bluuebunny/crossref_metadata_2025 huggingface dataset:
Ranitidine and cimetidine; drug interactions with single dose and steady‐state nifedipine administration.
Authors: Smith SR , Kendall MJ , Lobo J , Beerahee A , Jack DB , Wilkins MR
Published: July 2012

The effect of ranitidine 300 mg once daily and cimetidine 800 mg once daily on the disposition of nifedipine was studied in two groups of 12 volunteers. Both investigations were placebo‐controlled cross‐over studies. The first group received ranitidine, cimetidine or placebo for 5 days with 20 mg nifedipine given on the 5th day. Each period was separated by 1 week. The second group received nifedipine 10 mg three times daily for 5 days together with the H2‐receptor antagonist or placebo. Cimetidine produced a significant increase in the AUC of both single and steady state dosing of nifedipine. Peak nifedipine levels were significantly increased only in the chronic dose study compared to placebo. Ranitidine did not produce any significant changes in either study.
Additive renal effects of indomethacin and dipyridamole in man.
Authors: Seideman P , Sollevi A , Fredholm BB
Published: July 2012

The effect of dipyridamole alone and in combination with indomethacin was studied in 11 water loaded rheumatic patients with normal kidney function. The adenosine uptake inhibitor dipyridamole and the prostaglandin synthesis inhibitor indomethacin decreased diuresis by 25‐ 50% when given alone and by approximately 80% when combined. These effects were not associated with changes in renal PAH‐clearance, but may be partially related to a fall in GFR. Sodium excretion was decreased in parallel with the fall in GFR. In addition, both indomethacin and dipyridamole reduced the free water clearance. Theophylline at therapeutic plasma levels reversed the reduction in GFR and transiently counteracted the inhibition of tubular water and sodium excretion induced by combined dipyridamole and indomethacin treatment. The results suggest that endogenous adenosine and prostaglandins are both involved in the control of renal function in man, and that drugs that affect these two autocoids may interact to cause adverse effects in man.
Prescribing habits for children with acute gastroenteritis: a comparison over 5 years.
Authors: Choonara IA , Shoo EE , Owens GG
Published: July 2012

Prescriptions for children with acute gastroenteritis, requiring hospital admission were compared for the first 3 months of 1980 and 1985. Thirty‐three children were identified in 1980 compared with 30 in 1985. Of these, 20 were prescribed a total of 46 drugs by their general practitioners in 1980 compared with 12 and 15 respectively in 1985. Although general practitioners still prescribed more medicines than did hospital doctors the improvement over 5 years was statistically significant (P less than 0.05).
Effect of guanfacine on ambulatory blood pressure and its variability in elderly patients with essential hypertension.
Authors: Dupont AG , Vanderniepen P , Six RO
Published: July 2012

The effect of guanfacine (2 mg once daily) on ambulatory blood pressure was studied with the Remler M 2000 recorder in 16 elderly hypertensive patients during a randomized, double‐blind, placebo‐controlled, balanced, cross‐over study. Guanfacine significantly reduced heart rate and systolic and diastolic ambulatory blood pressure. The antihypertensive effect was maintained over the whole recording period. Systolic and diastolic blood pressure variability was not changed by guanfacine, neither when defined as standard deviation or variation coefficient of the mean, nor when defined as the range between the highest and lowest ambulatory blood pressure, suggesting that blood pressure variability is unrelated to sympathetic nervous system activity.
The assessment in man of the beta‐adrenoceptor blocking activity and cardioselectivity of H‐I 42 BS, a long acting beta‐adrenoceptor blocking drug.
Authors: Pringle TH , Deering AH , Scott MG , Harron DW , Shanks RG
Published: July 2012

The pharmacokinetic and pharmacodynamic effects of the beta‐ adrenoceptor antagonist H‐I 42 BS were examined in healthy subjects. In an open dose ranging study, H‐I 42 BS 50, 100, 200 and 400 mg were given as single oral doses to four subjects. H‐I 42 BS 400 mg caused maximum reduction in exercise heart rate (20.4 +/‐ 1.0%‐mean +/‐ s.d.) at 4 h and still reduced exercise heart rate at 96 h (18.4 +/‐ 7.2%). Seven subjects received in double‐blind, randomised order, single oral doses of H‐I 42 BS 50, 100 and 200 mg, atenolol 50 and 100 mg and placebo. H‐I 42 BS 400 mg was given in a single blind manner as the last dose of the study. Both H‐I 42 BS and atenolol reduced supine and standing heart rate and systolic blood pressure (P less than 0.05) although atenolol had the more marked effect. The maximum percent reduction of exercise heart rate after H‐I 42 BS 50 mg was 10.9 +/‐ 7.1%, after 100 mg was 18.7 +/‐ 5.8%, after 200 mg was 20.6 +/‐ 6.4% and after 400 mg was 21.9 +/‐ 8.2%. H‐I 42 BS 400 mg still caused 11.0 +/‐ 3.5% reduction at 168 h. Atenolol 50 mg caused maximum percent reduction of exercise heart rate of 26.0 +/‐ 6.0% but did not reduce exercise heart rate after 24 h. The mean peak plasma concentrations for all doses of H‐I 42 BS occurred at 5.1 +/‐ 1.5 h. The plasma elimination half‐life was 47.6 +/‐ 8.1 h. There was a linear correlation between the dose and AUC0‐infinity (r = 0.97). The cardioselectivity of H‐I 42 BS and atenolol was compared. Six subjects received in double‐blind random order H‐I 42 BS 100 and 400 mg, atenolol 50 mg and placebo. After each dose, graded infusions of isoprenaline were given until the heart rate increased by 50 beats min‐ 1. Dose‐response curves for heart rate, diastolic blood pressure, forearm blood flow and finger tremor were constructed. There was no difference in the dose‐response curves for forearm blood flow or finger tremor after H‐I 42 BS 400 mg or atenolol 50 mg. Atenolol 50 mg caused more attenuation (P less than 0.01) of the diastolic blood pressure response. These results indicate that H‐I 42 BS is a cardioselective beta‐adrenoceptor antagonist with a long duration of action in man.
The renal, cardiovascular and hormonal actions of human atrial natriuretic peptide in man; effects of indomethacin.
Authors: Miyamori I , Ikeda M , Matsubara T , Okamoto S , Koshida H , Yasuhara S , Morise T , Takeda R
Published: July 2012

