Cardiogenic Shock Prior to Percutaneous Coronary Intervention in ST-Elevation Myocardial Infarction: Outcomes and Predictors of Mortality (ANZACS-QI 73).

BACKGROUND & AIMS: Cardiogenic shock (CS) is a serious complication of acute myocardial infarction (MI) and is associated with significant mortality. We describe a contemporary, real-world cohort of patients with ST-elevation MI (STEMI) and CS, including 30-day mortality and clinically relevant predictors of mortality. METHODS: All patients presenting with STEMI who were treated with percutaneous coronary intervention (PCI) in New Zealand (2016 to 2020) were identified from the Aotearoa New Zealand All Cardiology Services Quality Improvement (ANZACS-QI) registry and stratified based on their Killip class on arrival to the cardiac catheterisation laboratory. Primary outcome was 30-day all-cause mortality. Multivariable analysis was used to identify predictors of mortality prior to PCI and to develop a mortality scoring system. RESULTS: In total, 6,649 patients were identified, including 192 (2.9%) Killip IV (CS) patients. Thirty-day mortality was 47.5% in patients with CS, 14.6% in those with heart failure without shock, and 3% in those without heart failure. Independent predictors of 30-day mortality for patients with CS were: estimated glomerular filtration rate <60 mL/min/1.73m2 (relative risk [RR] 1.89, 95% confidence interval [CI] 1.39-2.58), cardiac arrest (RR 1.54, 95% CI 1.15-2.06), diabetes (RR 1.31, 95% CI 1.01-1.70), female sex (RR 1.32, 95% CI 1.01-1.72), femoral arterial access (RR 1.42, 95% CI 1.06-1.90) and left main stem culprit (RR 2.16, 95% CI 1.65-2.84). A multivariable Shock score was developed which predicts 30-day mortality with good global discrimination (area under the curve 0.79, 95% CI 0.73-0.85). CONCLUSION: In this national cohort, the 30-day mortality for STEMI patients presenting with CS treated with PCI remains high, at nearly 50%. The ANZACS-QI Shock score is a promising tool for mortality risk stratification prior to PCI but requires further validation.

Spyglass: a framework for reproducible and shareable neuroscience research.

Scientific progress depends on reliable and reproducible results. Progress can also be accelerated when data are shared and re-analyzed to address new questions. Current approaches to storing and analyzing neural data typically involve bespoke formats and software that make replication, as well as the subsequent reuse of data, difficult if not impossible. To address these challenges, we created Spyglass, an open-source software framework that enables reproducible analyses and sharing of data and both intermediate and final results within and across labs. Spyglass uses the Neurodata Without Borders (NWB) standard and includes pipelines for several core analyses in neuroscience, including spectral filtering, spike sorting, pose tracking, and neural decoding. It can be easily extended to apply both existing and newly developed pipelines to datasets from multiple sources. We demonstrate these features in the context of a cross-laboratory replication by applying advanced state space decoding algorithms to publicly available data. New users can try out Spyglass on a Jupyter Hub hosted by HHMI and 2i2c: https://spyglass.hhmi.2i2c.cloud/.

Regional specialization manifests in the reliability of neural population codes.

The brain has the remarkable ability to learn and guide the performance of complex tasks. Decades of lesion studies suggest that different brain regions perform specialized functions in support of complex behaviors1-3. Yet recent large-scale studies of neural activity reveal similar patterns of activity and encoding distributed widely throughout the brain4-6. How these distributed patterns of activity and encoding are compatible with regional specialization of brain function remains unclear. Two frontal brain regions, the dorsal medial prefrontal cortex (dmPFC) and orbitofrontal cortex (OFC), are a paradigm of this conundrum. In the setting complex behaviors, the dmPFC is necessary for choosing optimal actions2,7,8, whereas the OFC is necessary for waiting for3,9 and learning from2,7,9-12 the outcomes of those actions. Yet both dmPFC and OFC encode both choice- and outcome-related quantities13-20. Here we show that while ensembles of neurons in the dmPFC and OFC of rats encode similar elements of a cognitive task with similar patterns of activity, the two regions differ in when that coding is consistent across trials ("reliable"). In line with the known critical functions of each region, dmPFC activity is more reliable when animals are making choices and less reliable preceding outcomes, whereas OFC activity shows the opposite pattern. Our findings identify the dynamic reliability of neural population codes as a mechanism whereby different brain regions may support distinct cognitive functions despite exhibiting similar patterns of activity and encoding similar quantities.

