bluuebunny/crossref_metadata_2025 huggingface dataset:
A comparison of verapamil and nifedipine on quality of life.
Authors: Palmer A , Fletcher A , Hamilton G , Muriss S , Bulpitt C
Published: July 2012

1. Aspects of quality of life (symptoms, psychological well‐being and activity) were evaluated by self‐administered questionnaires in a 4 month randomised double‐blind trial of titrated doses of verapamil slow release (n = 41) compared with nifedipine retard (n = 40). An untreated diastolic blood pressure of 95‐115 mm Hg was required for inclusion in the trial. 2. The mean age in both groups was 55 years. A significant difference between the two drugs was found in the average reporting of symptoms with an increase on nifedipine (P less than 0.01). The reporting of swollen ankles and flushing (P less than 0.05) increased on nifedipine, and nocturia (P less than 0.05) increased on verapamil. Measures of psychiatric morbidity tended to improve on verapamil and deteriorate on nifedipine. Only the change in cognitive function was significant between the drugs, being worse on nifedipine (P = 0.05). 3. There was no difference between the two groups in the fall in diastolic blood pressure (average 18 mm Hg on nifedipine and 17 mm Hg on verapamil). There was a significantly greater fall in systolic blood pressure on nifedipine (23 mm Hg) compared with verapamil (13 mm Hg) (P less than 0.01). 4. The two drugs differed in their effects on measures of quality of life. The improvements in symptomatic complaints and psychological well‐being on verapamil may have been due to inclusion in a trial, although we cannot exclude the possibility of a drug effect. Conversely the increase in symptoms and self‐assessed cognitive impairment on nifedipine were considered to be side‐effects of the drug.
Inhaled sodium metabisulphite induced bronchoconstriction: inhibition by nedocromil sodium and sodium cromoglycate.
Authors: Dixon CM , Ind PW
Published: July 2012

1. The effects of nedocromil sodium and sodium cromoglycate on bronchoconstriction induced by inhaled sodium metabisulphite have been studied in eight atopic subjects, three of whom had mild asthma. 2. Nedocromil sodium (4 mg, 7.8 × 10(‐6) M), sodium cromoglycate (10 mg, 24.1 × 10(‐6) M) and matched placebo were administered by identical metered dose inhalers 30 min before a dose‐response to sodium metabisulphite (5‐100 mg ml‐1) was performed. 3. Maximum fall in sGaw after placebo pre‐treatment was ‐43.9 +/− 3.3% baseline (mean +/− s.e. mean). At the same metabisulphite concentration maximum fall in sGaw after sodium cromoglycate was ‐13.0 +/− 3.6% and after nedocromil sodium was +4.3 +/− 6.8%. Nedocromil sodium prevented any significant fall in sGaw even after higher concentrations of metabisulphite. 4. Both nedocromil sodium, 4 mg, and sodium cromoglycate, 10 mg, inhibited sodium metabisulphite induced bronchoconstriction but nedocromil sodium was significantly more effective. Relative in vivo potency of the two drugs is broadly in line with other in vivo and in vitro studies.
The effect of oral salbutamol on cation transport measured in vivo in healthy volunteers.
Authors: Wood AJ , Brearley CJ , Aronson JK , Grahame‐Smith DG
Published: July 2012

1. We have measured the effect of oral salbutamol on cation transport in vivo by studying the disposition of an oral load of rubidium chloride in healthy treated volunteers and in untreated matched controls. 2. During the administration of salbutamol there was a significantly lower plasma rubidium concentration 5 h after the administration of the oral load of rubidium chloride, reflecting an increase in the net clearance of rubidium from the plasma into at least some tissues in vivo. 3. There was no difference in either intraerythrocytic rubidium concentrations or the pseudo‐rate constant for erythrocyte rubidium uptake in vivo after salbutamol. 4. Ex vivo incubation of whole blood preloaded in vivo with rubidium showed that the clearance of rubidium from the plasma was inhibited by 95% in the presence of the Na+,K(+)‐ATPase inhibitor digoxin. 5. These data suggest that salbutamol stimulates cation transport via Na+,K(+)‐ATPase in vivo into some tissues but not into the erythrocyte. 6. This pattern of change in rubidium disposition after salbutamol is completely different from the patterns of change we have seen in patients with essential hypertension or acute manic illness. We therefore suggest that the changes in erythrocyte rubidium uptake which we have previously described in vivo in patients with essential hypertension or acute manic illness do not result from beta 2‐adrenoceptor‐mediated catecholamine stimulation of Na+,K(+)‐ATPase.
The effect of miglitol and acarbose after an oral glucose load: a novel hypoglycaemic mechanism?
Authors: Joubert PH , Venter HL , Foukaridis GN
Published: July 2012

1. Alpha‐glucosidase inhibitors such as miglitol and acarbose lower blood glucose after a starch load in healthy volunteers and diabetic patients by interfering with the conversion of disaccharide to monosaccharide in the gastrointestinal tract. 2. The effect of placebo, 100 mg miglitol and 100 mg acarbose given 30 min prior to a 75 g oral glucose load was investigated in nine healthy Caucasian volunteers. 3. Miglitol produced a statistically significant fall in post‐peak blood glucose levels when compared with placebo and acarbose. Serum insulin did not change significantly. 4. As miglitol is well absorbed and acarbose is not, it is suggested that miglitol has a systemic hypoglycaemic effect, probably related to its close structural similarity to glucose, which warrants further investigation.
A correlation between severity of migraine and delayed gastric emptying measured by an epigastric impedance method.
Authors: Boyle R , Behan PO , Sutton JA
Published: July 2012

