bluuebunny/crossref_metadata_2025 huggingface dataset:
Comparison of quinapril and atenolol as single drugs or in combination with hydrochlorothiazide in moderate to severe hypertensives, using automated ambulatory monitoring.
Authors: Lacourciere Y. , Lefebvre J. , Provencher P. , Poirier L.
Published: July 2012

1. Forty patients with moderate to severe hypertension and daytime ambulatory diastolic blood pressure > or = 90 mm Hg were randomized double‐blind to once‐daily treatment with either quinapril up to 20 mg (n = 20) or atenolol up to 100 mg (n = 20) as single drugs or in combination with hydrochlorothiazide 25 mg over a period of 12 weeks. 2. Conventional and ambulatory blood pressure, heart rate, side effects and metabolic changes were compared at the end of the run‐in period on placebo, after 4 weeks on monotherapy and at the end of the 12‐week period of active treatment. 3. Quinapril and atenolol reduced conventional blood pressure equally with substantial additional effect seen on combination therapy. The two regimens induced a significant decrease in ambulatory BP. However, the atenolol treated ambulatory hypertensive group experienced significantly greater decreases in diastolic blood pressure during 24 h, awake and sleep periods than did the quinapril group. 4. Adverse reactions were mild with both drugs except for severe Raynaud phenomenon in one patient in the atenolol group. Triglyceride levels were significantly increased with atenolol alone and in combination with hydrochlorothiazide. 5. Thus, within the limits of the dose ranges tested, quinapril and atenolol as single drugs or in combination with hydrochlorothiazide reduce significantly conventional and ambulatory blood pressure in moderate to severe hypertensives, but atenolol is more effective in reducing ambulatory diastolic blood pressure.
Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers.
Authors: Wallen NH , Larsson PT , Broijersen A. , Andersson A. , Hjemdahl P.
Published: July 2012

1. A randomised double‐blind placebo‐controlled study was performed to investigate the effects of isosorbide dinitrate (ISDN; 20 mg orally) on various aspects of platelet function and fibrinolysis in vivo in 12 healthy volunteers. 2. Measurements were performed at rest (before and after tablet ingestion) and during platelet activation by adrenaline (0.4 nmol kg‐1 min‐1; 30 min infusion). 3. At rest, ISDN did not alter plasma concentrations of beta‐thromboglobulin (beta TG). EC50 values for ADP induced aggregation in vitro (Born aggregometry) or ex vivo filtragometry readings. Adrenaline markedly increased platelet aggregability in vivo as measured by filtragometry and elevated levels of beta TG in plasma. ISDN treatment did not affect these responses in the group as a whole. 4. Individuals responding to ISDN with more pronounced vasodilatation at rest showed a lesser increase in aggregability during the ensuing adrenaline infusion (r = ‐0.66, P = 0.02) despite higher adrenaline levels during ISDN. In individuals showing a significant decrease in systolic blood pressure (n = 8) ISDN tended to attenuate the adrenaline induced increase in platelet aggregability (filtragometry; P = 0.08), despite higher plasma adrenaline and noradrenaline levels after ISDN ingestion. 5. Plasma concentrations of ISDN and its active metabolites isosorbide‐5‐ mononitrate and isosorbide‐2‐mononitrate were not correlated to haemodynamic or platelet variables. 6. Fibrinolytic activity (t‐PA antigen and activity, PAI‐1 antigen and activity) increased similarly during the adrenaline infusion following ISDN and placebo. 7. It is concluded that ISDN may affect platelet aggregation responses to adrenaline in vivo, but only in individuals showing significant haemodynamic responses to ISDN.(ABSTRACT TRUNCATED AT 250 WORDS)
Molecular heterogeneity of the XbaI defined 44kb allele of the CYP2D locus within the Caucasian population.
Authors: Mura C. , Gerard N. , Vincent‐Viry M. , Galteau MM , Jacqz‐Aigrain E. , Krishnamoorthy R.
Published: July 2012

1. Cytochrome P450 debrisoquine (CYP2D6) activity is polymorphic and under genetic control. Most Caucasians are extensive metabolizers, but 5%‐10% are poor metabolizers. 2. Restriction fragment length polymorphism analysis of the CYP2D6 locus identifies a 29kb XbaI fragment, either normal (D6‐wt) or mutated, and three mutated XbaI alleles (44kb, 11.5kb and 16 + 9kb). The 44kb allele was initially considered as a poor metabolizer allele owing to a D6‐B mutation, but cases of 44kb allele not carrying the D6‐B, and therefore potentially functional, have been found. The degree of molecular heterogeneity of this allele was investigated by phenotype and genotype analysis of families. 3. Thirty‐one French Caucasian families, representing 117 individuals, possessing at least one 44kb allele in each family were selected. Phenotypes were determined using dextromethorphan, and the XbaI, NcoI and BamH1 RFLPs of 42 independent chromosomes were analyzed. 4. 80% of the XbaI 44kb alleles carried the CYP2D6‐B mutation and had an additional NcoI fragment (12.5kb or 4.8kb). The remaining 20% did not carry the CYP2D6‐B or A mutations and had no extra NcoI fragment. 5. Information on three families demonstrated that 44kb alleles not carrying the CYP2D6‐B mutation were associated with the extensive metabolizer phenotype. 6. We conclude that a substantial percentage of XbaI 44kb alleles is associated with a functional CYP2D gene, and therefore, that the XbaI 44kb allele is not consistently a poor metaboliser allele.
Capsaicin‐desensitization to the human nasal mucosa selectively reduces pain evoked by citric acid.
Authors: Geppetti P. , Tramontana M. , Del Bianco E. , Fusco BM
Published: July 2012

