Optimal Inhalation Profile of Pressurized Metered Dry Powder Inhaler Using a Valved Holding Chamber: A Dynamic Analysis.

Background: The combined use of a pressurized metered-dose inhaler and valved holding chamber (pMDI+VHC) is recommended to improve efficiency and safety; however, aerosol release is likely to vary with the inhalation maneuver. This in vitro study investigated the aerodynamic characteristics and aerosol release features of pMDI+VHC (Aerochamber, Trudell Medical International). Methods: The static and dynamic changes in the airway resistance (Raw) during inhalation (withdrawal) through pMDI+VHC were measured. Subsequently, the aerosol released from pMDI+VHC was measured using simplified laser photometry during withdrawal with either fast ramp-up then steady or slow ramp-up followed by gradual decrement at different intensities and times to peak flow (TPWF). Results: Raw increased linearly with changes in the withdrawal flow (WF) rate between 10 and 50 L/min. The slope was steep in the low WF range (<50 L/min) and became milder in the higher range. The aerosol mass tended to increase with an increase in the peak WF (PWF) of slow ramp-up profile. When three different WF increment slopes (TPWF: 0.4, 1.4, and 2.4 seconds) were compared, the released aerosol mass tended to decrease, and the aerosol release time was prolonged at longer TPWF. When the PWF was increased, the aerosol release time became shorter, and the withdrawn volume required for 95% aerosol release became larger; however, it did not exceed 0.4 L at suitable TPWF (0.4 seconds). Conclusion: Raw analysis suggests that inhalation at 30-50 L/min is suitable for pMDI+VHC in this setting. Rapid (TPWF, 0.4 seconds) inhalation, but not necessarily long (maximum 2.0 seconds) and deep (but larger than 0.55 L), is also recommended. Practically, direct inhalation to be weaker than usual breathing, as fast as possible, and far less than 2.0 seconds.

Dynamic Analysis of Aerosol Release from a Pressurized Metered Dose Inhaler Combined with a Valved Holding Chamber Using Simplified Laser Photometry.

Background: A pressurized metered dose inhaler combined with a valved holding chamber (pMDI+VHC) is used to prevent upper airway complications and improve the efficiency of inhaled drug delivery; however, the aerodynamic behavior of the released particles has not been well investigated. This study aimed at clarifying the particle release profiles of a VHC using simplified laser photometry. Methods: An inhalation simulator comprised a computer-controlled pump and a valve system that withdrew aerosol from a pMDI+VHC using a jump-up flow profile. A red laser illuminated the particles leaving VHC and evaluated the intensity of the light reflected by the released particles. Results: The data suggested that the output (OPT) from the laser reflection system represented particle concentration rather than particle mass, and the latter was calculated as OPT × instantaneous withdrawn flow (WF). Summation of OPT hyperbolically decreased with flow increment, whereas summation of OPT × instantaneous flow was not influenced by WF strength. Particle release trajectories consisted of three phases, namely increment with a parabolic curve, flat, and decrement with exponential decay phases. The flat phase appeared exclusively at low-flow withdrawal. These particle release profiles suggest the importance of early phase inhalation. The hyperbolic relationship between WF and particle release time revealed the minimal required withdrawal time at an individual withdrawal strength. Conclusions: The particle release mass was calculated as laser photometric output × instantaneous flow. Simulation of the released particles suggested the importance of early phase inhalation and predicted the minimally required withdrawal time from a pMDI+VHC.

In Vitro Comparison of Two Blister-Type Inhalers.

