Respiratory muscle strength and muscle endurance are not affected by acute metabolic acidemia

Respiratory muscle fatigue in asthma and chronic obstructive lung disease (COPD) contributes to respiratory failure with hypercapnia, and subsequent respiratory acidosis. Therapeutic induction of acute metabolic acidosis further increases the respiratory drive and, therefore, may diminish ventilatory failure and hypercapnia. On the other hand, it is known that acute metabolic acidosis can also negatively affect (respiratory) muscle function and, therefore, could lead to a deterioration of respiratory failure. Moreover, we reasoned that the impact of metabolic acidosis on respiratory muscle strength and respiratory muscle endurance could be more pronounced in COPD patients as compared to asthma patients and healthy subjects, due to already impaired respiratory muscle function. In this study, the effect of metabolic acidosis was studied on peripheral muscle strength, peripheral muscle endurance, airway resistance, and on arterial carbon dioxide tension (PaCO₂). Acute metabolic acidosis was induced by administration of ammonium chloride (NH₄Cl). The effect of metabolic acidosis was studied on inspiratory and expiratory muscle strength and on respiratory muscle endurance. Effects were studied in a randomized, placebo‐controlled cross‐over design in 15 healthy subjects (4 male; age 33·2 ± 11·5 years; FEV₁ 108·3 ± 16·2% predicted), 14 asthma patients (5 male; age 48·1 ± 16·1 years; FEV₁ 101·6 ± 15·3% predicted), and 15 moderate to severe COPD patients (9 male; age 62·8 ± 6·8 years; FEV₁ 50·0 ± 11·8% predicted). An acute metabolic acidemia of BE –3·1 mmol.L^?1 was induced. Acute metabolic acidemia did not significantly affect strength or endurance of respiratory and peripheral muscles, respectively. In all subjects airway resistance was significantly decreased after induction of metabolic acidemia (mean difference –0·1 kPa.sec.L^?1 [95%‐CI: ?0·1 –?0·02]. In COPD patients PaCO₂ was significantly lowered during metabolic acidemia (mean difference –1·73 mmHg [?3·0 –?0·08]. In healthy subjects and in asthma patients no such effect was found. Acute metabolic acidemia did not significantly decrease respiratory or peripheral muscle strength, respectively muscle endurance in nomal subjects, asthma, or COPD patients. Metabolic acidemia significantly decreased airway resistance in asthma and COPD patients, as well as in healthy subjects. Moreover, acute metabolic acidemia slightly improved blood gas values in COPD patients. The results suggest that stimulation of ventilation in respiratory failure, by induction of metabolic acidemia will not lead to deterioration of the respiratory failure.     

Effect of nasal air temperature on FEV1 and specific airways conductance

We investigated whether changes in nasal air temperature affect specific airway conductance (SGaw) and one second forced expiratory volume (FEV₁) in 10 asthmatic patients with a history of cold‐sensitive asthma and eight healthy subjects. An air‐stream (0·6 l s^–1) of –15°C, +22°C or +37°C was blown into both nostrils during a Valsalva manoeuvre. Each provocation consisted of 10 puffs of air, each of 15 s duration, at 1 min intervals. Before and at regular intervals after the provocations, SGaw and FEV₁ were determined. In asthmatics, after cold air provocation, SGaw fell 23% (P<0·01) and FEV₁ 8% (P<0·01). After the warm air provocations, SGaw rose 15% (P<0·01) and FEV₁ 6% (P<0·01). After the ambient air provocations, no significant changes occurred in SGaw or FEV₁. In the healthy subjects, the nasal provocations caused no significant changes in lung function. The present study shows that cold air in the nose causes a slight obstruction and warm air possibly a slight dilatation of the lower airways in patients with a history of cold‐sensitive asthma but not in healthy subjects.     

Calculation algorithms alter the breath‐by‐breath gas exchange values when abrupt changes in ventilation occur

The automatic metabolic units calculate breath‐by‐breath gas exchange from the expiratory data only, applying an algorithm (‘expiration‐only’ algorithm) that neglects the changes in the lung gas stores. These last are theoretically taken into account by a recently proposed algorithm, based on an alternative view of the respiratory cycle (‘alternative respiratory cycle’ algorithm). The performance of the two algorithms was investigated where changes in the lung gas stores were induced by abrupt increases in ventilation above the physiological demand. Oxygen, carbon dioxide fractions and ventilatory flow were recorded at the mouth in 15 healthy subjects during quiet breathing and during 20‐s hyperventilation manoeuvres performed at 5‐min intervals in resting conditions. Oxygen uptakes and carbon dioxide exhalations were calculated throughout the acquisition periods by the two algorithms. Average ventilation amounted to 6·1 ± 1·4 l min^?1 during quiet breathing and increased to 41·8 ± 27·2 l min^?1 during the manoeuvres (P<0·01). During quiet breathing, the two algorithms provided overlapping gas exchange data and noise. Conversely, during hyperventilation, the ‘alternative respiratory cycle’ algorithm provided significantly lower gas exchange data as compared to the values yielded by the ‘expiration‐only’ algorithm. For the first breath of hyperventilation, the average values provided by the two algorithms amounted to 0·37 ± 0·34 l min^?1 versus 0·96 ± 0·73 l min^?1 for O₂ uptake and 0·45 ± 0·36 l min^?1 versus 0·80 ± 0·58 l min^?1 for exhaled CO₂ (P<0·001 for both). When abrupt increases in ventilation occurred, such as those arising from a deep breath, the ‘alternative respiratory cycle’ algorithm was able to halve the artefactual gas exchange values as compared to the ‘expiration‐only’ approach.     

