A community cluster of influenza A(H1N1)pdm09 virus exhibiting cross-resistance to oseltamivir and peramivir in Japan, November to December 2013.

Six influenza A(H1N1)pdm09 viruses were detected in Sapporo, Japan, between November and December 2013. All six viruses possessed an H275Y substitution in the neuraminidase protein, which confers cross-resistance to oseltamivir and peramivir. No epidemiological link among the six cases could be identified; none of them had received neuraminidase inhibitors before specimen collection. The haemagglutinin and neuraminidase genes of the six viruses were closely related to one another, suggesting clonal spread of a single resistant virus.

Dirac versus Weyl fermions in topological insulators: Adler-Bell-Jackiw anomaly in transport phenomena.

Dirac metals (gapless semiconductors) are believed to turn into Weyl metals when perturbations, which break either time reversal symmetry or inversion symmetry, are employed. However, no experimental evidence has been reported for the existence of Weyl fermions in three dimensions. Applying magnetic fields near the topological phase transition from a topological insulator to a band insulator in Bi1-xSbx we observe not only the weak antilocalization phenomenon in magnetoconductivity near zero magnetic fields (B<0.4 T), but also its upturn above 0.4 T only for E//B. This "incompatible" coexistence between weak antilocalization and "negative" magnetoresistivity is attributed to the Adler-Bell-Jackiw anomaly ("topological" E·B term) in the presence of weak antilocalization corrections.

Topological phase transitions driven by magnetic phase transitions in Fe(x)Bi2Te3 (0≤x≤0.1) single crystals.

We propose a phase diagram for Fe(x)Bi2Te3 (0≤x≤0.1) single crystals, which belong to a class of magnetically bulk-doped topological insulators. The evolution of magnetic correlations from ferromagnetic to antiferromagnetic gives rise to topological phase transitions, where the paramagnetic topological insulator of Bi2Te3 turns into a band insulator with ferromagnetic-cluster glassy behavior around x∼0.025, and it further evolves to a topological insulator with valence-bond glassy behavior, which spans over the region from x∼0.03 up to x∼0.1. This phase diagram is verified by measuring magnetization, magnetotransport, and angle-resolved photoemission spectra with theoretical discussions.

Caffeine enhances the slow-pressor response to angiotensin II in rats. Evidence for a caffeine-angiotensin II interaction with the sympathetic nervous system.

The purpose of this study was to determine if caffeine augments the slow-pressor response to chronic low-dose infusions of angiotensin II (AII) or the rapid-pressor response to acute infusions of AII. AII was infused (125 ng/min i.p.) for 12 d via mini-osmotic pumps in four groups of rats: group I, intact rats not treated with caffeine (n = 9); group II, intact rats treated with caffeine (0.1% in drinking water, n = 9); group III, rats previously sympathectomized with 6-hydroxydopamine, but not treated with caffeine (n = 10); and group IV, rats previously sympathectomized with 6-hydroxydopamine and treated with caffeine (n = 10). Chronic low-dose AII infusions slowly elevated systolic blood pressure in all groups. Caffeine greatly augmented this slow-pressor response to AII in intact animals; however, caffeine failed to enhance AII-induced hypertension in sympathectomized rats. Caffeine pretreatment did not enhance the rapid-pressor response to acute intravenous infusions of AII. We conclude that caffeine augmented the slow-pressor effect of chronic low-dose infusions of AII via a mechanism that involved the sympathetic nervous system.

Chronic caffeine administration exacerbates renovascular, but not genetic, hypertension in rats.

The purpose of this study was to determine whether or not caffeine would exacerbate renovascular hypertension. Therefore, we examined the effects of chronic caffeine administration on arterial blood pressure in rats subjected to either unilateral renal artery clipping (2K-1C rats) or sham-operation. Animals in each group were randomly assigned to receive either 0.1% caffeine in their drinking water or normal drinking water, and systolic blood pressure was monitored for 6 wk. Caffeine markedly exacerbated the severity of hypertension in 2K-1C rats and caused histological changes consistent with malignant hypertension. 6 wk after surgery, systolic blood pressure, plasma renin activity, and creatinine clearance in control 2K-1C rats were 169 +/- 5 mmHg (mean +/- SEM), 4.4 +/- 0.5 ng AI X ml-1 X h-1, and 2.9 +/- 0.2 ml/min, respectively; as compared with 219 +/- 4 mmHg, 31.8 +/- 7.8 ng AI X ml-1 X h-1, and 1.4 +/- 0.3 ml/min, respectively, in 2K-1C rats receiving caffeine (all values were significantly different compared with control 2K-1C). Chronic caffeine administration did not alter systolic blood pressure, plasma renin activity, or creatinine clearance in sham-operated rats or spontaneously hypertensive rats. Chronic treatment with enalapril (a converting enzyme inhibitor) prevented the development of hypertension in control 2K-1C rats and caffeine-treated 2K-1C rats; however, withdrawal of enalapril precipitated a rapid rise in systolic blood pressure in caffeine-treated 2K-1C rats, but not in control 2K-1C rats. These experiments indicate that caffeine specifically exacerbates experimental renovascular hypertension and might worsen the hypertensive process in patients with renovascular hypertension.

