Total lung deposition of ultrafine particles in elderly subjects during controlled breathing

Ultrafine particulate matter (PM) in the air may be harmful to health, particularly in elderly subjects. From the dosimetry point of view, it is not known if the elderly subjects are more susceptible to exposure to ultrafine PM. We measured the total deposition fraction (TDF) of ultrafine PM (NMD = 0.04-0.1 microm in number median diameter) in the lungs of healthy, elderly subjects (age = 69 +/- 5 yr) and compared the results with those obtained from young adults (age = 31 +/- 4 yr) in an earlier study. Subjects inhaled the aerosols with six different breathing patterns: three different tidal volumes (V(t) = 500, 750, and 1000 ml) and two flow rates (Q) for each V(t). TDF was measured breath by breath in situ by measuring aerosol concentrations on inhalation and exhalation using an ultrafine condensation particle counter. Mean TDF (+/-SD) of the elderly subjects was 0.43 +/- 0.03, 0.36 +/- 0.04, 0.31 +/- 0.03, and 0.27 +/- 0.02 for NMD = 0.04, 0.06, 0.08, and 0.1 microm, respectively, for V(t) = 500 ml and Q = 250 ml/s. These and all other results were very similar to those of young adults. The results suggest that healthy, elderly subjects are not subjected to a greater respiratory dose of ultrafine PM than young adults under the same exposure conditions.     

MEASUREMENT OF TOTAL LUNG DEPOSITION OF INHALED ULTRAFINE PARTICLES IN HEALTHY MEN AND WOMEN

Ultrafine particles (< 0.10 µm in diameter) are present in great number in polluted urban air, thus posing a potential health risk. In this study, the total deposition fraction (TDF) of ultrafine aerosols with a narrow size distribution (number median diameter NMD = 0.04-0.1 µm and geometric standard deviation sigma_g = ~1.3) was measured in a group of young healthy adults (11 men and 11 women). TDF was obtained with 6 different breathing patterns: tidal volume (V_t) of 500 ml at respiratory flow rates (Q) of 150 and 250 ml/s; V_t = 750 ml at Q of 250 and 375 ml/s; and V_t = 1 L at Q of 250 and 500 ml/s. Aerosols were monitored continuously by a modified condensation nuclei counter while subjects were inhaling them with prescribed breathing patterns. For a given breathing pattern, TDF increased as particle size decreased, regardless of the breathing pattern used. For example, with V_t     

Measurement of total lung deposition of inhaled ultrafine particles in healthy men and women

Ultrafine particles (< 0.10 microm in diameter) are present in great number in polluted urban air, thus posing a potential health risk. In this study, the total deposition fraction (TDF) of ultrafine aerosols with a narrow size distribution (number median diameter NMD = 0.04-0.1 microm and geometric standard deviation sigma(g) = approximately 1.3) was measured in a group of young healthy adults (11 men and 11 women). TDF was obtained with 6 different breathing patterns: tidal volume (V(t)) of 500 ml at respiratory flow rates (Q) of 150 and 250 ml/s; V(t) = 750 ml at Q of 250 and 375 ml/s; and V(t) = 1 L at Q of 250 and 500 ml/s. Aerosols were monitored continuously by a modified condensation nuclei counter while subjects were inhaling them with prescribed breathing patterns. For a given breathing pattern, TDF increased as particle size decreased, regardless of the breathing pattern used. For example, with V(t) = 500 ml and Q = 250 ml/s, TDF (mean +/- SD) was 0.26 +/-.04, 0.30 +/-. 05, 0.35 +/-.05, and 0.44 +/-.07 for NMD = 0.10, 0.08, 0.06, and 0. 04 microm, respectively. For a given NMD, TDF increased with an increase in V(t) and a decrease in Q. TDF was greater for women than men at NMD = 0.04 microm within all breathing patterns used (p <.05), but the difference was smaller or negligible for larger sized particles. The results suggest that the TDF of ultrafine particles increases with a decrease of particle size and with breathing patterns of longer respiratory time, a pattern that is consistent with diffusion deposition of ultrafine particles. The results also suggest that there is a differential lung dose of ultrafine particles and thus there may be a differential health risk for men versus women.     