1. This study examined the ability of a bioimpedance method to detect the delay in gastric emptying which occurs during attacks of migraine. 2. In 64 non‐migraineur control patients and 46 migraine patients outside an attack, gastric emptying rates were within the predicted normal range. 3. In contrast, rates in 14 migraineurs during 20 attacks were delayed during severe or moderate attacks and were significantly correlated with the intensity of headache, nausea and photophobia. 4. The epigastric impedance method was generally well tolerated by patients and appears to merit further investigation as a clinical method of monitoring gastric emptying of liquids.
Pharmacodynamic without pharmacokinetic interaction between cicloprolol, a partial beta 1‐adrenoceptor agonist, and digoxin in healthy subjects.
Authors: Weber S , Kahan A , Pinquier JL , Julien J , Rosenzweig P , Bianchetti G , Morselli PL , Dessault O , De Lauture D , Strauch G
Published: July 2012

1. Cicloprolol is a partial beta 1‐adrenoceptor agonist considered for the treatment of patients with coronary artery disease and impaired left ventricular function. In such patients, digoxin remains in widespread use. 2. We assessed the pharmacokinetic and pharmacodynamic interaction between oral cicloprolol 50 mg day‐1 and oral digoxin 0.25 mg day‐1 in 10 healthy male volunteers, using a double‐blind, randomised protocol, during three 8 day periods. Digoxin was given alone during the first period to reach steady state; then digoxin was given with cicloprolol or placebo during the second and third periods, according to a cross‐over design. 3. No significant adverse effects were observed. 4. The pharmacokinetics of digoxin were not different significantly at the end of the placebo‐digoxin and cicloprolol‐digoxin periods. 5. A significant increase in minimum heart rate and mean nocturnal heart rate, assessed by 24 h Holter recordings, was observed at the end of the cicloprolol‐digoxin period as compared with the placebo‐digoxin period (means +/− s.e. mean, 57.1 +/− 3.2 beats min‐1 vs 52.2 +/− 3.1 beats min‐1, P less than 0.01; and 65.6 +/− 3.8 beats min‐1 vs 59.9 +/− 3.9 beats min‐1, P less than 0.01, respectively). 6. A significant increase in left ventricular ejection fraction and shortening fraction, assessed by echocardiography, was noted at the end of the cicloprolol‐digoxin period as compared with the placebo‐digoxin period (means +/− s.e. mean, 66.4 +/− 1.4% vs 61.3 +/− 1.2%, P less than 0.05; and 37.0 +/− 1.1% vs 33.3 +/− 0.9%, P less than 0.05, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)
Single‐dose effects of ibopamine hydrochloride on renal function in patients with congestive heart failure.
Authors: Kasmer RJ , Cutler RE , Munger MA , Jarvis RC , Hricik D , Nara AR , Goldberg P , Green JA
Published: July 2012

To examine the renal effects of ibopamine HCl we evaluated 15 patients with New York Heart Association Class II‐III congestive heart failure and mild renal insufficiency (creatinine clearance [CLcr] = 45‐85 ml min‐1). Diuretics and vasodilators were withheld and a sodium (Na+)‐ restricted diet was initiated. All patients exhibited positive Na+ balance at the time of evaluation. Hourly urine volumes, urine chemistries, serum chemistries, PAH and inulin/iothalamate clearances were determined 2 h pre and 4 h post a single 200 mg oral dose of ibopamine. Effective renal plasma flow, creatinine clearance, filtration fraction, and the fractional excretion of sodium and potassium were not significantly altered postdose. A significant increase in urine output and decrease in urine osmolality were seen at all time points postdose. A significant reduction in serum potassium (2 and 3 h) and blood urea nitrogen (1, 3 and 4 h) concentrations occurred. Measurements of glomerular filtration rate by inulin or [125I]‐iothalamate produced differing results in the patient groups studied. We conclude that a single dose of ibopamine does not produce significant improvements in renal function in patients with congestive heart failure, mild renal insufficiency and positive sodium balance.
The heart rate‐PR interval relationship: a model for evaluating drug actions on SA and AV nodal function.
Authors: Danter WR , Carruthers SG
Published: July 2012

The relationship between heart rate (HR) and PR interval (PR) has been investigated to determine inter‐subject variability, within‐subject variability and potential reference standards. Eight healthy male volunteers underwent upright graded submaximal treadmill exercise during eight separate study sessions. All subjects exhibited statistically significant negative linear relationships between PR and HR. Although there was considerable inter‐subject variability, there was little within‐subject variability in the interpolated PR at HR between 80 and 120 beats min‐1. The HR‐PR regression model has greatest validity within this HR range and for individual subjects rather than pooled or group data.
Nitrendipine therapy in asthmatic subjects.
Authors: Mulloy EM , Cormie P , Harvey J , Marley JE
Published: July 2012

Nitrendipine was given to eight patients with chronic stable asthma prior to a histamine challenge study and compared in a double‐blind cross‐over fashion with placebo. There were no significant differences in either the bronchoconstrictor effects of histamine, or in oxygen saturation during the histamine challenges, suggesting that nitrendipine should be safely tolerated if used to treat hypertension in patients with airflow obstruction.
Effect of activated charcoal on frusemide induced diuresis: a human class experiment for medical students.
Authors: Kivisto KT , Neuvonen PJ
Published: July 2012

We have introduced to the course in pharmacology for medical students a simple human experiment that demonstrates the efficacy of activated charcoal in gastrointestinal drug binding. Sixty‐one students were given 40 mg frusemide with water, water only, or 40 mg frusemide and 8 g activated charcoal with water either immediately or after different time intervals. The diuretic effect of frusemide was totally prevented when taken together with charcoal, but became apparent gradually when charcoal was taken after a lag time. This experiment is simple to carry out and demonstrates vividly the treatment principles of acute intoxications.
Central effects of the angiotensin‐converting enzyme inhibitor, captopril. I. Performance and subjective assessments of mood.
Authors: Currie D , Lewis RV , McDevitt DG , Nicholson AN , Wright NA
Published: July 2012

