Appropriateness of a 4 mg/kg gentamicin or tobramycin loading dose in post-operative septic shock patients

Objective: To determine the frequency with which early adequate peak serum concentrations (6–12 mg/litre) can be achieved following a 4 mg/kg loading dose of gentamicin or tobramycin in post-operative septic shock patients. Method: Eleven post-operative septic shock patients were grouped into (i) a control group ( n=7) who received the conventionl gentamicin or tobramycin dosing regimen of 2 mg/kg loading dose followed by a maintenance dose of approximately 1·5 mg/kg (peak and trough levels were measured after the third dose), and (ii) a study group ( n=4) who received a tobramycin or gentamicin 4 mg/kg loading dose, followed by 30 min, 3 h and 16 h serum drug level measurements. Pharmacokinetic parameters were calculated using a one-compartmental model. Differences in both groups were determined using Student's t-test. Results: Pharmacokinetic parameters in both groups showed no statistically significant difference. The dose from which peak levels were drawn was significantly higher in the study group (4 mg/kg vs. 1·66 mg/kg; P=0·001), which also resulted in higher but adequate peak serum concentrations (8·9±2·2 vs. 4·8±1·8 mg/litre). In the study group, linear regression analysis showed significant relationships between dose and peak concentrations and volume of distribution and peak concentrations ( r=0·96, P=0·01 and r=?0·96, P=0·01, respectively). Conclusion: One hundred per cent of the post-operative septic shock patients achieved target peak serum concentrations (mean 8·9±2·2 mg/litre) following a 4 mg/kg tobramycin or gentamicin loading dose. An expanded V_d (0·46±0·13 litres/kg) was also observed.     

Placental transfer and neonatal effects of propofol in caesarean section

Objective: To assess transplacental passage of propofol by measuring the levels in maternal and foetal plasma, and the possible relationship between the latter and the neonatal effects when propofol is used as an induction agent in obstetric anaesthesia for performing a caesarean section to terminate pregnancy. Methods: Intravenous propofol was administered as an anaesthesia-inducting agent at doses of 2 mg/kg in 10 healthy women (ASA I-II). The propofol concentrations were measured by high-performance liquid chromatography (HPLC). Results: After induction, hypnosis was achieved in all patients within 75 s, and it took 4–10 min to deliver the foetus. Apgar test scores were high in seven of the 10 neonates, in three cases the score was 5 or less. The mean values in venous maternal blood were 5·01±1·06 μg/ml 1 min after propofol administration and 1·47±0·35 μg/ml at the time of delivery. Propofol crossed the placental barrier with levels in the umbilical cord of 0·32±0·10 μg/ml in the vein and 0·22±0·08 μg/ml in the artery. Conclusion: Propofol plasma levels in the newborn at the time of delivery depend on the level in maternal plasma, and therefore on the dose used for induction and the time lapsed between the administration of the drug and the delivery of the foetus.     

Aminoglycoside pharmacokinetics in African-Americans with normal renal function

Objective: To compare aminoglycoside pharmaco?kinetics in African-Americans with normal renal function with published adult population values. Design: An Institutional Review Board approved concurrent study. Setting: The study was conducted at Howard University Hospital, Washington DC. Subjects: All subjects had serum creatinine levels of 1·5 mg/dl or less and were receiving aminoglycoside for suspected or documented Gram-negative infection, had no obvious underlying disease condition that could influence aminoglycoside pharmaco?kinetics and were aged 18 years or older. Main outcome measures: Volume of distribution (V_d), half-life ( t_1/2), elimination rate constant (K_e) and total body clearance ( Cl) were calculated using a one-compartment, open, linear pharmacokinetic model. Using an unpaired Student's t-test, the pharmaco?kinetic values of our patients were compared with general population values. Interventions: Patients receiving aminoglysides were identified by the pharmacist through the hospital's standard antibiotic order sheet. Twenty-five patients were enrolled after they met the inclusion criteria. Pharmacists made recommendations for dose change as part of standard of care when inappropriate doses were ordered. In collaboration with medical and nursing staff, the amount and time of dose administration, and steady-state peak and trough serum drug levels were stringently measured, documented on a data collection form and used to calculate pharmacokinetic values for our patients. The form was also used to document demographic information. Results: The following values were obtained: V_d 0·27±0·15 litres/kg, t_1/2 1·93±1·38 h, K_e 0·31±0·134/h (gentamicin), K_e 0·22±0·10/h (tobramycin), Cl 103·95±62·98 ml/kg/h (gentamicin) and Cl 118·96±84·83 ml/kg/h (tobramycin). These values are not significantly different from general population values. Following a mean tobramycin or gentamicin dose of 1·32±0·32 mg/kg ideal body weight (IBW)/dose or 1·11±0·33 mg/kg actual body weight (ABW)/dose every 8 h, patients achieved a mean peak and trough serum drug levels of 6·6±3·86 mg/litre and 1·03±0·68 mg/litre, respectively. Wide interpatient pharmacokinetic variability was also observed. Conclusions: We conclude that aminoglycoside pharmacokinetics in African-Americans seem to be consistent with the published general population values. Thus, initiating aminoglycoside regimens using population dosing guidelines appears to be appropriate. However, due to the observed wide interpatient pharmacokinetic variability, in?dividualized dosing is required with very close monitoring, to avoid or minimize toxicity.     

