Biomedical subjects

T Ooie

Publications and source records attributed to T Ooie.

At least 19 recordsLinked to original sources

PubMed2006

Molecular level damages of low power pulsed laser radiation in a marine bacterium Pseudoalteromonas carrageenovora.

AIM: To study the molecular level damages in a marine bacterium, Pseudoalteromonas carrageenovora, exposed to low power pulsed laser radiation from an Nd:YAG laser. METHODS AND RESULTS: The laser damages in bacterial DNA were monitored by studying the formation of apurinic/apyrimidinic (AP) sites. Molecular probe kits were used for this purpose. Occurrence of lesions in the cell walls was monitored under a transmission electron microscope (TEM). The results showed that laser radiation significantly increased the number of AP sites in the bacterial DNA. This increase corresponded to the laser fluence (J cm(-2)) and to the duration of laser irradiation. TEM observation showed the occurrence of lesions in bacterial cell walls upon laser irradiation. CONCLUSIONS: It is concluded that bacteria exposed to laser irradiation suffers DNA damages and resulted in broken cell walls. These events led to bacterial mortality. These are in addition to the mechanisms reported earlier such as the photochemical reactions occurring inside the cells upon exposure to low power laser. SIGNIFICANCE AND IMPACT OF THE STUDY: These results help us to understand the mechanisms of bacterial mortality on exposure to low power pulsed laser irradiation and are useful in formulating a laser treatment strategy to kill bacteria.

Cell Wall↗

PubMed2001

Single oral dose of geranylgeranylacetone induces heat-shock protein 72 and renders protection against ischemia/reperfusion injury in rat heart.

BACKGROUND: Induction of heat-shock proteins (HSPs) results in cardioprotection against ischemic insult. Geranylgeranylacetone (GGA), known as an antiulcer agent, reportedly induces HSP72 in the gastric mucosa and small intestine of rats. The present study tested the hypothesis that oral GGA would induce HSP72 in the heart and thus render cardioprotection against ischemia/reperfusion injury in rats. METHODS AND RESULTS: Cardiac expression of HSPs was quantitatively evaluated in rats by Western blot analysis. Ten minutes of whole-body hyperthermia induced HSP72 expression in the rat hearts. A single oral dose of GGA (200 mg/kg) also induced expression of HSP72, which peaked at 24 hours after administration. Therefore, isolated perfused heart experiments using a Langendorff apparatus were performed 24 hours after administration of 200 mg/kg GGA (GGA group) or vehicle (control group). After a 5-minute stabilization period, no-flow global ischemia was given for 20, 40, or 60 minutes, followed by 30 minutes of reperfusion. During reperfusion, the functional recovery was greater and the released creatine kinase was less in the GGA group than in the control group. Electron microscopy findings revealed that the ischemia/reperfusion-induced damage of myocardial cells was prevented in GGA-treated myocytes. CONCLUSIONS: The results suggest that oral GGA is cardioprotective against ischemic insult through its induction of HSP72.

Administration, Oral↗

PubMed2001

Single cell analysis of CAG repeat in brains of dentatorubral-pallidoluysian atrophy (DRPLA).

Somatic mosaicism of an expanded repeat is present in tissues of patients with triplet repeat diseases. Of the spinocerebellar ataxias associated with triplet repeat expansion, the most prominent heterogeneity of the expanded repeat is seen in dentatorubral-pallidoluysian atrophy (DRPLA). The common feature of this somatic mosaicism is the difference in the repeat numbers found in the cerebellum as compared to other tissues. The expanded allele in the cerebellum shows a smaller degree of expansion. We previously showed by microdissection analysis that the expanded allele in the granular layer in DRPLA cerebellum has less expansion than expanded alleles in the molecular layer and white matter. Whether this feature of lesser expansion in granule cells is common to other types of neurons is yet to be clarified. We used a newly developed excimer laser microdissection system to analyze somatic mosaicism in the brains of two patients, one with early- and another with late-onset DRPLA, and used single cell PCR to observe the cell-to-cell differences in repeat numbers. In the late onset patient, repeat expansion was more prominent in Purkinje cells than in granule cells, but less than that in the glial cells. In the early onset patient, repeat expansion in Purkinje cells was greater than in granule cells but did not differ from that in glial cells. These findings suggest that there is a difference in repeat expansion among neuronal subgroups and that the number of cell division cycles is not the only determinant of somatic mosaicism.