Pharmacokinetics of single‐dose rosiglitazone in chronic ambulatory peritoneal dialysis patients

Background: End‐stage renal disease (ESRD) is associated with marked alterations in the pharmacokinetics of many drugs, not only from reduction in renal clearance but also from changes in metabolic activity, bioavailability, volume of distribution and plasma protein binding. Objective: To study the pharmacokinetics of a single 8‐mg oral dose of rosiglitazone in patients with ESRD and requiring long‐term chronic ambulatory peritoneal dialysis (CAPD). Method: The medication was administered just before the first exchange of peritoneal dialysis fluid on the day that blood and peritoneal dialysate collection was performed. Results: In our CAPD patients the mean (±SD) T_max and T_1/2 of rosiglitazone were 1·20 ± 0·26 and 21·38 ± 21·96 h respectively. These values were different to those reported for healthy volunteers reported in previous studies. The mean area under the concentration–time curve (AUC_(0–∞)) and an average maximum observed plasma concentration (C_max) of rosiglitazone in our CAPD patients were 4203·56 ± 2916·97 ng h/mL and 409·67 ± 148·89 ng/mL respectively. These appear no different from those reported in healthy volunteers . Conclusion: The apparently significant difference in T_1/2 of rosiglitazone in CAPD patients compared with healthy volunteers suggest that dose adjustment may be necessary in order to avoid toxicity.     

A comparison of single plasma sample methods to estimate renal clearance using 99mTc‐ethylenedicysteine and 99mTc‐mercaptoacetyltriglycine

Several single sample methods for determination of ^99mTc‐mercaptoacetyltriglycine (MAG3) clearance are being used clinically. Kabasakal et al. proposed a similar formula for ^99mTc‐ethylenedicysteine (EC). This study was performed to compare his method with Bubeck et al. formula for ^99mTc‐MAG3 already in use. Twenty‐eight subjects divided in two groups were registered which included 22 patients with various renal diseases (group‐I) and six normal volunteers (group II). All subjects were studied twice using both the radiopharmaceuticals. The images and renogram parameters, that is T_MAX and T_1/2 of both the agents, were similar in all the subjects. The clearance of the ^99mTc‐EC was however considerably higher than ^99mTc‐MAG3 in both the groups (mean ± SEM =279 ± 14 ml min^?1/1·73 m² versus 177 ± 15 ml min^?1/1·73 m² in group‐I and 377 ± 11·90 ml min^?1/1·73 m² versus 238 ± 8·23 ml min^?1/1·73 m² in group II). This difference was more pronounced in cases with reduced renal functions. Among the Effective Renal Plasma Flow (ERPF) values determined from EC and MAG3 clearances in six normal volunteers, four cases only in MAG3 had ERPF below the lower limit. This study has demonstrated superiority of single sample method for ^99 mTc‐EC clearance over its analogous method for ^99mTc‐MAG3.     

