bluuebunny/crossref_metadata_2025 huggingface dataset:
The pharmacokinetics of perindopril in patients with liver cirrhosis.
Authors: Thiollet M , Funck‐Brentano C , Grange JD , Midavaine M , Resplandy G , Jaillon P
Published: July 2012

Perindopril is a non‐sulphydryl angiotensin converting enzyme (ACE) inhibitor which requires hydrolysis to its active metabolite, perindoprilat, to produce its effects. Ten cirrhotic patients with mild to severe disease were studied after oral administration of a single 8 mg dose of perindopril as its tert‐butylamine salt. Compared with a historical control group of young healthy volunteers receiving the same single oral dose of perindopril, mean AUC values of the prodrug perindopril were double in patients with liver cirrhosis (602 +/‐ 294 s.d. ng ml‐1 h vs 266 +/‐ 70 s.d. ng ml‐1 h) whereas the mean AUC of perindoprilat was found to be similar (134 +/‐ 139 ng ml‐1 h vs 120 +/‐ 29 ng ml‐1 h). The partial metabolic clearance of perindopril to perindoprilat was much lower in the cirrhotics (26 +/‐ 12 ml min‐1 vs 58 +/‐ 22 ml min‐1). The maximum inhibition of plasma ACE activity measured in the cirrhotic patients (87.5 +/‐ 5.1%) was comparable with that previously reported with perindopril in patients with mild hepatic impairment as well as in patients with essential hypertension. We suggest that liver cirrhosis may be associated with imparied deesterification of perindopril to its active metabolite perindoprilat but that no dosage adjustment of perindopril is required in cirrhotic patients.
Dose‐response study with high‐dose inhaled salmeterol in healthy subjects.
Authors: Maconochie JG , Forster JK
Published: July 2012

A double‐blind, placebo‐controlled, cross‐over study in 10 healthy male subjects has been carried out to investigate the non‐pulmonary effects of single inhaled doses of salmeterol 100 micrograms, 200 micrograms and 400 micrograms and salbutamol 400 micrograms from a metered‐dose inhaler. At all doses tested, salmeterol produced statistically significant changes in pulse rate, tremor, blood glucose and plasma potassium concentrations, compared with placebo. All changes were dosed related. A number of dose‐related adverse events including tremor, awareness of heart beat and headache were reported after salmeterol administration.
New drug treatments for HIV infection and AIDS. A review following the Seventh International Conference on AIDS, Florence 16‐21 June 1991.
Authors: Venning GR , Scott GM
Published: July 2012

1. OBJECTIVE‐To evaluate the status of clinical development of zidovudine and new drugs for the treatment of Human Immunodeficiency Virus (HIV) infections. 2. METHOD‐A critical review of the clinical trial reports and assessment of the design and methodology of the therapeutic trials. Evaluation of the drugs being tested and of the specific difficulties in testing drugs in AIDS. 3. CONCLUSIONS‐Drugs are being tested in a unique climate of public opinion characterised by (1) fast track criteria for regulatory approval (2) parallel track (compassionate release) of new drugs before adequate determination of safety and efficacy (3) resistance to the use of placebos in controlled trials.
Stereoselective disposition of flurbiprofen in uraemic patients.
Authors: Knadler MP , Brater DC , Hall SD
Published: July 2012

1. Both single and multiple oral doses of 50 mg racemic flurbiprofen were given to eight patients with mild to moderate renal impairment. The plasma and urine concentrations of the R‐ and S‐enantiomers of flurbiprofen and its major metabolites were measured by a stereoselective h.p.l.c. assay. 2. For R‐flurbiprofen the oral clearance (mean +/‐ s.d.: 38.3 +/‐ 12.8 vs 30.8 +/‐ 11.5 ml min‐1) and volume of distribution (Vz; 17.6 +/‐ 3.9 vs 14.6 +/‐ 2.5 l) were significantly greater (P less than 0.05) than for the S‐enantiomer. A significantly greater (P less than 0.05) percent of the dose was excreted in the urine R‐configuration (16.4 +/‐ 6.0 vs 10.9 +/‐ 4.2%). 3. Plasma protein binding of the enantiomers of flurbiprofen was determined by ultrafiltration. The unbound clearance and unbound Vz were not different between enantiomers consistent with the (not significantly) greater percent unbound of R‐flurbiprofen (0.079 +/‐ 0.014%) vs S‐flurbiprofen (0.064 +/‐ 0.015%). 4. Relative to normal volunteers, the uraemic subjects exhibited a significantly greater (P less than 0.05) oral clearance, Vz and percent unbound for both enantiomers; unbound clearance and unbound Vz did not differ from healthy controls. 5. The disposition of flurbiprofen enantiomers was not changed upon multiple dosing and no evidence of futile cycling was found. Adjustment of flurbiprofen dosing rate in uraemic subjects is not indicated on the basis of pharmacokinetics.
An evaluation of buffered aspirin and aspirin tablets in postoperative pain after third molar surgery.
Authors: Seymour RA , Weldon M , Kelly P , Nicholson E , Hawkesford JE
Published: July 2012

1. Single doses (500 and 1000 mg) of both buffered aspirin and aspirin tablets were compared with placebo in a randomised double‐blind trial of parallel design in patients with postoperative pain after third molar surgery. 2. Only buffered aspirin 500 mg provided significant pain relief (P = 0.016) during the 5 h investigation period. 3. A significant correlation (P = 0.004) was observed between overall pain scores after the various aspirin treatments and aspirin esterase activity. 4. Buffered aspirin preparations afforded a slight advantage over aspirin tablets in the control of postoperative pain after third molar surgery. However, the duration of analgesia was short (approximately 2 h). 5. Aspirin esterase activity appears to be an important determinant of the drug's efficacy in postoperative dental pain.
Sumatriptan and cerebral perfusion in healthy volunteers.
Authors: Scott AK , Grimes S , Ng K , Critchley M , Breckenridge AM , Thomson C , Pilgrim AJ
Published: July 2012

