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Biomedical subjects

I MacKenzie

Publications and source records attributed to I MacKenzie.

At least 19 recordsLinked to original sources
PubMed2003

Relationships between preclinical cardiac electrophysiology, clinical QT interval prolongation and torsade de pointes for a broad range of drugs: evidence for a provisional safety margin in drug development.

OBJECTIVE: To attempt to determine the relative value of preclinical cardiac electrophysiology data (in vitro and in vivo) for predicting risk of torsade de pointes (TdP) in clinical use. METHODS: Published data on hERG (or I(Kr)) activity, cardiac action potential duration (at 90% repolarisation; APD(90)), and QT prolongation in dogs were compared against QT effects and reports of TdP in humans for 100 drugs. These data were set against the free plasma concentrations attained during clinical use (effective therapeutic plasma concentrations; ETPC(unbound)). The drugs were divided into five categories: (1) Class Ia and III antiarrhythmics; (2) Withdrawn from market due to TdP; (3) Measurable incidence/numerous reports of TdP in humans; (4) Isolated reports of TdP in humans; (5) No reports of TdP in humans. RESULTS: Data from hERG (or I(Kr)) assays in addition to ETPC(unbound) data were available for 52 drugs. For Category 1 drugs, data for hERG/I(Kr) IC(50), APD(90), QTc in animals and QTc in humans were generally close to or superimposed on the ETPC(unbound) values. This relationship was uncoupled in the other categories, with more complex relationships between the data. In Category 1 (except amiodarone), the ratios between hERG/I(Kr) IC(50) and ETPC(unbound) (max) ranged from 0.1- to 31-fold. Similar ranges were obtained for drugs in Category 2 (0.31- to 13-fold) and Category 3 (0.03- to 35-fold). A large spread was found for Category 4 drugs (0.13- to 35700-fold); this category embraced an assortment of mechanisms ranging from drugs which may well be affecting I(Kr) currents in clinical use (e.g. sparfloxacin) to others such as nifedipine (35700-fold) where channel block is not involved. Finally, for the majority of Category 5 drugs there was a >30-fold separation between hERG/I(Kr) activity and ETPC(unbound) values, with the notable exception of verapamil (1.7-fold), which is free from QT prolongation in man; this is probably explained by its multiple interactions with cardiac ion channels. CONCLUSIONS: The dataset confirms the widely-held belief that most drugs associated with TdP in humans are also associated with hERG K(+) channel block at concentrations close to or superimposed upon the free plasma concentrations found in clinical use. A 30-fold margin between C(max) and hERG IC(50) may suffice for drugs currently undergoing clinical evaluation, but for future drug discovery programmes, pharmaceutical companies should consider increasing this margin, particularly for drugs aimed at non-debilitating diseases. However, interactions with multiple cardiac ion channels can either mitigate or exacerbate the prolongation of APD and QT that would ensue from block of I(Kr) currents alone, and delay of repolarisation per se is not necessarily torsadogenic. Clearly, an integrated assessment of in vitro and in vivo data is required in order to predict the torsadogenic risk of a new candidate drug in humans.

Animals↗
PubMed2001

A K(ATP) channel opener inhibited myocardial reperfusion action potential shortening and arrhythmias.

Low concentrations of certain K(ATP) channel openers have been reported to exert a moderate inhibitory effect on arrhythmias during post-ischaemic early myocardial reperfusion, but the accompanying effects on the time course of changes in action potentials in intact hearts have not yet been studied. We report that in rat isolated hearts, reperfusion following 10 min of regional no-flow ischaemia was associated with both an acute, marked, but transient, shortening of ventricular repolarisation (by 63%) during reperfusion, and a high incidence (90%) of ventricular tachyarrhythmias. The K(ATP) channel opener Ro 31-6930 [2-(6-cyano-2,2-dimethyl-2H-1-benzopyran-4-yl)-pyridine 1-oxide], delivered prior to ischaemia at a relatively low concentration (0.5 microM), significantly reduced the incidence and duration of reperfusion arrhythmias, and prevented the associated acute action potential shortening during reperfusion, each in a glibenclamide (1 microM)-sensitive manner (P<0.05, n=10-15 hearts). This was associated with a moderate and non-arrhythmogenic action potential shortening during ischaemia (a potentially "cardioprotective" effect). However, these data highlight the potential harm these drugs may cause, since a higher concentration of Ro 31-6930 caused marked shortening of action potentials and significant pro-arrhythmia during ischaemia.

