Associations of Alcohol Consumption with Cerebrospinal Fluid Biomarkers of Alzheimer's Disease Pathology in Cognitively Intact Older Adults: The CABLE Study.

BACKGROUND: The relationship between alcohol consumption and Alzheimer's disease (AD) pathology is unclear. Amyloid-ß (Aß) and tau biomarkers in cerebrospinal fluid (CSF) have been proven valuable in establishing prognosis in pre-clinical AD. OBJECTIVE: We sought to examine the associations between alcohol consumption and CSF AD biomarkers in cognitive intact subjects. METHODS: A total of 806 cognitively intact participants who had measurements of CSF Aß, pTau, and total Tau proteins and drinking characteristics were included from the Chinese Alzheimer's Biomarker and Lifestyle (CABLE) study. Linear and logistic regression analyses were utilized to explore the associations of alcohol consumption with CSF AD biomarkers. We examined the interaction effects of age, gender, and apolipoprotein epsilon (APOE) ɛ4 status on the relationships between the frequency of drinking and CSF biomarkers. RESULTS: The multiple linear regression analyses revealed significant differences in CSF AD biomarkers between infrequent drinking (< 1 times/week) and frequent drinking groups (≥1 times/week). Participants in frequent drinking group had higher CSF p-tau/Aß42 and tTau/Aß42. Frequent drinking was significantly associated with greater pTau and tTau abnormalities compared to the infrequent drinking group in older (> 65 years) participants. CONCLUSION: The present study showed significant associations between drinking frequency and CSF AD biomarkers in cognitively intact older adults. Alcohol consumption may have an influence on AD by modulating amyloid deposition and tau phosphorylation in the preclinical stage.

Changes in clinical trials of cancer drugs in mainland China over the decade 2009-18: a systematic review.

As a result of recent, substantial capacity building, a new landscape for cancer drug trials is emerging in China. However, data on the characteristics of cancer drug trials, and how they have changed over time, are scarce. Based on clinical trials published on the China Food and Drug Administration Registration and Information Disclosure Platform for Drug Clinical Studies, we aimed to systematically review changes over time in clinical trials of cancer drugs in mainland China from 2009 to 2018, to provide insight on the effectiveness of the pharmaceutical industry and identify unmet clinical needs of stakeholders. A total of 1493 trials of 751 newly tested cancer drugs were initiated. Increases over time were observed for the annual number of initiated trials, newly tested drugs, and newly added leading clinical trial units, with a sharp increase after 2016. Of the 1385 trials in which cancer types were identified, solid tumours (325 [23%] trials), non-small-cell lung cancer (232 [17%]), and lymphoma (126 [9%]) were the most common. A markedly uneven distribution was also observed in the geography of leading units with the largest number of leading units located in east China (50 [41%]) and the smallest number located in southwest China (4 [3%]). The growth trends we observed illustrate the progress in and increasing capability of cancer drug research and development achieved in mainland China over the decade from 2009. The low number of clinical trials on tumours with epidemiological characteristics unique to the Chinese population and the unbalanced geographical distribution of leading clinical trial units will provide potential targets for policy makers and other stakeholders. Further research efforts should address cancers uniquely relevant to Chinese populations, globally rare cancers, and the balance between equitable drug access, efficiency, and sustainability of cancer drug research and development in mainland China.

Effect of probenecid on pharmacokinetics and tolerability of olmesartan in healthy chinese volunteers.

