bluuebunny/crossref_metadata_2025 huggingface dataset:
Is cyclosporin A an inhibitor of drug metabolism?
Authors: Li G , Treiber G , Meinshausen J , Wolf J , Werringloer J , Klotz U
Published: July 2012

1. The potential for a drug interaction between cyclosporin A and midazolam was investigated since both compounds appear to be metabolized by the same cytochrome P‐450 isoenzyme. 2. In vitro evaluation of the binding of cyclosporin A to rat microsomal cytochrome P‐450 indicated a Ks‐value of 0.4 microM. In further studies with rat liver microsomes IC50‐values of 6, 8 and 70 microM cyclosporin A were determined for the inhibition of the metabolism of midazolam to its alpha‐OH‐,4‐OH‐ and di‐OH‐metabolites, respectively. 3. Comparative studies with human liver microsomes indicated IC50‐values of approximately 300 microM for the formation of alpha‐OH‐midazolam and of 65 microM for the formation of 4‐OH‐midazolam. 4. The pharmacokinetics of a single intravenous dose of midazolam (0.075 mg kg‐1) was studied in nine patients receiving cyclosporin A to prevent rejection of their transplanted kidneys. The average steady state blood concentrations of cyclosporin A, measured by r.i.a. using a specific monoclonal antibody, varied during a dosing interval between 175 and 600 ng ml‐1. 5. In these patients the hepatic elimination of midazolam was characterized by a mean t1/2 (+/− s.d.) of 2.3 +/− 1.2 h and a plasma clearance (CL) of 414 +/− 95 ml min‐1. These values were not different from those of normal human subjects (t1/2 = 1.5 to 4 h, CL = 350 to 700 ml min‐1). 6. From the results of the in vitro experiments it is concluded that cyclosporin A may potentially inhibit drug metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)
Mefloquine antimalarial prophylaxis in pregnancy: dose finding and pharmacokinetic study.
Authors: Nosten F , Karbwang J , White NJ , Honeymoon  , Bangchang K Na , Bunnag D , Harinasuta T
Published: July 2012

1. A dose finding pharmacokinetic study was performed in 20 Karen women in the third trimester of pregnancy receiving antimalarial prophylaxis with mefloquine. Ten received 250 mg mefloquine base weekly and ten received identical tablets of 125 mg base/week. 2. Both dose regimens were well tolerated. Malaria was prevented effectively, there were no serious adverse effects, all pregnancies proceeded normally, and there were no abnormalities in the babies followed up to 2 years. 3. The median time from dose administration to peak whole blood mefloquine concentration was 6 (range 3‐24) h. Mean (+/− s.d.) peak and trough concentrations in the seventh week were 722 +/− 279 and 488 +/− 155 ng ml‐1 with the 250 mg/week dose, and 390 +/− 81 and 185 +/− 53 ng ml‐1 with the 125 mg/week dose regimens respectively. These blood concentration values are lower than those reported previously in non‐ pregnant adults. 4. One and two compartmental models were fitted to the whole blood concentration‐time data. Mean (+/− s.d.) clearance (CL/F) was 0.78 +/− 0.27 ml min‐1 kg‐1, and the apparent terminal elimination half‐life (t1/2) was 11.6 +/− 7.9 days. 5. Further studies to determine the oral bioavailability of mefloquine are needed, but these results suggest that clearance may be increased in late pregnancy. These preliminary results of good efficacy without significant toxicity are encouraging, and a more extensive evaluation of mefloquine antimalarial prophylaxis in pregnancy is now warranted.
A dose‐ranging study to evaluate the beta‐adrenoceptor selectivity of single doses of betaxolol.
Authors: Irvine NA , Lipworth BJ , McDevitt DG
Published: July 2012

1. Six normal subjects were given single oral doses of betaxolol 10 mg (B10), 20 mg (B20), 40 mg (B40), 80 mg (B80), propranolol 40 mg (P40), or placebo (PL) in a single‐blind randomised cross‐over design. 2. beta 1‐adrenoceptor blockade was assessed by reductions in exercise heart rate. Betaxolol produced dose‐related reductions in exercise heart rate (beats min‐1) up to a ceiling at B40, after which B80 showed a lesser effect: (158 +/− 8 PL, 128 +/− 3 B10, 123 +/− 2 B20, 116 +/− 4 B40, 136 +/− 10 B80, 135 +/− 4 P40). All doses of betaxolol (except B80) produced greater reductions compared with P40: (B10 P less than 0.001, B20 P less than 0.005, B40 P less than 0.001). 3. beta 2‐adrenoceptor blockade was assessed by attenuation of finger tremor and cardiovascular responses to graded infusions of i.v. isoprenaline. Dose‐ response curves were constructed and the doses required to increase heart rate by 25 beats min‐1, finger tremor by 200%, calf blood flow by 0.5 ml dl‐1 min‐1, and decrease diastolic blood pressure by 10 mm Hg, after each treatment were calculated. These were then compared with placebo responses and expressed as dose‐ratios. 4. Dose‐ratios for finger tremor showed significant attenuation by all doses of betaxolol (compared with PL): B10 1.5 +/− 0.18 (P less than 0.05), B20 2.62 +/− 0.45 (P less than 0.005), B40 2.55 +/− 0.33 (P less than 0.001), B80 2.48 +/− 0.48 (P less than 0.01); and by P40 6.49 +/− 1.12 (P less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)
Comparative beta‐adrenoceptor blocking effects of propranolol, bisoprolol, atenolol, acebutolol and diacetolol on the human isolated bronchus.
Authors: Naline E , Sarria B , Ertzbischoff O , Ozanne P , Advenier C
Published: July 2012