Action Potentials↗
PubMed2001

Methods of collecting and evaluating non-clinical cardiac electrophysiology data in the pharmaceutical industry: results of an international survey.

OBJECTIVE: To assess current practice in the pharmaceutical industry for assessing the potential for QT interval prolongation by non-cardiovascular medicinal products. METHODS: The survey was based on responses from the Toxicology and (Safety) Pharmacology laboratories (a total of 74 laboratories) of 54 companies based in Europe, Japan/Asia and the USA, received between January and March 1999. RESULTS: All 54 companies conducted preclinical in vivo electrocardiography (EGG) evaluation of new active substances (NASs). Thirty of these companies also conducted in vitro cardiac electrophysiology studies on their compounds. The majority of in vivo work was done in conscious beagle dogs. There was no consistency within the industry in defining the magnitude of change in QT interval that is considered biologically important. Most companies considered a change greater than 10% to be important, although the design of the studies suggested that group sizes used may not give sufficient statistical power to detect this size of change. Bazett's formula was used by 41% of laboratories to correct QT for changes in heart rate, despite the fact that this formula is generally deemed to be unsuitable for use in dogs. For studies in anaesthetised dogs, the majority of laboratories used barbiturate anaesthesia, but researchers should be aware of the effects of this and some other anaesthetic agents on QT interval. As for in vitro cardiac electrophysiology, there was wide diversity in the testing methodologies, particularly with regard to the test species and tissue type. As with QT prolongation, there was no consensus on the degree of action potential prolongation to cause concern. For both in vitro and in vivo testing, the majority of companies tested a minimum of three dose (or concentration) levels in order to ascertain any dose-response relationship. CONCLUSIONS: The survey provides a snapshot of the practice in the industry prior to any internationally-agreed consensus on the most effective and efficient approaches to minimising the risk of QT prolongation by new drugs in man. It must be stated that for any given methodology, the 'majority view' in the industry is not necessarily best practice.

Action Potentials↗
PubMed2000

Do KATP channels open as a prominent and early feature during ischaemia in the Langendorff-perfused rat heart?

The objective was to investigate whether myocardial adenosine triphosphate-sensitive K+ (KATP) channels open during the first 10 min of regional ischaemia in Langendorff-perfused rat hearts. Changes in monophasic action potentials and arrhythmias were studied during myocardial ischaemia in both the presence and absence of pharmacological KATP modulation. Ligation of the left main coronary artery for 10 min did not shorten the action potential duration (APD). The APD50 and APD80 (15.5 +/- 1.0 and 38.1 +/- 2.3 ms, respectively [mean +/- S.E., n = 15 hearts], immediately prior to ligation) increased transiently during the first 4 min of ligation (by 160 and 79% respectively, P < 0.05), before returning to pre-ligation values, but without a significant below-baseline-shortening. The cardiac electrogram showed no accompanying ventricular tachyarrhythmia (VT). These results raised the possibility that the myocardial KATP channels had not opened during the ligation. The KATP opener Ro 31-6930 (0.5 and 5 microM) shortened the APD50 and APD80 during coronary ligation, to significantly below both their control and pre-occlusion values (P < 0.05), and caused a concentration-dependent increase in both the incidence and duration of VT during the ligation. Ro 31-6930 at 5 microM also shortened APD50 and APD80 even before ligation (by 50 and 62% respectively, P < 0.05), and abolished the normal APD-lengthening seen during ischaemia. The KATP blocker glibenclamide (1 microM) abolished both the APD-shortening and pro-arrhythmic effects of the KATP opener, both before and during coronary ligation, yet when delivered on its own, at the same concentration which abolished the effects of KATP activation, it had no significant effect on the APD changes seen during the coronary ligation alone. These results suggest that, in Langendorff-perfused rat hearts in the absence of drugs, KATP channels do not open during early myocardial ischaemia.

