bluuebunny/crossref_metadata_2025 huggingface dataset:
Tumor growth inhibitory effect of ADAMTS1 is accompanied by the inhibition of tumor angiogenesis
Authors: Obika Masanari , Ogawa Hiroko , Takahashi Katsuyuki , Li Jiayi , Hatipoglu Omer Faruk , Cilek Mehmet Zeynel , Miyoshi Toru , Inagaki Junko , Ohtsuki Takashi , Kusachi Shozo , Ninomiya Yoshifumi , Hirohata Satoshi
Published: July 2012

Angiogenesis plays an important role in tumor progression. Several reports have demonstrated that a disintegrin and metalloproteinase with thrombospondin motifs1 (ADAMTS1) inhibited angiogenesis via multiple mechanisms. The aim of this study was to investigate the effect of ADAMTS1 on endothelial cells in vitro and on tumor growth with regard to angiogenesis in vivo. We examined the effects of the transfection of ADAMTS1 using two constructs, full‐length ADAMTS1 (full ADAMTS1) and catalytic domain‐deleted ADAMTS1 (delta ADAMTS1). Transfection of both the full ADAMTS1 and delta ADAMTS1 gene constructs demonstrated the secretion of tagged‐ADAMTS1 protein into the conditioned medium, so we examined the effects of ADAMTS1‐containing conditioned medium on endothelial cells. Both types of conditioned media inhibited endothelial tube formation, and this effect was completely abolished after immunoprecipitation of the secreted protein from the medium. Both types of conditioned media also inhibited endothelial cell migration and proliferation. We then examined the impact of ADAMTS1 on endothelial cell apoptosis. Both conditioned media increased the number of Annexin V‐positive endothelial cells and caspase‐3 activity and this effect was attenuated when z‐vad was added. These results indicated that ADAMTS1 induced endothelial cell apoptosis. We next examined the effects of ADAMTS1 gene transfer into tumor‐bearing mice. Both full ADAMTS1 and delta ADAMTS1 significantly inhibited the subcutaneous tumor growth. Collectively, our results demonstrated that ADAMTS1 gene transfer inhibited angiogenesis in vitro and in vivo, likely as a result of the induction of endothelial cell apoptosis by ADAMTS1 that occurs independent of the protease activity.
Risk of injury after alcohol consumption from case–crossover studies in five countries from the Americas
Authors: Borges Guilherme , Orozco Ricardo , Monteiro Maristela , Cherpitel Cheryl , Then Eddy Pérez , López Víctor A. , Bassier‐Paltoo Marcia , Weil Donald A. , M de Bradshaw Aldacira
Published: July 2012

Aims

This study aimed to: (i) provide relative risk (RR) estimates between acute alcohol use and injuries from emergency departments (EDs) in the Dominican Republic, Guatemala, Guyana, Nicaragua and Panama, and (ii) test whether the RR differs if two control periods for the estimates were used.

Design

Case–crossover methodology was used to obtain estimates of the RR of having an injury within 6 hours after drinking alcohol, using a pair‐matching design with control periods of the same time of day on the day prior to injury, and the same time of day and day of week during the week prior to injury.

Setting

EDs.

Participants

A total of 2503 injured patients from EDs were interviewed between 2010 and 2011, with a response rate of 92.6%.

Measurements

Number of drinks consumed within 6 hours prior to the injury and in the two control periods.

Findings

The RR of injury after drinking alcohol was 4.38 [95% confidence interval (CI): 3.29–5.84] using the prior week as the control period, and 5.35 (CI: 3.50–8.17) using the prior day as a control period. The RR was 5.08 (CI: 4.15–6.23) in multiple matching. Those drinking one to two drinks had a RR of 4.85 (CI: 3.12–7.54); those drinking three to five drinks an RR of 5.00 (CI: 3.47–7.18); those drinking six to 15 drinks an RR of 4.54 (CI: 3.36–6.14); and those drinking 16 or more drinks an RR of 10.42 (CI: 4.38–24.79).

Conclusions

As in other countries, drinking alcohol is an important trigger for an injury in the Dominican Republic, Guatemala, Guyana, Nicaragua and Panama.
A frameshift mutation in the LYST gene is responsible for the Aleutian color and the associated Chédiak–Higashi syndrome in American mink
Authors: Anistoroaei R. , Krogh A. K. , Christensen K.
Published: July 2012

One of the colors of mink is Aleutian (aa)—a specific gun‐metal gray pigmentation of the fur—commonly used in combination with other color loci to generate popular colors such as Violet (aammpp) and Sapphire (aapp). The Aleutian color allele is a manifestation of mink Chédiak‐Higashi syndrome (CHS), which has been described in humans and several other species. As with forms of CHS in other species, we report that the mink CHS is linked to the lysosomal trafficking regulator (
LYST
) gene. Furthermore, we have identified a base deletion (c.9468delC) in exon 40 of
LYST, which causes a frameshift and virtually terminates the LYST product prematurely (p.Leu3156Phefs*37). We investigated the blood parameters of three wild‐type mink and three CHS mink. No difference in the platelet number between the two groups was observed, but an accumulation of platelets between the groups appears different when collagen is used as a coagulant. Microscopic analysis of peripheral blood indicates giant inclusions in the neutrophils of the Aleutian mink types. Molecular findings at the
LYST
locus enable the development of genetic tests for analyzing the color selection in American mink.
Brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS) in Merino sheep maps to a 1.1‐megabase region on ovine chromosome OAR2
Authors: Shariflou M. R. , Wade C. M. , Kijas J. , McCulloch R. , Windsor P. A. , Tammen I. , Nicholas F. W.
Published: July 2012