The renal, cardiovascular and hormonal effects of intravenous infusion of alpha‐human atrial natriuretic polypeptides (alpha‐hANP) at the concentrations of 0.0125, 0.025, 0.05, 0.1 microgram kg‐1 min‐1 for 20 min was studied in six male volunteers before and after indomethacin administration (150 mg day‐1, three times daily for 3 days). Dose‐ dependent diuresis and natriuresis were observed in all subjects between the concentrations of 0.025 and 0.1 microgram kg‐1 min‐1, which were not influenced by indomethacin. Diastolic blood pressure decreased significantly (P less than 0.05) at the higher dose (0.05 microgram kg‐ 1 min‐1) of alpha‐hANP, which was attenuated by indomethacin pretreatment. The plasma concentration of the immunoreactive alpha‐hANP was 73.7 +/‐ 25 pg ml‐1 on the control in subjects taking 200 mEq day‐1 of sodium, and significant diuresis occurred when plasma concentration reached approximately 330.5 +/‐ 74.4 pg ml‐1. alpha‐hANP infusion caused a dose‐dependent increase in cyclic GMP, no significant changes in plasma aldosterone and 18‐hydroxycorticosterone, which were not influenced by indomethacin pretreatment. Plasma renin did not change in response to alpha‐hANP infusion, which was significantly decreased (P less than 0.05) after indomethacin pretreatment. These results support that the renal effects of alpha‐hANP may be exerted by prostaglandin‐ independent mechanisms. The renal effects occur at lower doses, and cardiovascular changes occur at higher doses of alpha‐hANP.
Age‐dependence and free fatty acid modulation of binding kinetics at the benzodiazepine binding site of serum albumin in neonates and adults determined using fast reaction methods.
Authors: Menke G , Pfister P , Sauerwein S , Rietbrock I , Woodcock BG , Rietbrock N
Published: July 2012

Binding kinetics at the benzodiazepine binding site of albumin have been determined as a function of age and fatty acid concentration in serum from 32 neonates (umbilical cord blood), 28 adults aged 23‐65 years and 24 adults aged 66‐101 years using fluorescence‐time curves obtained in a Durrum‐Gibson stopped‐flow apparatus and the specific marker ligand dansylsarcosine. The binding reaction can be described by a 2‐step mechanism characterised by four constants: the association rate constant k2 and dissociation rate constant k‐2 for the rate limiting step‐2; the affinity constant KA' for the formation of an unstable intermediate complex in step‐1; the affinity constant KA for the overall reaction. There were marked differences in k2 between the three groups of subjects with highest values occurring in neonates (mean: 296 s‐1), intermediate values in adults aged 23‐65 years (mean: 200 s‐1, P less than 0.001) and lowest values in adults aged 66‐101 years (mean: 144 s‐1, P less than 0.001). The dissociation rate constants (k‐2) averaged 18.5 s‐1 overall, showed only minor changes with increasing age and corresponded to dissociation half‐lives of 42 ms, 38 ms and 33 ms for neonates, adults 23‐65 years and adults 66‐101 years respectively. KA' in neonates and in the group of elderly subjects were lower than in adults aged 23‐65 years.(ABSTRACT TRUNCATED AT 250 WORDS)
Plasma and whole blood mefloquine concentrations during treatment of chloroquine‐resistant falciparum malaria with the combination mefloquine‐sulphadoxine‐pyrimethamine.
Authors: Karbwang J , Looareesuwan S , Phillips RE , Wattanagoon Y , Molyneux ME , Nagachinta B , Back DJ , Warrell DA
Published: July 2012

Mefloquine‐sulphadoxine‐pyrimethamine (MSP) in combination has proved effective against multiple‐drug‐resistant falciparum malaria, but nothing is known about mefloquine absorption when it is given in this formulation. Nine Thai patients, aged 15‐51 years with uncomplicated chloroquine‐resistant falciparum malaria, took 11.2‐16.7 mg of mefloquine base per kilogram bodyweight as MSP tablets. All patients responded to treatment with fever and parasite clearance times of 61 +/‐ 29 h (mean +/‐ s.d.) and 52 +/‐ 24 h, respectively. The mean apparent absorption half‐time (t1/2abs) of mefloquine was 4.89 h (range 2.25‐ 9.72) and mean peak plasma concentration was 1815 ng ml‐1 (range 725‐ 3368). Peak plasma mefloquine concentrations in three patients who vomited within 2 h of treatment were 725, 956 and 1972 ng ml‐1. There was no significant difference between plasma and whole blood mefloquine concentrations during the first 48 h of treatment. Based on the elimination of parasitaemia, the plasma mefloquine concentrations are adequate for therapy of uncomplicated falciparum malaria although the relationship between plasma concentrations and therapeutic efficacy of mefloquine requires further study.
Placental transfer of flunitrazepam following intramuscular administration during labour.
Authors: Kanto J , Erkkola R , Kangas L , Pitkanen Y
Published: July 2012

After a single intramuscular dose of flunitrazepam 0.015 mg kg‐1 (n = 14) in women 37 to 41 weeks pregnant, the concentrations in the umbilical artery and amniotic fluid were significantly lower than in maternal venous plasma. Although the difference between the maternal venous and umbilical venous plasma concentrations was not significant, the mean fetomaternal ratio was 0.7. The plasma protein binding of flunitrazepam was 80 +/‐ 4% in the mother and 79 +/‐ 5% in the umbilical circulation. Both mothers and midwives subjectively estimated intramuscular flunitrazepam as a valuable sedative‐anxiolytic agent during the first stage of labour.
Pharmacokinetics of intravenous and oral sodium 2‐mercaptoethane sulphonate (mesna) in normal subjects.
Authors: James CA , Mant TG , Rogers HJ
Published: July 2012