1. The effect of sumatriptan on regional cerebral perfusion was studied in healthy volunteers. 2. Intravenous sumatriptan (2 mg) had no detectable effect on regional cerebral perfusion as measured using a SPECT system with 99technetiumm labelled hexemethylpropyleneamineoxime. 3. Sumatriptan had no effect on pulse, blood pressure or ECG indices. 4. All six volunteers experienced minor adverse effects during the intravenous infusion.
Dose‐dependent alpha 1‐adrenoceptor antagonist activity of the anti‐ arrhythmic drug, abanoquil (UK‐52,046), without reduction in blood pressure in man.
Authors: Tham TC , Guy S , Shanks RG , Harron DW
Published: July 2012

1. The dose‐dependency of the alpha 1‐adrenoceptor antagonist activity of the anti‐arrhythmic abanoquil (UK‐52,046) was investigated in 10 healthy male subjects who received serially increasing infusions of phenylephrine before and 2, 4, 8, 12, 24 and 48 h after single oral doses of abanoquil 0.25, 0.5 and 1 mg and placebo in a double‐blind randomised manner. 2. The doses of phenylephrine required to increase systolic BP by 20 mm Hg (PS20) were calculated using a quadratic fit to the individual dose‐response curves. 3. Abanoquil 0.25, 0.5 and 1 mg increased the PS20 in a dose‐dependent manner with effects which were maximal at 2 to 8 h and lasted for 24 to 48 h (P less than 0.05). Maximal dose ratios were: abanoquil 0.25 mg 2.0 +/‐ 0.9, 0.5 mg 2.4 +/‐ 1.3, 1 mg 3.4 +/‐ 1.1. 4. No change occurred in supine BP but a small increase (P less than 0.01) occurred in supine HR 8 h post‐dosing (64 +/‐ 9, 58 +/‐ 6 beats min‐1 for abanoquil 1 mg and placebo respectively). 5. Therefore abanoquil 0.25, 0.5 and 1 mg showed dose‐ dependent alpha 1‐adrenoceptor antagonist activity with no effect on supine BP.
Inhibition of histamine‐induced nasal obstruction by cetirizine in allergic rhinitis.
Authors: Braunstein G , Malaquin F , Fajac I , Melac M , Frossard N
Published: July 2012

This double‐blind randomized crossover placebo‐controlled study was designed to assess objectively the nasal antihistamine effect of cetirizine in patients with allergic rhinitis and control subjects. Nasal challenge was performed by nebulization of increasing doubling doses of histamine (0; 0.04 to 1.28 mg/nostril) in six patients with allergic rhinitis and six control subjects on cetirizine (2 x 10 mg daily for 3 days) or placebo. Sneezings were counted and nasal obstruction was assessed by subjective scoring and by objective measurement of nasal airway resistance by posterior rhinomanometry. Histamine induced sneezing and a dose‐dependent increase in nasal airway resistance and in perceived sensation of obstruction. Responses were greater in patients with allergic rhinitis compared with controls, although of borderline significance for nasal obstruction. Cetirizine totally abolished sneezing and significantly reduced increase in nasal airway resistance and perceived sensation of nasal obstruction both in normal and rhinitic subjects. Our results demonstrate by an objective measurement the nasal antihistamine effect of cetirizine. We propose this simple provocation test to assess the time‐course of the effect of antihistamines and to compare the relative potency of related compounds.
Pharmacokinetics of dipipanone after a single oral dose.
Authors: Paterson S
Published: July 2012

A single oral dose of Diconal (dipipanone HCl 10 mg, cyclizine HCl 30 mg) was given to six volunteers. The mean peak plasma dipipanone concentration was 29 ng ml‐1, the time to peak plasma concentration was 1‐2 h, the mean elimination half‐life was 3.5 h and the mean AUC was 156 ng ml‐1 min. Less than 1% of the dose was excreted in urine unchanged over 24 h.
A comparison of acipimox and nicotinic acid in type 2b hyperlipidaemia.
Authors: O'Kane MJ , Trinick TR , Tynan MB , Trimble ER , Nicholls DP
Published: July 2012

The side effect profiles and lipid lowering efficacy of nicotinic acid (1 g three times daily) and its analogue acipimox (250 mg three times daily) in type 2b hyperlipidaemia were compared in a double‐blind placebo controlled study. In the nicotinic acid group (n = 7) at 12 weeks there were significant reductions (P less than 0.05) with respect to placebo (n = 9) in total cholesterol (median and range) 6.6 mmol l‐1 (4.8‐8.4) vs 8.8 mmol l‐1 (7.5‐9.5), triglyceride 1.4 mmol l‐1 (0.5‐ 4.6) vs 2.8 mmol l‐1 (1.5‐9.5) and apoprotein B 88.6 mg dl‐1 (62.1‐114) vs 121.9 mg dl‐1 (88.0‐170.7). In contrast there was no significant alteration in lipids in the acipimox group (n = 12). Nicotinic acid was associated with a high incidence of side effects, principally cutaneous flushing, while acipimox was well tolerated by all patients.
The effect of celiprolol on glomerular filtration rate and renal blood flow in patients with chronic renal impairment and healthy volunteers.
Authors: Robson RA , Bridgman PG , Wells JE , Bailey RR , Lynn KL
Published: July 2012

A double‐blind, placebo controlled study investigated the effects of celiprolol, 200 mg daily for 7 days, on glomerular filtration rate (GFR) and estimated renal blood flow (ERBF) in eight healthy volunteers and eight patients with chronic renal insufficiency. In healthy volunteers the mean difference in GFR was 4.8 ml min‐1 (95% CI ‐8.2 to 17.7 ml min‐1) and the mean difference in ERBF was 49.8 ml min‐1 (95% CI ‐47.5 to 147 ml min‐1) after celiprolol. In patients with chronic renal insufficiency the mean difference in GFR was ‐2.1 ml min‐1 (95% CI ‐64.6 to 65.8 ml min‐1). The study had sufficient power to detect a 15% change in GFR for normals and 10% for patients, and for ERBF, changes of 14% and 23% were detectable. Celiprolol at a dose of 200 mg daily for 7 days can be used in patients with chronic renal insufficiency without adversely affecting GFR or ERBF.
pH‐feedback controlled infusions of ranitidine are no more effective than fixed‐dose infusions in reducing gastric acidity and variability in antisecretory responses.
Authors: Wilder‐Smith CH , Halter F , Hacki W , Merki HS
Published: July 2012

