bluuebunny/crossref_metadata_2025 huggingface dataset:
Pharmacokinetics of felodipine after intravenous and chronic oral administration in patients with congestive heart failure.
Authors: Dunselman PH , Edgar B , Scaf AH , Kuntze CE , Wesseling H
Published: July 2012

1. In a randomized, parallel, double‐blind study felodipine was administered to 11 and placebo to 12 patients with congestive heart failure. The kinetics of felodipine were studied after acute intravenous administration and after chronic oral treatment for 8 weeks. The relationship between cardiac output and pharmacokinetics was analyzed. The pharmacokinetic data were compared with data from young healthy individuals and hypertensive patients. 2. After oral therapy, significant correlations were found between cardiac output and AUC and systemic bioavailability (F). Furthermore, cardiac output before therapy was also significantly correlated with absorption characteristics. No relationship could be demonstrated between cardiac output and i.v. pharmacokinetics. A comparison of patients with heart failure and young healthy individuals revealed that the AUC was three times higher in heart failure patient, while Vss and the ratio of the AUC of the pyridine metabolite to that of felodipine were similar. Oral clearance was reduced by 50% and the terminal half‐life was concomitantly increased. Pharmacokinetic data for felodipine are similar in patients with heart failure to published data from elderly hypertensive patients. 3. An increase in liver blood flow during chronic oral therapy, induced by felodipine itself, appears to explain an increase in bioavailability and thus to higher plasma drug concentrations. Thus, it is advisable to start felodipine treatment at a low dosage in patients with congestive heart failure.
The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa.
Authors: Robertson DR , Wood ND , Everest H , Monks K , Waller DG , Renwick AG , George CF
Published: July 2012

1. The effect of age on the pharmacokinetics of levodopa administered alone and in the presence of carbidopa was investigated in young and elderly healthy volunteers. 2. The plasma clearance of levodopa following intravenous administration of 50 mg was 14.2 +/‐ 2.8 (s.d.) ml min‐1 kg‐1 in the elderly compared with 23.4 +/‐ 4.1 ml min‐1 kg‐1 in the young (P less than 0.01) which resulted in a 49% greater area under the plasma concentration‐time curve (AUC) in the older subjects (P less than 0.01). The volume of distribution (Vss) was lower in the elderly (1.01 +/‐ 0.29 l kg‐1) than in the young (1.65 +/‐ 0.39 l kg‐1) (P less than 0.002). 3. Following oral administration of 250 mg of levodopa the AUC was 2512 +/‐ 588 ng ml‐1h in the elderly compared with 1056 +/‐ 282 ng ml‐1h in the young (P less than 0.002). Cmax was also significantly greater in the elderly (P less than 0.05). The bioavailability of levodopa was significantly greater in the elderly (0.63 +/‐ 0.12 compared with 0.41 +/‐ 0.16, P less than 0.01). 4. In the presence of carbidopa, the plasma clearance of intravenous levodopa (50 mg) was reduced in both age groups but remained lower in the elderly (5.8 +/‐ 0.9 ml min‐1 kg‐1 compared with 9.3 +/‐ 1.0 ml min‐1 kg‐1; P less than 0.01). This resulted in a 54% greater AUC in the older subjects (P less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of halofantrine in man: effects of food and dose size.
Authors: Milton KA , Edwards G , Ward SA , Orme ML , Breckenridge AM
Published: July 2012

1. Plasma concentrations of halofantrine (Hf) and its putative principal plasma metabolite desbutyl halofantrine (Hfm) have been measured in two separate studies after oral administration of the hydrochloride salt. 2. Six healthy male volunteers each received single oral doses of 250, 500 and 1000 mg administered after an overnight fast. A washout period of at least 6 weeks was allowed between each dose. A further 250 mg single oral dose was administered to the same six subjects in a fasting state and after a standardised fatty meal in a randomised study, again with a washout period of at least 6 weeks. 3. AUC and maximum plasma concentration (Cmax) for Hf increased in proportion to the dose from 250‐500 mg. This increase was non‐ proportional when the dose was increased from 500 to 1000 mg. For Hfm, in the dose range 250‐500 mg, AUC but not Cmax increased in proportion in the increase in dose size. The increase in these parameters was non‐ proportional when the dose was increased from 500 to 1000 mg. Time to reach peak concentrations for Hf and Hfm and the elimination half‐life of Hf remained unchanged across the dosage range. 4. Following a fatty meal, Cmax for Hf was increased from 184 +/‐ 115 micrograms l‐1 (fasting) to 1218 +/‐ 464 micrograms l‐1 (fed). AUC for Hf was increased from 3.9 +/‐ 2.6 mg l‐1 h (fasting) to 11.3 +/‐ 3.5 mg l‐1 h following a fatty meal.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of slow‐release nicardipine on ambulatory and clinic blood pressure in mild hypertension.
Authors: Cox JP , Ryan J , O'Brien E , O'Malley K
Published: July 2012

