bluuebunny/crossref_metadata_2025 huggingface dataset:
Anticoagulant treatment of pulmonary embolism: impact and implications of the EINSTEIN PE study
Authors: Prandoni Paolo
Published: July 2012

Pulmonary embolism (PE), which can develop as a consequence of deep vein thrombosis (DVT), is a serious and potentially fatal venous thromboembolic event. Patients with PE are at increased risk of venous thromboembolism (VTE) recurrence and serious complications such as chronic thromboembolic pulmonary hypertension. Anticoagulants, namely heparins and vitamin K antagonists (VKAs), have been the main treatments for PE in patients who are haemodynamically stable. However, use of these agents can be complex and is associated with an increased risk of bleeding (a characteristic that is common to all anticoagulants). Simplified, effective treatment regimens for PE would be very beneficial for patients, physicians and payers. Compared with DVT, PE is a different clinical manifestation of VTE; phase III trials have now started to focus specifically on patients with PE. Trials in patients with PE can provide further information on the optimal management of these patients. Results of the phase III EINSTEIN PE study demonstrated non‐inferiority in the efficacy and safety of oral rivaroxaban compared with standard of care (enoxaparin/VKA) for the treatment of patients with acute symptomatic PE (with or without symptomatic DVT). Rates of major bleeding were significantly lower in patients receiving rivaroxaban. This review will discuss the findings of recent trials, particularly the potential impact of single, oral agents for both the initial and long‐term treatment of a range of patients with PE, and how these results may influence the clinical management of PE.
Biological roles and prognostic values of the epithelial–mesenchymal transition‐mediating transcription factors Twist, ZEB1 and Slug in diffuse large B‐cell lymphoma
Authors: Lemma Siria , Karihtala Peeter , Haapasaari Kirsi‐Maria , Jantunen Esa , Soini Ylermi , Bloigu Risto , Pasanen Anna‐Kaisa , Turpeenniemi‐Hujanen Taina , Kuittinen Outi
Published: July 2012

Aims:  To evaluate the biological roles and prognostic significance of the epithelial–mesenchymal transition (EMT)‐mediating transcription factors (TFs) Twist, ZEB1 and Slug in patients with diffuse large B‐cell lymphoma (DLBCL). EMT has been shown to enhance solid tumour metastasis, invasion, and proliferation.

Methods and results:  Expression of Twist, ZEB1 and Slug was evaluated immunohistochemically in eight samples from reactive lymphoid tissues and in diagnostic samples from 102 DLBCL patients treated with curative intent with R‐CHOP‐type chemotherapy. ZEB1 and Slug expression correlated with adverse disease presentation. However, cytoplasmic Slug expression was linked to a favourable disease outcome, whereas nuclear expression of ZEB1 indicated an adverse outcome.

Conclusions:  This study shows that an EMT‐like process occurs in lymphomas. Of the TFs investigated, ZEB1 seems to be the main one associated with adverse clinical presentation and clinical outcome. Surprisingly, Slug expression in cytoplasm was linked to a favourable prognosis. Further studies are needed to evaluate whether inhibition of ZEB1 could serve as a therapeutic target.
Comparison of the 2002 and 2010 TNM classification systems regarding outcome prediction in clear cell and papillary renal cell carcinoma
Authors: Pichler Martin , Hutterer Georg C , Chromecki Thomas F , Jesche Johanna , Kampel‐Kettner Karin , Groselj‐Strele Andrea , Hoefler Gerald , Pummer Karl , Zigeuner Richard
Published: July 2012

Aims:  A novel version of the tumour–node–metastasis (TNM) classification system for renal cell carcinoma (RCC) was introduced in 2010, although the prognostic significance with regard to different histological subtypes has not been explored. Therefore, the aim of our study was to compare the predictive ability of the 2002 and 2010 versions of the TNM classification system for clear cell and papillary RCC.

Methods and results:  Data from 2263 consecutive clear cell and 309 papillary RCC patients, operated at a single tertiary academic centre, were evaluated. According to TNM 2010, statistically significant differences for cancer‐specific survival (CSS) were observed for pT1a versus pT1b (P < 0.001) and pT3a versus pT3b (P < 0.004) in clear cell RCC; and pT1b versus pT2a (P = 0.002) and pT3b versus pT3c (P = 0.046) in papillary RCC. The c‐index for CSS in clear cell RCC was 0.74 and 0.73, and in papillary RCC 0.79 and 0.78, for the 2002 and 2010 versions of the TNM classification system, respectively.

Conclusions:  According to our data, the predictive ability of the 2010 version of the TNM classification system regarding CSS is not superior to the 2002 version, either in clear cell or in papillary RCC.
Expression of autophagy‐related markers beclin‐1, light chain 3A, light chain 3B and p62 according to the molecular subtype of breast cancer
Authors: Choi Junjeong , Jung Woohee , Koo Ja Seung
Published: July 2012

Aims:   To investigate the relationship between the expression of autophagy‐related proteins, including beclin‐1, light chain (LC) 3A, LC3B, and p62, and prognosis in invasive breast cancer.

Methods and results:   We constructed tissue microarrays from the breast cancer cells of 489 patients, and classified molecular subtypes using surrogate immunohistochemical stains. The tumoral expression levels of LC3A and LC3B were highest in triple‐negative breast cancer (TNBC) (P < 0.001), whereas these types of tumour had the lowest expression levels of these markers in the stroma (P = 0.005 and P < 0.001, respectively). Cytoplasmic beclin‐1 expression was highest in TNBC, but nuclear expression was lowest (P < 0.001). p62 cytoplasmic and nuclear expression were highest in HER2‐type tumours (P = 0.001 and P < 0.001, respectively). Tumoral LC3A and LC3B expression were associated with high histological grade (P < 0.001, and P < 0.028, respectively), but nuclear p62 expression was associated with lower histological grade (P = 0.004).

