bluuebunny/crossref_metadata_2025 huggingface dataset:
Absolute bioavailability and pharmacokinetics of medifoxamine in healthy humans.
Authors: Saleh S , Johnston A , Turner P
Published: July 2012

Medifoxamine is a new monoamine re‐uptake inhibiting antidepressant drug. Twelve volunteers received 100 mg by i.v. infusion over 15 min and 500 mg by mouth fasting. The treatments were given 1 week apart in a randomised cross‐over design. Venous blood samples (10 ml) were taken at intervals for 24 h for h.p.l.c. measurement of serum medifoxamine. A biexponential decline of serum medifoxamine concentration was observed after intravenous administration in all subjects and similar terminal elimination half‐lives were observed following both routes, indicating that oral absorption is not rate‐limiting. The absolute bioavailability of oral medifoxamine was 21%.
The influence of food on the pharmacokinetics of CGP 6140 (amocarzine) after oral administration of a 1200 mg single dose to patients with onchocerciasis.
Authors: Lecaillon JB , Dubois JP , Soula G , Pichard E , Poltera AA , Ginger CD
Published: July 2012

Eleven male patients from Mali with Onchocerca volvulus infections received in random order a 1200 mg single oral dose of CGP 6140 after an overnight fast and after food intake. The concentrations of CGP 6140 and of its N‐oxide metabolite, CGP 13231, were measured in plasma and urine. Mean (+/− s.d.) AUC CGP 6140 values were 67.0 +/− 10.8 mumol l‐1 h in fed and 22.0 +/− 17.2 mumol l‐1 h in fasting patients. The mean maximum concentrations (Cmax) in plasma +/− s.d. were 12.7 +/− 2.8 mumol l‐1 in fed and 4.7 +/− 4.1 mumol l‐1 in fasting patients. The median time to Cmax was 3 h in fed and 2 h in fasting patients. Mean (+/− s.d.) AUC of the N‐oxide metabolite was 59.9 +/− 10.7 mumol l‐1 h in fed and 23.4 +/− 16.2 mumol l‐1 h in fasting patients. The urinary recovery was less than 0.5% of dose for CGP 6140 in both fed and fasting conditions. It was 30.1 +/− 11.5 and 11.4 +/− 8.0% of the dose for the N‐oxide metabolite in fed and fasting conditions, respectively. Variability in plasma concentrations and urinary recovery of CGP 6140 and of the N‐oxide metabolite was greater in fasted patients. The low solubility of CGP 6140 in aqueous solutions at neutral pH and its higher solubility at acidic pH might explain the increase in bioavailability after food intake. The administration of CGP 6140 after food intake is therefore recommended for an optimal systemic effect.
Binding studies of platelet alpha 2‐ and lymphocyte beta 2‐ adrenoceptors in patients with cirrhosis.
Authors: MacGilchrist AJ , Deighton NM , Hamilton CA , Reid JL
Published: July 2012

Radioligand binding studies were performed on 10 patients with cirrhosis and 10 healthy subjects. Bmax and KD of platelet alpha 2‐ adrenoceptors, studied using [3H]‐yohimbine, were similar in both groups (Bmax 24.9 vs 22.1 fmol/10(9) platelets, P = 0.47; KD 4.6 vs 5.5 nmol 1‐1, P = 0.56). Bmax and KD of lymphocyte beta 2‐adrenoceptors, studied using [125I]‐iodocyanopindolol, were also similar in both groups (Bmax 24.0 vs 27.2 fmol mg‐1 protein, P = 0.55; KD 49.6 vs 55.3 pmol 1‐1, P = 0.65). In this model there is no evidence of adrenoceptor down‐regulation in cirrhosis despite the increased sympathetic activity in this condition.
D‐penicillamine does not increase urinary bismuth excretion in patients treated with tripotassium dicitrato bismuthate.
Authors: Nwokolo CU , Pounder RE
Published: July 2012

Twenty‐four urinary bismuth excretion was measured in five patients who had been treated with tripotassium dicitrato bismuthate, before and after single 1 g oral dose of D‐penicillamine. Before dosing with D‐ penicillamine, the median 24 h urinary bismuth output was 55 micrograms 24 h‐1 (range 17‐156 micrograms 24 h‐1) and following dosing with D‐ penicillamine the median 24 h urinary bismuth output was 53 micrograms 24 h‐1 (range 12‐156 micrograms 24 h‐1). D‐penicillamine does not facilitate the urinary excretion of bismuth, hence it is unsuitable for use as an oral chelator in patients with bismuth intoxication.
A comparison of dilevalol and placebo in the management of isolated systolic hypertension using ambulatory monitoring.
Authors: Silagy CA , McNeil JJ , Farish S , McGrath BP
Published: July 2012

1. The antihypertensive effect of dilevalol, a compound which combines beta‐adrenoceptor blocking and vasodilating properties due to beta 2‐ adrenoceptor agonism, was studied in nineteen patients with isolated systolic hypertension (ISH). A randomized, double‐blind, placebo‐ controlled, cross‐over trial with two 4 week treatment periods was used to compare the efficacy of once daily dosing with dilevalol (in the range of 100‐400 mg daily) against placebo. Assessment of response involved both casual blood pressure readings (amongst all patients) and 24 h ambulatory blood pressure monitoring (in ten of the nineteen patients). 2. A mean fall of 12/5 mm Hg (s.e. mean 3/2, P less than 0.05) and 9/3 mm Hg (s.e. mean 3/2, P less than 0.05) in supine and standing blood pressure respectively was observed with dilevalol. Mean heart rate was unchanged. The ambulatory monitoring profile demonstrated a smaller reduction in mean blood pressure (7/8 mm Hg) over the 24 h period and a reduction of 10/11 mm Hg over the daytime period. A blunting of the early morning increase in systolic pressure was observed with dilevalol. 3. The drug was well tolerated with light headedness and lethargy being reported more commonly than with placebo. Biochemical parameters were unaffected. 4. It is concluded that dilevalol in the doses used has a small but measurable antihypertensive effect as monotherapy in the treatment of ISH.
Selective beta‐adrenoceptor partial agonist effects of pindolol and xamoterol on skeletal muscle assessed by plasma creatine kinase changes in healthy subjects [see comments]
Authors: Tomlinson B , Cruickshank JM , Hayes Y , Renondin JC , Lui JB , Graham BR , Jones A , Lewis AD , Prichard BN
Published: July 2012

