajaguru S , Francis RJ , Walters GE , McEwen J , Durnin C
Published: July 2012

1. The pharmacokinetics of cilazapril and its active metabolite, cilazaprilat, were investigated in a three‐part crossover study in 12 healthy male volunteers aged 19‐38 years, excluding one subject who withdrew from the study. 2. Single 2.5 mg oral doses of cilazapril, and equivalent oral and intravenous doses of cilazaprilat were administered as aqueous solutions to the fasted subjects. There was an interval of 1 week between treatments. Concentrations of cilazapril and cilazaprilat in plasma and urine, and activities of angiotensin converting enzyme (ACE) in plasma were measured by radioenzymatic methods. 3. After 10 min infusion of cilazaprilat, the mean plasma concentration was 194 ng ml‐1, and ACE inhibition was almost 100%. The decline in concentrations was polyphasic, with mean half‐lives for the periods 1‐4 h and 24‐168 h of 0.90 and 46 h, respectively. Between 4 and 24 h the decline was non‐ linear, and ACE inhibition decreased from 91% to 67%. Urinary recovery of cilazaprilat averaged 91% of dose. 4. After oral cilazapril, the parent drug was rapidly absorbed and rapidly eliminated, with a mean maximum plasma concentration of 82 ng ml‐1 at 0.83 h and a single elimination half‐life of 1.3 h. Cilazaprilat peaked at 36 ng ml‐1 about 1.7 h after dosing and the decline in concentrations was biphasic, with half‐lives of 1.8 h and 45 h. After oral cilazaprilat, plasma concentrations were considerably lower, and the peak later (2.2 h). 5. Urinary recovery data indicated an absolute bioavailability for cilazaprilat of 57% (range 45‐75%) from oral cilazapril, but only 19% (range 8‐40%) from oral cilazaprilat.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of food on the pharmacokinetics and ACE inhibition of cilazapril.
Authors: Massarella JW , DeFeo TM , Brown AN , Lin A , Wills RJ
Published: July 2012

1. The influence of food on the pharmacokinetics and angiotensin‐ converting enzyme (ACE) inhibitory effects of oral 5 mg doses of cilazapril was investigated in a two‐way crossover study in 16 volunteers. 2. Plasma and urine concentrations of cilazaprilat, the active diacid metabolite of cilazapril, and plasma ACE activity were determined by a radio‐enzymatic method. 3. Cmax decreased by 30% (P less than 0.05) with a delay in (t)max of 1 h (P less than 0.05) and area under curve (AUC) was decreased by 14% (P less than 0.05). The elimination rate was unaltered. 4. Onset of ACE inhibition was delayed by approximately 30 min but degree and duration were unaffected. 5. The effect of food on the bioavailability of cilazapril at this dose would not be expected to be clinically significant.
A pharmacokinetic study of cilazapril in elderly and young volunteers.
Authors: Williams PE , Brown AN , Rajaguru S , Walters GE , McEwen J , Durnin C
Published: July 2012

1. Cilazaprilat is an inhibitor of angiotensin converting enzyme (ACE) and is the active metabolite of cilazapril. The pharmacokinetics of cilazaprilat, and the inhibition of plasma ACE were investigated in 12 elderly and 12 young healthy volunteers. 2. Single oral 1 mg doses of cilazapril were given to the elderly (age range 65‐83 years) and the young (age range 18‐31 years) in an open study. Plasma and urinary cilazaprilat concentrations, and plasma ACE activities were measured up to 72 h after dosing by radioenzymatic methods. 3. Cilazapril was well tolerated in both young and elderly subjects. Small falls in blood pressure were observed up to 8‐24 h after dosing. 4. The mean peak plasma cilazaprilat concentration in the elderly (11.5 ng ml‐1) was significantly greater (P less than 0.02) than the corresponding value in the young (8.3 ng ml‐1). Total and renal clearances were significantly lower (both P less than 0.05) in the elderly (12.8 and 5.11 h‐1) than in the young (16.0 and 7.21 h‐1). Total urinary recovery of cilazaprilat was similar for the two groups at about 43% of dose. 5. Plasma ACE inhibition was slightly greater in the elderly but the mean inhibition in the two groups did not differ by more than 10% at any time‐point from 1‐72 h. 6. The plasma concentrations of cilazaprilat required for 90% ACE inhibition were similar at 4.7 and 4.8 ng ml‐1 in the elderly and young respectively. 7. It is concluded that the age‐ related changes in cilazaprilat kinetics and in the degree of ACE inhibition are small.(ABSTRACT TRUNCATED AT 250 WORDS)
Influence of cilazapril on memory functions and sleep behaviour in comparison with metoprolol and placebo in healthy subjects.
Authors: Dietrich B , Herrmann WM
Published: July 2012