Conclusions:   Autophagy‐related markers are differentially expressed according to the molecular subtype of breast cancer. In particular, expression of LC3A, LC3B and beclin‐1 was highest in TNBC tumour cells, whereas that of LC3A and LC3B in the tumour stroma was lowest in TNBC.
Histopathological study of lymph node lesions in the acute phase of Kawasaki disease
Authors: Yokouchi Yuki , Oharaseki Toshiaki , Harada Mana , Ihara Fumie , Naoe Shiro , Takahashi Kei
Published: July 2012

Aims:  To review the histopathological features of cervical LNs, and to clarify the changes in extracervical LNs, in acute Kawasaki disease (KD).

Methods and results:  The samples were obtained from 33 patients with acute‐phase KD. We divided the LNs into those in the neck (n = 23) and those located elsewhere (n = 26), and investigated them histologically. Changes occur not only in the cervical region, but also in LNs throughout the body. Most lymphadenopathy is non‐specific, caused by sinus expansion and paracortical zone enlargement, but there are also necrotic lesions of various sizes that can be surmised to result from ischaemic changes in some LNs. Necrotic foci start to develop immediately below the capsule, and are accompanied by fibrin thrombi in the small vessels and perivascular nuclear debris. Especially in the case of cervical LNs with necrosis, a high degree of non‐purulent inflammation develops in the LN capsule and surrounding connective tissue.

Conclusions:  In addition to lymphadenopathy with necrosis, KD should be suspected if there is non‐purulent inflammation of the LN capsule and/or surrounding connective tissue featuring mainly monocytes/macrophages.
Genetic and phylogenetic evidence for horizontal gene transfer among ecologically disparate groups of marine Vibrio
Authors: Hoffmann Maria , Monday Steven R. , McCarthy Peter J. , Lopez Jose V. , Fischer Markus , Brown Eric W.
Published: July 2012

Vibrio represents a diverse bacterial genus found in different niches of the marine environment, including numerous genera of marine sponges (phylum Porifera), inhabiting different depths and regions of benthic seas, that are potentially important in driving adaptive change among Vibrio spp. Using 16S rRNA gene sequencing, a previous study showed that sponge‐derived (SD) vibrios clustered with their mainstream counterparts present in shallow, coastal ecosystems, suggesting a genetic relatedness between these populations. Sequences from the topA, ftsZ, mreB, rpoD, rctB and toxR genes were used to investigate the degree of relatedness existing between these two separate populations by examining their phylogenetic and genetic disparity. Phylogenies were constructed from the concatenated sequences of the six housekeeping genes using maximum‐parsimony, maximum‐likelihood and neighbour‐joining algorithms. Genetic recombination was evaluated using the incongruence length difference test, Split decomposition and measuring overall compatibility of sites. This combined technical approach provided evidence that SD Vibrio strains are largely genetically homologous to their shallow‐water counterparts. Moreover, the analyses conducted support the existence of extensive horizontal gene transfer between these two groups, supporting the idea of a single panmictic population structure among vibrios from two seemingly distinct, marine environments.
Long‐term outcome and prognostic factors of elderly patients with acute promyelocytic leukemia
Authors: Ono Takaaki , Takeshita Akihiro , Kishimoto Yuji , Kiyoi Hitoshi , Okada Masaya , Yamauchi Takahiro , Tsuzuki Motohiro , Horikawa Kentaro , Matsuda Mitsuhiro , Shinagawa Katsuji , Monma Fumihiko , Ohtake Shigeki , Nakaseko Chiaki , Takahashi Masatomo , Kimura Yukihiko , Iwanaga Masako , Asou Norio , Naoe Tomoki ,   the Japan Adult Leukemia Study Group
Published: July 2012

Studies focused on elderly acute promyelocytic leukemia (APL) are relatively limited. To evaluate prognostic impact in elderly APL, we compared the long‐term outcome of elderly APL patients (60–70 years) with younger patients (15–59 years) treated with all‐trans retinoic acid combined with anthracycline and cytarabine in the Japan Adult Leukemia Study Group (JALSG) APL97 study. Of 283 evaluable patients, 46 (16.3%) were elderly who had more frequent lower platelet (P = 0.04), lower albumin (P = 0.006) and performance status 3 (P = 0.02), higher induction death rate due to differentiation syndrome (P = 0.03), and non‐relapse mortality (NRM) during consolidation therapy (P = 0.001). Overall survival was significantly inferior in elderly patients (P = 0.005), but disease‐free survival and cumulative incidence of relapse were not. Better therapeutic approaches should be considered to reduce NRM during induction and consolidation therapy in elderly APL. This study was registered at http://www.umin.ac.jp/ctrj/ under C000000206.
Biological classification of depressive illness.
Authors: Coppen A. , Wood K.
Published: July 2012

1 A number of biological criteria have been used for refining clinical classification to identify patients who will respond to antidepressant treatment. 2 Subtypes of depressive illness have been postulated to occur depending on whether there is a relative deficiency of central noradrenaline or 5‐hydroxytryptamine. However, antidepressants having selective effects on amine systems have similar therapeutic effects and inhibition of re‐uptake of these amines does not correlate with clinical outcome. 3 An abnormal response to thyrotrophin‐releasing hormone has not been confirmed as specific for depressive illness. Failure to control for age and sex may account for some of the discordant findings. 4 It has been suggested that depressed patients secrete less growth hormone to a variety of stimuli. It appears that the predictive value of a growth hormone response for the diagnosis of endogenous depression is 53%. 5 The dexamethasone suppression test appears to have high sensitivity for the diagnosis of endogenous depression but low specificity and should therefore be used only in conjunction with clinical assessments.
The prevention of recurrent suicidal acts.
Authors: Montgomery SA , Roy D. , Montgomery DB
Published: July 2012