1. The antihypertensive efficacy of a long acting formulation of the calcium channel blocking drug, nicardipine, was assessed using clinic and ambulatory (Remler M2,000) blood pressure measurements. 2. Eleven patients with essential hypertension (mean +/‐ s.e. mean; 173 +/‐ 6.6/103 +/‐ 1.9 mmHg) completed a randomised double‐blind, placebo‐ controlled, cross‐over study. The dose of nicardipine used was 60 mg twice daily for 4 weeks. 3. Mean ambulatory blood pressure was reduced from 164 +/‐ 5.3/97 +/‐ 2.9 to 151 +/‐ 5.2/88 +/‐ 2.4 mmHg (P less than 0.01); this effect was shown to be sustained for 8 h after the morning dose. Mean ambulatory heart rate was not significantly affected by treatment. 4. Clinic lying systolic blood pressure was reduced on treatment from 169 +/‐ 7.1 to 157 +/‐ 5.9 mmHg (P less than 0.2) and diastolic blood pressure from 99 +/‐ 3.6 to 89 +/‐ 3.9 mmHg (P less than 0.05). 5. One patient was withdrawn because of dizziness and flushing while on nicardipine; vasodilatory side effects such as headache, palpitations and flushing on nicardipine were noted by three patients. 6. We conclude that the long acting formulation of nicardipine studied in a dose of 60 mg twice daily is effective as monotherapy and is relatively well tolerated in mild hypertension. 7. This study highlights the importance of ambulatory blood pressure measurement in detecting significant changes in blood pressure, thereby permitting the study of small numbers of patients.
Beta‐adrenergic receptor responsiveness to isoprenaline in humans: concentration‐effect, as compared with dose‐effect evaluation and influence of autonomic reflexes.
Authors: Martinsson A , Lindvall K , Melcher A , Hjemdahl P
Published: July 2012

1. Different techniques of assessing beta‐adrenoceptor sensitivity in vivo, by use of i.v. infusions or bolus injections of isoprenaline (ISO), were compared in healthy volunteers. The importance of autonomic reflexes for responses to ISO was evaluated by studying the influence of 'autonomic blockade' by atropine and clonidine, which antagonize muscarinic effects and reduce sympathetic activity, respectively. Estimates of in vivo responsiveness to ISO were compared with parameters reflecting beta 2‐adrenoceptor function in vitro in lymphocytes. 2. Heart rate responses to infused ISO were not significantly altered by 'autonomic blockade' when evaluated from concentration‐effect curves. When related to the infused dose of ISO, however, sensitivity was artefactually increased (P less than 0.05), as the plasma concentrations of ISO were 40% higher after atropine and clonidine. Heart rate responses to bolus injections of ISO were attenuated (P less than 0.05) by 'autonomic blockade', suggesting that facilitatory reflexes contribute to these non‐steady state responses. Intersubject variations in heart rate responsiveness to ISO were greater than the intrasubject variability caused by counterregulatory reflexes. 3. 'Autonomic blockade' lowered venous plasma noradrenaline at rest. The noradrenaline response to ISO infusion was attenuated and the diastolic blood pressure response enhanced, indicating that a counterregulatory vasoconstrictor reflex normally is activated by ISO‐ induced vasodilatation. The plasma cyclic AMP response to ISO, on the other hand, was unaffected by atropine and clonidine and reflects beta 2‐adrenoceptor responsiveness in vivo. 4. In vitro data for beta‐ adrenoceptor binding sites (Bmax;[125I]‐IHYP binding) and cyclic AMP responses to ISO in lymphocytes correlated with DBP and noradrenaline responses to infused ISO. No correlations were found between in vitro data and heart rate, plasma cyclic AMP or plasma glycerol responses to infused ISO in vivo. 5. During prolonged ISO infusions (in six other healthy subjects) physiological responses reached greater than 90% of their steady state level after 8 min, but no definite steady state level could be defined for the plasma concentration of ISO during 40 min of infusion. 6. The ISO infusion test showed a good reproducibility, especially when repeated on the same day. Evaluation of plasma concentration‐effect relationships increase the precision of the ISO infusion test as confounding inter‐ and intra‐individual variations in ISO concentrations (as caused by e.g. autonomic blockade) will be taken into account.(ABSTRACT TRUNCATED AT 400 WORDS)
Assessment of airways, tremor and chronotropic responses to inhaled salbutamol in the quantification of beta 2‐adrenoceptor blockade.
Authors: Lipworth BJ , Brown RA , McDevitt DG
Published: July 2012

1. The purpose of the study was to assess and compare the effects of inhaled salbutamol on heart rate (HR), finger tremor (Tr) and specific airways conductance (sGaw) in the measurement of beta 2‐adrenoceptor blockade in normal subjects. 2. Five healthy volunteers were given oral doses of atenolol 50 mg, 100 mg, 200 mg (A50, A100, A200), propranolol 40 mg (P40) or identical placebo (P1) in a single‐blind crossover design. 3. Three hours after drug ingestion, dose‐response curves were constructed using cumulative doses of inhaled salbutamol: 200 micrograms, 700 micrograms, 1700 micrograms, 3200 micrograms, 6200 micrograms. HR, Tr and sGaw were measured at each dose increment, made every 20 min. 4. Increasing doses of atenolol were associated with progressive reduction in salbutamol induced beta‐adrenoceptor responses. The greatest attenuation occurred with propranolol. These effects on beta‐adrenoceptor responses were similar for HR, Tr and sGaw. Geometric mean dose ratios (compared with placebo) for A50, A100, A200 and P40 were as follows HR: 1.98, 2.75, 4.29; Tr: 1.60, 3.78, 6.34, 80.50; sGaw: 1.08, 4.35, 12.30, 66.0 (no dose ratio was obtained for HR with P40). 5. These results showed that atenolol and propranolol attenuated the effects of salbutamol on HR to a similar degree as Tr and sGaw. Furthermore, the variability was least in the measurement of chronotropic responses, suggesting that this may be used to quantify beta 2‐adrenoceptor antagonism. The beta 1‐adrenoceptor selectivity of atenolol was a dose‐dependent phenomenon, although the beta 2‐ adrenoceptor blockade of A200 was much less than with P40.
Evaluation of the gastric absorption and emptying of drugs under various pH conditions using a simple intubation method: application to diclofenac.
Authors: Vidon N , Pfeiffer A , Godbillon J , Rongier M , Gauron S , Hirtz J , Bernier JJ , Dubois JP
Published: July 2012