Hospitalisation during lockdown-patients' beds-eye views.

AIMS: The global COVID-19 pandemic and lockdowns have affected the patterns of hospital presentations for non-COVID related illnesses. Apprehension and perceived risk of hospitalisation has been postulated to be a significant deterrent to presentation. This study aims to explore pandemic- and- lockdown-related concerns with regards to hospital admission from a patient's perspective. METHODS: A cross-sectional study was undertaken in the form of an inpatient questionnaire for patients admitted to a coronary care unit and the cardiology ward during the Level 4 lockdown. The questionnaire included six questions designed to gather patient perception of the impact of lockdown on their hospital presentation. RESULTS: Out of 91 patients who completed the questionnaire, 41 (45%) were >70 years old. Twenty (22%) patients answered that lockdown delayed or affected their decision to present to hospital. Within this cohort, there was a statistical difference between those aged 70 years and younger, and those over 70 years old (16/50 (32%) versus 4/41 (10%), p=0.011). CONCLUSIONS: Apprehension and concerns regarding the risk of COVID-19 was prevalent in a significant proportion of patients and affected/delayed their decision to present to hospital. This may partly explain lower rates of presentation during the pandemic.

Electrode pooling can boost the yield of extracellular recordings with switchable silicon probes.

State-of-the-art silicon probes for electrical recording from neurons have thousands of recording sites. However, due to volume limitations there are typically many fewer wires carrying signals off the probe, which restricts the number of channels that can be recorded simultaneously. To overcome this fundamental constraint, we propose a method called electrode pooling that uses a single wire to serve many recording sites through a set of controllable switches. Here we present the framework behind this method and an experimental strategy to support it. We then demonstrate its feasibility by implementing electrode pooling on the Neuropixels 1.0 electrode array and characterizing its effect on signal and noise. Finally we use simulations to explore the conditions under which electrode pooling saves wires without compromising the content of the recordings. We make recommendations on the design of future devices to take advantage of this strategy.

Very Elderly Patients With Acute Coronary Syndromes Treated With Percutaneous Coronary Intervention.

BACKGROUND: The rates of very elderly patients (≥85 years old) undergoing percutaneous coronary intervention (PCI) for acute coronary syndromes (ACS) are rapidly increasing. They are under-represented in clinical trials, and those who are included may not reflect the real-world population. We aim to review the clinical characteristics of very elderly patients undergoing PCI for ACS and identify factors associated with adverse outcomes. METHOD: All very elderly patients undergoing PCI for ACS in the Auckland region between January 2014 to December 2016 were included. Baseline clinical and procedural details were obtained, and the primary endpoint was all-cause mortality measured up to a maximum of 4 years. Secondary endpoints include recurrent myocardial infarction, unplanned revascularisation, stroke and major bleeding. RESULTS: A total of 186 patients were included for analysis (mean age 87.6±2.8 years, 51.6% male). Indications for PCI were ST-elevation myocardial infarction (STEMI) in 74 (39.8%), non-ST elevation myocardial infarction (NSTEMI) in 97 (52.2%) and unstable angina in 15 patients (8.1%). Successful PCI was completed in 180 patients. At a maximal follow-up of 4 years (mean 23.4 mo), the rates of all-cause mortality and recurrent myocardial infarction were 22.0% and 14.0% respectively. The risk of mortality was increased by the presence of diabetes (44.8% vs 17.8%, HR=3.0, 95%CI: 1.6-5.9, p=0.001), STEMI (33.8% vs 13.5%, HR=3.1, 95%CI: 1.6-5.9, p=0.001), and reduced eGFR (every -10 mL/min/1.73m2, HR=1.7, 95%CI: 1.3-2.1, p<0.0001). Major bleeding events while on dual antiplatelet therapy as defined by Bleeding Academic Research Consortium score ≥3 occurred in 14 patients (7.5%; 8 on ticagrelor, 6 on clopidogrel). CONCLUSION: Very elderly patients who undergo PCI for ACS have acceptable survival outcomes. STEMI, diabetes and impaired renal function were predictive of mortality in this elderly cohort.

The sifting of visual information in the superior colliculus.