Pharmacokinetics and bioavailability of montelukast sodium (MK-0476) in healthy young and elderly volunteers

A study was conducted to (i) characterize the multiple-dose pharmacokinetics of oral montelukast sodium (MK-0476), 10 mg d⁻¹ in healthy young subjects (N =12), (ii) evaluate the pharmacokinetics of montelukast in healthy elderly subjects (N =12), and (iii) compare the pharmacokinetics and oral bioavailability of montelukast between elderly and young subjects. Following oral administration of montelukast sodium, 10 mg d⁻¹ (the therapeutic regimen for montelukast sodium) for 7 d, there was little difference in the plasma concentration–time profiles of montelukast in young subjects between day 1 and day 7 dosing. On average, trough plasma concentrations of montelukast were nearly constant, ranging from 18 to 24 ng mL⁻¹ on days 3–7, indicating that the steady state of montelukast was attained on day 2. The mean accumulation ratio was 1·14, indicating that this dose regimen results in a 14% accumulation of montelukast. In elderly subjects, mean values of plasma clearance (Cl), steady-state volume of distribution (V_ss), plasma terminal half-life (t_1/2), and mean residence time in the body (MRT^IV) following a 7 mg intravenous (5 min infusion) administration of montelukast sodium in the elderly were 30·8 mL min⁻¹, 9·7 L, 6·7 h, and 5·4 h, respectively. Following a 10 mg oral dose, the bioavailability of montelukast in healthy elderly averaged 61%, very close to that (62%) determined previously in healthy young subjects. Also following the 10 mg oral administration, the mean values of AUC_0→∞, C_max, t_max, and t_1/2, and the mean plasma concentration–time profile of montelukast in the elderly, were generally similar to those in young subjects, indicating that age has little or no effect on the pharmacokinetics of montelukast. There is no need to modify dosage as a function of age. © 1997 John Wiley & Sons, Ltd.     

The effects of age and gender on the pharmacokinetics and pharmacodynamics in healthy subjects of the plasminogen activator, lanoteplase

AIMS

To investigate the influence of age and gender on the intravenous pharmacokinetics and pharmacodynamics of the plasminogen activator, lanoteplase.

METHODS

Forty healthy subjects (10 each of young males, elderly males, young females and elderly females) received a single bolus 10 kU kg⁻¹ intravenous dose of lanoteplase. Plasma from blood serially collected for 24 h post-dose was analyzed for lanoteplase (antigen), fibrinogen, plasminogen and α₂-antiplasmin concentrations, plasma plasminogen activation activity (PPAA) and rapid plasminogen activator inhibitor (PAI-1).

RESULTS

Lanoteplase mean total systemic clearance (CL_t) values ranged from 1.9 to 2.8 l h⁻¹ and mean steady-state volume of distribution (V_ss) values ranged from 12.3 to 15.6 l. Age-by-gender interactions were observed for lanoteplase CL_t (P = 0.04), but no differences were observed for V_ss or elimination half-life. Elderly females had a 27% lower mean CL_t than young females (95% CI for the difference 0.17, 1.27 l h⁻¹) and 32% lower CL_t than elderly males (95% CI for the difference 0.15, 1.65 l h⁻¹). PPAA AUC/dose values did not show an age-by-gender interaction. Haemostasis parameters indicated only a slight degree of systemic plasminogen activation.

CONCLUSIONS

Elderly females had a lower mean lanoteplase CL_t than elderly males and young females. However, no difference was observed between young and elderly females for the AUC/dose of PPAA. In addition, there were no age-related or gender-related differences observed in the other pharmacodynamic parameters measured.     