1 There have been few controlled prospective investigations into the prevention of suicidal behaviour and by and large they have failed to demonstrate the efficacy of social work, psychotherapy or psychiatric treatment. 2 A group of 58 high‐risk patients with multiple episodes of suicidal behaviour was treated with mianserin 30 mg at night or placebo in a six month double‐blind trial of the efficacy of an antidepressant in reducing suicidal behaviour. 3 Patients were screened for depression, schizophrenia and organic disease. Patients were diagnosed as suffering from personality disorders according to DSM‐III criteria mainly borderline or histrionic. 4 There was no significant difference in outcome between the mianserin and placebo treated group at any point in the six month study. 5 An item analysis of the MADRS showed that at entry the item ‘reduced appetite’ predicted subsequent suicidal attempt. The total MADRS score did not predict further suicidal acts at entry but was highly significant at four weeks. At four weeks the items ‘reduced sleep’ and ‘reduced appetite’ were highly significant predictors of further suicidal acts and the items ‘lassitude’, ‘suicidal thoughts’, ‘inability to feel’ and ‘pessimistic thoughts' were significant predictors.
Plasma levels and clinical response with imipramine in a study comparing efficacy with mianserin and nomifensine.
Authors: Montgomery SA , Roy D. , Wynne‐Willson S. , Robinson C. , Montgomery DB
Published: July 2012

1 The comparative antidepressant efficacy of 150 mg imipramine, 60 mg mianserin and 150 mg nomifensine was studied in 45 depressed patients in a six week double‐blind investigation. 2 In the efficacy analysis of 41 patients completing the study there was no overall significant difference in efficacy between the groups. Individual group comparisons showed no significant difference in response between mianserin and nomifensine, and mianserin and imipramine. There was a significant (z = 1.99, P less than 0.05) improved response in the imipramine compared with the nomifensine treated group. The imipramine treated group were significantly older. 3 No significant plasma concentration/clinical response relationships were demonstrated with nomifensine, mianserin, imipramine or desipramine. 4 Plasma level monitoring of imipramine recommended by some investigators does not seem to be appropriate.
A double‐blind trial of mianserin and nomifensine in depressed outpatients.
Authors: Hamouz W. , Van Dorth R. , Pinder RM , Stulemeijer SM
Published: July 2012

1 Following a seven day drug‐free period, 80 depressed outpatients were randomly allocated to receive mianserin 60 mg nocte or nomifensine 150 mg daily. Blindness was maintained by the use of a double‐dummy technique. 2 All measures of efficacy showed a trend in favour of mianserin throughout the four week trial, including the Hamilton Depression Scale (HDS), the Beck Self‐rating Depression Inventory (BDI), the Clinical Global Impression (CGI) and the Efficacy Index. 3 Significant advantages in efficacy for mianserin were observed at day 14 on the HDS and at days 7, 14 and 21 on the CGI. 4 Substantially more patients experienced marked or moderate improvement during treatment with mianserin than with nomifensine. Side‐effects were low with both drugs. 5 On the basis of the present trial and a previous comparison, mianserin appears to be a more effective antidepressant than nomifensine.
A double‐blind comparative trial with mianserin and amitriptyline in outpatients with major depressive disorders.
Authors: Feighner JP , Jacobs RS , Jackson RE , Hendrickson G. , Merideth CH , O'Meara PD
Published: July 2012

1 A double‐blind trial with parallel treatment groups was conducted to compare the safety and efficacy of mianserin with amitriptyline. 2 This was a six week trial with weekly visits. Measurements at each visit included: 21 item Hamilton Depression (HAMD) Scale. Clinical Global Impression (CGI) Scale and Treatment Emergent Symptom Scale (TESS). 3 Mianserin and amitriptyline were comparable with respect to efficacy. 4 More adverse experiences were reported by amitriptyline patients. The predominant amitriptyline adverse experiences were of the anticholinergic type; the predominant mianserin adverse experience was drowsiness/fatigue. 5 The Efficacy Index (EI), a scale combining efficacy and adverse experiences, clearly demonstrated the superiority of mianserin over amitriptyline.
Placebo‐controlled trial of mianserin and maprotiline in primary depressive illness: a preliminary report.
Authors: Edwards JG , Goldie A.
Published: July 2012

1 Preliminary results of a double‐blind placebo‐controlled trial of mianserin and maprotiline carried out in 58 outpatients with primary depressive illness are reported. 2 Patients received six weeks' treatment with 30 to 90 mg mianserin, 75 to 225 mg maprotiline or one to three capsules of placebo, all medication being taken at night. 3 There were statistically significant improvements in each treatment group and a better response to mianserin than to placebo or maprotiline on the Hamilton Rating Scale for Depression, after one week's treatment. 4 Neither mianserin nor maprotiline was superior to placebo after two or four weeks' treatment and relatively few patients completed six weeks' treatment because of a generally unsatisfactory response. 5 Unwanted effects were not particularly troublesome, though mianserin and maprotiline caused more drowsiness and blurred vision than did placebo, while maptrotiline produced more constipation than either of the other two treatments. 6 The importance of placebo‐ controlled trials of antidepressants is emphasized and the precautions that should be taken when they are carried out in outpatients are described.
Mianserin, maprotiline and intracardiac conduction.
Authors: Edwards JG , Goldie A.
Published: July 2012