Five beta‐adrenoceptor blockers, propranolol, acebutolol, diacebutolol, atenolol and bisoprolol, were tested for their antagonistic effect against isoprenaline on human isolated bronchi. The results showed (1) that only propranolol exerted a competitive antagonistic effect against isoprenaline (pA2 = 9.40 +/− 0.22, n = 7) whereas the other drugs did not, and (2) that, in the presence of beta‐adrenoceptor blockers in the plasma concentrations reported after a single usual therapeutic dose, the doses of isoprenaline giving the same bronchodilator effect must be multiplied by 32.6, 5.51, 4.63, 2.82 and 1.95 respectively with propranolol, diacetolol, acebutolol, atenolol, and bisoprolol. It was concluded that (1) atenolol and bisoprolol were the least potent drugs at bronchial level in therapeutic plasma concentrations and (2) that tests performed on the human isolated bronchus might be a useful screening procedure for new drugs with potential activity on the airways.
Pharmacokinetics of propofol when given by intravenous infusion.
Authors: Morgan DJ , Campbell GA , Crankshaw DP
Published: July 2012

We have previously shown with i.v. bolus studies that the elimination of propofol is much slower than previously reported. Now we have studied the implications of this for prolonged i.v. infusion of propofol in seven patients who received continuous infusions of propofol for up to 9 h. Values of elimination half‐life ranged from 13.1 to 44.7 h, systemic clearance from 1.02 to 1.63 l h‐1 and volume of distribution from 1390 to 3940 l and these were similar to those obtained with bolus administration. The large volume of distribution is consistent with the high octanol/blood partition coefficient, which was found to be 72.0. Despite the very long elimination half‐life, blood propofol concentrations appeared to approach steady state within 20 min rather than the 4‐5 half‐lives normally expected. This is because for this drug, which displays multicompartment pharmacokinetics, the rate of initial rise of blood concentrations is governed primarily by the very short distribution half‐life of the drug. Therefore, the long elimination half‐life of propofol is probably of little significance in designing infusions regimens, but the lower systemic clearance should be taken into account to avoid unwanted accumulation.
A mechanism of D‐(+)‐sotalol effects on heart rate not related to beta‐ adrenoceptor antagonism.
Authors: Funk‐Brentano C , Silberstein DJ , Roden DM , Wood AJ , Woosley RL
Published: July 2012

1. In order to determine whether the effects of d‐ or (+)‐sotalol on heart rate are mediated by beta‐adrenoceptor antagonism or might be due to other actions, we administered (+)‐sotalol (400 mg every 12 h), atenolol (50 mg every 12 h) and placebo to eight healthy volunteers in a randomized, double‐blind, crossover study. We also studied the affinity of human lymphocyte beta 2‐adrenoceptor for (+)‐sotalol, (‐)‐ sotalol, and (+/−)‐propranolol. 2. Compared with placebo, atenolol significantly reduced resting, standing and peak exercise heart rate whereas (+)‐sotalol significantly reduced standing and peak exercise heart rate, but not resting heart rate. Atenolol significantly reduced resting, standing and peak exercise blood pressure while (+)‐sotalol had no effect. 3. (+)‐sotalol and atenolol both shifted the relationship between isoprenaline dose and heart rate to the right by similar degrees at the dosages tested. 4. (+)‐sotalol but not atenolol significantly prolonged QTc interval. The degree of QTc prolongation due to (+)‐sotalol, which has been shown to parallel action potential prolongation in the sinus node, correlated significantly with the reduction in peak exercise. heart rate it produced (r = 0.71, n = 8, P less than 0.05). 5. The affinity of the human lymphocyte beta 2‐ adrenoceptor was approximately 60‐fold greater for (‐)‐sotalol (Ki, 108 +/− 12 nM) than for (+)‐sotalol (Ki, 6,410 +/− 1,020 nM), and approximately 20,000‐fold greater for (+/−)‐propranolol (Ki, 0.33 +/− 0.08 nM) than for (+)‐sotalol.(ABSTRACT TRUNCATED AT 250 WORDS)
Enalapril and nifedipine in the treatment of mild to moderate essential hypertension: a 6 month comparison.
Authors: Maclean D , Ramsay LE , Richardson PJ
Published: July 2012

1. In a double‐blind, randomised, parallel group study, 128 patients with sitting diastolic blood pressure between 95 and 125 mm Hg (Phase V) after 2‐4 weeks run‐in on placebo, received enalapril 10‐40 mg once daily (65 patients) or nifedipine retard 10‐40 mg twice daily (63 patients), utilising a double dummy technique. Dual target blood pressures were less than 150 mm Hg systolic and less than 90 mm Hg sitting diastolic. Inadequate responders had hydrochlorothiazide 12.5‐ 50 mg once daily added. 2. The 3 h post‐dose sitting blood pressures were lowered by 18/14 mm Hg (enalapril) and 20/14 mm Hg (nifedipine), but nifedipine gave greater standing reductions (16/13 mm Hg enalapril, 22/17 mm Hg nifedipine). The dual target blood pressures were achieved by 45% of those taking enalapril monotherapy and 43% of those taking nifedipine monotherapy. At the end of the hydrochlorothiazide phase the dual target pressures were achieved by 63% of the enalapril group and 56% of the nifedipine group. 3. Overall, 17 patients reported adverse events during the placebo run‐in. During the active treatment‐periods, 42 patients in the enalapril group experienced adverse events, as did 49 of those on nifedipine. Orthostatic effects were confined to those taking enalapril, whereas flushing/erythema, oedema and palpitations were more common in the nifedipine group. 4. Five patients in the enalapril and 14 in the nifedipine groups were withdrawn because of adverse events. One of those withdrawn on enalapril had angioneurotic oedema.(ABSTRACT TRUNCATED AT 250 WORDS)
Lack of effect of verapamil and isosorbide dinitrate on the hepatic clearance of indocyanine green in cirrhosis.
Authors: Merkel C , Bolognesi M , Angeli P , Finucci GF , Amodio P , Bellon S , Gatta A
Published: July 2012

1. Vasodilators are currently under investigation as possible therapeutic agents in the treatment of portal hypertension. Among them calcium‐channel antagonists and organic nitrates have been of particular interest. Few and conflicting data, however, have been reported on their effect on liver function. 2. Twenty patients with biopsy‐proven alcoholic cirrhosis were studied before and 25‐35 min following the acute administration of 5 mg verapamil i.v. (eight patients) or 5 mg isosorbide dinitrate sublingually (12 patients). The plasma clearance of indocyanine green (ICG) and its intrinsic hepatic clearance were used as indices of liver function. Seven further patients were investigated before and after a placebo infusion according to the same methodology. 3. No significant change in ICG kinetics was found after verapamil or isosorbide dinitrate.
Terfenadine, a potent histamine H1‐receptor antagonist in the treatment of grass pollen sensitive asthma.
Authors: Rafferty P , Jackson L , Smith R , Holgate ST
Published: July 2012