1. The antisecretory responses to pH‐feedback controlled (maximum dose 800 mg 24 h‐1) and fixed‐dose (0.25 mg kg‐1 h‐1) continuous infusions of ranitidine were compared in a randomised, placebo‐controlled, cross‐ over study in 10 healthy male volunteers. 2. To assess tolerance during repeated dosing with ranitidine, the same infusion regimens were given before and after 6 days oral dosing with ranitidine 300 mg four times daily. 3. With the pH‐feedback controlled infusion of ranitidine the median % time (interquartile range) with pH greater than 4 in the 24 h period was 57% (45‐76) before and 23% (17‐34) after 6 days oral dosing (P less than 0.001). The respective values with fixed‐dose infusion were 51% (38‐63) and 26% (15‐32) (P less than 0.002). 4. The median 24 h doses (interquartile range) of ranitidine given by feedback‐ controlled infusion before and after 6 days oral dosing were 675 mg (542‐728) and 749 mg (709‐760), respectively (P less than 0.01). The dose of ranitidine given by fixed‐rate infusion was 423 mg (393‐502) on both study days (P less than 0.001 vs feedback infusion). 5. Plasma gastrin concentrations remained slightly elevated after 6 days of oral ranitidine dosing, whereas pancreatic polypeptide plasma levels remained unchanged. 6. The antisecretory efficacy of infusions of ranitidine is significantly decreased by circadian stimuli and tolerance. Individually‐adapted infusions of high doses of ranitidine were not superior to fixed‐dose infusion of 0.25 mg kg‐1 h‐1 in overcoming this variability.
A pharmacokinetic and pharmacodynamic comparison of plain and enteric‐ coated prednisolone tablets.
Authors: Adair CG , McCallion O , McElnay JC , Scott MG , Hamilton BA , McCann JP , Stanford CF , Nicholls DP
Published: July 2012

1. Eight healthy volunteers and eight patients suffering from chronic obstructive pulmonary disease (COPD) received 30 mg prednisolone as plain (P) and enteric‐coated tablets (EP) in a randomised, cross‐over manner. Plasma prednisolone and cortisol and blood glucose were measured over 24 h. 2. Although absorption of prednisolone was considerably slower when administered as the enteric‐coated form, peak plasma drug concentrations and total AUC (0,24 h) were equivalent for the two formulations. Malabsorption of prednisolone was not observed. 3. The administration of EP was associated with significantly less adrenal suppression in volunteers than P as judged by measurement of AUC (0,24 h) values for endogenous cortisol. However, this difference did not reach statistical significance in the patient group. 4. Plasma cortisol concentrations declined more slowly following administration of the enteric‐coated form to both groups. The difference in time taken (median and range) to maximum suppression of cortisol was statistically significant (P less than 0.05) between P (2.5 h; 2‐4 h) and EP (4 h; 3‐ 12 h) preparations administered to volunteers. There was a similar significant difference (P less than 0.05) between P (2.5 h; 1‐4 h) and EP (7 h; 2‐12 h) in the patients. 5. Plasma cortisol concentrations were significantly lower at 24 h in patients receiving the enteric‐ coated product in association with higher terminal prednisolone concentrations. 6. Blood glucose concentrations increased over an 8 h period in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Prospective evaluation of a model for the prediction of milk:plasma drug concentrations from physicochemical characteristics.
Authors: Begg EJ , Atkinson HC , Duffull SB
Published: July 2012

1. Milk:plasma (M/P) drug concentration ratios predicted by a model utilizing pKa, plasma protein binding and octanol:water partition coefficients have been compared with actual M/P values for 10 basic drugs. 2. There was a close relationship between predicted and observed M/P ratios with a coefficient of determination r2 of 0.97. However, there was a proportional error. 3. The data were transformed by taking logs of predicted and observed (M/P + 1) values. Regression analysis resulted in an r2 of 0.95, an intercept on the Y‐axis not significantly different from zero and a slope not significantly different from one. 4. The 95% confidence interval around a single prediction revealed an error between 150% for the lowest and 23% for the highest M/P ratios. The error is therefore lowest for the drugs likely to have the greatest transfer into milk. 5. There was no significant bias in the predictions. 6. The model was refined by multiple linear regression analysis utilising the observed M/P ratios for the 10 basic drugs in addition to those of the original drugs. The revised equation resulted in an improvement in the explained variance. 7. Protein binding was the most important single predictor. 8. The results confirm that M/P ratios for basic drugs can be predicted accurately from their physicochemical characteristics.
The role of cytochrome P4502D6 in the metabolism of paroxetine by human liver microsomes.
Authors: Bloomer JC , Woods FR , Haddock RE , Lennard MS , Tucker GT
Published: July 2012

Paroxetine is a selective serotonin reuptake inhibitor possessing anti‐ depressant activity. Demethylenation of the methylenedioxy phenyl group is the initial step in its metabolism, the liberated carbon appearing in vitro as formate. A radioassay involving [14C‐methylenedioxy] paroxetine was developed and used to examine the role of cytochrome P4502D6 in paroxetine metabolism by human liver microsomes. The rate of formate production was much higher in microsomes from an extensive metaboliser of debrisoquine than from a poor metaboliser. Also, demethylenation of paroxetine was inhibited by the quinidine and quinine isomer pair in microsomes from the extensive metaboliser only. These observations strongly suggested that the process was catalysed by the enzyme cytochrome P4502D6. Metabolism could not be completely inhibited by quinidine, the residual activity representing the contribution of at least one other enzyme. The ability of microsomes from a poor metaboliser of debrisoquine to demethylenate paroxetine provided further evidence for the involvement of an enzyme distinct from P4502D6. This was confirmed by kinetic analysis of the process in microsomes from both poor and extensive metabolisers. It is concluded that, in man, the initial step of paroxetine metabolism is performed by at least two enzymes, one of which is cytochrome P4502D6.
Pharmacodynamics of venlafaxine evaluated by EEG brain mapping, psychometry and psychophysiology.
Authors: Saletu B , Grunberger J , Anderer P , Linzmayer L , Semlitsch HV , Magni G
Published: July 2012