1. The effects of selective beta‐adrenoceptor partial agonist activity on plasma creatine kinase (CK) and skeletal muscle symptoms were studied in normal volunteers. 2. A drug with beta 1‐selective partial agonist activity (xamoterol) and one with partial agonist activity acting mainly through beta 2‐adrenoceptors (pindolol) were each given for 3 weeks in a randomised double‐blind crossover study in 10 subjects. Five additional subjects received only one drug. Plasma CK levels were monitored during a baseline placebo run‐in phase, the active treatment period and a placebo washout phase which continued until CK levels returned to baseline. 3. The degree of beta‐ adrenoceptor antagonism was determined by the inhibition of exercise‐ induced tachycardia and was similar for the two drug doses used. 4. During pindolol administration plasma CK levels rose compared with pretreatment baseline levels and with levels during xamoterol administration which did not rise. After pindolol was withdrawn CK levels reached higher peaks in some subjects after 1‐5 days. 5. Muscle cramps were reported by five subjects during pindolol administration and by one of these subjects but to a lesser extent during xamoterol administration. 6. Pindolol may produce this effect, which was not seen with xamoterol, because of its specific beta 2‐adrenoceptor partial agonist activity. Elevations in plasma CK produced by this type of drug or its withdrawal may cause confusion in the diagnosis of muscle disease or myocardial infarction unless the myocardial isoenzyme is measured.
Beta‐adrenoceptors in human alveolar macrophages isolated by elutriation.
Authors: Hjemdahl P , Larsson K , Johansson MC , Zetterlund A , Eklund A
Published: July 2012

1. beta‐adrenoceptors on human alveolar macrophages obtained by bronchoalveolar lavage (BAL) from healthy smoking volunteers (n = 26) were characterized by studying cyclic AMP (cAMP) accumulation in intact macrophages evoked by adrenaline or isoprenaline, with or without appropriate antagonists and by radioligand binding to macrophage membranes, using [125I]‐iodopindolol (125IPIN) as beta‐adrenoceptor ligand. 2. In a second study, cAMP responses of alveolar macrophages to isoprenaline and PGE1 and of peripheral blood lymphocytes to isoprenaline were compared in smoking and non‐smoking healthy volunteers (n = 9 + 9), as our initial studies were performed in smokers, due to their higher cell yield. 3. BAL yielded 47 +/− 23 × 10(6) cells in smokers and 12 +/− 6 × 10(6) cells in non‐smokers with a recovery of 82 +/− 8% in the elutriation step (means +/− s.d.). The cell preparation consisted of 99.2 +/− 0.8% macrophages and their viability (trypan blue exclusion) was 97.5 +/− 5.2%. 4. Isoprenaline or adrenaline increased cAMP accumulation approximately 40‐fold with or without the phosphodiesterase inhibitor isobutylmethylxanthine (IBMX, 10(‐4) M), which enhanced basal and stimulated cAMP accumulation approximately five‐fold. Peak responses were seen after 2 min. EC50s for isoprenaline and adrenaline were 3‐5 × 10(‐7) M. Phentolamine did not alter responses to adrenaline, indicating absence of inhibitory alpha 2‐adrenoceptors. Propranolol inhibited isoprenaline induced cAMP accumulation stereoselectively; pD2‐values were 8.2 for (‐)‐ propranolol, 5.6 for atenolol and 7.5 for ICI 118,551, suggesting a predominance of beta 2‐adrenoceptors. 5. Specific 125IPIN binding to macrophage membranes was rapid and saturable. Non‐specific binding was determined in the presence of 1 microM (‐)‐propranolol. KD values were 71 +/− 7 pM and the density of specific binding sites was 36 +/− 3 fmol mg‐1 protein (three experiments on a membrane pool from 10 subjects; r values for Scatchard analyses = 0.98 +/− 0.01). Similar values were obtained when 200 microM isoprenaline (+ GTP) was used to assess non‐ specific binding. Competition experiments again showed stereoselectivity for propranolol and a predominance of beta 2‐ adrenoceptors, as judged by the displacement of specific 125IPIN binding by atenolol and ICI 118,551. 6. Macrophages from smokers responded with less marked cAMP accumulation upon stimulation with isoprenaline or PGE1 than did cells from non‐smokers (difference approximately 30%; P less than 0.05 for both agonists) in the presence of IBMX. Thus macrophages from smokers may produce less cAMP due to post‐receptor changes in responsiveness.(ABSTRACT TRUNCATED AT 400 WORDS)
Betaxolol and glucose‐insulin relationships: studies in normal subjects taking glibenclamide or metformin.
Authors: Sinclair AJ , Davies IB , Warrington SJ
Published: July 2012

1. The potential interaction between selective beta 1‐adrenoceptor blockers and sulphonylureas or biguanides was studied by comparing the beta 1‐adrenoceptor antagonist betaxolol with placebo in 12 normal subjects taking glibenclamide or metformin in a single‐blind crossover group study. 2. After a 4 day run‐in period on no treatment, six subjects took glibenclamide 2.5 mg twice daily, and six subjects took metformin 850 mg twice daily from day 5 to day 19. All subjects took betaxolol 20 mg daily from day 10 to day 13, and placebo from day 5 to day 10 and from day 13 to day 19. 3. Plasma glucose and insulin concentrations were measured fasting and 60 min after a standard breakfast for 3 successive days during each study treatment; plasma potassium, sodium and betaxolol concentrations were also measured. 4. Fasting glucose, insulin and potassium concentrations did not differ significantly between betaxolol and placebo treatment periods in either glibenclamide‐ or metformin‐treated groups. Post‐prandial glucose and insulin concentrations were lower and higher, respectively, relative to fasting concentrations but there was no significant difference between any of the treatment periods. Glibenclamide produced significant increases in insulin concentrations compared with drug‐free periods (P less than 0.01). Plasma potassium and sodium concentrations were not affected by any of the treatments. 5. Plasma betaxolol concentrations were adequate for beta 1‐adrenoceptor blockade. 6. This study suggests that selective beta 1‐adrenoceptor blockade with betaxolol does not change fasting or post‐prandial glucose‐insulin relationships during simultaneous treatment with either the sulphonylurea glibenclamide or the biguanide metformin.
Sleep laboratory studies on single dose effects of suriclone.
Authors: Saletu B , Frey R , Grunberger J , Krupka M , Anderer P , Musch B
Published: July 2012