Effects of intense exercise training on endothelium-dependent exercise-induced vasodilatation

To determine whether intense exercise training affects exercise-induced vasodilatation, six subjects underwent 4 weeks of handgrip training at 70% of maximal voluntary contraction. Exercise forearm vascular conductance (FVC) responses to an endothelium-dependent vasodilator (acetylcholine, ACH; 15, 30, 60 μg min^?1) and an endothelium-independent vasodilator (sodium nitroprusside, SNP; 1·6, 3·2, 6·4 μg min^?1) and FVC after 10 min of forearm ischaemia were determined before and after training. Training elicited significant (P<0·001) increases in grip strength (43·4 ± 2·3 vs. 64·1 ± 3·5 kg, before vs. after, mean ± SEM), forearm circumference (26·7 ± 0·4 vs. 27·9 ± 0·4 cm) and maximal FVC (0·4630 ± 0·0387 vs. 0.6258 ± 0·0389 units, P<0·05). Resting FVC did not change significantly with training (0·0723 ± 0·0162 vs. 0.0985 ± 0·0171 units, P>0·4), but exercise FVC increased (0·1330 ± 0·0190 vs. 0.2534 ± 0·0387 units, P<0·05). Before and after the training, ACH increased exercise FVC above the control (no drug) exercise FVC, whereas SNP did not. Training increased (P<0·05) the exercise FVC responses to ACH (0·3344 ± 0·1208 vs. 0.4303 ± 0·0858 units, before vs. after training, 60 μg min^?1) and SNP (0·2066 ± 0·0849 vs. 0.3172 ± 0·0628 units, 6·4 μg min^?1). However, these increases were due to the increase in control (no drug) exercise FVC, as the drug-associated increase in exercise FVC above control did not differ between trials (P>0·6). These results suggest that exercise FVC is increased by both exercise training and stimulating the release of endothelium-dependent vasodilators. However, training does not affect the vascular response to these vasodilators.     

Blood glucose concentration dependent ACTH and cortisol responses to prolonged exercise

Summary. The purpose of this study is to investigate responses of serum ACTH and cortisol concentration to low intensity prolonged exercise. In experiment 1, 10 subjects fasted for 12 h and performed bicycle exercise at 49·3%V?O₂max (±4·3%) until exhaustion or up to 3 h. During the early part of the exercise, serum ACTH and cortisol concentrations did not increase from the pre-exercise values (ACTH: 44±5 μg/1, cortisol: 139±52 μg/1). Whilst the time to serum ACTH concentration increasing varied among the subjects (60·180 min), the increases of this hormone occurred for all subjects (175±85 ng/1, P<0·05) when blood glucose concentration decreased to a critical level of 3·3 mmol/1. At the end of the exercise, blood glucose concentration decreased to 2·60±0·21 mmol/1, and serum ACTH and cortisol concentrations increased to 313±159 μg/1 and 371±151 μg/1, respectively. In experiment 2, four subjects performed the same intensity exercise until exhaustion, and were then given 600 ml of 20 g glucose solution, and immediately afterwards, they were asked to repeat the same exercise. The subjects continued the exercise for between 30 to 90 min until again reaching exhaustion. During the second exercise, blood glucose concentration increased to the pre-exercise value (2·72±0·58 to 4·00±0·22 mmol/1, P<0·05) and simultaneously, serum ACTH concentration decreased considerably (354±22 to 119±54 ng/1, P<0·05). The results of the present study suggest that serum ACTH and cortisol concentration during low intensity prolonged exercise may be dependent on blood glucose concentration.     