1. We have assessed the effect of a specific histamine H1‐receptor antagonist, terfenadine, in the treatment of atopic asthmatics during the grass pollen season. 2. Eighteen mild, grass pollen sensitive asthmatics (10F, 8M, mean +/− s.e. mean age 34.7 +/− 5.6 years), all of whom were controlled on inhaled beta 2‐adrenoceptor agonists alone, took part in a 9 week, double‐blind, crossover study using terfenadine 180 mg three times daily and placebo. Throughout the study patients recorded peak expiratory flow rate (PEFR) twice daily, symptoms of cough, wheeze, breathlessness and chest tightness (scored 0‐3), and their use of bronchodilators. Methacholine inhalation challenge tests were performed each week. Data were analysed by a method suitable for a two group, two period crossover trial with baseline measurements. 3. Terfenadine significantly reduced symptoms of cough by 76.9% (P less than 0.05) and wheeze by 46.9% (P less than 0.02). Symptoms of breathlessness and chest tightness were reduced by 16.8 and 30.3% respectively but these were not statistically significant. Morning and evening PEFR rose by 5.5 (P less than 0.001) and 6.2% (P less than 0.003) respectively on treatment with terfenadine and bronchodilator use fell by 40.3%. A progressive increase in methacholine sensitivity was seen in both treatment groups throughout the study but did not reach statistical significance. 4. We conclude that treatment with terfenadine during the grass pollen season in sensitive asthmatics reduced their symptoms and bronchodilator requirements and produced a modest improvement in their lung function without affecting the development of increased methacholine sensitivity that occurred during the grass pollen season.
The effect of food on serum concentrations of metopimazine.
Authors: Herrstedt J , Jorgensen M , Angelo HR
Published: July 2012

1. Six healthy volunteers were given single oral doses of the antiemetic metopimazine (MPZ), starting with trial (a) 20 mg preprandially and followed by trial (b) 50 mg preprandially. In trials (c) and (d) the doses were similar to those in trials (a) and (b), but MPZ was given postprandially. To evaluate intra‐individual variation in serum concentrations, trial (a) was repeated three times in four of the volunteers (trial (e)). 2. Blood samples were drawn and the serum concentrations of MPZ and its acid metabolite (AMPZ) were measured by h.p.l.c. 3. There was no evidence of dose‐dependent kinetics at the dose levels studied. 4. Median AUC values were 22.6, 16.2, 52.4 and 35.2 (trials (a), (b), (c) and (d), ng ml‐1 h). Food intake decreased the serum concentrations of MPZ, suggesting that MPZ should be taken preprandially.
Lack of effect of tenoxicam on dynamic responses to concurrent oral doses of glucose and glibenclamide.
Authors: Hartmann D , Korn A , Komjati M , Heinz G , Haefelfinger P , Defoin R , Waldhausl WK
Published: July 2012

1. In a single‐blind, placebo controlled study the influence of tenoxicam on responses of glucose, insulin and C‐peptide to oral doses of glucose and glibenclamide was examined in 16 healthy male volunteers. 2. The subjects received once daily doses of 2.5 mg glibenclamide for 12 days. From day 5 through 12 eight subjects received concomitantly 20 mg tenoxicam once daily and the remaining eight subjects received placebo. 3. On days 1, 4, 5 and 12 glibenclamide was taken with 75 g glucose and blood glucose, serum insulin and C‐peptide were measured over 5 h. Plasma levels of glibenclamide and tenoxicam (where appropriate) were followed over 10 h. 4. Characteristic parameters of blood glucose and insulin and C‐ peptide responses did not change significantly with time (day) and there was no difference between both treatment groups. 5. Baseline insulin increased from 11.7 mu l‐1 on day 1 to 15.6 mu l‐1 on day 4 (P = 0.009), likewise baseline C‐peptide increased from 478 pmol l‐1 to 530 pmol l‐1 (P = 0.05), but there was no further change in the subsequent treatment period. 6. The AUC of the glibenclamide plasma concentration‐time curve did not show changes with time or differences between treatment groups. The mean (s.d.) oral clearance of tenoxicam was 2.5 (1.5) ml min‐1 and appeared slightly higher than in previous studies. 7. It was concluded that tenoxicam did not affect overall glycoregulation in healthy subjects under glibenclamide steady state conditions.
Pharmacokinetics of the individual enantiomers of vigabatrin (gamma‐ vinyl GABA) in epileptic children.
Authors: Rey E , Pons G , Richard MO , Vauzelle F , D'Athis P , Chiron C , Dulac O , Beaumont D , Olive G
Published: July 2012

1. The pharmacokinetics of the enantiomers of vigabatrin were investigated after oral administration of a single 50 mg kg‐1 dose of the racemate to two groups of six epileptic children (I: 5 months‐2 years, II: 4‐14 years). 2. The mean (+/− s.d.) values of maximum plasma concentration and area under the plasma concentration‐time curve of the R(‐) enantiomer were significantly higher than those of S(+) vigabatrin in both groups: R(‐) Cmax: 21 +/− 6.6 (I)‐41.3 +/− 13.9 (II) vs S(+) Cmax: 13.9 +/− 4.5 (I)‐23.8 +/− 12.2 (II) mg l‐1; R(‐) AUC: 106 +/− 28.5 (I)‐147 +/− 34 (II) vs S(+) AUC: 90.9 +/− 27.9 (I)‐117 +/− 26 (II) mg l‐1 h. In group I, the half‐life of the R(‐) isomer was significantly shorter than that of the S(+) isomer; in group II, the half‐lives were comparable. 3. For the R(‐) enantiomer the area under the curve, and the elimination half‐life increased linearly with age. 4. During chronic administration (50 mg kg‐1 vigabatrin racemate twice a day for 4 days), the morning trough plasma drug concentrations did not increase.
In vitro metabolism of the biguanide antimalarials in human liver microsomes: evidence for a role of the mephenytoin hydroxylase (P450 MP) enzyme.
Authors: Helsby NA , Ward SA , Howells RE , Breckenridge AM
Published: July 2012