Intensity of Nordic Walking in young females with different peak O2 consumption

The purpose of this cross‐sectional study was to determine the physiological reaction to the different intensity Nordic Walking exercise in young females with different aerobic capacity values. Twenty‐eight 19–24‐year‐old female university students participated in the study. Their peak O₂ consumption (VO₂ peak kg^?1) and individual ventilatory threshold (IVT) were measured using a continuous incremental protocol until volitional exhaustion on treadmill. The subjects were analysed as a whole group (n = 28) and were also divided into three groups based on the measured VO₂ peak kg^?1 (Difference between groups is 1 SD) as follows: 1. >46 ml min^?1 kg^?1 (n = 8), 2. 41–46 ml min^?1 kg^?1 (n = 12) and 3. <41 ml min^?1 kg^?1 (n = 8). The second test consisted of four times 1 km Nordic Walking with increasing speed on the 200 m indoor track, performed as a continuous study (Step 1 – slow walking, Step 2 – usual speed walking, Step 3 – faster speed walking and Step 4 – maximal speed walking). During the walking test expired gas was sampled breath‐by‐breath and heart rate (HR) was recorded continuously. Ratings of perceived exertion (RPE) were asked using the Borg RPE scale separately for every 1 km of the walking test. No significant differences emerged between groups in HR of IVT (172·4 ± 10·3–176·4 ± 4·9 beats min^?1) or maximal HR (190·1 ± 7·3–191·6 ± 7·8 beats min^?1) during the treadmill test. During maximal speed walking the speed (7·4 ± 0·4–7·5 ± 0·6 km h^?1) and O₂ consumption (30·4 ± 3·9–34·0 ± 4·5 ml min^?1 kg^?1) were relatively similar between groups (P > 0·05). However, during maximal speed walking, the O₂ consumption in the second and third groups was similar with the IVT (94·9 ± 17·5% and 99·4 ± 15·5%, respectively) but in the first group it was only 75·5 ± 8·0% from IVT. Mean HR during the maximal speed walking was in the first group 151·6 ± 12·5 beats min^?1, in the second (169·7 ± 10·3 beats min^?1) and the third (173·1 ± 15·8 beats min^?1) groups it was comparable with the calculated IVT level. The Borg RPE was very low in every group (11·9 ± 2·0–14·4 ± 2·3) and the relationship with VO₂and HR was not significant during maximal speed Nordic Walking. In summary, the present study indicated that walking is an acceptable exercise for young females independent of their initial VO₂ peak level. However, females with low initial VO₂ peak can be recommended to exercise with the subjective ‘faster speed walking’. In contrast, females with high initial VO₂ peak should exercise with maximal speed.     

Comparison of airway conductance and FEV1 as measures of airway responsiveness to methacholine

When defining bronchial responsiveness in healthy, non‐asthmatic, subjects exposed in different working situations, it is not clear whether different outcome measures yield similar results. Therefore, the concentration and dose of methacholine that caused a 20% decrease in forced expiratory volume in 1 s (FEV₁) (PC20_FEV1 and PD20_FEV1), the corresponding change in Gaw and the relationship between the dose–response slope (DRS) for FEV₁ and Gaw was studied in different working populations and healthy control subjects (n=1038). The two outcome measures were compared in groups of subjects in whom differences in bronchial responsiveness could be anticipated [atopics (n=72) and non‐atopics (n= 207) and subjects exposed (n=54) and not exposed (n=32) to saw dust]. A bronchial challenge was also made before and after exposure in a swine confinement building, an exposure known to increase bronchial responsiveness (n=37). PD20_FEV1 was 1·7 mg in atopics and 4·9 mg in non‐atopics, 7·1 mg in saw dust exposed and >20 mg in non‐exposed subjects and 5·3 mg before and 0·79 mg after exposure to organic dust. There was a correlation between DRS_FEV1 and DRS_Gaw, r=0·87 (P<0·001). In subjects who were highly sensitive to methacholine a 20% change in FEV₁ corresponded to <40% change in Gaw, while a 20% decrease in FEV₁ corresponded to none or a minor decrease in Gaw in subjects with less methacholine‐sensitive airways. The ability to detect differences in bronchial responsiveness between groups, or to detect changes in bronchial responsiveness following exposure was approximately the same for FEV₁ and Gaw. The reproducibility was similar for both variables and a second measurement was within one doubling of the methacholine concentration of the first provocation in ≈95% of all measurements (n=41). In conclusion, with our methacholine provocation method, FEV₁ and Gaw had similar sensitivity in detecting small differences in bronchial responsiveness in healthy subjects.     

Reproducibility of orthostatic changes in cerebral oxygenation in healthy subjects aged 70 years or older

In the elderly, standing can frequently be accompanied by blood pressure (BP) changes and cerebral symptoms such as dizziness, fall, or even syncope, but this may vary from day‐to‐day. Therefore, we aimed to investigate the reproducibility of orthostatic responses of cerebral cortical oxygenation and systemic haemodynamics in elderly subjects. In 27 healthy elderly subjects (age 70–84 years), changes in systolic BP (SBP), diastolic BP (DBP), heart rate (HR) and stroke volume (SV) were continuously monitored by Finapres (Finger Arterial Pressure), and changes in oxyhaemoglobin ([O₂Hb]) and deoxyhaemoglobin ([HHb]) concentrations were continuously measured over the right frontal cortex by near infrared spectroscopy (NIRS) during supine rest and 10 min of active standing on two separate occasions. SBP and DBP increased by 6·7 ± 15·4 mmHg (P<0·05, mean ± SD) and 8·2 ± 6·4 mmHg (P<0·01), respectively, whereas HR increased by 9·5 ± 5·0 bpm (P<0·01) and SV decreased by –8·3 ± 7·4 ml (P<0·01) during standing on the first occasion. [O₂Hb] decreased by –3·9 ± 2·9 μmol l^–1 (P<0·01), while [HHb] increased by 1·8 ± 2·2 μmol l^–1 (P<0·01). Group‐averaged orthostatic changes in cortical oxygenation and systemic haemodynamics were very similar on the two occasions, although an intraindividual variation was found. Cortical oxygenation changes were not accompanied by severe cerebral symptoms. Active standing induced reproducible group‐averaged frontal cortical oxygenation declines in healthy elderly subjects, although an intraindividual day‐to‐day variability was present, possibly related to the variability of orthostatic BP responses. These findings indicate that cerebral autoregulation fails to compensate completely for postural changes in elderly subjects, which might predispose elderly subjects to ischaemic cerebral symptoms.     