Sodium diclofenac (50 mg) together with [14 C]‐PEG as a non‐absorbable marker were dissolved in 400 ml of water (A), phosphate buffer pH 7.5 (B) or a homogenized meal (C). Each of these was ingested in random order by six volunteers on 3 consecutive days. Some gastric absorption of the drug was established with C but the plasma drug concentration‐ time profiles mainly reflected the process of gastric emptying.
Inhibition of gastric secretion following single morning or twice daily oral administration of sufotidine to volunteers.
Authors: Johnston DA , Wormsley KG
Published: July 2012

1. The inhibitory effect of sufotidine, a new histamine H2‐receptor antagonist, on gastric secretion of acid and pepsin was studied in six healthy male volunteers. This was a three‐way, cross‐over, randomized, double‐blind study. On each of 3 study days, the drug in a dose of 600 mg, or placebo, was administered either once or twice daily at 08.00 and 20.00 h. 2. The morning dose of sufotidine maintained intragastric pH above 3 until 18.00 h. Twice daily sufotidine maintained the pH above 3 throughout the 24 h. The median 24 h concentration of acid was significantly reduced from 86.9 mmol l‐1 after placebo to 22.8 mmol l‐1 and 4.9 mmol l‐1 following the morning only or twice daily dose of sufotidine, respectively. Mean night‐time output of acid was reduced by 81% after the morning dose of sufotidine and by 97% following treatment with sufotidine twice daily. 3. We conclude that sufotidine, in the doses studied, markedly inhibits gastric secretion and may therefore prove useful in the treatment of peptic ulceration and oesophagitis.
Pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in young and elderly volunteers after single and multiple dextropropoxyphene dosage.
Authors: Flanagan RJ , Johnston A , White AS , Crome P
Published: July 2012

1. The pharmacokinetics of dextropropoxyphene (D) and nordextropropoxyphene (ND) have been studied in 12 healthy young (21‐28 years) and 12 healthy elderly (70‐79 years) male and female subjects. Each received 65 mg D and plasma D and ND concentrations were measured by h.p.l.c. with electrochemical detection for up to 7 days and again after 65 mg D, 3 times daily for 1 week. 2. There were no significant differences in median D and ND half‐life, AUC, Cmax and tmax between the male and female subjects in either group. Within the groups the mean D half‐life (h) was longer in the young after multiple dosing (mean +/‐ s.d.:13.2 +/‐ 5.2 and 23.7 +/‐ 11.3, P less than 0.05, paired t‐test) but there were no other significant differences. 3. Between the groups, the median single and multiple dose D and ND half‐lives were all significantly longer (P less than 0.02) and the median D AUC for both single and multiple doses was significantly higher (P less than 0.01 and P less than 0.05, respectively, Mann‐Whitney U‐tests) in the elderly. 4. There was no relation between multiple dose Cmax and other parameters such as single dose D half‐life. However, across the groups D and ND half‐lives after both single and multiple dosage correlated significantly with estimated creatinine clearance, the correlation being strongest with ND (r = ‐0.76 and ‐0.84, respectively).
Concentration‐effect relationships and individual responses to doxazosin in essential hypertension.
Authors: Donnelly R , Elliott HL , Meredith PA , Reid JL
Published: July 2012

1. This study investigates aspects of the pharmacokinetics, pharmacodynamics and concentration‐effect relationships in 10 patients with essential hypertension during acute and chronic treatment with doxazosin, an alpha 1‐adrenoceptor antagonist. 2. Following the first dose of doxazosin (2 mg) there were significant reductions in blood pressure, increases in heart rate and in plasma noradrenaline, and parallel rightward shifts of the phenylephrine pressor response curves, consistent with alpha‐adrenoceptor antagonism. There was no significant change in the pressor response to angiotensin II. 3. Using an integrated kinetic‐dynamic model, individual blood pressure responsiveness was characterised as the fall in blood pressure (mm Hg) per unit drug concentration. Responsiveness to the first dose of doxazosin was directly correlated with the responsiveness after 1 and 6 weeks treatment although there was a systemic reduction (of approximately 30%) which occurred during the first week of treatment. 4. Neither the acute nor long‐term responsiveness to doxazosin was related to age, plasma renin activity, plasma noradrenaline or the pretreatment sensitivity to phenylephrine. There was a significant relationship between responsiveness and the height of the initial (pretreatment) blood pressure. 5. Integration of pharmacokinetic and pharmacodynamic data provides a reproducible index of responsiveness which can be used to investigate the consistency of the long‐term anti‐ hypertensive response, to identify factors which influence the magnitude of the response, and to optimise the choice of dose and dose interval.
The effect of the circadian rhythm of vagal activity on bronchomotor tone in asthma.
Authors: Morrison JF , Pearson SB
Published: July 2012

1. The effect of the diurnal activity of the parasympathetic nervous system on bronchomotor tone and heart rate was studied in seven asthmatics with nocturnal asthma using both intravenous atropine and nebulised ipratropium at 04.00 h and 16.00 h. 2. A diurnal variation in vagal activity was demonstrated with higher vagal activity occurring at night. 3. There was a strong correlation between the initial response of both airway calibre and heart rate to vagal block both at 04.00 h and 16.00 h. However the duration of bronchodilation after vagal block was greater than with the heart rate suggesting differing sensitivities of pulmonary and cardiac muscarinic receptors to anticholinergic antagonists. 4. The bronchodilation seen after ipratropium was less than that after atropine suggesting that the intravenous route is preferable to study the physiological effect of vagal block in vivo.
Differential effect of continuous administration of beta‐adrenoceptor antagonists on antipyrine and phenytoin clearance.
Authors: Perrild H , Kayser L , Poulsen HE , Skovsted L , Jorgensen B , Hansen JM
Published: July 2012