A genome scan was conducted to map the autosomal recessive lethal disorder brachygnathia, cardiomegaly and renal hypoplasia syndrome (BCRHS) in Poll Merino sheep. The scan involved 10 affected and 27 unaffected animals from a single Poll Merino/Merino sheep flock, which were genotyped with the Illumina Ovine SNP50 BeadChip. Association and homozygosity mapping analyses located the disorder in a region comprising 20 consecutive SNPs spanning 1.1 Mb towards the distal end of chromosome OAR2. All affected animals and none of the unaffected animals were homozygous for the associated haplotype in this region. These results provide the basis for identifying the causative mutation(s) and should enable the development of a DNA test to identify carriers in the Poll Merino sheep population. Understanding the molecular control of BCRHS may provide insight into the fundamental genetic control and regulation of the affected organ systems.
Mitochondrial DNA and Y‐chromosome diversity in East Adriatic sheep
Authors: Ferencakovic M. , Curik I. , Pérez‐Pardal L. , Royo L. J. , Cubric‐Curik V. , Fernández I. , Álvarez I. , Kostelic A. , Sprem N. , Krapinec K. , Goyache F.
Published: July 2012

Variation in mitochondrial DNA (mtDNA) and Y‐chromosome haplotypes was analysed in nine domestic sheep breeds (159 rams) and 21 mouflon (
Ovis musimon) sampled in the East Adriatic. Mitochondrial DNA analyses revealed a high frequency of type B haplotypes, predominantly in European breeds, and a very low frequency of type A haplotypes, which are more frequent in some Asian breeds. Mitochondrial haplotype Hmt‐3 was the most frequent (26.4%), and 37.1%, 20.8% and 7.6% of rams had haplotypes one, two and three mutations remote from Hmt‐3 respectively. In contrast, Y‐chromosome analyses revealed extraordinary paternal allelic richness: HY‐6, 89.3%; HY‐8, 5.0%; HY‐18, 3.1%; HY‐7, 1.3%; and HY‐5, 1.3%. In fact, the number of haplotypes observed is comparable to the number found in Turkish breeds and greater than the number found in European breeds so far. Haplotype HY‐18 (A‐oY1/135‐SRYM18), identified here for the first time, provides a link between the haplotype HY‐12 (A‐oY1/139‐SRYM18) found in a few rams in Turkey and haplotype HY‐9 (A‐oY1/131‐SRYM18) found in one ram in Ethiopia. All mouflons had type B mtDNA haplotypes, including the private haplotype (Hmt‐55), and all were paternally monomorphic for haplotype HY‐6. Our data support a quite homogeneous maternal origin of East Adriatic sheep, which is a characteristic of European breeds. At the same time, the high number of haplotypes found was surprising and intriguing, and it begs for further analysis. Simultaneous analysis of mtDNA and Y‐chromosome information allowed us to detect a large discrepancy between maternal and paternal lineages in some populations. This is most likely the result of breeder efforts to ‘upgrade’ local populations using rams with different paternal origins.
Intravenous infusion of salbutamol in the treatment of asthma.
Authors: Spiro SG , Johnson AJ
Published: July 2012

The effects of i.v. infusion of increasing rates of salbutamol for up to 4 h were documented in ten convalescent asthmatic patients. 2 The major bronchodilator effect was seen at 4.16 mug/minute. A small further improvement occurred at infusion rates up to 25.0 mug/min but was not significantly better than that seen at the lower infusion rate. 3 Cardiovascular effects were minimal after 60 min at the lower rate and even at 25.0 mug/min mean heart rate rose by only 17.1 beats/minute. All patients tolerated the 4 h infusion well. 4 It is concluded that i.v. infusion of salbutamol may be a useful addition to the treatment of the patient with a severe attack of asthma.
Inhibition of gastric emptying and drug absorption by narcotic analgesics.
Authors: Nimmo WS , Heading RC , Wilson J , Tothill P , Prescott LF
Published: July 2012

The effect of intramuscular pethidine or diamorphine on gastric emptying and the absorption of orally administered paracetamol was assessed in eight normal subjects. 2 Both drugs produced a significant and striking delay in gastric emptying and absorption of paracetamol. 3 It seems inevitable that pethidine and diamorphine will retard the absorption of other orally administered drugs.
The effect of ageing on plasma pethidine concentration.
Authors: Chan K , Kendall MJ , Mitchard M , Wells WD
Published: July 2012

1. Plasma pethidine levels have been monitored after the administration of 1.5 mg/kg intramuscularly to a group of young (under 30) and old (over 70) subjects. 2. Plasma levels were consistently higher in the old group, this was most marked for the first three hours but for most of the study there was a more than two‐fold difference. 3. Differences in uptake from muscle and in metabolism were small and appeared unimportant. 4. Less pethidine was excreted in the elderly and this contributed to the overall differences in serum levels but was not important in explaining the marked disparity noted over the first three hours. 5. Red cell binding of pethidine by the young was much greater than by the old and if the differences in drug binding also applies to other tissues this would explain the high serum levels in the old and the increased incidence of side effects.
Can digoxin dose requirements be predicted?
Authors: Dobbs SM , Mawer GE , Rodgers M , Woodcock BG , Lucas SB
Published: July 2012