The acetylcholinesterase oxime reactivator HI-6 in man: Pharmacokinetics and tolerability in combination with atropine

In a double-blind, placebo-controlled, single-dose ascending pharmacokinetics and tolerance study, we evaluated the bispyridinium oxime HI-6 dichloride monohydrate (62.5, 125, 250, and 500 mg), administered intramuscularly with atropine sulphate, 2 mg, in 24 healthy male volunteers. The plasma HI-6 peak concentration (C_max) and area under the concentration—time curve (AUC) demonstrated linear pharmacokinetics with low intradose variability, suggestive of uniformity of effect among subjects. HI-6 (500 mg) attained plasma drug concentrations that appeared adequate for practical use as an antidote. The mean ± SD time to maximum plasma HI-6 concentration (t_max = 0.69 ± 0.21 h, n = 16), and absorption half-life (t/2_a = 0.17 ± 0.05 h) indicated rapid onset of effect. The volume of distribution (V_d = 0.25 ± 0.04 L kg^?1 TBW) approximated the extracellular fluid volume. A high total body clearance (CL = 252 ± 52 mL min^?1) and short apparent elimination half-life (t/2_e = 1.15 ± 0.19 h) were expected for this polar quaternary ammonium drug. The renal clearance (CL_r = 137 ± 33 mL min^?1), which approximated the expected glomerular filtration rate, and 24 h urinary excretion of unchanged drug (55 ± 10%) indicated substantial non-renal elimination. Blood pressure, heart rate, respiratory rate, electrocardiographic parameters, mental acuity, and vision were not altered. Adverse events and changes in serum, urine and semen laboratory tests were mild. The pharmacokinetics, safety, and apparent efficacy of HI-6 suggest it may be a superior oxime antidote against nerve agent poisoning.     

Influence of Biochemical Parameters of Liver Function on Vancomycin Pharmacokinetics

Abstract: The influence of biochemical parameters of hepatic function on vancomycin pharmacokinetics was retrospectively evaluated in 76 adult patients (age 18 to 81 years), from biochemistry data gathered during routine therapeutic drug monitoring. All subjects had normal serum creatinine levels. Vancomycin concentrations were determined by fluorescence polarization immunoassay in 101 paired serum samples. All data for vancomycin concentration versus time were fitted to a one-compartment model using the bayesian approach. Bilirubin, transaminases (n = 101), γ-glutamyl transferase (n=97), alkaline phosphatase (n=95), albumin (n=92) and lactate dehydrogenase (n=42) were determined. No strong correlation was seen between any of the pharmacokinetic and biochemistry parameters studied. In patients with hyperbilirubinaemia, the mean V_ss and t_1/2 were increased (V_ss: 0.75±0.31 versus 0.92±0.421 .kg^-1, p=0.020; t_1/2 5.93±3.30 versus 7.48±4.44 hr, p=0.049). When liver function was evaluated according to hepatic profile (normal, mildly altered and severely altered), no significant differences were observed in vancomycin pharmacokinetics among the groups. In conclusion, vancomycin pharmacokinetics are only weakly influenced by the biochemistry parameters of liver function.     

Ultrafine particulate matter exposure impairs vasorelaxant response in superoxide dismutase 2-deficient murine aortic rings

Studies have linked exposure to ultrafine particulate matter (PM) and adverse cardiovascular events. PM-induced oxidative stress is believed to be a key mechanism underlying observed adverse vascular effects. Advanced age is one factor known to decrease antioxidant defenses and confer susceptibility to the detrimental vascular effects seen following PM exposure. The present study was designed to investigate the vasomotor responses following ultrafine PM exposure in wild type (WT) and superoxide dismutase 2-deficient (SOD2^+/–) mice that possess decreased antioxidant defense. Thoracic aortic rings isolated from young and aged WT and SOD2^+/– mice were exposed to ultrafine PM in a tissue bath system. Aortic rings were then constricted with increasing concentrations of phenylephrine, followed by relaxation with rising amounts of nitroglycerin (NTG). Data demonstrated that ultrafine PM decreased the relaxation response in both young WT and young SOD2^+/– mouse aortas, and relaxation was significantly reduced in young SOD2^+/– compared to WT mice. Ultrafine PM significantly diminished the NTG-induced relaxation response in aged compared to young mouse aortas. After ultrafine PM exposure, the relaxation response did not differ markedly between aged WT and aged SOD2^+/– mice. Data demonstrated that the greater vascular effect in aortic rings in aged mice ex vivo after ultrafine PM exposure may be attributed to ultrafine PM-induced oxidative stress and loss of antioxidant defenses in aged vascular tissue. Consistent with this conclusion is the attenuation of NTG-induced relaxation response in young SOD2^+/– mice.