1. Antipyrine (1000 mg orally) clearance was studied 3 days before treatment with either atenolol (50 mg twice daily), metoprolol (100 mg twice daily), propranolol (80 mg twice daily) or placebo, and at day 5 and 18 during treatment. Phenytoin (100 mg intravenously) clearance was measured on days 0, 7 and 21 during treatment. 2. Antipyrine clearance was decreased by about 20% after 5 days of treatment with either propranolol or atenolol and this decrease persisted after 18 days of treatment. Antipyrine clearance did not change during treatment with either metoprolol or placebo. Phenytoin clearance did not change during any of the treatments.
Dose‐dependent effect and side‐effect of prostaglandin E1 in erectile dysfunction.
Authors: Schramek P , Waldhauser M
Published: July 2012

1. Recent work has demonstrated artificial penile erection after intracavernous injection of prostaglandin E1 (PGE1). A possible dose‐ response relationship between PGE1 and its erectile action was examined in a double‐blind, cross‐over designed, placebo‐controlled study. 2. Twenty patients aged (mean +/‐ s.d.) 45 +/‐ 10.5 years suffering from psychogenic erectile dysfunction were tested on four occasions. Subjects received four intracavernous injections of saline containing either no other substance, preservative, 5 micrograms or 10 micrograms PGE1. 3. Investigations revealed clear dose‐dependency of PGE1 in the grade and duration of erection achieved as well as in the latency between injection and achievement of erection (P less than 0.001). Saline and preservative did not induce erection. 4. Some local pain of varying grades did occur in 11/20 patients after 5 micrograms PGE1 and in 14/20 patients after 10 micrograms PGE1 injected intracavernously. This side‐effect was caused by PGE1 itself and also showed a clear dose‐ relation (P = 0.0035). 5. Prostaglandin E1 appears to be a promising substance for diagnostic and therapeutic purposes in erectile dysfunction. Despite the discomfort observed in some patients, PGE1 is very effective even in low doses. PGE1 10 micrograms is suggested as the appropriate initial diagnostic dose for intracavernous injection to differentiate between the normal and pathological cavernous‐vascular system.
Differences in the serum binding determinants of isradipine and darodipine‐consequences for serum protein binding in various diseases.
Authors: Pinquier JL , Urien S , Chaumet‐Riffaud P , Tillement JP
Published: July 2012

1. Serum protein binding of isradipine and darodipine, and serum concentrations of alpha 1‐acid glycoprotein (AAG), albumin (HSA) and non‐esterified fatty acids (NEFA) were measured in three groups of patients, I: healthy subjects (n = 20); II: patients with inflammatory disorders (n = 15) and III: patients with hepatic insufficiency (n = 17). 2. AAG was increased significantly in group II patients (P less than 0.001) and decreased in group III patients (P less than 0.001); HSA was decreased significantly in group II and group III patients (P less than 0.001). 3. The free percentage of isradipine was decreased significantly in group II patients (P less than 0.05) and increased in group III patients (P less than 0.05) and multivariate analysis showed that these variations were inversely related to changes in AAG concentration. 4. The free percentage of darodipine was increased significantly in group II and III patients (P less than 0.05) due to a decrease in HSA concentration, as shown by multivariate analysis. 5. The changes in free serum percentages of isradipine and darodipine were inversely related to concomitant changes in the concentration of the serum protein for which they showed the highest affinity, AAG for isradipine and HSA for darodipine, respectively. 6. The unexplained variability in the binding data was greater when AAG was the major determinant of binding (isradipine).
The effect of oral cilazapril and prazosin on the constrictor effects of locally infused angiotensin I and noradrenaline in human dorsal hand veins.
Authors: Belz GG , Beermann C , Schloos J , Kleinbloesem CH
Published: July 2012

The effects of the ACE inhibitor cilazapril (5 mg p.o.) and the alpha 1‐ adrenoceptor blocker prazosin (2 mg p.o.) were investigated on the dose‐ response curves to angiotensin I and to noradrenaline, administered locally in the hand veins in six healthy male volunteers in doses not producing systemic effects. Both angiotensin I and noradrenaline produced a dose‐dependent constriction of the congested veins. The angiotensin I effects were completely abolished after the administration of cilazapril but not significantly altered after the administration of prazosin. The noradrenaline dose‐response curves were shifted to the right (dose ratio about 10) by prazosin, but not by cilazapril. The data suggest that angiotensin I, after having been converted to angiotensin II exerts direct venoconstrictor effects which under resting conditions are not mediated by noradrenaline release.
Bioavailability of intranasal metoclopramide.
Authors: Ward MJ , Buss DC , Ellershaw J , Nash A , Routledge PA
Published: July 2012

After intranasal administration of metoclopramide, (5 mg in 0.5 ml sterile water) the maximum plasma concentration of 13.5 +/‐ 7.3 (mean +/‐ s.d.) ng ml‐1 was achieved. Absolute bioavailability was 50.5 +/‐ 29.5%, 110 +/‐ 41 min later. We conclude that the intranasal route does not allow rapid absorption of the drug and is not associated with greater bioavailability than the oral route.
Testing for bimodality in frequency distributions of data suggesting polymorphisms of drug metabolism‐histograms and probit plots.
Authors: Jackson PR , Tucker GT , Woods HF
Published: July 2012

1. The shape of histograms used to illustrate density distributions of indices of polymorphic drug metabolism was shown to be sensitive to the position of the cell divisions. 2. Non‐linearity of the probit plot was shown not to indicate bimodality of the original density distribution. Computer simulation was used to generate examples of unimodal density distributions with curvilinear probit plots. 3. Using the same technique probit plots for bimodal density distributions were constructed. Some were shown to differ less from the probit plots of certain unimodal distributions than did the original density distributions. 4. The position of the antimode was shown not to coincide with inflections seen in the probit plots. 5. A new method for determining the linearity of probit plots is suggested.
The influence of renal insufficiency and haemodialysis on the kinetics of ciprofibrate.
Authors: Ferry N , Bernard N , Pozet N , Gardes E , Cuisinaud G , Labeeuw M , Zech PY , Sassard J
Published: July 2012