A search for patient variables relevant to digoxin dose requirements was made in fourty‐three patients with a wide range of renal and hepatic function. The daily dose of digoxin to achieve a mean serum concentration of 1.5 ng/ml, the standardized dose, was calculated for each patient. The standardized dose correlated significantly with the following variables, in descending order of correlation coefficient; creatinine clearance, serum creatinine concentration, body weight and serum albumin concentration. An equation containing the two independent variables, creatinine clearance and serum albumin concentration, had a significantly stronger correlation with standardized dose than creatinine clearance alone. Attempts were made in each patient to predict the standardized dose using both empirical prescribing methods and the published nomograms. Although a maximum of 70% of the variance of the standardized dose was explained, this corresponded approximately to one patient in three having a predicted dose outside the 95% confidnece limits for the standardized dose. There remain important sources of individual variation in digoxin dose requirements yet to be identified. Future application of empirical prescribing methods, such as multiple linear regression and Bayes' theorem, to prescription for large, defined patient groups may improve dose prediction for individual patients.
A study of factors influencing drug disposition in chronic liver disease, using the model drug (+)‐propranolol.
Authors: Branch RA , James J , Read AE
Published: July 2012

The pharmacokinetics, following i.v. administration of (+)‐propranolol (40 mg) have been compared to in vitro measurement of protein binding and biochemical parameters of liver function in six normal subjects and twenty patients with stable chronic liver disease. The clearance of (+)‐ propranolol decreased with evidence of increasing severity of impairment of liver function correlating significantly with a fall in serum albumin, a rise in bilirubin and a prolongation in prothrombin index. The clearance of (+)‐propranolol correlated with and was numerically similar to the clearance of indocyanine green in normal subjects and also in patients with chronic liver disease. Protein binding was decreased in chronic liver disease, but this change was not related to changes in plasma proteins. In normal subjects and patients without ascites the volume of distribution increased with decreases in protein binding. Ascites was associated with a further increase in the volume of distribution. The considerable variation in half‐life largely depends on changes in liver blood flow, the degree of protein binding and the plasma protein pool size.
The influence of various factors in the in vitro distribution of haloperidol in human blood.
Authors: Hughes IE , Jellett LB , Ilett KF
Published: July 2012

Haloperidol is 89.6+/‐0.3% bound (mean+/‐s.e. mean) in human plasma under in vitro conditions and the free drug distributes rapidly between the plasma and the cellular elements of blood. The cell/plasma partition ratio was 1.12+/‐0.06 (mean+/‐s.e. mean). Alteration of plasma binding by dilution with buffer showed that uptake of haloperidol by the cellular elements of blood was proportional to free drug concentration. Bishydroxycoumarin (95 ot 286 mug/ml) reduced plasma binding of haloperidol and the displaced haloperidol was taken up by the cellular blood elements. The experiments indicate that the cellular compartment of blood as well as the plasma compartment may act as a sink for haloperidol and drug displacement interactions should therefore be interpreted with a knowledge of both of these compartments.
The effects of low doses of amylobarbitone sodium and diazepam on human performance.
Authors: Hart J , Hill HM , Bye CE , Wilkinson RT , Peck AW
Published: July 2012

The effects of diazepam (2.5 and 5 mg) and amylobarbitone sodium (50 and 100 mg) on performance and subjective effects were assessed in a group of twelve healthy subjects under standardised conditions. Treatments were administered orally at weekly intervals according to a balanced design and under double‐blind conditions. The tests of performance most sensitive to drug effects in these healthy subjects were either prolonged and monotonous and gave the subject no feedback on performance, or required short term memory for efficient execution. Auditory vigilance was significantly impaired (P less than 0.05) between 45 min and 1 h 45 min after all drug treatments except amylobarbitone sodium (100 mg), compared with performance after lactose. At the same time false reports were significantly increased after amylobarbitone sodium (100 mg) compared with all other active drugs but not with lactose. These effects had disappeared 4‐5 h post drug. Short term memory was impaired 1h 45 min after all treatments and impairment was dose related. No significant effects occurred 5h after treatment. Simple auditory reaction time was prolonged 2 h after the highest doses of amylobarbitone sodium and diazpam, and by amylobarbitone sodium (50 mg) 5 h 15 min after treatment. At this time the effects of diazepam had worn off. Digit symbol substitution was impaired by amylobarbitone sodium (50 and 100 mg), and diazepam (5 mg) after 2 h 45 minutes. No significant changes in visual search or tapping occurred after active drugs compared with lactose. Subjective ratings indicated both mental and motor impairment 2 h 45 min after all active preparations compared with scores after lactose though significant changes followed diazepam (2.5 mg) infrequently. Both correct detections and false reports in auditory vigilance tended to fall over the 6 separate days of testing, indicating an increase in caution. Visual search, short term memory, tapping and digit symbol substitution significantly improved with time, but there was no change in reaction time. From the limited information obtained by sampling blood at 3 and 6 h, no relationship between change in performance and plasma level was found in these subjects.
Effect of N‐desmethyldiazepam (nordiazepam) and a precursor, potassium clorazepate, on sleep in man.
Authors: Nicholson AN , Stone BM , Clarke CH , Ferres HM
Published: July 2012