Abbreviations: H₂O₂: hydrogen peroxide; NTG: nitroglycerin; PAH: polycyclic aromatic hydrocarbons; PE: l-phenylephrine; PM: particulate matter; ROS: reactive oxygen species; SOD2: superoxide dismutase 2 deficient; WT: wild type     

Safety and pharmacokinetics of a single oral dose of amisulpride in healthy elderly volunteers

Objective: Amisulpride is a substituted benzamide neuroleptic, which binds selectively to dopamine D₂ and D₃ receptors, mainly in the limbic structures. States of delusion and agitation occur frequently in the population aged more than 65 years, especially in demented patients and this sometimes requires the use of neuroleptics. The objectives of this study were to determine the safety and the pharmacokinetic profile of 50 mg of amisulpride administered orally as a single dose to elderly volunteers. Methods: Twenty healthy volunteers (10 men and 10 women) aged 65–79 years were included in this open trial. Frequent measurements of blood pressure and heart rate were made and ECG and blood samples were performed up to 72 h after drug intake. Results: The overall clinical and cardiovascular safety was satisfactory. The mean C_max of the racemate amisulpride in elderly people was 64.1 ± 6.7 ng · ml⁻¹, and was not different from the value of 56 ± 4.1 ng · ml⁻¹ in young subjects. As with the C_max, the mean values of t_1/2 and AUC in elderly people (15.6 ± 1.3 h and 667 ± 51 ng · ml⁻¹· h, respectively) were not different to values observed in young subject (respectively 11.7 ± 0.5 h and 603 ± 25 ng · ml⁻¹· h). Conclusions: A single oral dose of amisulpride was well tolerated and showed a similar pharmacokinetic profile in healthy elderly and young subjects. However, these findings should be confirmed after multiple dosing in a larger population in order to establish the lack of need of dosage adjustment in this elderly population. Received: 13 October 1997 / Accepted in revised form: 11 March 1998     

Exposure to High Environmental Temperature in the Sauna Does not Change Plasma Indocyanine Green (ICG) Clearance in Healthy Subjects

Abstract: Indocyanine green (ICG) was given intravenously (0.5 mg kg^-1) to seven healthy male volunteers in random order during a control session and a session in the sauna bath. The sauna bathing session consisted of three 10 min. stays in the sauna (temperature 85-95°, relative humidity 25-30%), separated by two 5-min. periods of resting at 22°. Blood samples were taken for 60 min. in order to calculate ICG plasma clearance (CI), volume of distribution (V_ss) and elimination half-life (t_1/2β). The mean±S.E.M. values of ICG plasma clearance, V_ss and t_1/2β for the control session and the sauna bathing session were 0.47±0.08 1 min.^-1 versus 0.39±0.04 1 min.^-1, 2.4±0.4 1 versus 2.3±0.2 1 and 3.9±0.3 min. versus 4.4±0.3 min., respectively. No statistically significant differences in the CI, t_1/2β or V_ss of ICG were detected between the control and sauna bathing sessions. The results suggest that short-term exposure to high ambient temperatures during sauna bathing does not affect hepatic blood flow. Consequently, short-term hyperthermia and associated changes in hepatic blood flow are assumed to have little, if any, effect on the hepatic clearance of drugs.     