Potent aquaretic agent. A novel nonpeptide selective vasopressin 2 antagonist (OPC-31260) in men.

Solute-free water diuretics (aquaretics) by antagonizing hydrosmotic vasopressin receptors (V2) may be useful in treating water-retaining diseases. The effects of intravenous administration of a newly developed nonpeptide, selective V2 antagonist, OPC-31260, at doses ranging from 0.017 to 1.0 mg/kg to groups of healthy, normally hydrated men were compared with those of 0.33 mg/kg furosemide and placebo. OPC-31260 increased the hypotonic urine volume dose dependently for the first 4 h, while furosemide induced sodium diuresis for 2 h. The absolute increase in the cumulative response in the urine to the highest doses of OPC-31260 was not significantly different from that to furosemide. The higher doses of OPC-31260 rapidly lowered urine osmolality for 2 h, particularly between minutes 15 and 45 (e.g., 1.0-mg/kg dose: 63 +/- 2 mOsm/kg in urine collected between minutes 30 and 45). In a marked hypotonic diuresis, mean free water clearance of the 4-h urine increased dose proportionally into the positive range, reaching 1.80 +/- 0.21 ml/min at 1.0 mg/kg. Whereas furosemide induced marked Na and K diuresis, OPC-31260 increased urinary Na excretion only slightly. At 4 h, 0.75 and 1.0 mg/kg of OPC-31260 almost doubled the plasma arginine vasopressin; and the higher doses increased plasma osmolality and plasma Na slightly, but did not alter plasma K, blood pressure, or heart rate. OPC-31260 thus safely induced a potent aquaretic effect in men.

Bisecting N-acetylglucosamine on K562 cells suppresses natural killer cytotoxicity and promotes spleen colonization.

beta 1-4 N-acetylglucosaminyltransferase (GnT-III) catalyzes the formation of bisecting N-acetylglucosamine (GlcNAc) in the biosynthesis of N-linked oligosaccharides. To examine the effect of bisecting GlcNAc on the natural killer (NK) cytotoxicity, the GnT-111 gene was introduced into NK-sensitive K562 cells that have no detectable GnT-III activity. We obtained three clones stably expressing high GnT-III (positive transfectants). Introduction of the GnT-III gene resulted in an increase of bisecting GlcNAc and a decrease of external sialic acid as well as tri- and tetraantennary sugars, as judged by flow cytometry. Compared to controls, the NK cytotoxicity was completely blocked against positive transfectants. The binding of effector cells to positive transfectants was also decreased. After s.c. injection into nude mice, positive transfectants produced spleen colonization, although no spleen lesions were formed by control cells. In nude mice depleted of NK cells by anti-asialo GM1 antibody, both positive transfectants and controls produced spleen colonization equally. These results indicate that K562 cells expressing GnT-III are resistant to NK cytotoxicity, resulting in spleen colonization in nude mice.

Automated PET-only quantification of amyloid deposition with adaptive template and empirically pre-defined ROI.

