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BACKGROUND: The cerebrospinal fluid (CSF) proteins beta-amyloid 42 (Abeta42) and Tau are believed to indirectly reflect some core pathological features of Alzheimer's disease (AD). Their topographic origin and their association with synaptic dysfunction are still not well understood. AIM: The present study aimed to explore possible associations between cerebral glucose metabolism and CSF Abeta42 as well as Tau protein levels in AD. METHODS: CSF analyses and (18)F-FDG PET scans were conducted on 32 patients with mild-to-moderate AD. Voxel-based statistical parametric correlations were computed for CSF protein levels and cerebral glucose metabolism. RESULTS: After correction for multiple comparisons, a strong positive association between CSF Abeta42 levels and glucose metabolism was identified for 2 extensive clusters located in the right temporal, prefrontal and anterior cingulate cortices. For CSF Tau protein, no association was observed for any brain region. CONCLUSIONS: These findings point to a significant association between synaptic dysfunction as measured with (18)F-FDG PET and CSF Abeta42 levels, but do not suggest a correlation between synaptic function and CSF Tau levels. [ABSTRACT FROM AUTHOR]

The antihypertensive effect of the orally active angiotensin-converting enzyme inhibitor captopril (SQ 14225) was assessed in 22 hypertensive patients of whom 17 were followed for periods ranging from 1 to 7 months. Of these, eight had essential hypertension, eight had renovascular hypertension, and six had hypertension associated with chronic renal failure. Blood pressure decreased markedly in all patients, including those with low renin levels. Nevertheless, the magnitude of blood pressure reduction correlated with the base-line plasma renin activity (r = 0.58, P less than 0.01). Increasing the dose of captopril from 25 to 200 mg did not enhance the amplitude of the antihypertensive effect but did increase its duration. Patients' blood pressure remained well controlled and free of side-effects with a maximal daily dose of up to 200 mg by mouth twice daily. Despite the blood pressure reduction, sodium excretion tended to increase, probably because of reduced aldosterone secretion. There was no evidence of orthostatic hypotension, and no escape from the antihypertensive effect was observed. These results indicate that chronic inhibition of the angiotensin-converting enzyme with an orally active compound offers a new, efficient, and well-tolerated approach to the treatment of hypertension. [ABSTRACT FROM AUTHOR]

Introduction: It is uncertain whether subjective cognitive decline (SCD) in individuals who seek medical help serves the identification of the initial symptomatic stage 2 of the Alzheimer's disease (AD) continuum., Methods: Cross-sectional and longitudinal data from the multicenter, memory clinic-based DELCODE study., Results: The SCD group showed slightly worse cognition as well as more subtle functional and behavioral symptoms than the control group (CO). SCD-A+ cases (39.3% of all SCD) showed greater hippocampal atrophy, lower cognitive and functional performance, and more behavioral symptoms than CO-A+. Amyloid concentration in the CSF had a greater effect on longitudinal cognitive decline in SCD than in the CO group., Discussion: Our data suggests that SCD serves the identification of stage 2 of the AD continuum and that stage 2, operationalized as SCD-A+, is associated with subtle, but extended impact of AD pathology in terms of neurodegeneration, symptoms and clinical progression., (© 2022 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Several Alzheimer's disease (AD) atrophy subtypes were identified, but their brain network properties are unclear. We analyzed data from two independent datasets, including 166 participants (103 AD/63 controls) from the DZNE-longitudinal cognitive impairment and dementia study and 151 participants (121 AD/30 controls) from the AD neuroimaging initiative cohorts, aiming to identify differences between AD atrophy subtypes in resting-state functional magnetic resonance imaging intra-network connectivity (INC) and global and nodal network properties. Using a data-driven clustering approach, we identified four AD atrophy subtypes with differences in functional connectivity, accompanied by clinical and biomarker alterations, including a medio-temporal-predominant (S-MT), a limbic-predominant (S-L), a diffuse (S-D), and a mild-atrophy (S-MA) subtype. S-MT and S-D showed INC reduction in the default mode, dorsal attention, visual and limbic network, and a pronounced reduction of "global efficiency" and decrease of the "clustering coefficient" in parietal and temporal lobes. Despite severe atrophy in limbic areas, the S-L exhibited only marginal global network but substantial nodal network failure. S-MA, in contrast, showed limited impairment in clinical and cognitive scores but pronounced global network failure. Our results contribute toward a better understanding of heterogeneity in AD with the detection of distinct differences in functional connectivity networks accompanied by CSF biomarker and cognitive differences in AD subtypes., (© The Author(s) 2021. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Frontotemporal dementia (FTD) is a clinically and genetically heterogeneous disorder. To which extent genetic aberrations dictate clinical presentation remains elusive. We investigated the spectrum of genetic causes and assessed the genotype-driven differences in biomarker profiles, disease severity and clinical manifestation by recruiting 509 FTD patients from different centers of the German FTLD consortium where individuals were clinically assessed including biomarker analysis. Exome sequencing as well as C9orf72 repeat analysis were performed in all patients. These genetic analyses resulted in a diagnostic yield of 18.1%. Pathogenic variants in C9orf72 (n = 47), GRN (n = 26), MAPT (n = 11), TBK1 (n = 5), FUS (n = 1), TARDBP (n = 1), and CTSF (n = 1) were identified across all clinical subtypes of FTD. TBK1-associated FTD was frequent accounting for 5.4% of solved cases. Detection of a homozygous missense variant verified CTSF as an FTD gene. ABCA7 was identified as a candidate gene for monogenic FTD. The distribution of APOE alleles did not differ significantly between FTD patients and the average population. Male sex was weakly associated with clinical manifestation of the behavioral variant of FTD. Age of onset was lowest in MAPT patients. Further, high CSF neurofilament light chain levels were found to be related to GRN-associated FTD. Our study provides large-scale retrospective clinico-genetic data such as on disease manifestation and progression of FTD. These data will be relevant for counseling patients and their families., (© 2021. The Author(s).)