Much of the early visual system is devoted to sifting the visual scene for the few bits of behaviorally relevant information. In the visual cortex of mammals, a hierarchical system of brain areas leads eventually to the selective encoding of important features, like faces and objects. Here, we report that a similar process occurs in the other major visual pathway, the superior colliculus. We investigate the visual response properties of collicular neurons in the awake mouse with large-scale electrophysiology. Compared to the superficial collicular layers, neuronal responses in the deeper layers become more selective for behaviorally relevant stimuli; more invariant to location of stimuli in the visual field; and more suppressed by repeated occurrence of a stimulus in the same location. The memory of familiar stimuli persists in complete absence of the visual cortex. Models of these neural computations lead to specific predictions for neural circuitry in the superior colliculus.

Cu oxidation kinetics through graphene and its effect on the electrical properties of graphene.

The oxidation kinetics of Cu through graphene were evaluated from the surface coverage of Cu oxide (F ox) by varying the oxidation time (t ox = 10-360 min) and temperature (T ox = 180-240 °C) under an air environment. F ox, as a function of time, well followed the Johnson-Mehl-Avrami-Kolmogorov equation; thus, the activation energy of Cu oxidation was estimated as 1.5 eV. Transmission electron microscopy studies revealed that Cu2O formed on the top of the graphene at grain boundaries (G-GBs), indicating that Cu2O growth was governed by the out-diffusion of Cu through G-GBs. Further, the effect of Cu oxidation on graphene quality was investigated by measuring the electrical properties of graphene after transferring. The variation of the sheet resistance (R s) as a function of t ox at all T ox was converted into one curve as a function of F ox. R s of 250 Ω sq-1 was constant, similar to that of as-grown graphene up to F ox = 15%, and then increased with F ox. The Hall measurement revealed that the carrier concentration remained constant in the entire range of F ox, and R s was solely related to the decrease in the Hall mobility. The variation in Hall mobility was examined according to the graphene percolation probability model, simulating electrical conduction on G-GBs during Cu2O evolution. This model well explains the constant Hall mobility within F ox = 15% and drastic F ox degradation of 15-50% by the concept that the electrical conduction of graphene is disconnected by Cu2O formation along with the G-GBs. Therefore, we systematically developed the oxidation kinetics of Cu through graphene and simultaneously examined the changes in the electrical properties of graphene.

Quantification of Etodolac in Human Plasma for Pharmacokinetics and Bioequivalence Studies in 27 Korean Subjects.

OBJECTIVE: We developed a simple and validated liquid chromatography tandem mass spectrometry( LC-MS/MS) for quantification of etodolac using pioglitazone as an internal standard (IS) to assess pharmacokinetics and to appraise bioequivalence of two formulations of etodolac (reference and tested) in 27 healthy Korean subjects. METHODS: Isocratic mobile phase consisted of 10 mM ammonium formate and acetonitrile were used to separate the analytes on a Gemini C18 column. Also, analytes were analyzed by MS/MS in multiple reaction monitoring (MRM) mode using the transitions of (M+H)+ ions, m/z 288.2→ 172.3 and m/z 357.1→ 134.2 for quantification of etodolac and IS each. The standard calibration curves displayed significant linearity within the range of 0.2-30.0 µ g/mL (r2=0.9956, 1/x2 weighting) with LLOQ of 0.1 µg/mL. RESULTS: The retention times of etodolac and the IS were 0.77 min and 0.57 min each, indicating the high-throughput potential of the proposed method. The pharmacokinetic parameters were calculated from the plasma samples and data form the reference and test drugs were represented as follows; Area under plasma concentration-time curve (AUCt) (78.03 vs. 84.00 µgxh/mL), AUC∞ (86.67 vs. 93.92 µgxh/mL), maximal plasma concentration (Cmax) (19.49 vs. 18.94 µg/mL), time for maximal concentrations (Tmax) (2.13 vs. 2.26 h), Plasma elimination half-life (T1/2) (8.12 vs. 8.47 h), elimination rate constant (λz) (0.0853 vs. 0.0818 h-1). Pharmacokinetic parameters with 90% confidence interval fall within the bioequivalence range of 80-125%. CONCLUSION: Thus, the new testified method was successfully applied for the pharmacokinetic and bioequivalence studies for two etodolac formulations.

Characterization of the mechanism of the NADH-dependent polysulfide reductase (Npsr) from Shewanella loihica PV-4: formation of a productive NADH-enzyme complex and its role in the general mechanism of NADH and FAD-dependent enzymes.