The metabolic activation of the arylbiguanide antimalarials proguanil (PG) and chlorproguanil (CPG) has been investigated in liver microsomes from three human livers. All three microsomal preparations activated the biguanides. The kinetic parameters for PG metabolism to cycloguanil (CG) were Km 21.8, 29.6 and 26.4 microM and Vmax 1.5, 5.9, and 8.2 pmol min‐1 mg‐1. The values for CPG conversion to chlorcycloguanil (CCG) were Km 12.9, 19.7 and 26.1 microM and Vmax 5.7, 4.8 and 3.6 pmol min‐1 mg‐1. The metabolic activation of both biguanides was competitively inhibited by the anticonvulsant mephenytoin. Sparteine and tolbutamide had no effect on biguanide metabolism. These data suggest an involvement of the mephenytoin hydroxylase enzyme, which exhibits a genetic polymorphism in man, in the metabolic activation of the biguanide antimalarials.
Changes in indocyanine green kinetics after the administration of enalapril to healthy subjects.
Authors: Geneve J , Le Dinh T , Brouard A , Bails M , Segrestaa JM , Caulin C
Published: July 2012

Enalapril maleate, an angiotensin converting enzyme inhibitor, is a vasodilator liable to modify regional blood flow. The effects of an oral dose of 40 mg enalapril maleate on indocyanine green (ICG) kinetics were assessed in nine healthy subjects. At 4 h after the administration of the drug, a 35% decrease in ICG clearance was observed (P less than 0.01) associated with a 23% decrease in its volume of distribution (P less than 0.02). The half‐life of ICG was not altered significantly by enalapril. These results suggest that the administration of enalapril maleate to healthy subjects may reduce apparent liver plasma flow and plasma volume, as a consequence of the pooling of blood in the hepatosplanchnic area.
A graphical presentation of the results of crossover trials [see comments]
Authors: Sheldon TA
Published: July 2012

1. Crossover designs are widely used in clinical trials. A graphical method of describing the data as well as visually indicating the extent of treatment * period interaction and overall treatment effect is presented. This plots the treatment differences between the periods for each individual against the mean of their treatment outcomes. It is recommended that this plot accompany the analysis of crossover trials in order to aid summary and interpretation especially for the non‐ statistician.
Attenuation of the pupillary light reflex in anxious patients.
Authors: Bakes A , Bradshaw CM , Szabadi E
Published: July 2012

1. The miotic responses evoked by brief light stimuli were compared between a group of 10 patients suffering from generalized anxiety disorder and 10 age‐ and sex‐matched healthy control subjects. 2. Resting pupil diameter in the dark did not differ significantly between the two groups. 3. In both groups, the amplitude of the light reflex was linearly related to the logarithm of the intensity of the light stimulus; responses in the anxious patient group had consistently lower amplitudes than those in the control group. 4. In both groups, the time taken for 75% recovery of the baseline pupil diameter following a light stimulus was linearly related to the logarithm of the light intensity; the 75% recovery times did not differ significantly between the two groups. 5. It is suggested that these results are consistent with a greater supranuclear inhibition of the parasympathetic oculomotor reflex arc in the anxious patients.
Comparative effects of quinine and quinidine on glucose metabolism in healthy volunteers.
Authors: Davis TM , Karbwang J , Looareesuwan S , Turner RC , White NJ
Published: July 2012

1. To investigate the relative effects of quinine and quinidine on glucose metabolism, 11 healthy males aged 17‐32 years were given three separate 1 h intravenous infusions; normal saline alone, quinine dihydrochloride 10 mg base kg‐1 body weight (BW) in normal saline, and quinidine dihydrochloride 10 mg base kg‐1 BW in normal saline. A constant infusion of 5 mg glucose kg‐1 ideal BW min‐1 was given for 1 h before and during each study. 2. Assessment of pancreatic beta cell function and tissue insulin sensitivity from plasma glucose and insulin concentrations at the end of the first hour using the Continuous Infusion of Glucose with Model Assessment (CIGMA) technique confirmed normal glucose tolerance for each subject on each test day. 3. Plasma glucose concentrations at 1 h were similar to those at 2 h. There was no significant difference between the plasma glucose profiles during the three infusion regimes (P greater than 0.05). Plasma insulin rose significantly during the second hour (P less than 0.0001); increments after quinine (geometric mean [‐1 s.d‐ +1 s.d.]; 47.0 [27.8‐79.4] mu l‐ 1) were significantly greater than those after quinidine (19.8 [6.1‐ 65.2] mu l‐1) and saline (7.5 [0‐21.5] mu l‐1; P less than 0.05). Plasma quinine concentrations at the end of the infusion (6.5 +/− 4.4 mg l‐1) correlated with insulin increments during the second hour (r = 0.662, P = 0.028) and were significantly greater than those of quinidine (3.0 +/− 0.8 mg l‐1; P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)
Bioactivation of dapsone to a cytotoxic metabolite: in vitro use of a novel two compartment system which contains human tissues.
Authors: Riley RJ , Roberts P , Coleman MD , Kitteringham NR , Park BK
Published: July 2012