BACKGROUND: Ellipta is a respiratory device that is a successor of the Diskus. A major difference between the devices is that Ellipta, especially the 2-strip type, includes a pair of blisters rather than a single blister as contained in Diskus. This study aimed to compare the particle-release properties and mechanical features of both devices. METHODS: A pump was used to evacuate air from each dry powder inhaler (DPI) with either a ramp-up or triangular pattern. The particle release volume and peak inspiratory flow of the DPIs were compared. Then the resistance of each component was measured. RESULTS: Both DPIs required specific threshold flows for particle release. Inspiratory flows exceeding the threshold values (Ellipta 11.3 ± 4.0 L/min and Diskus 29.7 ± 4.7 L/min using ramp-up inhalations; Ellipta 10.6 ± 2.1 L/min and Diskus 28.4 ± 5.2 L/min using triangular ones) did not further increase particle release volumes. The inspiratory flows required for Ellipta were significantly less than those for Diskus. The particle release volume exceeding threshold flow for Ellipta was approximately 2.62 (ramp-up) and 2.01 (triangular) times those of Diskus. The resistance of one blister was similar (0.44 cm H2O/L/min vs 0.42 cm H2O/L/min for Ellipta and Diskus, respectively). As Ellipta includes 2 parallel blisters, similar resistances suggest that Ellipta requires twice the flow of Diskus. The flow distributions for particle release in Ellipta and Diskus were 35.3 and 5.2% of the total inspiratory flow, respectively. CONCLUSIONS: The Ellipta required lower inspiratory flow than Diskus, which arises from a higher distribution to blister flow. Ellipta may be preferable to Diskus for patients with impaired pulmonary function.

Daily inhaled flow profiles and drug release from dry powder inhalers in patients with bronchial asthma.

BACKGROUND: Inhalation flow profiles may affect particle release from dry powder inhalers (DPIs). Currently available measures include a limited number of laboratory-measured parameters such as peak inhalation flow (PIF) and inhaled volume (inhV). We aimed to investigate whether parameters obtained under such conditions are valid in real-world settings and determine the effective inhalation profile. METHOD: We included seven asthmatics without recent deterioration and regularly inhaling Turbuhaler® or Diskus®. Daily inhalation profiles and particle release from either DPI were measured at home using a newly designed handy analyzer (real-life inhalation events recorder [RLEFR]), for ≥2 weeks. Inhalation pressure drop and signals of particle release during each inhalation were recorded. RESULTS: All patients inhaled daily with similar patient-specific profiles. The mean PIF and inhV were 91.9-31.6 L/min and 0.84-2.05 L, respectively. PIFs were smaller than those obtained in previous laboratory studies, and only one patient exceeded inhV of 2.0 L. The mean flow acceleration and particle emission were 39-571 L/min/s and 0.37-1.54 s, respectively. Particle release was sporadic in one Turbuhaler® user whose PIF was 31.6 L/min, appearing at 1.55 s of inhalation. Particle release from Turbuhaler® appeared to be PIF-dependent, but that from Diskus® was not. CONCLUSION: Inhalation flow profile measured at home is highly reproducible, but tends to be weaker and shorter than that measured in the laboratory. The results confirm that rapid inhalations from the start are required when using a DPI. RLEFR is a promising device for patient education and clinical studies. TRIAL REGISTRATION NUMBER: UMIN000045193.

[CHARACTERISTICS OF BUDEFORU® FOR BUDESONIDE AND FORMOTEROL MIXTURE].

BACKGROUND: Recently, BudeForu® (BF), a generic of Symbicort Turbuhaler® (SMB), is widely used in Japan. Although appearance of BF resembles to SMB, several differences in length, weight, and side-hole sizes are seen with precise inspection. As particle releases from the inhalation device is strongly influenced by its mechanical characteristics, we compared their particle release patterns. METHODS: An inhalation simulator generated either ramp-up or triangular (time to reach peak inhaling flow (PIF) = 0.42 s) inhalation pattern. Time trajectories of inhaled flow and released particles from either device were depicted with a photo-reflection method. Internal resistances of them were also measured. RESULTS: Particle release patterns of both dry powder inhalers resembled each other. Immediately after release from the inhaler, they reached the peak value and then completed in 0.5 s. In either ramp-up or triangular inspiration pattern, a single burst developed at early inhalation. There were linear relationships between PIFs and emitted doses. The regression lines using ramp-up patters were: Y = 0.00241 X - 0.039, r2 = 0.700, p ＜ 0.0001 (BF), Y = 0.00210 X - 0.038, r2 = 0.654, p ＜ 0.0001 (SMB), and those using triangular patterns were: Y = 0.00223X － 0.0015, r2 = 0.445, p ＜ 0.0001 (BF), and Y = 0.00229X － 0.0023, r2 = 0.687, p ＜ 0.0001 (SMB). Internal resistances of the BF and SMB were 0.105±0.004 and 0.119±0.105 cmH2O0.5/L/min respectively. CONCLUSIONS: Present experimental study suggested that aerodynamic characteristics of BF were quite similar to those of SMB.