The NADH-dependent polysulfide reductase (Npsr) from Shewanella loihica PV-4 is a member of the single cysteine-containing subset of the family of disulfide reductases represented by glutathione reductase. We have determined the kinetics of the reductive half-reaction of the enzyme with NADH using stopped-flow spectroscopy and kinetic isotope effects, and these results indicate that the reductive and oxidative half-reactions are both partially rate-limiting for enzyme turnover. During reaction with NADH, the reduced nucleotide appears to bind rapidly in an unproductive conformation, followed by the formation of a productive E·NADH complex and subsequent electron transfer to FAD. F161 of Npsr fills the space in which the nicotinamide ring of NADH would be expected to bind. We have shown that while this residue is not absolutely required for catalysis, it does assist in the forward commitment to catalysis through its role in the reductive half reaction, where it appears to enhance hydride transfer in the productive E·NADH complex. While the fluorescence and absorbance spectra of the stable redox forms of the wild-type and F161A mutant enzymes are similar, intermediates formed during reduction and turnover have different characteristics and appear to indicate that the enzyme-NADH complex formed just prior to hydride transfer on the F161A enzyme has weaker FAD-NADH interactions than the wild-type enzyme, consistent with a "looser" enzyme-NADH complex. The 2.7Å crystal structure of the F161A mutant was determined, and shows that the nicotinamide ring of NADH would have the expected freedom of motion in the more open NADH binding cavity.

Characterization of an NADH-dependent persulfide reductase from Shewanella loihica PV-4: implications for the mechanism of sulfur respiration via FAD-dependent enzymes.

The NADH-dependent persulfide reductase (Npsr), a recently discovered member of the PNDOR family of flavoproteins that contains both the canonical flavoprotein reductase domain and a rhodanese domain, is proposed to be involved in the dissimilatory reduction of S(0) for Shewanella loihica PV-4. We have previously shown that polysulfide is a substrate for this enzyme, and a recently determined structure of a closely related enzyme (CoADR-Rhod from Bacillus anthracis) suggested the importance of a bound coenzyme A in the mechanism. The work described here shows that the in vivo oxidizing substrates of Npsr are the persulfides of small thiols such as CoA and glutathione. C43S, C531S, and C43,531S mutants were created to determine the role of the flavoprotein domain cysteine (C43) and the rhodanese domain cysteine (C531) in the mechanism. The absolute requirement for C43 in persulfide or DTNB reductase activity shows that this residue is involved in S-S bond breakage. C531 contributes to, but is not required for, catalysis of DTNB reduction, while it is absolutely required for reduction of any persulfide substrates. Titrations of the enzyme with NADH, dithionite, titanium(III), or TCEP demonstrate the presence of a mixed-disulfide between C43 and a tightly bound CoA, and structures of the C43 and C43,531S mutants confirm that this coenzyme A remains tightly bound to the enzyme in the absence of a C43-CoA S-S bond. The structure of Npsr suggests a likely site for binding and reaction with the persulfide substrate on the rhodanese domain. On the basis of kinetic, titration, and structural data, a mechanism for the reduction of persulfides by Npsr is proposed.

Drug synergism of antihypertensive action in combination of telmisartan with lercanidipine in spontaneous hypertensive rats.

To examine drug synergism between angiotensin II AT1-receptor blocker and Ca(2+) channel blocker for lowering blood pressure (BP), telmisartan and lercanidipine were orally injected into to telemetered-spontaneous hypertensive rats and BP was monitored. The highest doses of both drugs (7.66 mg/kg of telmisartan and 1.92 mg/kg of lercanidipine) were clinically relevant at 80 and 20 mg human equivalent doses, respectively, and denoted as dose 1. After constructing the dose-response curve using 0 (vehicle-treated control), 1/16, 1/8, 1/4, 1/2 and 1 doses, all possible combinations of both drugs were tested. Drug synergism in combination therapy of telmisartan with lercanidipine was assessed by calculating the interaction index (γ) as evaluated by γ < 1. We found statistically significant drug synergism in the investigated (telmisartan: lercandipine) combinations of (1/8:1/4), (1/4:1) and (1/8:1). Our results suggest that the combination therapy of telmisartan and lercanidipine at lower doses are effective in lowering BP, and also reduce side effects caused by maximal doses of each drug. Therefore, drug combination of AT1-receptor blocker with Ca(2+) channel blocker is a clinically important tool for the management of hypertension and hypertension-related cardiovascular risks.