EEG,MAO-A inhibition,pharmacokinetics and safety of befloxatone in the elderly

Befloxatone is a new reversible and selective MAO-A inhibitor. The present study aimed to assess the pharmacodynamics (EEG profile and MAO-A inhibition using plasma levels of DHPG), pharmacokinetics and safety after a single dose of 10 mg of befloxatone compared to amitriptyline 50 mg in a randomized, double-blind, three-way crossover, placebo-controlled trial involving 12 elderly subjects. Befloxatone did not show any sedative profile on EEG as no significant changes occurred in slow delta and theta waves or in alpha waves. In contrast, befloxatone produced a non-significant decrease in delta relative power and a significant increase in the (12–40 Hz) beta waves compared to placebo and/or amitriptyline depending on the EEG lead. MAO-A inhibition by befloxatone was evidenced by a significant reduction in DHPG plasma levels (peak activity of −85 per cent and AUC_{0–24 h} of −46 per cent compared to placebo). The pharmacokinetics parameters obtained after a single 10-mg oral dose of befloxatone were: t_max, 2 h; C_max, 33·7 ng/ml; t_1/2β, 14·5 h; AUC_0–∞, 255 ng/ml for befloxatone and t_max, 2 h; C_max, 29·4 ng/ml; t_1/2β, 16 h; AUC_0–∞, 596 ng/ml for its main metabolite, O-demethyl befloxatone. These parameters are in the same range as those obtained in healthy young subjects. In conclusion, the present study demonstrated that a single oral dose of 10 mg of befloxatone is safe in the elderly, possesses potent MAO-A inhibition activity and the EEG profile of a non-sedative antidepressant and did not justify dose adjustment compared to young subjects. © 1997 John Wiley & Sons, Ltd.     

Smokers Have Reduced Nitric Oxide Production by Conducting Airways but Normal Levels in the Alveoli

Air exhaled by cigarette smokers contains reduced amounts of nitric oxide (NO). Measurement of NO at different expiratory flow rates permits calculation of NO production by the conducting airways (Vaw_NO) and alveolar concentration of NO (P_ALV). An independent measurement of diffusing capacity of the alveolar compartment (D_LNO) multiplied by P_ALV allows calculation of NO production by the alveoli (V_LNO). Twelve asymptomatic cigarette smokers and 22 age-matched nonsmokers had measurements of D_LNO and expired NO at constant expiratory flow rates varying from 60 to 1500 ml/s. Vaw_NO in smokers was only 22 ± 11 nl/min (mean ± standard deviation, SD) compared to 70 ± 37 nl/min in nonsmokers (p < .0001). In contrast, V_LNO showed no significant difference (smokers: 203 ± 104 nl/min, nonsmokers: 209 ± 74 nl/min, p = .86). These data show that the diminished NO expired by smokers results from diminished NO production by the tissues of the conducting airways but normal values produced by the alveoli.     

Pharmacokinetics of the novel anticonvulsant hepp after single intravenous administration of three different doses in dogs

HEPP (D, L-3-hydroxy-3-ethyl-3-phenylpropanamide) is a novel compound with a wide spectrum of anticonvulsant activity and relatively low toxicity. The aim of this investigation was to study the pharmacokinetics of HEPP in mongrel dogs and to assess its linearity after intravenous administration of 8, 15, and 30 mg kg^?1. A biphasic disappearance pattern with a rapid distribution phase was observed in the plasma concentration versus time curve. The mean terminal half-life (t_1/2β) was the same after the three doses (3.4±0.15h) and the mean half-lives of the distribution phase (t_1/2α) were not significantly different after the three doses (0.09±0.02, 0.08±0.07, and 0.11±0.03 h for 8, 15, and 30 mg kg^?1 respectively). The mean AUC_0-∞ values were 44.1±10.8, 72.1±8.8, and 127.4±23.2 μg h mL^?1, respectively, showing a linear increase. The individual values of AUC_0-∞ corrected for the administered dose (AUC_0-∞/D) were 0.29±0.04, 0.23±0.05, and 0.22±0.06 h mL^?1. These values were not statistically different. Neither the mean residence time (MRT=4.55±1.50, 4.90±1.32, and 5.07±1.95 h), the steady state volume of distribution (V_ss=0.86±0.11, 1.01±0.17, and 1.20±0.40 L kg^?1) nor the systemic clearance (Cl=3.36±0.82, 3.53±0.44, and 4.02±0.68 mL min^?1 kg^?1) showed significant differences between doses. The values of V_ss suggest that HEPP is distributed in the whole body fluid. The invariant pharmacokinetic parameters and the direct correlation between AUC_0-∞ and the dose suggest that the kinetics of HEPP in dogs are linear over the range of doses studied.     