Objective: To determine whether following a Mediterranean-like diet (MeDi) relates to cognitive functions and in vivo biomarkers for Alzheimer disease (AD), we analyzed cross-sectional data from the German DZNE-Longitudinal Cognitive Impairment and Dementia Study. METHOD: The sample (n=512, mean age: 69.5±5.9 years) included 169 cognitively normal participants and subjects at higher AD risk (53 with relatives with AD, 209 with subjective cognitive decline, and 81 with mild cognitive impairment). We defined MeDi adherence based on the Food Frequency Questionnaire. Brain volume outcomes were generated via voxel-based morphometry on T1-MRI and cognitive performance with an extensive neuropsychological battery. AD-related biomarkers (Aβ42/40 ratio, pTau181) in cerebrospinal fluid were assessed in n=226 individuals. We analyzed the associations between MeDi and the outcomes with linear regression models controlling for several covariates. Additionally, we applied hypothesis-driven mediation and moderation analysis., Results: Higher MeDi adherence related to larger mediotemporal gray matter volume (p<0.05 FWE corrected), better memory (β±SE = 0.03 ± 0.02; p=0.038), and less amyloid (Aβ42/40 ratio, β±SE = 0.003 ± 0.001; p=0.008) and pTau181 pathology (β±SE = -1.96±0.68; p=0.004). Mediotemporal volume mediated the association between MeDi and memory (40% indirect mediation). Finally, MeDi favorably moderated the associations between Aβ42/40 ratio, pTau181 and mediotemporal atrophy. Results were consistent correcting for ApoE-ε4 status., Conclusion: Our findings corroborate the view of MeDi as a protective factor against memory decline and mediotemporal atrophy. Importantly, they suggest that these associations might be explained by a decrease of amyloidosis and tau-pathology. Longitudinal and dietary intervention studies should further examine this conjecture and its treatment implications., (© 2021 American Academy of Neurology.)

Background: The hippocampus and its subfields (HippSub) are reported to be diminished in patients with Alzheimer's disease (AD), bipolar disorder (BD), and major depressive disorder (MDD). We examined these groups vs healthy controls (HC) to reveal HippSub alterations between diseases. Methods: We segmented 3T-MRI T2-weighted hippocampal images of 67 HC, 58 BD, and MDD patients from the AFFDIS study and 137 patients from the DELCODE study assessing cognitive decline, including subjective cognitive decline (SCD), amnestic mild cognitive impairment (aMCI), and AD, via Free Surfer 6.0 to compare volumes across groups. Results: Groups differed significantly in several HippSub volumes, particularly between patients with AD and mood disorders. In comparison to HC, significant lower volumes appear in aMCI and AD groups in specific subfields. Smaller volumes in the left presubiculum are detected in aMCI and AD patients, differing from the BD group. A significant linear regression is seen between left hippocampus volume and duration since the first depressive episode. Conclusions: HippSub volume alterations were observed in AD, but not in early-onset MDD and BD, reinforcing the notion of different neural mechanisms in hippocampal degeneration. Moreover, duration since the first depressive episode was a relevant factor explaining the lower left hippocampal volumes present in groups., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Hansen, Singh, Bartels, Brosseron, Buerger, Cetindag, Dobisch, Dechent, Ertl-Wagner, Fliessbach, Haynes, Heneka, Janowitz, Kilimann, Laske, Metzger, Munk, Peters, Priller, Roy, Scheffler, Schneider, Spottke, Spruth, Teipel, Tscheuschler, Vukovich, Wiltfang, Duezel, Jessen and Goya-Maldonado.)