Ventilatory response and arterial potassium concentration during incremental exercise in patients with chronic airways obstruction

Summary. The relationship of ventilation response (V?_E) to arterial potassium concentration (K⁺) during ramp incremental exercise was assessed in nine patients with chronic obstructive pulmonary disease (COPD), and in 10 healthy subjects. For COPD patients the maximum oxygen uptake (VO_max) was 19.6±3.8 ml kg^-1 min^-1 (± SD), and percentage of forced expired volume at 1 s (% FEV₁) was 47.8 ± 10.4%. In healthy subjects, Vo₂max was 44.4±7.0 ml kg^-1 min^-1 and FEV₁, was 89.7 ± 7.4%. Breath-by-breath determinations for V?_E, oxygen uptake (V?o₂) and carbon dioxide output (V?co₂), as well as determinations for K⁺, partial pressure of oxygen (Po₂), partial pressure of carbon dioxide (Pco₂), pH and lactate in arterial blood were performed during a workout on an exercise bicycle at a ramp function work rate of 20 W min^-1, preceded by a 40 min warm-up period. The major findings in the present study are: (1) that there is a linear relation between ventilation and arterial K⁺ concentration during ramp exercise in both healthy subjects and COPD patients; (2) that the slope of the V?_E-K⁺ relationship is significantly lower in COPD patients (16.2 ± 7.31 min^-1 mM^-1) than in normal subjects (37.4 ± 6.91 min^-1 mM^-1, P<0.01); and, (3) that the slope of the V?_E-K⁺ relationship is significantly related to the ability to ventilate during maximal exercise in both healthy subjects and COPD patients (P<0.05). It is thought that the significantly reduced slope of the V?_E-K⁺ relationship in the COPD patients could be interpreted as a reduced sensitivity to the stimulus and/or as a mechanical impairment of the ventilation.     

Pharmacokinetics and safety of bromotetrandrine (BrTet, W198) after single-dose intravenous administration in healthy Chinese volunteers

Objective: To investigate the safety and pharmacokinetics of bromotetrandrine (BrTet, W198), a novel inhibitor of P‐glycoprotein (P‐gp), after single‐dose i.v. infusion in healthy Chinese volunteers. Methods: We conducted a randomized, dose‐escalating, phase I clinical study for that purpose. Thirty healthy subjects received BrTet at the doses of 10, 20 or 30 mg/m² by i.v. infusion. Plasma and urine concentrations of bromotetrandrine were determined by using a liquid chromatography–tandem mass spectrometric (LC/MS/MS) method. AUC was calculated by the trapezoidal rule extrapolation method. C_max, T_max, t_1/2α, t_1/2β, Cl and V_d were compiled from the plasma concentration–time data. Results: Bromotetrandrine was generally well tolerated at all doses. No serious or severe adverse events were found in the study. The pharmacokinetic parameters of BrTet after single i.v. infusion doses of BrTet 10, 20 and 30 mg/m² were as follows: T_max were 1·5 h in three groups, C_max were 24·79, 39·59 and 64·31 μg/L, t_1/2α were 0·37, 0·29 and 0·30 h, t_1/2β were 62·88, 56·45 and 52·20 h. AUC_0–194h were 345·83, 688·15 and 1096·28 μg h/L, Cl were 23·68, 25·69 and 25·66 L h/m², V_d were 157·73,156·96 and 140·73 L/m². In urine, the total eliminate rate of originate compound was 0·61 ± 0·19%. Conclusions: This study suggested that bromotetrandrine was well tolerated in healthy volunteers within the dose range evaluated. The pharmacokinetics parameters of bromotetrandrine indicated that the compound was rapidly distributed and accumulated in the tissues, and slowly cleared from plasma, which supported the use of BrTet for a once or twice dosing per chemotherapy cycle.     