DNA Mutational Analysis↗

PubMed2001

Effect of essential hypertension on cardiac autonomic function in type 2 diabetic patients.

OBJECTIVES: The aim of this study was to examine the effects of essential hypertension on cardiac autonomic function in type 2 diabetic patients. BACKGROUND: Hypertension is common in type 2 diabetic patients and is associated with a high mortality. However, the combined effects of type 2 diabetes and essential hypertension on cardiac autonomic function have not been fully elucidated. METHODS: Thirty-three patients with type 2 diabetes were assigned to a hypertensive diabetic group (n = 15; age: 56 +/- 8 years, mean +/- SD) or an age-matched normotensive diabetic group (n = 18, 56 +/- 6 years). Cardiac autonomic function was assessed by baroreflex sensitivity (BRS), heart rate variability (HRV), plasma norepinephrine concentration and cardiac 123I-metaiodobenzylguanidine (MIBG) scintigraphic findings. RESULTS: Baroreflex sensitivity was lower in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.05). The early and delayed myocardial uptake of 123I-MIBG was lower (p < 0.01 and p < 0.05, respectively), and the percent washout rate of 123I-MIBG was higher (p < 0.05) in the hypertensive diabetic group. However, the high frequency (HF) power and the ratio of low frequency (LF) power to HF power (LF/HF) of HRV and plasma norepinephrine concentration were not significantly different. The homeostasis model assessment index was higher in the hypertensive diabetic group than it was in the normotensive diabetic group (p < 0.01). CONCLUSIONS: Our results indicate that essential hypertension acts synergistically with type 2 diabetes to depress cardiac reflex vagal and sympathetic function, and the results also suggest that insulin resistance may play a pathogenic role in these processes.

3-Iodobenzylguanidine↗

PubMed2001

Development of a new method for assessing the cardiac baroreflex: response to downward tilting in patients with diabetes mellitus.

OBJECTIVE: To investigate the clinical value of a new non-invasive method for assessing baroreflex sensitivity using downward tilting. PATIENTS: 34 patients with diabetes mellitus, mean (SD) age, 53.6 (11.8) years. DESIGN: Arterial blood pressure and ECG were recorded simultaneously while the patients were on a tilt table. After 20 minutes at a 70 degrees upright tilt, the patients were returned to the supine position at a speed of 3.2 degrees /s (downward tilting baroreflex sensitivity test, DT-BRS). A beat to beat systolic blood pressure increase associated with a corresponding lengthening of the RR interval was noted during downward tilting. Baroreflex sensitivity was also assessed using the conventional method of an intravenous injection of phenylephrine (Phe-BRS). Heart rate variability was analysed during rest and tilting. RESULTS: The slope of the regression line for systolic blood pressure v RR interval during downward tilting was highly correlated with Phe-BRS (r = 0.83, p < 0.0001). Both DT-BRS and Phe-BRS were correlated with the high frequency (HF) component of resting heart rate variability (p < 0.005) and with the ratio of the low frequency to the high frequency component (LF/HF) during upright tilting (p < 0.005). DT-BRS and Phe-BRS were also correlated with the difference between rest and tilting values of HF and LF/HF (p < 0.005). CONCLUSIONS: DT-BRS provides a physiological, non-invasive method for determining baroreflex sensitivity and may be a useful index of reflex cardiac vagal and sympathetic function in patients with diabetes mellitus.

Adult↗

PubMed2000

Malignant neurocardiogenic vasovagal syncope associated with chronic exaggerated vagal tone.

A head-up tilt test was performed in a 23-year-old woman with a history of two syncopal episodes. The patient developed abrupt syncope with 48 seconds of sinus arrest. Analysis of the high frequency (HF) power of heart rate variability over 24 hours before and after metoprolol therapy showed a significantly elevated HF power in this patient compared to age- and sex-matched healthy subjects. It is suggested that an exaggerated resting vagal tone might be associated with the pathogenesis of prolonged asystole in our patient.

Adult↗

PubMed2000

Suppression of cesium-induced ventricular tachyarrhythmias by atrial natriuretic peptide in rabbits.