1. In a double‐blind, placebo‐controlled study the effects of venlafaxine‐a novel nontricyclic compound inhibiting neuronal uptake of serotonin, noradrenaline and to a lesser extent dopamine‐were investigated utilizing EEG brain mapping, psychometric and psychophysiological measures. 2. Sixteen healthy volunteers (eight males, eight females) aged 21‐36 years received randomized and at weekly intervals single oral doses of placebo, 12.5 mg, 25 mg and 50 mg venlafaxine. EEG recordings, psychometric and psychophysiological tests, and evaluation of pulse, blood pressure and side‐effects were carried out at 0, 2, 4, 6, and 8 h. 3. EEG brain mapping demonstrated that venlafaxine exerted a significant action on human brain function as compared with placebo at all three doses, characterized mostly by attenuation of absolute power, increase of relative delta/theta and beta, and decrease of alpha power, as well as by an acceleration of the total centroid fronto‐temporally and by its slowing centrally and parietally. These findings are similar to antidepressants such as imipramine. Topographically, drug‐induced alterations were most pronounced over both fronto‐temporal and the right temporal to temporo‐ occipital regions. 4. Psychometric and psychophysiological investigations demonstrated significant dose‐dependent psychotropic properties of the drug. Multivariate statistics exhibited an improvement of both the noopsyche (e.g. attention, concentration, attention variability, memory, fine motor activity, reaction time performance) and thymopsyche (e.g. drive, wakefulness)) but also significant psychophysiological activation (e.g. in c.f.f., pupillary and skin conductance measures). 5. Time‐efficiency calculations showed significant central effects from the 2nd hour onwards, with increasing differences between placebo and treatment up to the 8th hour. Nausea was the most frequent complaint and appeared dose dependent.
The excretion of dothiepin and its primary metabolites in breast milk.
Authors: Ilett KF , Lebedevs TH , Wojnar‐Horton RE , Yapp P , Roberts MJ , Dusci LJ , Hackett LP
Published: July 2012

1. The excretion of dothiepin, nordothiepin, dothiepin‐S‐oxide and nordothiepin‐S‐oxide into breast milk was studied in eight women. Exposure to drug was measured in five of their infants, and possible drug‐related effects were assessed in all eight infants. 2. Using pre‐ feed milk samples mean (+/‐ s.e. mean) milk:plasma (M:P) ratios were 0.78 +/‐ 0.12, 0.85 +/‐ 0.16, 1.18 +/‐ 0.29 and 1.86 +/‐ 0.29 for dothiepin, nordothiepin, dothiepin‐S‐oxide and nordothiepin‐S‐oxide, respectively. In post‐feed milk samples, the mean M:P ratio for dothiepin (1.59 +/‐ 0.32) was significantly greater (P less than 0.05) but M:P ratios for the metabolites were similar. 3. Mean total calculated infant daily doses, (in dothiepin equivalents and as a percent of the maternal dose) were 0.58% for dothiepin, 0.23% for nordothiepin, 2.47% for dothiepin‐S‐oxide, and 1.17% for nordothiepin‐S‐ oxide. 4. Plasma samples were obtained from five infants. In one, both dothiepin and nordothiepin were below their minimum quantifiable levels (2 micrograms l‐1) while in four others both dothiepin‐S‐oxide and nordothiepin‐S‐oxide were below their minimum quantifiable levels (10 micrograms l‐1). No adverse effects were found in any of the eight infants. 5. Use of dothiepin by depressed mothers is unlikely to be a significant hazard to their breast‐feeding infants.
The influence of particle size on the bioavailability of inhaled temazepam.
Authors: Fee JP , Collier PS , Launchbury AP , Clarke RS
Published: July 2012

1. Temazepam was administered by aerosol using a standard protocol to healthy volunteers. Two studies are reported in which different dosage formulations were used: a) 30 mg of the 5 mu diameter particle (n = 6); b) 10 mg of the 2 mu diameter particle (n = 6). 2. An open crossover design was followed in each study. On one occasion in both studies subjects used a gargling procedure to remove drug which had been deposited in the mouth and oropharynx. 3. Serial venous blood samples were drawn for a period of 24 h. The mean total AUC of the 5 mu preparation was significantly reduced by gargling (3153 ng ml‐1 h to 1066 ng ml‐1 h) (F = 0.32). Gargling also had a significant effect on the mean AUC(0‐1 h). 4. In contrast gargling had no significant effect on the mean AUC associated with the smaller diameter particle preparation (630 ng ml‐1 h) vs 397 ng ml‐1 h (F = 0.74). 5. These findings also indicate that temazepam deposition in the pulmonary tree is enhanced by the use of a 2 mu rather than a 5 mu diameter particle. However, the plasma drug concentrations achieved are unlikely to produce a sufficiently marked sedative effect for endoscopic investigations such as gastroscopy.
Cyclosporin metabolism by human gastrointestinal mucosal microsomes.
Authors: Webber IR , Peters WH , Back DJ
Published: July 2012