Amyloid PET is useful for early and/or differential diagnosis of Alzheimer's disease (AD). Quantification of amyloid deposition using PET has been employed to improve diagnosis and to monitor AD therapy, particularly in research. Although MRI is often used for segmentation of gray matter and for spatial normalization into standard Montreal Neurological Institute (MNI) space where region-of-interest (ROI) template is defined, 3D MRI is not always available in clinical practice. The purpose of this study was to examine the feasibility of PET-only amyloid quantification with an adaptive template and a pre-defined standard ROI template that has been empirically generated from typical cases. A total of 68 subjects who underwent brain (11)C-PiB PET were examined. The (11)C-PiB images were non-linearly spatially normalized to the standard MNI T1 atlas using the same transformation parameters of MRI-based normalization. The automatic-anatomical-labeling-ROI (AAL-ROI) template was applied to the PET images. All voxel values were normalized by the mean value of cerebellar cortex to generate the SUVR-scaled images. Eleven typical positive images and eight typical negative images were normalized and averaged, respectively, and were used as the positive and negative template. Positive and negative masks which consist of voxels with SUVR ⩾1.7 were extracted from both templates. Empirical PiB-prone ROI (EPP-ROI) was generated by subtracting the negative mask from the positive mask. The (11)C-PiB image of each subject was non-rigidly normalized to the positive and negative template, respectively, and the one with higher cross-correlation was adopted. The EPP-ROI was then inversely transformed to individual PET images. We evaluated differences of SUVR between standard MRI-based method and PET-only method. We additionally evaluated whether the PET-only method would correctly categorize (11)C-PiB scans as positive or negative. Significant correlation was observed between the SUVRs obtained with AAL-ROI and those with EPP-ROI when MRI-based normalization was used, the latter providing higher SUVR. When EPP-ROI was used, MRI-based method and PET-only method provided almost identical SUVR. All (11)C-PiB scans were correctly categorized into positive and negative using a cutoff value of 1.7 as compared to visual interpretation. The (11)C-PiB SUVR were 2.30 ± 0.24 and 1.25 ± 0.11 for the positive and negative images. PET-only amyloid quantification method with adaptive templates and EPP-ROI can provide accurate, robust and simple amyloid quantification without MRI.

Lead neuropathy: 2. Random distribution of segmental demyelination among "old internodes" of myelinated fibers.

One-hundred teased fibers of proximal and of distal sural nerve of five rats fed lead carbonate for 3 months were evaluated to see whether the pattern of segmental demyelination was random or clustered. If the evaluation was done by the length of the "territory of an old internode" (the region of one Schwann cell) a significant departure from randomness could not be shown for the majority of nerves. However, if the evaluation was by regions with and without myelin a highly clustered pattern of segmental demyelination was found. Since several remyelinated internodes form following internodal segmental demyelination, of one "old internode" the latter method of analysis would be expected to show clustering even though Schwann cell damage was random. Therefore the second method of analysis cannot be used to assess randomness of Schwann cell involvement in neuropathy. We interpret these studies as supporting the concept that Schwann cells are primarily and ubiquitously involved in lead neuropathy of the rat. Possible mechanisms of such primary Schwann cell injury are direct damage from lead of the intrafascicular interstitial fluid or from increased intrafascicular interstitial pressure.

Studies to improve fixation of human nerves. IV. Effect of time elapsed between death and glutaraldehyde fixation on density of microtubules and neurofilaments.

Glutaraldehyde fixation of rat peroneal nerves after the animal was killed (simulated autopsy) was associated with a statistically significant decrease of density (number per unit area) of microtubules (MT) in comparison with controls (simulated biopsy). The density of MT decreased progressively with prolongation of time elapsed prior to glutaraldehyde fixation (1, 6, and 12 hours). Such a time effect was not demonstrated for density of neurofilaments.

Studies to improve fixation of human nerves. V. Effect of temperature, fixative and CaCl2 on density of microtubules and neurofilaments.

Utilizing morphometry of electron micrographs of nerves of rat fixed with different schedules of fixation it was concluded that: irrespective of the fixative, fixation at low temperature is associated with markedly low densities of microtubules (MT) of myelinated and of unmyelinated fibers; of the various fixatives tested 2% glutaraldehyde in 0.1 M cacodylate buffer without 0.025 M CaCl2 was associated with the highest density of MT of myelinated fibers and the addition of 0.025 M CaCl2 to a 2% glutaraldehyde fixative solution is associated with abnormally low densities of MT in myelinated and unmyelinated fibers. An effect of temperature, fixative and added CaCl2 on neurofilaments density was not demonstrated. Using the criterion of density of MT and assuming that these studies on rat nerves can be applied to biopsied nerve of man, fixation of human nerves should be at room or body temperature, and the fixative solution should not contain 0.025 M CaCl2.

Lead neuropathy. 1) Morphometry, nerve conduction, and choline acetyltransferase transport: new finding of endoneurial edema associated with segmental demyelination.