1. Kallidin (5‐500 nmol), hypertonic saline (0.9‐20% NaCl) or low pH medium (citric acid: pH 2.5‐1) applied (50 microliters) to the human nasal mucosa produced a pain response (evaluated by a visual analogue scale) that was related to the concentration of the peptide, NaCl or hydrogen ions, respectively. 2. Application (50 microliters) of capsaicin (50 nmol) to the human nasal mucosa produced overt pain. After repeated administrations (once a day for 5‐7 days) to one nostril this effect underwent almost complete desensitization, while in the contralateral nostril, treated with the vehicle, the response to capsaicin was unaffected. 3. The pain response produced in the human nasal mucosa by topical application (50 microliters) or kallidin (50‐ 500 nmol), NaCl (10‐20%) or citric acid (pH 1.5‐1) solutions was then studied before and after local capsaicin desensitization. 4. The pain response to pH 1.5 or 1 citric acid was markedly reduced (by 60% and 75%, respectively) in the capsaicin‐treated nostril. However, the pain response to 10% or 20% NaCl or the mild pain response to 50 or 500 nmol kallidin were unaffected by capsaicin pre‐treatment. 5. The present results suggest that prolonged topical capsaicin treatment to the human nasal mucosa may lead to selective desensitization to certain algesic stimuli such as capsaicin itself and hydrogen ions.
Modulation of capsaicin induced airway reflexes in humans: effect of monoamine oxidase inhibition.
Authors: Choudry NB , Studham J. , Harland D. , Fuller RW
Published: July 2012

1. In animal studies monoamine oxidase (MAO) inhibition has been shown to reduce the cough response through elevation of 5‐HT in the central nervous system. In this study the effect of selective inhibition of the two subtypes of MAO (MAO‐A and MAO‐B) was studied on human airway reflexes. 2. Capsaicin‐induced cough and reflex increase in respiratory resistance were measured in nine normal volunteers before and after MDL 72394 (MAO‐A inhibitor) 16 mg or MDL 72974A (MAO‐B inhibitor) 12 mg. 3. Neither inhibitor altered capsaicin‐induced cough. Following treatment with MDL 72394, however, the capsaicin‐induced reflex increase in resistance was enhanced, by 5.97 +/‐ 2.1 fold of the placebo value at 1 h. 4. Thus, neurotransmitters in the central nervous system which are substrate for MAO‐A (i.e. noradrenaline, 5‐HT) may be involved in the control of capsaicin‐induced reflex bronchoconstriction.
Pharmacokinetics of 2‐fluorodideoxycytidine (2FddC) in patients infected with human immunodeficiency virus.
Authors: Williams PE , Muirhead GJ , Sereni D. , Rousseau FS , Edelman K. , Hooker M.
Published: July 2012

1. The aim of this study was to estimate an oral dosage regimen of 2FddC giving peak plasma drug concentrations close to the antiretroviral IC50 of 150 ng ml‐1. 2. A total of 55 doses (40 intravenous infusions and 15 oral solutions) were given to 21 patients. One group (n = 6‐11) received single doses of 0.01 mg kg‐1 intravenously (i.v.), 0.1 mg kg‐1 i.v. and 0.1 mg kg‐1 orally (p.o.) in that order. The other group (n = 8‐10) received single doses of 0.03 mg kg‐1 i.v., 0.3 mg kg‐1 i.v. and 0.3 mg kg‐1 p.o. in that order. Blood and urine samples were collected up to 24 h after each dose for drug assay by h.p.l.c.‐u.v. 3. The peak plasma concentrations of 2FddC were proportional to dosage across the range 0.03 to 0.3 mg kg‐1. After intravenous dosing, the mean (%CV) volume of distribution was 60 (28) 1 and the mean (CV%) plasma clearance was 23 (23) 1 h‐1. On average, 71% of the dose was recovered unchanged in urine and renal clearance exceeded concurrent creatinine clearance. 4. Plasma concentrations reached mean peaks of 37 and 96 ng ml‐1 after oral doses of 0.1 and 0.3 mg kg‐1, respectively. The mean absolute bioavailability was 50% within a 95% confidence interval of 20 to 80%. 5. The adverse events were usually mild or moderate in severity and were generally attributed to the disease rather than the drug.(ABSTRACT TRUNCATED AT 250 WORDS)
A placebo controlled double‐blind evaluation of the pharmacodynamics of fengabine vs amitriptyline following single and multiple doses in elderly volunteers.
Authors: Fairweather DB , Kerr JS , Hilton S. , Hindmarch I.
Published: July 2012

1. The effects of fengabine were compared with those of amitriptyline in healthy elderly volunteers. Doses were administered double‐blind and assessments were made before and after ingestion. 2. Psychomotor performance and cognitive ability were measured using tests of choice reaction time, tracking, critical flicker fusion threshold, memory scanning and word recognition. Subjective feelings were assessed using the Leeds sleep evaluation questionnaire (LSEQ) and line analogue rating scales (LARS). 3. Pharmacokinetic data suggest that fengabine may induce its own metabolism following repeated dosing. 4. The findings of this study show that fengabine 200 mg and 400 mg does not produce any noticeable behavioural toxicity in elderly volunteers, in contrast to amitriptyline which had a disruptive effect throughout.
The reproducibility of quinine bioavailability.
Authors: Paintaud G. , Alvan G. , Ericsson O.
Published: July 2012

Plasma concentrations of quinine were measured in six healthy volunteers after a duplicate administration of 15 mg kg‐1 of quinine hydrochloride orally and the administration of 15 mg kg‐1 of quinine dihydrochloride as an infusion over 6 h. Quinine absorption rate devised by deconvolution was shown to be complete in less than 2 h. The mean (+/‐ s.d.) fraction available (F) was 0.76 (0.11) after both oral doses and maximum plasma drug concentrations occurred at 1.90 (0.83) h and 2.00 (0.30) h, respectively. The reproducibility of absorption was high, with a within‐subject coefficient of variation of less than 10% for Cmax, AUC and F. Thus, quinine absorption is extensive, fast and reproducible in healthy volunteers.
A simple collection method for saliva in children: potential for home monitoring of carbamazepine therapy.
Authors: Chee KY , Lee D. , Byron D. , Naidoo D. , Bye A.
Published: July 2012