1. A two compartment system, comprising two adjacent teflon chambers separated by a semi‐permeable membrane, has been devised with which to investigate the generation of drug metabolites that are toxic to human cells in vitro. 2. Compartment A contained a drug‐metabolising system (human liver microsomes +/− NADPH) and compartment B contained target cells (human mononuclear leucocytes). The semi‐permeable membrane retained protein (m.w. greater than 10,000) but allowed equilibration (within 1 h) of drug and drug metabolites, during which time cells remained viable. 3. Incubation of dapsone (100 microM) with human microsomal protein (2 mg ml‐1) and NADPH (1 mM) in compartment A caused cell death (8.7 +/− 1.8%) in compartment B, which was reduced significantly (P less than 0.05) by the addition of glutathione (500 microM). Dapsone in the absence of NADPH was not cytotoxic. 4. Chemical analysis showed the presence of dapsone hydroxylamine as the only stable metabolite in both compartment A (5.2 +/− 0.4% incubated drug) and compartment B (3.5 +/− 0.5%). 5. Irreversible binding of dapsone to cells was significantly (P less than 0.05) reduced by omission of NADPH (85 +/− 13 pmol/10(6) cells) or addition of glutathione (103 +/− 9) compared with control values (153 +/− 51).
Conjugation pathways in liver disease.
Authors: Pacifici GM , Viani A , Franchi M , Santerini S , Temellini A , Giuliani L , Carrai M
Published: July 2012

1. The activities of microsomal glucuronyltransferase and thiomethyltransferase, and those of cytosolic sulphotransferase, acetyltransferase, glutathione transferase and thiomethyltransferase were measured in abnormal (cirrhosis and chronic hepatitis) and normal livers. 2. Glucuronyltransferase and sulphotransferase were investigated with 2‐naphthol and ethinyloestradiol as substrates. p‐ Aminobenzoic acid, benzo(a)pyrene‐4,5‐epoxide and 2‐mercaptoethanol were the substrates of acetyltransferase, glutathione transferase and thiomethyltransferase, respectively. 3. Enzyme activities are expressed as nmol min‐1 incubation mg‐1 protein and the averages (+/− s.d.) are given. With 2‐naphthol as substrate, the glucuronyltransferase activity was 6.55 +/− 4.10 (abnormal liver, n = 33) and 7.81 +/− 4.02 (normal liver, n = 26) (NS); whereas sulphotransferase activity was 0.28 +/− 0.18 (abnormal liver, n = 35) and 0.68 +/− 0.43 (normal liver, n = 26) (P less than 0.01). Glucuronyltransferase activity towards ethinyloestradiol was 102.5 +/− 56.9 (abnormal liver, n = 30) and 107 +/− 59.9 (normal liver, n = 26) (NS), whereas sulphotransferase activity was 57.2 +/− 36.0 (abnormal liver, n = 35) and 122 +/− 67.6 (normal liver, n = 28) (P less than 0.01). Acetyltransferase activity was 0.84 +/− 0.83 (abnormal liver, n = 35) and 3.84 +/− 1.65 (normal liver, n = 26) (P less than 0.01). Glutathione transferase activity was 0.83 +/− 0.68 (abnormal liver, n = 35) and 2.90 +/− 1.59 (normal liver, n = 25) (P less than 0.01) and thiomethyltransferase activity was 1.00 +/− 0.69 (abnormal liver, n = 34) and 3.99 +/− 1.49 (normal liver, n = 25) (P less than 0.01). 4. Liver disease lowers the activities towards the substrates studied of sulphotransferase, acetyltransferase, glutathionetransferase and thiomethyltransferase but not that of glucuronyltransferase.(ABSTRACT TRUNCATED AT 250 WORDS)
A prospective study of cyclosporine concentration in relation to its therapeutic effect and toxicity after renal transplantation.
Authors: Lindholm A , Dahlqvist R , Groth GG , Sjoqvist F
Published: July 2012

1. Cyclosporine (CsA) concentrations in plasma and whole blood were monitored prospectively in 66 consecutive kidney transplant recipients for 6 months after transplantation or until graft loss. Immunosuppression was based on treatment with CsA and prednisolone in 27 patients and CsA, azathioprine and prednisolone in 39 patients. 2. Whole blood and plasma samples (separated at 37 degrees C) were collected 10‐12 h after CsA dosage twice weekly over the first 3 months and thereafter once weekly. CsA concentrations were measured by high pressure liquid chromatography (h.p.l.c.) in plasma, by specific and non‐specific monoclonal radioimmunoassays (r.i.a.) in whole blood, and by polyclonal r.i.a. and polyclonal fluorescence polarization immunoassay (f.p.i.a.) in whole blood and plasma. 3. There were no differences between the treatment schedules regarding graft or patient survival, occurrence of acute rejection, nephrotoxicity or infection. 4. CsA concentrations were significantly lower at the time of acute rejection than one week earlier based on all of the analytical methods used except f.p.i.a. 5. The lowest CsA concentration, recorded during the first month after transplantation, was significantly lower in patients with than in patients without experience of acute rejection episodes when the CsA concentrations were measured by polyclonal r.i.a. in whole blood and plasma and by specific and non‐specific monoclonal r.i.a. in whole blood, but not by h.p.l.c. in plasma or polyclonal f.p.i.a. in whole blood or plasma. 6. The highest CsA concentration recorded during the second post‐transplantation month, was higher in patients with acute nephrotoxicity than in those without nephrotoxicity when CsA was measured by specific monoclonal r.i.a. in whole blood (471 +/− 409 ng ml‐1 vs 327 +/− 150 ng ml‐1, P less than 0.05), but not by the other methods. 7. The mean plasma h.p.l.c. concentration of CsA measured by h.p.l.c. during the first month after transplantation was significantly higher in patients who suffered from systemic infection than in patients who did not (116 +/− 70 ng ml‐1 vs 82 +/− 52 ng ml‐1; P less than 0.05). 8. Thus, significant relationships between CsA concentrations and clinical events were apparent using assay methods specific for CsA as well as using polyclonal r.i.a., but not using polyclonal f.p.i.a. When h.p.l.c. was used, however, plasma drug concentrations were often below the limit of determination. Our results suggest that specific analysis of CsA in whole blood allows the best distinction between patients who respond favourably and less favourably to treatment with CsA.
Actions of zopiclone and carbamazepine, alone and in combination, on human skilled performance in laboratory and clinical tests.
Authors: Kuitunen T , Mattila MJ , Seppala T , Aranko K , Mattila ME
Published: July 2012