1. In a double‐blind, placebo‐controlled sleep laboratory study single doses of suriclone, a new non‐benzodiazepine anxiolytic binding to benzodiazepine receptors, were investigated with respect to sleep and awakening. 2. Sixteen healthy young volunteers spent 10 nights in the sleep laboratory: 1 adaptation night, 1 baseline night and 4 drug nights (placebo; 0.2 mg, 0.4 mg suriclone; 2 mg lorazepam as reference drug) and 4 subsequent wash‐out nights (drug‐interval: 1 week). Somnopolygraphic investigations (22.30 h to 06.00 h) were commenced 0.5 h after drug‐intake. A self‐rating scale for sleep and awakening quality as well as psychometric tests were completed in the morning. 3. Hypnotic effects were most pronounced after lorazepam in regard to total sleep time and sleep efficiency. After lorazepam as well as after 0.4 mg suriclone nocturnal awakenings decreased significantly as compared with placebo, which was reflected in an improved subjective sleep quality after both dosages. Suriclone 0.2 mg did not induce any alterations in all night sleep. 4. In the morning, well‐being, drowsiness and reaction time performance deteriorated after lorazepam as compared with placebo but not after suriclone. The latter was significantly superior to lorazepam with respect to subjective awakening quality, well‐being, emotional rapport, drowsiness and attention. 5. Blood pressure and pulse remained unchanged after all of the drugs. Critical flicker frequency and muscle strength decreased only after lorazepam as compared with placebo.
A double‐blind, placebo controlled, cross‐over comparison of the analgesic effect of ibuprofen 400 mg and 800 mg on laser‐induced pain.
Authors: Nielsen JC , Bjerring P , Arendt‐Nielsen L , Petterson KJ
Published: July 2012

1. The analgesic efficacy of single oral doses (400 mg, 800 mg) of ibuprofen on argon laser‐induced pain was studied in a double‐blind, placebo controlled, three way cross‐over comparison. Ten healthy volunteers participated. 2. Pain thresholds and plasma concentrations of the S‐ and R‐enantiomers of ibuprofen were measured every hour up to 8 h after medication. 3. Ibuprofen (400 mg) produced an analgesic effect significantly superior (P less than 0.05) to placebo 1‐4 h after medication. Ibuprofen (800 mg) was significantly superior to placebo 2‐ 4 h after administration. No differences were found between 400 mg and 800 mg, when hourly threshold differences were compared. 4. Comparing total analgesic effect (area under effect curve), both active medications were superior to placebo (P less than 0.01‐0.05), and 400 mg was superior to 800 mg (P less than 0.05). 5. Peak plasma concentrations of S‐ and R‐ibuprofen occurred between 1.2 and 1.5 h. Concentrations after the 800 mg dose were higher than those after the 400 mg dose at all times.
End‐stage renal disease and non‐narcotic analgesics: a case‐control study.
Authors: Morlans M , Laporte JR , Vidal X , Cabeza D , Stolley PD
Published: July 2012

1. To assess the risk of end‐stage renal disease (ESRD) associated with the regular use of three classes of non‐narcotic analgesics, we performed a case‐control study of 340 patients with ESRD on a haemodialysis maintenance program and 673 hospital controls. 2. The overall odds ratio estimate for non‐narcotic analgesics taken at least every other day for 30 days or longer before the first symptom of renal disease was 2.89 (95% CI, 1.78 to 4.68). 3. The risk increased in relation to the use duration. 4. The previous regular consumption of combinations containing phenacetin was strongly associated with ESRD (odds ratio, 19.05; 95% CI, 2.31 to 157.4). The odds ratio for previous regular consumption of salicylates was 2.54 (95% CI, 1.24 to 5.20) and for pyrazolones 2.16 (95% CI, 0.87 to 5.32). 5. An analysis for possible confounding by a history of repeated headaches, arthritis, kidney stones, hypertension, and diabetes did not alter the results. 6. The odds ratio estimates for different pathological subgroups of ESRD patients in relation to previous use of any non‐narcotic analgesic were glomerulonephritis. 10.57 (95% CI, 1.25 to 89.0), interstitial nephritis, 3.33 (95% CI, 1.21 to 9.17), cystic kidney disease, 0.71 (95% CI, 0.25 to 1.97), and unknown, 5.15 (95% CI, 2.29‐11.57). 7. The results of this study suggest that the regular consumption of analgesics should be routinely considered as a risk factor for any non‐ congenital cause of chronic renal failure. They also suggest that the risk of ESRD associated with the regular consumption of phenacetin is much higher than the risk associated with other non‐narcotic analgesics.
Fractionated ifosfamide therapy produces a time‐dependent increase in ifosfamide metabolism.
Authors: Lewis LD , Fitzgerald DL , Harper PG , Rogers HJ
Published: July 2012