1 High speed surface electrocardiograms were recorded in 35 patients during the baseline and after four weeks' treatment in a placebo‐ controlled trial of mianserin and maprotiline in primary depressive illness. 2 Measurements of the RR, PR and QT intervals, QRS width and T wave height were made blind to patient, drug and treatment interval and compared with plasma drug concentrations. The presence or absence of cardiac arrhythmias was recorded. 3 The only significant findings were an increased heart rate and PR interval and decreased QTc interval in the maprotiline group. Only one patient receiving maprotiline had a cardiac arrhythmia. There was no significant correlation between measurements of ECG parameters and plasma drug levels. 4 The results confirm the lack of cardiac effects of mianserin and show both anticholinergic activity and effects of an intracardiac conduction in the case of maprotiline. The mechanisms of these effects are discussed.
Mianserin, maprotiline and the electroencephalogram.
Authors: Sedgwick EM , Edwards JG
Published: July 2012

1 EEGs were recorded from patients with depressive illness before and after four weeks of treatment with mianserin, maprotiline or placebo. 2 Visual analysis of the records showed a small but statistically significant increase in frequency of beta activity in the mianserin group. 3 One subject taking maprotiline developed spike and wave discharges but had no convulsive seizures. 4 The findings do not support those of previous studies. It seems that changes seen in the EEG early after treatment are not sustained for four weeks.
Noradrenaline and 5‐hydroxytryptamine modulation of brain dopamine function: implications for the treatment of Parkinson's disease.
Authors: Jenner P. , Sheehy M. , Marsden CD
Published: July 2012

1 Dopamine deficiency in the brain is the prime biochemical deficit in Parkinson's disease, but loss of noradrenaline and 5HT also may contribute. 2 In rats, 5HT‐containing neurones originating from the dorsal and median raphe nuclei innervate forebrain dopamine‐containing areas so as to impose an inhibitory regulatory tone on dopamine function. However, this interaction between brain dopamine and 5HT‐ containing neuronal systems is complex, and the effect produced appears dependent on the relative activity of each system. 3 Anatomical evidence for innervation of dopamine‐containing brain regions by noradrenaline fibres in the rat is scanty, but functional studies suggest the existence of inputs which facilitate dopamine function. 4 Drug therapy designed to increase or decrease brain 5HT function has had no consistent effect in Parkinson's disease. 5 Manipulation of brain noradrenergic activity in Parkinson's disease had little effect, although the noradrenaline precursor L‐threo‐DOPS may reduce freezing attacks. 6 Until more specific drug molecules are available the role of brain noradrenergic and 5HT mechanisms in Parkinson's disease remains uncertain.
Mianserin and blood dyscrasias.
Authors: Clink HM
Published: July 2012

1 The haematological side‐effects of mianserin have been studied. 2 There are 26 reported cases, of which 19 appear to show a definite association with the drug. A high proportion are female. 3 A reversible agranulocytosis has been most commonly observed, occurring between four and six weeks of treatment. On cessation of therapy, the counts have recovered. 4 Three patients have died, following a longer course of treatment. Two of these were septicaemic and the third, thrombocytopenic in addition. This is probably related to a failure of marrow recovery owing to the longer exposure, in the third case progressing to aplasia. 5 The number of reported dyscrasias is extremely small compared with the number of courses of mianserin prescribed. 6 It is desirable that a blood examination should be made at four weeks after starting treatment with mianserin to identify those patients at risk.
The pharmacokinetics of mianserin.
Authors: Shami M. , Elliott HL , Kelman AW , Whiting B.
Published: July 2012

1 The pharmacokinetics of mianserin hydrochloride have been determined in eight normal healthy volunteers, mean age 27, and 14 elderly patients, mean age 76. 2 Mianserin was administered to volunteers by intravenous infusion (0.011 mg/kg/min for 15 min) and, on another occasion, by mouth, in a single dose of 30 mg. Elderly patients received a single oral dose of 40‐60 mg. 3 The terminal elimination half‐life was significantly prolonged in the elderly. In young subjects it was 9.6 +/‐ 1.9 (s.d.) h. In the elderly it was 27 +/‐ 13.1 (s.d.) h. 4 Apparent oral clearance was significantly reduced in the elderly. In young subjects it was 87.1 +/‐ 32 (s.d.) h. In the elderly, it was 38.1 +/‐ 14.8 (s.d.) h. 5 These kinetic differences may have an important bearing on the sedative effects of mianserin.
Effects of acute and chronic cilazapril treatment in spontaneously hypertensive rats.
Authors: Fischli W , Hefti F , Clozel JP
Published: July 2012

1. The effects of acute and chronic treatment with cilazapril, a new ACE inhibitor, on peripheral vasculature and renal excretory function were assessed in spontaneously hypertensive rats. Regional blood flow and cardiac output were measured by the radioactive microspheres technique. 2. Acute treatment (3 mg kg‐1 intravenously) reduced mean arterial blood pressure from 171 +/‐ 7 to 140 241 +/‐ 7 mm Hg (P less than 0.001), chronic treatment (1 x 10 mg kg‐1 day‐1 orally for 9 weeks) from 191 +/‐ 5 to 122 +/‐ 3 mm Hg P less than 0.001). With both kinds of treatments cardiac output was unchanged. Heart rate was slightly decreased (‐9%, P less than 0.05) with chronic treatment. Acutely, the main effect of cilazapril was a decrease of the renal vascular resistance (‐41%, P less than 0.001) associated with an increase of the fraction of the cardiac output distributed to the kidney (+46%, P less than 0.001). Chronically, cilazapril decreased regional vascular resistance in most of the peripheral vascular beds except the heart. 3. With a high dose of cilazapril (10 mg kg‐1 orally) both acute and chronic treatment increased diuresis (+107% and +92%, P less than 0.001) and natriuresis (/124% and +111%, P less than 0.001) with a slight increase in kaliuresis. However, with a low dose (1 mg kg‐ 1 orally) the kidneys responded only to chronic treatment. 4. It is concluded that chronic treatment with cilazapril decreases arterial blood pressure more than acute treatment. This effect seems to be due to a greater peripheral vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)
Aspects of molecular biology and biochemistry of the cardiac renin‐ angiotensin system.
Authors: Lindpaintner K , Jin M , Wilhelm M , Toth M , Ganten D
Published: July 2012