Background: Early identification of individuals at risk of dementia is mandatory to implement prevention strategies and design clinical trials that target early disease stages. Subjective cognitive decline (SCD) and neuropsychiatric symptoms (NPS) have been proposed as potential markers for early manifestation of Alzheimer's disease (AD). We aimed to investigate the frequency of NPS in SCD, in other at-risk groups, in healthy controls (CO), and in AD patients, and to test the association of NPS with AD biomarkers, with a particular focus on cognitively unimpaired participants with or without SCD-related worries., Methods: We analyzed data of n = 687 participants from the German DZNE Longitudinal Cognitive Impairment and Dementia (DELCODE) study, including the diagnostic groups SCD (n = 242), mild cognitive impairment (MCI, n = 115), AD (n = 77), CO (n = 209), and first-degree relatives of AD patients (REL, n = 44). The Neuropsychiatric Inventory Questionnaire (NPI-Q), Geriatric Depression Scale (GDS-15), and Geriatric Anxiety Inventory (GAI-SF) were used to assess NPS. We examined differences of NPS frequency between diagnostic groups. Logistic regression analyses were carried out to further investigate the relationship between NPS and cerebrospinal fluid (CSF) AD biomarkers, focusing on a subsample of cognitively unimpaired participants (SCD, REL, and CO), who were further differentiated based on reported worries., Results: The numbers of reported NPS, depression scores, and anxiety scores were significantly higher in subjects with SCD compared to CO. The quantity of reported NPS in subjects with SCD was lower compared to the MCI and AD group. In cognitively unimpaired subjects with worries, low Aß42 was associated with higher rates of reporting two or more NPS (OR 0.998, 95% CI 0.996-1.000, p < .05)., Conclusion: These findings give insight into the prevalence of NPS in different diagnostic groups, including SCD and healthy controls. NPS based on informant report seem to be associated with underlying AD pathology in cognitively unimpaired participants who worry about cognitive decline., Trial Registration: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

Background: Autoimmune-mediated encephalitis is a disease that often encompasses psychiatric symptoms as its first clinical manifestation's predominant and isolated characteristic. Novel guidelines even distinguish autoimmune psychosis from autoimmune encephalitis. The aim of this review is thus to explore whether a wide range of psychiatric symptoms and syndromes are associated or correlate with autoantibodies., Methods: We conducted a PubMed search to identify appropriate articles concerning serum and/or cerebrospinal fluid (CSF) autoantibodies associated with psychiatric symptoms and syndromes between 2000 and 2020. Relying on this data, we developed a diagnostic approach to optimize the detection of autoantibodies in psychiatric patients, potentially leading to the approval of an immunotherapy., Results: We detected 10 major psychiatric symptoms and syndromes often reported to be associated with serum and/or CSF autoantibodies comprising altered consciousness, disorientation, memory impairment, obsessive-compulsive behavior, psychosis, catatonia, mood dysfunction, anxiety, behavioral abnormalities (autism, hyperkinetic), and sleeping dysfunction. The following psychiatric diagnoses were associated with serum and/or CSF autoantibodies: psychosis and schizophrenia spectrum disorders, mood disorders, minor and major neurocognitive impairment, obsessive-compulsive disorder, autism spectrum disorders (ASD), attention deficit hyperactivity disorder (ADHD), anxiety disorders, eating disorders and addiction. By relying on these symptom clusters and diagnoses in terms of onset and their duration, we classified a subacute or subchronic psychiatric syndrome in patients that should be screened for autoantibodies. We propose further diagnostics entailing CSF analysis, electroencephalography and magnetic resonance imaging of the brain. Exploiting these technologies enables standardized and accurate diagnosis of autoantibody-associated psychiatric symptoms and syndromes to deliver early immunotherapy., Conclusions: We have developed a clinical diagnostic pathway for classifying subgroups of psychiatric patients whose psychiatric symptoms indicate a suspected autoimmune origin., Competing Interests: The authors declare no conflict of interest., (© 2020 The Author(s).)