1. Fifteen patients received 1.5 g m‐2 of ifosfamide intravenously over 0.5 h every day for 5 days. Twenty‐one courses of treatment were studied. Plasma was assayed for ifosfamide by gas liquid chromatography and plasma alkylating activity was measured using the nitrobenzylpyridine (NBP) reaction. 2. A pharmacokinetic analysis revealed a significant decrease in the median (range) elimination half‐ life of ifosfamide from 7.2 (2.8‐14.2) h on day 1 to 4.6 (2.3‐7.7) h on day 5 (P less than 0.001, Wilcoxon's test) with a concomitant significant increase in the median (range) clearance from 66 (31‐148) ml min‐1 on day 1 to 115 (52‐381) ml min‐1 on day 5 (P less than 0.001). There was no significant change in the volume of distribution on day 5 compared with day 1. 3. There was a highly significant 223% increase in the median (range) plasma nitrobenzylpyridine alkylating activity area under the curve on day 1 from 16 (0.6‐105) nmol nor nitrogen mustard equivalents ml‐1 h to 52 (13‐238) nmol nor nitrogen mustard equivalents ml‐1 h on day 5. 4. During five courses of treatment (in five patients in the group) 24 h urine samples were collected on days 1 and 5. The median (range) renal clearance of ifosfamide on day 1 was 6.8 (1.3‐16.2) ml min‐1 compared with 5.7 (1.3‐ 15.3) ml min‐1 on day 5. This difference was not significant. The median (range) metabolic clearance of ifosfamide in these five patients on day 1 was 78.6 (39.9‐141.2) ml min‐1 and 132.6 (54.6‐149.5) ml min‐1 on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)
The effect of cholestyramine and activated charcoal on glipizide absorption.
Authors: Kivisto KT , Neuvonen PJ
Published: July 2012

1. The interference of cholestyramine and activated charcoal with the absorption of glipizide was studied. 2. In a cross‐over study comprising three phases, single doses of cholestyramine (8 g), activated charcoal (8 g) or water only were given to six healthy volunteers together with a single dose of glipizide. 3. The absorption of glipizide was moderately (29%, P less than 0.01) reduced by cholestyramine and greatly reduced (81%, P less than 0.01) by activated charcoal. 4. If cholestyramine and glipizide are used concomitantly, glipizide should be taken 1‐2 h beforehand. In acute glipizide overdosage, activated charcoal can be used to reduce absorption.
Propranolol oxidation by human liver microsomes‐the use of cumene hydroperoxide to probe isoenzyme specificity and regio‐ and stereoselectivity.
Authors: Otton SV , Gillam EM , Lennard MS , Tucker GT , Woods HF
Published: July 2012

1. Three oxidations of the enantiomers of propranolol were studied in human liver microsomes under two reaction conditions. Previous in vitro studies had established that two of the livers were from poor metaboliser (PM) phenotypes for the debrisoquine 4‐hydroxylase (cytochrome P‐450IID6) and the remaining seven were from extensive metaboliser (EM) phenotypes. 2. In the presence of NADPH and oxygen 4‐ and 5‐hydroxylation of propranolol occurred in microsomes from all nine livers, as did propranolol N‐desisopropylation. R(+)‐propranolol was oxidized preferentially along the three pathways, although enantioselectivity observed for N‐desisopropylation may have arisen not only from stereoselectivity in formation rates, but also from stereoselectivity in subsequent microsomal metabolism, possibly by monoamine oxidase. The involvement of monoamine oxidase in the further microsomal metabolism of N‐desisopropylpropranolol was indicated by inhibition of the metabolism of this compound when incubated with phenelzine. 3. Cumene hydroperoxide has been proposed to support only the activity of cytochrome P450IID6. This is consistent with the observations that a) propranolol 4‐ and 5‐hydroxylation occurred in microsomes from the EM livers only and b) side‐chain oxidation was not observed under these conditions in either PM or EM livers. 4. Using cumene hydroperoxide to support the reactions, the 4‐hydroxylation of propranolol showed little enantioselectivity, whereas S(‐)‐propranolol was 5‐hydroxylated about twice as fast as the R(+)‐enantiomer. There were highly significant correlations between the rates of 4‐ and 5‐ hydroxylation of R(+)‐propranolol (r = 0.96, P less than 0.001, n = 7 livers) and of S(‐)‐propranolol (r = 0.98, P less than 0.001). Both oxidations were described by single‐site Michaelis‐Menten kinetics. 5. The findings suggest that P450IID6 is involved in both the 4‐ and 5‐ hydroxylations of propranolol, but that these metabolites can also be formed by other P450 isoenzymes. It is confirmed that P450IID6 does not contribute to the N‐desisopropylation of propranolol. Furthermore, the finding that mephenytoin did not inhibit the appearance of this metabolite is not consistent with the results of in vivo studies suggesting the involvement of the same enzyme in the side‐chain oxidation of propranolol and the 4‐hydroxylation of mephenytoin.
Apomorphine‐induced blinking and yawning in healthy volunteers.
Authors: Blin O , Masson G , Azulay JP , Fondarai J , Serratrice G
Published: July 2012

Yawning and spontaneous blink rate (SBR) are two physiological reflexes which have been incompletely examined but one neurobiological step of these two behaviours seems, at least in part, dopamine‐dependent. The reference dopaminergic agonist, apomorphine hydrochloride (0.5, 1, and 2 micrograms kg‐1 s.c.), was compared with a placebo in a double‐blind latin‐square design, and was shown to induce yawning and increase SBR in a population of eight healthy volunteers. These two behavioral effects were not dose‐related. The individual SBR differences were correlated with the individual number of yawns for all the four treatments at the 10‐30 min interval. Thus, parallel yawning and SBR behaviour suggests a similar pharmacological mechanism. Apomorphine‐ induced yawning and blinking may be therefore of use in the evaluation of central dopaminergic pathways in man.
Midazolam and nitrazepam in the maternity ward: milk concentrations and clinical effects.
Authors: Matheson I. , Lunde PK , Bredesen JE
Published: July 2012