1 The effect of N‐desmethyldiazepam (nordiazepam, 5 and 10 mg) and potassium clorazepate (15 mg, a precursor of nordiazepam) on sleep was studied in six healthy adult males. Electroencephalography (EEG) was used for sleep measures, and analogue scales were used for subjective assessments of well‐being and sleep quality. 2 Effects on total sleep time were limited to the night of ingestion. There were increases with nordiazepam (5 and 10 mg) (P = 0.05) and 0.001 respectively), and with clorazepate (15 mg) (P = 0.01). Sleep onset latencies were shortened, particularly with nordiazepam, and awakening to stage 0 activity was reduced, by both drugs. The latency to stage 3 was reduced by nordiazepam (5 and 10 mg) (P = 0.05). 3 There were no effects of nordiazepam (5 mg) on the duration (min) of sleep stages. Nordiazepam (10 mg) and clorazepate (15 mg) reduced the duration of stage 0 and stage 1, and there were increases in stage 2. Reduced stage 1 and increased stage 2 sleep were observed during the recovery night. No effects were observed with stage 3, but there was evidence that stage 4 activity was depressed on the recovery night only. No effects were observed on REM sleep, except that the appearnace of the first REM period was delayed with clorazepate (15 mg) P = 0.01). The effect of nordiazepam (10 mg) and clorazepate (15 mg) were comparable, and each modified sleep for about 28‐30 h after ingestion. 4 With nordiazepam (10 mg) and clorazepate (15 mg) the subjects, as a group, reported improved sleep, but subjective assessments of well‐being were not altered. Correlations were calculated for sleep measures and subjective assessments.
Assessment of alpha‐ and beta‐adrenoceptor blocking actions of labetalol.
Authors: Richards DA , Tuckman J , Prichard BN
Published: July 2012

Isoprenaline dose‐response curves plotting increases in heart rate before and after labetalol are suggestive of competitive antagonism at beta‐adrenoceptor sites. Phenylephrine dose‐response curves using increases in systolic pressure before and after labetalol are suggestive of competitive antagonism at alpha‐adrenoceptor sites. The ratio of alpha:beta‐adrenoceptor antagonism induced by labetalol is approximately 1:3. Peak pharmacological responses after a single oral dose of labetalol (400 mg) occurred between 90‐120 min after administration.
Changes in reaction time and drug plasma concentrations after nitrazepam and glutethimide.
Authors: Curry SH , Whelpton R , Scott DF
Published: July 2012

1 The effects of nitrazepam, glutethimide and placebo were assessed in a double‐blind cross‐over study with five healthy human subjects, using reaction time, and relating changes to drug concentrations in the plasma. 2 After glutethimide in all five subjects, and after nitrazepam in four subjects, larger doses led to higher concentrations in plasma and to greater changes in reaction time; one subject displayed the higher nitrazepam concentrations and the greater effect following the smaller dose. 3 The relationship between change in reaction time and concentration appeared to be mainly a within‐subject dose‐effect relationship, with the peak concentration in plasma as the ‘dose’ and the area under the reaction time curve as the effect.
Haemodynamic long‐term effects of metoprolol at rest and during exercise in essential hypertension.
Authors: Lund‐Johansen P , Ohm OJ
Published: July 2012

1 Twelve men with untreated essential hypertension in WHO stage I were studied on an outpatient basis to evaluate the haemodynamic long‐term effect of a new beta‐adrenoceptor blocker, metoprolol. 2 Oxygen consumption, heart rate, cardiac output (Cardiogreen) and intraarterial brachial pressure were recorded at rest in a supine and sitting position and during steady state work at 300, 600 and 900 kpm/min. 3 The subjects were treated with metoprolol (dose 50‐250 mg/day) as the sole drug for 1 year and the haemodynamic study was repeated. 4 Mean arterial blood pressure was reduced about 12% at rest and 9% during exercise. The heart rate was decreased about 22% at rest and 20% during exercise. There was no significant compensatory increase in the stroke volume and consequently the cardiac index was reduced about 22% at rest sitting and about 17% during exercise. There was no decrease in total peripheral resistance. 5 No side‐effects were seen. 6 The major haemodynamic long‐term effects of metoprolol in mild and moderate essential hypertension resemble those seen by other beta‐adrenoceptor blockers like alprenolol, atenolol and timolol. The study has not given support to the assumption that metoprolol should cause less depression in cardiac output than other beta‐adrenoceptor blockers.
Phenytoin concentrations in mixed, parotid and submandibular saliva and serum measured by radioimmunoassay.
Authors: Paxton JW , Whiting B , Stephen KW
Published: July 2012

1 Concentrations of phenytoin in mixed, parotid and submandibular saliva and serum were determined in normal subjects after an oral dose, using a specific double antibody radioimmunoassay which requires only 20 micronl fluid. 2 Semi‐log concentration‐time plots of phenytoin concentration in mixed saliva and serum gave good parallelism after the initial 14 h post‐administration period. 3 The mean ratio of the mixed saliva: serum phenytoin concentration was 10.3% +/‐ 1.5 (s.d.) in seven normal subjects. 4 Phenytoin concentrations found in separate parotid and submandibular salivary fractions did not differ but were significantly greater (P less than 0.001) than those found in mixed saliva. 5 Phenytoin concentrations in all salivary fractions were independent of the volume of fluid produced and the degree of stimulation. 6 The rate of phenytoin secretion in the parotid and submandibular fluid was proportional to the salivary flow rate. 7 These data suggest that mixed saliva may be a suitable medium for the monitoring of phenytoin concentrations and may provide a non‐invasive alternative to the direct determination of phenytoin in serum.
Pharmacokinetics of pivmecillinam.
Authors: Parsons RL , Hossack GA , Paddock GM
Published: July 2012