Steady-state pharmacokinetics of tenofovir disoproxil fumarate in human immunodeficiency virus-infected Chinese patients

Background: The pharmacokinetic (PK) profile of tenofovir disoproxil fumarate in Chinese adults infected with HIV is unknown.

Methods: A pilot, prospective, open-label study was performed to investigate the steady-state PK profile of tenofovir disoproxil fumarate in 15 Chinese HIV-infected patients among whom eight patients were treated with 300 mg tenofovir disoproxil fumarate, 300 mg lamivudine and 400/100 mg lopinavir/ritonavir, and seven with 300 mg tenofovir disoproxil fumarate, 300 mg lamivudine and 400 mg nevirapine. The plasma concentrations of tenofovir over the 24-h dosing interval were determined by HPLC. The PK parameters were calculated using the non-compartmental model in WinNonlin software.

Results: The PK parameters of tenofovir in the 15 patients were determined as follows (mean ± SD): AUC_{(0-24 h)}, 4074.7 ± 1551.9 ng?h/mL; C_max,ss, 447.1 ± 217.4 ng/mL; C_trough,ss, 98.7 ± 36.7 ng/mL; t_max,ss, 1.3 ± 0.4 h; plasma t_1/2, 21.8 ± 7.6 h; and CL_ss/F, 45.8 ± 13.0 L/h.

Conclusion: Tenofovir demonstrated slower elimination rate and increased plasma concentration in Chinese patients compared to previously published data from Caucasian or African subjects, which may be associated with the higher incidences of renal and bone resorption dysfunction observed in our patient population. Clinicians should be cautious of the differing PK characteristics of tenofovir among people of different races.     

Pharmacokinetic properties of albiflorin and paeoniflorin after oral administration of pure compound,Radix Paeoniae alba extract and Danggui-Shaoyao-San extract to rats

This study compared the pharmacokinetics of albiflorin (ALB) and paeoniflorin (PAE), respectively, after oral administration of ALB, PAE, Radix Paeoniae alba (RPA) extract, and Danggui-Shaoyao-San (DSS) extract to rats on separate occasions. Analytes were detected simultaneously with liquid chromatography-tandem mass spectrometry. Noncompartmental pharmacokinetic parameters were calculated. After oral administration of RPA and DSS extract to rats, ALB reached maximum concentrations of 4637 ± 2774 ng/ml (0.40 ± 0.14 h) and 226 ± 122 ng/ml (0.35 ± 0.14 h) and PAE reached maximum concentrations of 2132 ± 560 ng/ml (0.40 ± 0.14 h) and 143 ± 65 ng/ml (0.45 ± 0.11 h), respectively. Compared to the AUC_0 ? t value (1122 ± 351 and 722 ± 158 ng h/ml for ALB and PAE, respectively) after administration of monomers, larger AUC_0 ? t value of ALB (4755 ± 2560 ng h/ml) and PAE (2259 ± 910 ng h/ml) after administration of RPA extract and smaller AUC_0 ? t value of ALB (411 ± 118 ng h/ml) and PAE (242 ± 126 ng h/ml) after administration of DSS extract were obtained. The C _max, AUC, and K _el of ALB and PAE were remarkably increased (P < 0.05, 0.01 or 0.005) during oral administration of RPA extract in comparison to that of DSS extract.     