1. In a controlled, randomized, double‐blind study the influence of cilazapril and metoprolol on learning and memory functions and on sleep behaviour was investigated in healthy young volunteers under steady‐ state conditions. Twenty‐three subjects were given either 2.5 mg cilazapril, 200 mg metoprolol, or placebo for 14 days in a latin square design separated by washout periods of 7 days. 2. To test memory functions different modalities‐verbal, visual, numerical associative and two dimensional spatial memory were tested for recent anterograde recall, both short‐term (less than 10 s) and middle‐term (up to 15 min) were selected. The test had a content similar to that used in daily life situations. The sleep behaviour was tested both by objective (all night sleep EEG) and subjective measures. 3. Neither antihypertensive drug had an observable influence on memory performance at the dosages used under steady‐state conditions. However, sleep was disturbed during metoprolol, while cilazapril could not be differentiated from placebo. The effects of metoprolol on sleep behaviour were observed in the objective and subjective measures. There was more frequent awakening during the night with the subjective complaint of difficulties in sleeping through. 4. From this study it is concluded that cilazapril has no major effect on memory functions and sleep behaviour. This is only true for the dosages given and under steady‐state conditions.
Antihypertensive effects and pharmacokinetics of single and consecutive doses of cilazapril in hypertensive patients with normal or impaired renal function.
Authors: Shionoiri H , Gotoh E , Sugimoto K , Takasaki I , Minamisawa K , Ishii M
Published: July 2012

1. A 1.25 mg dose of cilazapril, a new angiotensin‐converting enzyme (ACE) inhibitor, was administered orally to two groups of hypertensive patients, five with normal renal function (NRF) and seven with impaired renal function (IRF), once daily for 5 or 8 consecutive days. Blood pressure, heart rate and serum ACE activity were measured up to 24 h following the initial and the last dose. Plasma level profiles of cilazapril and its active diacid were also evaluated on the first and the last day of treatment. 2. Cilazapril induced significant falls in both systolic and diastolic blood pressures without increasing heart rate. The antihypertensive effect was evident within 1 h after drug administration and was sustained for up to 24 h, particularly after consecutive dosing. 3. Serum ACE activity was markedly suppressed over 24 h. The recovery of ACE activity was delayed in the IRF group when compared with the NRF group. 4. Plasma concentrations of the active diacid in the IRF group were higher than in the NRF group with significant differences in the peak concentrations and area under the plasma concentration‐time curve (AUC). The plasma concentration profile for the parent drug was similar for both the NRF and IRF groups. 5. A significant inverse correlation was found between the creatinine clearance and the AUC for the diacid. 6. Cilazapril is a potent ACE inhibitor with a prolonged duration of antihypertensive effect and is a useful agent for controlling blood pressure in hypertensives either with NRF or IRF. In patients with severe renal impairment the dose of cilazapril should be reduced.
Haemodynamic and hormonal effects of cilazapril in comparison with propranolol in healthy subjects and in hypertensive patients.
Authors: Kleinbloesem CH , Erb K , Essig J , Breithaupt K , Belz GG
Published: July 2012

1. The purpose of the present studies was to compare the pharmacodynamic profile of the new ACE inhibitor cilazapril with the beta‐adrenoceptor antagonist propranolol in healthy subjects and in hypertensive patients. 2. Hormonal and haemodynamic responses at rest and after pharmacological interventions with angiotensin I and isoprenaline were investigated in six healthy volunteers following a 1 week treatment with placebo, propranolol (120 mg day‐1) and cilazapril (2.5 mg day‐1) in a double‐blind cross over design with a wash‐out period of 1 week between the different treatments. 3. Cilazapril induced a pronounced increase of plasma renin activity and angiotensin I concentrations, whereas after propranolol both parameters decreased. After both compounds slight decreases in angiotensin II concentrations were found. After the pharmacological challenges with angiotensin I and isoprenaline specific effects of the ACE inhibitor and beta‐ adrenoceptor blocker were found respectively. 4. Seventeen hypertensive patients received after a 2 week placebo period in random order cilazapril (2.5 mg day‐1) or propranolol (120 mg day‐1) for 3 weeks. A cross over design switched the patients to the other treatment. On the last day of each treatment period blood pressure, heart rate, cardiac output and total peripheral resistance were determined at rest and during handgrip test. In addition, bicycle exercise test was done and blood lactate concentrations were determined. 5. At rest blood pressure was lowered by both drugs, but total peripheral resistance increased after propranolol and decreased after cilazapril. After hand grip test, blood pressure was lowered after both drugs, but peripheral resistance decreased only after cilazapril.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetic and pharmacodynamic interactions between the ACE inhibitor cilazapril and beta‐adrenoceptor antagonist propranolol in healthy subjects and in hypertensive patients.
Authors: Belz GG , Essig J , Erb K , Breithaupt K , Hoogkamer JF , Kneer J , Kleinbloesem CH
Published: July 2012

1. Six healthy subjects received cilazapril (2.5 mg once daily), propranolol (120 mg once daily), the combination of both and placebo for a period of 1 week each (wash‐out phase 1 week). 2. Propranolol and cilazapril reduced systolic and diastolic blood pressure (BP) by 7 mm Hg at peak when compared with placebo. However after the combination, this reduction was more than doubled (18 mm Hg) and lasted longer. 3. There was a trend to lower and later peak concentrations for both drugs after administration of the combination. No clinically relevant pharmacokinetic interactions between cilazapril and propranolol were found. 4. The effects on blood pressure were confirmed in hypertensive patients (BP diastolic greater than 95 mm Hg). Thirteen patients were randomly allocated cilazapril (2.5 mg day‐1) or propranolol (120 mg day‐ 1] as part of a cross‐over design. This was then followed by the combination. All treatment periods were of 3 weeks duration and all measurements were done 2 h after drug administration. 5. Cilazapril lowered the median sitting diastolic BP by 8 mm Hg, and propranolol by 9 mm Hg, whereas the combination reduced the diastolic BP by 19 mm Hg. 6. The results of these studies, attempting to elucidate drug‐drug interactions, showed that combined use of propranolol and cilazapril resulted in a more pronounced and longer lasting blood pressure reduction, in healthy subjects and in patients with hypertension.
The effect of theophylline on thyrotoxic tremor.
Authors: Buss DC , Phillips DI , Littley MD , Marshall RW , Routledge PA , Lazarus JH
Published: July 2012