Adenosine amine congener mitigates noise-induced cochlear injury.

Hearing loss from noise exposure is a leading occupational disease, with up to 5% of the population at risk world-wide. Here, we present a novel purine-based pharmacological intervention that can ameliorate noise-induced cochlear injury. Wistar rats were exposed to narrow-band noise (8-12 kHz, 110 dB SPL, 2-24 h) to induce cochlear damage and permanent hearing loss. The selective adenosine A(1) receptor agonist, adenosine amine congener (ADAC), was administered intraperitoneally (100 microg/kg/day) at time intervals after noise exposure. Hearing thresholds were assessed using auditory brainstem responses and the hair cell loss was evaluated by quantitative histology. Free radical damage in the organ of Corti was assessed using nitrotyrosine immunohistochemistry. The treatment with ADAC after noise exposure led to a significantly greater recovery of hearing thresholds compared with controls. These results were upheld by increased survival of sensory hair cells and reduced nitrotyrosine immunoreactivity in ADAC-treated cochlea. We propose that ADAC could be a valuable treatment for noise-induced cochlear injury in instances of both acute and extended noise exposures.

Effect of electrokinetic stabilizers on the physicochemical properties of propofol emulsions.

The aims of the present study were to elucidate the potential mechanism of propofol emulsion destabilization following the addition of lidocaine, and to evaluate the effects of various electrokinetic stabilizers on the physicochemical properties of lidocaine-propofol emulsions. The assessments included pH observations and determination of the maximum globule diameter (MGD) and zeta potential (ZP). The MGD of propofol emulsions increased up to several tens mum following the addition of 50 mg of lidocaine to 200mg of propofol, and the proposed destabilization mechanism involves localization of protonated lidocaine molecules between lecithin molecules in propofol emulsions, which consequently leads to increased ZP. The ZP of propofol emulsions containing acidic amino acid or neutral amino acid increased following the addition of lidocaine, and a charge reversal occurred. Therefore, the MGD of emulsions increased to several tens (m. However, the MGD of emulsions that contained basic amino acids or basic compounds remained below 5 (m, despite the addition of large amounts lidocaine (50 mg), and the ZP did not pass through the point of zero charge. In conclusion, our results provide not only further insight into the physical stability of propofol emulsions containing lidocaine, but also a better understanding of the administration of propofol in existing applications.

High performance liquid chromatographic analysis of rabeprazole in human plasma and its pharmacokinetic application.

A simple and sensitive HPLC method for the analysis of rabeprazole in plasma is described using UV detection in the presence of lorazepam as the internal standard. Rabeprazole and lorazepam were extracted with ethyl ether and quantitated using a reverse-phase C(18) column. The method was specific as there were no interfering peaks in the human plasma eluting at the retention times of rabeprazole and lorazepam. The method was fully validated in human plasma for the concentration range of 20.0-1000.0 ng/ml. The correlation coefficients were greater than 0.999. Extraction recoveries were 72.3% for the drug and 79.1% for the internal standard. The method was simple, reliable, and accurate for the quantitation of rabeprazole in human plasma. The same plasma samples, which were collected in healthy male volunteers administered a 20 mg tablet of Pariet, were analyzed by HPLC and LC/MS/MS. As a result of that, there was no significant difference between pharmacokinetic parameters. The suitability of HPLC method for pharmacokinetic studies was verified by determining the relevant pharmacokinetic parameters.

Application of instrumental evaluation of color for the pre-formulation and formulation of rabeprazole.

The aims of this study were to fast screen the compatibility of rabeprazole and excipients using a spectrocolorimeter and to examine the relationship between the color change value and drug contents/drug degradation products in solid dosage forms. The color change values of rabeprazole-excipient mixtures were measured using a spectrocolorimeter, with six tablet formulations compressed using a single-punch instrumental tablet press. The rabeprazole and degradation products contents in the tablets were analyzed using an HPLC method, with the color change values of the tablets measured using spectrocolorimetery for 4 weeks. These experiments indicated that the instrumental evaluation of color was a speedy, simple and useful tool in the determination of the interaction between the drug and excipients, as well as in the formulation of solid dosage forms. The relationships of the % reduced drug contents versus the color change value, and those of the % drug degradation products versus the color change value were exponentially increased in formulations containing zinc stearate. On stress testing, the color change value of rabeprazole was inconsistent with previous reports, as the degradation of rabeprazole can be greatly influenced by humidity as well as temperature. Consequently, these results highlight the potential of color formation in the application of pre-formulation and formulation of drugs.