The in vitro metabolism of the immunosuppressant cyclosporin (CsA) by human gastrointestinal mucosal microsomes has been studied. Macroscopically normal intestinal (n = 4) and liver (n = 2) tissue was obtained from kidney transplant donors, and microsomes prepared. Intestinal metabolism was most extensive with duodenal protein (15% conversion to metabolites M1/M17 after 2 h incubation at 37 degrees C; metabolite measurement by h.p.l.c). Western blotting confirmed the presence of P‐4503A (enzyme subfamily responsible for CsA metabolism) in duodenum and ileum tissue, but not in colon tissue. The results of this study indicate that the gut wall may play a role in the first‐pass metabolism of CsA, and could therefore be a contributory factor to the highly variable oral bioavailability of CsA.
The influence of gastrointestinal transit on drug absorption in healthy volunteers.
Authors: Riley SA , Sutcliffe F , Kim M , Kapas M , Rowland M , Turnberg LA
Published: July 2012

1. The effect of variability of gastric emptying and oro‐caecal transit on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorthiazide and salicylic acid has been studied in six healthy subjects. Each subject was studied on five separate occasions: three times under basal conditions, once following metoclopramide and once following codeine pretreatment in an attempt to speed and slow transit respectively. 2. Inter‐subject variability of gastric emptying, oro‐ caecal transit and the rate and extent of drug absorption was considerable. 3. The absorption of salicylic acid appeared rate‐limited by gastric emptying but the rate and extent of frusemide, atenolol and hydrochlorthiazide absorption were unrelated to measures of gastric emptying or oro‐caecal transit. 4. Codeine phosphate caused a two‐fold delay in oro‐caecal transit but did not influence gastric emptying while metoclopramide had no significant effect on either function. 5. Metoclopramide and codeine had no significant effect on the rate or extent of absorption of any of the study drugs. 6. Within the limits of this experiment, oro‐caecal transit time did not appear to be an important determinant of frusemide, atenolol, hydrochlorothiazide or salicylic acid absorption. Other factors must account for the observed variability in drug absorption.
Effects of a non‐absorbable osmotic load on drug absorption in healthy volunteers.
Authors: Riley SA , Kim M , Sutcliffe F , Kapas M , Rowland M , Turnberg LA
Published: July 2012

1. We have studied the effects of a non‐absorbable osmotic load on the absorption of a multicomponent solution of frusemide, atenolol, hydrochlorothiazide and salicylic acid in six healthy volunteers. 2. Each subject was studied on up to four separate occasions. The drugs were administered in one of four solutions: a) a mannitol/electrolyte solution, b) a double‐strength mannitol/electrolyte solution, c) a glucose/electrolyte solution and d) water. Lactulose or sulphasalazine were added as oro‐caecal transit markers. Lactulose was included in the mannitol‐ and glucose‐based solutions, adding a further non‐absorbable osmotic load, and sulphasalazine was added to the water, adding little osmotic load. 3. The absorption of atenolol and hydrochlorothiazide was two‐ to three‐times less from all lactulose‐containing solutions than from the sulphasalazine‐containing solution. The absorption of frusemide and salicylic acid was similar from all four solutions. 4. The largest non‐absorbable osmotic load impaired the absorption of atenolol and hydrochlorothiazide most and the incorporation of glucose only partly restored absorption. 5. These results suggest that transmucosal water movement is an important determinant of atenolol and hydrochlorothiazide absorption but is less relevant for the absorption of frusemide and salicylic acid. Furthermore, these data demonstrate a previously unrecognised interaction between a commonly prescribed laxative‐lactulose, and atenolol and hydrochlorothiazide.
Discrepancy between bioavailability as estimated from urinary recovery of frusemide and total diuretic effect.
Authors: Alvan G , Paintaud G , Eckernas SA , Grahnen A
Published: July 2012

1. Frusemide was given at a dose of 60 mg as two oral controlled release (CR) formulations and as plain tablets in a randomised, balanced, three way cross over design to 26 healthy volunteers. Urinary volume, and contents of frusemide, sodium, chloride and potassium were measured in samples taken over 24 h. 2. There was a marked difference between the CR formulations on one hand and the plain tablets on the other, in excretion of frusemide and diuresis vs time. The total diuretic/saluretic effect was only marginally lower (19 and 28% respectively, P less than 0.05) after CR compared with plain tablets although the fraction absorbed was markedly decreased (39 and 51% lower, respectively, P less than 0.05), estimated as urinary recovery of frusemide. The total diuresis of the two CR formulations did not differ although the urinary recovery was significantly different (P less than 0.05). 3. The diuretic effect vs frusemide excretion rate showed minimal counter‐clockwise hysteresis after plain tablets while the CR formulations produced clockwise hysteresis indicating tolerance. 4. In agreement with the concept of efficiency, the higher diuretic/saluretic effect per amount of excreted frusemide may be a consequence of the slower output of frusemide in urine with the CR formulations compared with plain tablets. The major part of the pharmacological effect was produced with a higher efficiency after CR compared with plain tablets. It should be noted that the pharmacokinetics of a drug and its pharmacodynamic potency independently determine the total response.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of renal function on the renal clearance of morphine and its glucuronide metabolites in intensive‐care patients.
Authors: Milne RW , Nation RL , Somogyi AA , Bochner F , Griggs WM
Published: July 2012

1. The relationships between renal creatinine clearance and the renal clearances of morphine, morphine‐3‐glucuronide (M3G) and morphine‐6‐ glucuronide (M6G) were studied in fifteen intensive‐care patients who were receiving morphine sulphate by constant intravenous infusion and who had diverse renal function. 2. An arterial blood sample was collected before and after a 4‐5 h urine collection. Plasma and urine concentrations of morphine, M3G and M6G were measured by h.p.l.c. Plasma binding of all three compounds in drug‐free plasma from healthy volunteers was determined by ultrafiltration. Measured renal creatinine clearance (CLCr, meas) was calculated from plasma and urinary creatinine concentrations (from h.p.l.c.). Also, creatinine clearance was predicted (CLCr, pred) from routine laboratory determination of plasma creatinine (Jaffe method). 3. There were significant linear relationships (P less than 0.001) between CLCr, meas and the renal clearances of morphine, M3G and M6G. The unbound renal clearance of morphine exceeded CLCr, meas (P less than 0.002) while the unbound renal clearances of M3G and M6G did not differ from CLCr, meas (P greater than 0.5). 4. In ten of the patients who received a constant infusion of morphine for at least 6 h, the dose‐normalised plasma concentrations of M3G and M6G increased with decreasing CLCr, pred. Significant (P less than 0.001) relationships were observed between the reciprocal of CLCr, pred and the dose‐normalised plasma concentrations of M3G and M6G. 5. The results indicate the importance of renal function in determining the renal clearances and plasma concentrations of M3G and M6G during intravenous infusion with morphine in intensive‐care patients.
Enhancement of the oral absorption of cyclosporin in man.
Authors: Drewe J , Meier R , Vonderscher J , Kiss D , Posanski U , Kissel T , Gyr K
Published: July 2012