1. The effect of intravenous aminophylline on theophylline‐induced tremor were studied in six hyperthyroid patients before and after treatment to euthyroidism. 2. Baseline tremor power was significantly greater in the hyperthyroid compared with the euthyroid state (P less than 0.05). 3. Aminophylline produced a significantly greater increase in tremor power in the hyperthyroid compared with euthyroid state. 4. There was a significant increase in plasma theophylline clearance and reduction in t1/2 elimination when patients were hyperthyroid but volume of distribution did not change. 5. Intravenous aminophylline potentiates the tremor produced in hyperthyroidism despite an increase in plasma theophylline clearance. A pharmacodynamic mechanism is therefore likely.
Failure of ethamsylate to reduce aspirin‐induced gastric mucosal bleeding in humans.
Authors: Daneshmend TK , Stein AG , Bhaskar NK , Hawkey CJ
Published: July 2012

1. We investigated the effect of the haemostatic agent ethamsylate on aspirin‐induced gastric mucosal bleeding. 2. Eighteen healthy subjects were studied three times: at the end of 48 h periods of treatment with (a) placebo, (b) aspirin 600 mg four times daily, (9 doses) and (c) aspirin 600 mg four times daily with each dose preceded by ethamsylate 500 mg. 3. At the end of each treatment period gastric mucosal bleeding into timed gastric washings was quantified using the orthotolidine reaction. 4. Aspirin increased bleeding from a rate on placebo of 1.2 microliters 10 min‐1 geometric mean (95% confidence limits) (0.7‐1.8) microliters 10 min‐1 to 20.0 (11.6‐34.2) microliters 10 min‐1, (P less than 0.01). The rate of bleeding after aspirin preceded by ethamsylate [14.1 (8.5‐23.4) microliters 10 min‐1] was not significantly different from that after aspirin alone. 5. We conclude that ethamsylate does not reduce acute aspirin‐induced gastric mucosal bleeding in healthy humans.
The increase in urinary excretion of 6 beta‐hydroxycortisol as a marker of human hepatic cytochrome P450IIIA induction.
Authors: Ged C , Rouillon JM , Pichard L , Combalbert J , Bressot N , Bories P , Michel H , Beaune P , Maurel P
Published: July 2012

1. Urinary excretion of 6 beta‐hydroxycortisol, hepatic microsomal cortisol 6 beta‐hydroxylase and the specific content of several forms of cytochrome P450 were measured in 8 to 14 patients before and after treatment with rifampicin (600 mg orally per day for 4 days). 2. Rifampicin treatment produced an average five fold increase in daily excretion of urinary 6 beta‐hydroxycortisol. 3. Cortisol 6 beta‐ hydroxylase activity increased from 15 +/‐ 6 pmol min‐1 mg‐1 in organ donors (considered as 'control subjects') to 87 +/‐ 31 pmol min‐1 mg‐1 in rifampicin treated patients. 4. Among three forms of human P450 (P450IA, IIC and IIIA), (1), (2), measured by Western blots, only P450IIIA was significantly induced by the antibiotic. 5. Only antibodies against P450IIIA selectively inhibited cortisol 6 beta‐ hydroxylase in human liver microsomes. 6. Cortisol 6 beta‐hydroxylase was correlated with P450IIIA specific content. 7. The urinary level of 6 beta‐hydroxycortisol correlated with liver microsomal cortisol 6 beta‐ hydroxylase and P450IIIA specific content. 8. We conclude that P450IIIA is predominantly responsible for cortisol 6 beta‐hydroxylase activity in human liver microsomes and that urinary 6 beta‐hydroxycortisol is a marker of the induction of this cytochrome P450.
Bioactivation of dapsone to a cytotoxic metabolite by human hepatic microsomal enzymes.
Authors: Coleman MD , Breckenridge AM , Park BK
Published: July 2012

1. Using human mononuclear leucocytes as target cells, we have investigated the bioactivation of dapsone (DDS) to a cytotoxic metabolite in the presence of microsomes from nine human livers. Values for NADPH dependent toxicity ranged from 8.8‐27% (15.8 +/‐ 5.9%) and were similar to those for microsomes from control mice, 16‐24% (19.0 +/‐ 4.8%). 2. Microsomes prepared from mice induced with either phenobarbitone or beta‐naphthoflavone did not produce significantly more NADPH dependent toxicity than microsomes prepared from control mice. 3. Cytotoxicity was abolished not only by ascorbic acid, but also by sub‐physiological concentrations of N‐acetylcysteine and glutathione. 4. DDS was metabolised in vitro to a hydroxylamine (metabolic conversion 3.1 +/‐ 1.5%), which was oxidised further to a cytotoxic metabolite which also became irreversibly bound to protein.
Atrial natriuretic peptide and urinary prostaglandins in man.
Authors: Benzoni D , Geoffroy J , Waeber B , Brunner HR , Biollaz J , Sassard J
Published: July 2012