1 The plasma concentration/time curves of ampicillin and mecillinam in normal subjects were measured after oral administration of ampicillin (500 mg) and pivmecillinam (400 and 600 mg). 2 Similar plasma concentration/time curves of ampicillin and mecillinam in the starved normal subjects followed oral administration of ampicillin (500 mg) and pivmecillinam (600 mg). 3 The plasma concentration/time curve of mecillinam was measured in the same normal subjects after oral administration of pivmecillinam (400 mg) with a reproducible standardized Lundh test meal. 4 There was no statistically significant difference in the plasma concentration/time curve of mecillinam after pivmecillinam/400 mg) and the meal compared with the plasma concentration/time curve after oral pivmecillinam (400 mg) was given to the same subjects when starved. After administration of pivmecillinam (400 mg) with meal, Tasc was significantly delayed beyond the value obtained when the subjects were starved. 5 The pharmacokinetics of pivmecillinam in coeliac disease are normal. This finding contrasts with previous studies on the pharmacokinetics of another pivaloyloxymethylpenicillin ester, pivampicillin, in this condition.
Digoxin measurements in general practice.
Authors: Holt DW , Williamson JD , Volans GN
Published: July 2012

1 As part of a prospective study on the use of digoxin in a general practice, plasma digoxin concentrations were measured in all patients receiving the drug. 2 A low mean plasma digoxin concentration was observed, suggesting a cautious approach to digitalization. 3 The correlation between plasma digoxin concentration and signs or symptoms commonly used in the assessment of digoxin effect was poor. 4 It was concluded that the measurement of plasma digoxin could be of assistance in a variety of clinical settings within a general practice.
Ciclazindol and mazindol on glucose uptake into human isolated skeletal muscle: no interaction of mazindol with methysergide.
Authors: Kirby MJ , Turner P
Published: July 2012

1 Ciclazindol, like mazindol, produced a significant concentration‐ dependent increase in glucose‐uptake into human skeletal muscle in both the presence and absence of insulin. 2 Methysergide, which inhibits the action of fenfluramine on glucose‐uptake into skeletal muscle, did not influence the effect of mazindol.
The effect of mental arithmetic in normotensive and hypertensive subjects, and its modification by beta‐adrenergic receptor blockade.
Authors: Nyberg G , Graham RM , Stokes GS
Published: July 2012

1 The effects of a 5‐min period of sustained mental arithmetic upon blood pressure and heart rate were determined in several groups of healthy subjects and hypertensive patients. 2 The arithmetic produced significant increases in heart rate and blood pressure (both systolic and diastolic) in both normotensive and hypertensive subjects. 3 The blood pressure changes were neither attenuated nor enhanced by the prior administration of basis. 4 In subjects habituated to the test the heart rate increase was unaffected by the drugs, but in those less familiar with the test it was usually attenuated. 5 Although the beta1‐ adrenoceptor selective blocker, metoprolol, caused decreases in baseline values for blood pressure and heart rate similar to those observed with the use of the two non‐selective blockrs, it was shown in a double‐blind crossover comparison with propranolol that the haemodynamic changes provoked by the mental arithmetic were not less in the presence of beta1‐receptor blockade than when both beta1‐ and beta2‐ receptors were blocked. 6 These findings suggest that, during beta2‐ adrenoceptor blockade, the haemodynamic effects of minor mental stress are not exaggerated because of uncompensated alpha‐receptor mediated vasoconstriction, such as occurs following adrenaline infusion.
Adverse reactions to procainamide.
Authors: Lawson DH , Jick H
Published: July 2012

1 Data from a comprehensive drug surveillance programme are analysed to provide details of procainamide use and toxicity in medical wards of teaching hospitals in five countries. 2 Out of a total of 488 recipients 9.2% had one or more adverse effect attributed to the drug; common effects being arrhythmias, gastro‐intestinal upsets and drug fever. Although occasionally of major severity, no patient died as a consequence of procainamide toxicity. 3 Toxicity was directly related to total daily dose and duration of hospitalization but was not related to age, weight of the patient or presenting urea or albumin concentrations.
Iotroxamide studies in man‐plasma binding, renal and biliary excretion studies in jaundiced and anicteric patients.
Authors: Doran J , Vennart W , Richmond CR , Bell GD
Published: July 2012

1.A decrease in the plasma binding of iotroxamide was found in jaundiced people. 2. The decrease in binding was associated with an enhancement in renal excretion. 3. Iotroxamide consistently gave higher biliary iodine concentrations than ioglycamide.
The electrocardiogram in the assessment of the effect of drugs on cardiac arrhythmias.
Authors: Reid DS
Published: July 2012

The search for the ideal antiarrhythmic drug continues since none of the available agents offers optimum antiarrhythmic therapy. The continuing search coupled with the interest in the mechanisms of cardiac arrhythmias has led to the development of new techniques for the study of arrhythmias and antiarrhythmic drugs. In this article it is proposed to discuss the electrocardiographic methods used in the assessment of antiarrhythmic drugs. Firstly, to discuss the electrocardiogram in the assessment of the clinical electrophysiological properties of a drug and secondly, the electrocardiogram in the assessment of the value of the drug in the management of cardiac arrhythmias in man.
Amitriptyline‐ and mianserin‐induced changes in acquisition of paired‐ association learning‐task.
Authors: Liljequist R , Seppala T , Mattila MJ
Published: July 2012

1 The double‐blind study on twenty healthy students was an attempt at assessing the effects of 2‐week's treatment with amitriptyline (25 mg three times a day) and mianserin (10 mg three times a day), each alone or separatively inbibed with alcohol (0.5 g/kg) on the immediate memory and on the acquisition of a paired‐association learning‐task. 2 Amitriptyline impaired both the short‐term memory‐span and acquisition, and alcohol potentiated these effects. The action of mianserin did not deviate significantly from that of the placebo, and it also failed to interact with alcohol. 3 It is concluded that the decrement in learning capacity, that occurs after the 2‐week's treatment with therapeutic doses of amitriptyline, reflects changes in both the intrinsic and the regulatory mechanisms of learning.
Desensitization of the beta‐adrenoceptor of lymphocytes from normal subjects and patients with phaeochromocytoma: studies in vivo.
Authors: Greenacre JK , Conolly ME
Published: July 2012