The pharmacokinetics of mesna (sodium 2‐mercaptoethane sulphonate) and its inactive disulphide, dimesna, were investigated using high performance liquid chromatography in six normal subjects following intravenous and oral administration of 800 mg mesna. The mean maximum mesna concentration after i.v. administration was 111 (s.d. +/‐ 28.3) nmol ml‐1 and the mean maximum dimesna concentration was 183 (s.d. +/‐ 41.6) nmol ml‐1. Following oral mesna dosing the mean peak mesna concentration was 19.6 (s.d. +/‐ 10.2) nmol ml‐1 but mesna was only found in the plasma of five of the six subjects. The mean peak dimesna concentration was 22.5 (s.d. +/‐ 12.4) nmol ml‐1. Following i.v. mesna administration, the mean half‐life of mesna was 21.8 (s.d. +/‐ 3.1) min and total body clearance 1.23 (s.d. +/‐ 0.31) l kg‐1 h‐1. The mean half‐ life of dimesna was 1.17 (s.d. +/‐ 0.32) h. It was not possible to determine their half‐lives after oral mesna administration. The mean mesna concentration in the 0‐4 h urine collection was 9.6 (s.d. +/‐ 10.7; range 1.4‐28.7) nmol ml‐1 following i.v. mesna injection. After oral mesna the highest mesna concentration occurred in either the 0‐4 or 4‐8 h urine collections. The mean peak mesna concentration was 2.5 (s.d. +/‐ 1.7) mumol ml‐1 (c.f. estimated uroprotective concentration of 1.7 mumol ml‐1). The mean 4 h urinary clearance of the uroprotective species mesna was 0.413 (s.d. +/‐ 0.136) l kg‐1 h‐1. After both i.v. and oral mesna the urinary excretion of mesna is predominantly during the first 4 h.(ABSTRACT TRUNCATED AT 250 WORDS)
Interaction of mixed micelles formed from glycocholic acid and lecithin with the protein binding of various drugs.
Authors: Guentert TW , Oie S , Paalzow L , Frey BM , Brandt R , Aarons LJ , Rowland M
Published: July 2012

Mixed micelles (MM) formed from glycocholic acid and lecithin are suited to solubilize lipophilic drugs for intravenous use. To test for possible drug‐drug interactions, the protein binding of a series of agents known to bind to different sites on albumin (diazepam, warfarin, ketoprofen, frusemide, probenecid) and additionally (prazosin, quinidine, propranolol) or exclusively (disopyramide) to alpha 1‐acid glycoprotein or to transcortin (prednisolone) was determined in the presence and absence of MM. Concentrations of MM, corresponding to the maximum possible plasma concentration achieved by injecting the highest clinical doses of MM into the systemic circulation, had little or no effect on the unbound fractions of drugs known to bind exclusively to albumin. Only at five times higher MM concentrations were the free fractions substantially increased (by up to 45%). Unbound fractions of drugs bound with high affinity but low capacity to alpha 1‐acid glycoprotein were increased between 50‐85% even at ‘therapeutic’ doses of MM. The present study suggests that drugs solubilized by MM should be given by slow injection or infusion to patients already receiving drugs which are highly bound to alpha 1‐acid glycoprotein.
Ibopamine (SK&F 100168) pharmacokinetics in relation to the timing of meals.
Authors: Scott SC , Locke‐Haydon J , Pready NS , Buller NP , Cregeen RJ
Published: July 2012

The effect of the timing of a standard meal relative to a single oral dose of 200 mg ibopamine, on the appearance of its pharmacologically active metabolite, epinine, in plasma was investigated in a randomised crossover study in 12 healthy volunteers. After a 12 h fast, ibopamine was administered either in the fasting state (no meal), or 1 h before, 0.5 h before, immediately after, 2 h after or 3 h after a standardised meal. Blood samples taken immediately before and at intervals for 3 h after dosing were analysed for free epinine. Maximum concentration (Cmax), time to Cmax(tmax), and area under the concentration‐time curve (AUC) for free epinine in plasma were calculated. When compared with the fasting state, Cmax and AUC0‐3h were significantly reduced when ibopamine was given immediately after or 2 h after a meal. AUC was also reduced for ibopamine given 0.5 h before a meal. tmax was significantly delayed when ibopamine was given immediately after, or 2 or 3 h after a meal. Thus, administration of ibopamine with or shortly after a meal reduced the rate and extent of appearance of free epinine in plasma. The clinical significance of reduced epinine levels on acute dosing in the presence of food is unknown.
Oral nafazatrom in man: effect on inhaled antigen challenge.
Authors: Fuller RW , Maltby N , Richmond R , Dollery CT , Taylor GW , Ritter W , Philipp E
Published: July 2012

The effect of oral nafazatrom (Bay g6575, 2 × 3 g) or placebo on inhaled antigen challenge was assessed in a double‐blind study. In four subjects antigen challenge resulted in an immediate fall of 93.2 +/− 3.36% in airflow at 40% of vital capacity (Vp40) and a 45.85 +/− 4.95% reduction in forced partial expiratory volume at one second (FEV1). Neither nafazatrom nor placebo had any effect on baseline lung function or that after challenge. Leukotriene B4 was generated by ex vivo stimulus of blood with ionophore A23187, and quantified by high performance liquid chromatography (h.p.l.c.)‐radioimmunoassay. No inhibition of LTB4 formation occurred ex vivo following oral nafazatrom, although addition of 10(‐5) M nafazatrom to blood in vitro significantly inhibited LTB4 release. Peak plasma nafazatrom levels during the study ranged from 3.3 × 10(‐7) M to 1.47 × 10(‐6) M which are below the concentration (10(‐5) M) at which significant 5‐ lipoxygenase inhibition occurs in vitro. Oral nafazatrom is ineffective as a 5‐lipoxygenase inhibitor in man, probably because of poor bioavailability after administration.
Some observations on the effects of a calcium channel blocker, nitrendipine, in early human pregnancy.
Authors: Lawrence MR , Broughton Pipkin F
Published: July 2012