BACKGROUND: Olmesartan is an angiotensin II receptor antagonist and is effective and well tolerated in the treatment of arterial hypertension. Probenecid is a well-established hypouricemic agent for the treatment of hyperuricemia and gout. OBJECTIVE: The goal of this study was to examine the impact of coadministration of probenecid on the pharmacokinetic parameters and tolerability of olmesartan in healthy volunteers. METHODS: In a randomized, open-label, 2-way crossover study, 12 volunteers received 2 oral treatments (olmesartan alone or olmesartan plus probenecid) separated by 4 days. Blood samples were obtained for a 48-hour pharmacokinetic evaluation after drug administration. Tolerability was assessed by monitoring vital signs and laboratory tests before and after administration of the study drug. RESULTS: Pharmacokinetic parameters were evaluated in 6 male and 6 female healthy volunteers (mean age, 22 [range, 20-25] years]; weight, 56.0 [range, 51.0-60.0] kg). Probenecid coadministration increased olmesartan Css-av, AUC0→∞, and AUC0-48 by 40%, 50%, and 50%, respectively (P = 0.018, 0.000, 0.000, respectively), but there was no statistical significance for Tmax, t1/2, Css-max, and Css-min between olmesartan plus probenecid and olmesartan alone (P = 0.697, 0.053, 0.521, and 0.734, respectively). No serious adverse event (AE) was reported during the study. The proportion of volunteers with AEs in the olmesartan plus probenecid period (5 of 12 [42%]) was higher than that in the olmesartan-alone period (1 of 12 [8%]). All of the AEs during the olmesartan plus probenecid period were abnormal routine urine test results. The AE in olmesartan-alone period was dizziness. All AEs were classified as mild and considered to be at least possibly related to treatment. All volunteers recovered from the AEs by 2 weeks after the end of the study. CONCLUSIONS: Probenecid increases the exposure speed of olmesartan by increasing the AUC0-48, AUC0→∞, and Css-av. The combined treatment of olmesartan medoxomil with probenecid may increase the occurrence of genitourinary side effects. ClinicalTrials.gov identifier: NCT01907373.

[Clinical observation of isolated congenital anosmia].

OBJECTIVE: To introduce 8 patients with isolated congenital anosmia and to discuss the clinical manifestations, imaging characteristics and family characteristics of this rarely seen disorder. METHODS: Eight patients with isolated congenital anosmia treated between April 2007 and April 2012 were reviewed retrospectively. There were 4 males and 4 females. A detailed medical history collection, physical examination, nasal endoscopy, T&T and Sniffin'Sticks subjective olfactory function tests, olfactory event-related potentials sinonasal computed tomography scan and sex hormones level monitoring were performed in all patients. Seven cases underwent magnetic resonance image of olfactory pathway examination. RESULTS: All patients were anosmia without evidence of other defects. ENT physical examination, nasal endoscopy and computed tomography scan were normal except 4 cases with obvious nasal septum deviation, 2 cases with concha bullosa. Subjective olfactory test indicated all of them were anosmia. Olfactory event-related potentials were obtained in only 1 patient. Magnetic resonance imaging revealed the smaller or atrophy olfactory bulb and olfactory tract in five cases, the absence of olfactory bulbs and tracts in two case. A female patient did not have MRI examination because of wearing IUDs. Detection of 8 patients of sex hormones were normal. Family characteristics: 3 patients showed family inheritance pattern. CONCLUSIONS: The diagnosis of isolated congenital anosmia should be based on chief complaint, medical history, physical examination, olfactory test, nasal endoscopy, olfactory testing, olfactory imaging and olfactory event-related potentials. Magnetic resonance image of olfactory pathway and olfactory event-related potentials have important value for the diagnosis. More attention should be paid to the genetic susceptibility of the family.

[Functional magnetic resonance imaging of brain activation in early period after olfactory adaptation].