1 Following the observation that lymphocyte beta‐adrenoceptor responsiveness was not depressed in asthmatics treated only with non‐ adrenergic drugs we have explored the effects of prolonged exposure to beta‐adrenoceptor agonists in normal subjects. 2 Treatment with oral salbutamol (12‐16 mg/kg/day for 10 days), or with inhaled salbutamol (3000 microgram/day for 8‐10 days) resulted in a significant reduction in lymphocyte beta‐adrenoceptor responsiveness. 3 A 48 h infusion of isoxsuprine (10 mg/h) resulted in a marked depression of lymphocyte beta‐adrenoceptor responsiveness (P less than 0.001). 4 Prolonged elevation of endogenous catecholamines caused by phaeochromocytoma was also associated with a marked depression of lymphocyte beta‐ adrenoceptor responsiveness (P less than 0.001). 5 There was no evidence that an increase in phosphodiesterase activity could explain the reduced cyclic AMP response. 6 It is concluded that diminished beta‐ adrenoceptor response occurs as a response to prolonged exposure to beta‐adrenoceptor agonists. It is likely that the diminished response seen in asthmatic subjects can be explained on a similar basis and does not indicate an inherent cellular defect. 7 The possible clinical significance of such changes in asthmatics are discussed.
Comparison of plasma and saliva levels of metoprolol and oxprenolol.
Authors: Dawes CP , Kendall MJ , John VA
Published: July 2012

1 Plasma and saliva levels of metoprolol and oxprenolol have been compared in two groups of healthy volunteers. 2 Mean salivary oxprenolol levels were lower than, but closely related to the corresponding plasma levels (r=0.93), the mean ratio of saliva:plasma concentration being 0.42. 3 Mean salivary metoprolol concentrations were considerably greater thatn the corresponding plasma levels and the relationship between the concentrations in the two fluids was less clear. 4 The evidence presented suggests that oxprenolol diffuses passively whilst metoprolol is actively secreted into saliva. The mechanism involved in the active process is not known.
Disposition of sodium valproate in epileptic patients.
Authors: Perucca E , Gatti G , Frigo GM , Crema A , Calzetti S , Visintini D
Published: July 2012

1 Serum levels of valproic acid have been determined at fixed intervals after the administration of single oral and intravenous doses (800 mg) to six epileptic patients receiving chronic treatment with other antiepileptic drugs. 2 Serum levels declined monoexponentially shortly after the intravenous administration. Biological half‐lives averaged 9.0 +/− 1.4 h (s.d.). Volumes of distribution were 0.175 +/− 0.025 l/kg. There was a statistically significant negative correlation between volumes of distribution and serum half‐lives (P less than 0.005). 3 After oral doses serum levels rose rapidly to peak values within 0.5–2 h. Biological availability was 96 +/− 9%. 4 Comparison with a previous study performed according to the same protocol in healthy volunteers showed significantly increased volumes of distribution and rates of elimination in the patients. Total serum clearance was 85% higher in the patients as compared to the healthy subjects (P less than 0.001). Possible explanations for these findings are discussed.
Circulatory and alpha‐adrenoceptor blocking effects of phentolamine.
Authors: Richards DA , Woodings EP , Prichard BN
Published: July 2012

1 Intravenously administered phentolamine provoked immediate decreases in diastolic blood pressure but increases in heart rate and cardiac output. 2 These immediate circulatory effects had largely disappeared twenty minutes after administration and at this time phentolamine did not inhibit increases in blood pressure which were provoked during hand immersion in ice‐cold water. 3 Log dose‐response curves of noradrenaline induced increases in systolic and diastolic pressure 20 min after intravenous phentolamine were shifted to the right in a parallel manner compared with the curves before phentolamine administration. 4 It was concluded that the immediate and short acting effects induced by phentolamine are due to a non‐specific vasodilator effect but in addition phentolamine causes a longer acting alpha‐ adrenoceptor blockade at vascular adrenoceptor sites. However, by producing both pre‐ and post‐synaptic alpha‐adrenoceptor blockade this may explain why this drug exerts only a weak antihypertensive effect.
The effects of indomethacin on arachidonic acid and prostaglandins e2 and f2alpha levels in human skin 24 h after u.v.B and u.v.C irradiation.
Authors: Black AK , Greaves MW , Hensby CN , Plummer NA , Warin AP
Published: July 2012

1 Clinically normal human abdominal skin was irradiated with either three times its minimal erythema dose (MED) of ultraviolet B (u.v.B) or six MEDs of ultraviolet C (u.v.C) radiation. In both instances erythema was maximal at 24 h. 2 Exudate was recovered by a suction bulla technique from normal and irradiated skin at 24 h after irradiation. 3 Arachidonic acid, prostaglandins E2 and FSalpha, as measured by GC–MS, were significantly elevated at 24 h. Radioimmunoassay also showed increased PGF2alpha‐like concentrations. 4 Oral indomethacin only partially reduced the erythema resulting from both types of radiation but totally suppressed the elevation of PGE 2 and F2alpha concentrations. 5 Topical indomethacin also suppressed u.v.B‐induced increases in prostaglandins E2 and F2alpha. Unexpectedly, the vehicle alone produced a similar suppressive effect on prostaglandins although erythema appeared unaltered. 6 Most of the arachidonic acid metabolized by indomethacin‐sensitive pathways is not converted to prostaglandins E2 and F2alpha in human skin.
Clonidine withdrawal. Mechanism and frequency of rebound hypertension.
Authors: Geyskes GG , Boer P , Mees Dorhout EJ
Published: July 2012