1. The oral absorption of cyclosporin from three new semi‐solid oral formulations was compared with the standard soft gelatine preparation in twelve healthy male volunteers. One formulation was based on a solid micellar solution, while the other two, with different in vitro release properties, were based on a microemulsion principle. 2. The results showed that the solid micellar solution and the faster releasing microemulsion formulation increased the extent of absorption on average by 45.2 and 49.0%, respectively, compared with the reference soft gelatine capsule.
Contrasting effects of fluconazole and ketoconazole on phenytoin and testosterone disposition in man.
Authors: Touchette MA , Chandrasekar PH , Milad MA , Edwards DJ
Published: July 2012

Nine healthy male subjects received oral fluconazole 400 mg daily, ketoconazole 200 mg twice daily or no treatment for 6 days according to a randomized, cross‐over design. A single 250 mg oral dose of phenytoin suspension was administered on day 5 and serum phenytoin concentrations were measured over the following 48 h. Serum testosterone concentrations were measured for 10 h after each dose of phenytoin. Ketoconazole had no significant effect on phenytoin concentrations while the mean AUC(0,48) for phenytoin was significantly higher with fluconazole (195.2 +/‐ 47.8 micrograms ml‐1 h) than control (146.3 +/‐ 49.6 micrograms ml‐1 h). At 48 h, the serum phenytoin concentration averaged 1.72 micrograms ml‐1 under control conditions and 3.99 micrograms ml‐1 with fluconazole (132% increase). AUC(0,10) for testosterone was 42% lower than control after ketoconazole administration (P less than 0.05) but increased by 33% from 55.6 +/‐ 9.4 ng ml‐1 h (control) to 73.8 +/‐ 12.6 ng ml‐1 h with fluconazole. AUC(0,10) values for the testosterone precursors androstenedione and 17 alpha‐hydroxyprogesterone were significantly higher in the fluconazole treatment phase as were concentrations of luteinizing hormone. The mechanism and clinical significance of the increase in testosterone concentration caused by fluconazole remains to be determined.
Impairment of carbamazepine‐10, 11‐epoxide elimination by valnoctamide, a valpromide isomer, in healthy subjects.
Authors: Pisani F , Fazio A , Artesi C , Oteri G , Spina E , Tomson T , Perucca E
Published: July 2012

The effect of the valpromide isomer valnoctamide (VCD, 200 mg three times daily for 8 days), an over‐the‐counter tranquillizer, on the elimination kinetics of a single oral dose of carbamazepine‐10, 11‐ epoxide (CBZ‐E, 100 mg) was investigated in healthy subjects. During VCD treatment, the half‐life of CBZ‐E was prolonged significantly compared with control (19.7 +/‐ 6.7 h vs 6.9 +/‐ 2.0 h, means +/‐ s.d., P less than 0.01), and its oral clearance decreased four‐fold (from 109.6 +/‐ 30.7 to 28.8 +/‐ 11.1 ml h‐1 kg‐1, P less than 0.01). These findings indicate that VCM, like valpromide, strongly inhibits epoxide hydrolase in vivo.
Studies with low dose intravenous diacid ACE inhibitor (perindoprilat) infusions in normotensive male volunteers.
Authors: MacFadyen RJ , Lees KR , Reid JL
Published: July 2012

1. Intravenous ACE inhibitor therapy is of increasing importance in the treatment of patients with unstable heart failure after myocardial infarction. Available pharmacokinetic and concentration effect data with this route of administration are limited. 2. The pharmacokinetics and blood pressure responses to perindoprilat were studied during prolonged low dose (1 mg) infusions in eight normotensive salt replete male volunteers. 3. Subjects received randomised, single (subject) blinded therapy with saline placebo (30 ml) over 3 h or active treatment (1 mg in 30 ml) over 1 h, 3 h or 6 h by constant rate infusion. 4. Significant falls in blood pressure greater than placebo were noted with active infusions without changes in heart rate. Mean maximal plasma perindoprilat concentrations reflected the rate of infusion (1 h, 51.5 +/‐ 11.4 ng ml‐1; 3 h, 30.4 +/‐ 8.4 ng ml‐1; 6 h 19.0 +/‐ 4.0 ng ml‐1) and mean maximal plasma ACE inhibition was less with slower infusions (1 h, 95.7 +/‐ 0.5%; 3 h 92.3 +/‐ 2.7%; 6 h 87.4 +/‐ 5.1%, P less than 0.013). 5. Concentration‐time profiles showed a sigmoid drug accumulation profile with delay in the early accumulation of drug particularly during the 3 h and 6 h infusions. The pharmacokinetic data was assessed by statistical comparison of a hierarchy of standard compartmental models and non linear saturable binding models. A non linear model incorporating elements to describe both tissue and plasma binding of the drug provided the best fit to observed data. 6. Low dose constant rate infusions are a means of optimising intravenous ACE inhibitor therapy to allow individual dose titration.(ABSTRACT TRUNCATED AT 250 WORDS)
The analgesic activity of morphine‐6‐glucuronide.
Authors: Osborne R , Thompson P , Joel S , Trew D , Patel N , Slevin M
Published: July 2012