1. In a randomized study of 22 patients in a maternity ward, the residual concentrations of two hypnotics, midazolam 15 mg p.o. and nitrazepam 5 mg p.o., in early breast milk and plasma were measured 7 h after intake on day 2 to day 6 postpartum. Milk pH, milk fat and binding to plasma proteins were also investigated. Sleep variables were scored on questionnaires. 2. No measurable (less than 10 nmol l‐1) concentrations of drug in milk were found in the group receiving 15 mg midazolam at night, either after the first night or after the fifth night. Additional investigations in two mothers demonstrated that midazolam and its hydroxymetabolite disappeared rapidly from milk with undetectable levels after 4 h. The mean (s.d.) milk to plasma ratio for midazolam was 0.15 (0.06) in six paired samples. It may be assumed that practically no midazolam is transferred via early milk to the baby if the baby is nursed more than 4 h after tablet intake. 3. Milk nitrazepam concentrations increased significantly from the first (30 nmol l‐1) to the fifth morning (48 nmol l‐1) in the group receiving 5 mg nitrazepam at night. The mean (s.d.) milk to plasma ratio of nitrazepam after 7 h was 0.27 (0.06) in 32 paired samples, and did not vary from day 1 to day 5. Plasma protein binding of nitrazepam in puerperal women was found to be lower than that in plasma of healthy controls. The average amount of nitrazepam received by the breast‐fed baby in the morning was calculated to increase from 1 to 1.5 micrograms 100 ml‐1 breast milk, from days 1 to 5. In the mothers nitrazepam was associated with better hypnotic effect, but a higher incidence of complaints than midazolam. 4. Milk pH, assuming anaerobic conditions, was found in 10 women to average 6.91 +/‐ 0.09 (s.d.) on days 2‐6 postpartum, which is less than previously reported. 5. It is concluded that both hypnotics may be used safely for a few days in the maternity ward. However, possible long‐term effects in the suckling infant of small doses of benzodiazepines ingested with breast milk remain to be investigated.
Comparison of the monoamine oxidase inhibiting properties of two reversible and selective monoamine oxidase‐A inhibitors moclobemide and toloxatone, and assessment of their effect on psychometric performance in healthy subjects.
Authors: Berlin I. , Zimmer R. , Thiede HM , Payan C. , Hergueta T. , Robin L. , Puech AJ
Published: July 2012

1. The effects of two reversible, predominantly monoamine oxidase‐A (MAO‐A) inhibitors, moclobemide (150 mg three times daily) and toloxatone (400‐200‐400 mg day‐1) on monoamine metabolites and psychometric performance were compared in a double‐blind placebo controlled crossover study in 12 healthy subjects. 2. After 7 days of moclobemide/toloxatone/placebo administration subjects were hospitalized for 24 h on day 8. Blood samples were drawn every 2 h for determination of plasma noradrenaline (NA), 3,4‐dihydroxyphenylglycol (DHPG), homovanillic acid (HVA) and 5‐hydroxyindolacetic acid (5‐HIAA). Urine was collected for measurements of normetanephrine and 3‐ methoxytyramine excretion. Psychometric performance (short‐ and long‐ term memory, critical flicker fusion frequency, choice reaction time) and subjective feelings were assessed before each drug intake (in the morning, at noon, in the evening). 3. Compared with placebo, both reversible monoamine oxidase inhibitors decreased the plasma concentration of DHPG and HVA. The overall fall in DHPG (AUC from 0 to 24 h) was 44% during moclobemide and 12% during toloxatone (P less than 0.001) and the overall decrease in HVA was 38% and 20% (P less than 0.005) on moclobemide and toloxatone, respectively. 4. Before the next drug intake, MAO‐A inhibition, as judged by the decrease of plasma DHPG concentration, was significantly different from placebo with moclobemide but not with toloxatone. 5. Moclobemide, but not toloxatone, exerted a moderate, but significant inhibition of the deamination of 5‐hydroxytryptamine (5‐HT) as judged by the fall in plasma 5‐HIAA concentration. Neither drug influenced plasma NA concentration. 6. A significant rise in urinary excretion of normetanephrine was observed on moclobemide and to a lesser extent on toloxatone. The urinary excretion of 3‐methoxytyramine was significantly raised by moclobemide but not by toloxatone. 7. Neither moclobemide nor toloxatone altered memory function, vigilance, subjective feelings or sleep characteristics of the subjects.
A comparison of the effects of zolpidem and placebo on respiration and oxygen saturation during sleep in the healthy elderly.
Authors: Rhodes SP , Parry P. , Hanning CD
Published: July 2012

1. In a double‐blind placebo controlled trial, zolpidem 10 mg, a new imidazopyridine hypnotic drug, was administered to 10 elderly female patients and placebo to 11, all recovering from hip and knee replacement surgery. Respiratory monitoring with an inductance plethysmograph and pulse oximeter showed that treatment over a 4 night period did not increase significantly the severity, frequency or duration of hypoxaemic episodes leading to SaO2 less than 90% or less than 85% when compared with placebo. Confidence intervals (corrected for baseline differences) for the median differences between the two groups on night 7, the fourth night of treatment, were from ‐1.85 to 0.480 and from ‐1.07 to 0 respectively for the frequency, and from ‐ 0.76 to 0.15 and ‐0.5 to 0 for the duration of the hypoxaemic episodes. The incidence of sleep related respiratory disturbances was not significantly increased compared with placebo on any night. 2. Respiratory monitoring using a simple inductance plethysmograph and pulse oximeter is acceptable to patients and staff. 3. The evaluation of all hypnotic and sedative drugs should include their effects on respiration during sleep.
Digital blood flow and 5‐hydroxytryptamine receptor blockade after ketanserin in patients with Raynaud's phenomenon.
Authors: Marasini B. , Bassani C.
Published: July 2012

1. The effect of ketanserin on digital blood flow and 5‐ hydroxytryptamine (5‐HT)‐induced platelet aggregation was studied in 18 patients with Raynaud's phenomenon. 2. Measurements were made before and after a single dose of 20 mg ketanserin and again after 1 month of continuous treatment with 20 mg ketanserin three times a day. 3. Digital blood flow was assessed by changes in digital pulse volume; platelet aggregation by changes in light transmission after challenge with 10(‐5) M 5‐HT. 4. Ketanserin induced a rise in digital blood flow and blocked the platelet response to 5‐HT; the two events were not correlated and were independent of subjective improvement. 5. These data do not support the suggestion that 5‐HT2‐receptor blockade is of major importance in the dilatory effect of ketanserin in Raynaud's phenomenon.
Leukotrienes in the sputum and urine of cystic fibrosis children.
Authors: Sampson AP , Spencer DA , Green CP , Piper PJ , Price JF
Published: July 2012