1. The kinetics of the hypolipidaemic drug, ciprofibrate, were studied after a single oral dose (100 mg) in subjects with normal renal function (n = 6), patients with mild (n = 6) and severe (n = 6) renal insufficiency as well as in haemodialysed patients (n = 5). 2. Under fasting conditions, ciprofibrate, was absorbed rapidly in subjects with normal renal function, and its apparent elimination half‐life was approximately 81 h. Both renal clearance (0.15 ml min‐1) and cumulative renal excretion (less than 7% of the administered dose) were low. 3. Mild renal insufficiency did not alter the pharmacokinetics of ciprofibrate, but severe renal impairment significantly reduced both its renal clearance and cumulative urinary excretion and increased the apparent elimination half‐life. 4. A 5 h haemodialysis session did not lower the plasma concentrations of ciprofibrate. 5. It is concluded that, from a pharmacokinetic point of view, a reduction in the dosage of ciprofibrate should be considered in patients with a glomerular filtration rate below 30 ml min‐1/1.73 m2.
Frusemide, ACE inhibition, renal dopamine and prostaglandins: acute interactions in normal man.
Authors: MacDonald TM , Craig K , Watson ML
Published: July 2012

1. The acute effects of intravenous frusemide (30 mg) on prostaglandin dependent renal haemodynamics, urinary prostaglandin excretion, urinary dopamine excretion and electrolyte excretion were studied in six salt replete healthy volunteers with and without pretreatment with the angiotensin converting enzyme (ACE) inhibitor, ramipril (5 mg) and compared with the effects of ramipril alone in order to clarify the role of the renin‐angiotensin system in these responses. 2. Frusemide increased natriuresis (UNaV), kaliuresis (UKV), inulin clearance and plasma renin activity (PRA) and ramipril pretreatment significantly enhanced these effects suggesting that the acute generation of angiotensin II (AII) may attenuate these actions of intravenous frusemide. 3. Frusemide increased para‐aminohippurate (PAH) clearance, osmolar clearance and urine flow but did not change filtration fraction or urinary kallikrein excretion. Pretreatment with ramipril did not affect these responses. 4. Frusemide increased the excretion of urinary PGE2 and 6‐keto‐PGF1 alpha. Ramipril pretreatment did not suppress this rise in prostaglandin excretion. Since the frusemide induced prostaglandin dependent renal haemodynamic changes were also not suppressed with ACE inhibition, this suggests that in salt‐replete volunteers AII does not significantly modulate renal prostaglandin production after frusemide. 5. Urinary free dopamine excretion increased with frusemide alone. With ramipril pretreatment this rise showed a tendency to increase. AII may therefore inhibit the rise in urinary dopamine excretion after frusemide. However this requires further study.
Concentration‐response relationships for salicylate‐induced ototoxicity in normal volunteers.
Authors: Day RO , Graham GG , Bieri D , Brown M , Cairns D , Harris G , Hounsell J , Platt‐ Hepworth S , Reeve R , Sambrook PN , et al
Published: July 2012

1. Ototoxicity is a common and troublesome side‐effect of high‐dose aspirin treatment but there has been little previous study of the relationships between the degree of ototoxicity and the plasma concentrations of salicylate. 2. In order to investigate the relationships between aspirin dose, total and unbound plasma salicylate concentrations and ototoxicity, eight normal volunteers were dosed with aspirin 1.95, 3.25, 4.55 and 5.85 g day‐1 for 1 week at each dose level, the doses being administered in random order and double‐blind, 2 weeks apart. 3. Ototoxic effects measured were hearing loss in decibels (dB) over six frequencies and tinnitus intensity, estimated both by electronic matching and a fixed interval scale (FIS). Measurements were taken after steady‐state concentrations of salicylate had been achieved. 4. Total and unbound plasma salicylate concentrations increased disproportionately with increasing daily doses of aspirin. The increase in the unbound salicylate was relatively greater since the percentage of salicylate unbound in plasma increased over the dose range investigated from a mean of 3.9% to 10.4%. 5. Hearing loss and tinnitus intensity increased progressively with the aspirin dosage and increasing concentrations of total and unbound plasma salicylate concentrations. These ototoxic symptoms were observed at lower concentrations of total salicylate than previously reported. 6. There was a linear relationship between hearing loss and unbound salicylate concentrations. 7. Further work is required to test the hypothesis that unbound plasma salicylate concentration is a better predictor of salicylate‐induced ototoxicity than total plasma salicylate concentration.
Benorylate hydrolysis by human plasma and human liver.
Authors: Williams FM , Moore U , Seymour RA , Mutch EM , Nicholson E , Wright P , Wynne H , Blain PG , Rawlins MD
Published: July 2012

1. Benorylate (4‐acetamido phenyl‐O‐acetylsalicylate) hydrolysis in vitro by human plasma and by human liver microsomes and cytosol has been investigated. 2. Benorylate was hydrolysed by a route involving initial hydrolysis of the acetyl group to yield phenetsal followed by hydrolysis to paracetamol and salicylate. Hydrolysis via acetylsalicylate was minor. 3. Benorylate was more actively hydrolysed by liver cytosol than microsomes and about 10 times faster than plasma. 4. Following a single oral dose benorylate (4 g) to volunteers only salicylate and paracetamol were detected in the plasma. 5. The therapeutic effects of benorylate appear to be mediated by salicylate and paracetamol.
Beta‐adrenoceptor responses to inhaled salbutamol in the elderly.
Authors: Lipworth BJ , Tregaskis BF , McDevitt DG
Published: July 2012