BACKGROUND: Intravenous injection of cesium chloride (Cs) causes ventricular tachyarrhythmias in rabbits. We investigated whether these tachyarrhythmias were caused by increased pressure load and whether they could be suppressed by atrial natriuretic peptide (ANP). METHODS AND RESULTS: Cs was injected in a bolus dose (1.5 mmol/kg), which was repeated 20 minutes later. Rabbits were then divided into 3 groups: control, ANP-treated, and hydralazine-treated groups. ANP or hydralazine was administered between the first and second Cs injections. The experiments were performed during intrinsic sinus rhythm (protocol A) or during ventricular pacing (protocol B). In protocol A, the second injection of Cs in the control group induced early afterdepolarizations and ventricular tachycardia, which were preceded by a marked increase in left ventricular end-diastolic pressure (LVEDP). Both ANP and hydralazine significantly suppressed Cs-induced increase in LVEDP. The arrhythmia score after the second injection of Cs was significantly lower in the ANP-treated and hydralazine-treated group compared with the control group (P < .005 and P < .05, respectively). In protocol B, the duration of left ventricular monophasic action potential and early afterdepolarization amplitude before and/or after the injections of Cs did not differ significantly between control and ANP-treated groups. CONCLUSIONS: Our results suggest that increased pressure load may play a role in the arrhythmogenic effect of Cs. The protective effect of ANP against Cs-induced ventricular tachycardia may be explained in part by a reduction in pressure overload. However, this effect might also be explained by the diverse action of ANP on the cardiovascular system.

Action Potentials↗

PubMed2000

Radiofrequency catheter ablation from the left sinus of Valsalva in a patient with idiopathic ventricular tachycardia.

We report the case of a 54-year-old woman with idiopathic VT originating in the left ventricular outflow tract. She initially presented with palpitations and light-headedness. The morphology of the PVCs exhibited an inferior axis and tall R waves were noted in all the precordial leads. Spontaneous PVCs were transiently terminated by an intravenous injection of adenosine triphosphate. Radiofrequency catheter ablation from the left sinus of Valsalva successfully abolished the PVCs and the VT.

Catheter Ablation↗

PubMed2000

Preceding stimulus frequency-dependent potentiation of the postrest shortening of the action potential duration in rabbits.

Action potential duration (APD) in rabbit ventricular myocardium shortens after a rest period (postrest shortening). However, the effects of preceding stimulus frequency on the postrest shortening have not been elucidated. We recorded transmembrane action potentials (TAPs) and monophasic action potentials (MAPs) from the rabbit ventricle. In in vitro experiments. repetitive regular stimuli (S1) at cycle lengths ranging between 500 to 3000 ms were followed by a single extrastimulus (S2) at a coupling interval of 5000 ms. A decrease in S1S1 interval resulted in a progressive shortening of the duration of TAP (TAPD) elicited by S2 (S2-TAPD), which was potentiated by increasing extracellular calcium concentration ([Ca2+]o) or application of ouabain and was inhibited by lowering [Ca2+]o or verapamil. Application of ryanodine was most effective in lengthening S2-TAPD following a short S1S1 interval. 4-aminopyridine and E4031 caused marked lengthening of S2-TAPD when S1S1 was long. However, the lengthening effect was attenuated and disappeared with a shorter S1S1 interval. In in vivo experiments, regular ventricular pacing (S1) at cycle lengths ranging between 250 to 1000 ms was followed by a single extrastimulus (S2) with a coupling interval (S1S2) of 1500 ms. A decrease in the S1S1 interval also resulted in progressive shortening of the duration of MAP elicited by S2. Our results indicate that the postrest shortening is potentiated by an increase in the preceding stimulus frequency in the rabbit ventricle, in which the function of sarcoplasmic reticulum may play a significant role.

Action Potentials↗

PubMed1999

H2-blocker modulates heart rate variability.

The use of H2-blockers in the treatment of patients with peptic ulcer has become popular. However, this treatment has adverse cardiovascular effects. The aim of this study was to investigate proarrhythmic rhythm and autonomic nervous activity by analyzing heart rate variability in patients treated with omeprazole, ranitidine, and plaunotol. Nineteen patients (mean age 67.5 +/- 2.7 years) with active gastric ulcer were treated with omeprazole (20 mg/day) for 8 weeks, then ranitidine (300 mg/day) for the next 4 months, and finally plaunotol (240 mg/day). At each stage of the treatment, Holter electrocardiography was performed, and heart rate variability and arrhythmias analyzed. Heart rate variability yielded power in the low- (0.04-0.15 Hz) and high-frequency components (0.15-0.4 Hz). Although both ranitidine and omeprazole induced little change in cardiac rhythm, the high-frequency power was higher (10.3 +/- 0.8 vs 8.6 +/- 0.6 ms, P < 0.05) and the ratio of low-to-high frequency power was lower (1.41 +/-0.10 vs 1.59 +/- 0.09. P < 0.05) during ranitidine than during plaunotol treatment. Cosinor analysis of heart rate variability revealed a decreased amplitude of low-frequency power during omeprazole compared with during ranitidine and plaunotol treatment. Ranitidine modulated high-frequency power which may be related to the adverse cardiovascular effects of H2-blocker.