Morphometric and pathologic studies along the length of the peripheral nervous system were obtained in groups of rats fed 4% lead carbonate for 3 and 6 months and in match-fed controls. The number and diameter histograms of L6 cytons of spinal ganglia and of myelinated fibers of proximal and distal portions of peroneal and sural nerve were not significantly different from the control groups. On the other hand, segmental demyelination occurred approximately as frequently in proximal as in distal parts of nerves. At 3 months approximately 1/3 of teased myelinated fibers showed changes of segmental demyelination (Condition C), or of remyelination after segmental demyelination (Condition F) or of both segmental demyelination and of remyelination (Condition D), while at 6 months more than 4/5ths of fibers showed these changes. As expected, regression lines of axonal area on number of lamellae of myelin, were less steep in nerves of rats fed on lead for 6 months as compared to controls. Axonal transport of choline acetyltransferase in lead neuropathy did not differ from that in control rats. As expected from the studies of others, conduction velocity of myelinated fibers of caudal nerve were low. A new finding was the often quite striking increase of transverse fascicular area of peripheral nerves. This was due to edema which appeared to develop at about the time of onset os segmental demyelination. Although the edema may be an epiphenomenon, it could be an important observation bearing on the development of lead neuropathy. It would be important to know next whether or not the blood nerve barrier is altered in lead neuropathy.

Development and application of a simple microassay for adenosine in rat plasma.

Adenosine may be a physiological modulator of vascular smooth muscle tone, sympathetic neurotransmission, renin release, and renal and cardiac function. To facilitate the elucidation of the physiological role of adenosine, a microassay for adenosine was developed that allows accurate quantitation of adenosine in 75 microliters of rat plasma, thus permitting multiple determinations of plasma adenosine levels in an individual rat without inducing hemodynamic perturbations due to blood loss. The technique employs a simple and rapid extraction of plasma with a reverse-phase Sep-Pak cartridge and exploits the increased mass sensitivity of microbore high performance liquid chromatography. The assay was verified by demonstrating a linear relationship between the amount of adenosine added to plasma and the amount detected by the assay, a linear relationship between the rate of adenosine infusion into rats and plasma adenosine levels, and the absence of measurable adenosine levels in plasma incubated with adenosine deaminase. The mean arterial plasma level of adenosine in the anesthetized rat was determined to be 119 +/- 28 (SD) ng/ml (n = 10). With the use of this assay, renal venous plasma levels of adenosine were found to be elevated sixfold in two-kidney, one clip Goldblatt hypertensive rats (1 week postclipping) compared with sham-operated controls. Given the known effects of adenosine on renin release, these data support a role for endogenous adenosine as a regulator of renin release in renovascular hypertension.

Hemodynamic effects of adenosine in conscious hypertensive and normotensive rats.

Mean arterial pressure and heart rate were measured during intra-aortic arch (i.a.a.), intravenous, and suprarenal artery (s.r.a.) infusions of adenosine in conscious, unrestrained normotensive Wistar-Kyoto rats (WKY) and spontaneously hypertensive rats (SHR) in the absence and presence of ganglionic blockade. In both groups, i.a.a. and i.v. infusions of adenosine induced comparatively larger dose-dependent reductions in mean arterial pressure than did s.r.a. infusions. In WKY, i.a.a. and i.v. infusions of adenosine were equipotent in reducing mean arterial pressure. In contrast, i.a.a. infusion of adenosine was approximately twice as potent as i.v. infusion in SHR. Also, SHR were approximately 6.5 and 2.6 times more sensitive to i.a.a. and i.v. infusions of adenosine, respectively, than were WKY. Further, i.a.a. and s.r.a. infusions of adenosine caused tachycardia in WKY, while i.v. infusions did not alter heart rate. In SHR, neither i.a.a. nor s.r.a. infusion of adenosine altered heart rate, but i.v. infusion induced a profound bradycardia. In ganglionic-blocked WKY that received a norepinephrine infusion to restore blood pressure and heart rate to pre-ganglionic blockade levels, depressor responses to i.a.a. infusion of adenosine were unchanged while the increase in heart rate was abolished. In SHR, ganglionic blockade markedly decreased the depressor response to i.a.a. and i.v. infusions of adenosine and abolished the bradycardic response to i.v. infusion. These results suggest that adenosine is an effective hypotensive agent in both WKY and SHR; however, marked between-strain differences exist in the cardiovascular response to adenosine. These differences most likely are due to changes in adenosine-pulmonary interactions and increases in the importance of adenosine-autonomic interactions in SHR.

Adenosine in renin-dependent renovascular hypertension.

