Positron emission tomography with [18F]flutemetamol and [11C]PiB for in vivo detection of cerebral cortical amyloid in normal pressure hydrocephalus patients.

BACKGROUND AND PURPOSE: This study determined the correlation between uptake of the amyloid positron emission tomography (PET) imaging agent [(18) F]flutemetamol and amyloid-ß measured by immunohistochemical and histochemical staining in a frontal cortical biopsy. METHODS: Fifteen patients with possible normal pressure hydrocephalus (NPH) and previous brain biopsy obtained during intracranial pressure monitoring underwent [18F]flutemetamol PET. Seven of these patients also underwent [11C] Pittsburgh compound B (PiB) PET. [18F]Flutemetamol and [11C]PiB uptake was quantified using standardized uptake value ratio (SUVR) with the cerebellar cortex as a reference region. Tissue amyloid-ß was evaluated using the monoclonal antibody 4G8, Thioflavin-S and Bielschowsky silver stain. RESULTS: [18F]Flutemetamol and [11C]PiB SUVRs correlated with biopsy specimen amyloid-ß levels contralateral (r = 0.86, P < 0.0001; r = 0.96, P = 0.0008) and ipsilateral (r = 0.82, P = 0.0002; r = 0.87, P = 0.01) to the biopsy site. Association between cortical composite [(18) F]flutemetamol SUVRs and [11C]PiB SUVRs was highly significant (r = 0.97, P = 0.0003). CONCLUSIONS: [18F]Flutemetamol detects brain amyloid-ß in vivo with moderate to high sensitivity and high specificity. This agent, therefore, represents a valuable new tool to study and verify the presence of amyloid-ß pathology, both in patients with possible NPH and among the wider population.

Night-time bioavailability of levodopa/carbidopa/entacapone is higher compared to controlled-release levodopa/carbidopa.

OBJECTIVE: Controlled-release levodopa/carbidopa (CR-LC) is often used to provide prolonged control of night-time motor symptoms in patients with Parkinson's disease (PD). Levodopa/carbidopa/entacapone (LCE) provides higher bioavailability of levodopa compared with levodopa/carbidopa formulations and has been shown to be effective in PD patients with wearing-off symptoms. The aim of this study was to compare the bioavailability of levodopa after a single evening dose (administered at 10 p.m.) of LCE 200 or CR-LC 200. METHODS: This was an open-label, randomized, crossover study in healthy subjects. The main pharmacokinetic (PK) parameters were AUC, Cmax, C6h and t1/2 of levodopa. RESULTS: A single evening dose of LCE 200 was associated with significantly better bioavailability compared with CR-LC 200. In line with increased bioavailability of levodopa, LCE 200 induced more nausea. CONCLUSIONS: The results of this study demonstrate that a single bedtime dose of LCE 200 provides higher bioavailability of levodopa compared to CR-LC 200.

Early effects of 5-fluorouracil, epirubicin and cyclophosphamide therapy on common laboratory tests.

BACKGROUND: Combination chemotherapy with 5-fluorouracil, epirubicin and cyclophosphamide (FEC) is now used for adjuvant therapy of breast cancer. The effects of FEC on common laboratory tests are important when interpreting test results during the treatment. PATIENTS AND METHODS: Common hormonal tests (e.g., serum gonadotrophins, testosterone, prolactin, dehydroepiandrosterone sulphate, cortisol, parathyroid hormone (PTH), thyroid function tests), haematological blood counts and biochemical tests including specific proteins and lipids of seven women with metastatic breast cancer were assessed at baseline and before the 3rd and the 5th cycles: RESULTS: Statistically significant increases were noted in serum PTH, free triiodothyronine, sodium, prealbumin and cholesterol, but decreases in white blood cell count, alpha-1-antitrypsin, as well as immunoglobulins A and M. CONCLUSION: Except for serum PTH, cholesterol and WBC count, the changes were small. The diagnoses of diseases based on serum PTH and cholesterol test results may be influenced by FEC treatment.

Early effects of adjuvant tamoxifen therapy on serum hormones, proteins and lipids.

Tamoxifen is widely used as an adjuvant treatment for breast cancer. To correctly interpret laboratory test results during tamoxifen treatment, clinicians should be aware of the possible effects of the drug on laboratory tests. This study investigated the effects on serum hormones, proteins, lipids and common biochemistry in seven postmenopausal women with breast cancer during 3 months after initiating the therapy. Statistically significant decreases occurred in serum gonadotropins, alkaline phosphatase, calcium, total protein, prealbumin, orosomucoid, haptoglobin, immunoglobin M and total cholesterol whilst significant increases occurred in serum sex hormone-binding globulin (SHBG), cortisol, parathyroid hormone, aspartate aminotransferase, urate, alpha-1-antitrypsin and ceruloplasmin. The alterations could result from tamoxifen therapy, radiation or changes in lifestyle. All the changes, apart from serum urate, remained within the reference limits. In addition, only serum gonadotropins, SHBG, urate and cholesterol showed clinically significant changes. Alterations in the other laboratory tests are unlikely to disturb diagnoses based on laboratory test results during tamoxifen therapy.

