Current Clinical Pharmacology

ISSN: 1574-8847

Current Clinical Pharmacology
Volume 3, Number 2, May 2008

Contents


Validating Diagnostic Tests, Correct and Incorrect Methods, New Developments Pp. 70-76
Ton J. Cleophas, Jolanda Droogendijk and Bas M. van Ouwerkerk
[Abstract]


Pioglitazone and Rosiglitazone: Effects of Treatment with a Thiazolidinedione on Lipids and Non Conventional Cardiovascular Risk Factors Pp. 77-84
Giuseppe Derosa and Sibilla A.T. Salvadeo
[Abstract]


Targeted Therapies in Breast Cancer: Established Drugs and Recent Developments Pp. 85-98
Jeanett Fischgräbe and Pia Wülfing
[Abstract]


Radiopharmaceuticals in Neurological and Psychiatric Disorders Varvara Valotassiou, Greta Wozniak, Nikolaos Sifakis, Pp. 99-107
Nikolaos Demakopoulos and Panagiotis Georgoulias
[Abstract]


Enhancing the Cytotoxic Activity of Novel Targeted Therapies – Is There a Role for a Combinatorial Approach? Pp. 108-117
Wai Man Liu
[Abstract]


Efficacy and Safety Evaluation of Fixed Dose Combination of Cefepime and Amikacin in Comparison with Cefepime Alone in Treatment of Nosocomial Pneumonia Patients Pp. 118-122
Manu Chaudhary, Sanjay Mohan Shrivastava, Lallu Varughese and Rajesh Sehgal
[Abstract]


Amyloid Beta Protein and Tau in Cerebrospinal Fluid and Plasma as Biomarkers for Dementia: A Review of Recent Literature Pp. 123-131
Suzanne V. Frankfort, Linda R. Tulner, Jos P.C.M. van Campen, Marcel M. Verbeek, René W.M.M. Jansen and Jos H. Beijnen
[Abstract]


The Molecular Basis of Class Side Effects Due to Treatment with Inhibitors of the VEGF/VEGFR Pathway Pp. 132-143
Jeanine M. Roodhart, Marlies H. Langenberg, Els Witteveen and Emile E. Voest
[Abstract]




Abstracts


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Validating Diagnostic Tests, Correct and Incorrect Methods, New Developments
Ton J. Cleophas, Jolanda Droogendijk and Bas M. van Ouwerkerk

Background: Clinical developments of new treatments are impossible without adequate diagnostic tests. Several working parties including the Consolidated Standard Randomized Trials (CONSORT) movement and the Standard for Reporting Diagnostic Accuracy (STARD) group have launched quality criteria for diagnostic tests. Particularly, accuracy-, reproducibility- and precision-assessments have been recommended, but methods of assessment have not been defined so far.

Objective: To summarize correct and incorrect methods and new developments for that purpose.

Results and conclusions: A diagnostic test can be either qualitative like the presence of an elevated erythrocyte sedimentation rate to demonstrate pneumonia, or quantitative like ultrasound flow velocity to estimate invasive electromagnetic flow velocity.

Qualitative diagnostic tests can be assessed for

-accuracy using sensitivity / specificity / overall accuracy, and receiver operated (ROC) curves,
-reproducibility using Cohen’s kappas,
-precision using confidence intervals of sensitivity / specificity / overall accuracy.

Quantitative diagnostics tests can be assessed for

-accuracy using a linear regression line (y = a + b x) and testing a = 0.00 / b = 1.00,
-reproducibility using duplicate standard errors, repeatability coefficients or intraclass correlations,
-precision by calculating confidence intervals. Improved confidence intervals can be obtained by data modeling.

A significant linear correlation between the diagnostic test and the gold standard test does not correctly indicate adequate accuracy. A small mean difference between repeated measures or a significant linear relationship between repeated measures does not indicate adequate reproducibility.

New developments include continuous ROC curves, intraclass correlations, and Bland-Altman agreement tests for the accuracy assessments of quantitative diagnostic tests.


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Pioglitazone and Rosiglitazone: Effects of Treatment with a Thiazolidinedione on Lipids and Non Conventional Cardiovascular Risk Factors
Giuseppe Derosa and Sibilla A.T. Salvadeo

The so-called central or upper-body obesity has been shown to play a key role in the development of insulin resistance and lipid abnormalities that commonly are associated with metabolic syndrome. Reducing free fatty acids (FFA) levels improves insulin resistance and lipid profile in metabolic syndrome. The established approach to improving FFA metabolism in obesity is based on inhibition of lipolysis, weight loss and treatment with thiazolidinediones (TZDs). Thiazolidinediones effect on lipids and lipid metabolism will be reviewed, particularly as regard their activity on the abnormal FFA metabolism, related to insulin-resistance. The many questions still unsolved about the molecular mechanisms, the large spectrum of action and the similarities and differences between rosiglitazone and pioglitazone action on lipid metabolism have been reviewed as well as the effect of these new insulin-sensitizers on non conventional cardiovascular risk factors.