We have developed a method of monitoring plasma concentrations of antiepileptic drugs which uses salivary samples, and is suitable for home monitoring in children. To validate the method, paired plasma and saliva samples from 39 children aged between 2 and 15 years were assayed for carbamazepine and its active metabolite, carbamazepine‐ 10,11‐epoxide by h.p.l.c. The method uses a gauze‐wrapped cotton ball with attached string, to absorb saliva which is then separated using a syringe and plunger. There was no adsorption of CBZ and CBZ‐E and they were stable over 1 month in a domestic freezer. Plasma and salivary free CBZ and CBZ‐E concentrations were highly correlated (r2 = 0.99 and 0.98, respectively).
Do diuretics cause magnesium deficiency?
Authors: Davies DL , Fraser R.
Published: July 2012

1. Controlled trials, of which there are few, do not substantiate claims that diuretics play a role in causing magnesium deficiency. Consequently, the vast majority of patients taking conventional doses of thiazide diuretics (i.e. bendrofluazide 2.5 mg day‐1 or equivalent) do not need magnesium supplements. On balance, potassium‐sparing diuretics tend to increase serum and intracellular magnesium content; this should not be taken as evidence of prior magnesium deficiency. It remains theoretically possible that large doses of loop diuretics given more than once daily for long periods could induce negative magnesium balance and magnesium deficiency. However, it has been difficult to run appropriately controlled trials in conditions where such therapy is needed (i.e. heart failure) and until more reliable information becomes available no absolute recommendation can be made. 2. Methods for the measurement of intracellular free magnesium levels are now available and are more relevant to the assessment of magnesium deficiency than total intracellular magnesium content; the complex relationship between intracellular free and total magnesium content remains to be defined. Future work involving the effect of diuretics on intracellular free magnesium measurements should make every attempt to avoid the errors of trial design and multiple publication that litter current and past literature.
The basis of the histamine assay in human skin: II. Wheal formation.
Authors: Carey C. , Clark M. , Lopez‐Gil JA , Vere DW
Published: July 2012

1. Subepidermal injection of histamine solutions in isotonic saline in four subjects evoked whealing after a mean delay of 2.6 min, this estimate being derived by regression modelling. 2. Wheal growth was better modelled by the logarithm of time than by time, suggesting that wheal size depends upon assisted diffusion of histamine in the dermis. 3. Wheal growth was piecemeal, not continuous, consistent with the successive involvement of neighbouring vascular territories. 4. Wheal growth was completed by 9 min after injection.
Effects of zolpidem on saccadic eye movements and psychomotor performance: a double‐blind, placebo controlled study in healthy volunteers.
Authors: Richens A. , Mercer AJ , Jones DM , Griffiths A. , Marshall RW
Published: July 2012

1. Peak saccade velocity provides a valuable means of assessing the sedative effect of drugs in humans. The present study investigated the effects of zolpidem, an imidazopyridine hypnotic, on saccade velocity in healthy volunteers after single and repeated administration. 2. Zolpidem 5 mg, 10 mg and 20 mg significantly and dose dependently depressed peak saccade velocity during the 1.5 h after a single administration. On the morning after zolpidem administration, peak saccade velocity had returned towards pretreatment levels. Nitrazepam 10 mg also significantly depressed peak saccade velocity but the effect was maintained the following morning. The saccade response to zolpidem (5 and 10 mg) was undiminished after the seven nightly doses. 3. Nightly administration of zolpidem improved subjective sleep quality and there was no evidence of rebound insomnia following cessation of drug treatment.
Peripheral benzodiazepine receptors in platelets of epileptic patients.
Authors: Larkin JG , McKee PJ , Thompson GG , Brodie MJ
Published: July 2012

Tolerance to the anticonvulsant effect of benzodiazepines is likely to involve changes at the central benzodiazepine‐GABA receptor complex. Peripheral benzodiazepine receptors (pBZRs), which can be measured in platelets, may also be involved. Using a binding assay with [3H]‐PK 11195 as radioligand, pBZRs were assayed in platelets of patients taking a variety of antiepileptic drugs (AEDs). Comparisons were made with untreated patients. pBZR receptor density (mean +/‐ s.e. mean) was increased vs controls (8083 +/‐ 557 fmol mg‐1 protein) in the platelets of patients taking a polypharmacy regime including the benzodiazepine clobazam (12661 +/‐ 1011 fmol mg‐1 protein, P < 0.005) and also in those receiving sodium valproate as monotherapy (15003 +/‐ 1756 fmol mg‐ 1 protein, P < 0.01). The significance of these findings is unclear, but the use of a specific pBZR antagonist may be a promising avenue for investigating the mechanism of BZ tolerance and its prevention.
The pharmacokinetics of piroxicam in elderly persons with and without renal impairment.
Authors: Rudy AC , Figueroa NL , Hall SD , Brater DC
Published: July 2012

1. Piroxicam pharmacokinetics were assessed in three groups of subjects: (1) young healthy volunteers, (2) healthy elderly subjects (mean +/‐ s.d. creatinine clearance 88 +/‐ 13 ml min‐1), and (3) elderly patients with renal insufficiency (creatinine clearance 60 +/‐ 10 ml min‐1) following the administration of piroxicam 20 mg as a single dose and after chronic dosing of 20 mg once daily for 4 weeks. 2. Piroxicam and 5'‐hydroxypiroxicam concentrations were measured by h.p.l.c. in serum and urine samples collected for 96 h after the single dose and for 144 h after chronic dosing. Unbound concentrations of piroxicam were determined by ultrafiltration. 3. Elimination half‐ lives, steady state concentrations of piroxicam and 5'‐ hydroxypiroxicam, clearances of total and unbound piroxicam, volumes of distribution normalized for body weight, and urinary recovery of 5'‐ hydroxypiroxicam were not influenced by age or renal function. Volumes of distribution after the single dose were significantly lower in women compared with men (mean +/‐ s.d. 10.0 +/‐ 2.9 l vs 12.9 +/‐ 5.0 l; 95% confidence interval of the difference 0.1 to 5.6). 4. Percent unbound piroxicam values were 1.46 +/‐ 0.3% after the single dose and 1.45 +/‐ 0.2% at steady state. There were significant reductions in clearance and clearance of unbound piroxicam between single and chronic doses. The half‐lives of 5'‐hydroxypiroxicam (80.9 +/‐ 44 h) were significantly longer than those of piroxicam (54.9 +/‐ 26 h) after chronic dosing.
An assessment of lacidipine and atenolol in mild to moderate hypertension.
Authors: Lyons D , Fowler G , Webster J , Hall ST , Petrie JC
Published: July 2012