Aged↗

PubMed1999

Noninvasive assessment of the cardiac baroreflex: response to downward tilting and comparison with the phenylephrine method.

OBJECTIVES: We studied the relation between changes in systolic blood pressure and RR interval during downward tilting in comparison with assessment of baroreflex sensitivity (BRS) measured by the phenylephrine method (Phe-BRS) and with measures of heart rate variability (HRV). BACKGROUND: The method most extensively used for assessing BRS involves bolus injections of phenylephrine. Several noninvasive methods proposed to assess BRS have not been widely applied in the clinical setting. METHODS: Sixteen healthy male volunteers were studied (mean age +/- SD 27.5+/-4.6 years). Arterial blood pressure using tonometry and electrocardiogram was simultaneously recorded. After 20 min of 70 degrees upright tilting, the table was returned to supine position at a speed of 3.2 degrees/s. Subsequently, BRS was assessed using an intravenous bolus injection of phenylephrine (2 to 3 microg/kg). Heart rate variability under resting conditions also was analyzed. RESULTS: In all subjects, a beat to beat systolic blood pressure increase associated with corresponding RR interval lengthening was observed during downward tilting as well as during phenylephrine administration. During both testing procedures, these two variables showed linear correlation, and the slope of regression line during downward tilting (DT-BRS) correlated significantly with Phe-BRS (r = 0.79, p = 0.0003). The DT- and Phe-BRS also correlated significantly with the high frequency component of resting HRV (r = 0.70, p = 0.0023 for DT-BRS; r = 0.58, p = 0.0185 for Phe-BRS). CONCLUSIONS: We conclude that in a small homogeneous group DT-BRS provided an assessment of reflex cardiac vagal function comparable to that obtained by the phenylephrine method.

Adult↗

PubMed1999

Beneficial effects of long-term treatment with enalapril on cardiac function and heart rate variability in patients with old myocardial infarction.

BACKGROUND: The beneficial effects of the early use of angiotensin-converting enzyme inhibitors (ACEis) in patients with acute myocardial infarction (MI) are well documented. However, the effects of ACEis in patients with an old MI and preserved cardiac function have not yet been studied. We examined the effects of 12 months of enalapril treatment in patients with previous MI. METHODS AND RESULTS: Thirteen patients with an old MI and no overt congestive heart failure (CHF), aged 70 +/- 2 years, were treated with enalapril for 12 months. We also included 13 age- and sex-matched control patients who had a similar clinical background but were not treated with enalapril. Holter electrocardiography and echocardiography were performed at entry and after 12 months of treatment. Heart rate variability, low- and high-frequency powers (LF and HF), and the ratio between LF and HF (LF/HF) were analyzed. Changes from baseline to 12 months in HF, LF/HF, left ventricular end-diastolic dimension (LVEDD), and end-systolic dimension (LVESD) were significantly different in the enalapril group (HF, 8.1 +/- 0.9 to 9.3 +/- 0.9 milliseconds: LF/HF, 1.65 +/- 0.11 to 1.53 +/- 0.16; LVEDD, 57.2 +/- 1.6 to 54.7 +/- 1.6 mm; LVESD, 40.0 +/- 2.4 to 36.3 +/- 1.9 mm) compared with the control group (HF, 8.9 +/- 0.9 to 8.5 +/- 0.7 milliseconds; LF/HF, 1.78 +/- 0.18 to 1.88 +/- 0.15; LVEDD, 52.3 +/- 2.5 to 55.9 +/- 2.2 mm; LVESD, 32.5 +/- 2.6 to 36.1 +/- 2.6 mm; P < .05). The delta change (delta) in LVESD between the end and the start of study correlated inversely with deltaHF (r = -0.56; P < .05) and positively with deltaLF/HF (r = 0.65; P < .01). CONCLUSION: Our results suggest possible ongoing structural changes in patients with old MI even in the absence of overt CHF. Enalapril seemed to prevent such changes and to restore cardiac autonomic tone toward normal. Further prospective studies using a larger sample size are warranted to confirm potential beneficial effects of ACEis in patients with previous MI and preserved left ventricular function.