Measurement of cardiac output with non-invasive Aesculon impedance versus thermodilution

Background: This study compared the non‐invasive thoracic electrical bioimpedance Aesculon^® technique (TEB_Aesculon) with thermodilution (TD) to evaluate whether TEB_Aesculon may offer a reliable means for estimating cardiac output (CO) in humans. Material and method: Cardiac output was measured with TD and TEB_Aesculon in 33 patients, with a mean age ± SEM of 59 ± 2·7 years, that underwent right heart catheterization for clinical investigation of pulmonary hypertension or severe heart failure. Four to five CO measurements were performed with each technique simultaneously in 33 patients at rest, 11 during exercise and seven during NO inhalation. Result: Cardiac output correlated poorly between TEB_Aesculon and TD at rest (r = 0·46, P<0·001), during exercise (r = 0·35, P<0·013) and NO inhalation (r = 0·41, P<0·017). CO was higher for TEB_Aesculon than TD with 0·86 ± 0·14 l min^?1 at rest (P<0·001) and 2·95 ± 0·69 l min^?1 during exercise (P<0·003), but similar during NO inhalation, with a tendency (P<0·079) to be 0·44 ± 0·19 l min^?1 higher for TEB_Aesculon than TD. CO increased from rest to exercise for TEB_Aesculon and TD with 6·11 ± 0·6 l min^?1 (P<0·001) and 3·91 ± 0·36 l min^?1 (P<0·001), respectively; an increase that was higher (P<0·002) for TEB_Aesculon than TD. During NO inhalation, compared to rest, CO decreased for TEB_Aesculon with 0·62 ± 0·11 l min^?1 (P<0·002), but not significantly for TD with 0·21 ± 0·12 l min^?1 (P<0·11). Bland–Altman analysis showed a poor agreement between TEB_Aesculon and TD. Conclusion: TEB_Aesculon overestimated CO compared to TD with ～17% at rest and ～34% during exercise, but the techniques showed similar results during NO inhalation. CO, furthermore, correlated poorly between TEB_Aesculon and TD. TEB_Aesculon may at present not replace TD for reliable CO measurements in humans.     

Whole saliva and plasma levels of clozapine and desmethylclozapine

Background: Therapeutic drug monitoring of clozapine as an aid in the treatment of schizophrenic states is commonly used in our hospital. Objective: Development of a high-performance liquid chromatographic method for the deter?mination of clozapine (CLZ) and its major metabolite desmethylclozapine (DMCLZ) in plasma and saliva, and investigation of the relationship between plasma concentrations of CLZ and DMCLZ and concentrations in saliva in patients treated with clozapine. Methods: Subjects were either inpatients or outpatients with a DSM IV diagnosis of schizophrenia ( n=34). Determination of CLZ and DMCLZ saliva concentrations appeared to be a satisfactory method to check compliance to treatment, particularly in outpatients. Results: Mean CLZ and DMCLZ plasma concentrations were 432±264 ng/ml (±SD) (range 90–1310 ng/ml) and 257±144 ng/ml (range 55–580 ng/ml), respectively. The CLZ/DMCLZ plasma ratio was equal to 1·7±0·5 (daily dosage 7·2±2·3 mg/kg, n=34). Mean CLZ plasma and saliva levels were 336±157 ng/ml (range 90–580 ng/ml) and 159±86 ng/ml (range 40–364 ng/ml), respectively ( r=0·56, n=14). Mean DMCLZ plasma and saliva levels were 196±112 ng/ml (range 55–481 ng/ml) and 109±67 ng/ml (range 40–250 ng/ml), respectively ( r=0·73, n=14). Mean CLZ/DMCLZ ratios determined in plasma and saliva were 1·9±0·6 (range 1·0–3·4) and 1·7±0·6 (range 1·0–3·2), respectively ( r=0·85, n=14). CLZ and DMCLZ saliva concentrations appear to be useful for checking compliance to treatment, in particular among outpatients.     