Assessment of MAO-B occupancy in the brain with PET and [11C]-L-deprenyl-D2: a dose-finding study with a novel MAO-B inhibitor, EVT 301.

Inhibition of monoamine oxidase type B (MAO-B) activity in the brain is a putative strategy for the treatment of Alzheimer's disease (AD). We performed a dose-selection and validation study of a novel, reversible MAO-B inhibitor, EVT 301. Sixteen healthy volunteers received selegiline (10 mg) or EVT 301 (25, 75, or 150 mg) daily for 7-8 days, and four subjects with AD received 75 mg of EVT 301. MAO-B occupancy in the brain was assessed using positron emission tomography (PET) with [11C]-L-deprenyl-D2. EVT 301 was found to dose-dependently occupy MAO-B in the human brain, with occupancy ranging from 58-78% at a dose of 25 mg to 73-90% at a dose of 150 mg. The corresponding occupancy after selegiline was 77-92%. Determination of MAO-B inhibition in blood platelets underestimated the actual brain occupancy achieved with EVT 301. A daily EVT 301 dose of 75 or 150 mg appears suitable for clinical efficacy studies in patients with AD.

PET amyloid ligand [11C]PIB uptake is increased in mild cognitive impairment.

BACKGROUND: Patients with mild cognitive impairment (MCI) have increased risk to develop Alzheimer disease (AD). In AD increased brain amyloid burden has been demonstrated in vivo with PET using N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) as a tracer. OBJECTIVE: To investigate whether patients with amnestic MCI would show increased [(11)C]PIB uptake, indicating early AD process. METHODS: We studied 13 patients with amnestic MCI and 14 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating the region-to-cerebellum ratio in each voxel over 60 to 90 minutes. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. RESULTS: The SPM analysis showed that patients with MCI had significantly higher [(11)C]PIB uptake vs control subjects in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate showing the most prominent differences. These results were supported by the automated ROI analysis in which MCI patients showed in comparison with healthy control subjects increased [(11)C]PIB uptake in the frontal cortex (39% increase from the control mean, p < 0.01), the posterior cingulate (39%, p < 0.01), the parietal (31%, p < 0.01) and lateral temporal (28%, p < 0.001) cortices, putamen (17%, p < 0.05), and caudate (25%, p < 0.05). Individually, in the frontal cortex and posterior cingulate, 8 of 13 patients with MCI had [(11)C]PIB uptake values above 2 SD from the control mean. MCI subjects having at least one APOE epsilon4 allele tended to have higher [(11)C]PIB uptake than MCI subjects without APOE epsilon4. CONCLUSIONS: At group level the elevated N-methyl-[(11)C]2-(4'-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) uptake in patients with mild cognitive impairment (MCI) resembled that seen in Alzheimer disease (AD). At the individual level, about half of the MCI patients had [(11)C]PIB uptake in the AD range, suggestive of early AD process.

Voxel-based analysis of PET amyloid ligand [11C]PIB uptake in Alzheimer disease.

BACKGROUND: PET studies with N-methyl-[(11)C]2-(4':-methylaminophenyl)-6-hydroxybenzothiazole ([(11)C]PIB) have revealed an increased tracer uptake in several brain regions in Alzheimer disease (AD). OBJECTIVE: To employ voxel-based analysis method to identify brain regions with significant increases in [(11)C]PIB uptake in AD vs healthy control subjects, indicative of increased amyloid accumulation in these regions. METHODS: We studied 17 patients with AD and 11 control subjects with PET using [(11)C]PIB as tracer. Parametric images were computed by calculating a region-to-cerebellum ratio over 60 to 90 minutes in each voxel. Group differences in [(11)C]PIB uptake were analyzed with statistical parametric mapping (SPM) and automated region-of-interest (ROI) analysis. RESULTS: SPM showed increased uptake (p < 0.001) in the frontal, parietal, and lateral temporal cortices as well as in the posterior cingulate and the striatum. No significant differences in uptake were found in the primary sensory and motor cortices, primary visual cortex, thalamus, and medial temporal lobe. These results were supported by automated ROI analysis, with most prominent increases in AD subjects in the frontal cortex ([(11)C]PIB uptake 163% of the control mean) and posterior cingulate (146%) followed by the parietal (146%) and temporal (145%) cortices and striatum (133%), as well as small increases in the occipital cortex (117%) and thalamus (115%). CONCLUSIONS: Voxel-based analysis revealed widespread distribution of increased [(11)C]PIB uptake in Alzheimer disease (AD). These findings are in accordance with the distribution and phases of amyloid pathology in AD, previously documented in postmortem studies.