1. Leukotrienes (LTs) are potent pro‐inflammatory mediators with actions relevant to the pathophysiology of cystic fibrosis (CF), including increased mucus production, bronchoconstriction, leucocyte chemotaxis, and increased vascular permeability. We have therefore investigated the potential role of LTs in children with CF. Leukotriene E4 levels were assessed in the urine of 30 normal (N) children (aged 1.3‐12.7 years) and 30 CF children (1.6‐14.3 years). Sputum from 13 of the CF children was analysed from LTB4, LTC4, LTD4, and LTE4. LTs were separated by reversed‐phase h.p.l.c. and quantitated by radioimmunoassay. 2. Urinary LTE4 levels were log normally distributed, with geometric mean values (95% confidence intervals) of N: 88.4 (71.3‐ 111) pmol mmol‐1 creatinine (n = 30), and CF: 112 (70.6‐177) pmol mmol‐ 1 creatinine (n = 30; P greater than 0.05). Of the CF subjects, 33% had urinary LTE4 levels above 200 pmol mmol‐1 creatinine, compared with 3.3% of the N children. 3. In sputum, mean (+/‐ s.e. mean) LT concentrations were (pmol g‐1), LTB4: 44.3 +/‐ 10.8, LTC4: 4.9 +/‐ 1.3, LTD4: 1.8 +/‐ 0.9, and LTE4: 67.7 +/‐ 18.9 (n = 13). 4. Urinary LTE4 levels correlated significantly with sputum LTE4 levels (r = 0.673, P = 0.012), and with sputum levels of total cysteinyl‐LTs (r = 0.660, P = 0.014). 5. In conclusion, total cysteinyl‐LT content in sputum is 10‐ fold higher than previously reported, consisting primarily (91%) of LTE4. The high levels of LTE4 and LTB4 in sputum suggest involvement of LTs in the pathophysiology of CF. Urinary LTE4 levels may prove useful as a marker for cysteinyl‐LT production in sputum.
The interaction of phenytoin and carbamazepine with combined oral contraceptive steroids.
Authors: Crawford P. , Chadwick DJ , Martin C. , Tjia J. , Back DJ , Orme M.
Published: July 2012

Patients taking oral contraceptive steroids (OCS) are known to suffer contraceptive failure while taking anticonvulsants such as phenobarbitone, phenytoin and carbamazepine. We have studied the single dose kinetics of ethinyloestradiol (EE2); 50 micrograms, and levonorgestrel (Ng); 250 micrograms in groups of women before and 8‐12 weeks after starting therapy with phenytoin (n = 6) and carbamazepine (n = 4). The area under the plasma concentration‐time curve (AUC) was measured over a 24 h period for each steroid and significant reductions were seen with both anticonvulsants. Phenytoin reduced the AUC for EE2 from 806 +/‐ 50 (mean +/‐ s.d.) to 411 +/‐ 132 pg ml‐1 h (P less than 0.05) and for Ng from 33.6 +/‐ 7.8 to 19.5 +/‐ 3.8 ng ml‐1 h (P less than 0.05). Carbamazepine reduced the AUC for EE2 from 1163 +/‐ 466 to 672 +/‐ 211 pg ml‐1 h (P less than 0.05) and for Ng from 22.9 +/‐ 9.4 to 13.8 +/‐ 5.8 ng ml‐1 h (P less than 0.05). These changes are compatible with the known enzyme inducing effects of phenytoin and carbamazepine. Patients taking these anticonvulsants will need to be given increased doses of OCS (equivalent to 50‐100 micrograms EE2 daily) to achieve adequate contraceptive effects.
Beta‐adrenoceptor control of immune function in congestive heart failure.
Authors: Maisel AS , Michel MC
Published: July 2012

1. We have determined the number of beta‐adrenoceptors and the isoprenaline‐stimulated cAMP generation in lymphocyte subsets. The in vitro beta‐adrenergic sensitivity was greatest in Tsuppressor/cytotoxic‐ and natural killer cells and smallest in Thelper‐ and B‐cells. B lymphocytes appear to have a poor receptor coupling to adenylate cyclase as they have many beta‐adrenoceptors but generate only little cAMP in response to isoprenaline. 2. A 7 day treatment of healthy volunteers with terbutaline decreased the number of circulating cells in those lymphocyte subsets with a high in vitro sensitivity to beta‐ adrenoceptor stimulation (i.e. Tsuppressor/cytotoxic‐ and natural killer cells) but not in those with a poor in vitro sensitivity (i.e. Thelper‐ and B‐lymphocytes). 3. Similar alterations of circulating lymphocyte subsets were found in patients with congestive heart failure (CHF). These alterations were not related to the aetiology of CHF but to its severity and could be correlated with plasma catecholamine levels. 4. We conclude that prolonged exposure to beta‐adrenoceptor agonists or enhanced sympathetic activity can decrease the number of circulating lymphocytes with an increase in the Thelper‐ /Tsuppressor/cytotoxic‐cell ratio.
Beta‐adrenoceptor responsiveness in hypertension: effects of dietary NaCl intake.
Authors: Feldman RD
Published: July 2012

1. Adrenergic responsiveness may be an important determinant of peripheral resistance in man. We have demonstrated that vascular beta‐ adrenergic responsiveness is reduced in young borderline hypertensive subjects. A parallel defect in beta‐adrenergic mediated adenylyl cyclase activity and beta‐adrenoceptor affinity for agonists also has been identified in lymphocytes from borderline hypertensive subjects. In contrast, it is unclear whether cardiac beta‐adrenergic responsiveness is altered. 2. The reduction in lymphocyte and vascular beta‐adrenergic responsiveness is corrected when hypertensive subjects are fed a low sodium chloride diet. This pattern of regulation differs from that seen in young normotensive subjects fed a low NaCl diet where either reduced or unchanged beta‐adrenergic responsiveness has been reported. 3. These studies suggest a generalized defect in beta 2‐ adrenergic responsiveness in borderline hypertensive subjects and demonstrate important differences between normotensive and hypertensive subjects in the pattern of beta‐adrenoceptor regulation mediated by dietary sodium intake. The mechanism by which dietary sodium modulates beta‐adrenergic responsiveness is yet to be determined.
Neuropeptides in hypertension: role of neuropeptide Y and calcitonin gene related peptide.
Authors: Westfall TC , Han SP , Knuepfer M. , Martin J. , Chen XL , del Valle K. , Ciarleglio A. , Naes L.
Published: July 2012