The purpose of the present study was to evaluate and compare the responsiveness of beta 2‐adrenoceptors in elderly and young subjects. Seven healthy elderly volunteers (72 +/‐ 3 years) were given cumulative doses of inhaled salbutamol (100 micrograms‐4000 micrograms) or placebo, following pre‐treatment with propranolol 40 mg or placebo. Finger tremor (Tr), plasma potassium (K), and heart rate (HR) were measured at each dose step. There were dose‐dependent increases in Tr (P less than 0.001) and HR (P less than 0.001) and falls in K (P less than 0.001), which were completely attenuated by propranolol (P less than 0.001). Comparison with dose‐response curves in a group of young (Y) subjects (24 +/‐ 3 years) given an identical dose protocol of salbutamol showed no evidence of subsensitivity of beta 2‐adrenoceptor responses in the elderly (E) group (mean and 95% confidence intervals for maximum responses): delta K −0.90 (‐1.1(‐)−0.82) mmol l‐1 Y, −0.82 (‐1.04(‐)‐0.60) mmol l‐1 E, delta Tr 274 (213‐335)% Y, 269 (197‐342)% E, delta HR 25 (21‐28) beats min‐1 Y, 26 (21‐31) beats min‐1 E.
Treatment of congestive heart failure‐state of the art and future trends.
Authors: Parmley WW
Published: July 2012

1. Cardiac failure is a clinical syndrome of symptoms and signs, which can be confirmed by imaging or invasive haemodynamic techniques. It may be caused by systolic or diastolic dysfunction, but systolic dysfunction rarely occurs alone. It is important to ascertain the degree to which each contributes, and the precise aetiology of the condition, particularly in relation to surgically correctable lesions. 2. Non‐pharmacological approaches including weight loss, salt restriction and lifestyle changes may be beneficial in some patients, and diuretics, which reduce the load on the heart, are the traditional baseline therapy. 3. Digitalis has been used where problems with contractility predominate, but its beneficial effect has been disputed, and expectations of improvement in patients in sinus rhythm should not be too high. 4. Vasodilators have been considered as the next line of treatment. Arteriolar dilators tend to increase cardiac output, but have little effect on pulmonary artery wedge pressure, and venodilators tend to have the opposite effect. Probably both actions are necessary and angiotensin converting enzyme (ACE) inhibitors, which have both, have proved effective in terms of symptoms and survival. 5. Various other inotropic agents have been tried. Phosphodiesterase inhibitors improve exercise tolerance, but may increase the probability of serious arrhythmias, already a significant cause of sudden death. beta 1‐ partial adrenoceptor agonists such as xamoterol have shown some promise, and anti‐arrhythmic therapy has also been considered. 6. Drugs which prevent progression of myocardial damage would prove a great advance, and beta‐adrenoceptor antagonists and calcium channel blockers appear to have considerable potential in this area.
The management of heart failure and the scope for new therapies: what role for xamoterol?
Authors: Campbell RW
Published: July 2012

1. Current therapy of heart failure leaves much to be desired. Not all patients respond, and many agents lose their effects with time. 2. Newer agents may be effective but toxic, and some which have a beneficial action when given intravenously have proved disappointing when used orally. 3. The value of digoxin in patients in sinus rhythm is open to debate, and diuretics, although useful acutely in reducing fluid overload, do not appear to improve prognosis. 4. Vasodilators increase effort capacity and reduce symptoms, possibly conferring some long‐term benefit, and angiotensin converting enzyme (ACE) inhibitors improve symptoms and decrease mortality in a wide range of patients. 5. Positive inotropes may be effective in the short term, but they increase myocardial oxygen demand and show tachyphylaxis with no prognostic benefit. 6. Xamoterol (Corwin, Carwin, Corwil, Xamtol, ICI 118,587) is a partial sympathetic agonist with approximately 50% of the activity of a pure agonist, which provides inotropic support at rest, and protection against excess sympathetic activity on exercise. 7. It is compatible with other therapies and has shown no serious toxicity. 8. It should be considered at present as an adjunct to diuretic and/or ACE inhibitor therapy, although it may be useful alone; its role will become clearer as its effects on mortality are established.
Effect of xamoterol on peripheral blood vessels in healthy subjects.
Authors: Fitzgerald DE
Published: July 2012

Changes in peripheral blood flow in response to increasing doses of xamoterol with or without a beta 2‐adrenoceptor blocking agent were assessed in eight healthy volunteers. Xamoterol produced increases in femoral artery diameter, blood volume flow and velocity flow. In the brachial and posterior tibial arteries, systolic blood pressure rose, and in the brachial artery, diastolic blood pressure fell. None of these effects was affected by beta 2‐adrenoceptor blockade. The actions of xamoterol on the circulation are consistent with direct stimulation of myocardial beta 1‐adrenoceptors.
The efficacy and safety of chronic oral administration of xamoterol to patients with severe heart failure treated with ACE inhibitors.
Authors: Pouleur H , Hanet C , Rousseau MF
Published: July 2012

Xamoterol 200 mg twice daily was given for 2 months to nine patients with severe heart failure already being treated with angiotensin converting enzyme (ACE) inhibitors. Left ventricular end‐diastolic pressure fell from 28 to 13 mmHg and end‐systolic volume fell from 115 to 106 ml m‐2; indices of contractility improved and ejection fraction rose from 33 to 38%. The time constant of ventricular relaxation, T1, improved from 62 to 44 ms. Exercise tolerance improved. Thus, in this group of patients with severe heart failure, xamoterol produced benefits in systolic and diastolic function. There were no adverse effects.
Contrasting effects of single doses of pindolol and xamoterol on left ventricular diastolic function.
Authors: Rousseau MF , Pouleur H , Debaisieux JC , Van Eyll C , Charlier AA
Published: July 2012