1. Possible interactions of zopiclone and carbamazepine on human skilled performance were studied in a randomized, double‐blind, crossover trial with 12 healthy young subjects. 2. Psychomotor performance (coordination, reactions, attention, cognition) and subjective effects (VAS) were measured and venous blood sampled before and 1.5, 3, 4.5 and 6 h after single oral doses of placebo, 7.5 mg of zopiclone and 600 mg of carbamazepine, which were given alone or combined. Clinical test for drunkenness (CTD) was done 2 and 5 h after drug intake. 3. Both zopiclone and carbamazepine, when administered alone, impaired performance on laboratory tests, the decrements being recorded 1.5 to 6 h after intake. In line with the plasma concentrations, the zopiclone effects peaked earlier (at 1.5 h) and lasted for a shorter time than those of carbamazepine. Zopiclone had a more pronounced effect on perceptual and cognitive functions (digit substitution) and it affected extraocular muscle tone (Maddox wing), whereas carbamazepine had stronger effects on attention. Additive pharmacodynamic actions were found in most tests after the combined treatment with zopiclone and carbamazepine. 4. CTD proved to be less sensitive than the laboratory tests in revealing drug‐induced decrement of performance after administration of one agent alone. However, it revealed the combined decremental effects of zopiclone and carbamazepine. 5. When the drugs were given together, the absorption of drugs was retarded. Carbamazepine‐10,11‐epoxide levels were lower after intake of the drug combination than those measured after intake of carbamazepine alone. 6. The results suggest that the clinical tests developed to detect alcohol effects do not necessarily reveal drug‐ induced impairment of performance.
Daytime wakefulness following a bedtime oral dose of zolpidem 20 mg, flunitrazepam 2 mg and placebo.
Authors: Bensimon G , Foret J , Warot D , Lacomblez L , Thiercelin JF , Simon P
Published: July 2012

1. The effects of zolpidem 20 mg, flunitrazepam 2 mg and placebo, administered at bed time, were studied in 12 healthy young male volunteers. 2. The assessments included, at awakening, subjective ratings of overnight sleep, cognitive function, psychomotor performance (digit symbol substitution, choice reaction time, flicker fusion threshold), subjective ratings of alertness, and plasma assay of residual drug concentration. Daytime sleep propensity during the day after dosing was evaluated with the multiple sleep latency test. 3. Compared with placebo, both active drugs improved subjective assessment of the ease of getting to sleep. At awakening, under flunitrazepam treatment, the reduction of performance, on memory and psychomotor tests, paralleled an increased subjective rating of sleepiness, but zolpidem treatment left subjects unimpaired compared with placebo. Similarly, daytime sleep propensity was enhanced throughout the following day under flunitrazepam treatment, but not under zolpidem treatment. Plasma assay for residual drug concentration at awakening found significant amounts of flunitrazepam and marginal amounts of zolpidem. 4. Results indicate that zolpidem 20 mg is devoid of residual effects in a range of tasks that were sensitive enough to demonstrate a prolonged wakefulness impairment following flunitrzepam 2 mg in healthy volunteers.
Induction of polymorphic 4′‐hydroxylation of S‐mephenytoin by rifampicin.
Authors: Zhou HH , Anthony LB , Wood AJ , Wilkinson GR
Published: July 2012

Studies were performed in 13 healthy subjects to determine whether treatment with rifampicin results in induction of the metabolism of mephenytoin. Daily dosing with 600 mg rifampicin for 22 days caused a three to eightfold increase in the 0‐8 h urinary R/S ratio of mephenytoin following oral administration (100 mg) of racemic drug to extensive metabolizers of the anticonvulsant. This was accompanied by a 40 to 180% increase in the 0‐8 h urinary excretion of the 4′‐hydroxy metabolite. Four weeks after discontinuing rifampicin, both metabolic indices had returned to their baseline values. By contrast, rifampicin had no effect on either measures of metabolism in subjects of the poor metabolizer phenotype. Thus, it appears that the activity of the enzyme (P‐450 MP) mediating the genetically determined 4'‐hydroxylation of S‐ mephenytoin can be significantly modulated by enzyme inducing agents such as rifampicin and possibly environmental agents with a similar ability.
Lack of relationship between glibenclamide metabolism and debrisoquine or mephenytoin hydroxylation phenotypes.
Authors: Dahl‐Puustinen ML , Alm C , Bertilsson L , Christenson I , Ostman J , Thunberg E , Wikstrom I
Published: July 2012

The pharmacokinetics of a single oral dose of 1.75 mg glibenclamide were studied in 15 healthy Caucasians including five poor metabolisers of debrisoquine and five poor metabolisers of S‐mephenytoin. Plasma glibenclamide concentrations and the urinary concentrations of trans‐4‐ and cis‐3‐hydroxyglibenclamide were analyzed by h.p.l.c. Thirty‐six +/− 6% (mean +/− s.d., n = 15) of the given dose of glibenclamide was excreted in 48 h urine as hydroxylated metabolites, 27 +/− 4% as trans‐ 4‐hydroxyglibenclamide and 8 +/− 2% as cis‐3‐hydroxyglibenclamide. There were no differences in the plasma pharmacokinetics of glibenclamide or in the urinary excretion of the metabolites between poor and extensive metabolisers of debrisoquine, neither between the two mephenytoin hydroxylator phenotypes. The study thus indicates that the disposition of glibenclamide is not influenced by these two independent polymorphisms of drug oxidation.
Effects of felodipine on atrial natriuretic peptide in hypertensive non‐ insulin dependent diabetes mellitus.
Authors: Jeffrey RF , Capewell S , Brown J , Collier A , Hajducka C , Lee MR
Published: July 2012

Eighteen patients with non‐insulin dependent diabetes mellitus and hypertension were treated during two 4 week periods with the calcium antagonist felodipine or placebo in a double‐blind, randomised, cross‐ over study. Mean systemic blood pressure was significantly lower on felodipine, without producing a deleterious effect on diabetic control. Felodipine was associated with an increment in plasma renin concentration but plasma aldosterone and the renal outputs of sodium and dopamine were similar on both treatments. Plasma atrial natriuretic peptide levels were significantly reduced following felodipine treatment.
D‐penicillamine and D‐penicillamine‐protein disulphide in plasma and synovial fluid of patients with rheumatoid arthritis.
Authors: Joyce DA , Day RO
Published: July 2012