Background: Dysfunction of the cholinergic basal forebrain (cBF) is associated with cognitive decline in Alzheimer's disease (AD). Multimodal MRI allows for the investigation of cBF changes in-vivo. In this study we assessed alterations in cBF functional connectivity (FC), mean diffusivity (MD), and volume across the spectrum of AD. We further assessed effects of amyloid pathology on these changes., Methods: Participants included healthy controls, and subjects with subjective cognitive decline (SCD), mild cognitive impairment (MCI), or AD dementia (ADD) from the multicenter DELCODE study. Resting-state functional MRI (rs-fMRI) and structural MRI data was available for 477 subjects, and a subset of 243 subjects also had DTI data available. Differences between diagnostic groups were investigated using seed-based FC, volumetric, and MD analyses of functionally defined anterior (a-cBF) and posterior (p-cBF) subdivisions of a cytoarchitectonic cBF region-of-interest. In complementary analyses groups were stratified according to amyloid status based on CSF Aβ42/40 biomarker data, which was available in a subset of participants., Results: a-cBF and p-cBF subdivisions showed regional FC profiles that were highly consistent with previously reported patterns, but there were only minimal differences between diagnostic groups. Compared to controls, cBF volumes and MD were significantly different in MCI and ADD but not in SCD. The Aβ42/40 stratified analyses largely matched these results., Conclusions: We reproduced subregion-specific FC profiles of the cBF in a clinical sample spanning the AD spectrum. At least in this multicentric cohort study, cBF-FC did not show marked changes along the AD spectrum, and multimodal MRI did not provide more sensitive measures of AD-related cBF changes compared to volumetry., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Subjective cognitive decline (SCD) can represent a preclinical stage of Alzheimer's disease. Diffusion tensor imaging (DTI) could aid an early diagnosis, yet only few monocentric DTI studies in SCD have been conducted, reporting heterogeneous results. We investigated microstructural changes in SCD in a larger, multicentric cohort., Methods: 271 participants with SCD, mild cognitive impairment (MCI) or Alzheimer's dementia (AD) and healthy controls (CON) were included, recruited prospectively at nine centers of the observational DELCODE study. DTI was acquired using identical protocols. Using voxel-based analyses, we investigated fractional anisotropy (FA), mean diffusivity (MD) and mode (MO) in the white matter (WM). Discrimination accuracy was determined by cross-validated elastic-net penalized regression. Center effects were explored using variance analyses., Results: MO and FA were lower in SCD compared to CON in several anterior and posterior WM regions, including the anterior corona radiata, superior and inferior longitudinal fasciculus, cingulum and splenium of the corpus callosum (p < 0.01, uncorrected). MD was higher in the superior and inferior longitudinal fasciculus, cingulum and superior corona radiata (p < 0.01, uncorrected). The cross-validated accuracy for discriminating SCD from CON was 67% (p < 0.01). As expected, the AD and MCI groups had higher MD and lower FA and MO in extensive regions, including the corpus callosum and temporal brain regions. Within these regions, center accounted for 3-15% of the variance., Conclusions: DTI revealed subtle WM alterations in SCD that were intermediate between those in MCI and CON and may be useful to detect individuals with an increased risk for AD in clinical studies.

Cerebrospinal fluid (CSF) biomarkers are widely used in the diagnosis of dementia. Even though there is a causal correlation between apolipoprotein E ( APOE) genotype and amyloid-beta (Aβ), the determination of APOE is currently not supported by national or international guidelines. We compared parallel measured CSF biomarkers of two independent laboratories from 126 patients who underwent clinical dementia diagnostics regarding the APOE genotype. APOE ε4 reduces Aβ1-42 (Aβ 42 ) and Aβ 42 to Aβ 1-40 ratio (Aβ 42/40 ) but not total Tau or phospho-181 Tau CSF levels. Higher discordance rates were observed for Aβ 42 and subsequently for Aβ 42/40 in APOE ε4 carriers compared with noncarriers, and the correlation between the two laboratories was significantly lower for Aβ 42 in APOE ε4 positive patients compared with patients without APOE ε4. These observations demonstrate that the evaluation of CSF Aβ biomarkers needs to be interpreted carefully in the clinical context. Different immunoassays, disparate cutoff values, and APOE should be respected.

The cerebrospinal fluid (CSF) biomarkers amyloid-β 42 (Aβ 42 ), total Tau, and phospho-181-Tau represent important diagnostic tools to support the clinical diagnosis of Alzheimer's disease (AD). Acquiring CSF by lumbar puncture is considered a moderately invasive procedure, while blood sampling is minimally invasive with calculable risks and can be performed by trained non-medical staff. Thus, the identification of reliable and robust blood biomarkers of AD-related neuropathology would be significantly advantageous in daily practice and would allow more patients to be screened. In this study, we performed a multiplex amyloid-β assay to simultaneously measure Aβ 40 and Aβ 42 . We analyzed how well Aβ 40 , Aβ 42 , and the Aβ 42 to Aβ 40 ratio (Aβ 42/40 ) could differentiate between patients suffering from dementia either due or not due to AD. In addition, we studied different factors affecting Aβ levels in plasma. Plasma Aβ 42/40 level was significantly lower in patients with dementia due to AD than in those with dementia due to other causes. Aβ 42/40 correlated weakly between plasma and CSF, but did not differ between amyloid-PET positive or negative patients. Furthermore, we found that kidney function influences Aβ 40 and Aβ 42 plasma levels, but not Aβ 42/40 level. Liver function, age, and sex do not affect Aβ levels in plasma.