Optimal Inhalation Flow Pattern from Turbuhaler Predicted by Laser Photometry.

Background: The emitted dose (ED) from most dry powder inhalers (DPIs) is almost independent of peak inspiratory flow (PIF) above a certain value, which is specific to the individual DPI. However, the ED of the Turbuhaler® (TBH) increases linearly with PIF increments. This study investigated the powder clearance and clinical utility of TBH performance features by using the photo-reflection method (PRM), a type of laser photometry. Methods: Pulmicort® (PLM) (containing budesonide only) and Symbicort® (SMB) (drugs with lactose particles) were inspired with a ramp-up pattern of several PIF intensities using a vacuum pump. Time trajectories of particle release and PIF were then compared. Results: The particle-release trajectories from both types of DPIs were similar, consisting of a sharp increment phase (∼0.15 seconds) followed by exponential decay. Both onset to the peak of particle-release time and particle-release times were not affected by PIF changes when the PIF was >40 L/min. EDs from both TBHs were linearly related to PIFs, and the slope of the regression equation for SMB was 2.4-fold larger than that of PLM. The peak of the released particles (PKIED) was also linearly related to PIF. A linear relationship was also observed between ED and PKIED in both TBHs, and these regression lines overlapped. Conclusion: EDs from the TBH were dependent on PKIED. Therefore, rapid, initially strong, and deep inhalation should be advised while using the TBH. PRM could measure the fine and small amount of particles released from the TBH.

Correcting Photo Reflection Method Output and Its Application in the Dynamic Analysis of Particle Release from Dry Powder Inhalers.

Background: The photo reflection method (PRM) is used to measure light reflected from particles released from dry powder inhalers (DPIs). This simple method depicts time trajectories of released drugs; however, it underestimates the number of particles at high peak inhalation flow rates (PIFs). In this study, we aimed to correct this underestimation and clarify whether long inhalation is necessary for capsule-type DPIs, using this unique method. Methods: To establish quantitative measurements using the PRM, several types of DPIs were inhaled with square-wave inhalations at different PIFs using an inhalation simulator, and the total emitted dose (TED) and the release time of the TED (TTED) were measured. Next, capsule-type DPIs were inhaled using inhalation patterns of patients with chronic obstructive pulmonary disease (COPD), and particle release time trajectories were recorded. Results: For all DPIs, except for Turbuhaler® (TBH), both TED and TTED were hyperbolically decreased with an increase in the PIF of square-wave inhalations. TED correction using the TTED showed flat TED changes at high PIF ranges. The patient inhalation analysis showed that the corrected TEDs of seven COPD inhalation patterns were not significantly different. The PRM further revealed that the inhaled flow rate and release time of all seven patterns were sufficient to release particles in the capsule. Conclusions: The inhaled flow rate and TTED that exceeded specific conditions enabled complete particle release from the DPIs except for TBH. Therefore, an extremely long inhalation is not required for capsule-type DPIs. Our corrected time trajectory analysis using the PRM provides a new strategy for the particle release analysis of DPIs.

Analysis of Drug Release Dynamics of the Reservoir-type Dry Powder Inhalers.

OBJECTIVE: Dry powder inhalers (DPIs) are classified as capsule, blister, and reservoir types. Currently, two reservoir-type DPIs, i.e., TurbuhalerTM (TBH) and GenuairTM (GNA), are available, but their physical characteristics differ. Therefore, we compared their drug release patterns. METHODS: An inhalation f low simulator was set to reach peak inhalation f low (PIF) at two time points, 0.4 s (rapid) or 1.5 s (moderate), and then the drug release from both the DPIs were compared. RESULTS: The amount of drug release from the TBH increased linearly with increase in PIF, and the amounts were higher during rapid inhalation than during moderate inhalation. The GNA had a threshold flow for drug release, above which the flow was PIF-dependent (rapid) or independent (moderate). With rapid inhalation, drug release was dependent on the peak value and releasing time in both the DPIs. With moderate inhalation, the peak flow dependency of the TBH was attenuated, whereas that of the GNA remained time-dependent. CONCLUSION: Rapid and strong inhalation are best for drug release in both the DPIs, but a longer inhalation was required for the GNA. Therefore, if a patient cannot inhale rapidly, then a moderately rapid and long inhalation could be considered, but strong inhalation is still mandatory for TBH.