Aged↗

PubMed1999

Evaluation of autonomic influences on QT dispersion using the head-up tilt test in healthy subjects.

Our objective was to examine the autonomic influence on QT interval dispersion using the head-up tilt test in healthy subjects. RR and QT intervals, heart rate variability, and plasma norepinephrine concentration were measured in the supine position and tilting to 70 degrees for 20 minutes using a footboard support in 15 healthy male volunteers (mean age +/- SD: 28.0 +/- 4.5 years). The rate-corrected QT interval (QTc) was calculated using Bazett's formula, and QT and QTc dispersions were defined as the maximum minus minimum values for the QT and QTc, respectively, from the 12-lead ECG. Spectral analysis of the heart rate variability generated values for the low- and high-frequency powers (LF and HF) and their ratio (LF/HF). Compared with values obtained in the supine position, tilting significantly increased QT (P < 0.05) and QTc dispersion (P < 0.01), the LF/HF ratio (P < 0.0001), and plasma norepinephrine concentration (P < 0.0001), and significantly decreased HF (P < 0.0001). QTc dispersion was positively correlated with the LF/HF ratio and plasma norepinephrine concentration, and negatively correlated with HF. These results suggest that head-up tilt testing increases QT dispersion by increasing sympathetic tone and/or decreasing vagal tone in healthy subjects.

Adult↗

PubMed1998

Change in heart rate variability preceding ST elevation in a patient with vasospastic angina pectoris.

A case of vasospastic angina (VSA) in a 62-year-old man with frequent ST elevation throughout the day was reported. His coronary angiogram showed that intracoronary methylergometrine had induced total occlusion due to a vasospasm. Analysis by Holter monitoring suggested that the autonomic nervous system would contribute differently to the initiation of the coronary spasm depending on whether the VSA attacks occurred during the daytime or at night. During the nighttime, the high-frequency power (HF: 0.15-0.4 Hz) decreased during the 2 min before ST elevation, and the heart rate increased immediately before ST elevation. The low-frequency power (LF: 0.04-0.15 Hz) and the ratio of LF to HF (LF/HF) did not significantly change before ST elevation. In contrast, each of the heart rate variability components and the heart rate did not significantly change before ST elevation during the daytime. Thus, the pathophysiology of VSA during the daytime and nighttime seems to be different in its relation to autonomic tone. During the nighttime, vagal withdrawal may be a component of the mechanisms leading to VSA, while during the daytime, a change in autonomic tone may not play a major role in this case.

Angina Pectoris↗

PubMed1998

Role of circadian rhythmicity in the heart rate variability preceding non-sustained ventricular tachycardia.

The difference in sympathovagal activity preceding non-sustained ventricular tachycardia (NSVT) was examined between patients with and without a circadian rhythm. Thirty-three patients' Holter monitoring data (41 NSVT episodes) were analyzed regarding the frequency domain measures (low-frequency component [LF: 0.04-0.15 Hz], high-frequency component [HF: 0.15-0.4 Hz], and the ratio of LF to HF [LF/HF]) for each 15-min average from 120 min before each episode of NSVT. The presence of a circadian rhythm was accepted when the rhythm adaptation was significant by cosinor analysis and the acrophase was located at night (22.00-06.00h) in HF (HF-positive group, n=17), and during the daytime (10.00-20.00h) in LF/HF (LF/HF-positive group, n=12). The negative groups were identified by the absence of a circadian rhythm (HF-negative group, n=16; LF/HF-negative group, n=21). The serial changes in the HF power before NSVT were significantly different between the HF-positive and -negative groups (p<0.05). The HF increased from 75-60 min before NSVT in the HF-positive group, whereas the HF decreased from 60-45 min in the HF-negative group. The serial changes in the LF/HF ratio were not significantly different between the LF/HF-positive and -negative groups. Thus, the circadian rhythmicity of vagal activity seems to have an important role in the genesis of NSVT.

Aged↗

PubMed1997

Prediction of in vivo drug metabolism in the human liver from in vitro metabolism data.