CYP3A4 mediates dextropropoxyphene N-demethylation to nordextropropoxyphene: human in vitro and in vivo studies and lack of CYP2D6 involvement

1.?The individual cytochrome P450 isoforms in dextropropoxyphene N-demethylation to nordextropropoxyphene were determined and the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in cytochrome P4502D6 (CYP2D6) extensive (EM) and poor (PM) subjects were characterized.

2.?Microsomes from six CYP2D6 extensive metabolizers and one CYP2D6 poor metabolizer were used with isoform specific chemical and antibody inhibitors and expressed recombinant CYP enzymes. Groups of three CYP2D6 EM and PM subjects received a single 65-mg oral dose of dextropropoxyphene, and blood and urine were collected for 168 and 96 h, respectively.

3.?Nordextropropoxyphene formation in vitro was not different between the CYP2D6 extensive metabolizers (K_m = 179 ± 74 μM, Cl_int = 0.41 ± 0.26 ml mg^?1 h^?1) and the PM subject (K_m = 225 μM, Cl_int = 0.19 ml mg^?1 h^?1) and was catalysed predominantly by CYP3A4. There was no apparent difference in the pharmacokinetics of dextropropoxyphene and nordextropropoxyphene in CYP2D6 EM and PM subjects.

4.?CYP3A4 is the major CYP enzyme catalysing the major metabolic pathway of dextropropoxyphene metabolism. Hence variability in the pharmacodynamic effects of dextropropoxyphene are likely due to intersubject variability in hepatic CYP3A4 expression and/or drug–drug interactions. Reported CYP2D6 phenocopying is not due to dextropropoxyphene being a CYP2D6 substrate.     

Pharmacokinetic and pharmacodynamic effects of YM087, a combined V1/V2 vasopressin receptor antagonist in normal subjects

Objective: The pharmacokinetic and pharmacodynamic properties of YM087, (4′-[(2-methyl-1,4,5,6-tetrahydroimidazo[4,5-d][1]benzazepin-6-yl)-carbonyl]-2-phenylbenzanilide monohydrochloride), a new orally active, dual V₁/V₂ receptor antagonist were characterised in healthy normotensive subjects. Methods: Six subjects were randomly allocated to receive, at 1-week intervals, a single oral dose of 60 mg YM087 and a single i.v. dose of 50 mg YM087 in an open-label, crossover study. Results: YM087 had an oral bioavailability of 44% and a short half-life. Upon oral and i.v. administration of YM087, a significant sevenfold increase in urine flow rate and a fall in urinary osmolality (from 600 mosmol/l to less than 100-mosmol/l) were observed with a peak effect 2 h after drug intake suggesting effective vasopressin V₂ receptor blockade. Simultaneously, significant increases in plasma osmolality (from 283 ± 1.3 mosmol/l to 288 ± 1.0 mosmol/l after i.v. and from 283 ± 2.1 mosmol/l to 289 ± 1.7-mosmol/l after oral administration) and vasopressin levels (from 1.5 ± 0.3 pg/ml to 3.7 ± 0.6 pg/ml after i.v. and from 0.9 ± 0.1 pg/ml to 3.9 ± 0.7 pg/ml after oral administration) were found. When administered i.v., YM087 inhibited the vasopressin-induced skin vasoconstriction, suggesting a blockade of V₁ receptors. However, the YM087-induced antagonism of V₁ receptors was less pronounced than V₂ receptor blockade. Conclusion: These data show that YM087 is an effective dual V₁/V₂ receptor antagonist in man. Received: 17 February 1999 / Accepted in revised form: 18 August 1999     