OBJECTIVE: To explore the brain activation before and in early period after olfactory adaptation using functional magnetic resonance imaging, and discuss the mechanisms of olfactory adaptation. METHODS: Ten right-handed, normosmic subjects underwent 2 times of olfactory stimulation tasks with the interval of 20 minutes. The odorant used was isovaleric acid. The fMRI data was processed by the SPM5 software. Rating odor intensity and valence using visual analogue scale (VAS), and the results of 2 tasks were statistically analyzed. RESULTS: There was no significant difference between 2 tasks on both intensity and hedonicity scores. In task 1, the brain activation in bilateral cerebellum, frontal (including orbitofrontal gyrus), insula, thalamus, cingulate gyrus, putamen, amygdala, piriform cortex, the left inferior parietal lobule, precentral gyrus, right hippocampus, pallidum, middle temporal gyrus, supramarginal gyrus. In task 2, only the right middle frontal gyrus activated, and the voxels decreased significantly. Paired t-test results showed that: (task1-task2) activated regions in left precentral gyrus, frontal lobe (including the orbitofrontal gyrus), insula, right superior temporal gyrus, cerebellum; (task2-task1) activation in the left inferior parietal lobule and right lingual gyrus. CONCLUSIONS: The sensitivity of brain activation is still at a low level, when subjects had recovered from adaptation in subjective olfactory perception. Underwent repeated olfactory stimulation, second olfactory cortex plays less role on olfactory perception and advanced processing.

The relative bioavailability and fasting pharmacokinetics of three formulations of olmesartan medoxomil 20-mg capsules and tablets in healthy Chinese male volunteers: An open-label, randomized-sequence, single-dose, three-way crossover study.

BACKGROUND: Olmesartan medoxomil is an angiotensin II-receptor antagonist used in the treatment of hypertension. It is a prodrug and is converted to the pharmacologically active compound on de-esterification by arylesterase in the gastrointestinal tract. OBJECTIVE: This study investigated the relative bioavailability and fasting pharmacokinetic properties of olmesartan after single doses of a 20-mg test tablet, a 20-mg test capsule, and a commercially available 20-mg reference tablet in healthy Chinese male volunteers. The study was conducted to satisfy Chinese State Food and Drug Administration regulatory requirements for approval of a generic formulation of olmesartan medoxomil. METHODS: This study had an open-label, randomized-sequence, single-dose, 3-treatment, 3-period crossover design. Healthy volunteers were randomly assigned in a 1:1:1 ratio to receive a single 20-mg dose of the test tablet, test capsule, or reference tablet, each administered after a 12-hour overnight fast, followed by a 1-week washout period and administration of the alternate formulation. Blood samples were obtained at baseline and at 0.5, 1, 1.5,2,2.5,3,4,6,8,12,24,36, and 48 hours after dosing. Tolerability was assessed based on vital signs and laboratory values obtained before and after administration of study drug. The formulations were assumed to be bioequivalent if the 90% CIs for the log-transformed ratios of C(max), AUC(0-t), and AUC(0-∞) were within the predetermined equivalence range (70%-143% for C(max); 80%-125% for AUC(0-t) and AUC(0-∞)), as established by the Chinese State Food and Drug Administration. RESULTS: Twenty-one healthy male subjects (mean age, 21 years [range, 18-25 years]; weight, 62.1 kg [range, 54.0-80.0 kg]) were enrolled in and completed the study. No period or sequence effect was observed. The mean AUC(0-∞) values for the test tablet, test capsule, and reference tablet were 3993 (1070), 3567 (850), and 3849 (872) ng/mL/h, respectively. The 90% CIs for the log-transformed ratios of test tablet to reference tablet for C(max), AUC(0-48), and AUC(0-∞) were 103.9 to 124.9, 94.0 to 111.5, and 94.4 to 111.7, respectively (all, P = NS). The corresponding 90% CIs for the log-transformed ratios of test capsule to reference tablet were 90.8 to 109.2, 84.9 to 107.9, and 85.1 to 100.7 (all, P = NS). Ten adverse events were reported during the study; 7 subjects complained of pain during blood sampling, and 3 had a blocked venous catheter. No treatment-related adverse events were reported or observed. CONCLUSIONS: In this single-dose crossover study in healthy Chinese male volunteers, the test and reference formulations of olmesartan medoxomil 20-mg capsules and tablets met the regulatory criteria for assuming bioequivalence. The 3 formulations were well tolerated.