Effects of a thromboxane antagonist (BM 13·177) during endotoxin-induced pulmonary vasoconstriction in sheep

Summary. We investigated the effect of a thromboxane antagonist, BM 13·177, during endotoxin-induced pulmonary vasoconstriction in sheep. In control animals intravenous E-coli endotoxin (1 μg/kg) caused a transient increase of pulmonary artery and airway pressure paralleled by large concentration increases of TXB₂: in comparison peak plasma concentrations of 6-keto-PGFlα (a prostacyclin metabolite) were small and delayed in time. Pre-treatment with BM 13·177 (bolus 5 mg/kg), followed by 0·75 mg/kg/min intravenously) abolished the rise of pulmonary artery and airway pressure. Plasma concentrations of TXB₂ and 6-keto-PFGla were similar to controls. These and previous investigations imply that BM 13·177 specifically antagonizes TXA₂ on the putative receptor in pulmonary vascular and airway smooth muscle.     

Drug monitoring during the treatment of AIDS-associated Pneumocystis carinii pneumonia with trimethoprim-sulfamethoxazole

Objective: To monitor trimethoprim and sulfamethoxazole plasma levels in patients with AIDS-associated Pneumocystis carinii pneumonia Method: Trimethoprim–sulfamethoxazole steady-state plasma concentrations were measured by high-pressure liquid chromatography during 37 episodes of Pneumocystis carinii pneumonia in patients with AIDS. Initially, 15–23 mg/kg/day trimethoprim and 75–115 mg/kg/day sulfamethoxazole were given i.v. Assuming a therapeutic range for trimethoprim from 4 to 10 μg/ml, the doses were adjusted if trimethoprim levels were found to be outside this range Results: Mean concentrations were 6·7±3·3 μg/ml for trimethoprim and 187±56 μg/ml for sulfamethoxazole. A widespread inter-patient range was found and could be decreased after dose adjustment. Enzyme inducing co-medication did not influence plasma concentrations. In patients with coexisting chronic liver disease, significantly increased sulfamethoxazole plasma levels were observed. A correlation could be demonstrated between serum creatinine and trimethoprim plasma levels. Adverse reactions associated with co-trimoxazole occurred during 65% of treatment periods and increased with increasing trimethoprim-sulfamethoxazole levels, as well as increasing length of treatment. Therapy only had to be prematurely discontinued in one patient. Overall mortality was 2·7%Conclusion: Monitoring of co-trimoxazole levels during the treatment of P. carinii pneumonia in AIDS may help in reducing the high variability of plasma-concentrations and in avoiding severe side-effects especially associated in patients with chronic liver disease or renal failure     

Influence of CYP2C9 and CYP2C19 genetic polymorphisms on pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers

Background and objective: CYP2C9 is the major contributor to gliclazide metabolic clearance in vitro, while the pharmacokinetics of gliclazide modified release are affected mainly by CYP2C19 genetic polymorphisms in vivo. This study aims to investigate the influence of CYP2C9 and CYP2C19 genetic polymorphisms on the pharmacokinetics and pharmacodynamics of gliclazide in healthy Chinese Han volunteers. Methods: Eighteen healthy Han subjects with various combinations of CYP2C9 and CYP2C19 genotypes received 80 mg gliclazide. Plasma gliclazide concentrations were measured by a liquid chromatography–tandem mass spectrometry method for 84 h and plasma glucose and insulin levels were measured up to 15 h post‐dose. Results and discussion: There was no difference in either pharmacokinetic and or pharmacodynamic parameters of gliclazide when group A (CYP2C9*1/*1, CYP2C19 extensive metabolizers) was compared with group B (CYP2C9*1/*3, CYP2C19 *1/*1). When group C (CYP2C9*1/*1 and CYP2C19 poor metabolizers) was compared with group A, the AUC_0–∞ and C_max in group C were significantly higher [83·94 ± 40·41 vs. 16·39 ± 5·10 μg·h/mL (P = 0·000) and 1·50 ± 0·85 vs. 0·45 ± 0·18 μg/mL (P = 0·000)], and the oral clearance was significantly lower [1·17 ± 0·63 vs. 5·38 ± 1·86 L/h (P = 0·000)]. The half‐life of gliclazide was also significantly prolonged in group C subjects when compared with that of group A (33·47 ± 12·39 vs. 19·34 ± 10·45 h), but the difference was not significant (P = 0·052). The increase in serum glucose level at 11 h after dosing (ΔC_glu11) in group C was significantly higher than that of group A (?1·08 ± 0·42 vs. 0·22 ± 1·01 mmol/L, P = 0·022). The corresponding insulin levels showed no difference between the two groups. Conclusion: CYP2C9*3 was not associated with any change in the disposition of gliclazide. CYP2C19 polymorphisms appear to exert the dominant influence on the pharmacokinetics of gliclazide in healthy Chinese Han subjects, and may also affect the observed pharmacodynamics of the drug as a result.     