Our previous studies support the hypothesis that activation of the renin-angiotensin system by renal ischemia elevates adenosine levels and that adenosine acts in a negative feedback loop to limit renin release and to mitigate some of the hypertension-producing effects of angiotensin II. To further test this hypothesis, we compared the time course of caffeine-induced increases in plasma renin activity with the time course of changes in plasma levels of adenosine in two models of renin-dependent renovascular hypertension. Also, we compared the effects of caffeine on plasma renin activity and arterial blood pressure in renin-dependent versus renin-independent renovascular hypertension. In comparison to sham-operated rats, plasma levels of adenosine in the left and right renal veins and aorta were elevated severalfold in two-kidney, one clip rats (2K1C) 1 week after left renal artery clipping. However, adenosine levels declined during the second and third weeks after clipping. In 2K1C rats treated chronically with caffeine, plasma renin activity was markedly elevated during the first week after operation as compared to non-caffeine-treated 2K1C rats. However, during the second and third weeks after clipping, caffeine had lesser effects on plasma renin activity. A temporal relationship between plasma adenosine levels and caffeine-induced hyperreninemia was also observed in rats with aortic ligation. Caffeine accelerated hypertension in 2K1C rats and rats with aortic ligation (renin-dependent renovascular hypertension), but it had no effect on plasma renin activity or blood pressure in one-kidney, one clip rats (renin-independent renovascular hypertension). These results lend further support to the hypothesis that adenosine functions to mitigate the renin-angiotensin system in renin-dependent renovascular hypertension.

Effects of atrial natriuretic factor on hormone-induced renin release.

The purpose of this study was to determine whether or not atrial natriuretic factor can act directly on the juxtaglomerular cell in vivo to inhibit hormone-induced renin release. To achieve this objective the interaction between synthetic atrial natriuretic factor and two different renin secretagogues was examined. To exclude any indirect effect of atrial natriuretic factor on renin release due to changes in sodium delivery to the macula densa, all studies were conducted in nonfiltering, canine kidneys. In one series of studies renin release was stimulated by intrarenal infusions of norepinephrine (3 micrograms/kg/min), and in a second series of studies renin release was induced by intrarenal infusions of prostacyclin (0.1 micrograms/kg/min). In both studies intrarenal infusions of atrial natriuretic factor (0.3 micrograms/kg/min), which provided supraphysiological levels of atrial natriuretic factor in the renal arterial plasma, failed to attenuate hormone-induced renin release. In contrast, adenosine, a well-known inhibitor of renin release, abolished the renin release response to both hormones. These data indicate that, at the dose used in this study, synthetic atrial natriuretic factor does not act directly on the juxtaglomerular cell to attenuate hormone-induced renin release. Further, these results imply that circulating endogenous atrial natriuretic factor cannot directly attenuate juxtaglomerular cell responsiveness.

Intrapatient comparison of acute hemodynamic, hormonal, and natriuretic responses to captopril versus enalapril in liver cirrhosis.

We compared acute hemodynamic, hormonal, and natriuretic responses to a single oral dose of captopril (50 mg) versus enalapril maleate (10 mg) administered to eight patients with biopsy-proved liver cirrhosis. Although the two angiotensin-converting enzyme (ACE) inhibitors lowered (p less than 0.05) blood pressure with no change in heart rate during the early postdose period, captopril produced a greater (p less than 0.05) hypotensive effect than did enalapril. Enalapril caused a greater (p less than 0.01 to 0.05) ACE inhibition than did captopril during the 2- to 48-hour postdose period. Plasma renin activity increased (p less than 0.05) with the two drugs and returned toward baseline by 12 hours after administration. Plasma aldosterone levels, elevated before drug administration, were decreased by the two drugs in a stepwise fashion, but the suppressive effect was greater (p less than 0.01 or p less than 0.05) after captopril than after enalapril. Natriuresis was greater (p less than 0.05) during the first 24-hour period after enalapril than after captopril. The findings indicate that the acute pharmacodynamic responses to the two ACE inhibitors differ in patients with liver cirrhosis. However, the mechanism(s) of the divergent effects of the two drugs and the clinical implications remain obscure from this single-dose study.

Effects of a sustained thromboxane synthase inhibition on exercise-induced changes in eicosanoid formation, catecholamine concentration, and platelet aggregation in humans.