Pharmacokinetics of Trazodone During Multiple Dosing to Psychiatric Patients

Abstract: Steady-state pharmacokinetics of trazodone were investigated over a period of 4 weeks in seven psychiatric patients after repeated oral administrations of 50, 100, and 150 mg twice daily for one, one, and two consecutive weeks, respectively. Unchanged trazodone was determined by high performance liquid chromatography after a basic extraction. A steady-state level of serum trazodone was achieved for the 50 mg dose within 36 hr, while a new steady state level after increasing the dose to 100 mg and then 150 mg twice daily apparently was achieved at 12 hr. Trazodone showed linear pharmacokinetics within the dosage range investigated. The following main parameters were calculated at steady state for psychiatric patients (mean±S.D.): t_1/2 = 7.0±1.2, V_β/F = 0.50±0.131/kg and Cl_t/F = 3.2±0.51/hr. These pharmacokinetic parameters did not differ significantly from those earlier reported in healthy subjects after a single dose administration of 100 mg when based on an oral availability of trazodone of 65%.     

Elderly Patients Require Higher Doses of Sugammadex for Rapid Recovery from Deep Neuromuscular Block

This study compared the doses of sugammadex needed for rapid recovery from deep neuromuscular blockade (NMB) between young and elderly adults. Twenty‐two young (20–40 yrs) and 22 elderly (≥70 yrs) adults were enrolled, and deep NMB of 1–2 post‐tetanic counts was maintained with rocuronium intraoperatively. Predetermined doses of sugammadex were given at the end of surgery starting at 4.0 mg/kg for the first patient of each group. Doses were decreased or increased in following patients by 0.5 mg/kg, depending on the ‘success’ or ‘failure’ of rapid recovery in the preceding patient. ‘Success’ was defined as adequate recovery (train‐of‐four ratio 0.9) within 2 min. after sugammadex administration. The median (range) of ages was 29 (20–40) and 73 (70–84) yrs for the young and elderly adults, respectively. Doses of sugammadex facilitating adequate recovery from deep NMB within 2 min. in each patient population with 50% and 95% probability were defined as ED₅₀ and ED₉₅, respectively. The ED₅₀ estimated by the Dixon's method was significantly higher in the elderly compared to young adults [4.2 ± 0.4 mg/kg versus 3.3 ± 0.3 mg/kg, p < 0.001]. The ED₅₀ (83% CI) estimated by isotonic regression was 4.5 (4.2–5.0) mg/kg in elderly adults and 3.3 (3.2–3.4) mg/kg in young adults. The ED₉₅ (95% CI) estimated by isotonic regression was 5.4 (4.9–5.5) mg/kg and 4.4 (3.9–4.5) mg/kg in the elderly and young adults, respectively. In conclusion, dose adjustments of sugammadex should be considered when rapid recovery from deep NMB is needed in elderly adults.     

Ventilation,CO2 Production,and CO2 Exposure Effects in Conscious,Restrained CF-1 Mice

Abstract: Respiratory rate (f), tidal volume (V_T) and carbon dioxide production (V_ECO₂) were measured in restrained, conscious CF-1 mice. Mean f ± S.D. and mean V_T ± S.D. were 270 ± 8 breaths/min. and 0.123 ± 0.024 ml (STPD) for male, and 274 ± 15 breaths/min. and 0.115 ± 0.023 ml (STPD) for female mice, respectively. V_EO₂ was obtained from a rebreathing (closed loop) system. The maximum V_ECO₂ (STPD) amounted to 95.5 ± 15.4 ml/(kg min.) in males and to 72.7 ± 4.2 ml/(kg min.) in females. The CO₂ concentration in the closed loop system increased slowly during a 30 min. rebreathing period and reached a concentration of about 2.7%. No effect was seen on f and on V_T. Dynamic (abrupt) exposure up to 10.3% CO₂ had no effect on f in male mice, whereas V_T increased from 112% (2.3% CO₂) to 181% (10.3% CO₂). The estimated O₂ concentrations decreased from 20.5% to 18.7% with increasing CO₂ exposure. The equivalent CO₂ experiments with O₂ kept at 16% by N₂ administration showed that the lower O₂ concentration added an additional drive on the respiratory centre.