Perfusion heterogeneity does not explain excess muscle oxygen uptake during variable intensity exercise

The association between muscle oxygen uptake (VO₂) and perfusion or perfusion heterogeneity (relative dispersion, RD) was studied in eight healthy male subjects during intermittent isometric (1 s on, 2 s off) one‐legged knee‐extension exercise at variable intensities using positron emission tomography and a‐v blood sampling. Resistance during the first 6 min of exercise was 50% of maximal isometric voluntary contraction force (MVC) (HI‐1), followed by 6 min at 10% MVC (LOW) and finishing with 6 min at 50% MVC (HI‐2). Muscle perfusion and O₂ delivery during HI‐1 (26 ± 5 and 5·4 ± 1·0 ml 100 g^?1 min^?1) and HI‐2 (28 ± 4 and 5·8 ± 0·7 ml 100 g^?1 min^?1) were similar, but both were higher (P<0·01) than during LOW (15 ± 3 and 3·0 ± 0·6 ml 100 g^?1 min^?1). Muscle VO₂ was also higher during both HI workloads (HI‐1 3·3 ± 0·4 and HI‐2 4·1 ± 0·6 ml 100 g^?1 min^?1) than LOW (1·4 ± 0·4 ml 100 g^?1 min^?1; P<0·01) and 25% higher during HI‐2 than HI‐1 (P<0·05). O₂ extraction was higher during HI workloads (HI‐1 62 ± 7 and HI‐2 70 ± 7%) than LOW (45 ± 8%; P<0·01). O₂ extraction tended to be higher (P = 0·08) during HI‐2 when compared to HI‐1. Perfusion was less heterogeneous (P<0·05) during HI workloads when compared to LOW with no difference between HI workloads. Thus, during one‐legged knee‐extension exercise at variable intensities, skeletal muscle perfusion and O₂ delivery are unchanged between high‐intensity workloads, whereas muscle VO₂ is increased during the second high‐intensity workload. Perfusion heterogeneity cannot explain this discrepancy between O₂ delivery and uptake. We propose that the excess muscle VO₂ during the second high‐intensity workload is derived from working muscle cells.     

Alterations in VO2max and the VO2 plateau with manipulation of sampling interval

Background: The most accepted criterion for confirming attainment of VO₂max is a plateau in oxygen consumption (VO₂) at VO₂max, but its incidence varies. Aims: To compare VO₂max and VO₂ plateau incidence across various sampling intervals, and to examine predictors of the change in VO₂ (ΔVO₂) at VO₂max. Methods: Sedentary, recreationally‐active, and endurance‐trained subjects (n = 108, age = 24·2 ± 6·2 year) completed incremental exercise on the treadmill or cycle ergometer. Gas exchange data were obtained breath‐by‐breath and time‐averaged every 15, 30, and 60 s. VO₂max attainment was verified with the Taylor et al. (1955) criterion (ΔVO₂ at VO₂max ≤2·1 ml kg^?1 min^?1). Multiple regression was used to examine predictors of ΔVO₂ at VO₂max. Results: VO₂ plateau incidence was higher using breath‐by‐breath (81%) and 15 (91%) and 30 s time averaging (89%) versus 60 s averaging (59%). Compared to 60 s averaging, VO₂max was significantly higher (P<0·05) when data were obtained breath‐by‐breath and with 15 and 30 s time‐averaging compared to 60 s sampling. VO₂max was not related to VO₂ plateau incidence. Respiratory rate was a significant predictor of ΔVO₂ at VO₂max in endurance‐trained subjects. Conclusion: More frequent data acquisition revealed higher VO₂max and incidence of the VO₂ plateau compared to 60 s time averaging. Secondary criteria to verify VO₂max attainment should not be used, as they do not discern between subjects who do and do not reveal a plateau in VO₂ at VO₂max.     

Pulmonary vasodilatation and augmentation of right ventricular function following terbutaline infusion in severe chronic pulmonary disease

Summary. Twenty patients with a median age of 61 years and a median forced expired volume in 1 s (FEV₁) after bronchodilatating therapy of 0·55 1 were studied in order to measure the effect of intravenous terbutaline on bronchial tone, cardiac function, pulmonary haemodynamics, gas exchange, and oxygen transport capacity during rest and in 10 patients during exercise. Terbutaline infusion during rest resulted in an increase in heart rate from 84 to 103 beats min^-1 (P < 0·01), a decrease in mean systemic arterial pressure from 95 to 80 mmHg (P < 0·02), an unchanged mean pulmonary arterial pressure (18 mmHg), an increase in cardiac index from 2·89 to 3·86 1 min^-1 m^-2 (P < 0·01), an increase in right ventricular ejection fraction from 45 to 53% (P < 0·01), an increase in left ventricular ejection fraction from 63 to 67% (NS), an unchanged arterial oxygen tension, and an increase in calculated oxygen delivery from 533 to 638 ml O₂ min^-1 m^-2 (P < 0·01). During exercise terbutaline infusion resulted in an increase in heart rate from 108 to 120 beats min^-1 (P < 0·05), a decrease in mean systemic arterial pressure from 117 to 106 mmHg (P < 0·01), a decrease in mean pulmonary arterial pressure from 29 to 22 mmHg (P < 0·01), an increase in cardiac index from 4·53 to 4·64 min^-1 m^-2 (NS), an unchanged arterial oxygen tension, and an increase in the calculated oxygen delivery from 834 to 856 ml O₂ min^-1 m^-2 (NS). It was concluded that terbutaline augments right ventricular function: increases right ventricular ejection fraction and decreases right ventricular end-diastolic volume, and further decreases pulmonary vascular resistance without decreasing arterial oxygen tension, and increases oxygen delivery in patients with chronic pulmonary disease during rest and exercise.     