1. Central effects of single doses of captopril (12.5, 25 and 50 mg) were studied in fourteen healthy male subjects. Two placebos and an active control drug, oxazepam (15 mg), were included, together with a single dose of atenolol (100 mg). The drugs were administered double‐ blind at 11.00 h, and performance and subjective feelings were assessed before and from 1.5‐2.5 h and 3.5‐4.5 h after ingestion. 2. Performance was assessed using digit symbol substitution, continuous attention, letter cancellation, choice reaction time, finger tapping, immediate and short‐term memory, together with critical flicker fusion and two flash fusion. Subjects assessed their mood and well‐being on a series of 12 visual analogue scales. 3. Captopril did not impair performance on any of the tests, but improved short‐term memory (P less than 0.05) and increased the number of letters cancelled (P less than 0.05). Oxazepam reduced the number of substitutions completed in the digit symbol test (P less than 0.01), accuracy on continuous attention (P less than 0.05), number of letters cancelled (P less than 0.05), and rate of finger tapping (P less than 0.05), and increased choice reaction time (P less than 0.001). Atenolol reduced the rate of finger tapping (P less than 0.05), but increased the number of letters cancelled (P less than 0.05). 4. No effects on mood or on subjective feelings were evident with captopril. Oxazepam reduced subjective alertness (P less than 0.05), and atenolol increased feelings of sleepiness (P less than 0.05). 5. Although these observations suggest that central effects may exist with captopril, no adverse consequences have been established on performance or on subjective assessment of mood. Captopril may, therefore, be an appropriate drug for hypertensive patients engaged in skilled activity.
Chronic administration of N‐acetylcysteine fails to prevent nitrate tolerance in patients with stable angina pectoris.
Authors: Hogan JC , Lewis MJ , Henderson AH
Published: July 2012

1. Reduced availability of sulphydryl groups in vascular smooth muscle cells may contribute to the development of tolerance to the action of the organic nitrovasodilators. 2. Eight patients with stable angina were treated with 10 mg of transdermal glyceryl trinitrate per 24 h, together with 400 mg N‐acetylcysteine, a sulphydryl group donor, or matching placebo three times daily in a double‐blind randomised crossover manner for two periods of 4 days with intervening washout period of 3 days off these drugs. Other therapy remained unaltered during the study. 3. Blood pressure, heart rate and symptom‐limited treadmill walking time were measured in the pre‐treatment control state and 4 h after starting treatment on day 1 and day 4 of each glyceryl trinitrate treatment period. 4. The changes seen on day 1 were attenuated by day 4 to an equal extent in N‐acetylcysteine and placebo treatment periods. 5. These results suggest that chronic oral administration of N‐acetylcysteine fails to prevent the development of tolerance to the anti‐anginal or haemodynamic effects of glyceryl trinitrate.
The disposition of primidone in elderly patients.
Authors: Martines C , Gatti G , Sasso E , Calzetti S , Perucca E
Published: July 2012

1. The pharmacokinetics and metabolism of primidone at steady‐state were studied in 10 elderly patients aged 70‐81 years and eight control subjects aged 18‐26 years. 2. Primidone half‐lives and clearance values (mean +/− s.d.) were similar in the elderly and in the young (12.1 +/− 4.6 vs 14.7 +/− 3.5 h and 34.8 +/− 9.0 vs 33.2 +/− 7.2 ml h‐1 kg‐1 respectively. 3. The serum concentrations of the metabolites phenylethylmalonamide (PEMA) and phenobarbitone relative to those of parent drug were higher in the elderly than in the young, the difference being significant (P less than 0.01) in the case of PEMA. 4. The renal clearances of primidone, phenobarbitone and PEMA were moderately decreased in the elderly but this reduction was statistically significant only for PEMA. Elderly patients excreted a reduced proportion of unchanged primidone and an increased proportion of PEMA in urine. 5. Ageing is associated with a greater accumulation of PEMA, which is unlikely to have a major clinical significance.
Tremor and the anti‐obesity drug BRL 26830A.
Authors: Connacher AA , Lakie M , Powers N , Elton RA , Walsh EG , Jung RT
Published: July 2012

The thermogenic beta 3‐adrenoceptor agonist BRL 26830A has been shown to increase weight loss in dieting subjects but tremor was a frequent adverse effect. We have investigated the magnitude and nature of this tremor after a single oral dose in 18 subjects. Two complementary techniques were used to attach the recording apparatus to the subjects to give both isotonic and isometric measures of tremor. Increases of 84% and 40% respectively were found due to exaggeration of physiological tremor presumably mediated through concomitant beta 2‐ adrenoceptor stimulation. The use of beta 3‐adrenoceptor agonist drugs in the treatment of obesity may increase but the development of an agent without tremor inducing properties would be an obvious advantage.
Lack of effect of ponsinomycin on the pharmacokinetics of nicoumalone enantiomers.
Authors: Couet W , Istin B , Decourt JP , Ingrand I , Girault J , Fourtillan JB
Published: July 2012

Pharmacokinetic interaction between ponsinomycin‐nicoumalone was studied in six subjects who received an 8 mg oral dose of racemic nicoumalone alone and 4 days into an oral regimen of ponsinomycin 800 mg twice daily. The concentrations of R(+) and S(‐)‐nicoumalone in plasma were measured using a stereospecific h.p.l.c. assay. The disposition characteristics of nicoumalone enantiomers in the control phase of this study were similar to those reported previously with the exception of the data for one subject whose oral clearance for S(‐)‐ nicoumalone was seven times lower than those in the other subjects. A statistically significant effect of ponsinomycin on the kinetics of R(+) and S(‐)‐nicoumalone was not demonstrated.
Pharmacokinetics of CGP 6140 (amocarzine) after oral administration of single 100‐1600 mg doses to patients with onchocerciasis.
Authors: Lecaillon JB , Dubois JP , Awadzi K , Poltera AA , Ginger CD
Published: July 2012