[IS IT NECESSARY TO PROHIBIT SIDE-HOLE CLOSURE IN USE OF THE DRY POWDER INHALERS?]

BACKGROUND: In use of Ellipta (EPT), Diskus (DKS) or Turbuhaler (TBH), an instruction not to close side holes is sometimes given, but validity of such instruction has not been proved. METHOD: Using an inhalation simulator we measured peak inhaled flow (PIF), peak inhaled pressure (PIP) and amount of the drug release from these DPIs before and after closure of side holes (SHC). In the case of EPT, incomplete obstruction was also assessed. RESULTS: SHC increased internal resistance by 2.8 times in TBH, 1.0 in DKS, and 1.28 (incomplete obstruction) and 1.86 (complete) in EPT. Inhaled flows at pressure of -15cmH2O were 14L/min in TBH, 47 in DKS and 34 in EPT (incomplete obstruction). SHC suppressed drug release from TBH but statistical significance was not obtained. Drug release was not suppressed by SHC in DKS, while it was almost half during SHC in EPT. The level of PIF decreased by SHC was serious since fine particles generation is not expected. Such severe decreases were not found in DKS and EPT. CONCLUSION: SHC severely inhibited drug release from TBH, but almost no effects on DKS. Such negative effect was limited in usual use of EPT.

Appropriate use of a dry powder inhaler based on inhalation flow pattern.

BACKGROUND: An optimal inhalation flow pattern is essential for effective use of a dry powder inhaler (DPI). We wondered whether DPI instructors inhale from a DPI with an appropriate pattern, and if not, whether self-training with visual feedback is effective. METHODS: Subjects were 14 pharmacists regularly engaged in instruction in DPI use. A newly designed handy inhalation flow visualizer (Visual Trainer: VT) was used to assess inhalation profiles and to assist in self-training. With a peak inhalation flow rate (PIFR) > 50 L/min, time reaching PIFR (TPF) < 0.4 s, inhalation volume (VI) > 1 L, and flow at 0.3 s after the onset of inhalation (F0.3) > 50 L/min, the pattern was considered optimal. RESULTS: Using Diskus or Turbuhaler 12 and 10 subjects respectively inhaled with a suitable PIFR. Those with a satisfactory F0.3 were 10 and 7 respectively. The TPF was short enough in only 1 and 2 respectively. All 14 subjects inhaled deeply (VI) through Diskus, and 10 did so through Turbuhaler. In the self-training session, only 3 subjects satisfied all three variables at the first trial, while 2 or 3 trials were required in other subjects. Among the three variables, optimal TPF was the most difficult to attain. Once a satisfactory inhalation pattern was achieved using one DPI, eleven out of 12 subjects inhaled with a satisfactory pattern through the other DPI. CONCLUSION: Visualization of the inhalation flow pattern facilitates the learning of proper inhalation technique through a DPI.

Impact of holding position during inhalation on drug release from a reservoir-, blister- and capsule-type dry powder inhaler.

OBJECTIVE: To determine whether drug release may be impaired by tilting some dry powder inhalers (DPIs). METHODS: Using an inhalation simulator, we measured drug release from Turbuhaler® (TBH), Diskus® (DKS) and Breezhaler® (BZH) at several peak inhaled flow rates (PIFs) while the DPIs were held at level and tilted (80°). Drug release was then measured from all three DPIs at 0, 30, 60 and 90° of tilt, and capsule rotation was also recorded. RESULTS: Drug release from TBH was flow-dependent while that from DKS and BZH was flow-independent. With TBH, the plot of drug release vs. PIF either at level or at tilted position scattered along approximately the same regression lines. With DKS and BZH, drug release at tilted position was significantly lower than that while at level. With DKS the decrease was almost 20%, while with BZH, drug release frequently failed. With BZH, significant reductions in drug release were observed while the device was tilted by 30-90°. CONCLUSION: The position in which the DPI is held may affect drug delivery, especially when using BZH.