Normovolemia defined according to cardiac stroke volume in healthy supine humans

Background: Both hypovolemia and a fluid overload are detrimental for outcome in surgical patients but the effort to establish normovolemia is hampered by the lack of an operational clinical definition. Manipulating the central blood volume on a tilt table demonstrates that the flat part of the Frank‐Starling curve is reached when subjects are supine and that finding may be applicable for a clinical definition of normovolemia. However, it is unknown whether stroke volume (SV) responds to an increase in preload induced by fluid administration. Methods: In 20 healthy subjects (23 ± 2 years, mean ± SD), SV was measured by esophageal Doppler before and after fluid administration to evaluate whether SV increases in healthy, non‐fasting, supine subjects. Two hundred millilitres of a synthetic colloid (hydroxyethyl starch, HES 130/0·4) was provided and repeated if a ≥10% increment in SV was obtained. Results: None of the subjects increased SV ≥10% following fluid administration but there was a minor increase in mean arterial pressure (92 ± 15 to 93 ± 12 mmHg, P = 0·01), while heart rate (HR) (66 ± 12 beats min^?1; P = 0·32), cardiac output (4·8 ± 1·1 l min^?1; P = 0·25) and the length of the systole corrected to a HR of 60 beats/min (corrected flow time; 344 ± 24 ms; P = 0·31) did not change. Conclusion: Supporting the proposed definition of normovolemia, non‐fasting, supine, healthy subjects are provided with a preload to the heart that does not limit SV suggesting that the upper flat part of the Frank‐Starling relationship is reached.     

Effect of cytochrome P450 3A4 inhibitor ketoconazole on risperidone pharmacokinetics in healthy volunteers

What is known and objective: Risperidone is an atypical antipsychotic agent used for the treatment of schizophrenia. It is mainly metabolized by human cytochrome P450 CYP2D6 and partly by CYP3A4 to 9‐hydroxyrisperidone. Ketoconazole is used as a CYP3A4 inhibitor probe for studying drug–drug interactions. We aim to investigate the effect of ketoconazole on the pharmacokinetics of risperidone in healthy male volunteers. Methods: An open‐label, randomized, two‐phase crossover design with a 2‐week washout period was performed in 10 healthy male volunteers. The volunteers received a single oral dose of 2 mg of risperidone alone or in combination with 200 mg of ketoconazole, once daily for 3 days. Serial blood samples were collected at specific periods after ingestion of risperidone for a period of 96 h. Plasma concentrations of risperidone and 9‐hydroxyrisperidone were determined using a validated HPLC–tandem mass spectrometry method. Results and discussion: After pretreatment with ketoconazole, the clearance of risperidone decreased significantly by 34·81 ± 15·10% and the T_1/2 of risperidone increased significantly by 28·03 ± 40·60%. The AUC_0–96 and AUC_0–∞ of risperidone increased significantly by 66·61 ± 43·03% and 66·54 ± 39·76%, respectively. The Vd/f of risperidone increased significantly by 39·79 ± 53·59%. However, the C_max and T_max of risperidone were not significantly changed, indicating that ketoconazole had minimal effect on the absorption of risperidone. The C_max, T_max and T_1/2 of 9‐hydroxyrisperidone did not decrease significantly. However, the Cl/f of 9‐hydroxyrisperidone increased significantly by 135·07 ± 124·68%, and the Vd/f of 9‐hydroxyrisperidone decreased significantly by 29·47 ± 54·64%. These changes led to a corresponding significant decrease in the AUC_0–96 and AUC_0–∞ of 9‐hydroxyrisperidone by 47·76 ± 22·39% and 48·49 ± 20·03%, respectively. Ketoconazole significantly inhibited the metabolism of risperidone through the inhibition of hepatic CYP3A4. Our results suggest that besides CYP2D6, CYP3A4 contributes significantly to the metabolism of risperidone. What is new and Conclusion: The pharmacokinetics of risperidone was affected by the concomitant administration of ketoconazole. If a CYP3A4 inhibitor is used concomitantly with risperidone, it is necessary for the clinicians to monitor their patients for signs of adverse drug reactions.     