1. In order to assess the effects of atrial natriuretic factor on the renal biosynthesis of prostaglandins (PG), the urinary excretion of PGE2, PGF2 alpha, 6‐keto‐PGF1 alpha and thromboxane (Tx)B2 were followed in eight salt‐loaded healthy volunteers infused for 2 h with a non hypotensive dose of human atrial natriuretic peptide (hANP, 0.7 nmol min‐1). 2. Within 1 h, hANP, infusion produced a marked increase in the urinary PG output, especially of PGE2 and 6‐keto‐PGF1 alpha (188 +/‐ 21% and 202 +/‐ 24% of the pre‐infusion values respectively), followed by a significant decrease during the recovery period. 3. No correlations could be uncovered between the urinary excretion of sodium and that of any of the PGs. In contrast, during the infusion of hANP, the urinary output of PGE2 and of 6‐keto‐PGF1 alpha was found positively related to the urinary flow rate (r = 0.42; P less than 0.05; n = 32 and r = 0.43; P less than 0.05; n = 32 respectively) as well as during the recovery period (r = 0.66, P less than 0.001; n = 32 and r = 0.55; P less than 0.01; n = 32 respectively). 4. It was concluded that, in man, infusion of a non hypotensive dose of hANP is followed by a rise in urinary PG excretion presumably reflecting enhanced renal PG biosynthesis. This increased urinary PG excretion does not seem to be involved in the natriuretic action of hANP but might participate to its diuretic effect.
The effect of phentolamine on basal and pethidine‐induced inhibition of gastric emptying in healthy volunteers.
Authors: Petring OU
Published: July 2012

1. The effect of phentolamine 5 mg i.v. on basal and pethidine‐induced inhibition of gastric emptying of semisolid TC‐99m labelled Chelex‐100 resin/oatmeal was studied in ten healthy volunteers. 2. Each volunteer acted as his/her own control. 3. Basal gastric emptying remained unchanged after administration of phentolamine. 4. Administration of phentolamine reversed the pethidine‐induced inhibition of gastric emptying.
Lisinopril dose‐response relationship in essential hypertension.
Authors: Gomez HJ , Cirillo VJ , Sromovsky JA , Otterbein ES , Shaw WC , Rush JE , Chrysant SG , Gradman AH , Leon AS , MacCarthy EP
Published: July 2012

1. This was a multicentre, double‐blind, parallel study in 216 patients with mild to moderate (supine diastolic blood pressure = 95‐115 mm Hg) essential hypertension. 2. After a 4‐week placebo washout, patients were randomized to placebo or lisinopril 1.25, 5.20 or 80 mg once daily for 6 consecutive weeks. Supine and erect blood pressure was measured 24 h postdose at the end of weeks ‐2, 0, 2, 4, and 6. 3. There was a linear dose‐response relationship for both supine and erect blood pressure. Diastolic blood pressure reductions in the lisinopril 20 and 80 mg day‐1 groups were significantly greater than in the placebo or lisinopril 1.25 and 5 mg day‐1 groups. 4. Lisinopril, at doses up to 80 mg day‐1, was well tolerated.
Comparison of the immediate and long‐term effects of captopril and isosorbide dinitrate as adjunctive treatment in mild heart failure.
Authors: Wilkes NP , Barin E , Hoschl R , Stokes GS , Nelson GI
Published: July 2012

1. The efficacy of captopril and isosorbide dinitrate (ISDN) as adjunctive therapy to digoxin and diuretics in mild heart failure was compared in a double‐blind study. 2. Twenty‐one patients were randomly allocated to captopril (twice or three times daily) or ISDN. Eighteen patients completed a protocol of placebo run‐in, dose titration and maintenance treatment for 3 months. 3. Symptom‐limited exercise tolerance, ejection fraction and radionuclide indices of diastolic function estimated by gated blood pool scan did not change with either treatment. 4. Captopril improved functional class (Canadian Cardiovascular Society) and reduced requirements for increased diuretic dosage at both 1 and 3 months of maintenance treatment. Patients treated with ISDN required increased diuretic and did not improve their functional class. Differences between the treatments were significant only for diuretic dosage requirements. 5. We conclude that adjunctive therapy of mild heart failure with captopril administered twice daily provides a diuretic‐sparing effect and may improve functional class during 3 months of maintenance treatment.
A dose rising study of the safety and effects on serum prolactin of SK&F 101468, a novel dopamine D2‐receptor agonist.
Authors: Acton G , Broom C
Published: July 2012

1. SK&F 101468, a non phenolic indolone derivative, has been characterised preclinically as a novel, potent and specific dopamine D2‐ receptor agonist. 2. Its tolerability and effects on serum prolactin were investigated in 14 healthy male volunteers in a study of the first administration of SK&F 101468 to man. 3. Doses between 80 micrograms and 2.5 mg caused statistically significant (P less than 0.05) lowering of basal and food stimulated serum prolactin, relative to placebo, over a 6 h post treatment period. 4. SK&F 101468 was well tolerated up to 1 mg with symptoms of nausea and postural hypotension at higher doses.
A comparison of the ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops in normal human volunteers.
Authors: al‐Sereiti MR , Coakes RL , O'Sullivan DP , Turner P
Published: July 2012