Kinetic profile of carbamazepine in an adult Portuguese outpatient population

Objective : The aim of our work was to define the kinetic profile of carbamazepine (CBZ), in order to improve on dosing schedules through a Bayesian approach. Method: Carbamazepine dose/steady-state trough concentrations data pairs and associated information were collected retrospectively on a population of adult epileptic patients. Results: Fifty patients (index population) with two or more available concentrations (total of 174 determinations) met our inclusion criteria. Patients were taking CBZ (200–1800 mg/day) in mono- or polytherapy regimens. The analysis assumed a one-compartimental model with first-order absorption and elimination. Due to the data source (only trough concentrations were measured as part of hospital routine), the volume of distribution was fixed at 1·19 l/kg. The final estimates for CL were: 0·075± 0·027 (mono- and polytherapy), 0·069±0·020 (monotherapy), and 0·106±0·037 l/h/kg (poly?therapy). In order to validate these results, we assessed their predictive capacity using 18 new patients (validation population), submitted to the same inclusion criteria and using Prediction-Error analysis. The results suggested a different CL value for our population compared to earlier published clearance values. The results also pointed to an increased metabolic rate associated with polytherapy. The prediction capacity of the optimization method derived from a Portuguese population made in an a priori evaluation indicated a low error (–0·04 μg/ml), close to the theoretical zero value. Conclusion: Our results provide specific data on CBZ disposition in a Portuguese population and given the wide variability in the literature values, our data may help improve dosing of CBZ in Portuguese patients.     

Effects of dipyridamole and theophylline on reactive hyperaemia in subcutaneous adipose tissue in humans

Summary. The importance of adenosine for reactive hyperaemia in subcutaneous adipose tissue was studied in healthy volunteers, using the adenosine uptake inhibitor dipyridamole (bolus 0·1 mg/kg i.v. followed by infusion of 0·7 μg/kg/min) and the adenosine receptor antagonist theophylline (4 or 6 mg/kg i.v.). Basal blood flow, total blood flow and hyperaemia (total minus basal flow) after a 20-min arterial occlusion were measured in the distal femoral region by the ¹³³Xe washout technique with and without drug treatment. Basal blood flow (mean±SEM) was 2·4 ± 0·3 ml/min/100 g, while total post-occlusive flow and total reactive hyperaemia were 97·3 ±8·4 and 61·8 ± 6·5 ml/100 g, respectively, without drug treatment. Basal blood flow was unaffected by dipyridamole but the total flow and hyperaemia were enhanced by 49 ± 24 and 60 ± 31%, respectively (P<·005 for both). This enhancement was due to increases in both amplitude and duration of the hyperaemia. Neither basal blood flow, total post-occlusive flow nor hyperaemia were significantly altered by theophylline. The amplitude of the enhanced hyperaemia during dipyridamole was not significantly counteracted by simultaneous theophylline treatment (6 mg/kg) but the duration of hyperaemia was reduced from 13 ± 1 to 8 ± 1 min (P<0·01). The results suggest that endogenous adenosine does not regulate basal blood flow or reactive hyperaemia of limited duration in human adipose tissue. However, reactive hyperaemia may be enhanced by pharmacological elevation of endogenous adenosine levels.     

The efficacy and toxicity of two dosing-regimens of amikacin in neonates with sepsis