Background: Deep phenotyping and longitudinal assessment of predementia at-risk states of Alzheimer's disease (AD) are required to define populations and outcomes for dementia prevention trials. Subjective cognitive decline (SCD) is a pre-mild cognitive impairment (pre-MCI) at-risk state of dementia, which emerges as a highly promising target for AD prevention., Methods: The German Center for Neurodegenerative Diseases (DZNE) is conducting the multicenter DZNE-Longitudinal Cognitive Impairment and Dementia Study (DELCODE), which focuses on the characterization of SCD in patients recruited from memory clinics. In addition, individuals with amnestic MCI, mild Alzheimer's dementia patients, first-degree relatives of patients with Alzheimer's dementia, and cognitively unimpaired control subjects are studied. The total number of subjects to be enrolled is 1000. Participants receive extensive clinical and neuropsychological assessments, magnetic resonance imaging, positron emission tomography, and biomaterial collection is perfomed. In this publication, we report cognitive and clinical data as well as apolipoprotein E (APOE) genotype and cerebrospinal fluid (CSF) biomarker results of the first 394 baseline data sets., Results: In comparison with the control group, patients with SCD showed slightly poorer performance on cognitive and functional measures (Alzheimer's Disease Assessment Scale-cognitive part, Clinical Dementia Rating, Functional Activities Questionnaire), with all mean scores in a range which would be considered unimpaired. APOE4 genotype was enriched in the SCD group in comparison to what would be expected in the population and the frequency was significantly higher in comparison to the control group. CSF Aβ42 was lower in the SCD group in comparison to the control group at a statistical trend with age as a covariate. There were no group differences in Tau or pTau concentrations between the SCD and the control groups. The differences in all measures between the MCI group and the AD group were as expected., Conclusions: The initial baseline data for DELCODE support the approach of using SCD in patients recruited through memory clinics as an enrichment strategy for late-stage preclinical AD. This is indicated by slightly lower performance in a range of measures in SCD in comparison to the control subjects as well as by enriched APOE4 frequency and lower CSF Aβ42 concentration., Trial Registration: German Clinical Trials Register DRKS00007966 . Registered 4 May 2015.

Background and Aims: Several risk factors for schizophrenia have yet been identified. The aim of our study was to investigate how certain childhood and adolescent risk factors predict the age of onset of psychosis in patients with and without a familial component (i.e. a relative with schizophrenia or schizoaffective disorder)., Methods: Aside from the age of onset of psychosis, we examined the risk factors for schizophrenia including obstetric complications, birth during winter or spring, behavioral deviances or delayed motor and speech development, exposure to adverse life events and exposure to substance use within a group of 100 patients (45 female, 55 male) with a mean age (± standard deviation) of 35.15 ± 13.21., Results: Birth complications and cannabis abuse are predictors for an earlier onset of schizophrenia in patients with non-familial schizophrenia. No environmental risk factors for an earlier age of onset in familial schizophrenia have been identified., Conclusions: Certain environmental risk factors for schizophrenia seem to have an impact on the age of onset of psychosis in non-familial schizophrenia, they do not seem to have an impact on familial schizophrenia.

A hyperphosphorylated, ubiquitinated form of TDP-43, known as pathologic TDP-43, was shown to be a central component of ubiquitin-positive, tau-negative and alpha-synuclein-negative inclusions in frontotemporal lobar degeneration (FTLD-U) and amytrophic lateral sclerosis (ALS). To investigate the role of the TDP-43 gene in sporadic forms of frontotemporal dementia (FTD), we genotyped 10 single nucleotide polymorphisms covering the entire TDP-43 genomic region, including the MASP2 gene in 173 patients with sporadic FTD (including 7 patients that were diagnosed with FTD and ALS) and 184 matched controls from Germany. Although we could observe a weak trend towards a potential disease association in a few FTD/ALS patients, no significant association with sporadic FTD could be demonstrated. There is no evidence, that common variants in TDP-43 confer a strong risk to the development of sporadic FTD.