1. The aim of this randomised, double‐blind four way crossover study was to assess the interaction between the new calcium antagonist, lacidipine and atenolol, in patients with mild to moderate hypertension. 2. Sitting blood pressure at 4 h post‐dosing with lacidipine (4 mg) and atenolol (100 mg) alone was significantly lower compared with placebo (137/89 +/‐ 3/3 mmHg; 142/89 +/‐ 5/3 mmHg; and 154/98 +/‐ 5/3 mmHg respectively; P < 0.001). Co‐administration of both drugs produced a significant additive effect compared with atenolol and lacidipine alone (124/80 +/‐ 4/2 mmHg; P < 0.002). 3. Heart rate on treatment with lacidipine alone was significantly greater at 4 h compared with placebo (86 +/‐ 1 beats min‐1 and 74 +/‐ 2 beats min‐1 respectively; P < 0.001). When both drugs were used in combination, there was a significant decrease in pulse rate compared with lacidipine alone (58 +/‐ 1 beats min‐1 and 86 +/‐ 1 beats min‐1 respectively; P < 0.001). 4. Home blood pressure recordings confirmed the statistically significant reduction in blood pressure on co‐dosing (120/82 +/‐ 10/2 mmHg) compared with lacidipine (140/92 +/‐ 5/3 mmHg) and atenolol (146/90 +/‐ 6/3 mmHg) given alone (P < 0.05). 5. Lacidipine alone produced a significant exercise tachycardia compared with atenolol alone and the atenolol/lacidipine combination (97 +/‐ 8 beats min‐1; 65 +/‐ 4 beats min‐1 and 75 +/‐ 7 beats min‐1 respectively; P < 0.001). Exercise tolerance was not adversely affected by the co‐administration of both lacidipine and atenolol.
Beta‐adrenoceptor blockers in atrial fibrillation: the importance of partial agonist activity [see comments]
Authors: Channer KS , James MA , MacConnell T , Rees JR
Published: July 2012

1. The ideal drug treatment for atrial fibrillation will control resting heart rate, blunt exercise induced tachycardia whilst not exacerbating nocturnal bradycardia. Monotherapy with digoxin may not be ideal. We have compared the effect of combining digoxin (0.25 mg daily) with atenolol 50 mg and 100 mg or pindolol 5 mg twice daily and 15 mg twice daily in a cross‐over randomised single‐blind trial in eight symptomatic patients (six male; mean age 62 years) with poorly controlled atrial fibrillation. 2. Heart rate control was measured by 24 h ECG at baseline on digoxin therapy and after 2 weeks with each treatment. Symptom scores for breathlessness and palpitation were measured using visual analogue scales. 3. The addition of both beta‐ adrenoceptor blockers significantly reduced mean diurnal maximum heart rate from baseline (all P < 0.001 ANOVA). Atenolol at both doses caused a greater reduction than either dose of pindolol (P < 0.001 ANOVA). Nocturnal maximum heart rate was not significantly reduced from baseline by either beta‐adrenoceptor blocker, but both doses of pindolol caused increases in nocturnal maximum heart rate compared with atenolol (P < 0.001 ANOVA). 4. Atenolol caused a reduction in diurnal minimum heart rate compared with baseline and caused a reduction in nocturnal minimum heart rate whereas pindolol caused an increase (P < 0.001 ANOVA). 5. Atenolol 100 mg caused longer nocturnal pauses compared with baseline but pindolol 15 mg twice daily reduced the number of nocturnal pauses > 1.5 s (P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of ACE inhibitors on oxidation of human low density lipoprotein.
Authors: Godfrey EG , Stewart J , Dargie HJ , Reid JL , Dominiczak M , Hamilton CA , McMurray J
Published: July 2012

Oxidation of low density lipoprotein (LDL) may be instrumental in the development of atherosclerosis. We have examined the effect of the angiotensin converting enzyme (ACE) inhibitors captopril and quinaprilat and the ‐SH containing compound N‐acetylcysteine on LDL oxidation. Oxidation of isolated human LDL was initiated with CuCl2. Conjugated diene formation (monitored spectrophotometrically at 234 nm) gave a measure of LDL oxidation. Captopril inhibited LDL oxidation but quinaprilat did not. The lag phase to the rapid increase in absorbance at 234 nm determined was 109 (65‐157) min median and range for control samples and rose to 209 (168‐305) min with captopril 10 microM, a ratio of 2.1:1 for drug to control (P = 0.01). N‐acetylcysteine had a similar effect to captopril (drug to control lag time ratio 2.0:1, with NAC 10 microM), i.e. suggesting resistance to oxidation was due to the ‐SH group of both drugs. Captopril may have a potentially anti‐ atherosclerotic property not shared by other ACE inhibitors.
Oxidative activation of proguanil and dapsone acetylation in Thai soldiers.
Authors: Edstein MD , Shanks GD , Teja‐Isavadharm P , Rieckmann KH , Webster HK
Published: July 2012

The prevalence of putative poor metaboliser (PM) phenotypes of proguanil oxidation in Caucasian populations is 3‐10%. The PM frequency in Oriental populations is unknown. In this study the plasma metabolic ratios of proguanil and dapsone to their principal metabolites cycloguanil and monoacetyldapsone were determined in Thai soldiers receiving antifolate drug combinations for malaria prophylaxis. The distribution ratio of proguanil to cycloguanil (PROG/CYC) was highly skewed with no evidence of bimodality. Assuming subjects with a PROG/CYC ratio greater than 10 are PMs from studies in Caucasians, the incidence of PMs in the soldiers would be 18% (30 of 170). The mean PROG/CYC ratio for PMs in the Thai soldiers was 31.2 +/‐ 28.9 (n = 30) compared with 25.5 +/‐ 2.5 (n = 3) in a study of Caucasians. The corresponding values for putative EMs were 5.4 +/‐ 2.1 (n = 140) and 2.4 +/‐ 0.2 (n = 134). Similar to other Oriental populations, Thais were found to be predominantly (76%, 173 of 228) rapid acetylators of dapsone.
The pharmacokinetics of ketorolac enantiomers following intramuscular administration of the racemate.
Authors: Hayball PJ , Wrobel J , Tamblyn JG , Nation RL
Published: July 2012