What is known and objective: Neonatal sepsis is one of the most common reasons for admission to neonatal units in developing countries. Aminoglycosides widely used in its treatment are usually administered two or three times a day. Less frequent doing may be more convenient and as effective. We aim to compare the efficacy and safety (nephrotoxicity) of once daily vs. twice daily dosing of amikacin in neonates with suspected or proven sepsis and report on the drug’s pharmacokinetics in these subjects. Methods: Thirty neonates of gestational age ≥36 weeks and body weight ≥2500 g with suspected or proven sepsis were randomized to receive amikacin either at a dose of 15 mg/kg once per day; group I (n = 15), or a dose of 7·5 mg/kg twice per day, group II (n = 15). All neonates received classical treatment of sepsis including antibiotics, hemodynamic support, inotropic support based on blood pressure levels and size of the heart in chest X‐ray, if needed. Amikacin was infused over 1 h. Peak and trough serum samples for amikacin were measured for all infants at steady state. Nephrotoxicity was assessed by serum creatinine and urinary N‐acetyl β‐d ‐glucosaminidase before and 7 days after therapy. Clinical efficacy was compared using both observation of clinical status and normalization of laboratory tests. Results: All the patients in group I had achieved a trough level <10 μg/mL and two patients had trough concentration >10 μg/mL in group II. No significant difference between group I and group II in either baseline or day 7 serum creatinine was demonstrated (P > 0·05). No significant difference was found between the two groups in clinical efficacy or renal toxicity. The calculated pharmacokinetic parameters were in group I and II, respectively: clearance =63·8 ± 15·9 mL/kg/h and 73·5 ± 18·1 mL/kg/h; volume of distribution =0·54 ± 0·09 L/kg and 0·61 ± 0·13 L/kg, half‐life =6·1 ± 1·0 h and 5·95 ± 1·1 h. What is new and conclusion: As expected, amikacin given once every 24 h to septic neonates of ≥36 weeks of gestation achieved higher peak levels and lower trough concentrations than the twice daily regimen. Treatment with once daily regimen did not lead to more nephrotoxicity than with a twice‐daily regimen, and showed comparable efficacy.     

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.     

Muscle ammonia and amino acid metabolism during dynamic exercise in man

Summary. The effect of dynamic exercise on muscle and blood ammonia (NH₃) and amino acid contents has been investigated. Eight healthy men cycled at 50% and 97% of maximal oxygen uptake for 10 min and 5·2 min (to fatigue), respectively. Biopsies (quadriceps femoris muscle), arterial and femoral venous blood samples were obtained at rest and during exercise. Muscle NH₃ at rest and after submaximal exercise was (x?±SE) 0·5±0·1 mmol/kg dry muscle (d.m.) and increased to 4·1 ±0·5 mmol/kg d.m. at fatigue (P<0·001). The total adenine nucleotide (TAN) pool (TAN=ATP+ADP+AMP) did not change after submaximal exercise but decreased significantly at fatigue (P<0·01). The decrease in TAN was similar to the increase in NH₃. Muscle lactate was 3±1 mmol/kg d.m. at rest and increased to 104±5 mmol/kg d.m. at fatigue. Whole blood and plasma NH₃ did not change significantly during submaximal but both increased significantly during maximal exercise (P<0·001). During maximal exercise the leg released 7,120 μmol/min of lactate, whereas only 89 μmol/min of NH₃ were released. NH₃ accumulation in muscle could buffer only 3% of the hydrogen ions released from lactate, and NH₃ release could account for only 1% of the net hydrogen ion transport out of the cell. Muscle glutamine was constant throughout the study, whereas glutamate decreased and alanine increased during exercise (P<0·001). No significant changes in either arterial whole blood glutamine or glutamate were observed. Arterial plasma glutamine and glutamate concentrations, however, increased and decreased (P<0·001), respectively, during exercise. It is concluded that (1) muscle and blood NH₃ levels increase only during strenuous exercise and (2) NH₃ accumulation is of minor importance for regulating acid-base balance in body fluids during exercise.     

Plasma lipid and lipoprotein profile in elderly female runners

Plasma lipid and lipoprotein profiles were compared in elderly female runners (RU: n= 15, aged 66 ± 5 years, body fat 20 ± 4%, training distance 35 ± 15 km week¹, V?O_2max 36 ± 4 ml kg¹ min¹, mean ± SD) and age-matched untrained women (UT: n= 28, 66 ± 4 years, body fat 26 ± 6%, V?O_2max 26 ± 3 ml kg¹ min¹). There were insignificant differences in total cholesterol (RU: 5·04 ± 0·60 vs. UT: 5·48 ± 0·85 mmol 1¹), HDL-cholesterol (RU: 1·97 ± 0·41 vs. UT: 1·91 ± 0·36 mmol 1¹) and LDL-cholesterol (RU: 2·72 ± 0·59 vs. UT: 3·03 ± 0·80 mmol 1¹) between the two groups. Plasma triglyceride concentration of the runners was significantly lower than that of the untrained women (RU: 0·80 ± 0·27 vs UT: 1·14 ± 0·36 mmol 1¹, P < 0·01). No difference was observed in the LDL-cholesterol/HDL-cholesterol ratio between the two groups (RU: 1·45 ± 0·51 vs UT: 1·64 ± 0·53 units). These results suggest that regularly performed running of 35 km week¹ in elderly women does not further elevate their HDL-cholesterol level which is already high compared to the levels found in elderly men. However, elderly female runners appear to be protected against age-related increases in the levels of triglyceride and LDL-cholesterol.     