1. The effect of neuropeptide Y (NPY) on cardiovascular function at three levels of the noradrenergic axis where the peptide is known to co‐ exist with noradrenaline (NA) and or adrenaline (A) was studied in normotensive Sprague‐Dawley (SD), Wistar‐Kyoto (WKY) or spontaneously hypertensive rats (SHR). 2. In the perfused mesenteric arterial bed, NPY and the structurally similar peptide intestinal polypeptide (PYY) decreased the periarterial nerve stimulation induced release of NA and potentiated the increase in perfusion pressure to nerve stimulation or exogenously applied agonists (e.g. angiotensin, vasopressin, phenylephrine). In contrast to NPY and PYY, C‐terminal NPY fragments inhibited NA release and produced a parallel decrease in perfusion pressure thus supporting the concept of Y1 (post) and Y2 (pre) NPY receptors. 3. In the mesenteric artery of SHR the prejunctional inhibitory effect of NPY was attenuated while the postjunctional response was enhanced. 4. Following intrathecal (Int) injection of NPY, there was a decrease in blood pressure, total peripheral resistance (predominantly by a decrease in mesenteric vascular resistance) and renal nerve activity. The depressor effect of Int NPY was attenuated in the SHR. 5. Unilateral injections of NPY into the posterior hypothalamic nucleus increased blood pressure, hindquarter and renal vascular resistance and renal nerve activity. The pressor effect was enhanced in the SHR. 6. Periarterial nerve stimulation of the perfused mesenteric artery produced a frequency dependent vasodilation in beds pretreated with guanethidine and precontracted with methoxamine.(ABSTRACT TRUNCATED AT 250 WORDS)
Adenosine bronchoconstriction in asthma: investigations into its possible mechanism of action.
Authors: Ng WH , Polosa R. , Church MK
Published: July 2012

1. Inhaled adenosine and its parent nucleotide, adenosine 5′‐ monophosphate (AMP) provoke bronchoconstriction in atopic and asthmatic individuals but not in normal subjects. 2. In clinical studies, histamine H1‐receptor antagonists, cyclo‐oxygenase inhibitors and the mast cell 'stabilising' drugs, sodium cromoglycate and nedocromil, protect against the effects of adenosine bronchoprovocation suggesting the involvement of secondary mast cell mediator release. 3. Adenosine and its analogues potentiate histamine and leukotriene release from mast cells activated by other stimuli in vitro, and may also increase net mediator release from mast cells by counteracting the inhibitory effect of circulating adrenaline. 4. Although adenosine fulfils many of the criteria required for a mediator in asthma, its importance is not fully understood, and the mechanisms by which it provokes bronchoconstriction in asthmatic subjects is far from concluded. 5. Two possibilities are that either adenosine acts directly on luminal mast cells to upregulate histamine secretion, or it acts to initiate neuronal reflexes which stimulate histamine release indirectly and possibly activate peptidergic and/or cholinergic pathways.
The role of platelet activating factor in allergic respiratory disease.
Authors: Page CP
Published: July 2012

1. Platelet activating factor (PAF) is an ether‐linked phospholipid capable of eliciting many of the factors of the allergic response including bronchoconstriction, mucosal oedema, eosinophil infiltration and bronchial hyperresponsiveness. 2. A wide range of selective PAF receptor antagonists have now been described which have been reported to reduce many aspects of allergen‐induced inflammatory responses in experimental animals. 3. Early clinical studies have indicated that some of these drugs are also effective PAF antagonists in man, but no controlled studies have been reported using these compounds in patients with allergic asthma. 4. The gingkolide mixture BN 52063 has recently been reported to inhibit allergen‐induced cutaneous inflammation in man; a response which has certain pathological similarities to allergen‐ induced late‐onset airways obstruction in the lung. 5. Therefore, drugs antagonizing the actions of PAF may well lead to a better understanding of and may be a novel therapeutic approach for allergic respiratory disorders.
Differential regulation of human cardiac beta‐adrenergic and muscarinic receptors by chronic beta‐adrenoceptor antagonist treatment.
Authors: Motomura S. , Deighton NM , Zerkowski HR , Khamssi M. , Brodde OE
Published: July 2012

In patients undergoing coronary artery bypass grafting chronic beta 1‐ adrenoceptor antagonist treatment increased right atrial beta 1‐ adrenoceptor number, did not affect beta 2‐adrenoceptor number and decreased muscarinic M2‐receptor number. Concomitantly, the M2‐receptor‐ mediated negative inotropic effect of carbachol was reduced, while the beta 1‐adrenoceptor‐mediated positive inotropic effect of noradrenaline was not altered. The beta 2‐ adrenoceptor mediated positive inotropic effect of procaterol, however, was markedly enhanced. We conclude that chronic beta 1‐adrenoceptor antagonist treatment increases beta 1‐ adrenoceptor number, sensitizes beta 2‐adrenoceptor function and desensitizes M2‐receptor function in the human heart.
Effect of hypo‐ and hyperthyroidism on binding of [3H]‐nitrendipine to myocardial and brain membranes.
Authors: Kosinski C. , Gross G. , Hanft G.
Published: July 2012