1. The ocular hypotensive effect of 0.025% bromocriptine and 0.25% timolol eye drops was compared in nine healthy human volunteers, using non‐contact tonometry. 2. Considering all post‐dosing measurements compared with placebo and including the baseline values as continuous independent variables, using multiple linear regression analysis, both bromocriptine and timolol had a significant ocular hypotensive effect (P less than 0.0001) in the treated eye with a significant but lesser effect in the contralateral eye. 3. In the concentrations used, timolol was more efficacious than bromocriptine in lowering intraocular pressure (P less than 0.025). 4. Using other forms of vehicles for bromocriptine to improve efficacy and studying the ocular hypotensive effect of topical application of other dopamine‐2‐receptor agonists such as pergolide and lisuride was suggested.
Salicylate pharmacokinetics in patients with rheumatoid arthritis.
Authors: Owen SG , Roberts MS , Friesen WT , Francis HW
Published: July 2012

1. The pharmacokinetics of salicylic acid (SA) and its major metabolite salicyluric acid (SU) were studied in nine patients with rheumatoid arthritis following a 900 mg oral dose of acetylsalicylic acid and during 6 weeks of chronic administration of enteric coated aspirin (3,900 mg day). Response to therapy was also monitored. 2. The various pharmacokinetic parameters determined in the study were similar to those observed in other single dose salicylate studies amongst healthy volunteers but were not predictive of salicylate concentration in the chronic dose study. 3. Plasma concentrations of SA (total and unbound) were found to decline significantly over the 6 weeks and plasma SU concentrations increased. 4. During the chronic dosing study, there was a significant increase in the Vmax (total and unbound) for the formation of SU, whilst the Km and SU clearance remained constant. Also, the elimination rate constant (k) for salicylate was not significantly affected. 5. Therapeutic response to salicylate therapy was not significantly affected by the decline in SA concentrations.
Bioelectrical impedance modelling of gentamicin pharmacokinetic parameters.
Authors: Zarowitz BJ , Pilla AM , Peterson EL
Published: July 2012

1. Bioelectrical impedance analysis was used to develop descriptive models of gentamicin pharmacokinetic parameters in 30 adult in‐patients receiving therapy with gentamicin. 2. Serial blood samples obtained from each subject at steady state were analyzed and used to derive gentamicin pharmacokinetic parameters. 3. Multiple regression equations were developed for clearance, elimination rate constant and volume of distribution at steady state and were all statistically significant at P less than 0.05. 4. Clinical validation of this innovative technique is warranted before clinical use is recommended.
Gentamicin volume of distribution as a power function of body weight.
Authors: Keller F
Published: July 2012

Gentamicin volume of distribution (V) was related to body weight (W) in 183 obese, normal weight and infant patients as reported in five published studies. In contrast to the usually postulated simple proportionality (V = bW) a linear function was found (V = a + bW) with an intercept (a = 2.5 +/‐ 0.49) significantly different from zero (P = 0.0001) and a slope (b = 0.19 +/‐ 0.10) significantly different (P = 0.0001) from the mean factor of proportion (b = 0.35 +/‐ 0.19). As compared with the linear function, a power function (V = 0.57 W 0.79) approximated even more closely the dependence of gentamicin volume on body weight (r = 0.94 vs r = 0.81). The difference between both functions was more than 50% only for body weight less than 5 kg. It is concluded that the relation between gentamicin volume of distribution and body weight is non‐linear.
Structural requirements for bioactivation of anticonvulsants to cytotoxic metabolites in vitro.
Authors: Riley RJ , Kitteringham NR , Park BK
Published: July 2012

The formation of cytotoxic metabolites from the anticonvulsants phenytoin and carbamazepine was investigated in vitro using a hepatic microsomal enzyme system and human mononuclear leucocytes as target cells. Both drugs were metabolised to cytotoxic products. In order to assess the structural requirements for this bioactivation, a series of structurally related compounds was investigated. It was found that molecules which contain either an amide function or an aryl ring may undergo activation in vitro, but only the metabolism‐dependent toxicity of the latter is potentiated by pre‐treatment of the target cells with an epoxide hydrolase inhibitor. Taken collectively, these data are consistent with the concept that reactive epoxide metabolites of both phenytoin and carbamazepine may produce toxicity in individuals with an inherited deficiency in epoxide hydrolase.
Effect of oxpentifylline on blood viscosity and cerebral blood flow in man.
Authors: Brown MM
Published: July 2012

The effects of intravenous oxpentifylline on blood viscosity and cerebral blood flow were studied in eight patients with cerebrovascular disease using a double‐blind placebo controlled design. A single dose of 200 mg oxpentifylline in 10 ml saline was given by intravenous injection over 10 min and compared with 10 ml saline alone. Whole blood and plasma viscosity were measured in a Contraves LS 30 coaxial viscometer at shear rates of 0.7 and 94.5 s‐1. Cerebral blood flow was measured by the non‐invasive intravenous xenon133 clearance method. The measurements were made before and then 30 min after the start of the injection of drug or saline alone. Oxpentifylline was found to have no significant effect on blood viscosity or cerebral blood flow.
Slow release nifedipine plus atenolol in chronic stable angina pectoris.
Authors: Challenor VF , Waller DG , Renwick AG , George CF
Published: July 2012