Effect of the novel antipsychotic drug perospirone on P-glycoprotein function and expression in Caco-2 cells.

OBJECTIVE: Perospirone (PER) is a novel atypical antipsychotic drug for the treatment of schizophrenia and other psychotic disorders. The multidrug resistance transporter, P-glycoprotein (Pgp), is involved in the efflux transport of several antipsychotics across the blood-brain barrier (BBB). The aim of the present study was to evaluate the modulating effect of PER on both Pgp activity and expression in Caco-2 cell monolayers. METHODS: The effects of PER were analyzed by means of rhodamine 123 (Rhd 123) assays, and those of Pgp expression were analyzed by flow cytometry and reverse transcriptase-PCR. RESULTS: Perospirone at concentrations of 0.01-30 microM, which were found to be non-cytotoxic towards the Caco-2 cells, was observed to inhibit Pgp-mediated efflux transport of Rhd 123 in the cells as well as to down-regulate the cellular Pgp protein and MDR1 mRNA levels in a concentration-dependent manner. In the rhodamine accumulation assays, 30 microM PER produced a 429% increase of the cellular Rhd 123 concentration, which exceeded the inhibitory effect of the well-known Pgp inhibitor verapamil. CONCLUSION: Our findings provide experimental evidence that PER is an inhibitor of Pgp which interferes directly and indirectly with the function of Pgp.

Ultra-performance liquid chromatography-tandem mass spectrometry for the determination of atypical antipsychotics and some metabolites in in vitro samples.

The ultra-performance liquid chromatography-electrospray tandem mass spectrometry (UPLC-ESI-MS/MS) method has been developed to perform the determination of quetiapine, perospirone, aripiprazole and quetiapine sulfoxide in in vitro samples in less than 3 min. The UPLC separation was carried out using an Acquity UPLC BEH C18 column (100 mm x 2.1mm i.d., 1.7 microm particle size) that provided high efficiency and resolution in combination with high linear velocities. The UPLC system was coupled to a Waters Micromass Quattro Premier XE tandem quadrupole mass spectrometer. This system permits high-speed data acquisition without peak intensity degradation, and produces sharp and narrow chromatographic peaks (w(h) about 2.5s) of compounds. The determination was performed in multiple reaction monitoring (MRM) mode. The quantification parameters of the developed method were established, obtaining instrumental LODs lower than 0.005 microg/l and a repeatability at a low concentration level lower than 10% CV (n=10). Finally, the method was successfully applied to the analysis of atypical antipsychotics and some metabolites in in vitro samples.

Effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia.

OBJECTIVE: To study the effect of erythromycin on metabolism of quetiapine in Chinese suffering from schizophrenia. METHODS: Nineteen patients received multiple doses of quetiapine (200 mg, twice daily) with or without co-administered erythromycin (500 mg, three times daily). Blood samples were collected at specified time intervals for determination of plasma concentrations of quetiapine and some of its metabolites. RESULTS: With erythromycin co-administration: for quetiapine, maximal plasma concentration (Cmax), area under concentration-time curve of 0-infinity h (AUC0-infinity) and terminal-phase elimination half-life time (t1/2) increased 68, 129 and 92%, respectively, and clearance (CL) and terminal elimination rate constant (Ke) decreased 52% and 55%, respectively; for quetiapine sulfoxide (QTP-SF), Cmax, AUC0-infinity and AUC ratio decreased 64, 23, and 70%, respectively, and t1/2 increased 211%; for 7-hydroxy-quetiapine (QTP-H), Ke and AUC ratio decreased 61% and 45%, respectively, and t1/2 increased 203%; for 7-hydroxy-N-desalkyl-quetiapine (QTP-ND), Cmax, AUC0-infinity and AUC ratio decreased 36, 40 and 71%, respectively. CONCLUSION: Erythromycin has a noticeable effect on the metabolism of quetiapine. When quetiapine is co-administered with CYP3A inhibitors such as erythromycin, the dosing regimen should be modified according to quetiapine TDM.