The cellular initiation of coagulation by the tissue factor (TF)-activated factor VII complex is transiently inhibited by endogenous tissue factor pathway inhibitor-1 (TFPI-1), whereas exogenously added TFPI-1 is targeted to a degradation pathway. This study investigates the relevance of glycosyl phosphatidylinositol (GPI) anchoring for the anticoagulant properties of TFPI-1. Experiments were performed with the human cell line ECV304 using liposomal gene transfer. For GPI anchoring of TFPI-1 we used a fusion protein of TFPI-1 and the GPI attachment sequence of decay-accelerating factor (GPI-TFPI-1), and compared it with wild-type TFPI-1. We measured TF and TFPI-1 surface expression by flow cytometry and TF proteolytic activity by a chromogenic assay for activated factor X generation. After transfection of GPI-TFPI-1, surface expression of TFPI-1 increased to 134 +/- 9% of mock transfected cells (mean +/- SEM, P = 0.004), and transfection with wild-type TFPI-1 did not significantly alter TFPI-1 surface expression. After transfection with GPI-TFPI-1, TF activity was reduced by 18 +/- 9% compared with mock transfections (P = 0.003), whereas after transfection with TFPI-1 wild type no significant inhibition was observed. This effect was not due to altered TF expression. GPI anchoring is an essential prerequisite for surface expression of TFPI-1 and inhibition of TF activity. Gene transfer of GPI-anchored TFPI, therefore, may be an efficient tool to inhibit local TF-induced coagulation.

1 The new converting enzyme inhibitor RHC 3659 was tested in 15 male volunteers. The study consisted of two parts: first, the ability of a single oral dose (5, 10, 20, 40 or 80 mg) to inhibit the pressor response to exogenous angiotensin I was tested with blood pressure and heart rate monitored continuously through an intraarterial catheter. A dose-related shift to the right of the pressor response curve to angiotensin I was observed with a peak occurring within 0.5 to 1 h. The pressor response to angiotensin II was unaffected. 2 In the second part, plasma renin and converting enzyme activity, angiotensin II and aldosterone were measured serially before and up to 8 h after administration of a single oral dose of RHC 3659. As expected. plasma angiotensin II and aldosterone fell within 30 min while plasma renin activity increased. Plasma converting enzyme activity was suppressed at 0.5 h in a dose-related manner with levels still below 30% of control 4 h following 80 mg of the inhibitor. 3 However, in vitro the enzyme-inhibitor complex seemed quited fragile since during storage of the plasma samples at -20 degrees C, converting enzyme activity increased significantly already within days (P less than 0.001, n = 28) and continued to rise for more than 2 months. This fragility may explain the seemingly lower potency of RHC 3659 when compared to captopril. No side effects were observed.

Three subjects diagnosed as having idiopathic acquired cold urticaria were studied to assess the ability of orally administered tiaramide to inhibit the wheal induced following cold challenge with ice cubes placed in contact with the skin, and to establish the safety of multiple doses of 250 mg, q.i.d., for one week administered after a single oral dose of 500 mg. Two subjects completed the study. One subject was known to be unresponsive to antihistamines for allergy and the second was intolerant of antihistamines due to side effects. A third subject discontinued treatment due to an adverse reaction experienced while on the study medication. The skin of the forearm of each subject was exposed to cold stimuli for 1, 2, 3, 4, and 5 minutes by placing five ice cubes on the ventral surface at one minute intervals, and removing all simultaneously five minutes after contact with the first cube. The challenge sites were observed for ten minutes and the area of the wheal, intensity of edema and the time of contact necessary to induce the skin response were recorded. The results of this provocative test following the single and multiple dosage administration of tiaramide were compared to baseline skin responses. After one week of tiaramide treatment at 250 mg, q.i.d., both subjects who completed the study had a markedly attenuated skin response to cold challenge and no adverse effects. Our results suggest that absorbable compounds that can inhibit mast cell degranulation may be efficacious in cold urticaria and of particular value in treating patients who do not respond to standard therapy.

Indapamide, 2.5 mg administered once daily for periods up to 36 months, was found to be safe and effective for the long-term control of mild to moderate hypertension. The effects of hydrochlorothiazide, 50 mg, and indapamide, 2.5 mg, were studied in two randomized, double-blind, multicenter trials. Data from the two multicenter trials (20 study sites) were pooled for purposes of comparison. Significant reductions in systolic and diastolic blood pressure, with patients in both supine and standing positions, occurred in both groups within the first 8 weeks of treatment. This effect was maintained throughout the active treatment period. Success, as determined by the therapeutic success rate (percentage of patients with decreases of standing phase V diastolic blood pressure of at least 10 mm Hg or to below 90 mm Hg), occurred in 53% of the patients given hydrochlorothiazide and in 56% of the indapamide-treated patients. During the study period, the nature, frequency, and severity of adverse reactions were similar for both groups. There was no clinically significant difference between the treatment groups for the laboratory assessments. Patients who completed the multicenter trials were eligible for participation in an ongoing long-term extension study of the safety of indapamide. Data are available for periods up to 36 months and demonstrate neither augmentation of clinical or laboratory adverse effects nor any potentially harmful indicators that could be attributed to prolonged treatment.