In an effort to characterize an interaction between the eicosanoids and sympathoadrenal system on platelet aggregation, we tried to determine if a sustained thromboxane A2 (TXA2) synthase inhibition would modulate changes in eicosanoid formation, catecholamine concentration, and platelet aggregation induced by a physical stress. We measured thromboxane B2 (TXB2), 11-dehydro-TXB2, 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha), norepinephrine, and epinephrine in vivo and platelet aggregation ex vivo before and after a treadmill exercise with and without the oral doses (400 mg twice daily for 7 days) of a new selective TXA2 synthase inhibitor (DP-1904) in nine healthy male subjects. The exercise tests performed on the pretreatment day (day 0) and posttreatment day (day 7) gave a similar result. DP-1904 caused a decrease in serum and urinary TXB2 and urinary 11-dehydro-TXB2 (p less than 0.001 to p less than 0.01) and an increase in serum 6-keto-PGF1 alpha (p less than 0.001 to p less than 0.05) throughout the dosing interval on days 4 and 7. Despite the drug effect on eicosanoid formation at rest and after exercise, the exercise-induced plasma norepinephrine and epinephrine concentrations did not differ between days 0 and 7. The 7-day treatment decreased (p less than 0.01) platelet aggregation induced both by adenosine diphosphate and by collagen at rest. However, the exercise increased (p less than 0.01) platelet aggregation by the two aggregators, resulting in the disappearance of the drug-induced antiaggregatory effects observed at rest. The treatment with a TXA2 synthase inhibitor does not appear to attain the antithrombotic action during an exercise despite the occurrence of a sustained endoperoxide shunting.

Kinetics and dynamics of enalapril in patients with liver cirrhosis.

The pharmacokinetics and pharmacodynamics (blood pressure, heart rate, serum angiotensin-converting enzyme, and plasma renin activity) of enalapril and enalaprilat were studied after oral administration of enalapril maleate (10 mg) to seven biopsy-proven cirrhotic patients and to seven healthy subjects. The mean Cmax, AUC, and urinary excretion of enalapril and enalaprilat were greater and less (p less than 0.01), respectively, and mean oral clearance of enalapril was less (p less than 0.01) in the cirrhotic group than in the healthy group. However, there was no significant difference in the mean total drug (enalapril plus enalaprilat) excretion between the two groups. Blood pressure fell (p less than 0.05) only at 3 or 4 hours postdose, with no change in heart rate in the two groups. Serum angiotensin-convering enzyme (ACE) decreased (p less than 0.001) and plasma renin activity (PRA) increased (p less than 0.05) in the two groups. The magnitude of the percentage of inhibition of ACE activity was comparable between the two groups. Serum enalaprilat concentration correlated (p less than 0.001) with the percentage of inhibition of ACE activity. The results suggest that the bioactivation of enalapril to enalaprilat is considerably impaired in patients with cirrhosis but that the pharmacodynamic effects do not appear to be blunted in those patients. The mechanism and clinical implications remained unclear.

Smoking accelerates absorption of inhaled neutrophil elastase inhibitor FK706.

PURPOSE: We compared the pharmacokinetics of the inhaled novel neutrophil elastase inhibitor FK706 between healthy nonsmokers and smokers. METHODS: Six healthy nonsmokers and six smokers inhaled 50 to 400 mg FK706 in two different doses. Series of plasma concentrations of the SSS form of FK706 (pharmacologically active epimer) were analyzed model dependently and independently. Pharmacokinetic parameters obtained from each group were compared after standardization by doses. RESULTS: The plasma concentration-time curve of inhaled FK706 was apparently different between smokers and nonsmokers. The maximum plasma concentrations (Cmax) were significantly higher in the smokers than in the nonsmokers (smokers, 1.47 +/- 0.62 ng/mL/mg; nonsmokers, 0.49 +/- 0.14 ng/mL/mg [mean +/- SD; P < .01]). The time to reach Cmax (tmax) and elimination half-life (t1/2) were statistically smaller in the smokers compared with the tmax and elimination t1/2 in the nonsmokers (tmax in smokers, 0.44 +/- 0.27 hours; tmax in nonsmokers, 1.17 +/- 0.39 hours [P < .01]; t1/2 in smokers, 1.23 +/- 0.40 hours; t1/2 in nonsmokers, 2.73 +/- 0.57 hours [P < .01]). The area under the plasma concentration-time curve and plasma clearance were not significantly different between the two groups. Model-dependent pharmacokinetic analysis, assuming a flip-flop model, revealed that the absorption rate constant (ka) was about 10 times greater in smokers than the ka in nonsmokers. CONCLUSION: Significant increases of Cmax and ka and reductions of tmax and elimination t1/2 of the inhaled FK706 were observed in the healthy smokers, suggesting that the smoking habit accelerates the drug absorption after inhalation. These results suggest that we should pay attention to the drug-related adverse events caused by smoking, especially when the drug has a narrow therapeutic range.