The effects of a dihydropyridine calcium channel antagonist, nitrendipine 20 mg orally, have been investigated in 24 women in the first trimester human pregnancy in a double‐blind, placebo controlled study. The effects on systemic arterial pressure, pulse rate (PR), blood loss at termination of pregnancy (TOP), plasma renin, renin substrate and aldosterone concentrations and platelet aggregation to adenosine diphosphate 0.5 microM, adrenaline bitartrate 0.1‐1.0 microM, thrombin 0.05 u ml‐1 and sodium arachidonate 0.1‐0.2 mM were studied. Administration of nitrendipine was associated with a statistically‐ significant fall in diastolic pressure (BPD) the magnitude of which was directly related to the individual peak concentrations of the drug (P less than 0.02). No significant effects were observed on systolic pressure (BPS);PR rose slightly. Baseline variability of all three parameters fell in the nitrendipine‐treated group over the first 2 h but then increased significantly (BPS, P less than 0.05; BPD, P less than 0.025; PR, P less than 0.005). There was a positive association in both placebo and treated groups between the rates of change of BPD and PR (P less than 0.005 for both); nitrendipine exerted a highly significant (P less than 0.001) effect on this association compatible with its effect as a vasodilator. Blood loss consequent on TOP did not differ in the two groups (nitrendipine 104 +/‐ 16 ml; placebo 114 +/‐ 20 ml). There were no significant differences in basal or stimulated hormone concentrations in the two groups. The ex vivo platelet aggregatory response in whole blood to 0.1 mM sodium arachidonate was inhibited by nitrendipine (P less than 0.05); responsiveness to the other aggregatory agents studied was not changed. There was a wide individual variation in both time to peak concentration of nitrendipine and the size of the peak, making classical pharmacokinetic analysis impossible. The median time after ingestion to peak concentration was 105 min; the median concentration was 7.8 ng ml‐1. These data suggest that, in the context of the severe vasoconstriction and platelet aggregability of pregnancy‐induced hypertension, further studies of this drug in pregnancy are warranted.
Intestinal metabolism of ethinyloestradiol and paracetamol in vitro: studies using Ussing chambers.
Authors: Rogers SM , Back DJ , Orme ML
Published: July 2012

The intestinal mucosal metabolism of ethinyloestradiol (EE2) and paracetamol (P) has been studied in vitro in Ussing chambers. Histologically normal jejunum or ileum was obtained from 19 patients undergoing various resections. The muscularis externa was stripped off the mucosa and the mucosal sheets mounted between two perspex chambers. Tissue viability was routinely assessed by measurement of the transmural potential difference. The percentage of steroid in the serosal chamber, 2 h after addition of EE2 (2 microCi; 80 ng) to the mucosal chamber was 2.3 +/‐ 0.8% (mean +/‐ s.d.) which comprised unconjugated drug (0.4 +/‐ 0.3%), sulphate conjugates (0.7 +/‐ 0.5%) and glucuronides (0.9 +/‐ 0.8%). In the mucosal chamber, 56.6 +/‐ 11.4% was unconjugated steroid, 33.3 +/‐ 12.4% sulphate conjugates and 2.1 +/‐ 2.3% glucuronides. Small amounts of the oxidation products 2‐hydroxy and 16‐hydroxy‐EE2 were present. At 2 h, the percentage of paracetamol in the serosal chamber was 3.2 +/‐ 1.4% (of added P; 2 microCi; 50 ng) of which 0.5 +/‐ 0.3% was paracetamol sulphate (PS) and 0.1% was paracetamol glucuronide (PG). In the mucosal chamber 2.4 +/‐ 0.8% and 1.0 +/‐ 0.2% was present as PS and PG respectively. The total amount of paracetamol conjugated was approximately 4.0%. When paracetamol in the mucosal chamber was increased to 50 micrograms (i.e. by a factor of 1000) there was a decrease in the percentage of added drug metabolized to PS and an increase in formation of PG. The glucuronide:sulphate ratio was increased from 0.34 to 3.56. Competition for sulphation was evident when both paracetamol and EE2 were presented to the intestinal mucosa.(ABSTRACT TRUNCATED AT 250 WORDS)
The paradoxical effect of cimetidine and ranitidine on glibenclamide pharmacokinetics and pharmacodynamics.
Authors: Kubacka RT , Antal EJ , Juhl RP
Published: July 2012

The potential interactions between H2‐receptor antagonists, cimetidine and ranitidine, and glibenclamide were studied in 15 non‐smoking male volunteers. The study consisted of six treatment phases. Treatment A (3 h oral glucose tolerance test) consisted of 75 g dextrose in 300 ml carbonated water. Treatment B consisted of one 5 mg tablet of glibenclamide in addition to a glucose tolerance test. Treatment C, cimetidine 300 mg orally four times daily for 4 days and Treatment D, ranitidine 150 mg orally twice daily for 4 days were administered in a randomized, crossover fashion. On day 3 of Treatments C and D, subjects received an oral glucose tolerance test. On day 4 of Treatments C and D, subjects received 5 mg of glibenclamide in addition to cimetidine (Treatment E) or ranitidine (Treatment F) and an oral glucose tolerance test. Compared with the control treatment, cimetidine increased the glibenclamide AUC (973 vs 710 ng ml‐1 h), but during ranitidine dosing glibenclamide AUC (726 ng ml‐1 h) was not significantly different from the control. Apparent oral glibenclamide clearance decreased from 8.25 l h‐1 under the control treatment to 6.0 l h‐1 following cimetidine but was unchanged during ranitidine (7.97 l h‐1). Plasma glucose concentrations were unexpectedly higher when glibenclamide was administered with cimetidine or ranitidine (glucose AUC 237 mg dl‐1 h, 228 mg dl‐1 h) when compared with glibenclamide administered alone (195 mg dl‐1 h, P less than 0.0001). Plasma insulin concentrations were significantly elevated when H2‐receptor antagonists and glibenclamide were administered concurrently.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics of erythromycin in patients with severe cirrhosis. Respective influence of decreased serum binding and impaired liver metabolic capacity.
Authors: Barre J , Mallat A , Rosenbaum J , Deforges L , Houin G , Dhumeaux D , Tillement JP
Published: July 2012