1. The effects of adding slow release nifedipine in doses of 20 mg and 40 mg twice daily to atenolol therapy (50 mg twice daily) were assessed in 18 patients with chronic stable angina. 2. The addition of the lower dose of nifedipine to atenolol did not significantly alter the weekly consumption of glyceryl trinitrate or the mean number of anginal attacks as assessed by diary cards. However, 2 h after dosing there was a significant prolongation during stress testing in the time to onset of both 1 mm ST depression on the ECG (by 28%) and to angina (by 37%) compared with atenolol alone, but no benefit was apparent by 12 h after dosing. 3. At a dose of 40 mg twice daily, nifedipine significantly reduced glyceryl trinitrate consumption by 25% and the number of anginal attacks by 36%. The times to onset of ST depression and angina were increased by 37% and 55% respectively at 2 h and by 24% and 26% respectively 12 h after dosing. 4. Analysis of the frequency distribution of anginal attacks showed decreasing efficacy with time after administration of nifedipine. The overall results also suggest a relationship between efficacy and the plasma nifedipine concentration, with a mean 20% improvement in time to development of angina occurring at a nifedipine plasma concentration of approximately 30‐40 ng ml‐1. 5. In conclusion, the reduction of effort‐related angina by nifedipine is related to its plasma concentration and the effective duration of action of the 20 mg slow release formulation is less than 12 h.
CNS‐related subjective symptoms during treatment with beta 1‐ adrenoceptor antagonists (atenolol, metoprolol): two double‐blind placebo controlled studies.
Authors: Dimenas E , Dahlof C , Olofsson B , Wiklund I
Published: July 2012

1. Whilst a number of studies have investigated whether metoprolol and atenolol, the most widely used beta 1‐adrenoceptor antagonists, differ with regard to CNS‐related subjective symptoms, few placebo‐controlled studies using standardised questionnaires have been performed. 2. In the present report, the findings of two randomised, double‐blind, cross‐ over studies in healthy volunteers are presented. The subjects were treated with placebo and atenolol (100 mg once daily) (Study 1) and metoprolol (100 mg once daily) and placebo (Study 2). 3. Subjective experiences were evaluated using a standardised instrument, the Minor Symptoms Evaluation‐profile (MSE‐profile), which was filled in 4, 8 and 24 h after intake of the tablets. A Type A questionnaire was also completed by the subjects. 4. At 4 h both metoprolol and atenolol were found to affect negatively vitality and contentment, but these effects had declined after 8 h. A significant adverse effect on sleep was shown for atenolol compared with placebo, while no negative effect was observed for metoprolol. No significant differences were found in relation to Type A behaviour and beta‐adrenoceptor blockade. The number of subjects with Type A personality was, however, low. 5. The results of the studies indicate that the subjective symptoms of the beta 1‐ adrenoceptor blockers are mild, and that the effects appear consistently with the recognised pharmacokinetic profiles of the two drugs.
Garlic, onions and cardiovascular risk factors. A review of the evidence from human experiments with emphasis on commercially available preparations [see comments]
Authors: Kleijnen J , Knipschild P , Ter Riet G
Published: July 2012

1. Claims for beneficial effects on cholesterol levels, fibrinolytic activity, and platelet aggregation are attributed both to fresh garlic and onions (or their extracts) and to commercially available preparations. 2. Regarding fresh garlic, the claims have been confirmed, but so far only at very high dosages. 3. For onions and commercially available supplements contradictory results have been reported. 4. All published trials showed severe methodological shortcomings. Some trials were not randomized and/or not blinded whilst this was possible, and in only one of every three studies more than 25 patients participated in each treatment group. In no trial was prognostic comparability of the treatment and the control groups ascertained. At the moment there is inadequate scientific justification for garlic supplementation.
Stereoselective disposition of flecainide in relation to the sparteine/debrisoquine metaboliser phenotype.
Authors: Gross AS , Mikus G , Fischer C , Hertrampf R , Gundert‐Remy U , Eichelbaum M
Published: July 2012

1. The disposition of the enantiomers of the antiarrhythmic drug flecainide has been studied in five extensive (EM) and five poor (PM) metabolisers of sparteine/debrisoquine after administration of 50 mg of racemic flecainide acetate under conditions of high urinary flow rate and acidic urinary pH. 2. In the EM subjects there were no significant differences in the oral clearance, half‐life or urinary excretion of (+)‐S‐ and (‐)‐R‐flecainide. 3. In the PM subjects differences in the pharmacokinetics of S‐ and R‐flecainide were observed. The oral clearance of R‐flecainide (467 +/‐ 109 ml min‐1) was less (P less than 0.03) than that of the S‐enantiomer (620 +/‐ 172 ml min‐1). The half‐ life of R‐flecainide (12.9 h) was longer (P less than 0.03) than that of S‐flecainide (9.8 h). The renal clearance of the two enantiomers was, however, comparable and similar to that observed in the EM subjects. The urinary recovery of R‐flecainide (15.6 +/‐ 3.7 mg) was greater (P less than 0.03) than that of the S‐enantiomer (12.0 +/‐ 3.7 mg). The enantioselective disposition observed in PMs is therefore due to greater impairment in the metabolism of R‐ than S‐flecainide. 4. The urinary recoveries of two major metabolites of flecainide, meta‐O‐ dealkylated flecainide (MODF) and the meta‐O‐dealkylated lactam of flecainide (MODLF) were lower (P less than 0.05) in PMs, 12.0% +/‐ 3.1% and 8.2% +/‐ 3.2% of the dose administered, respectively, than in EMs of 17.7% +/‐ 3.3% and 16.5% +/‐ 3.3%, respectively. 5. One PM subject had a greatly diminished flecainide metabolic capacity and a rare genotype, as assigned by Xbal RFLP analysis.
Differential effect of aspirin on thromboxane and prostaglandin biosynthesis in man.
Authors: Ritter JM , Cockcroft JR , Doktor HS , Beacham J , Barrow SE
Published: July 2012