1. Recent evidence for the existence of extrarenal tissue renin‐ angiotensin systems has raised the question of whether such a system also exists in the heart. 2. Evidence is presented for a cardiac renin‐ angiotensin system based on molecular biological and biochemical data. In addition, the question of whether the components of this system interact as a locally integrated, biologically functioning unit is addressed. 3. Using radio‐labelled cRNA probes prepared from specific cDNA fragments, renin and angiotensin gene expression in atria and ventricles of the rat heart have been documented by Northern blot and liquid hybridization analysis. Relative signal strength for both mRNAs was highest in the atria, followed by the right and left ventricle. 4. Using specific, h.p.l.c.‐controlled RIAs for angiotensin peptides, the presence of both angiotensin I and angiotensin II in all anatomical regions of the monkey and rat heart have been demonstrated; similarly, presence of converting enzyme activity was also ascertained by direct in vitro determinations. 5. Additional experiments evaluating the spontaneous release of angiotensin from rat isolated, perfused hearts revealed a bimodal pattern of high, but rapidly declining rates during the first hour (perhaps representing washout of a pool sequestrated from plasma), followed by a prolonged period of steady, low level release, consistent with the secretion of locally synthesized protein. 6. In separate experiments aimed at examining the possible local integration of the components of the cardiac renin‐angiotensin system, angiotensin II concentrations were measured in the coronary sinus effluent of rat isolated, perfused hearts.(ABSTRACT TRUNCATED AT 250 WORDS)
Effects of chronic heart failure on the responsiveness to angiotensin I and to angiotensin converting enzyme inhibition with cilazapril in rats.
Authors: Clozel JP
Published: July 2012

1. The effects of heart failure due to chronic myocardial infarction on the responsiveness to injected angiotensin I and ACE inhibition by intravenous cilazapril (1 mg kg‐1) were evaluated. 2. For this purpose one group of 17 rats with a 4‐week old myocardial infarction was compared with a group of 10 sham operated rats. 3. Heart failure increased markedly the responsiveness of the renal and mesenteric vascular beds to ACE inhibition which produced a vasodilation in these two vascular beds. 4. This increased responsiveness was most likely due to a stimulation of the renin‐angiotensin system without any change of sensitivity to angiotensin I of the renal and mesenteric vascular beds. 5. Cilazapril produced the same level of ACE inhibition in both groups of rats.
Involvement of the kallikrein‐kinin system in the antihypertensive effect of the angiotensin converting enzyme inhibitors.
Authors: Waeber B , Juillerat‐Jeanneret L , Aubert JF , Schapira M , Nussberger J , Brunner HR
Published: July 2012

1. Studies were performed in normal subjects and in rats to assess the effect of angiotensin converting enzyme (ACE) inhibition on the kallikrein‐kinin system. As ACE is identical to kininase II, one of the enzymes physiologically involved in bradykinin degradation, bradykinin may be expected to accumulate during ACE inhibition. 2. A competitive antagonist of bradykinin was used to explore in unanaesthetized rats the contribution of circulating bradykinin to blood pressure control under ACE inhibition. 3. No evidence was found for a role of this vasodilating peptide in the blood pressure lowering effect of acute ACE inhibition. 4. The plasma activity of carboxypeptidase N (= kininase I), another pathway of bradykinin degradation, remained intact during a 1 week course of treatment with an ACE inhibitor in normal subjects. This therefore indicates that bradykinin formed during ACE inhibition can still be metabolized.
Correlation between plasma concentration of cilazapril and haemodynamic and hormonal effects in healthy man.
Authors: Burnier M , Mooser V , Nussberger J , Waeber B , Brunner HR
Published: July 2012

1. The haemodynamic and humoral effects of cilazapril, a new angiotensin converting enzyme (ACE) inhibitor, were evaluated in normotensive healthy volunteers. 2. Single oral doses of 1.25, 2.5, 5 and 10 mg of cilazapril inhibited ACE by greater than or equal to 90% and induced the expected pattern of changes of the renin‐angiotensin‐ aldosterone‐system. 3. Cilazapril had a long duration of action, since some ACE inhibition was still present 72 h after drug intake. 4. Cilazapril administered intravenously at doses of 5 and 20 micrograms kg‐1 for 24 h did not produce any significant effects. 5. During repeated administration of cilazapril for 8 days, no accumulation of cilazaprilat was observed and the clinical tolerance was excellent. 6. In normal volunteers, cilazapril administered orally acts as a potent inhibitor of converting enzyme.
The assessment of ACE activity in man following angiotensin I challenges: a comparison of cilazapril, captopril and enalapril.
Authors: Essig J , Belz GG , Wellstein A
Published: July 2012