Alterations in laboratory test results during adjuvant breast cancer treatment.

An increasing number of women is treated with adjuvant cyclophosphamide, methotrexate and 5-fluorouracil therapy for breast cancer. The effects of the chemotherapy on many laboratory tests are, however, inadequately known. This study investigates the effects of the treatment on various laboratory tests. Fifteen premenopausal women receiving adjuvant cyclophosphamide, methotrexate and 5-fluorouracil chemotherapy and optional radiotherapy were included in the study. Common hormonal, biochemical, hematological, protein and lipid laboratory tests were taken serially during a 10-month follow-up. Twelve women became amenorrheic. Their serum follicle stimulating hormone and luteinising hormone concentrations increased accordingly. Other serum hormones (testosterone, androstenedione, sex hormone-binding globulin, prolactin, dehydroepiandrosterone sulfate, cortisol, parathyroid hormone and thyroid hormones) changed only slightly. Hemoglobin concentration and white blood cell count decreased slightly. Serum alanine aminotransferase, alkaline phosphatase, lactate dehydrogenase, creatine kinase, angiotensin-converting enzyme, amylase, glucose, potassium, phosphate, urea and triglycerides concentrations increased slightly whereas serum bilirubin, haptoglobin, and immunoglobulin A and M decreased slightly. Serum alpha1-antitrypsin fluctuated around the baseline concentration. Other test results remained at their pretreatment concentrations. With the exception of increases in serum gonadotrophins, the changes observed were slight and the mean concentrations remained within reference limits. Therefore, cyclophosphamide, methotrexate and 5-fluorouracil adjuvant treatment is unlikely to complicate the diagnosis of other diseases.

Reminders of drug effects on laboratory test results.

Drug effects on laboratory test results are difficult to take into account without an online decision support system. In this study, drug effects on hormone test results were coded using a drug-laboratory effect (DLE) code. The criteria that trigger the reminders were defined. To issue reminders, it was necessary to write a computer program linking the DLE knowledge base with databases containing individual patient medication and laboratory test results. During the first 10 months, 11% of the results from hormone samples were accompanied by one or more DLE reminders. The most common drugs to trigger reminders were glucocorticoids, furosemide, and metoclopramide. Physicians facing the reminders completed a questionnaire on the usefulness of the reminders. All respondents considered them useful. In addition, DLE reminders had caused 74% of respondents to refrain from additional, usually performed examinations. In conclusion, drug effects on laboratory tests should always be considered when interpreting laboratory results. An online reminder system is useful in displaying potential drug effects alongside test results.

Frequency and clinical outcome of potentially harmful drug metabolic interactions in patients hospitalized on internal and pulmonary medicine wards: focus on warfarin and cisapride.

Drug metabolic interactions present potential risks in patient care, but their frequency and relative importance as a clinical problem remains unclear. To assess the frequency and clinical outcome of potentially harmful drug metabolic interactions in hospitalized patients, the authors performed a survey of the medication data of patients treated on internal and pulmonary medicine wards in a university hospital. The database was searched for concomitantly administered drug pairs that would, according to Hansten and Horn's drug interaction database, carry a high risk for a clinically harmful metabolic drug interaction. Coadministrations involving warfarin or cisapride were subjected to further analysis regarding clinical outcome. A total of 142 patients were exposed to 150 interactions with potentially harmful clinical outcome, resulting in a frequency of 0.9% (95% CI 0.7% to 1.0%). Inhibition of warfarin metabolism by metronidazole produced significant overanticoagulation as evidenced by elevated international normalized ratio values, whereas inducers (rifampicin and phenobarbital) of warfarin metabolism significantly reduced the efficacy of warfarin. One case of minor bleeding and one case of clavicular vein thrombosis were detected as possible consequences of disturbed anticoagulation. The coadministration of cisapride and erythromycin significantly prolonged the corrected QT (QTc) interval and was associated with clinical symptoms of cardiac arrhythmias. Coadministration of cisapride with fluconazole or miconazole was not associated with prolongation of the QTc interval or cardiac sequelae. Evaluations of patient materials are needed to assess the clinical relevance of metabolic drug interactions.