Impaired left ventricular diastolic dysfunction is common in patients with ischaemic heart failure. The beta 1‐adrenoceptor partial agonist xamoterol was compared with pindolol, a beta‐adrenoceptor blocker with intrinsic sympathomimetic activity, in a haemodynamic study in 17 patients with ischaemic heart disease. Pindolol caused left ventricular end‐diastolic pressure, wall stress and T1 to rise, whereas xamoterol produced improvements in all three parameters. These results suggest that xamoterol may be of greater benefit to patients in heart failure.
Long‐term efficacy of xamoterol (a beta 1‐adrenoceptor partial agonist) in patients with mild to moderate heart failure.
Authors: Sorensen EV , Faergeman O , Day MA , Snow HM
Published: July 2012

This study was designed to assess the efficacy of xamoterol in 14 patients with mild to moderate heart failure over a period of 18 months. A beneficial effect on exercise capacity and a lowering of heart rate on exercise was sustained, and ejection fraction did not change, although some deterioration may be expected over this length of time in patients with heart failure. Xamoterol is safe and effective, and its benefits are maintained over at least 18 months.
Why are converting enzyme inhibitors vasodilators?
Authors: Vanhoutte PM , Auch‐Schwelk W , Biondi ML , Lorenz RR , Schini VB , Vidal MJ
Published: July 2012

1. The primary action of the converting enzyme inhibitors to prevent the formation of angiotensin II can explain a decrease in peripheral vascular resistance in patients with elevated, but not in those with normal or reduced plasma renin levels. 2. The inhibition of the breakdown of bradykinin will potentiate the vasodilator properties of the endogenously produced peptide. These include direct relaxation of certain vascular smooth muscle, production of vasodilator prostanoids and release of endothelium‐derived relaxing factor(s). The greater release of the latter in the kidney could exert a negative feedback on the release of renin. 3. In addition, converting enzyme inhibitors may directly (by a prejunctional effect) and indirectly (by curtailing the production of angiotensin II) reduce the release of noradrenaline in the blood vessel wall. 4. Converting enzyme inhibitors may also directly reduce the responsiveness of vascular smooth muscle to vasoconstrictor stimuli (e.g. alpha‐adrenoceptor activation). 5. The different effects of these therapeutic agents may concur to induce peripheral vasodilatation.
Angiotensin and the remodelling of the myocardium.
Authors: Weber KT , Janicki JS
Published: July 2012

1. From a morphologic standpoint, the myocardium has three compartments: cardiac myocytes; intramyocardial coronary arteries with a microcirculation; and an interstitium composed largely of fibrillar collagen. As long as intercompartmental equilibrium exists, myocardial mechanics and energetics and myocyte viability will each be preserved. 2. The hypertrophic process seen with left ventricular pressure overload secondary to renovascular hypertension alters this equilibrium because of the adverse remodelling of intramural coronary arteries and fibrillar collagen. The pathogenetic mechanism(s) responsible for the observed myocardial fibrosis, having reactive and reparative components, remains to be elucidated. 3. Attractive circumstantial evidence, however, has been obtained to incriminate circulating angiotensin II in this process. Five lines of evidence favouring the role of angiotensin II in promoting the reactive perivascular and interstitial fibrosis and the reparative fibrosis are presented, including the potential cardioprotective effects of angiotensin converting enzyme inhibitors.
ACE inhibitors in acute and chronic ischaemia: current status and future promise.
Authors: Sonnenblick EH , Zhao M , Eng C , LeJemtel TH , Factor SM , Capasso J , Anversa P
Published: July 2012

1. Myocyte loss, reactive hypertrophy, dynamic ischaemia with ‘stunning’, and ventricular wall remodelling are all involved in the initiation and progression of myocardial failure which is ischaemic in origin. 2. The effects of ACE inhibitors to reduce preload and afterload has potentially salutary effects in these settings. Moreover, sulphyl containing ACE inhibitors may have further actions in reducing free radicals and their damage in the acute phases of these events. 3. These promising initial studies warrant further exploration.
Relationships between structure and effects of ACE inhibitors: comparative effects in myocardial ischaemic/reperfusion injury.
Authors: Przyklenk K , Kloner RA
Published: July 2012

1. Coronary artery reperfusion has become the treatment of choice for evolving myocardial infarction. 2. While there is no question that timely restoration of coronary blood flow is essential for the salvage of ischaemic myocardium, coronary reperfusion has also been associated with potentially deleterious consequences. Specifically, the viable tissue salvaged by reperfusion remains ‘stunned’‐i.e., exhibits prolonged abnormalities in contractile function‐for hours to days following reflow. Furthermore, it has been suggested that reperfusion per se may lethally injure some myocytes that were only reversibly injured prior to restoration of blood flow. 3. ACE inhibitors such as captopril and enalapril have been shown to reduce indices of myocardial injury (infarct size, creatine kinase release) and enhance contractile function of stunned myocardium in experimental models of coronary occlusion followed by reperfusion. These effects of ACE inhibitors have largely been attributed to the reduction in myocardial O2‐demand and increase in myocardial blood flow associated with blunting of angiotensin II formation. 4. Recent studies suggest that the effects of some ACE inhibitors‐particularly captopril‐may not solely be explained on the basis of ACE inhibition. In fact, sulphydryl (‐SH) containing ACE inhibitors such as captopril appear to act as scavengers of oxygen‐derived free radical species thought to be important in the pathogenesis of both postischaemic contractile dysfunction and ischaemia/reperfusion induced myocyte necrosis. 5. Thus, ‐SH containing ACE inhibitors‐which both inhibit ACE and scavenge cytotoxic free radicals‐may offer a suitable form of treatment for myocardial ischaemia/reperfusion injury.
Clinical implications for therapy: possible cardioprotective effects of ACE inhibition.
Authors: Dzau VJ
Published: July 2012