The density of calcium channel binding sites as determined by [3H]‐ nitrendipine binding was found to be decreased in hearts of hyperthyroid rats but hardly altered by hypothyroidism. In contrast, dihydropyridine binding sites in the cerebral cortex were unaffected by dysthyroid states. Myocardial [3H]‐nitrendipine binding sites were also decreased after treatment of the animals with isoprenaline but not in spontaneously hypertensive rats. These findings suggest that myocardial hypertrophy is not necessarily accompanied by a loss of calcium channels and that thyroid hormone regulates the density of [3H]‐ nitrendipine binding sites in a tissue‐specific manner.
Effect of erythropoietin on parameters of sympathetic nervous activity in patients undergoing chronic haemodialysis.
Authors: Fritschka E. , Neumayer HH , Seddighi S. , Thiede HM , Distler A. , Philipp T.
Published: July 2012

The effect of erythropoietin (rHu‐EPO) on blood pressure and on parameters of sympathetic nervous activity of patients undergoing chronic haemodialysis treatment was evaluated in a controlled and randomized 6‐months study. Both groups did not differ significantly at the onset of the study in terms of dialysis protocol, haematological parameters, blood chemistry, weight, blood pressure and parameters of sympathetic nervous activity. Haemoglobin increased from 7.0 +/‐ 0.3 g dl‐1 to 10.0 +/‐ 0.3 g dl‐1 by 6 months on rHu‐EPO (n = 11) and remained constant in the control group (n = 11). After 6 months diastolic blood pressure was higher in the treatment group compared with the control group as well as compared with pretreatment values, whereas reactivity to exogenous noradrenaline and platelet alpha 2‐ adrenoceptor densities ([3H]‐yohimbine‐ and [3H]‐UK 14,304‐binding sites) were lower. Plasma noradrenaline concentration increased during rHu‐EPO compared with pretreatment values, while dry weights were unchanged during the study. The results demonstrate alterations of some parameters of sympathetic nervous activity during rHu‐EPO‐therapy which were absent in the control group.
Prostaglandin E2 inhibits and indomethacin enhances noradrenaline release in isolated kidneys of adult spontaneously hypertensive rats.
Authors: Rump LC , Wilde K. , Schollmeyer P.
Published: July 2012

Renal neurotransmission and its modulation by prostaglandin (PG) E2 (0.06 microM) and indomethacin (10 microM) was investigated in isolated kidneys of adult spontaneously hypertensive (SHR) and normotensive control (WKY) rats. After preincubation with [3H]‐noradrenaline the renal nerves were stimulated. The stimulation induced (S‐I) outflow of radioactivity was taken as an index of noradrenaline release. The S‐I outflow of radioactivity from SHR and WKY kidneys was similar but S‐I pressor responses were enhanced in kidneys of SHR. PGE2 inhibited and indomethacin enhanced the S‐I outflow of radioactivity in kidneys of WKY and SHR to a similar extent. This inhibitory effect of PGE2 is due to activation of inhibitory prejunctional PGE2 receptors. Neuronally released noradrenaline stimulates a local formation of PGE2 which then transjunctionally inhibits noradrenaline release. Renal noradrenaline release in the adult SHR and its modulation by PGs is not altered. An enhanced postjunctional responsiveness of the renal vasculature may contribute to the maintenance of hypertension in the adult SHR.
Modulation of noradrenaline release from rat cortical kidney slices: effects of angiotensin I and II.
Authors: Rump LC , Schuster MJ , Wilde K. , Schollmeyer P.
Published: July 2012

Rat kidney slices were incubated with [3H]‐noradrenaline and placed into a superfusion chamber between two platinum electrodes. The kidney slices accumulated and stored radioactivity. In kidney slices taken from rats whose sympathetic nerve terminals were destroyed by pretreatment with 6‐hydroxydopamine accumulation of radioactivity was abolished. The alpha 2‐adrenoceptor antagonist idazoxan (0.1‐1 microM) enhanced but tetrodotoxin (TTX, 1 microM) or omission of calcium from the superfusion solution abolished the stimulation induced (S‐I) outflow of radioactivity. Angiotensin (A) I (3‐300 nM) and AII (1‐100 nM) enhanced S‐I outflow of radioactivity. The effect of AI was markedly attenuated by the angiotensin converting enzyme inhibitor captopril (3 microM) and that of AII was blocked by the AII receptor antagonist saralasin (1 microM). These results suggest that the kidney slice preparation is a valid technique to study modulation of renal noradrenaline release. Endogenous noradrenaline released from sympathetic nerves in rat kidney slices activates prejunctional alpha 2‐ adrenoceptors to inhibit its own release. AII, which can also be formed locally from AI in these kidney slices, activates prejunctional AII receptors to facilitate renal noradrenaline release.
Effect of calcium and beta‐adrenoceptor antagonists on beta‐ adrenoceptor density and Gs alpha expression in human atria.
Authors: Jones CR , Fandeleur P. , Harris B. , Buhler FR
Published: July 2012

In 21 patients undergoing open heart surgery the effects of the beta‐ adrenoceptor antagonists propranolol and sotalol and the calcium antagonist nifedipine (alone or in combination) on right atrial beta‐ adrenoceptor density and G protein expression were studied. The non‐ selective beta‐adrenoceptor antagonists increased both right atrial beta 1‐ and beta 2‐adrenoceptor density; this increase was not affected by nifedipine. There was no correlation between beta‐adrenoceptor density and expression of the G protein subunit Gs alpha suggesting independent regulation of the gene expression for G proteins and their coupled receptors.
Tissue and plasma angiotensin converting enzyme and the response to ACE inhibitor drugs.
Authors: MacFadyen RJ , Lees KR , Reid JL
Published: July 2012

1. There is a body of circumstantial and direct evidence supporting the existence and functional importance of a tissue based RAS at a variety of sites. 2. The relation between circulatory and tissue based systems is complex. The relative importance of the two in determining haemodynamic effects is unknown. 3. Despite the wide range of ACE inhibitors already available, it remains unclear whether there are genuine differences related to tissue specificity. 4. Pathological states such as chronic cardiac failure need to be explored with regard to the contribution of tissue based ACE activities in generating acute and chronic haemodynamic responses to ACE inhibitors. 5. The role of tissue vs plasma ACE activity may be clarified by study of the relation between drug concentration and haemodynamic effect, provided that the temporal dissociation is examined and linked to circulating and tissue based changes in ACE activity, angiotensin peptides and sympathetic hormones.