Left ventricular response to graded isometric exercise in patients with coronary heart disease

Summary. The effects of graded isometric exercise on left ventricular performance were characterized in 11 male patients (53 ± 2 years) with coronary artery disease (CAD) and in 12 normal subjects (11 male and one female, 36 ± 5 years). The echocardiographic indices of left ventricular function at rest were similar in both groups. Heart rate and blood pressure increased significantly in both groups in response to 40 and 60% of handgrip maximal voluntary contraction (MVC). Left ventricular end-diastolic dimension increased significantly (from 50 ± 1 to 56 ± 1 mm; P < 0·01) with 60% of MVC in CAD group but not in the healthy subjects. The patients with CAD also exhibited significant (P < 0·01) increases in end-systolic dimension (from 34 ± 1 to 40 ± 2 with 40% and to 44 ± 1 mm with 60% MVC). End-diastolic and end-systolic dimensions did not change during isometric exercise in the healthy subjects. Mean velocity of circumferential shortening (mV_CF) increased with 60% MVC in normal subjects. In the CAD group mV_CF decreased significantly (from 1.08 ± 0·06 to 0·86 ± 0·06 with 40% and to 0·74 ± 0·04 d·s^-1 with 60% MVC; P < 0·01). At comparable mean blood pressures, mV_CF was significantly lower in the CAD group than in normal subjects. These results demonstrate that progressive deterioration of left ventricular function during increasing levels of isometric exercise in patients with CAD can be detected with echocardiography.     

Peripheral blood flow changes in response to postexercise cold water immersion

This study compared the effect of postexercise water immersion (WI) at different temperatures on common femoral artery blood flow (CFA), muscle (total haemoglobin; tHb) and skin perfusion (cutaneous vascular conductance; CVC), assessed by Doppler ultrasound, near‐infrared spectroscopy (NIRS) and laser Doppler flowmetry, respectively. Given that heat stress may influence the vascular response during cooling, nine men cycled for 25 min at the first ventilatory threshold followed by intermittent 30‐s cycling at 90% peak power until exhaustion at 32·8 ± 0·4°C and 32 ± 5% RH. They then received 5‐min WI at 8·6 ± 0·2°C (WI₉), 14·6 ± 0·3°C (WI₁₅), 35·0 ± 0·4°C (WI₃₅) or passive rest (CON) in a randomized, crossover manner. Heart rate (HR), mean arterial pressure (MAP), muscle (T_mu), thigh skin (T_thigh), rectal (T_re) and mean body (T_body) temperatures were assessed. At 60 min postimmersion, decreases in T_re after WI₃₅ (?0·6 ± 0·3°C) and CON (?0·6 ± 0·3°C) were different from WI₁₅ (?1·0 ± 0·3°C; P<0·05), but not from WI₉ (?1·0 ± 0·3°C; P = 0·074–0·092). WI₉ and WI₁₅ had reduced T_body, T_thigh and T_mu compared with WI₃₅ and CON (P <0·05). CFA, tHb and CVC were lower in WI₉ and WI₁₅ compared with CON (P<0·05). tHb following WI₉ remained lower than CON (P = 0·044) at 30 min postimmersion. CVC correlated with tHb during non‐cooling (WI₃₅ and CON) (r² = 0·532; P<0·001) and cooling recovery (WI₉ and WI₁₅) (r² = 0·19; P = 0·035). WI₉ resulted in prolonged reduction in muscle perfusion. This suggests that CWI below 10°C should not be used for short‐term (i.e. <60 min) recovery after exercise.     

Influence of CYP2D6*10 on the pharmacokinetics of metoprolol in healthy Korean volunteers

Background and objective: Genetic polymorphism of CYP2D6 leads to differences in pharmacokinetics of CYP2D6 substrates. The CYP2D6*10 allele is clinically important in Koreans because of its high frequency in Asians. We investigated whether the pharmacokinetics of metoprolol was altered by the presence of the CYP2D6*10 allele in Korean subjects. Methods: One hundred and seven volunteers were recruited and grouped as CYP2D6*1/*1, CYP2D6*1/*10 and CYP2D6*10/*10 according to their genotypes. Metoprolol tartrate 100 mg (Betaloc^®) was administered orally once to each subject in these three groups (n = 6, 7 and 5, respectively). The pharmacokinetic parameters of metoprolol and its metabolite, α‐hydroxymetoprolol, and the metabolic ratio for the three groups were estimated and compared. Results and discussion: The area under the plasma concentration–time curve (AUC_0→∞), the maximum plasma concentration (C_max) and the elimination half‐life (T_1/2) of metoprolol and α‐hydroxymetoprolol for the CYP2D6*10/*10 group were all significantly different from those of the CYP2D6*1/*1 group (P < 0·05). The AUC_0→∞s of metoprolol were 443·7 ± 168·1, 995·6 ± 321·4 and 2545·3 ± 632·0 ng·h/mL, and the AUC_0→∞s of α‐hydroxymetoprolol were 1232·0 ± 311·2, 1344·0 ± 288·1 and 877·4 ± 103·4 ng·h/mL for groups CYP2D6*1/*1, *1/*10 and *10/*10, respectively. The corresponding T_1/2 values of metoprolol were 2·7 ± 0·5, 3·2 ± 1·3 and 5·0 ± 1·1 h, while those of α‐hydroxymetoprolol were 5·4±1·5, 6·0 ± 1·4 and 10·5 ± 4·2 h, respectively. The metabolic ratios of the three groups were significantly different (P < 0·05). Conclusion: The CYP2D6*10 allele altered the pharmacokinetics of metoprolol in Korean subjects and is likely to affect other drugs metabolized by the CYP2D6 enzyme, similarly.     