1. The plasma pharmacokinetics of D‐penicillamine (D‐pen) and D‐ penicillamine‐albumin disulphide (D‐pen‐alb) were examined over a dosage interval in six patients with rheumatoid arthritis. In two of these, 24 h synovial fluid profiles of D‐pen and D‐pen‐alb were also obtained. 2. D‐pen was undetectable in plasma at the beginning of the study. The peak concentration (5.4 +/− 1.2 microM) occurred at between 45 min and 2 h and the mean elimination half‐life was 0.6 h. D‐pen‐alb, however, was present at a mean plasma concentration of 19.1 microM prior to dosage, peaked at 26.2 microM and was eliminated with a half‐ life of 40 h. 3. D‐pen concentrations in synovial fluid rose more slowly and peaked lower than in plasma. D‐pen‐alb was present in synovial fluid of the patients at 50.1% and 83.6%, respectively, of the simultaneous plasma concentration prior to dosage. Concentrations varied during the study interval, corresponding to changes in plasma concentrations. 4. These results demonstrate that D‐pen forms stable conjugates with protein in treated patients. The presence of D‐pen‐alb in relatively high concentrations throughout the dosage interval contrasts with the low concentrations and rapid elimination of D‐pen. Both D‐pen and D‐pen‐alb were also shown to be present at the putative site of drug action (the inflamed synovial joint) in concentrations lower than those in plasma.
Central effects of the angiotensin‐converting enzyme inhibitor, captopril. II. Electroencephalogram and body sway.
Authors: Nicholson AN , Wright NA , Zetlein MB , Currie D , McDevitt DG
Published: July 2012

1. Effects of single doses of captopril (12.5, 25 and 50 mg) on the electroencephalogram (EEG) and on body sway were studied in fourteen healthy male subjects. Oxazepam (15 mg), as an active control, and two placebos were included in the study, together with a single dose of atenolol (100 mg). Medication was administered double‐blind at 11.00 h, and assessments made before and at 2 and 4 h after drug ingestion. 2. There were no changes in the EEG with captopril. Oxazepam reduced the circadian rise in alpha activity, while atenolol decreased beta power. Delta activity was modified by both oxazepam and atenolol. 3. A reduction in lower frequencies of body sway (0.05‐1 Hz) occurred with captopril, while the spectra were unaffected by oxazepam. Atenolol increased (P less than 0.05) activity in the frequency range 0.75‐2.75 Hz. 4. These observations suggest that captopril is free of central effects such as sedation that may occur with beta‐adrenoceptor antagonists. Reduced body sway with captopril could reflect improved integration of central and peripheral control of posture.
Withdrawal phenomena after atenolol and bopindolol: hormonal changes in normal volunteers.
Authors: Walden RJ , Tomlinson B , Graham B , Smith C , Betteridge DJ , Prichard BN
Published: July 2012

1. In order to observe and compare the withdrawal phenomena which follow treatment with the beta‐adrenoceptor blocking drugs, bopindolol (with partial agonist activity PAA) and atenolol (without PAA), two groups of six normal volunteers were studied before, during and after 16 days drug administration. 2. Measurements of plasma levels of cortisol, prolactin, insulin, noradrenaline, adrenaline, glucose and potassium were made during a pre‐treatment baseline period, on maximum dose and for 21 days after drug withdrawal. Isoprenaline infusions were given to determine sensitivity of heart rate responses and haemodynamic changes measured in response to physiological manoeuvres. 3. Following atenolol withdrawal the results show hormonal evidence of adrenergic overactivity in the form of elevation of plasma cortisol, insulin and glucose levels. After bopindolol withdrawal there was, in contrast, an overshoot of plasma prolactin and a persistent elevation of plasma potassium and adrenaline post‐isoprenaline. 4. The hormonal changes which follow withdrawal of atenolol and bopindolol are associated with haemodynamic changes reported elsewhere (Walden et al., 1990). 5. These observations provide confirmatory evidence of a post beta‐adrenoceptor blockade withdrawal syndrome which differs between the two drugs studied and this may reflect the properties of the drugs, in particular the PAA of bopindolol.
Withdrawal phenomena after atenolol and bopindolol: haemodynamic responses in healthy volunteers.
Authors: Walden RJ , Tomlinson B , Graham B , Liu JB , Prichard BN
Published: July 2012

1. The effect of withdrawal of atenolol and bopindolol administration was studied in 12 normal volunteers; six on each drug. 2. Following sub‐ maximal cycle‐ergometer exercise training six sets of base‐line observations were made of heart‐rate (HR) and blood pressure (BP) responses; supine, 60 degrees head‐up tilt, during graduated isoprenaline infusion and sub‐maximal cycle exercise. 3. The results show that withdrawal phenomena occur following both drug treatments. Atenolol produced a hypersensitivity to isoprenaline and a small overshoot of HR in response to physiological manoeuvres. In contrast bopindolol produced a prolonged state of reduced sensitivity to isoprenaline and some evidence of overshoot of HR with physiological manoeuvres. The differences between the responses may be explained by the different properties of the two beta‐adrenoceptor blocking drugs. 4. Some subjects showed clear evidence of overshoot of HR and BP on exercise demonstrating that certain individuals may be more prone to have withdrawal effects than others. 5. The length of time during which withdrawal phenomena can occur is probably longer than has previously been realised. 6. Hormonal changes were found in the withdrawal period (Walden et al., 1990).
Felodipine ER formulation in the treatment of mild hypertension: efficacy and tolerability vs placebo.
Authors: Bossini A , Di Veroli C , Cavallotti G , Cagli V
Published: July 2012