The concentrations of CGP 6140 [4‐nitro‐4′‐(N‐methyl‐ piperazinylthiocarbonylamido)‐diphenylamine] and of its N‐oxide metabolite, CGP 13,231, were measured in plasma and urine after single oral dose of 100‐1600 mg of CGP 6140 to 41 fasted Ghanaian patients with Onchocerca volvulus infections. The absorption of CGP 6140 was rapid and its terminal elimination half‐life was about 3 h. The plasma concentrations of CGP 6140 were essentially proportional to the dose. A greater variability in plasma concentrations was apparent after the 800 and 1600 mg doses indicating a poor bioavailability of the drug administered in fasting conditions to several patients. In plasma, the concentrations of CGP 13,231 were similar to those of CGP 6140. The amount of CGP 13,231 excreted in urine was 25‐40% of the dose of CGP 6140 whereas only 1.5% was excreted as unchanged drug. If a single dose of drug is used for the treatment, the plasma concentration would be maintained for 3‐4 h at a high level. At 8 h, the concentration falls to about 10% of the Cmax. If sustained plasma concentrations of the drug are needed for efficacy, twice daily administration would maintain the minimum concentration at about 10% of the Cmax.
Hepatic drug clearance: the effect of age using indocyanine green as a model compound.
Authors: Wynne HA , Goudevenos J , Rawlins MD , James OF , Adams PC , Woodhouse KW
Published: July 2012

The hepatic extraction ratio and clearance of indocyanine green (ICG) were determined and used to derive apparent liver blood flow in nine subjects between the ages of 22 and 83 years. There was no correlation between the hepatic extraction ratio of ICG and age (rs = ‐0.435, NS). There was a significant negative correlation between both ICG clearance and age (rs = ‐0.710, P less than 0.05) and apparent liver blood flow and age (rs = ‐0.750, P less than 0.05). These results validate the comparison of liver blood flow values derived from ICG clearance in humans over a wide age range and confirm that liver blood flow does fall with age.
The effects of beta‐adrenoceptor antagonists and levomepromazine on the metabolic ratio of debrisoquine.
Authors: Kallio J , Huupponen R , Seppala M , Sako E , Iisalo E
Published: July 2012

The in vivo inhibitory effect of five beta‐adrenoceptor antagonists and levomepromazine on debrisoquine metabolism was assessed in 37 subjects. The debrisoquine phenotyping test was performed before and after 7 days' treatment with oxprenolol (40 mg three times daily), propranolol (20 mg three times daily), timolol (10 mg twice daily), pindolol (5 mg twice daily), metoprolol (50 mg twice daily) or levomepromazine (10 mg daily), each of which was given to six‐seven subjects. No clear change in the urinary metabolic ratio of debrisoquine/4‐OH‐debrisoquine (MR) was seen with any of the single beta‐adrenoceptor antagonist treatments, but the MR value increased significantly when all beta‐ adrenoceptor blocker treatments were considered together. Debrisoquine metabolism was clearly impaired after levomepromazine 10 mg daily for 7 days; the mean MR increased from 1.24 +/− 1.6 to 4.70 +/− 5.23 (P = 0.018) and the excretion of 4‐hydroxydebrisoquine decreased from 0.92 +/− 0.46 mg to 0.31 +/− 0.19 mg (P = 0.043). Thus, levomepromazine changes MRs towards those characteristic of phenotypically poor metabolizers, but beta‐adrenoceptor antagonists at the doses examined have only a marginal effect.
Clomipramine vs desipramine vs placebo in the treatment of diabetic neuropathy symptoms. A double‐blind cross‐over study.
Authors: Sindrup SH , Gram LF , Skjold T , Grodum E , Brosen K , Beck‐Nielsen H
Published: July 2012

1. The effect of clomipramine and desipramine on diabetic neuropathy symptoms was examined in a double‐blind, randomised, placebo controlled, cross‐over study for 2 + 2 + 2 weeks. Drug doses were adjusted according to the sparteine phenotype, i.e. extensive metabolisers were treated with 75 mg clomipramine day‐1 and 200 mg desipramine day‐1 whereas poor metabolisers were treated with 50 mg day‐ 1 of both drugs. Nineteen patients completed the study. 2. Plasma concentration of clomipramine plus desmethylclomipramine was 70‐510 nM in extensive metabolisers, vs 590 and 750 nM in two poor metabolisers. Desipramine levels were 130‐910 nM, vs 860 and 880 nM. 3. Both clomipramine and desipramine significantly reduced the symptoms of neuropathy as measured by observer‐ and self rating in comparison with placebo. Clomipramine tended to be more efficacious than desipramine. Patients with a weak or absent response on clomipramine had lower plasma concentrations (clomipramine plus desmethyl‐clomipramine less than 200 nM) than patients with a better response. For desipramine a relationship between plasma concentration and effect was not established. 4. Side effect ratings did not differ for clomipramine and desipramine and on both drugs three patients withdrew due to side effects. 5. Compared with earlier results obtained with imipramine dosed on the basis of plasma level monitoring, clomipramine and desipramine on fixed doses appeared less efficacious whereas the side effect profiles were the same. At least for clomipramine, appropriate dose adjustment on the basis of plasma level monitoring may increase the efficacy.
The influence of clinical and pharmacological factors on enuresis treatment with imipramine.
Authors: de Gatta MM Fernandez , Galindo P , Rey F , Gutierrez J , Tamayo M , Garcia MJ , Dominguez‐Gil A
Published: July 2012