Pharmacokinetic parameters were studied after i.v. infusion of erythromycin (500 mg) in five patients with alcoholic cirrhosis and six normal subjects. Serum AAG levels were 4.7 +/− 2.4 mumol l‐1 in cirrhotics and 10.3 +/− 2.1 +/− mumol l‐1 in normals. The unbound fraction (fu) of erythromycin was significantly higher in cirrhotic patients (58.3 +/− 17.7%) than in normal subjects (30.5 +/− 2.8%, P less than 0.01), and a negative correlation was found between fu values and serum AAG (r = −0.867, P less than 0.01). Due to increase in fu, volume of distribution (Vss) was significantly augmented in cirrhotics (85.5 +/− 23.8 l vs 57.6 +/− 14.8 l, P less than 0.05). Serum clearance of unbound erythromycin (CLu) was significantly reduced in cirrhotic patients (42.2 +/− 10.1 l h‐1 vs 113.2 +/− 44.2 l h‐1 in normal subjects, P less than 0.01). This led to marked elevation of serum concentrations of unbound drug and was entirely explained by the decrease of non renal (i.e. hepatic intrinsic) clearance (31.6 +/− 7.5 l h‐1 in cirrhotics, 98.6 +/− 41.5 l h‐1 in normals, P less than 0.02); renal clearance remained unchanged. It is concluded that in cirrhotic patients, low serum AAG levels and reduced liver metabolic capacity may lead to marked changes in pharmacokinetics of erythromycin, and that similar results might be expected for drugs which exhibit the same serum binding and pharmacokinetic behaviour as erythromycin.
Effect of prostacyclin on the perfusion pressure and on the vasoconstrictor response of angiotensin II in the human isolated foetal placental circulation.
Authors: de Soares Moura R
Published: July 2012

The effect of prostacyclin infusion on the perfusion pressure and on the vasoconstrictor response to three doses of angiotensin II was investigated in six full‐term human placentas. The placentas were perfused with a modified Krebs‐Henseleit solution and placenta perfusion pressure was recorded. Prostacyclin 5 × 10(‐8) M, infused through the foetal placental circulation, produced a significant decrease in placental vascular resistance. The vasodepressor effect of prostacyclin persisted throughout the perfusion period and promptly disappeared when the infusion was stopped. The pressor response of angiotensin II was significantly reduced by prostacyclin infusion. These data suggest an interaction between the vascular effects of prostacyclin and angiotensin II on the placental circulation that might be important in the control of foetal placental blood flow.
The effects of propranolol and metoprolol on skin blood flow in diabetic patients.
Authors: Hyer SL , Taylor D , Barham J , Wilson J , Shaw J , Vince FP
Published: July 2012

The effect of 2 weeks treatment with propranolol or metoprolol on skin blood flow (SBF) at rest was examined in 12 diabetic patients with essential hypertension in whom gross large vessel disease had been excluded. Neither drug significantly altered resting skin blood flow. However we cannot exclude an important difference between the two beta‐ adrenoceptor blockers because of the great variability of SBF within subjects. A larger study and/or more accurate methods of measuring SBF are needed to determine if beta 1‐selective adrenoceptor antagonists differ from non‐selective beta‐adrenoceptor blockers with respect to skin blood flow.
Specificity of the inhibitory effect of dextropropoxyphene on oxidative drug metabolism in man: effects on theophylline and tolbutamide disposition.
Authors: Robson RA , Miners JO , Whitehead AG , Birkett DJ
Published: July 2012

Two groups of six healthy male volunteers were studied to assess the possibility of an interaction between dextropropoxyphene and theophylline or tolbutamide using a randomised, crossover design. Subjects received theophylline 125 mg 8 hourly or tolbutamide 500 mg i.v. with and without dextropropoxyphene hydrochloride 65 mg 8 hourly. Theophylline 8‐hydroxylation was reduced by a mean of 17% but there were no changes in theophylline 1‐demethylation, theophylline 3‐ demethylation or tolbutamide hydroxylation.
The importance of the response of the renin‐angiotensin system in determining blood pressure changes with sodium restriction.
Authors: MacGregor GA
Published: July 2012

There is controversy about the efficacy of sodium restriction in the treatment of hypertension. Short‐term restriction of sodium intake in normotensive subjects causes little or no fall in blood pressure. This lack of response of blood pressure to sodium restriction appears to be due, at least in part, to a reactive rise in renin and angiotensin II. In patients with essential hypertension there is suppression of the renin‐angiotensin system particularly as blood pressure becomes more severe. With sodium restriction there is less of a rise in renin and angiotensin II compared with normotensive subjects and patients have a greater fall in blood pressure compared with normotensive subjects but the effect is less in mild compared to severe hypertension. As the formation of angiotensin II can now be blocked by the use of a converting enzyme inhibitor, the combination of moderate salt restriction in conjunction with a converting enzyme inhibitor is likely to be more effective in lowering blood pressure than either treatment on its own.
Evolution of diuretics and ACE inhibitors, their renal and antihypertensive actions‐parallels and contrasts.
Authors: Lant AF
Published: July 2012