Action Potentials↗
PubMed1999

Survey on repeat prescribing for acid suppression drugs in primary care in Cornwall and the Isles of Scilly.

BACKGROUND: Repeat prescriptions for acid suppression therapy represent an important burden on health care resources. AIM: To determine the prevalence of acid suppression therapy and its indications by general practitioners (GPs) in a larger sample of practices than previous studies. METHOD: Practices in Cornwall and the Isles of Scilly were invited to identify the number of patients on repeat prescription for acid suppression drugs in their practice, to review the indication for treatment in a sample of 50 patients, and to indicate the mode of review of these patients. RESULTS: Out of 77 practices, 42 (55%) participated in the study. Overall, 5% of patients were authorized to receive a repeat prescription for acid suppression drugs. Repeat rates varied between practices, from 1.68% to 11.11%. Repeat rates increased with age and were higher in men than in women. Only 41% of patients had a proven diagnosis of gastro-oesophageal reflux disease or peptic ulcer. A review of notes was the most frequent way (36%) stated by GPs to review acid suppression therapy. CONCLUSION: The repeat rate found in our study was higher than that found in previous studies. A high proportion of older patients in Cornwall, as well as a continuing increase in the prescription of acid suppression drugs, may account for these results.

Adolescent↗
PubMed1993

Differential class III and glibenclamide effects on action potential duration in guinea-pig papillary muscle during normoxia and hypoxia/ischaemia.

1. Microelectrode recording techniques were used to study the effects of several potassium channel blockers which are considered to be Class III antiarrhythmic compounds. The effects of (+)-sotalol, UK-66,914, UK-68,798 and E-4031 on action potential duration (APD) were determined in guinea-pig isolated papillary muscles. The compounds were evaluated under normoxic or hypoxic/ischaemic conditions at 36.5 degrees C and compared to glibenclamide, which is considered to be a blocker of ATP-dependent potassium channels. Prolongation of action potential duration at 90% repolarization (APD90) was taken as an indirect measure of potassium channel blockade. 2. Under normoxic conditions, the Class III compounds prolonged APD in a concentration-dependent manner. According to EC15 values, the order of potency of the Class III compounds was found to be UK-68,798 > E-4031 > UK-66,914 > (+)-sotalol. Glibenclamide did not significantly prolong APD90 under normoxic conditions. 3. Perfusion with an experimental hypoxic or ischaemic bathing solution produced qualitatively similar effects on action potentials. Over a period of 20-25 min in either of the experimental solutions, there was a small decrease in action potential amplitude (APA) and a prominent shortening of APD. The ischaemic solution also depolarized the resting membrane potential by about 15 mV. 4. (+)-Sotalol and UK-66,914 did not reverse the shortening of APD induced by perfusion with hypoxic Krebs solution. High concentrations of glibenclamide (10 microM) and UK-68,798 (30 and 60 microM) partially reversed the hypoxia-shortened APD. Glibenclamide was more potent and exhibited a greater time-dependent action than UK-68,798. 5. During experimental ischaemia, the Class III compound E-4031 (10 microM, n = 7) produced small, but significant, increases in the APD90 (11 +/-3 ms after 20 min) which were not clearly time-dependent(14 +/- 4 ms after 30 min). UK-68,798 (10 microM) also produced a small, but insignificant, increase in APD90(12 =/-6 ms at 20 min, n = 4). Higher concentrations of UK-68,798 (30 and 60 microM, n = 4) did not produce a consistently significant increase in APD90 during ischaemia: significance was only attained after 20 min in the presence of 60 microM UK-68,798 (24 +/- 12 ms). However, in marked contrast to the effects of the Class III compounds, glibenclamide (10 microM) produced large time-dependent increases in ischaemic APD90 (34 +/- 11 ms at 7 min, n = 9) which were significant 15 min or more after drug addition(52 +/- 12 ms at 20 min, n = 7; 74 +/- 5 ms at 30 min, n = 6).6. The present microelectrode data suggest that blockers of ATP-dependent potassium channels, such as glibenclamide, might prove to be more effective than Class III compounds against ischaemia-induced shortening of cardiac action potentials.