Nadolol, a nonselective beta adrenoceptor antagonist, was evaluated in 9 normal sybjects with essential hypertension for ability to inhibit exercise-induced changes in double-product (systolic pressure x heart rate). Propranolol and placebo were included as positive and negative controls. The beta antagonists were administered orally in single doses at 10, 20, 40, and 80 mg on a crossover basis. Both nadolol and propranolol induced comparable dose-related inhibition of double-product. Duration of beta receptor blockade was greater with nadolol than with propranolol; significant inhibition of double-product occurred 24 hr after a single 80-mg dose of nadolol. The antihypertensive effect of nadolol was evaluated in another series of 46 subjects with essential hypertension. The dose of nadolol ranged from 80 to 320 mg once daily. Consistent decreases in supine heart rate (20%) and diastolic blood pressure (9%) from baseline were observed. During steady state, the oral daily dose of nadolol was proportional to the minimum steady-state serum concentration (Cmin) of nadolol (r = 0.75, p less than 0.001) obtained just before the next dose of nadolol. Statistically significant correlation was observed between the antihypertensive effect and the Cmin for nadolol (r = 0.45, p less than 0.05).

We investigated the antihypertensive effect of the angiotensin converting-enzyme inhibitor SQ 14225 in 12 hypertensive patients for periods of three to 24 weeks. Blood pressure decreased in all patients (from 177 +/- 8/110 +/- 2 to 136 +/- 6/88 +/- 2 mm Hg--mean +/- S.E.); oral doses ranged from 400 to 1000 mg daily. Concomitant effects noted were small increases in plasma potassium concentration and pulse rate. One patient experienced a transient febrile reaction. Plasma renin activity rose during treatment, plasma aldosterone decreased, and angiotensin-converting-enzyme activity was virtually eliminated. There was no significant correlation between pretreatment plasma renin activity and degree of blood-pressure fall with SQ 14225. The exact mechanisms contributing to the blood-pressure-lowering effect of this agent remain unclear. SQ 14225 is a promising new antihypertensive agent, effective in patients refractory to traditional medical therapy.

The passage of two antibiotics, cephradine and epicillin, into the milk of 12 lactating women and the amniotic fluid of 48 pregnant women was investigated. All women were given a 500-mg capsule every six hours for at least two days prior to our taking multiple biologic samples from them. Constant levels of both antibiotics were reached in the milk of lactating women as well as in the amniotic fluid of mid-term and full-term pregnant women during the sample period. The ratio of drug concentrations in serum to that in milk was about 5.0 for each antibiotic. In the midtrimester women, the ratio of concentrations in serum to amniotic fluid of both antibiotics was approximately 1.0, suggesting the development of an equilibrium between these two compartments. This ratio was 0.2 for both drugs in the full-term women, demonstrating that the antibiotics concentrated in the amniotic fluid compartment.

1 Nadolol excretion was studied in 24 patients with chronic renal failure. 2 The amount of nadolol excreted during the 120-h period after receiving the drug ranged from less than 1% in functionally anephric, patients up to 11.5% in patients with average creatinine clearance of 57.9 +/- 3.6 ml/min/1.73 m2. 3 Renal clearance of nadolol was found to correlate with creatinine clearance; nadolol elimination is retarded in patients with renal failure. 4 Nadolol serum half-life is prolonged in proportion to the remaining renal function. Therefore, dosage intervals in renal patients receiving nadolol should be adjusted to creatinine clearance. 5 Haemodialysis effectively reduced serum concentration of the drug; it may therefore be a useful therapy for drug intoxication.

The disposition of captopril, an angiotensin-converting enzyme inhibitor with antihypertensive properties, was studied in 10 normal male subjects after a single 100-mg tablet of 35S-labeled drug. Average absorption parameters for unchanged captopril in blood were Tmax 0.93 +/- 0.08 hr and Cmax 800 +/- 76 ng/ml. For total radioactivity in blood the values were Tmax 1.05 +/- 0.08 hr and Cmax 1,580 +/- 90 ng/ml (as captopril equivalents). Because of the curvilinearity of the semilogarithmic plots of blood concentrations of captopril:time, elimination half-life (t1/2) of unchanged drug could not be determined. At 1 hr unchanged captopril accounted for about 52% of total radioactivity in blood, and the dimeric disulfide metabolite of captopril accounted for about 10%. In the first 5 days after dosing, an average of about 68% of the radioactive dose was recovered in urine and 18% in feces. The distribution of radioactivity in the first 24-hr urine sample (66% of the dose) was 58% captopril (38% of dose), 2% captopril disulfide (1.5% of dose), and 40% unidentified polar metabolites (26% of dose).