The emergence of diuretic drugs and angiotensin converting enzyme (ACE) inhibitors ranks amongst the major therapeutic advances of modern medicine. The discovery of these drug groups arose largely by chance, yet each has dramatically influenced the treatment of congestive cardiac failure and arterial hypertension. The central role which diuretics have had in the management of both oedema and hypertension hinges on their ability to induce a net renal excretion of solute and water by selective interference with either active or passive ion transport processes in different segments of the nephron. Irrespective of sites of action, the continued antihypertensive action of diuretics is characterized by a reduction in plasma volume and extracellular fluid (ECF) volume that lasts for as long as the diuretic is given. The mechanism of this effect remains unclear but may involve autoregulatory reactions that leave cardiac output unaltered but maintain a sustained reduction in total peripheral resistance. ACE inhibitors also lower blood pressure by decreasing total peripheral resistance, leaving cardiac output, plasma volume and ECF volume unchanged. The detailed way these haemodynamic changes are achieved remains unknown but inhibition of converting enzyme present not only in the kidney but also in many extrarenal tissue sites, appears important. In both hypertension and cardiac failure, however, the kidney acts as a key target organ for ACE inhibitors. The increased renal vascular resistance and inappropriate renal salt excretion are reversed with enhanced renal blood flow and saluresis. Both angiotensin II (AII) and vasopressin‐mediated contraction of glomerular mesangial cells is inhibited, making glomerular filtration more efficient. Reduced aldosterone secondary to blockade of AII formation contributes to saluresis whilst encouraging positive potassium balance. ACE inhibition also impairs breakdown of kinins which may contribute to intrarenal and peripheral vasodilation either on their own or via release of prostaglandins and other vasoactive substances. The hypotensive actions of diuretics are potentiated by ACE inhibition primarily through blockade of AII formation and prevention of secondary aldosteronism. In combination, these drugs permit low doses to be used because of their synergistic effects. Caution has to be exercised whenever ACE inhibition is used, without and especially with diuretics, in the management of renovascular hypertension and other low‐perfusion states. In these circumstances, AII plays an important autoregulatory role in preserving glomerular filtration through an increase in post‐glomerular resistance.(ABSTRACT TRUNCATED AT 400 WORDS)
Studies of mefloquine bioavailability and kinetics using a stable isotope technique: a comparison of Thai patients with falciparum malaria and healthy Caucasian volunteers.
Authors: Looareesuwan S , White NJ , Warrell DA , Forgo I , Dubach UG , Ranalder UB , Schwartz DE
Published: July 2012

1 A mefloquine hydrochloride tablet (250 mg base equivalent to 4.8 +/‐ 0.6 mg kg‐1; mean +/‐ s.d.) and deuterium labelled mefloquine hydrochloride solution (250 mg base) were given to six adult male Thai patients with acute falciparum malaria and six healthy Swiss adult male volunteers (equivalent to 3.5 +/‐ 0.1 mg kg‐1). 2 The relative bioavailability of the tablet formulation derived from comparison of the areas under the plasma concentration‐time curves was similar in both groups; 87 +/‐ 11% and 89 +/‐ 10% (mean +/‐ s.d.). 3 The rate of drug absorption appeared to be similar in the two groups but peak plasma mefloquine concentrations were approximately three times higher in the Thai patients (1004 +/‐ 276 ng ml‐1 for the tablet and 1085 +/‐ 280 ng ml‐1 for the suspension) compared with the Swiss volunteers (319 +/‐ 73 ng ml‐1 for the tablet, and 369 +/‐ 121 ng ml‐1 for the suspension). 4 Estimates of the oral clearance CLpo of unlabelled mefloquine were significantly lower (17.5 +/‐ 4.4 ml h‐1 kg‐1) in the Thai patients compared with 28.8 +/‐ 3.5 ml h‐1 kg‐1 in the Swiss volunteers; P less than 0.05). Terminal elimination half‐lives were significantly shorter in the patients (10.3 +/‐ 2.5 days) than in the volunteers (16.7 +/‐ 1.9 days; P less than 0.005). Differences of a similar magnitude were observed when comparing the pharmacokinetic parameters derived from the deuteromefloquine plasma concentrations. 5 Both genetic and disease related factors are likely to account for the large pharmacokinetic differences between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of triprolidine and dipipanone in the cold induced pain test, and the central nervous system of healthy volunteers.
Authors: Telekes A , Holland RL , Withington DA , Peck AW
Published: July 2012

1 Twelve healthy volunteers took part in a study of the interaction between the antihistamine triprolidine and the opioid dipipanone in the cold induced pain (CP) test and tests of sedation. They received placebo, triprolidine 2.5 mg, dipipanone 8 mg or the combination of the two active treatments according to a double‐blind, randomised, balanced, crossover design. 2 Antihistamine activity was demonstrated by triprolidine reducing the size of wheals and flares produced by intradermal histamine 1.6 micrograms. However, triprolidine produced no analgesia in the CP test, nor did it enhance the analgesia produced by dipipanone alone. 3 Neither treatment alone produced statistically significant sedation, assessed by visual analogue scales (VAS), side effect check list, body sway and reaction times. However, the combination did cause significant sedation. 4 Dipipanone reduced pupil size, depressed respiration, and decreased salivation. Triprolidine had no effects on pupil size and respiration, but reduced salivation slightly. It was concluded that histaminergic (H1) mechanisms are unlikely to be involved in pain produced by cold.
Effect of arachidonic acid on anthralin inflammation.
Authors: Lawrence CM , Shuster S
Published: July 2012

1 The effect of topical arachidonic acid on anthralin inflammation was studied using sequential measurements of erythema (reflectance photometry) and oedema (calipers). 2 Topical arachidonic acid in concentrations which produced a small short‐lived inflammatory response greatly augmented the initial phase and depressed the later phase of the inflammatory response to anthralin. 3 The initial augmentation was inhibited by concomitant administration of alpha‐tocopherol. 4 It is suggested that free radical formation by anthralin has a direct action on membrane substrates such as arachidonic acid forming inflammatory products by a non‐enzymic process.
Prolactin response to low dose sulpiride.
Authors: McMurdo ME , Howie PW , Lewis M , Marnie M , McEwen J , McNeilly AS
Published: July 2012