As a new approach to predicting in vivo drug metabolism in humans, scaling of in vivo metabolic clearance from in vitro data obtained using human liver microsomes or hepatocytes is described in this review, based on the large number of literature data. Successful predictions were obtained for verapamil, loxtidine (lavoltidine), diazepam, lidocaine, phenacetin and some other compounds where CLint,in vitro is comparable with CLint,in vivo. On the other hand, for some metabolic reactions, differences in CLint,in vitro and CLint,in vivo greater than 5-fold were observed. The following factors are considered to be the cause of the differences: (1) metabolism in tissues other than liver, (2) incorrect assumption of rapid equilibrium of drugs between blood and hepatocytes, (3) presence of active transport through the sinusoidal membrane, and (4) interindividual variability. Furthermore, the possibility of predicting in vivo drug metabolic clearance from results obtained using a recombinant system of human P450 isozyme was described for a model compound, YM796, where the predicted metabolic clearances obtained from the recombinant system, taking account of the content of the P450 isozyme CYP3A4 in the human microsomes, were comparable with the observed clearances using human liver microsomes containing different amounts of CYP3A4. Even in the case where the first-pass metabolism exhibits nonlinearity, it appears to be possible to predict in vivo metabolic clearance from in vitro metabolic data.

Biological Transport, Active↗

PubMed1997

Quantitative brain microdialysis study on the mechanism of quinolones distribution in the central nervous system.

Brain interstitial fluid (ISF) concentrations, which regulate the toxicodynamic effect of quinolone antimicrobial agents (quinolones) in the central nervous system, have been determined for norfloxacin, ofloxacin, fleroxacin, and pefloxacin using a quantitative brain microdialysis technique. Steady-state brain ISF concentrations of the quinolones were 7-30 times lower than the unbound serum concentrations due to restricted distribution in the brain. Cerebrospinal fluid concentrations of the quinolones were approximately twice as high as the brain ISF concentrations, except for norfloxacin. Thus, it seems that an active efflux transport system across the blood-brain barrier is responsible for maintaining brain ISF concentrations lower than unbound serum concentrations at steady-state. A good correlation was observed for norfloxacin, ofloxacin, fleroxacin, and pefloxacin between brain ISF concentrations and total brain concentrations. Moreover, a relatively small difference was observed among the quinolones for the in vitro brain slice-to-medium concentration ratio, compared with an 11-fold difference in the in vivo brain-to-unbound serum concentration ratio after intravenous infusion. These results indicate that the different quinolones studied all exhibit similar apparent binding and/or uptake by brain parenchyma, with an average brain ISF-to-total brain concentration ratio of 0.688.

4-Quinolones↗

PubMed1997

Distributed model analysis of 3'-azido-3'-deoxythymidine and 2',3'-dideoxyinosine distribution in brain tissue and cerebrospinal fluid.

The restricted distribution of 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxyinosine (DDI) in brain tissue and cerebrospinal fluid (CSF) has been analyzed using the distributed model. The distribution volume of AZT and DDI in brain tissue (V(br)) was found to be 1.07 +/- 0.09 and 0.727 +/- 0.030 ml/g brain, respectively, in an in vitro brain slice uptake study. The pharmacokinetic parameters were obtained by fitting the concentration-time profiles of AZT and DDI in brain tissue and CSF after i.v. or i.c.v. administration taking the value of V(br), the CSF bulk flow rate (2.9 microl/min), and the surface area of the cerebroventricular ependyma (2.0 cm2), using a nonlinear least squares program combined with a fast inverse Laplace transform. The efflux transport clearance (PS(BBB,eff)) across the blood-brain barrier (BBB) and the symmetrical permeability clearance (PS(BBB)) across the BBB for AZT were calculated as 179 and 10.3 microl/min/g brain, respectively. The efflux transport clearance (PS(CSF,eff)) across the blood-cerebrospinal fluid barrier (BCSFB) and the symmetrical permeability clearance (PS(CSF)) across the BCSFB for AZT were calculated as 227 and 28.3 microl/min/ml CSF, respectively. For the distribution of DDI, the PS(BBB,eff) and PS(BBB) were 79.2 and 2.03 microl/min/g brain, respectively, while the PS(CSF,eff) and PS(CSF) for DDI were 196 and 5.88 microl/min/ml CSF, respectively. Based on simulation studies using the fitted parameters, a significant degree of efflux transport across the BBB and BCSFB has been suggested to be responsible for the restricted distribution of AZT and DDI in brain tissue and CSF, respectively.

Animals↗