Action Potentials↗
PubMed1990

Effects of pinaverium on voltage-activated calcium channel currents of single smooth muscle cells isolated from the longitudinal muscle of the rabbit jejunum.

1. Smooth muscle cells of the longitudinal muscle of the rabbit jejunum were dispersed by enzyme treatment and recordings of membrane current were made in the whole-cell mode by patch clamp technique. The action of pinaverium bromide on the voltage-dependent inward current of single isolated smooth muscle cells was studied in solutions containing normal concentrations of calcium or high concentrations of barium at room temperature. 2. Pinaverium reduced the voltage-dependent inward current with an IC50 of 1.5 microM. This IC50 is similar to those of verapamil, diltiazem and flunarizine on these cells as described by others. Occasionally evidence of a potentiating action of pinaverium on the inward current was seen. 3. Repetitive stimulation of the cells did not increase blockade of inward current by pinaverium unlike the use-dependent blockade seen with verapamil, methoxyverapamil, and diltiazem in these and in other smooth muscle cells. 4. The inactivation of inward current was studied by holding at various potentials for 2 or 10 s before evoking inward current. The voltage at which current was 50% available was changed very little by pinaverium although other calcium entry blockers, for example the dihydropyridines, have been reported to produce appreciable negative shifts which indicate considerable voltage-dependence of their blockade. This may indicate that pinaverium has similar affinities for the closed available and inactivated calcium channel states so that blockade is not appreciably voltage-dependent.

Animals↗
PubMed1990

Meningiomas presenting with paranasal sinus involvement.

Extracranial paranasal spread of meningiomas is uncommon. We describe the management of four cases, all of which first presented to an oto-rhino-laryngologist for an opinion. We suggest that greater use of modern imaging techniques could lead to earlier diagnosis. The natural history of extracranial spread is relatively benign but the management of regrowth of residual disease is difficult. We therefore suggest radical surgery in the first instance provided that the patients general health and configuration of the tumour allow.

Adult↗
PubMed1988

Regulation of voltage-dependent excitatory responses to alpha,beta-methylene ATP, ATP and non-adrenergic nerve stimulation by dihydropyridines in the guinea-pig vas deferens.

Simultaneous recordings of mechanical and intracellular electrical activity were obtained from the guinea-pig vas deferens, where nerve stimulation, ATP and the stable nucleotide analogue alpha,beta-methylene ATP elicited excitatory responses. Excitatory junction potentials and action potentials were elicited by low-frequency (trains of pulses, generally less than or equal to 2 Hz) field stimulation. alpha,beta-Methylene ATP and ATP elicited only concentration-dependent depolarizations at low concentrations, while higher concentrations elicited a superimposed action potential discharge which was accompanied by mechanical contraction. The voltage threshold at which action potential discharge was initiated by these three stimuli was about -45 mV (resting membrane potential averaged -66 mV). Action potential discharges and contractile responses were antagonized by nifedipine and augmented by Bay K 8644 at concentrations (1 and 0.5 microM, respectively) which exhibited only small effects on either excitatory junction potential amplitudes or nucleotide-induced depolarizations. Bay K 8644 enhanced and nifedipine antagonized the repolarization (rectification) phase of action potential discharge elicited by nerve stimulation and drugs; after-hyperpolarizations were prominent in the presence of Bay K 8644 (0.1-5 microM). Excitatory junction potentials were antagonized after exposure to alpha,beta-methylene ATP. This antagonistic effect of alpha,beta-methylene ATP was also observed following depolarizations elicited in the absence and presence of nifedipine (1 microM). Noradrenaline was approximately 50-100 times less potent than alpha,beta-methylene ATP in eliciting action potential discharge and contraction. It was only when a high concentration of noradrenaline was used (about 60-100 microM) that the noradrenaline-induced depolarization attained the voltage threshold for action potential initiation. These results illustrate the similarity of the electrical components which underlie excitation by nerve stimulation and adenine nucleotides in the vas deferens, and demonstrate the ability of dihydropyridines to regulate voltage-dependent events associated with both the generation and inactivation of muscle action potentials. These are probably voltage-dependent calcium currents and calcium-activated potassium currents, respectively. Neither excitatory junction potentials nor the mechanism of desensitization of the ATP purinoceptor by alpha,beta-methylene ATP involve voltage-dependent calcium channels.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed1988