1 Prolactin levels in response to sulpiride were studied in healthy volunteers. 2 Oral doses of 1 mg‐50 mg sulpiride or placebo were given. 3 A 3 mg sulpiride dose produced similar levels to those achieved with both 10 mg and 50 mg. 4 Circadian effects were studied showing no significant differences in the prolactin response to sulpiride. 5 Acute or chronic responses showed an attenuation with chronic sulpiride treatment to 50% of the peak levels attained with acute treatment. 6 These results indicate that sulpiride retains its potent ability to produce prolactin release even at the low doses studied here.
Glucose tolerance in hypertensive patients during treatment with the calcium antagonist, felodipine.
Authors: Hedner T , Elmfeldt D , von Schenck H , Sjogren E , Smith U
Published: July 2012

1 Twelve non‐diabetic hypertensive male patients insufficiently controlled by a diuretic were included in a double‐blind, randomised study. In addition placebo or felodipine was given for 4 weeks followed by a 2 week wash‐out period, after which the alternative treatment was given for another 4 weeks. At the end of each treatment period an oral glucose tolerance test (OGTT) was performed and blood pressure, plasma noradrenaline and felodipine levels were measured. 2 There was no change in either glucose, insulin or glucagon levels during the OGTT after felodipine compared with placebo. Blood pressure was significantly reduced during the dosage interval of felodipine (12 h). Plasma noradrenaline increased significantly after felodipine. Side effects were few. 3 In a separate open study 58 hypertensive patients were treated with felodipine in addition to a diuretic and a beta‐ adrenoceptor blocker for up to 1 year. There were no significant changes in fasting blood glucose levels during the study.
N‐monodesmethyldiltiazem is the predominant metabolite of diltiazem in the plasma of young and elderly hypertensives.
Authors: Montamat SC , Abernethy DR
Published: July 2012

1 Twelve young (ages 30‐39 years) and twelve elderly (ages 65‐83 years) hypertensives were administered diltiazem twice daily for 2 weeks at doses up to 240 mg day‐1. 2 Plasma was analysed for diltiazem, N‐ monodesmethyldiltiazem, and desacetyldiltiazem concentrations after a single 10 min intravenous infusion of 21.8 mg diltiazem HCl on day 1 and after the morning oral dose of 120 mg diltiazem base on day 14. 3 N‐ monodesmethyldiltiazem accumulated to higher plasma concentrations than desacetyldiltiazem at steady state on day 14 in both age groups. 4 Prolongation of plasma diltiazem half‐life occurred after 2 weeks of oral diltiazem therapy in both age groups. 5 There were no significant differences between the young and elderly with regard to half‐life, area under the curve, and the peak and trough plasma concentrations of diltiazem, N‐monodesmethyldiltiazem, and desacetyldiltiazem; systemic clearance and volume of distribution of diltiazem were also similar in both groups.
Disopyramide protein binding in plasma from patients with nephrotic syndrome during the exacerbation and remission phases.
Authors: Echizen H , Saima S , Ishizaki T
Published: July 2012

1 Plasma protein binding of disopyramide was determined twice in plasma from seven patients with severe nephrotic syndrome when the disease activity was markedly different for each patient (mean +/‐ s.d. of serum albumin 21 +/‐ 4 vs 29 +/‐ 3 g l‐1 (P less than 0.05), proteinuria 13.6 +/‐ 9.6 vs 2.2 +/‐ 1.7 g day‐1 (P less than 0.01), and alpha 1‐acid glycoprotein 0.34 +/‐ 0.12 vs 0.95 +/‐ 0.28 g l‐1 (P less than 0.01) during the exacerbation vs remission phases, respectively). 2 Plasma samples containing disopyramide at the concentrations of 0.2‐ 12.0 micrograms ml‐1 were analysed by ultrafiltration. The free fractions at the proposed therapeutic concentration range (2.0‐6.0 micrograms ml‐1) were significantly (P less than 0.01) greater during the exacerbation phase than during the remission phase. 3 Multiple linear regression analysis revealed that the free fraction of disopyramide at 3.0 micrograms ml‐1 correlated much better with alpha 1‐ acid glycoprotein (partial correlation coefficient = 0.85, P less than 0.01) than with albumin (partial correlation coefficient = 0.25, P less than 0.05). 4 The binding data of disopyramide analysed by a model assuming one specific binding site and nonspecific binding(s) demonstrated that the capacity constant correlated significantly (r = 0.97, P less than 0.001) with plasma alpha 1‐acid glycoprotein. 5 The results suggest that a total concentration of disopyramide within the therapeutic range may not be a reliable guide for a safe dosing scheme in patients with severe nephrotic syndrome, particularly during the exacerbation period.(ABSTRACT TRUNCATED AT 250 WORDS)
Pharmacokinetics and renal elimination of desferrioxamine and ferrioxamine in healthy subjects and patients with haemochromatosis.
Authors: Allain P , Mauras Y , Chaleil D , Simon P , Ang KS , Cam G , Le Mignon L , Simon M
Published: July 2012