Exhalation immediately before inhalation optimizes dry powder inhaler use.

OBJECTIVE: Although exhalation immediately prior to inhalation (EPI) from dry powder inhalers (DPIs) is universally advised, its benefit has not been investigated. The objective of this study to assess the effects of EPI on inhaled flow from a DPI. METHODS: We measured peak inhaled flow rate (PIFR) and inhaled gas volume of 25 volunteers unfamiliar with DPIs. They inhaled strongly and deeply through a flow meter either with or without EPI before and after connecting Turbuhaler or Diskus. RESULTS: Median PIFR increased significantly with EPI both without connection to DPIs (178.8 versus 140.4 L min(-1)), and with connection to Diskus (75.6 versus 67.8 L min(-1)), or to Turbuhaler (51.0 versus 48.0 L min(-1)). As a result, the number of subjects whose PIFR exceeded 60 L min(-1) was significantly increased with connection to either Diskus (76 versus 64%) or to Turbuhaler (24 versus 4%). EPI significantly increased median inhaled volume both without connection to DPIs (2.84 versus 1.84 L), and with connection to Diskus (1.95 versus 1.66 L), or to Turbuhaler (1.86 versus 1.28 L). EPI significantly increased F0.2 (flow at 0.2 s after onset of inhalation) and AC30 (flow acceleration at 30 L min(-1)), parameters representing the rate of flow increase during the early phase of inhalation, in all the three groups. CONCLUSIONS: EPI increases PIFR which may augment drug dispersion and facilitate fine particle generation from a DPI.

[Dynamic characteristics of flow trainer for dpi and its clinical relevance].

BACKGROUND: Trainer devices are widely employed for flow instruction in the use of dry powder inhalers (DPI). However, their aerodynamic characteristics in actual use have yet to be investigated. METHODS: We recorded inhalation flow signals and sounds produced from trainers for Diskus®, Symbicort®, Pulmicort® and Twisthaler® while five volunteers inhaled from the trainers with various inhalation patterns. RESULTS: Inhalation flow was classified into four patterns; the best, trapezoid, delayed peak and others. All the trainers exhibited flow-thresholds with appropriate precision for instruction. Sound intensity from the Diskus® trainer was almost proportional to inhaled flow rate, and it may be useful for flow pattern estimation. In other trainers, when flow exceeded some thresholds, sounds abruptly developed and continued with high intensity. Thus, they may be convenient for recognizing appropriate flow rates. In all trainers, when the subjects inhaled rapidly and forcefully, sound developed at 0.19-0.24 s after the onset of inhalation. Thus, with this flow pattern, trainers may indicate a flow rate approaching the peak of drug dispersion from the DPI. When the subject inhaled less rapidly, the threshold for sound development decreased by 10%. CONCLUSION: The instructor in DPI use should be aware of the aerodynamic characteristics of each individual trainer. Rapid inhalation should also be encouraged.

[Resistances of dry powder inhalers and training whistles and their clinical significance].

BACKGROUND: Flow resistance of dry powder inhaler (DPI) is important information when physician choose a suitable DPI to individual patient. We previously reported flow resistances of several DPIs and training devices. In the present in vitro study, we measured resistances of new DPIs and new trainers. METHOD: Flow resistances were obtained from driving pressure and flow through the devices. RESULTS: All devices had parabolic relationships between the driving pressure and flow. Resistances were: 8.44 ± 0.45×10-2(mean±SD) for Elipta®, 5.53±0.13×10-2 for Breezhaler®, 7.27 ± 0.40×10-2 for new Diskhaler®, 12.15 ± 0.40×10-2 for Swinghaler®, 7.07 ± 0.24×10-2 for new Diskus trainer, 8.72 ± 0.4.5×10-2(√cmH2O/L/min) for Elipta trainer. Sounding threshold of Diskus trainer was 38.1 ± 5.1 and that of Elipta trainer was 39.9 (meidan) L/min. INTERPRETATIONS: In change from Diskus® to Elipta®, flow instruction is not necessary. Breezhaler® is a suitable DPI for patients with low pulmonary function but patients should be alert to avoid excessively high inhalational flow. In flow instruction, a flow higher than trainer sounding should be advised.