1. Effects of a single intravenous dose of aspirin (600 mg) on bradykinin‐stimulated prostaglandin (PG) and on thromboxane (TX) biosynthesis were determined in nine healthy male volunteers. Plasma concentrations of 6‐oxo‐PGF1 alpha and 13,14‐dihydro‐15‐oxo‐PGF2 alpha were measured in samples obtained during repeated 10 min intravenous infusions of bradykinin before and up to 6 h after the dose of aspirin. TXB2 was measured in serum from blood allowed to clot at 37 degrees C. 2. Aspirin inhibited bradykinin stimulated PG and platelet TX biosynthesis 0.5 h after the dose. Serum TXB2 remained low, whereas PG synthesis recovered within 6 h. 3. Effects of intravenous sodium salicylate (600 mg) were studied identically in eight subjects. Prostanoid biosynthesis was not inhibited. 4. Biosynthesis of prostacyclin and TXA2 under basal conditions was studied in eight subjects by measuring 2,3‐dinor‐6‐oxo‐PGF1 alpha and 2,3‐dinor‐TXB2 in hourly urine samples obtained during and after intravenous infusion of aspirin and, on a separate occasion, of vehicle. 5. Aspirin infusion reduced urinary excretion of both metabolites greater than 90%, but excretion of 2,3‐dinor‐6‐oxo‐PGF1 alpha recovered more rapidly than did that of 2,3‐dinor‐TXB2. 6. We conclude that cyclo‐oxygenase is rapidly synthesised in bradykinin‐responsive tissues in vivo and that this reflects similarly rapid enzyme biosynthesis in tissues that produce PGI2 under basal conditions.
Enhanced gastric mucosal bleeding with doses of aspirin used for prophylaxis and its reduction by ranitidine.
Authors: Kitchingman GK , Prichard PJ , Daneshmend TK , Walt RP , Hawkey CJ
Published: July 2012

1. We evaluated injury to the human gastric mucosa caused by low doses of aspirin and its prophylaxis by ranitidine. On two separate occasions, 30 subjects took aspirin 300 mg daily for 12 days either with or without ranitidine 150 mg, 30 min before aspirin. This dose of aspirin caused more than a 5 fold increase in gastric bleeding, from control values of 0.5 microliters 10 min‐1 (95% confidence limits 0.3‐ 0.8 microliters 10 min‐1) to 2.8 microliters 10 min‐1 (1.9‐4.1 microliters 10 min‐1, P less than 0.01) after 5 days of aspirin. Adaptation did not occur and the gastric bleeding rates remained elevated at 3.4 microliters 10 min‐1 (1.9‐6.1 microliters 10 min‐1) after 12 days of aspirin consumption (P less than 0.01). 2. Coadministration of ranitidine significantly raised intragastric pH and reduced aspirin induced bleeding to 1.5 microliters 10 min‐1 (1.0‐2.3 microliters 10 min‐1) after 5 days and 1.6 (1.0‐2.5 microliters 10 min‐ 1) after 12 days (P less than 0.05). 3. Although these values were higher than control levels our results raise the possibility that coadministration of ranitidine may reduce the incidence of peptic ulceration and gastrointestinal haemorrhage which is increasingly reported in some subjects taking low dose aspirin for vascular prophylaxis.
Factors affecting free (unbound) lignocaine concentration in suspected acute myocardial infarction.
Authors: Routledge PA , Stargel WW , Barchowsky A , Wagner GS , Shand DG
Published: July 2012

1. Free plasma lignocaine concentrations were measured for up to 48 h after constant infusion of the drug in 41 subjects with suspected acute myocardial infarction. 2. The free plasma lignocaine clearance at 12 h was significantly and proportionately related to body weight and to the presence of mild (Killip Class II) heart failure, with an 18% reduction in free clearance in the latter condition. 3. The free plasma lignocaine was not related to sex, age or the presence of confirmed acute myocardial infarction, when corrected for the effects of body weight and presence of heart failure. 4. Free plasma lignocaine concentration 1 h after a fixed loading dose were also significantly related to body weight and presence of heart failure but not to sex, age or proven acute myocardial infarction. 5. The data indicate that correction of loading and maintenance infusion for body weight and presence of (even mild) heart failure should somewhat reduce variability in free (and presumably active) plasma lignocaine concentrations but that the free plasma lignocaine concentration at 12 h is most accurately predicted by measuring the free (and to a lesser extent total) plasma lignocaine concentration at 1 h.
Morphine metabolism in children.
Authors: Choonara IA , McKay P , Hain R , Rane A
Published: July 2012