1. The aim of the studies was to develop a new methodology to estimate the pharmacodynamic properties and potency of angiotensin converting enzyme (ACE) inhibitors in man. 2. Angiotensin I dose‐response curves were derived by continuous infusion of angiotensin I in increasing dose steps; steady state was reached within 3 min. 3. Interaction between angiotensin I (agonist) and ACE inhibitors (antagonist) was characterized according to Schild‐plot methodology by measuring agonist dose‐response curves using diastolic blood pressure in the absence and the presence of varying doses of the antagonist. 4. Cilazapril shifted the angiotensin I dose‐response curves to the right. A twofold shift (apparent Ki‐dose) was observed with approximately 0.6 mg cilazapril. 5. The effect of angiotensin I on diastolic blood pressure was determined before and up to 36 h after administration of 25 mg captopril, 10 mg enalapril, 4 mg cilazapril and a placebo orally. The pharmacodynamic half‐life of captopril was about 2 h, whereas the effect of enalapril and cilazapril was about 4 h. 6. Angiotensin I dose‐ response curves are useful methods of investigating the pharmacodynamic properties of ACE‐inhibitors in man.
Effects of ACE inhibition with cilazapril on splanchnic and systemic haemodynamics in man.
Authors: Gasic S , Heinz G , Kleinbloesem C , Korn A
Published: July 2012

1. There is recent experimental evidence that the renin‐angiotensin‐ system may play an essential role in producing splanchnic vasoconstriction. However, controversy exists as to the influence of ACE inhibition on splanchnic haemodynamics in man. We therefore investigated whether cilazapril, a structurally new and long‐acting ACE inhibitor, interacts with angiotensin I‐dependent changes in splanchnic haemodynamics in man, using an experimental model. 2. The effects of cilazapril on angiotensin I‐induced splanchnic and systemic haemodynamics were studied in seven normotensive men using the hepatic venous catheter technique (indocyanine‐green dye), right‐heart catheterisation (thermodilution method), intra‐arterial blood pressure monitoring and systolic time‐intervals. Dose‐responses to angiotensin I were determined under control conditions and 60 min after ACE inhibition with 5 mg oral cilazapril. Angiotensin I was infused intravenously at constant rates in an increasing dose‐sequence until systolic blood pressure was greater than 30 mm Hg. 3. ACE inhibition with cilazapril did not change basal splanchnic or systemic haemodynamics to any relevant extent. The angiotensin I dependent increase in systemic and pulmonary resistance and pulmonary capillary wedge pressure was attenuated by cilazapril, as indicated by the shift of the dose‐response curves to the right. In the splanchnic vascular bed angiotensin I dose‐dependently increased splanchnic vascular resistance and also wedge hepatic venous pressure and decreased splanchnic blood flow. These angiotensin I induced haemodynamic changes were clearly suppressed by cilazapril. The angiotensin I dose needed to produce a 30% increase in splanchnic vascular resistance, given as mean and s.e. mean, was 1.7 +/‐ 0.3 micrograms min‐1 during control‐trials vs 7.3 +/‐ 1.3 micrograms min‐1 after ACE inhibition with cilazapril (P less than 0.001). 4. We conclude that, in man, the influence of cilazapril on acute angiotensin I‐mediated haemodynamic responses is present in the splanchnic vascular bed, and that the overall effects of cilazapril are consistent with both arterial and venous effects of the ACE inhibitor. Cilazapril effectively counteracts angiotensin I‐induced splanchnic vasoconstriction.
The effects of cilazapril alone and in combination with frusemide in healthy subjects.
Authors: Johnston GD , Passmore AP
Published: July 2012

1. In a fourway double‐blind placebo controlled study, the effects of cilazapril, a new angiotensin converting enzyme inhibitor, on renal function and the responses to intravenous frusemide were studied in a group of twelve salt depleted male volunteers. 2. Cilazapril produced an increase in effective renal plasma flow and urinary output of prostaglandin E2 metabolite (PGE2‐M) but no effect on sodium, potassium or water excretion. 3. Pretreatment with cilazapril antagonised the effects of frusemide on glomerular filtration, PGE2‐M and sodium excretion.
The effect of acute ACE inhibition on atrial natriuretic peptide.
Authors: Doorenbos CJ , van Brummelen P
Published: July 2012

1. The effect of acute angiotensin converting enzyme (ACE) inhibition on the plasma concentrations of atrial natriuretic peptide (ANP) was investigated in a single‐blind placebo controlled crossover study in healthy volunteers. 2. Intravenous infusion of 2 mg cilazaprilat resulted in a significant and short lasting inhibition of ACE as evidenced by a decrease of plasma angiotensin II and an increase in plasma renin activity. 3. When compared with placebo cilazaprilat lowered diastolic pressure and increased heart rate significantly. 4. No effect of cilazaprilat was found on plasma ANP levels, suggesting that angiotensin II does not mediate ANP release.
Antihypertensive effects of nitrendipine and cilazapril alone, and in combination in hypertensive patients with chronic renal failure.
Authors: Kloke HJ , Huysmans FT , Wetzels JF , Sluiter HE , Kleinbloesem CH , Koene RA
Published: July 2012