A single dose of racemic ketorolac (30 mg of tromethamine salt, Toradol) was administered by bolus intramuscular injection to four young, healthy volunteers. The concentrations of total (bound plus unbound) (R)‐ and (S)‐ketorolac were measured in plasma for 9 h after dosing. The mean +/‐ s.d. clearance of (S)‐ketorolac (45.9 +/‐ 10.1 ml h‐1 kg‐1) exceeded (P = 0.0032) that of the (R)‐enantiomer (19.0 +/‐ 5.0 ml h‐1 kg‐1). The mean +/‐ s.d. AUC ratio for (S)‐ketorolac:(R)‐ ketorolac (0.442 +/‐ 0.043) was significantly different from unity (P = 0.0001). The steady‐state volume of distribution of (S)‐ketorolac (0.135 +/‐ 0.022 l kg‐1) was significantly different (P = 0.0013) from that of its optical antipode (0.075 +/‐ 0.014 l kg‐1) and the half‐ lives of (S)‐ and (R)‐ketorolac (2.35 +/‐ 0.23 h and 3.62 +/‐ 0.79 h, respectively) were also significantly different (P = 0.026). These data indicate that the disposition of ketorolac in man is subject to marked enantioselectivity and, because of possible differences in biological activity of (S)‐ and (R)‐ketorolac, emphasize the need to monitor separate stereoisomer concentrations of the drug if pharmacological data are to be interpreted correctly.
Neither cimetidine nor probenecid affect the pharmacokinetics of tenoxicam in normal volunteers.
Authors: Day RO , Geisslinger G , Paull P , Williams KM
Published: July 2012

The effect of pretreatment with cimetidine (1 g day‐1, 7 days) and of probenecid (1 g twice daily, 4 days) on the pharmacokinetics of tenoxicam (single oral dose, 20 mg) was studied in six healthy volunteers. Cmax was increased significantly when tenoxicam was given with probenecid (2.8 micrograms ml‐1 alone, 3.5 micrograms ml‐1 after probenecid; P < 0.005). No other pharmacokinetic parameters were altered significantly by either drug. It is concluded that neither cimetidine nor probenecid affects the pharmacokinetics of tenoxicam in a clinically important way.
The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin.
Authors: Lehto P , Kivisto KT , Neuvonen PJ
Published: July 2012

The effect of ferrous sulphate on the absorption of norfloxacin, ciprofloxacin and ofloxacin was studied in three separate, two‐period crossover trials, each involving eight healthy volunteers. After an overnight fast, a single dose of norfloxacin (400 mg), ciprofloxacin (500 mg) or ofloxacin (400 mg) was administered with and without ferrous sulphate (corresponding to 100 mg elemental iron). The absorption of all the fluoroquinolones studied was significantly reduced when they were co‐administered with ferrous sulphate. The reduction in the area under the plasma drug concentration‐time curve from 0 to 24 h was most marked in the case of norfloxacin, while ofloxacin was least affected by ferrous sulphate. The AUC of norfloxacin was reduced by 73% (P < 0.001) and its peak plasma concentration by 75% (P < 0.01) by concomitant ingestion of ferrous sulphate. The AUC and peak plasma concentration of ciprofloxacin were reduced by 57% (P < 0.001) and 54% (P < 0.01), respectively, by ferrous sulphate. Concomitant ingestion of ferrous sulphate reduced the AUC and peak plasma concentration of ofloxacin by 25% (P < 0.01) and 36% (P < 0.01), respectively. Similar results were obtained with respect to the urinary recoveries of each fluoroquinolone. We recommend that norfloxacin and ciprofloxacin should not be taken together with ferrous sulphate. It would also be advisable not to take ofloxacin with ferrous sulphate, especially if the organism causing infection is only moderately susceptible.
Plasma concentrations of betamethasone after topical application of betamethasone 17‐valerate: comparison with oral administration.
Authors: Kubota K , Lo ES , Huttinot G , Andersen PH , Maibach HI
Published: July 2012

Plasma concentrations of betamethasone were measured by r.i.a. after oral administration of 0.6 mg betamethasone and topical application of betamethasone 17‐valerate in the same five healthy subjects. Betamethasone 17‐valerate was prepared as a suspension in medical grade pressure sensitive adhesive and applied to a 100 cm2 area on the back for 28 h. Mean maximum plasma concentrations were 5.0 and 0.24 ng ml‐1 and mean AUC values were 75.4 and 7.74 ng ml‐1 h after oral and topical administrations, respectively. The mean plasma elimination half‐life of betamethasone after the removal of topical betamethasone 17‐valerate was 16.6 h which was twice that after oral administration, 8.1 h. Betamethasone 17‐valerate may require application to the skin more than twice daily.
Blood concentrations of dopexamine in patients during and after orthotopic liver transplantation.
Authors: Gray PA , Jones T , Park GR
Published: July 2012

Blood concentrations of dopexamine were measured in five female patients during and after orthotopic liver transplantation. Each patient received a continuous infusion of the drug (2 micrograms kg‐1 min‐1), starting at induction of anaesthesia and finishing 48 h afterwards. Blood concentrations of dopexamine increased rapidly at the start of the infusion, to a mean (range) value of 64 (40‐150) ng ml‐1 after 20 min. Blood concentrations of dopexamine increased further during the anhepatic period of surgery, to 236 (180‐410) ng ml‐1. On reperfusion of the donor liver, concentrations of dopexamine decreased rapidly, reaching similar values to the maximum seen during the dissection period. Steady‐state was not reached during either the dissection or anhepatic periods. From 1‐2 h after revascularisation the mean (range) steady‐state concentration was 85 (69‐102) ng ml‐1 corresponding to a mean (range) clearance of 24 (20‐29) ml min‐1 kg ‐1. These results suggest that the liver plays a significant role in the clearance of dopexamine.
Pharmacokinetic study of yohimbine and its pharmacodynamic effects on salivary secretion in patients treated with tricyclic antidepressants.
Authors: Bagheri H , Picault P , Schmitt L , Houin G , Berlan M , Montastruc JL
Published: July 2012