[Flow and inspiratory pressure characteristics of In-Check(tm) and training whistles].

BACKGROUND: The optimal inhalation effort using dry powder inhalers (DPI's) varies with the specific inhaler. Accordingly, the device used for instruction in the proper use of the specific DPI should have physical characteristics similar to the actual DPI. However, the precision with which these devices mimic the actual DPI's has not been established. METHODS: We measured mouthpiece pressure (PI) and flow through the In-Check with an added flow resistance (for DiskusTM, DiskhalerTM, PulmicortTM, HandihalerTM, and ClickhalerTM) and the training whistles (for Diskus, Pulmicort, SymbicortTM, TwisthalerTM) at different inhalation pressures. RESULTS: Both the In-Check with an added flow resistance for individual DPI and the training whistles for each DPI had parabolic PI-flow relationships similar to the actual DPI. When a curve was drawn from direct readings of the In-Check scale, it fell consistently below that based on the pneumotachometer values. PI-flow curves of the actual DPI fell below both of the above curves. Among the same type of DPI, PI-flow relationships resembled each other, but one of 13 in the Diskus group demonstrated curves above and one of 6 in Pulmicort demonstrated curves below the others. The flows at which sounds were generated from the whistle were between 25-50 L/min. CONCLUSIONS: Both In-Check and training whistles had suitable PI-flow relationships. Flow readings taken directly from In-Check tended to be lower than the measured value. A few training whistles might generate sounds with efforts below the optimal one.

Minimal inspiratory flow from dry powder inhalers according to a biphasic model of pressure vs. flow relationship.

Inhalation therapy using the dry powder inhaler (DPI) is now the first choice for obstructive pulmonary diseases. We previously measured relationships between inspiratory pressure (PI) and flow rate of almost all of the DPIs available in Japan, and described an importance of inspiratory efforts. In the present study, we further analyzed the data obtained in the previous study. Although there were linear relationships between PI and flow2, the slope became steeper when PI was less than a certain value (critical PI, existed between 15-20 cmH2O). When PI was less than critical PI, linear rather than parabolic regression between PI and flow yielded better fits (r > 0.90, p < 0.001). Inspiratory flows at the critical PI were 53.9 (Diskus), 65.8 (Diskhaler), 45.9 (Turbuhaler for Pulmincort), 48.6 (Turbuhaler for Symbicort) and 38.0 l/min (Twisthaler). These findings suggested that flow through the DPI becomes laminar rather than turbulent flow in the range below critical PIs. We suggest that patients should inhale from the DPIs with inspiratory pressure higher than critical PI.

[The relationship between inspiratory pressure and flow through dry powder inhaler available in Japan].

OBJECTIVE: Recently many of the inhaled drugs are provided as dry powder formula and prescribed for such diseases as COPD and asthma exacerbation. Inspiratory flow rate through the dry powder device (DPI) has a significant influence on therapeutic response in these disease conditions. We planned to measure flow vs. pressure relationships of almost all of the DPIs available in Japan. METHODS: Driving pressure (PI) and flow through the DPI were measured and the linear regression lines between PI and flow(2) were drawn. RESULTS: The slope and intercept of the regression lines were as follows: Turbuhaler for Pulmicort 79.26 (l/s)(2)/cmH2O, 626 (l/s)(2), Turbuhaler for Symbicort 88.99, 688, Twisthaler 56.37, 478, Diskus 125.98, 872, Diskhaler, 166.98, 780, Handihaler, 54.88, 498, Clickhaler, 78.37, 452. We drew P(I) vs flow curves of each DPIs for instruction of DPI devices to the patients. CONCLUSION: Inspiratory pressure is an excellent parameter to indicate optimal flow through DPI. Early escalation of medication may be important in the patients using Turbuhaler or Twisthaler that has higher resistance in inspiratory channel.

Spirometric and flow-volume curve analysis in rats, and optimal parameters for estimating obstructive impairment.