1. The circulating and tissue renin‐angiotensin systems (RAS) contribute importantly to cardiovascular homeostasis. Systemic and/or local activation of the RAS is seen in many pathological conditions of the cardiovascular system (e.g. hypertension and congestive heart failure). Increased angiotensin production participates in the pathophysiology of these and other disease states. Accordingly, inhibitors of the renin angiotensin system have a broad spectrum of therapeutic efficacy. 2. Angiotensin‐converting enzyme (ACE) inhibitors are effective antihypertensive agents that do not adversely affect serum lipid levels. In addition, they reduce left ventricular hypertrophy. 3. ACE inhibitors cause coronary vasodilation and reduce ventricular work and wall stress. They have been shown to reduce experimental infarct size and to increase anginal threshold in humans. 4. After experimental or human myocardial infarction that results in significant left ventricular dysfunction, ACE inhibitors prevent ventricular dilatation and development of congestive heart failure, and may improve survival. 5. ACE inhibitors can prevent ventricular fibrillation and contractile impairment (stunned myocardium) associated with reperfusion injury after experimental myocardial ischaemia. 6. ACE inhibitors reduce preload and afterload, improve exercise capacity, reduce ventricular arrhythmias, and improve patient survival in clinical cardiac failure. 7. Taken together, inhibition of the RAS may potentially result in primary as well as secondary protective effects on the cardiovascular system.
L‐648,051, a novel cysteinyl‐leukotriene antagonist is active by the inhaled route in man.
Authors: Evans JM , Barnes NC , Zakrzewski JT , Sciberras DG , Stahl EG , Piper PJ , Costello JF
Published: July 2012

1. We have studied some of the pharmacological properties of inhaled L‐ 648,051 which has been shown to be a selective cysteinyl‐leukotriene (LT) antagonist in vitro and in vivo in various animal models. 2. The effects of three different doses (1.6, 6.0 and 12.0 mg) on the bronchoconstriction induced by inhaled LTD4 have been investigated in normal male subjects in a series of double‐blind, placebo controlled studies. Furthermore, the specificity of the drug has been investigated by challenging subjects with histamine after pre‐inhalation of 12.0 mg L‐648,051. 3. At all doses L‐648,051 partially blocked the bronchoconstriction induced by LTD4 inhalation in a dose related manner. At a dose of 12.0 mg, L‐648,051 decreased the maximum fall in specific airways conductance (sGaw) (placebo, 49% vs L‐648,051, 21%, P less than 0.01) and shortened the time to recovery from LTD4‐induced bronchoconstriction (placebo, 41 min vs L‐648,051, 19 min, P less than 0.01). 4. There was no evidence of partial agonist activity, and no effect on histamine‐induced bronchospasm. Inhaled L‐648,051 at all doses was well tolerated. 5. We conclude that LT antagonism is possible by the inhaled route in man. Inhaled L‐648,051 is an active and selective LT‐antagonist in man which is well tolerated and may prove to be a useful drug for assessing the role of leukotrienes in asthma and other lung diseases.
Individualised aminoglycoside dosage based on pharmacokinetic analysis is superior to dosage based on physician intuition at achieving target plasma drug concentrations [see comments]
Authors: Begg EJ , Atkinson HC , Jeffery GM , Taylor NW
Published: July 2012

1. A prospective randomised trial was conducted to compare aminoglycoside dose prediction based on individually measured pharmacokinetic data, with dosage based on physician intuition. 2. After 2 days of therapy more patients in the pharmacokinetic group had achieved both peak (6‐10 mg 1(‐1] and trough (1‐2 mg 1(‐1] target plasma concentrations (P = 0.007), peaks alone (P = 0.01) and troughs alone (P = 0.01). Their mean (s.e. mean) peak concentration was 6.49 +/‐ 0.39 mg 1(‐1) compared with 4.27 +/‐ 0.52 mg 1(‐1) in the control group (P = 0.001), with trough concentrations of 1.44 +/‐ 0.22 mg 1(‐1) and 0.94 +/‐ 0.21 mg 1(‐1) respectively (P = 0.054). 3. After 5 days of therapy, peak and trough concentrations were still significantly higher in the pharmacokinetic group despite empirical dose adjustment (P = 0.01 and P = 0.013 respectively). 4. The mean (s.e. mean) daily dose of aminoglycoside was higher in the computer group (312 +/‐ 17 mg vs 203 +/‐ 13 mg, P = 0.001). 5. These findings suggest that dose estimation based on measured pharmacokinetic parameters is superior at achieving target plasma drug concentrations.
Neuromuscular blockade with vecuronium in paediatric patients with burn injury.
Authors: Mills AK , Martyn JA
Published: July 2012

1. The effect of body surface area (BSA) burn injury on neuromuscular pharmacodynamics of vecuronium was evaluated. 2. The neuromuscular responses of 15 burned children were compared with those in five controls. 3. The effective dose for 50% suppression of twitch tension (ED50) was 34 micrograms kg‐1 for patients with less than 40% BSA burn, 55 micrograms kg‐1 for 40‐60% BSA burn, and 65 micrograms kg‐1 for patients with greater than 60% BSA burn. These values were significantly higher than the value for control patients, which was 18 micrograms kg‐1. 4. Burn injury induces a resistance to the neuromuscular effects of vecuronium, the magnitude of which is related to burn size.