1. Felodipine is a new calcium‐antagonist dihydropyridine derivative with a high degree of selectivity for smooth muscle of arteriolar resistance vessels, as opposed to cardiac cells. 2. In this double‐ blind, cross‐over study the antihypertensive efficacy and tolerability of the new extended release (ER) formulation of felodipine 10 mg, once daily, in patients with mild essential hypertension was evaluated. After a 4‐week single‐blind placebo period 28 patients (15 males; mean age 48 +/− 12 years) were randomized to receive felodipine 10 mg ER once daily or placebo for 4 weeks and the alternative treatment for a further 4 weeks. Supine blood pressure and heart rate were measured in the out‐patients department every 2 weeks, 22‐24 h after the last drug administration. 3. Felodipine 10 mg ER induced a significant reduction in blood pressure in comparison with placebo (from 149 +/− 16/97 +/− 6 to 140 +/− 12/89 +/− 6 mm Hg). Heart rate remained unchanged. Seven patients dropped‐out; five during felodipine ER administration and two during placebo. 4. A once daily dose of felodipine ER significantly reduces blood pressure in mild hypertensive patients 22‐24 h after administration. It is well tolerated and the adverse events are related to its pharmacodynamic effects.
Effect of UK‐52,046, an alpha 1‐adrenoceptor antagonist, on baroreflex function in man.
Authors: McKaigue JP , Harron DW
Published: July 2012

1. In a placebo controlled study (six healthy male subjects), the effects of UK‐52,046 (0.4 microgram kg‐1 i.v.) and prazosin (0.25 mg i.v.) on baroreflex function were compared, at doses which produced antagonism to phenylephrine, but which had no effect on supine blood pressure. 2. Baroreflex function [delta R‐R interval ms mm Hg‐1 change in SBP] was assessed following increases in systolic blood pressure (SBP) with phenylephrine and during the Valsalva manoeuvre. 3. At these doses neither UK‐52,046 nor prazosin had an effect on supine SBP or heart rate; however following prazosin, standing SBPs at 5 s (69.7 +/− 7.6 mm Hg) and at 3 min (65.5 +/− 11.7 mm Hg) were less than the respective pre‐treatment (P less than 0.05) values (96.0 +/− 2.9, 110.3 +/− 6.2 mm Hg) and placebo (82.7 +/− 5.6, 98.7 +/− 11.1 mm Hg). UK‐ 52,046 had no significant effects on standing SBP at 5 s or 3 min. At 5 s, pre‐ and post‐treatment R‐R intervals (584 +/− 26, 541 +/− 27 ms respectively) were not significantly different with prazosin, but at 3 min the post‐treatment R‐R interval following prazosin (519 +/− 17 ms) was less (P less than 0.05) than the pre‐treatment value (658 +/− 36 ms). 4. UK‐52,046 had no effect on baroreflex sensitivity (12.7 +/− 1.3 ms mm Hg‐1) compared with placebo (17.9 +/− 2.7 ms mm Hg‐1).(ABSTRACT TRUNCATED AT 250 WORDS)
Nitrendipine and the humoral control of sodium homeostasis.
Authors: Forsyth DR , Roberts CJ
Published: July 2012

1. Nine healthy volunteers received 10 mg nitrendipine or placebo orally in random order. 2. In the subsequent 5 h urinary sodium excretion was 20% higher after nitrendipine, without any significant difference between the volume of urine excreted after nitrendipine or placebo. Mean blood pressure fell by 5 mm Hg (P less than 0.001), and mean heart rate increased by 5 beats min‐1 (P less than 0.01) after nitrendipine but did not change after placebo. 3. These changes were accompanied by a significant elevation in plasma renin activity (P less than 0.001). A fall in plasma aldosterone following placebo appeared to be attenuated by nitrendipine. Plasma noradrenaline increased to a peak 3 h after nitrendipine administration (P less than 0.05) but did not change following placebo. A fall in the excretion of 6‐keto PGF1 alpha following placebo was attenuated by nitrendipine. The total excretion of 6‐keto PGF1 alpha after nitrendipine was significantly greater (P less than 0.05) than after placebo but not difference in the total excretion of PGE2 was detected. Nitrendipine did not affect urinary kallikrein excretion. 4. The natriuretic action of nitrendipine is not mediated by the kallikrein‐kinin system, but may be related to changes in renal prostaglandins.
The pharmacokinetics and activation of proguanil in man: consequences of variability in drug metabolism.
Authors: Helsby NA , Ward SA , Edwards G , Howells RE , Breckenridge AM
Published: July 2012

1. Based on the ratio of drug to active metabolite excreted in urine approximately 3% of a healthy Caucasian population showed a reduced ability to convert proguanil to cycloguanil. 2. Pharmacokinetic analysis showed that this observation resulted from a reduced oral clearance of proguanil in these individuals (245, 534 and 552 ml min‐1) compared with the rest of the population (858 +/− 482 ml min‐1). 3. Peak plasma concentrations of active metabolite were significantly lower in these subjects (54.2, 26.8 and 51.7 ng ml‐1) compared with the rest of the population (141 +/− 45.2 ng ml‐1). 4. The observed variability may result from the polymorphic metabolism of proguanil in man.
Sinemet‐ferrous sulphate interaction in patients with Parkinson's disease.
Authors: Campbell NR , Rankine D , Goodridge AE , Hasinoff BB , Kara M
Published: July 2012

1. This study examined the effects of administering ferrous sulphate 325 mg with Sinemet (100/25 tablet) on levodopa and carbidopa bioavailability and on signs of Parkinson's disease in nine patients. 2. Ferrous sulphate ingestion with Sinemet resulted in a decrease in levodopa area under the curve (AUC) of 30% (P less than 0.01) and a greater than 75% decrease in carbidopa AUC. Despite a strong relationship between reductions in levodopa AUC and reductions in Sinemet efficacy (r = 0.83, P less than 0.01), the average reduction in Sinemet's efficacy associated with ferrous sulphate did not achieve statistical significance (P = 0.055). 3. Chemical studies indicate that iron forms chemical complexes with carbidopa in a similar manner to levodopa and is a likely mechanism for the drug interactions. 4. AUC when a Sinemet tablet is taken concurrently with a ferrous sulphate tablet appears to be clinically significant in some but not all patients. The clinical significance of repeated ingestion of ferrous sulphate with Sinemet requires further studies.