1. It has been reported that calcium antagonists lower blood pressure more effectively in salt replete hypertensive patients with a low plasma renin activity (PRA), whereas angiotensin converting enzyme (ACE) inhibitors are more effective in salt depleted patients with a high level of PRA. An inverse relationship between the antihypertensive effects of these two groups of drugs might therefore be expected. 2. Since salt retention and inappropriately high levels of PRA are said to contribute to hypertension in patients with chronic renal failure (CRF), an additive antihypertensive effect with both drugs might also be expected in such patients. 3. To test these hypotheses, we investigated the acute and chronic antihypertensive effects of the calcium antagonist nitrendipine and the new ACE inhibitor cilazapril, given alone, and in combination, in a double‐blind, randomized, placebo controlled study of 11 hypertensive patients with chronic renal failure who had a mean pretreatment blood pressure of 149 +/‐ 3/96 +/‐ 2 mm Hg. Patients received nitrendipine 10 mg, cilazapril 1.25 or 2.5 mg depending on creatinine clearance, or placebo once daily orally. Nitrendipine and cilazapril were also combined at the same doses. 4. Nitrendipine and cilazapril were equally effective, with a maximal acute reduction of mean arterial pressure (MAP) of 5.3 +/‐ 1.8% and 8.0 +/‐ 1.9%, and after 1 week of treatment 5.0 +/‐ 2.4% and 8.1 +/‐ 1.8%, respectively. In individual patients no inverse relationship between the blood pressure responses to the two drugs was found.(ABSTRACT TRUNCATED AT 250 WORDS)
The influence of prostaglandin inhibition by indomethacin on blood pressure and renal function in hypertensive patients treated with cilazapril.
Authors: Kirch W , Stroemer K , Hoogkamer JF , Kleinbloesem CH
Published: July 2012

1. In a placebo‐controlled double‐blind cross‐over study lasting 6 weeks, twenty patients with essential hypertension were treated with placebo for 2 weeks followed by oral cilazapril 2.5 mg once a day or oral indomethacin 50 mg twice daily for 2 weeks. Afterwards they received the combination of both drugs for a further 2 weeks. 2. Cilazapril significantly lowered systolic and diastolic blood pressure for a period of 24 h post administration. 3. Indomethacin significantly attenuated the antihypertensive activity of cilazapril. This was more pronounced in those patients who were treated for the initial 2 weeks with indomethacin plus placebo (and subsequently with cilazapril in addition) than in the subjects who first received cilazapril plus placebo and then the combination. 4. Correspondingly the decrease of plasma renin activity (PRA) and urinary prostaglandin excretion (PGE2) was more pronounced in those patients treated initially with indomethacin. 5. The effect of indomethacin on the antihypertensive effect of cilazapril appears to depend upon the sequence of drug administration.
The influence of cilazapril on indices of autonomic function in normotensives and hypertensives.
Authors: Elliott HL , Ajayi AA , Reid JL
Published: July 2012

1. In two single dose studies, acute blood pressure reduction with cilazapril was not associated with any significant change in supine or erect heart rate in either normotensives or hypertensives. 2. To investigate the lack of reflex cardioacceleration, a series of autonomic function tests was undertaken when there was maximum ACE inhibition, maximum evidence of angiotensin II withdrawal and the lowest blood pressure. 3. There was no evidence that cilazapril had any significant impact on indices of sympathetic nervous activity or the integrity of baroreflex mechanisms. 4. The results for the bradycardic response to apnoeic facial immersion, suggested enhanced parasympathetic activity, consistent with the withdrawal of the vagolytic actions of angiotensin II. 5. These results suggest that the absence of a heart rate response to ACE inhibition is not related to a profound sympatho‐inhibitory effect or an impairment of baroreflex function. While there is some evidence of enhanced cardiac parasympathetic tone it seems unlikely that this is the sole explanation for the lack of cardioacceleration.
Pharmacokinetics and effects on renal function following cilazapril and hydrochlorothiazide alone and in combination in healthy subjects and hypertensive patients.
Authors: Nilsen OG , Sellevold OF , Romfo OS , Smedsrud A , Grynne B , Williams PE , Kleinbloesem CH
Published: July 2012

1. Possible interactions between cilazapril and hydrochlorothiazide with respect to pharmacokinetics and renal effects were investigated in healthy subjects (single dose) and in hypertensive patients (multiple dosing). 2. No significant pharmacokinetic interaction was found between cilazapril and hydrochlorothiazide. 3. Cilazapril showed weak saluretic properties as compared with hydrochlorothiazide, but increased the saluretic effects of hydrochlorothiazide. 4. Cilazapril attenuated the hypokalaemia observed with hydrochlorothiazide in hypertensive patients. 5. The effect on blood pressure reduction obtained from the combination of cilazapril and hydrochlorothiazide lasted longer than that of cilazapril alone.
EEG brain mapping in evaluating the time‐course of the central action of DUP 996‐a new acetylcholine releasing drug.
Authors: Saletu B , Darragh A , Salmon P , Coen R
Published: July 2012

1. In a double‐blind, placebo‐controlled study the encephalotropic effects of DUP 996, a novel phenylindolinone derivative for Alzheimer's disease enhancing the release of acetylcholine in cholinergic nerve terminals in the brain only when its release is triggered, were studied with special consideration of the pharmacodynamic time‐course. 2. Thirteen healthy male volunteers aged 18‐40 years received randomized and at weekly intervals, single oral doses of placebo and 30 mg DUP 996. Blood sampling for plasma concentration analysis, EEG recordings and evaluation of pulse, blood pressure and side effects were carried out at 0, 1, 2, 4, 8, 12 and 24 h. 3. Computer‐assisted spectral analysis of the EEG and subsequent topographic brain mapping of the drug‐induced EEG changes demonstrated significant central effects of DUP 996 suggesting vigilance‐improving properties. The findings were characterized mostly by an augmentation of total power as well as by an increase of absolute power in the alpha and alpha‐adjacent beta activity. 4. Time‐course investigations demonstrated two pharmacodynamic peaks: a first one in the 2nd h and a second one in the 12th h. In detail CNS effects increased up to the 2nd h, showed a drop in the 4th h, increased again thereafter to peak in the 12th h. Even in the 24th h there were significant differences between DUP 996 and placebo. The latter suggests an indirect effect and/or an active metabolite, as the parent drug is rapidly absorbed and has a rather short plasma half‐life between 1‐3 h. 5. DUP 996‐induced EEG‐changes over time were most pronounced over temporo‐occipital, temporo‐frontal, parietal and frontal regions, e.g. over brain areas afflicted most by Alzheimer's disease. 6. Evaluation of vital signs, laboratory findings and ECG as well as adverse effects showed a very good tolerability of DUP 996.
The effect of pregnancy in humans on the pharmacokinetics of stable isotope labelled phenytoin.
Authors: Dickinson RG , Hooper WD , Wood B , Lander CM , Eadie MJ
Published: July 2012