1. The pharmacokinetics, cardio‐respiratory effects and analgesic effects of intravenous morphine‐6‐glucuronide were studied in 20 cancer patients with pain. Four different dose levels (0.5, 1, 2, and 4 mg 70 kg‐1) were studied. Plasma concentrations of morphine‐6‐glucuronide were measured for 12 h after dosing. Pulse rate, respiratory rate and blood pressure were monitored, and pain relief was measured using two rating scales and a visual analogue scale. 2. The mean elimination half‐ life (+/‐ s.d.) of morphine‐6‐glucuronide was 3.2 +/‐ 1.6 h. The mean AUC standardised to a dose of 1 mg 70 kg‐1 was 390 +/‐ 263 nmol l‐1 h. Mean morphine‐6‐glucuronide clearance was 96 +/‐ 38 ml min‐1. There was a direct relationship between morphine‐6‐glucuronide plasma clearance and calculated creatinine clearance (r = 0.81, P less than 0.001). 38 +/‐ 22% of the dose of morphine‐6‐glucuronide was recovered unchanged in the urine in 24 h. No morphine or morphine‐3‐glucuronide was detected in the plasma or urine of any patient after morphine‐6‐ glucuronide treatment. 3. Morphine‐6‐glucuronide exerted a useful analgesic effect in 17/19 assessable patients for periods ranging between 2 and 24 h. No correlation was observed between dose or plasma morphine‐6‐glucuronide concentrations, and duration or degree of analgesia. No clinically significant changes in cardio‐respiratory parameters were observed. No patients reported sedation or euphoria. Nausea and vomiting were notably absent in all cases. 4. Morphine‐6‐ glucuronide is an effective and well‐tolerated analgesic. It is likely that the majority of the therapeutic benefit of morphine is mediated by morphine‐6‐glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)
Drugs acting on calcium channels: potential treatment for ischaemic stroke.
Authors: Alps BJ
Published: July 2012

Calcium subserves a ubiquitous role in the organisation of cell function. Ca2+ channels which control influx may be modified in disease states. Animal models of cerebral ischaemia do present some problems when investigating potential therapies involving Ca2+ channels. However, it is important not to be too rigid in searching for models which exactly mimic the human disease state, when even the best experimental approaches fall short of such an ideal. There are differences between different classes of calcium entry blocking drugs with regard to their activity on Ca2+ channels and transmembrane Ca2+ movement. Some calcium antagonists may also affect ion channels other than Ca2+, and this potential is exemplified by the novel ion channel modulator RS‐87476, which affords experimental neurocytoprotection. Limitation of intracellular Na+ influx during ischaemia‐induced depolarization may be useful.
Flosequinan does not affect systemic and regional vascular responses to simulated orthostatic stress in healthy volunteers.
Authors: Duranteau J , Pussard E , Edouard A , Samii K , Berdeaux A , Giudicelli JF
Published: July 2012

1. The effects of a single oral dose (100 mg) of flosequinan on systemic and regional (forearm, splanchnic and renal) vascular responses to simulated orthostatic stress (lower body negative pressure, LBNP) were investigated in nine healthy male volunteers, in a double‐blind, placebo‐controlled crossover study. 2. Forty‐five minutes after its administration and before LBNP, flosequinan induced a significant decrease in total peripheral and in forearm vascular resistances without any concomitant change in arterial pressure, in heart rate and in the investigated biological parameters (plasma catecholamines, arginine vasopressin and renin activity). 3. After flosequinan and placebo, LBNP induced similar decreases in central venous pressure at all levels of LBNP (‐10, ‐20 and ‐40 mm Hg) and in pulse pressure at LBNP ‐40 mm Hg. LBNP‐induced increase in forearm vascular resistance was significantly more marked after flosequinan than after placebo at all levels of LBNP, and this was also true for splanchnic vascular resistance but at LBNP ‐40 mm Hg only. However, inasmuch as the basal values of these two parameters before LBNP were lower after flosequinan than after placebo, their final values after LBNP ‐40 mm Hg were similar. Finally, LBNP‐induced changes in renal vascular resistance, glomerular filtration rate and filtration fraction as well as in plasma catecholamines, arginine vasopressin and renin activity were similar after flosequinan and placebo at all levels of LBNP. 4. Flosequinan affected neither reflex control of heart rate (phenylephrine test) nor non‐specific vasoconstrictor responses (cold pressor test). (ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of gamma‐hydroxybutyric acid in alcohol dependent patients after single and repeated oral doses.
Authors: Ferrara SD , Zotti S , Tedeschi L , Frison G , Castagna F , Gallimberti L , Gessa GL , Palatini P
Published: July 2012

1. The pharmacokinetics of gamma‐hydroxybutyric acid (GHB) were studied in 10 alcohol dependent subjects after single and repeated therapeutic oral doses (25 mg kg‐1 every 12 h for 7 days). 2. GHB was readily absorbed and rapidly eliminated (tmax = 20‐45 min; mean t1/2z 27 +/‐ 5 s.d. min). Urinary recovery of unchanged GHB was negligible (less than 1% of the dose). gamma‐butyrolactone was not detected in either plasma or urine, indicating that lactonization of GHB does not occur in vivo. 3. The multiple‐dose regimen resulted neither in accumulation of GHB nor in time‐dependent modification of its pharmacokinetics. 4. In five subjects, the data were consistent with nonlinear elimination kinetics of GHB. Administration of a 50 mg kg‐1 dose to these subjects resulted in significant increases in dose‐normalized AUC, t1/2z and mean residence time. 5. Doubling of the dose also resulted in a significant increase in tmax with little change in Cmax. 6. At the administered doses, GHB did not accumulate in the plasma and caused no serious side effects.
The use of cimetidine to reduce dapsone‐dependent methaemoglobinaemia in dermatitis herpetiformis patients.
Authors: Coleman MD , Rhodes LE , Scott AK , Verbov JL , Friedmann PS , Breckenridge AM , Park BK
Published: July 2012