A single oral dose of 10 mg of SQ 10,996-14C was absorbed slowly by 3 normal male volunteers, with peak plasma concentrations achieved 6 hr after ingestion; the plasma half-life was about 38.5 hr. On average, 82.3 +/- 3.5% of the radioactivity present in the 2 hr plasma sample was bound to plasma proteins. These volunteers excreted an average of 31 and 52% of the dose in the urine and feces, respectively. All subjects excreted minor amounts of 14CO2 in the expired air. No unchanged SQ 10,996-14C was found in the urine. Three unidentified metabolites were excreted in urine. SQ 10,996-14C was excreted in the feces only as unchanged drug, suggesting that the drug is incompletely absorbed. The volunteers tolerated the drug well and experienced no adverse effects.

The efficacy of a once-daily combination of chlorthalidone 50 mg plus triamterene 50 mg or chlorthalidone 100 mg plus triamterene 100 mg was compared to that of chlorthalidone 50 mg or 100 mg. This double-blind study was carried out in eighty-eight patients over a treatment period of 12 weeks. All patients entered the active medication period of 12 weeks after a placebo run-in period of 3 to 7 days, during which pretibial or malleolar pitting oedema averaging 2 to 4 mm developed. All patients started at the lower doses, i.e. forty-one started on chlorthalidone 50 mg plus triamterene 50 mg and forty-seven started on chlorthalidone 50 mg. The protocol provided for doubling the dose (but not for reducing it thereafter) at any time during the 12-week period when control of oedema was deemed inadequate. Eight of the combination therapy patients and sixteen of those on chlorthalidone required the higher doses. By Week 12, 96% of the chlorthalidone plus triamterene patients and 100% of the chlorthalidone patients had shown a reduction of at least 2 mm in depth of pits, and 92% and 72%, respectively, had complete disappearance of oedema. The decreases in pitting oedema were paralleled by mean weight losses of 2.4 kg and 3.1 kg, respectively, for the combination treatment group and the chlorthalidone group. Average serum potassium levels throughout the 12-week treatment period were 3.70 mEq/L for the patients taking the combination compared to 3.41 mEq/L of those taking chlorthalidone.(ABSTRACT TRUNCATED AT 250 WORDS)

Indapamide is a new antihypertensive diuretic agent indicated for the treatment of hypertension and edema. Indapamide shows an alteration in vascular reactivity to calcium and other agonists, suggesting the possibility of a direct vascular effect. The drug is recommended in doses of 2.5 to 5 mg once a day. It is rapidly and completely absorbed from the gastrointestinal tract, resulting in maximal blood levels in approximately 2.3 hours. Coadministration of indapamide with food or antacids does not reduce bioavailability. Linear proportionality of blood concentration with increasing doses is evident following both single and multiple doses. Other pharmacokinetic parameters are not dose related. Indapamide is widely distributed in the body with extensive binding to erythrocytes. Binding to plasma proteins is approximately 76%. Disappearance of indapamide from the blood is biphasic, with a terminal half-life of approximately 16 hours. Renal clearance represents less than 10% of the total systemic clearance of the parent drug, showing the dominant role of hepatic clearance. Studies of 14C-labeled indapamide in humans demonstrate that 70% of the radioactivity is excreted in urine and 23% in feces. Indapamide is extensively metabolized; less than 7% of the dose is excreted in urine as unchanged compound. Studies of patients with renal impairment showed little or no accumulation of indapamide in the blood in comparison to patients with normal renal function. Clinical studies demonstrate that indapamide has diuretic properties. Free water clearance studies indicate a site of action in the cortical diluting segment of the distal tubules. No adverse effect of indapamide on renal function is evident in normal volunteers, hypertensive patients, or geriatric hypertensive patients, as determined by glomerular filtration rate or effective renal plasma flow. Hemodynamic studies of indapamide in patients with mild to moderate hypertension show a significant (p less than 0.05) decrease in mean blood pressure (16%) and total peripheral resistance (15%). No other significant hemodynamic effects are evident. The data suggest that indapamide may produce antihypertensive activity through a dual mechanism of action--diuretic and direct vascular. Additionally, it appears to be safe even for patients with impaired renal function.