1. The aim of this study has been to evaluate the response to imipramine treatment in enuretic children through the use of a series of clinical and pharmacological variables and by applying a multivariate (principal components) analysis technique. 2. The study was carried out on 146 children whose ages ranged from 5 to 14 years, and who received variable doses of imipramine (12.5 to 100 mg day‐1). 3. The quantitative variables analyzed were: drug dosage, serum levels of imipramine and its metabolite desipramine, the relationship between them both, the duration of treatment, age and weight. 4. The qualitative variables were: compliance, presence of side‐effects, enuretic and/or psychiatric antecedents, intelligence quotient (I.Q.), the existence (or absence) of related pathologies, sex, and the type of enuresis. 5. The response to treatment was quantified by means of the percentage of decrease in frequency of enuresis as compared with the initial frequency. 6. The results obtained show that the variables which are most associated with the reduction of enuresis are, in decreasing order: the dosage of imipramine administered, the duration of treatment, compliance and the level/dose ratio for the sum of the drug and metabolite levels.
Investigations into the potential effects of multiple dose ketorolac on the pharmacokinetics and pharmacodynamics of racemic warfarin.
Authors: Toon S , Holt BL , Mullins FG , Bullingham R , Aarons L , Rowland M
Published: July 2012

1. The potential interaction between racemic warfarin given as a 25 mg single oral dose and chronically administered ketorolac was studied in 12 young healthy male volunteers. 2. Ketorolac produced no major change in the pharmacokinetics of (R)‐ or (S)‐warfarin. 3. Ketorolac did not alter the pharmacodynamic profile of racemic warfarin. 4. Ketorolac increased template bleeding time by a factor of 1.35 as compared with placebo. 5. The results suggest that the ketorolac‐warfarin interaction is unlikely to be of major clinical significance; however, combined use of ketorolac and warfarin in patients should be undertaken with due caution and appropriate monitoring.
The use of cimetidine as a selective inhibitor of dapsone N‐ hydroxylation in man.
Authors: Coleman MD , Scott AK , Breckenridge AM , Park BK
Published: July 2012

1. The N‐hydroxylation of dapsone is thought to be responsible for the methaemoglobinaemia and haemolysis associated with this drug. We wished to investigate the effect of concurrent administration of cimetidine (400 mg three times per day) on the disposition of a single dose (100 mg) of dapsone in seven healthy volunteers in order to inhibit selectively N‐hydroxylation. 2. The AUC of dapsone (31.0 +/− 7.2 micrograms ml‐1 h) was significantly increased (P less than 0.001) in the presence of cimetidine (43.3 +/− 8.8 micrograms ml‐1 h). 3. Peak methaemoglobin levels observed after dapsone administration (2.5 +/− 0.6%) were significantly (P less than 0.05) reduced in the presence of cimetidine (0.98 +/− 0.35%). 4. The percentage of the dose excreted in urine as the glucuronide of dapsone hydroxylamine was significantly (P less than 0.05) reduced in the presence of cimetidine (34.2 +/− 9.3 vs 23.1 +/− 4.2%). 5. Concurrent cimetidine therapy might reduce some of the haematological side‐effects of dapsone.
Absence of magnesium sparing effect of a single dose of triamterene in combination with frusemide in healthy male adults.
Authors: van Meyel JJ , Smits P , Gribnau FW
Published: July 2012

In a study of cross‐over randomized design in 12 healthy volunteers we compared the effect on magnesium excretion after administration of single oral doses of frusemide 40 mg (F) and of frusemide 40 mg in combination with a single dose of triamterene 50 mg (F+T). F as well as F+T induced significant increases in volume, sodium and magnesium mean 24 h output as compared with 24 h renal excretion without medication. Addition of triamterene to frusemide significantly reduced the 24 h potassium excretion, but did not attenuate the excretion of magnesium. The time to reach the maximum magnesium excretion rate after F as well as after F+T administration was similar to that of the sodium excretion rate. We conclude that triamterene does not inhibit the magnesiuric effects of frusemide in healthy male adults.
Further development of a morphine hydrogel suppository.
Authors: Cole L. , Hanning CD , Robertson S. , Quinn K.
Published: July 2012

1. A sustained release monolithic morphine hydrogel suppository (MHS) was developed and administered to five volunteers. 2. The MHS delivered a mean of 55 mg morphine over 12 h. The mean plasma morphine concentration was 15 ng ml‐1 from 2 to 12 h after administration. 3. Plasma morphine concentrations were comparable with those reported for the same dose given orally over the same time period. 4. The morphine hydrogel suppository appears to be an effective means of delivering morphine and may be of value in the management of chronic pain.
Amphetamine‐like effects in humans of the khat alkaloid cathinone.
Authors: Brenneisen R. , Fisch HU , Koelbing U. , Geisshusler S. , Kalix P.
Published: July 2012

1. The chewing of khat leaves as a stimulant is common in certain countries, and the effects of this material are supposed to be due to the phenylalkylamine alkaloid cathinone. In order to determine the effects of this substance in humans, a single oral dose of cathinone or placebo was administered to six healthy male volunteers in a double‐ blind, random order crossover study. 2. Cathinone produced increases in blood pressure and in heart rate, and these changes were concomitant with the presence of cathinone in blood plasma. 3. The physical and mental changes that the subjects reported during the experiment indicated that cathinone has in humans euphorigenic and psychostimulant effects. 4. These observations support the assumption that cathinone is the constituent mainly responsible for the effects of khat, and they show that this alkaloid has also in humans amphetamine‐like effects.
An investigation of the role of metabolism in dapsone‐induced methaemoglobinaemia using a two compartment in vitro test system.
Authors: Tingle MD , Coleman MD , Park BK
Published: July 2012