Multiple dose pharmacokinetics of quetiapine and some of its metabolites in Chinese suffering from schizophrenia.

AIM: To study the multiple dose pharmacokinetics of quetiapine and its sulfoxide-, 7-hydroxy-, 7-hydroxy-N-dealkyl-metabolites in Chinese suffering from schizophrenia. METHODS: Twenty-one patients (11 females and 10 males) were given quetiapine twice daily to control the symptoms. After the dose reached 200 mg twice daily, blood were sampled to study the pharmacokinetics. The plasma concentrations of quetiapine and its metabolites were assayed by HPLC-MS. RESULTS: The main pharmacokinetic parameters of quetiapine, 7-hydroxy-N-dealkyl-quetiapine, quetiapine sulfoxide, and 7-hydroxy-quetiapine were as follows: tmax were 2.0 (0.3-5.0), 4.0 (1.5-6.0), 3.0 (0.5-5.0), and 3.0 (0.5-5.0) h respectively; t1/2 were (7+/-3), (9.4+/-2.7), (7+/-3), and (8+/-5) h, respectively; Cmax(SS) were (678+/-325), (19+/-5), (451+/-216), and (58+/-22) microg/L, respectively; Cmin(SS) were (51+/-68), (3.3+/-1.6), (35+/-36), and (5+/-4) microg/L, respectively; Cav(SS) were (295+/-144), (13+/-4), (209+/-71), and (28+/-9) micro/L, respectively; AUC(0-12)(SS) were (3,538+/-1 728), (153+/-44), (2,512+/-854), and (335+/-104) microg.h.L(-1), respectively; AUC(0-infinite)(SS) were (5,534+/-4 198), (287+/-107), (3,858+/-2 012), and (529+/-262) microg.h.L(-1), respectively; Ke were (0.11+/-0.03), (0.079+/-0.019), (0.11+/-0.03), and (0.103+/-0.028) h(-1), respectively; CL/F and V/F of quetiapine were (67+/-25) L.h(-1) and (672+/-394) L, respectively. The plasma concentrations for the four compounds reached a steady state within 48 h at the dose of 200 mg initiation. These parameters were not statistically different between genders. CONCLUSIONS: Quetiapine was absorbed quickly, distributed widely, and metabolized mainly to be quetiapine sulfoxide. The elimination speeds of quetiapine and its three metabolites were similar. Gender had no effect on the pharmacokinetics of quetiapine and its metabolites. The clinical dosage regime caused no drug accumulation.

Simultaneous determination of quetiapine and three metabolites in human plasma by high-performance liquid chromatography-electrospray ionization mass spectrometry.

AIM: To develop a high performance liquid chromatography-electrospray mass spectrometry (HPLC-MS/ESI) method for simultaneous determination of quetiapine and its sulfoxide-, 7-hydroxy-, 7-hydroxy-N-dealkyl-metabolites in human plasma. METHODS: The HPLC separation of the compounds was performed on a Kromasil C18, (5 microm, 4.6 mm.150 mm) column, using water (formic acid: 1.70 mmol/L, ammonium acetate: 5.8 mmol/L)-acetonitrile (65:35) as mobile phase, with a flow-rate of 0.95 mL/min. The compounds were ionized in the electrospray ionization (ESI) ion source of the mass spectrometer and detected in the selected ion recording (SIR) mode. The samples were extracted using solid-phase extraction columns. RESULTS: The calibration curves were linear in the ranges of 10-2000 microg/L for quetiapine, 1-200 microg/L for its metabolites, respectively. The average extraction recoveries for all the four samples were above 85 %. The methodology recoveries were much higher than 95 %. The intra-day and inter-day RSD are less than 15 %. CONCLUSION: The method is accurate, sensitive, and simple for study of pharmacokinetics and metabolic mechanism of quetiapine in patients at therapeutic dose.