1. To investigate the mechanism of the fall in steady‐state plasma phenytoin concentration relative to drug dose that occurs during pregnancy, single dose pharmacokinetic studies with stable isotope labelled phenytoin were carried out at different stages of pregnancy, and 2 to 4 months post‐natally, in five epileptic women receiving regular oral therapy with the drug. 2. Steady‐state apparent plasma clearances of phenytoin (dose/steady‐state concentration) correlated closely with simultaneous plasma clearances of the intravenous stable‐ isotope drug (measured as dose/AUC) suggesting that the patients were complaint with therapy when their phenytoin dosage requirement increased during the pregnancy, and that the oral drug was fully bioavailable. 3. In retrospect, two of the five subjects were probably studied too early post‐natally for phenytoin elimination kinetics to have returned to non‐pregnant values. Despite this, (i) the mean +/‐ s.d. t 1/2 for phenytoin was statistically significantly shorter in pregnancy than post‐natally (31 +/‐ 14 vs 39 +/‐ 28 h), (ii) the mean +/‐ s.d. whole plasma clearance was also statistically significant greater (0.025 +/‐ 0.012 vs 0.021 +/‐ 0.013 kg‐1 h‐1) and (iii) the mean +/‐ s.d. Vmax for phenytoin elimination was statistically significantly greater in pregnancy (1170 +/‐ 600 mg day‐1) than post‐ natally (780 +/‐ 470 mg day‐1). Although the mean +/‐ s.d. apparent Km was higher in pregnancy (18.2 +/‐ 8.4 mg l‐1, expressed in terms of whole plasma drug concentrations, compared with 10.2 +/‐ 7.4 mg l‐1 post‐natally), the difference was not statistically significant. However, if the apparent Km value was expressed in terms of plasma water phenytoin concentrations the difference (pregnant 2.50 +/‐ 0.85 mg l‐1: post‐natally 1.16 +/‐ 0.65 mg l‐1) was statistically significant. 4. Human pregnancy appears to result in an increased capacity to eliminate phenytoin.
Effect of quinidine on the dextromethorphan O‐demethylase activity of microsomal fractions from human liver.
Authors: Broly F , Libersa C , Lhermitte M , Bechtel P , Dupuis B
Published: July 2012

1. The kinetics of dextromethorphan O‐demethylation were measured in microsomes prepared from five human livers, both in the absence and in the presence of quinidine. 2. For each liver and over the concentration range of dextromethorphan examined (4.2‐3400 microM), this reaction involved an enzymatic component of high affinity, with an apparent Michaelis‐Menten constant (Km) of 4.6 +/‐ 1.8 microM (mean +/‐ s.d.) and a maximum velocity (Vmax) of 4.2 +/‐ 3.5 nmol mg‐1 h‐1 (mean +/‐ s.d.). 3. Quinidine was a potent and competitive inhibitor of the activity of this component (mean Ki +/‐ s.d. of 0.025 +/‐ 0.008 microM) as it is for other oxidation reactions which have already been found to co‐segregate with the debrisoquine‐type polymorphism. 4. With microsomes from four of the five livers studied, there was evidence of a second enzymatic component of activity characterized by a similar Vmax and about 20‐fold higher Km compared with the high affinity component. The activity of this low affinity component was unaffected by quinidine in the concentrations studied.
Comparison of Sawchuk‐Zaske and Bayesian forecasting for aminoglycosides in seriously ill patients.
Authors: Denaro CP , Ravenscroft PJ
Published: July 2012

1. Individual pharmacokinetic parameters and predicted steady‐state serum concentrations of aminoglycosides were calculated by Sawchuck‐ Zaske (SZ) and Bayesian methods. 2. Predicted concentrations were compared with observed steady‐state concentrations for 36 seriously ill patients with systemic infections. Four aminoglycoside concentrations were used for the SZ method. Differing numbers of serum aminoglycoside samples were used in the Bayesian parameter estimation: one sample Bayesian used one post‐infusion concentration, two sample Bayesian used a trough plus one post‐infusion concentrations and four sample Bayesian used a trough plus three post‐infusion concentrations. 3. 79% of the SZ predictions were with +/‐ 2 mg l‐1 of the observed peak concentrations, and 72% of the two sample Bayesian predictions were within the same range. 82% of SZ and the two sample Bayesian predictions were within +/‐ 1 mg l‐1 of the observed trough concentrations. 4. A confidence interval comparison of estimated pharmacokinetic parameters and precision for the predicted concentrations showed no important differences between the SZ and the two sample Bayesian. The four sample Bayesian was the most precise method. 5. We conclude that the Bayesian forecasting method utilizing a trough plus one post‐infusion concentrations is as useful as the SZ method which requires three to four serum concentrations in individualizing aminoglycoside therapy for seriously ill patients.