1. We have utilized a two compartment system in which two teflon chambers are separated by a semi‐permeable membrane in order to investigate the role of metabolism in dapsone‐induced methaemoglobinaemia. Compartment A contained a drug metabolizing system (microsomes prepared from human liver +/‐ NADPH), whilst compartment B contained target cells (human red cells). 2. Incubation of dapsone (1‐ 100 microM) with human liver microsomes (2 mg protein) and NADPH (1 mM) in compartment A (final volume 500 microliters) led to a concentration‐ dependent increase in the methaemoglobinaemia (15.4‐18.9% at 100 microM) compared with control (2.3 +/‐ 0.4%) detected in the red cells within compartment B. In the absence of NADPH dapsone had no effect. 3. Of the putative dapsone metabolites investigated, only dapsone‐ hydroxylamine caused methaemoglobin formation in the absence of NADPH (40.6 +/‐ 6.3% with 100 microM). However, methaemoglobin was also detected when monoacetyl‐dapsone, 4‐amino‐4′‐nitro‐diphenylsulphone and 4‐aminoacetyl‐4′‐nitro‐diphenylsulphone were incubated with human liver microsomes in the presence of NADPH. 4 Dapsone‐dependent methaemoglobin formation was inhibited by addition of ketoconazole (1‐1000 microM) to compartment A, with IC50 values of 285 and 806 microM for the two liver microsomal samples studied. In contrast, methaemoglobin formation was not inhibited by cimetidine or a number of drugs pharmacologically‐ related to dapsone. The presence of glutathione or ascorbate (500 microM) did not alter the level of methaemoglobin observed.
Control of blood pressure in hypertensive patients with felodipine extended release or nifedipine retard.
Authors: Littler WA
Published: July 2012

1. This multicentre hospital study compared the antihypertensive efficacy and the tolerability of once daily felodipine extended release (ER) with twice daily nifedipine retard (R) in hypertensive patients inadequately controlled on metoprolol monotherapy. 2. One hundred patients, aged 20‐70 years, whose seated diastolic blood pressure was 100‐115 mmHg after 4 to 6 weeks of metoprolol (200 mg day‐1) monotherapy, were randomised, double‐blind, to receive felodipine ER 10 mg once daily or nifedipine R 20 mg twice daily for 8 weeks. The dosage of felodipine or nifedipine was doubled if seated diastolic blood pressure exceeded 95 mmHg, 2 or 4 weeks after randomisation. Metoprolol 200 mg once daily was taken throughout the trial. 3. Fifty‐one patients received felodipine ER and 49 nifedipine R; 46 and 45 respectively completed the 8 week trial. About half of patients on each treatment needed the higher dose. The baseline characteristics of the felodipine and nifedipine groups were generally well balanced. 4. Seated diastolic blood pressure was reduced by 17 mmHg for felodipine (24 h post‐dose) and by 9 mmHg for nifedipine (12 h post‐dose), a difference between treatments of 8 mmHg (95% confidence interval 5 to 12 mmHg, P less than 0.0001). The attained blood pressures at the end of the study (felodipine 90 +/‐ 10, mmHg, mean +/‐ s.d.; nifedipine 95 +/‐ 10) were also significantly different (95% confidence interval for the 5 mmHg difference, ‐9 to ‐1 mmHg, P less than 0.02).(ABSTRACT TRUNCATED AT 250 WORDS)
An evaluation of the alpha‐adrenoceptor antagonism produced by SK&F 86466 in healthy normotensive males.
Authors: Schafers RF , Elliott HL , Howie CA , Reid JL
Published: July 2012

SK&F 86466 is a novel, potent alpha‐adrenoceptor antagonist which, in animal experiments, is reported to show a high selectivity for alpha 2‐ adrenoceptors at both pre‐ and post‐junctional sites. The effects of two intravenous doses of 80 and 200 micrograms kg‐1 of SK&F 86466 were assessed in a placebo‐controlled, double‐blind, randomised study in eight young, healthy, normotensive males. Two indices of alpha‐ adrenoceptor activity were investigated: i) Pressor responsiveness to the relatively selective alpha 1‐adrenoceptor agonist phenylephrine and to the preferential alpha 2‐adrenoceptor agonist alpha‐ methylnoradrenaline. ii) Circulating levels of noradrenaline. SK&F 86466 at a dose of 200 micrograms kg‐1 produced rightward shifts of the pressor dose‐response curves to both agonists: a 1.4 fold shift for phenylephrine (P = 0.023) and a 1.6 fold shift for alpha‐ methylnoradrenaline (P = 0.051). Erect plasma noradrenaline sampled at 105 min into the infusion was significantly increased from 2.9 to 5.0 nmol l‐1 by SK&F 86466 200 micrograms kg‐1 (P = 0.002). The change in the phenylephrine responses indicates post‐junctional alpha 1‐ adrenoceptor blockade and the rise in noradrenaline is consistent with pre‐junctional alpha 2‐adrenoceptor antagonist activity. Overall the results of this study suggest that SK&F 86466, at a dose of 200 micrograms kg‐1, causes both alpha 1‐ and alpha 2‐adrenoceptor antagonism in human subjects.
Lack of effect of co‐trimoxazole on the pharmacokinetics and pharmacodynamics of nifedipine.
Authors: Edwards C. , Monkman S. , Cholerton S. , Rawlins MD , Idle J.R. , Ferner RE
Published: July 2012

The pharmacokinetics of nifedipine and its primary oxidised metabolite, M‐I were studied in nine healthy volunteers following a single oral dose of 20 mg nifedipine alone or after pretreatment with oral co‐ trimoxazole. Following pretreatment with co‐trimoxazole, no significant effect was detected on maximum plasma concentration, elimination half‐ life, or area under the plasma concentration‐time curve of either nifedipine or M‐I, nor on the blood pressure response to nifedipine.
Morphine sulphation in children.
Authors: Choonara I. , Ekbom Y. , Lindstrom B. , Rane A.
Published: July 2012