The pharmacokinetic parameters and the time course of the effect after acute oral administration of yohimbine on salivary secretion in patients treated with tricyclic antidepressants were investigated. Yohimbine (10 mg) increased both salivary outflow and plasma noradrenaline levels for 4 h. Pharmacokinetic parameters (t1/2, tmax, Cmax and AUCexp) and plasma concentrations of noradrenaline were higher in patients treated with tricyclic antidepressants than in controls. At this dose, yohimbine induced a relatively large number of side effects. A lower dose (4 mg) increased salivary secretion for 3 h without any side effects in patients treated with tricyclic antidepressants but not in healthy volunteers. These data describe an interaction between yohimbine and tricyclic antidepressants and thus show that a relatively low dose (4 mg) of yohimbine could be useful in the treatment of dry mouth due to tricyclic antidepressants.
Pharmacokinetic and ‐dynamic studies with a new anxiolytic, suriclone, utilizing EEG mapping and psychometry.
Authors: Saletu B , Grunberger J , Linzmayer L , Semlitsch HV , Anderer P , Chwatal K
Published: July 2012

1. In a double‐blind, placebo‐controlled, cross‐over study, acute pharmacokinetic, neurophysiological and psychotropic effects of suriclone, a new cyclopyrrolone derivative, were investigated and compared with alprazolam. 2. Fifteen normal young volunteers received randomized oral single doses of placebo, 0.1, 0.2 and 0.4 mg suriclone as well as 1 mg alprazolam as reference compound. Investigations were carried out before and 1, 2, 4, 6 and 8 h after drug administration. 3. Pharmacokinetic investigations by radioimmunoassay showed a dose‐ dependent fast rise of plasma concentrations with a peak at 1 h and a rapid decline thereafter. Both the Cmax and the AUC values exhibited a linear relationship to dose. 4. EEG brain mapping demonstrated significant CNS effects of both compounds, characteristic for tranquillizers (increase of beta, decrease of alpha and increase of delta activity; attenuation of total power and acceleration of the centroid, i.e. centre of gravity frequency). When compared with alprazolam, suriclone exerted less sedative effects. 5. Time‐efficacy calculations showed the pharmacodynamic peak effect of suriclone from the 2nd to the 4th hour, and of alprazolam in the 1st hour. Dose‐ efficacy calculations showed that the most pronounced CNS changes occurred after 1 mg alprazolam, followed by 0.4, 0.2 and 0.1 mg suriclone. 6. Psychometric investigations demonstrated no significant effects after the two lower doses of suriclone, while 0.4 mg and 1 mg alprazolam induced a decrement both in noopsychic and thymopsychic variables seen after higher doses of anxiolytic sedatives. Psychophysiology (critical flicker fusion, pupillometry, and skin conductance measures) pulse rate, systolic and diastolic blood pressure remained unchanged. 7. Psychophysiology (critical flicker fusion, pupillometry and skin conductance measures) showed differential dose‐ dependent effects. Pulse rate, systolic and diastolic blood pressure remained unchanged. Anxiolytic‐characteristic side‐effects (tiredness, drowsiness, etc.) occurred predominantly after the highest doses 0.4 mg suriclone and 1 mg alprazolam.
EEG profile of litoxetine after single and repeated administration in healthy volunteers.
Authors: Patat A , Trocherie S , Thebault JJ , Rosenzweig P , Dubruc C , Bianchetti G , Morselli PL , Court LA
Published: July 2012

1. Litoxetine is a selective serotonin reuptake inhibitor with antidepressant activity in animal models and in depressed patients. 2. This double‐blind, cross‐over, placebo‐controlled study was carried out in 12 healthy young male volunteers. The aim was to assess the EEG profile of litoxetine in parallel with its pharmacokinetics after a single dose or multiple administrations for 4 days (6 doses) of two dosages (10 mg and 25 mg). Spectral analysis of four EEG leads (F4‐T4, F3‐T3, T4‐02 and T3‐01) was done up to 12 h post‐dose. 3. In single or multiple doses, litoxetine induced EEG changes characterised by a dose‐ related increase in fast beta energies, mainly beta 2, without any changes in slow waves (delta and theta). A slight reduction in alpha activity occurred only after repeated doses. 4. EEG changes occurred after a single oral administration and lasted at least 12 h with litoxetine blood concentrations ranging from 4 to 10 ng ml‐1. With repeated administrations, the pharmacodynamic steady‐state was achieved as the increase in beta 2 energies was the same before and 12 h post‐ dose. These effects occurred with litoxetine blood concentrations ranging from 3 to 7 ng ml‐1 with the 10 mg dosage and from 8 to 18 ng ml‐1 with the 25 mg dosage. The EEG profile did not change after 4 days of repeated administration, indicating that tolerance did not develop. 5. Cmax and AUC showed proportionality between the administered dosages of 10 and 25 mg.(ABSTRACT TRUNCATED AT 250 WORDS)
Psychomotor performance and antihypertensive treatment.
Authors: Kalra L , Swift CG , Jackson SH
Published: July 2012

1. The aim of treatment of hypertension is prevention of cardiovascular complications without adverse drug reactions. Psychomotor performance can be measured objectively yet there remains uncertainty concerning the psychomotor effects of antihypertensive drugs during chronic treatment. This uncertainty is partly due to the confounding adverse effects of cerebrovascular disease and hypertension itself. There are as yet insufficient good quality data on psychomotor effects with which to differentiate between the commonly used agents. However, in general, the beneficial effect of lowering blood pressure tends to more than offset any adverse effects of the agent used.
The effect of anticholinergic bronchodilator therapy on cough during upper respiratory tract infections.
Authors: Lowry R , Wood A , Higenbottam T
Published: July 2012