OATP1B1 388A>G polymorphism and pharmacokinetics of pitavastatin in Chinese healthy volunteers

Purpose: To investigate the contribution of the most frequent single nucleotide polymorphism (SNPs) of the organic anion transporting polypeptide 1B1 (OATP1B1) 388A>G to the pharmacokinetics of pitavastatin in Chinese healthy volunteers. Methods: Eighteen healthy volunteers participated in this study. Group 1 consisted of nine subjects who were of 388AA wild‐type OATP1B1 genotype. Group 2 consisted of seven subjects with the 388GA genotype and two 388GG homozygotes. Two milligram of pitavastatin was administered orally to the volunteers. The plasma concentration of pitavastatin was measured for up to 48 h by liquid chromatography–mass spectrometry (LC–MS). Results: The pharmacokinetic parameters of pitavastatin were significantly different between the two genotyped groups. The concentration (C_max) value was higher in the 388GA + 388GG group than that in the 388AA group (39·22 ± 8·45 vs. 22·90 ± 4·03 ng/mL, P = 0·006). The area under the curve to the last measurable concentration (AUC_0–48) and area under the curve extrapolated to infinity (AUC_0–∞) of pitavastatin were lower in the 388AA group than in the 388GA + 388GG group (100·42 ± 21·19 vs. 182·19 ± 86·46 ng h/mL, P = 0·024; 108·12 ± 24·94 vs. 199·64 ± 98·70ng h/mL, P = 0·026) respectively. The oral clearance (Cl/F) was lower in the 388GA + 388GG group than that in the 388AA group (12·46 ± 4·79 vs. 19·21 ± 3·74/h, P = 0·012). The elimination of half‐life (t_1/2) and peak concentration times (T_max) values showed no difference between these groups. Conclusions: The OATP 388A>G polymorphism causes significant alterations in the pharmacokinetics of pitavastatin in healthy Chinese volunteers and this may well be clinically significant.     

Smoking behaviour modulates pharmacokinetics of orally administered clopidogrel

Background and objectives: Clopidogrel is an important antiplatelet drug that is effective in preventing thrombotic events, especially for patients undergoing percutaneous coronary intervention. The therapeutic usefulness of clopidogrel has been limited by documented inter‐individual heterogeneity in platelet inhibition, which may be attributable to known clopidogrel pharmacokinetic variability. The objective of this study was to assess the influence of smoking cigarettes and abnormal body weight on the pharmacokinetics of clopidogrel. Methods: Seventy‐six healthy adult male volunteers were selected randomly. Each subject received a single 75 mg oral dose of clopidogrel after overnight fast. Clopidogrel carboxylate plasma levels were measured and non‐compartmental analysis was used to determine peak plasma concentration (C_max), time to peak plasma concentration (T_max), elimination half‐life (t_1/2e), and area under the curve (AUC_0→∞). Results: One‐third of volunteers were smokers (n = 27) and one‐half had abnormal body weight (n = 39). Smokers had lower AUC_0→∞ (smokers: 6·24 ± 2·32 μg/h/mL vs. non‐smokers: 8·93 ± 3·80 μg/h/mL, P < 0·001) and shorter half‐life (smokers: 5·46 ± 2·99 vs. non‐smokers: 8·43 ± 4·26, P = 0·001). Smoking behaviour had no influence on C_max (P = 0·3) and T_max (P = 0·7). There was no statistically significant difference in C_max, AUC_0→∞, T_max and t_1/2e between volunteers with abnormal body weight and normal body weight. However the difference in body weight of the two groups was relatively narrow (mean ± SE; 26·93 ± 0·16 vs. 23·11 ± 0·27). In general, the pharmacokinetic parameters were characterized by considerable inter‐individual differences (C_max = 3·09 ± 0·99 μg/mL, CV = 32%), (T_max =0·76 ± 0·24 h, CV = 31·6%), (AUC_0→∞ = 7·98 ± 3·58 μg/h/mL, CV = 44·8%), and (t_1/2e = 7·38 ± 4·10 h, CV = 55·6%). Conclusion: Smoking is a significant factor affecting the pharmacokinetics of clopidogrel, following administration of a single 75 mg dose in healthy young volunteers. The study supports smoking‐cessation recommendations. Further studies are required to evaluate the influence of smoking and body weight on the pharmacokinetics of the active metabolite of clopidogrel and on the clinical effects of any differences observed.