1. The frequency and pathophysiology of the clonidine withdrawal syndrome was studied in fourteen hypertensive patients on chronic clonidine therapy. 2. After sudden cessation of clonidine (900 microgram daily) almost all of the patients showed an excessive increase of the heart rate and blood pressure. Seven of the fourteen patients had subjective symptoms, in three severe enough to require interruption of observation by therapeutic intervention 12 to 60 h after the last dose of clonidine. After clonidine withdrawal, NAE increased to abnormally high values in correlation with the blood pressure (P less than 0.01) and heart rate (P less than 0.001), whereas PRA even decreased initially, probably secondary to the rise of the blood pressure, and only rose, although not significantly, 48 h after withdrawal. PRA was not correlated with NAE, heart rate, or blood pressure. 3. It is concluded that the clonidine withdrawal phenomenon is a frequently occurring and potentially dangerous syndrome. Overactivity of the sympathetic nervous system is mainly responsible, without the mediation of the renin angiotensin system. This also explains our experience that adrenergic beta‐receptor blocking drugs do not prevent the rise in BP, although they alleviate some of the symptoms.
A controlled trial of labetalol (Trandate), propranolol and placebo in the management of mild to moderate hypertension.
Authors: Pugsley DJ , Nassim M , Armstrong BK , Beilin L
Published: July 2012

1. Labetalol, a new drug combining alpha‐and beta‐adrenoceptor blocking properties, has been compared with placebo in a double‐blind crossover study of a group of patients with mild to moderate essential hypertension (blood pressure 150/100 to 189/114 mmHg). 2. Labetalol and propranolol lowered blood pressure satisfactorily in the supine position, but labetalol reduced blood pressure more in the erect posture and following exercise and induced less bradycardia. Thus alpha‐ as well as beta‐adrenoceptor blocking actions appear to contribute to blood pressure reduction. 3. Side effects attributable to labetalol were few. The effective dose ratio labetalol: propranolol was 2.5:1 (w/w). 4. Labetalol, a new form of hypotensive agent, merits further controlled assessment of its usefulness in relation to existing drugs.
A pharmacokinetic study of doxapram in patients and volunteers.
Authors: Robson RH , Prescott LF
Published: July 2012

1. Following intravenous bolus injections or brief infusions in healthy volunteers, plasma concentrations of doxapram declined in a multi‐ exponential fashion. The mean half‐life from 4‐12 h was 3.4 h (range 2.4‐4.1h), the mean apparent volume of distribution was 1.5 1 kg‐1 and the whole body clearance was 370 ml min‐1. 2. Enteric‐coated capsules of doxapram base were absorbed rapidly after an initial delay, and the systemic availability was about 60%. 3. Doxapram is extensively metabolized and less than 5% of an i.v. dose was excreted unchanged in the urine in 24 h. A metabolite (AHR 5955) was present in plasma in amounts comparable to the parent compound and had a similar half‐life. 4. The disposition of doxapram appears to be similar in healthy volunteers and patients with respiratory failure. 5. The previously held belief that plasma concentrations fall rapidly when an infusion is stopped is only true following short duration infusions. The pharmacokinetic properties of doxapram are such that steady‐state plasma concentrations will not be achieved for many hours with the recommended constant rate infusion regime.
Responses of human and baboon arteries to prostaglandin endoperoxides and biologically generated and synthetic prostacyclin: their relevance to cerebral arterial spasm in man.
Authors: Boullin DJ , Bunting S , Blaso WP , Hunt TM , Moncada S
Published: July 2012

1 Isolated strips of human or baboon basilar, middle cerebral, vertebral or common carotid arteries were set up in an isolated organ bath or in a superfusion cascade system. 2 These arteries relaxed to prostacyclin but contracted to prostaglandin endoperoxide (PGH2). 3 Human and baboon isolated arteries also generated prostacyclin from exogenous endoperoxide (PGH2). 4 Human arteries generated prostacyclin 36 h post‐mortem but not 40 h post‐mortem. The biologically generated prostacyclin relaxed the basilar artery and overcame the contractile effects of PGH2. 5 Thromboxane A2‐like activity generated during human platelet aggregation by arachidonic acid caused contractions of the human basilar artery. 6 Prostacyclin reversed contractions of human basilar arteries caused by an unidentified vasoconstrictor factor in cerebrospinal fluid obtained from patients with cerebral arterial vasospasm after subarachnoid haemorrhage following rupture of cerebral arterial aneurysms. 7. The above vasospasm may be due at least in part to disordered physiological control of the calibre of cerebral arteries caused by diminished synthesis of prostacyclin.
The effects of beta‐adrenoceptor blockade on renin, angiotensin, aldosterone and catecholamines at rest and during exercise.
Authors: Lijnen PJ , Amery AK , Fagard RH , Reybrouck TM , Moerman EJ , de Schaepdryver AF
Published: July 2012

1 beta‐adrenoceptor blockade with metoprolol provoked, both at rest and during exercise, a decrease of 'active' renin and angiotensin II together with an increase of 'inactive' renin and unchanged 'total' renin. The significant exercise‐provoked increases in angiotensin II, plasma renin activity and 'active', 'inactive' and 'total' renin when on placebo, were reduced by metoprolol. 2 No significant change in serum sodium and potassium and in plasma aldosterone was found during beta‐adrenoceptor blockade at rest. During exercise plasma aldosterone dropped significantly without any change in serum sodium or potassium. 3 Plasma noradrenaline increased significantly at rest on metoprolol. The increase in plasma noradrenaline and adrenaline during exercise was similar on placebo and on metoprolol.
Serum, tear and salivary concentrations of methotrexate in man.
Authors: Steele WH , Stuart JF , Whiting B , Lawrence JR , Calman KC , McVie JG , Baird GM
Published: July 2012