CRE-mediated transcription and COX-2 expression in the pilocarpine model of status epilepticus.

Status epilepticus (SE) triggers neuronal death, reactive gliosis and remodeling of synaptic circuitry, thus leading to profound pathological alterations in CNS physiology. These processes are, in part, regulated by the rapid upregulation of both cytotoxic and cytoprotective genes. One pathway that may couple SE to transcriptionally dependent alterations in CNS physiology is the CREB (cAMP response element-binding protein)/CRE (cAMP response element) cascade. Here, we utilized the pilocarpine model of SE on a mouse strain transgenic for a CRE-reporter construct (beta-galactosidase) to begin to characterize how seizure activity regulates the activation state of the CREB/CRE pathway in both glia and neurons of the hippocampus. SE triggered a rapid (4-8 h post-SE) but transient increase in CRE-mediated gene expression in the neuronal sublayers. In contrast to neurons, SE induced a lasting increase (up to 20 days) in CRE-mediated transcription in both reactive astrocytes and microglia. CRE-mediated gene expression correlated with expression of the pro-inflammatory enzyme cyclooxygenase-2 (COX-2). To examine the role of CREB in SE-induced COX-2 expression, we generated a transgenic mouse strain that expresses A-CREB, a potent repressor of CREB-dependent transcription. In these animals, the capacity of SE to stimulate COX-2 expression was markedly attenuated, indicating that CREB is a key intermediate in SE-induced COX-2 expression. Collectively these data show that SE triggers two waves of CREB-mediated gene expression, a transient wave in neurons and a long-lasting wave in reactive glial cells, and that CREB couples SE to COX-2 expression.

The effect of lidocaine on the globule size distribution of propofol emulsions.

In this study, we sought to determine the globule size distribution of a propofol/lidocaine mixture as a function of lidocaine concentration and time elapsed after mixing in a standard formulation of propofol emulsion (Diprivan) and in a new formulation containing L-lysine to improve stability. The globule size was measured with a laser diffraction technique. The median diameter of the globule size in 20 mL of Diprivan immediately after the addition of 0, 10, 20, 30, 40, and 50 mg of lidocaine was similar to that of chylomicrons, ranging from 0.28 +/- 0.01 micro m to 0.30 +/- 0.02 micro m, over the whole range of lidocaine concentration. However, the maximum diameter increased slightly (from 0.97 +/- 0.01 micro m to 2.90 +/- 0.07 micro m) as the concentration of lidocaine increased. At 6 h after adding lidocaine, the maximum globule size had increased slightly (to 2.98 +/- 0.04 micro m) with 20 mg of lidocaine and increased considerably (to 51.76 +/- 0.62 micro m) when 30 mg of lidocaine was added. At 2 h after the addition of 50 mg of lidocaine, the maximum globule diameter had increased to 52.2 +/- 1.92 micro m. The maximum globule diameter in the propofol emulsion to which L-lysine was added as a stabilizer did not exceed 3.0 micro m even when the largest amount of lidocaine was added. This study demonstrated that when 30 mg of lidocaine was added to 20 mL of Diprivan and the solution was left for a period of time, the globule size increased. Its increase was minimized by the addition of L-lysine to the propofol emulsion.

Interspecies comparison of the oral absorption of itraconazole in laboratory animals.

The oral absorption and disposition of itraconazole were studied in rats, rabbits and dogs. Serum levels of itraconazole and its active metabolite, hydroxyitraconazole, were determined by a validated HPLC method. The absorption of itraconazole was relatively rapid in rats and dogs but was slower in rabbits. The terminal elimination half-life (T 1/2lambda(z)), time to the peak concentration (Tmax), dose and weight normalized area under the curve (AUC) and the peak concentration (Cmax) of itraconazole found in the dog were comparable to those reported in humans. As in humans, the metabolite to parent drug AUC ratios in rats and dogs were greater than unity but was less in rabbits. The dog appears to be an appropriate animal model while the rat, not the rabbit, may be used as an alternative animal model in predicting the oral absorption of itraconazole in humans.