The metabolism of morphine was studied in nine children and seven preterm neonates receiving a continuous infusion of morphine. All the neonates and three children had detectable concentrations of morphine‐3‐ sulphate (M3S) in urine. None of the neonates or the children had detectable concentrations of morphine‐6‐sulphate (M6S) in urine. None of the children had detectable concentrations of M3S in plasma. The M3S/morphine ratios were significantly higher in neonates than children (P less than 0.01), suggesting that morphine sulphation decreases after the neonatal period. The amount of M3S formed, even in neonates, is low suggesting that this is a minor metabolic pathway.
Long term high dose morphine, ketamine and midazolam infusion in a child with burns.
Authors: Cederholm I. , Bengtsson M. , Bjorkman S. , Choonara I. , Rane A.
Published: July 2012

The metabolism of morphine and ketamine was studied in a 14 month old child with extensive burns, who received infusions of both drugs for more than 30 days. The mean plasma clearance of morphine was 29 ml min‐ 1 kg‐1 and the plasma ratios of morphine‐6‐glucuronide to morphine were similar to those previously reported in children. The mean plasma clearance of ketamine was 32 ml min‐1 kg‐1 which is greater than that previously reported in older children and adults. There were no complications despite high dose long term therapy with morphine, ketamine and midazolam.
Synthetic peptides of the hamster beta 2‐adrenoceptor as substrates and inhibitors of the beta‐adrenoceptor kinase.
Authors: Benovic JL , Onorato J. , Lohse MJ , Dohlman HG , Staniszewski C. , Caron MG , Lefkowitz RJ
Published: July 2012

1. The beta‐adrenoceptor is one of a number of G protein‐coupled receptors which have been proposed to contain seven transmembrane alpha‐ helices. The function of this receptor appears to be regulated by phosphorylation by a specific enzyme, the beta‐adrenoceptor kinase. Synthetic peptides which comprise each of the proposed intra‐ and extracellular domains of the beta 2‐adrenoceptor have been tested as potential substrates and inhibitors of the beta‐adrenoceptor kinase. 2. Two peptides which encompass the middle and terminal portions of the carboxyl tail of the receptor served as substrates by beta‐adrenoceptor kinase. The kinetics of the phosphorylation reaction, however, suggest that these peptides are 10(6)‐fold poorer substrate than the agonist occupied receptor. 3. A number of synthetic peptides also served as inhibitors of beta 2‐adrenoceptor phosphorylation by beta‐adrenoceptor kinase. In particular, a peptide which comprised the first intracellular loop of the beta 2‐adrenoceptor (amino acids 56‐74) inhibited most effectively with an IC50 of 40 microM. 4. These results suggest that multiple intracellular regions of the beta‐receptor may serve as potential sites of interaction with beta‐adrenoceptor kinase. Moreover, these regions may serve as potential targets for the development of specific inhibitors of beta‐adrenoceptor kinase which could be used to block homologous desensitization.
G protein coupling of receptors to ionic channels and other effector systems.
Authors: Birnbaumer L. , Yatani A. , VanDongen AM , Graf R. , Codina J. , Okabe K. , Mattera R. , Brown AM
Published: July 2012

1. Four questions raised by previous studies that had shown activation of K+ channels by alpha subunits of the type 3 Gi protein are addressed in the present communication: a) are K+ channels specific for one Gi? b) are there more ionic channels under direct G protein control? c) can we confirm using recombinant G alpha s the results obtained with biochemically resolved G alpha s and continue ascribing the regulatory effector to this part of the alpha beta gamma holo‐G protein? and d) can we confirm that a single G alpha, Gs alpha in this case, is able to affect more than one type of effector function? 2. We found Gi alpha s are isoforms, that there exist also Gi‐insensitive, Go‐responsive K+ channels and that G alpha s can be multifunctional. Thus, a single receptor will elicit cellular responses that will depend on the endogenous G protein as well as the type of effector function expressed in it. 3. In another set of experiments we found that G beta gamma s, be they derived from human erythrocytes, human placenta, bovine brain or bovine retina, all inhibit Gk‐gated K+ channel activity as seen in inside out membrane patches with GTP as the driving nucleotide. In addition we noted that inhibition was much more effective under basal (no agonist in the pipette) than agonist stimulated conditions, as reported in earlier experiments in which beta‐adrenoceptors, Gs and catalytic unit of adenylyl cyclase had been incorporated into phospholipid vesicles. 4. We propose that one of the roles of G beta gamma s in membranes is to quench ligand independent G protein activation by unoccupied receptors. Other roles of G beta gamma s are: a) by re‐associating with GDP‐G alpha s, to promote interaction with receptors, and b) by dissociating from activated R.G alpha *GTP.beta gamma, to allow for receptor dissociation from GTP‐activated G alpha s, which is required to satisfy the catalytic mode of receptor action.
Receptors, inositol polyphosphates and intracellular Ca2+.
Authors: Nahorski SR
Published: July 2012

1. A large number of cell‐surface receptors catalyse the activation of phospholipase C via a guanine nucleotide exchange protein and generate at least two important intracellular second messengers. One of these, inositol(1,4,5) trisphosphate, binds to specific intracellular receptors and releases Ca2+ from intracellular stores. 2. Subsequent metabolism of this messenger is complex, proceeding either by dephosphorylation or phosphorylation routes with the latter generating inositol(1,3,4,5) tetrakisphosphate which may have additional functional significance in Ca2+ homeostasis. 3. Calculations of the relative rates of metabolism through these routes as well as the development of new analogues of inositol polyphosphates have helped our understanding of these important cell signalling systems.
Independent sensitization of beta‐adrenoceptors and adenylate cyclase in acute myocardial ischaemia.
Authors: Strasser RH , Marquetant R. , Kubler W.
Published: July 2012