1. Methotrexate handling has been studied in four patients with psoriasis and eleven patients with neoplastic disease. 2. Methotrexate levels in serum, tears and saliva were measured by radioimmunoassay while protein binding studies were performed by continuous ultrafiltration. 3. There was a close correlation between methotrexate concentrations in tears and serum (P less than 0.001, r = 0.714). Parotid salivary and serum methotrexate levels were similarly correlated (P less than 0.001, r = 0.557) but not mixed salivary and serum levels (P greater than 0.1, r = 0.232). 4. The mean protein binding was 95.11% +/‐ 2.26 (s.d.) while the ratio of methotrexate levels in tears to the free serum methotrexate level was 1:1.04. The corresponding parotid salivary level: free serum level ratio was 1:18.11. 5. No relationship could be determined between the methotrexate levels in tears and conjunctivitis observed in some of the patients under study.
Effect of a single oral dose of aspirin on the platelet aggregation response to arachidonic acid.
Authors: Bye A , Lewis Y , O'Grady J
Published: July 2012

1 The platelet aggregation response to arachidonic acid ex vivo was measured in six volunteers daily before and for 10 days after a single oral dose of 600 mg aspirin. 2 Arachidonic acid induced aggregation of platelets from all subjects before aspirin and aggregation occurred after an interval which varied inversely with the concentration of arachidonic acid. No aggregation occurred for 4 days after aspirin; a reduced response, compared with pre‐aspirin values, was obtained on the 5th, 6th and 8th day. The values on days 7, 9 and 10 were not consistently different from the pre‐aspirin values. In 6 subjects 24 h after aspirin ingestion the addition of 10–25% v/v normal platelets restored the aggregation response. 3 It is concluded that aspirin has an effect on the platelet precursors in the marrow in addition to its effect on circulating platelets.
The effect of assay methods on plasma levels and pharmacokinetics of theophylline: HPLC and EIA.
Authors: Ishizaki T , Watanabe M , Morishita N
Published: July 2012

1 The effects of two assay methods, HPLC and EIA, on theophylline plasma levels (n = 254) and pharmacokinetics (n = 6) were examined on blood samples obtained from asthmatic patients and normal adult male volunteers. 2 The standard curves obtained and the plasma level values during plasma level monitoring of theophylline measured with two methods are well correlated each other within concentration range of 2.5 to 20.0 microgram/ml (P less than 0.001). EIA, however in general, appears to give a lower value than HPLC. 3 The values of plasma theophylline half‐life and clearance analyzed using a two‐compartment open system model were found different between the two assay methods and dissimilar to those previously reported by using ultraviolet method. 4 The sampling end‐point and/or assay sensitivity particularly to measure a lower level of theophylline (less than 2.5 microgram/ml) can influence the pharmacokinetics for a potent bronchodilator with a narrow therapeutic margin, theophylline.
Specific radioimmunoassay of amitriptyline and nortriptyline.
Authors: Brunswick DJ , Needelman B , Mendels J
Published: July 2012

1 Antisera to nortriptyline were prepared by immunizing rabbits with N‐ succinylnortriptyline‐bovine serum albumin conjugate. 2 A sensitive radioimmunoassay has been developed for the tricyclic antidepressants amitriptyline and nortriptyline. 3 amitriptyline and nortriptyline are separated from each other and from interfering metabolites before assay. 4 Using [3H]‐imipramine and [3H]‐succinylnortriptyline as tracers the radioimmunoassay can measure amitriptyline and nortriptyline levels down to 2–3 ng/ml using 0.05 ml plasma sample. 5 Agreement between the radioimmunoassay and a gas‐chromatographic assay was excellent for both amitriptyline and nortriptyline.
Antihypertensive effect of a non‐selective (propranolol) and a cardioselective (metoprolol) beta‐adrenoceptor blocking agent at rest and during exercise.
Authors: Clausen N , Damsgaard T , Mellemgaard K
Published: July 2012

1 The antihypertensive effects at rest and during physical exercise of the non‐selective beta‐adrenoceptor blocker propranolol and the cardioselective beta‐adrenoceptor blocker metoprolol were compared in a double‐blind cross‐over study. 2 Eighteen patients with mild hypertension entered the trial. One patient was withdrawn from the study due to side effects on both drugs. 3 The two beta‐adrenoceptor blockers were compared using doses earlier shown to have the same beta‐ adrenoceptor blocking potency, as measured by their effect on exercise tachycardia in healthy men. 4 Arterial blood pressure was reduced to the same extent by propranolol and metoprolol at rest as well as during submaximal work. 5 It is concluded that the antihypertensive effect of beta‐adrenoceptor blockers is mainly mediated through blockade of the beta 1‐adrenoceptors.
Pituitary tumours during pregnancy in mothers treated with bromocriptine.
Authors: Griffith RW , Turkalj I , Braun P
Published: July 2012

1 Out of 805 previously infertile women in whom pregnancy was achieved on bromocriptine treatment, 137 were diagnosed as having pituitary tumours. 2 In nine of these, tumour‐related complications occurred during pregnancy, chiefly visual field impairment. Surgical intervention was considered necessary in two patients. In a third patient reinstitution of bromocriptine produced remission of symptoms. 3 Although the frequency of serious complications was low, the present state of knowledge indicates that surgery or irradiation of pituitary tumours should be preferred, at least as the first line of treatment, for patients contemplating pregnancy.