Voltage-dependent calcium channels in smooth muscle cells.

Channels highly selective for calcium, which open when the membrane is depolarized, have been found in all smooth muscle cells examined, whether or not they can generate action potentials. The current through these channels can also be carried by barium and is blocked by cadmium, cobalt, or manganese. If single smooth muscle cells of rabbit ear artery are held at -80 mV under voltage clamp, stepping to more positive potentials elicits an inward current which appears at about -60 mV and is well sustained; at more positive potentials, peak current is achieved within 10-20 ms and current then inactivates substantially. Maximum current in solutions with 1.5 mM calcium is found at -10 mV and in solutions with high calcium or barium concentrations the characteristics of the inward current are considerably altered. Low- and high-threshold components of current, possibly due to different populations of calcium channels, can be distinguished. Nifedipine reduces inward current at more positive test and holding potentials but potentiates inward current if the test and holding potentials are in a more negative range.

Animals↗
PubMed1988

Comparative study of the actions of AP5A and alpha,beta-methylene ATP on nonadrenergic, noncholinergic neurogenic excitation in the guinea-pig vas deferens.

1. The agonistic and antagonistic effects of two nucleotide analogues, P1,P5-di-(adenosine-5') pentaphosphate (AP5A) and alpha,beta-methylene ATP (alpha,beta-Me ATP), have been compared in the guinea-pig isolated vas deferens. 2. In organ bath studies, both AP5A and alpha,beta-Me ATP were approximately 100 times more potent than ATP in producing phasic contractions of the vas deferens smooth muscle. Repeated additions of either agonist (1-10 microM) produced desensitization to a subsequent addition of the test substance. AP5A and alpha,beta-Me ATP were approximately equipotent in the production of desensitization. 3. After desensitization had been produced in the vas deferens by AP5A or alpha,beta-Me ATP, excitatory responses elicited by ATP (100-150 microM) and nonadrenergic field stimulation (2-20 Hz) were blocked, whereas those elicited by carbachol (1-10 microM) were augmented. 4. Intracellular electrical recordings demonstrated that AP5A and alpha,beta-Me ATP produced similar effects on membrane activity of the vas deferens. Concentration-dependent depolarizations alone were produced by both substances until the voltage threshold for action potential discharge was attained; thereafter, action potential discharges were superimposed on the depolarization and an accompanying phasic contraction was recorded. Upon restoration of the membrane potential to its control value (5-10 min after addition of either AP5A or alpha,beta-Me ATP), excitatory junction potentials (e.j.ps) elicited by field stimulation (up to 3 Hz) and spontaneous e.j.ps were reduced by AP5A (greater than 0.1 microM) in a concentration-dependent manner (as previously described for alpha,beta-Me ATP). 5. The antagonistic effects of APA on mechanical responses elicited by field stimulation were more quickly reversed on washout of AP5A than were the effects of X,f-Me ATP, suggesting some dissimilarity in their mechanism of action at the receptor level. 6. The antagonistic effects of AP5A on the nonadrenergic contractile responses of the vas deferens were not produced by the structurally related P',P4-di-(adenosine-5') tetraphosphate (AP4A) even with cumulative concentrations up to 200 pM. 7. Desensitization of P2-purinoceptors can be produced by some nucleotide analogues such as AP5A and a,fi-Me ATP, whose activity may arise partly because of their structural conformation and stability.

Action Potentials↗