Pharmacokinetics and pharmacodynamics of intravenous dexmedetomidine in healthy Korean subjects

What is known and Objective: Dexmedetomidine is a selective alpha2‐adrenoreceptor agonist used for sedation in critically ill patients. The current study aimed to evaluate the pharmacokinetics (PKs), pharmacodynamics and tolerability of intravenous dexmedetomidine in healthy Korean subjects. Methods: A randomized, double‐blind, placebo‐controlled study with three parallel dosage groups was conducted. Twenty‐four subjects were randomly assigned to placebo or one of three dexmedetomidine dosing regimens, 3 μg/kg/h for 10 min followed by 0·17 μg/kg/h for 50 min (low dose), 6 μg/kg/h for 10 min followed by 0·34 μg/kg/h for 50 min (middle dose) and 3·7 μg/kg/h for 35 min followed by 0·7 μg/kg/h for 25 min (high dose). Serial blood samples for PK analysis were taken up to 12 h. PK parameters were determined using non‐compartmental methods (WinNonlin^®), and a population PK model was developed using nonmem ^®. The sedative effect of dexmedetomidine was assessed by Ramsay sedation score and visual analogue scales/sedation. Adverse events, clinical laboratory tests, electrocardiograms, physical examinations and vital signs were monitored for tolerability assessment. Results: Six subjects were assigned to each of the three active treatment group or placebo group. The AUC_last of the low‐, middle‐ and high‐dose group were 1096·8 ± 119·9 (mean ± SD) ng*h/L, 2643·0 ± 353·2 ng*h/L and 5600·6 ± 411·0 ng*h/L, respectively. PK of dexmedetomidine was best described using a two‐compartment model. The typical value of the population model can be calculated using the following equations: central volume of distribution (L) = 19·9 (age/27)^0·954, peripheral volume of distribution (L) = 59·4, clearance (L/h) = 33·7 (albumin level/4·3)^1·42 and inter‐compartment clearance (L/h) = 67·7. Sedative effects were significantly increased by dexmedetomidine compared to placebo. The blood pressure and heart rate were decreased, but oxygen saturation was maintained stable. What is new and Conclusion: Dexmedetomidine shows linear PK characteristics and dose‐dependent sedative effects. A two‐compartment population PK model was developed for healthy Korean subjects. The PK parameter estimates are similar in Koreans and Caucasians.     

In cirrhotic patients reduced muscle strength is unrelated to muscle capacity for ATP turnover suggesting a central limitation

Background and aims: We investigated whether in patients with liver cirrhosis reduced muscle strength is related to dysfunction of muscle mitochondria. Methods: The mitochondrial respiratory capacity of the tibial anterior muscle was evaluated in seven patients and eight healthy control subjects by ³¹P nuclear magnetic resonance spectroscopy (³¹PMRS) to express ATP turnover in vivo and by respirometry of permeabilized fibres from the same muscle to express the in vitro capacity for oxygen consumption. Results: Maximal voluntary contraction force for plantar extension was low in the patients (46% of the control value; P<0·05), but neither the capacity for mitochondrial ATP synthesis, V_max‐ATP (0·38 ± 0·26 vs. 0·50 ± 0·07 mM s^?1; P = 0·13) nor the in vitro VO_2max (0·52 ± 0·21 vs. 0·48 ± 0·21 μmol O₂ (min g wet wt.)^?1P = 0·25) were lowered correspondingly. Also, the activity of citrate synthesis and the respiratory chain complexes II and IV were similar in patients and controls. However during the contractions, the contribution to initial anaerobic ATP production from glycolysis relative to that from PCr was reduced in the patients (0·73 ± 0·22 vs. 0·99 ± 0·09; P<0·01). Conclusions: These results demonstrate that the markedly lower capacity for force generation in patients with liver cirrhosis is unrelated to their capacity for muscle ATP turnover, but the attenuated initial acceleration of anaerobic glycolysis suggests that these patients could be affected by a central limitation to force generation.     