We obtained flow-volume (F-V) curves in anesthetized rats by applying positive pressure on the body surface. To obtain the best curve, tracheal intubation with either a 12 or 13 gauge catheter and a surface pressure greater than 56 cmH(2)O was necessary. Peak expiratory flow rate (PEFR) and forced vital capacity (FVC) were shown to be optimal parameters for estimation of bronchoconstriction induced by methacholine inhalation while FEV(0.05) (forced expiratory volume at 0.05 s) and FEV(0.10) were of limited usefulness for this purpose. The descending segment of the F-V curve consisted of two or three phases, with later phases shortened during bronchoconstriction. In conclusion, PEFR and FVC are optimal parameters for estimation of bronchoconstriction in rats. The decreases in PEFR and FVC may reflect constriction in large and smaller airways, respectively.

Decrease in glomerular filtration rate by plasma low-density lipoprotein cholesterol in subjects with normal kidney function assessed by urinalysis and plasma creatinine.

OBJECTIVE: It has not been well defined whether plasma low-density lipoprotein cholesterol (LDL-C) progresses arteriolosclerosis (arteriosclerosis of small arteries) or not. Estimated glomerular filtration rate (e-GFR) is an indicator of the function of renal arterioles and capillaries of glomeruli. The relationship between e-GFR and plasma LDL-C was studied to estimate the effect of plasma LDL-C on the function of renal arterioles and capillaries of glomeruli to speculate the effect of plasma LDL-C on arteriolosclerosis. METHODS AND RESULTS: Major coronary risk factors; blood pressure, plasma lipids, and fasting plasma glucose were compared among 4 groups of examinees of a health evaluation and promotion center separated by e-GFR, namely, Control group, Group 1, 2, 3 from highest e-GFR to lowest e-GFR. Numbers of total male and female subjects were 4602 and 2920, respectively. Plasma LDL-C levels were significantly high in Group 2 and 3 in all male subjects and high in Group 1, 2, and 3 in male subjects with age of fifties, compared with Control group. Plasma LDL-C levels were significantly high in Group 1, 2, and 3 in all female subjects and high in Group 2 and 3 in female subjects with age of fifties, compared with Control group. Plasma levels of LDL-C were not significantly different at each years of age in subjects with age of fifties in both sex. BMI and waist circumference were higher in male subjects with low e-GFR but not in female subjects. Blood pressure and fasting plasma glucose were not high in subjects in Group 1, 2, and 3, compared with Control group in all subjects and subjects with age of fifties in both sex. CONCLUSIONS: We concluded that the high plasma level of LDL-C was the major risk factor among coronary risk factors to reduce GFR probably due to impairing the function of renal arterioles and capillaries of glomeruli in subjects with normal kidney function assessed by urinalysis and plasma creatinine.

Aerosolized methacholine-induced bronchoconstriction and pulmonary hyperinflation in rats.

The body plethysmography (BPG) is a useful tool for analyzing pulmonary function in small animals because it simultaneously measures airway resistance (R (aw)) and functional residual capacity (FRC). We previously described a BPG with the enclosed environment maintained at body temperature and water vapor-saturated. We found dose-dependent increases in R (aw) in response to inhaled methacholine (Mch) with no apparent increase in FRC in intratracheally intubated rats without paralysis. To resolve this apparent inconsistency in clinical observations, we repeated the study using a newly developed BPG that allowed us to shorten the interval between Mch-inhalation and measurements by about two-thirds. Using Mch concentrations of 0, 0.5, 1.0, 2.0 and 4.0 mg/ml each for 2 min, both parameters increased in a dose-dependent fashion with FRC (mean +/- SE) values of 3.77 +/- 0.16, 4.43 +/- 0.26, 4.75 +/- 0.34, 5.02 +/- 0.49 and 5.34 +/- 0.38 ml and R (aw) values of 18.6 +/- 3.9, 21.6 +/- 4.9, 35.0 +/- 6.9, 49.0 +/- 8.8 and 65.7 +/- 8.8 ml/s/Pa, respectively. Immediate measurement after Mch-inhalation demonstrated profound bronchoconstriction associated with dose-dependent increases in FRC.