1. Oxitropium bromide (Oxivent), an anticholinergic bronchodilator, inhibits coughing induced by hypotonic aerosols in both asthmatic and non‐asthmatic individuals. We have now extended this work to investigate whether this antitussive activity is reproducible in cough associated with viral infection. 2. The effect of oxitropium bromide (200 micrograms three times daily) on cough and pulmonary function has been studied in 56 non‐asthmatic volunteers with upper respiratory tract infections (URTI) in a double‐blind, randomised, parallel group, placebo controlled study over 10 days. 3. Lung function, symptom questionnaire and cough response to ultrasonically nebulised distilled water (UNDW) inhalation were initially recorded within 72 h of development of cough and again after the 10 day treatment period. By use of a diary card at home, frequency and severity of cough, nocturnal symptoms and general malaise were assessed daily throughout the treatment period using 5 cm visual analogue scales (VAS). Peak expiratory flow rate (PEFR) was recorded thrice daily before treatment over this 10 day period. 4. VAS scores of symptoms and UNDW‐induced cough frequency all decreased over the 10 days of observation whether oxitropium bromide or placebo was administered. The mean PEFR showed a statistically significant fall in morning values during the early stages of infection which lessened with recovery but no effect of treatment with oxitropium bromide was observed (P > 0.05). 5. Oxitropium bromide, which inhibits the cough response to UNDW, does not offer an effective therapy for cough associated with an upper respiratory tract viral infection.
The renal clearance of cefuroxime and ceftazidime and the effect of probenecid on their tubular excretion.
Authors: Verhagen CA , Mattie H , Van Strijen E
Published: July 2012

1. The renal tubular excretion of cefuroxime and ceftazidime in relation to the coadministration of probenecid was investigated in eight and two healthy subjects, respectively. 2. Cefuroxime or ceftazidime were administered by i.v. infusion and 1 g probenecid was administered orally after steady state plasma concentrations of the cephalosporin were reached. 3. In a second session the same antibiotic was administered at increasing infusion rates such that three different levels of plasma drug concentration were achieved. 4. The renal clearance of antibiotic was calculated based upon unbound plasma concentration, and tubular clearance was estimated by subtracting inulin clearance from the renal clearance of the antibiotic. 5. Non‐ linear regression analysis was used to estimate parameters describing the saturability of tubular excretion and the effect of probenecid inhibition, i.e. EC50 and Rtub, max, could be established for cefuroxime: EC50 was 248 (s.d. 130) mg l‐1 and Rtub, max was 1.852 (s.d. 0.577) mg h‐1. Tubular excretion of ceftazidime was practically zero. The EC50 of probenecid for inhibition of the tubular excretion of cefuroxime was 0.80 (s.d. 0.31) mg l‐1. 6. The results indicate that in the therapeutic plasma concentration range of cefuroxime its renal clearance is not saturated. Probenecid at therapeutic doses will block tubular excretion of cefuroxime almost completely.
Inhibition of gastric alcohol dehydrogenase activity by histamine H2‐ receptor antagonists has no influence on the pharmacokinetics of ethanol after a moderate dose.
Authors: Mallat A , Roudot‐Thoraval F , Bergmann JF , Trout H , Simonneau G , Dutreuil C , Blanc LE , Dhumeaux D , Delchier JC
Published: July 2012

Ethanol undergoes gastric first pass metabolism by alcohol dehydrogenase (ADH). We have shown that cimetidine and famotidine both cause competitive inhibition of human gastric ADH in vitro. However, in a randomized 4‐way cross‐over study in 12 healthy subjects a 7‐day course of treatment with cimetidine (800 mg day‐1), ranitidine (300 mg day‐1) or famotidine (40 mg day‐1), did not modify the pharmacokinetics of ethanol given as a post‐prandial 0.3 g kg‐1 dose. We conclude that gastric mucosal concentrations of histamine H2‐receptor blockers achieved after oral dosing are probably too low to cause significant inhibition of gastric ADH in vivo.
The role of S‐mephenytoin 4'‐hydroxylase in imipramine metabolism by human liver microsomes: a two‐enzyme kinetic analysis of N‐ demethylation and 2‐hydroxylation.
Authors: Chiba K , Saitoh A , Koyama E , Tani M , Hayashi M , Ishizaki T
Published: July 2012

1. The metabolism of imipramine (N‐demethylation and 2‐hydroxylation) was studied in relation to the activity of S‐mephenytoin 4'‐hydroxylase in human liver microsomes. 2. Eadie‐Hofstee plots for the formation of despiramine and 2‐hydroxyimipramine were biphasic, suggesting that at least two enzymes are involved in both the N‐demethylation and 2‐ hydroxylation of imipramine by human liver microsomes. 3. The respective mean (+/‐ s.d.) kinetic parameters for the N‐demethylation and 2‐hydroxylation of imipramine derived from a two‐enzyme kinetic analysis were: Km1 = 1.1 +/‐ 0.4 and 1.6 +/‐ 0.6 microM, Vmax1 = 0.11 +/‐ 0.03 and 0.15 +/‐ 0.07 nmol mg‐1 min‐1, and Vmax1/Km1 = 0.10 +/‐ 0.02 and 0.09 +/‐ 0.04 ml mg‐1 min‐1; Km2 = 214 +/‐ 84 and 257 +/‐ 148 microM, Vmax2 = 2.22 +/‐ 0.69 and 0.53 +/‐ 0.15 nmol mg‐1 min‐1, and Vmax2/Km2 = 0.011 +/‐ 0.001 and 0.003 +/‐ 0.002 ml mg‐1 min‐1. 4. With regard to imipramine N‐demethylation and 2‐hydroxylation at 2 microM (representing high‐affinity reactions) and at 400 microM (representing low‐affinity reactions), only N‐demethylation at 2 microM showed a close correlation with the 4'‐hydroxylation of S‐mephenytoin (rs = 0.952, P < 0.01; n = 10 livers). 5. Concentrations up to 250 microM S‐ mephenytoin inhibited the N‐demethylation of imipramine (2 microM), but no further inhibition was observed using concentrations from 250 to 750 microM. 6. Imipramine inhibited S‐mephenytoin 4'‐hydroxylation competitively with a Ki value of 12.5 microM.(ABSTRACT TRUNCATED AT 250 WORDS)
Multicentre hospital drug utilization study on the prophylaxis of venous thromboembolism. The Venous Thromboembolism Study Group of the Spanish Society of Clinical Pharmacology.
Authors: Valles JA , Vallano A , Torres F , Arnau JM , Laporte JR
Published: July 2012