1. We have attempted to reduce dapsone‐dependent methaemoglobinaemia formation in six dermatitis herpetiformis patients stabilised on dapsone by the co‐administration of cimetidine. 2. In comparison with control, i.e. dapsone alone, methaemoglobinaemia due to dapsone fell by 27.3 +/‐ 6.7% and 26.6 +/‐ 5.6% the first and second weeks after commencement of cimetidine administration. The normally cyanotic appearance of the patient on the highest dose of dapsone (350 mg day‐ 1), underwent marked improvement. 3. There was a significant increase in the trough plasma concentration of dapsone (2.8 +/‐ 0.8 x 10(‐5)% dose ml‐1) at day 21 in the presence of cimetidine compared with control (day 7, 1.9 +/‐ 0.6 x 10(‐5)% dose ml‐1, P less than 0.01). During the period of the study, dapsone‐mediated control of the dermatitis herpetiformis in all six patients was unchanged. 4. Trough plasma concentrations of monoacetyl dapsone were significantly increased (P less than 0.05) at day 21 (1.9 +/‐ 1.0 x 10(‐5)% dose ml‐ 1) compared with day 7 (1.6 +/‐ 0.9 x 10(‐5)% dose ml‐1:control). 5. Over a 12 h period, 20.6 +/‐ 8.9% (day 0) of a dose of dapsone was detectable in urine as dapsone hydroxylamine. Significantly less dapsone hydroxylamine was recovered from urine at day 14 (15.0 +/‐ 8.4) in the presence of cimetidine, compared with day 0 (control: P less than 0.05). 6. The co‐administration of cimetidine may be of value in increasing patient tolerance to dapsone, a widely used, effective, but comparatively toxic drug.
Inhibitors of imipramine metabolism by human liver microsomes.
Authors: Skjelbo E , Brosen K
Published: July 2012

1. The aromatic 2‐hydroxylation of imipramine was studied in microsomes from three human livers. The kinetics were best described by a biphasic enzyme model. The estimated values of Vmax and Km for the high affinity site ranged from 3.2 to 5.7 nmol mg‐1 h‐1 and from 25 to 31 microM, respectively. 2. Quinidine was a potent inhibitor of the high affinity site for the 2‐hydroxylation of imipramine in microsomes from all three human livers, with apparent Ki‐values ranging from 9 to 92 nM. This finding strongly suggests that the high affinity enzyme is CYP2D6, the source of the sparteine/debrisoquine oxidation polymorphism. 3. The selective serotonin reuptake inhibitors (SSRI), paroxetine, fluoxetine and norfluoxetine were potent inhibitors of the high affinity site having apparent Ki‐values of 0.36, 0.92 and 0.33 microM, respectively. Three other SSRIs, citalopram, desmethylcitalopram and fluvoxamine, were less potent inhibitors of CYP2D6, with apparent Ki‐values of 19, 1.3 and 3.9 microM, respectively. 4. Among 20 drugs screened, fluvoxamine was the only potent inhibitor of the N‐demethylation of imipramine, with a Ki‐value of 0.14 microM. 5. Neither mephenytoin, citalopram, diazepam, omeprazole or proguanil showed any inhibition of the N‐demethylation of imipramine and the role of the S‐mephenytoin hydroxylase for this oxidative pathway could not be confirmed.
Ipratropium bromide delivered orally by metered dose inhaler does not decrease salivary flow in normal subjects.
Authors: Thomas VE , O'Connell F , Harrison AJ , Fuller RW
Published: July 2012

A randomised placebo‐controlled cross‐over group study was conducted to ascertain the occurrence and duration of xerostomia induced by 240 micrograms (high dose) and 120 micrograms (low dose) of ipratropium bromide (IPB) delivered by metered dose inhaler (MDI) into the mouth in normal subjects. Salivary output was higher with both doses of IPB than with placebo though the differences were not statistically significant. IPB was less palatable than placebo as indicated on visual analogue scale (VAS) and the taste of the drug may have caused a reflex increase in salivary output from the major salivary glands which would have masked any possible local effect of the drug on the smaller submucosal glands of the mouth. IPB delivered into the oral cavity by MDI is therefore not a suitable treatment for hypersalivation.
Ocular hypotensive effects of medifoxamine.
Authors: Saleh S , Turner P
Published: July 2012

Medifoxamine is a novel monoamine re‐uptake inhibiting antidepressive drug which preferentially inhibits dopamine reuptake. In human volunteer studies it has been found to reduce significantly intraocular pressure after single oral doses of 300‐1000 mg, and to produce a small but statistically significant miosis. Its maximal ocular hypotensive action was less than that of oral timolol 20 mg.
A comparison of gastric emptying rate after cimetidine and ranitidine measured by applied potential tomography.
Authors: Mushambi MC , Trotter TN , Barker P , Rowbotham DJ
Published: July 2012

Gastric emptying was measured using applied potential tomography (APT) after crossover administration of 800 mg cimetidine and 300 mg ranitidine orally. Ten volunteers were studied, each on two occasions. Two hours after taking ranitidine or cimetidine, the volunteer was given a liquid and gastric emptying was measured over 60 min. There was a small but statistically significant delay in gastric emptying following ranitidine compared with cimetidine (P less than 0.04). The median (range) time to 50% emptying (t50) was 24 (15‐60) min after ranitidine compared with 22 (15‐46) min after cimetidine.
Update on nitrate tolerance.
Authors: Parker JO
Published: July 2012

1. It is now recognised that nitrate therapy designed to provide effects throughout 24 h each day induces tolerance. Such tolerance may be partial or complete and is associated with diminished haemodynamic and clinical effects. 2. The mechanism of tolerance is not completely understood but it seems to be related to the depletion of reduced sulphydryl groups in vascular smooth muscle and to the activation of counter‐regulatory forces. These include elevated plasma catecholamines, arginine vasopressin and plasma renin activity. Activity of the renin‐angiotensin system is associated with sodium and water retention and plasma volume expansion. The increase in vasoconstrictor influences and augmented plasma volume could modulate the effect of nitrate‐induced vasodilatation.