1. Acute myocardial ischaemia provokes sensitization of the adenylate cyclase system. This sensitization could be differentiated in a receptor‐linked and an enzyme‐linked sensitization. The increase in the number of beta‐adrenoceptors in the plasma membranes was observed already after 15 min of global ischaemia (50 +/‐ 2 to 67 +/‐ 6 fmol mg‐ 1 protein) and persisted after 50 min of ischaemia. The maximally isoprenaline‐stimulated adenylate cyclase activity rose from 66 +/‐ 7 to 100 +/‐ 10 pmol cAMP min‐1 mg‐1 protein after 15 min of global ischaemia indicating the receptor‐mediated sensitization of the beta‐ adrenergic system. However, after 50 min of ischaemia the isoprenaline‐ stimulated adenylate cyclase was reduced by about 50% despite the continuous increase of beta‐adrenoceptors in the plasma membranes. 2. Additionally direct stimulation of the adenylate cyclase by forskolin revealed an increased enzyme activity after 15 min of global ischaemia (300 +/‐ 20 vs 378 +/‐ 25 pmol cAMP min‐1 mg‐1). Prolonged periods of ischaemia, however, caused a decline of the total adenylate cyclase activity (232 +/‐ 24 pmol cAMP min‐1 mg‐1 protein). This demonstrates an enzyme‐specific sensitization of the adenylate cyclase, which in contrast to the rise in beta‐adrenoceptors is only transient. This enzyme‐specific sensitization or the late inactivation of the enzyme occur independently of receptor activation and cannot be prevented by beta‐adrenoceptor blockade (10(‐6) M alprenolol) prior to the ischaemic insult.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of DA1‐ and DA2‐receptors in the control of blood pressure.
Authors: Hieble JP , Eden RJ , de Mey C.
Published: July 2012

1. Endogenous dopamine, acting through specific receptors on blood vessels, renal tubules and adrenal cortical cells, may play a role in the development and maintenance of the hypertensive state. 2. In hypertensive patients, activation of the DA1‐receptor with intravenous fenoldopam produces a rapid and sustained reduction in blood pressure, in contrast to the tachyphylaxis seen in some rat models. 3. Activation of the DA2‐receptor also represents a viable antihypertensive approach, based on the chronic efficacy of hydergine. However, none of the recently developed selective DA2‐receptor agonists has been shown to reduce blood pressure in man. 4. Since animal experiments suggest qualitatively different antihypertensive profiles for quinpirole and SK&F 101468, both presumed to be selective agonists at the DA2‐ receptor, it may be possible to design new DA2‐receptor agonists more effective as antihypertensive drugs. 5. Dopamine receptors at different sites, even if of the same subtype, can be differentially regulated; this may be a consequence of activation of multiple second messenger systems by receptor occupation.
The role of 5‐hydroxytryptamine and 5‐hydroxytryptaminergic mechanisms in hypertension.
Authors: van Zwieten PA , Blauw GJ , van Brummelen P.
Published: July 2012

1. The possible role of 5‐hydroxytryptamine (5‐HT) and 5‐HT‐receptors in hypertension, already suggested by Page in 1954, has been subject to a renaissance of interest owing to the development of antihypertensive drugs which interact with 5‐HT‐receptors. These drugs, like ketanserin, urapidil and flesinoxan are used as tools to study the role of 5‐HT and its receptors in hypertension. 2. The following arguments would plead in favour of a certain role of 5‐HT and 5‐HT‐receptors in the pathogenesis and maintenance of hypertension: hyperresponsiveness of blood vessels from hypertensive patients and animals to 5‐HT‐induced constriction; the antihypertensive/vasodilator activity of the 5‐HT2‐ receptor antagonist ketanserin; enhanced sensitivity of platelets from hypertensives to 5‐HT. 3. However, at least as many arguments would deny a role of peripheral 5‐HT in hypertension, like for instance: the fact that 5‐HT is not a generally accepted pressor agent, whereas its concentration in the circulating blood is subthreshold; the hyperresponsiveness of vessels from hypertensives is not specific for 5‐ HT; the elevated local concentration of 5‐HT released by platelets is mainly limited to the microcirculation; the 5‐HT2‐receptor antagonist ketanserin is the only agent of this type which lowers blood pressure, other 5‐HT2‐receptor blockers like ritanserin and LY 53587 being inactive. 4. The various data and arguments available do not unequivocally support a relevant role of peripheral 5‐HT and its receptors in hypertensive disease.(ABSTRACT TRUNCATED AT 250 WORDS)
Atrial natriuretic peptide (ANP) as a neuropeptide: interaction with angiotensin II on volume control and renal sodium handling.
Authors: Unger T. , Badoer E. , Gareis C. , Girchev R. , Kotrba M. , Qadri F. , Rettig R. , Rohmeiss P.
Published: July 2012

1. Angiotensin II (ANG II) and atrial natriuretic peptide (ANP) are functionally antagonistic circulating hormones involved in blood pressure and body fluid regulation. An inappropriate atrial secretion of ANP has been implicated in the pathogenesis of hypertension, but clinical and experimental results on the role of ANP in hypertension are still conflicting. 2. In the brain both peptides have been localized in close proximity, preferentially in areas involved in central cardiovascular, electrolyte and volume control. ANP was shown to inhibit ANG II‐induced drinking, release of pituitary hormones and natriuresis, and to induce sodium retention when given alone. 3. These findings suggest that also in the brain ANG II and ANP exert functionally antagonistic effects. However, in contrast to their peripheral effects, ANG II induces natriuresis while ANP appears to cause antinatriuresis in the brain.
Contractions to 5‐hydroxytryptamine in human coronary artery and human saphenous vein.
Authors: Borton M. , Neligan M. , Wood F. , Dervan P. , Goggins K. , Docherty J.R.
Published: July 2012

Isometric contractions were obtained to 5‐hydroxytryptamine receptor agonists in human saphenous vein and human coronary artery. Based on the interaction with the 5‐HT2 receptor antagonist ketanserin, both 5‐ HT1 and 5‐HT2 receptors are involved in contractions of human saphenous vein, but the predominant subtype involved in contractions of human coronary artery is the 5‐HT1 receptor.