1. Thromboembolic disease (TED) is an important cause of in‐hospital morbidity and mortality. Although different prophylactic approaches have been shown to be effective and cost‐effective, surveys have suggested that they are underused. The aim of this study was to estimate the prevalence of use of TED prophylaxis in our hospitals. 2. All patients admitted on a specified day to the Internal Medicine and General Surgery wards of seven Spanish university hospitals were included in the study. They were identified cross‐sectionally and followed up until discharge or for 15 days. Information about the following variables was collected: risk factors for venous thromboembolism, prophylactic measures used (if any), contraindications to the use of each specific drug or other prophylactic measure, and dosage schedule of the drug used, if any. 3. Nine hundred and thirty‐ nine patients (53% men) were studied. The most common risk factors for venous thromboembolism were: age > or = 40 years (802; 85%), major surgery (298; 32%), immobilization > or = 6 days (285; 30%), obesity (241; 26%), and cancer (202; 22%). 4. Prophylactic measures were used in 320 patients (34%). Of these, 297 (93%) received heparin, mainly as low molecular weight heparins (248, 78%); physical measures were rarely used. 5. Five hundred and eighty‐three patients (62%) fulfilled criteria for moderate or high risk of venous thromboembolism; only 275 (47%) of them received any form of prophylaxis.(ABSTRACT TRUNCATED AT 250 WORDS)
Cefpiramide kinetics and plasma protein binding in cholestasis.
Authors: Demontes‐Mainard F , Vincon G , Labat L , Amouretti M , Necciari J , Kieffer G , Bannwarth B
Published: July 2012

Cefpiramide is a new parenteral cephalosporin mainly excreted in the bile. Eight patients with cholestasis and 11 healthy subjects received a single 1 g i.v. dose. Cefpiramide concentrations in plasma and urine were measured by h.p.l.c. and plasma binding was determined by ultrafiltration. Total clearance of cefpiramide (mean +/‐ s.d.) was 15.5 +/‐ 7.1 ml min‐1 in patients and 25.6 +/‐ 4.6 ml min‐1 in healthy subjects. As a result, the terminal elimination half‐life was longer in patients (12.0 +/‐ 2.9 h vs 5.3 +/‐ 0.9 h). Owing to impaired biliary elimination of cefpiramide in cholestasis, the urinary recovery of unchanged drug in patients was about five times greater than in healthy subjects (85.1 +/‐ 10.3% vs 16.2 +/‐ 3.9%). Plasma binding was significantly lower in cholestasis (fu = 0.23 +/‐ 0.13 vs 0.02 +/‐ 0.004 in healthy subjects). Accordingly, the dosage regimen of cefpiramide should be modified in patients with cholestasis.
The effect of physiological manoeuvres on the absorption of inhaled nedocromil sodium.
Authors: Ghosh SK , Neale MG , Patel KR
Published: July 2012

In a previous study we showed, in both asthmatic patients and in healthy subjects, a marked increase in plasma concentration of nedocromil immediately following an exercise challenge with associated FEV1 measurements. To identify which component of the exercise challenge is responsible, we have now studied the effect of various manoeuvres on plasma nedocromil concentration in eight healthy subjects after inhalation of 1 ml nedocromil solution (1% w/v) via a Wright nebuliser. Each patient was dosed on six occasions, separated by at least 3 days. Between 15 and 23 min after dosing one of the following manoeuvres was performed: control (no manoeuvre); steady exercise for 8 min, a series of FEV1 measurements, exercise plus FEV1 measurements, three Valsalva manoeuvres and hyperventilation for 3 min. Mean plasma drug concentrations under control conditions were similar at 15 and 23 min after dosing. However, there were significant increases in plasma drug concentration following exercise, FEV1 manoeuvres and exercise plus FEV1 manoeuvre. There were no significant changes in plasma drug concentration following Valsalva manoeuvres and hyperventilation. The results suggest that certain manoeuvres increase the absorption of nedocromil sodium, probably as a consequence of an increase in lung volume.
Effects on platelet functions and pharmacokinetics of azapropazone and ketorolac tromethamine given as single parenteral doses.
Authors: Pallapies D , Peskar BA , Brune K , Geisslinger G
Published: July 2012

The biosynthesis of thromboxane (TX) B2 and immunoreactive prostaglandin (PG) F2 alpha in clotting whole blood ex vivo as well as collagen‐induced platelet aggregation were determined before and up to 72 h after intravenous injection of 600 mg azapropazone 2H2O and intramuscular injection of 30 mg ketorolac tromethamine in six healthy subjects. The drug doses were selected on the basis of comparable analgesic activity (maximal recommended analgesic dose). Both platelet aggregation and prostanoid biosynthesis were inhibited by racketorolac to a significantly greater extent and for a longer period of time than by azapropazone. Correlations between serum concentrations and the inhibitory effects on TXB2 biosynthesis were observed for both drugs. Using the sigmoidal Emax model the mean serum concentration of azapropazone inhibiting platelet TXB2 generation by 50% (EC50) was found to be 98.1 +/‐ 41.9 (s.d.) micrograms ml‐1, a value 1000 times higher than that for rac‐ketorolac. The moderate inhibition of platelet function by azapropazone as compared with rac‐ketorolac might be an advantage with regard to its use as a post‐operative analgesic.