1. The metabolism of morphine was studied in 12 children and nine premature neonates on a continuous infusion of morphine (10‐360 micrograms kg‐1 h‐1). 2. The mean plasma clearance of morphine was significantly higher in children than neonates (25.7 and 4.7 ml min‐1 kg‐1, respectively) (P less than 0.01). 3. All the neonates and children had detectable concentrations of morphine‐3‐glucuronide (M3G) in plasma. All the children and five neonates had detectable concentrations of morphine‐6‐glucuronide (M6G) in plasma or urine. 4. The M3G/morphine ratios in plasma and urine, and M6G/morphine ratios in urine were significantly higher in children than neonates (P less than 0.01), suggesting that morphine glucuronidation capacity is enhanced after the neonatal period. 5. There was no difference in the M3G/M6G ratio in children and neonates, indicating a parallel development of both glucuronidation pathways.
Effect of short‐acting nitroglycerin on heart rate: evaluation by a self‐monitoring device.
Authors: Lahtela JT , Sotaniemi EA
Published: July 2012

The efficacy of two sublingual nitroglycerin formulations was compared in 10 healthy subjects and 10 patients with ischaemic heart disease. A new microcomputerized device was used to record and analyze heart rate. The rise in heart rate began 1‐1.5 min after administration of nitroglycerin tablets and was maximal within 3 min. The effect was more rapid with a quickly dissolving compound. The recording equipment was reliable, simple to use and inexpensive.
The influence of food on the pharmacokinetics of ‘biphasic’ nifedipine at steady state in normal subjects.
Authors: Rimoy GH , Idle JR , Bhaskar NK , Rubin PC
Published: July 2012

Previous studies following single dose administration have suggested that the pharmacokinetics of various nifedipine formulations could be influenced by the timing of associated food consumption. In order more closely to reflect the clinical situation we have carried out a study at steady state using a ‘biphasic’ formulation comprising ‘rapid’ and ‘retarded’ drug release components. Fifteen normal subjects took 20 mg ‘biphasic’ nifedipine 12 hourly for 10 days. Studies were carried out on days 4, 7 and 10. On these days the nifedipine was taken 2 h or 1 h before or immediately following a light breakfast. A light breakfast influenced neither the rate nor the extent of nifedipine absorption nor the rate or extent of major metabolite appearance. We conclude that at steady state the timing of a light meal is unlikely to alter in any clinically important manner the pharmacokinetics of nifedipine released from ‘biphasic’ tablets.
Interindividual and interethnic differences in the demethylation and glucuronidation of codeine.
Authors: Yue QY , Svensson JO , Alm C , Sjoqvist F , Sawe J
Published: July 2012

1. The 8 h urinary excretion of codeine and seven of its metabolites was compared in 149 healthy Swedish Caucasians and 133 healthy Chinese following a single oral dose of 25 mg codeine phosphate. 2. The total 8 h urinary recovery of drug‐related material was 74 +/‐ 24% in the Caucasians and 60 +/‐ 14% in the Chinese (P less than 0.001). The excretion of unchanged codeine was significantly higher in the Chinese (7.2%) compared with the Caucasians (4.3%, P less than 0.001). 3. The Caucasians excreted significantly greater proportions of codeine‐6‐ glucuronide (C6G) (62%) than the Chinese (44%) (P less than 0.001). The frequency distribution of the log metabolic ratio (MR) for glucuronidation (codeine/C6G) was shifted towards higher values in the Chinese population. Males in both groups and Chinese smokers had significantly lower glucuronidation MRs than females and non‐smokers in the respective populations (P less than 0.001). 4. The frequency distribution of the MR for O‐demethylation (codeine/morphine (M) + M‐3 and M‐6‐glucuronide (M3G and M6G) + normorphine (NM) was highly skewed in the Caucasians, suggestive of a bimodal distribution. There was a 160‐fold interindividual variation in this MR. A unimodal distribution of the log O‐demethylation MR was observed in Chinese. The Caucasians excreted less M and more M6G than did the Chinese (P less than 0.001). 5. Significantly more norcodeine (NC) and less NC‐glucuronide (NCG) were excreted in the Chinese compared with the Caucasians (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Codeine O‐demethylation co‐segregates with polymorphic debrisoquine hydroxylation.
Authors: Yue QY , Svensson JO , Alm C , Sjoqvist F , Sawe J
Published: July 2012

1. A single oral dose of codeine (25 mg) was given to 132 healthy Swedish Caucasians who had previously been phenotyped with respect to debrisoquine hydroxylation. The ‘metabolic ratios’ (MR) in urine of codeine O‐demethylation (codeine/(morphine (M) + morphine‐3‐ and 6‐ glucuronides (M3G and M6G) + normorphine], N‐demethylation (codeine/(norcodeine (NC) + norcodeine glucuronide + normorphine (NM]) and glucuronidation (codeine/codeine‐6‐glucuronide (C6G] were calculated following h.p.l.c. analysis of urine samples collected over 8 h. 2. There was a significant correlation between the log MR for debrisoquine hydroxylation and the log MR for codeine O‐demethylation (rs = 0.77, P less than 0.001). The poor debrisoquine hydroxylators had MRs of codeine O‐demethylation between 8.3 and 55.1, while the values for extensive hydroxylators were between 0.4 and 5.5. 3. The poor debrisoquine hydroxylators excreted significantly less M, M3G, M6G and NM, while the urinary recovery of C6G and NC was significantly higher in these subjects compared to the extensive hydroxylators. 4. The MRs for glucuronidation and N‐demethylation did not exhibit a bimodal distribution, and were not related to the MR of debrisoquine hydroxylation. 5. No associations were found between sex, body‐weight, smoking habits, age, urine volume or urine pH and the O‐demethylation of codeine. 6. The O‐demethylation of codeine to form M appears to be under the same polymorphic genetic control as the 4‐hydroxylation of debrisoquine.