Kinetics of 13CO2 elimination after ingestion of 13C bicarbonate: the effects of exercise and acid base balance

Abstract. In order to investigate the effects of muscular work and preceding exercise on the retention of exogenous labelled bicarbonate, we studied the effects of oral administration of [¹³C]bicarbonate (0·1 mg kg^-1) in five subjects at rest before exercise and during and after 1 h of treadmill walking at 73% VO_2max on three separate occasions. Elimination of CO₂ from labelled bicarbonate was 62·6±8·1% at rest, 103·6±11·3% during exercise (P<0·01) and 43·0±4·7% during recovery from exercise (P= 0·01). During exercise mean residence time (MRT) was shorter than at rest (35±7 min vs. 54±9min, P < 0·02) and CO₂ pool size was larger (998±160 ml CO₂kg^-1, vs. 194±28ml CO₂kg^-1, P < 0·001). Compared to values obtained at rest, during recovery from exercise, MRT and CO₂ pool size were reduced (34±5min, P < 0·05; 116±19 ml CO₂kg^-1, P < 0·02, respectively). In an additional five subjects acidosis and alkalosis were induced prior to administration of oral [¹³C]bicarbonate at rest. Elimination of bicarbonate was lower during acidosis (46·1±5·6%, P < 0·01) but was unaltered (50·9±5·6%, NS) during alkalosis, compared to the values obtained at resting pH. During acidosis MRT and CO₂ pool size decreased (37±3min, P<0·01 and 123±10ml CO₂kg^-1, P < 0·01, respectively) whereas in alkalosis MRT was unchanged (65±8 min NS) but CO₂ pool size was increased (230±23ml CO₂kg^-1, P < 0·05). The kinetics of elimination of ¹³CO₂ from administered bicarbonate after exercise are different to those at rest and resemble acidosis. The appropriate correction factor for sequestered ¹³C should be used in metabolic studies of the post-exercise state when using ¹³C tracers.     

The pathophysiology of the insulin-like growth factor axis in fetal growth failure: a basis for programming by undernutrition?

Abstract. Recent evidence suggests that a number of adulthood conditions, including non-insulin dependent diabetes mellitus (NIDDM) and lipid and cardiovascular abnormalities are associated with intra-uterine growth retardation (IUGR). It is possible that this arises from programming of endocrine axes during development as a result of an adverse intra-uterine environment. Insulin-like growth factors (IGFs) are mitogenic polypeptides which stimulate cellular proliferation and differentiation and are important in human fetal development. The functions of IGFs are modulated by specific high affinity binding proteins (IGFBPs). IGFBP-1 is antagonistic to the insulin-like and growth promoting effects of IGF-I, and IGFBP-3 holds IGFs in the circulation by associating with IGFs and an acid labile subunit to form a ternary complex. Using specific radioimmunoassays and fetal serum obtained during diagnostic cordocentesis we have investigated the role of the IGF/IGFBP axis in human fetal development. In a study of 130 singleton pregnancies we have examined levels of immunoreactive IGFs and IGFBPs in normally grown fetuses (AGA), starved small fetuses affected by uteroplacental insufficiency (UPI), and non-starved small fetuses (SGA). IGF-1 was significantly lower in the UPI group (n= 14, 7·8±0·6 μg l^-1), than in either the SGA group (n= 22, 31·4±3·5 μg l^-1, P= 0·0001) or the AGA group (n= 94, 36·3±1·9 μg l^-1, P= 0·0001). IGFBP-3 showed similar changes (UPI: 682·6±50·0 μg l^-1; SGA: 831·9±55·5 μg l^-1; AGA: 847·7±19·8 μg l^-1). In contrast, IGFBP-1 levels were significantly higher in the UPI group (312·4±57·5 μg l^-1) than in either the SGA group (132·6±39·5 μg l^-1, P= 0·009) or the AGA group (116·9±25·4 μg l^-1, P= 0·003), and the normal inverse relationship between IGFBP-1 and insulin levels was lost in the UPI group. IGFBP-2 levels showed a similar pattern (UPI: 2510·3±178·0 μg l^-1; SGA: 878·5±80·3μg l^-1, P= 0·0001; AGA: 791·6±27·0 μg l^-1, P= 0·0001). Thus, there are clear differences between the two groups of SGA fetuses. It is possible that in utero‘programming’ of the IGF/IGFBP axis, as a result of fetal undernutrition, may be important in the pathogenesis of disease in adulthood.