1 Desferrioxamine mesylate (DM) (10 mg kg‐1 = 15.24 mumol kg‐1) was given by intramuscular injection to five healthy subjects and to six patients with haemochromatosis, after informed consent. 2 Desferrioxamine (DFA), ferrioxamine (FeA), aluminoxamine (AlA), aluminium (Al) and iron (Fe) were measured in plasma, before and 10, 20, 30, 60 min and 2, 4, 6, 8, 12 h after DM injection and in urine collected over a 6 h period the day before and the day of administration. 3 The predominant form in plasma from control subjects was DFA whereas FeA predominated in plasma from patients. In controls, rapid and slow phases of decline in plasma DFA concentrations were found, with half‐lives of 1.0 h and 6.1 h, respectively. In the patients, only a single phase of decline was observed, with a half‐life of 5.6 h. Total clearances of DFA were 296 ml h‐1 kg‐1 in controls and 239 ml h‐1 kg‐1 in patients. 4 The amount of FeA eliminated in urine during 6 h was significantly lower in controls (8.0 +/‐ 4.6 mumol) than in patients (129.2 +/‐ 40.0 mumol), with respective renal clearances estimated over 6 h of 516 ml h‐1 kg‐1 and 1,716 ml h‐1 kg‐1. DFA elimination was similar in both groups and its renal clearance estimated over 6 h was 91 ml h‐1 kg‐1 in controls and 85 ml h‐1 kg‐1 in patients. 5 Since there was no overlap in the 1 h DFA/FeA plasma ratio between controls and patients, this might be useful as an index of iron overload.
Histamine and allergen induced changes in nasal airways resistance measured by anterior rhinomanometry: reproducibility of the technique and the effect of topically administered antihistaminic and anti‐ allergic drugs.
Authors: Corrado OJ , Ollier S , Phillips MJ , Thomas JM , Davies RJ
Published: July 2012

1. Changes in nasal airways resistance (NAR) following the topical application of histamine and allergen solutions were measured by passive anterior rhinomanometry. 2. The repeatability of five consecutive measurements of resting NAR prior to provocation with histamine or allergen (expressed as the coefficient of variation) was 32.8% and following instillation of saline control solution 37.2%. 3. The repeatability of five consecutive measurements of NAR during the nasal obstruction produced by histamine and allergen was similar to that recorded prior to provocation; the coefficients of variation (median values) being 39.6% and 33.1% respectively. The degree of variability was not related to the dose of agonist or the degree of nasal obstruction. 4. The reproducibility of histamine or allergen induced changes in NAR on four separate weekly occasions showed no significant intra‐subject differences. 5. The effects of sodium cromoglycate (SCG), clemastine and ketotifen administered to the nasal mucosa 30 min before provocation with histamine and allergen were compared in a random order, double‐blind, placebo controlled study. 6. Clemastine and SCG, but not ketotifen, significantly inhibited the nasal response to increasing concentrations of histamine. None of the drugs administered in the concentrations used in this study significantly inhibited the nasal response to allergen.
Effect of food and various antacids on the absorption of tenoxicam.
Authors: Day RO , Lam S , Paull P , Wade D
Published: July 2012

1 Twelve healthy volunteers received a single oral dose of tenoxicam 20 mg on six occasions separated by 3 weeks. 2 The six occasions were: fasted overnight; postprandial; fasting and 15 ml aluminium hydroxide gel; postprandial and 15 ml aluminium hydroxide gel; fasting and 15 ml aluminium and magnesium hydroxide gel; postprandial and 15 ml aluminium and magnesium hydroxide gel. 3 Twenty plasma samples were collected over 15 days following dosing with tenoxicam. 4 The following kinetic parameters for plasma tenoxicam were compared: peak concentrations, time taken to reach peak concentrations, area under the plasma concentration‐time curve (AUC) and half‐life of elimination. 5 Food lengthened the time taken to reach peak tenoxicam concentrations (5.82 +/‐ 4.6 vs 1.84 +/‐ 1.0 h in the fasting state; P less than 0.02) and marginally reduced the peak concentrations achieved. AUC was not affected by any of the different regimens. 6 These effects of food on tenoxicam bioavailability are unlikely to be of clinical significance during chronic dosing with the drug.
Jejunal and ileal absorption of oxprenolol in man: influence of nutrients and digestive secretions on jejunal absorption and systemic availability.
Authors: Godbillon J , Vidon N , Palma R , Pfeiffer A , Franchisseur C , Bovet M , Gosset G , Bernier JJ , Hirtz J
Published: July 2012

1 Study I evaluated the absorption of oxprenolol in the ileum, compared to jejunum, in healthy volunteers by an intestinal perfusion technique. Around 80 mg of drug were delivered as a saline solution directly in the small bowel. 2 Samples taken 30 cm distally to the site of perfusion showed that 63% of perfused oxprenolol was absorbed in the jejunum and 48% in the ileum; the differences were significant. 3 The plasma concentration‐time profiles were similar for the two perfusions. The AUC and Cmax values of free and conjugated oxprenolol for the jejunal perfusion were significantly lower than those of ileum. They showed large but consistent intersubject variations in the two treatments. 4 Study II investigated, using the same technique, the influence of nutrients and digestive secretions on jejunal absorption and systemic availability of this drug. A saline (in treatments A and B) or a nutrient (in treatment C) solution containing oxprenolol was perfused into the jejunum below a balloon either inflated (A) or deflated (B and C). 5 The disappearance rate of oxprenolol from the jejunum was unaffected by endogenous secretions. The mean amount of drug absorbed along a 30‐cm jejunal segment accounted for 52 (A) and 57% (B) of the total amount perfused. The intestinal absorption rate was markedly increased in the presence of nutrients (mean amount absorbed 96% for C). 6 The change in the rate of disappearance from the intestine had no effect on the systemic availability of oxprenolol (mean AUC values 8740, 8250 and 8020 nmol l‐1 h for A, B and C, respectively) or its elimination from plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Post marketing surveillance of captopril (for hypertension): a preliminary report.
Authors: Chalmers D , Dombey SL , Lawson DH
Published: July 2012

1 The methodology and interim results of a post marketing surveillance of captopril, the first orally active angiotensin converting enzyme inhibitor are presented. 2 Utilising viewdata technology, details of hypertensive patients were entered directly into a mainframe computer. This allowed day to day monitoring of events; a facility not available with paper‐based methods. 3 The design of the study allowed analysis of results including some details of efficacy, concomitant therapy, any disease symptoms and reasons for withdrawal. These factors could be categorised according to sex and age. 4 This preliminary report is based on the first 13,295 patients entered from July 1983 with follow‐ up until January 1985. The results of the study confirm the safety of captopril in the patients studied.