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Targeted Therapies in Breast Cancer: Established Drugs and Recent Developments
Jeanett Fischgräbe and Pia Wülfing

In the past few years many encouraging advancements have been made in understanding the molecular mechanisms underlying carcinogenesis and tumor progression. These improvements have led to the identification of promising new targets for cancer therapy. There has been much success with the HER2 targeting antibody trastuzumab (Herceptin^®) in the treatment of early stage and metastatic breast cancer. Consequently, several antibodies inhibiting cellular signaling of VEGF and EGFR were tested with respect to their efficacy in breast cancer. In phase II and III clinical trials the humanized anti-VEGF antibody bevacizumab (Avastin^®) alone or in combination with capecitabine exhibited responses in patients with metastatic breast cancer. Recent developments focus on small molecules interfering with different signal transduction pathways in tumor cells. Numerous inhibitors of EGF and VEGF receptor tyrosine kinases and farnesyl transferases are in early stages of clinical development for breast cancer. Another promising approach is the targeting of endothelins and their two G-protein coupled receptors (ET_AR und ET_BR). In this article, we will shortly outline well established targeted treatments and discuss the current development of novel agents to be utilized for molecular targeted breast cancer therapy. Due to the heterogeneity of disease and varying response to conventional systemic therapies, these new perceptions may lead to substantial patient benefit and provide a promising basis for future clinical application.


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Radiopharmaceuticals in Neurological and Psychiatric Disorders Varvara Valotassiou, Greta Wozniak, Nikolaos Sifakis, Nikolaos Demakopoulos and Panagiotis Georgoulias

The development of functional brain nuclear medicine techniques and their application in the investigation of neuropsychiatric disorders, have contributed significantly in the illumination of the underlying pathophysiological processes of these disorders. Furthermore, Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) brain studies provide information in early diagnosis, differential diagnosis, development of new drugs, and monitoring the response to therapeutic management.

SPECT and PET brain imaging require the use of radiopharmaceuticals that cross the intact Blood Brain Barrier (BBB). Such radiotracers have been used in regional Cerebral Blood Flow (rCBF) SPECT and PET imaging and brain metabolism imaging with PET; these are well established methods in the diagnosis and management of various cerebral vascular diseases (e.g. stroke, dementia, epilepsy).

Advances in radiotracer chemistry have resulted in the development of molecular imaging which represents the molecular and cellular processes of neurochychiatric diseases. SPECT and PET molecular imaging has become available for the study of acetylcholinergic, dopaminergic and serotonergic systems, as well as for benzodiazepine and opioid receptors, with promising results. More studies are needed to validate the role of molecular imaging in the clinical practice of neuropsychiatric disorders.


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Enhancing the Cytotoxic Activity of Novel Targeted Therapies – Is There a Role for a Combinatorial Approach?
Wai Man Liu

The increased understanding of the pathogenetic and oncogenic pathways underlying cancer has allowed the successful development of novel approaches to treating the disease. The use of drugs to correct specific genetic defects responsible for the biological behaviour of cancer cells has been successfully applied to the clinic. These have included agents that interfere with cell proliferation and cell cycle signalling, neo-vascularisation, and DNA integrity. As a number of these processes also determine cellular survival, these novel agents can work to lower the cytotoxic threshold for conventional drugs. Consequently, a combinatorial drug approach could potentially be a valuable strategy for improving therapy. Unfortunately, targeting and inactivating a single pathway can adversely promote redundant parallel signalling pathways, which then maintain the aberrant status quo. Indeed, the intrinsic heterogeneity of tumours can preclude the successful application of a single targeted therapy. However, combinatorial drug approaches can be employed to surmount this multi-faceted characteristic of cancer.

This article will highlight a number of novel targeted therapies that have been developed, some of which are currently undergoing clinical evaluation, and will also appraise the potential beneficial interactions that they may have with convetional cytotoxic drugs.


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Efficacy and Safety Evaluation of Fixed Dose Combination of Cefepime and Amikacin in Comparison with Cefepime Alone in Treatment of Nosocomial Pneumonia Patients
Manu Chaudhary, Sanjay Mohan Shrivastava, Lallu Varughese and Rajesh Sehgal

Nosocomial pneumonia is the most frequent and leading cause of morbidity and mortality. Pseudomonas aeruginosa the most frequent causative agent is intrinsically resistant to most antibiotics. The study was aimed at comparing the efficacy and safety of fixed dose combination (FDC) of Cefepime and Amikacin with that of Cefepime alone in treatment of patients suffering from nosocomial pneumonia.

Patients (n=200) suffering from nosocomial pneumonia participated in an open labeled, two arm, randomized, compara-tive, multicentric trial. One group (n=100) of patients were treated with intravenous injection of Cefepime and Amikacin FDC 2.5 g b.i.d and other group (n=100) of patients were treated with intra-venous injection of Cefepime alone 2.0 g b.i.d, for 7–10 days. Outcome of therapy was evaluated on the basis of clinical and bacteriological evaluation.

Clinical and bacteriological successful outcomes were significantly higher in the patients treated with Cefepime and Amikacin FDC than Cefepime alone treated patients. Analysis of patients infected with Pseudomonas aeruoginosa amongst the two treatment arms indicated that clinical and bacteriological success rate is significantly higher in Cefepime and Amikacin FDC treated patients than Cefepime alone treated group. No major adverse events were observed in both the treatment arms.

In conclusion, fixed dose combination of Cefepime and Amikacin was more effective in the treatment of nosocomial pneumonia than Cefepime alone.


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Amyloid Beta Protein and Tau in Cerebrospinal Fluid and Plasma as Biomarkers for Dementia: A Review of Recent Literature Suzanne V. Frankfort, Linda R. Tulner, Jos P.C.M. van Campen, Marcel M. Verbeek, René W.M.M. Jansen and Jos H. Beijnen

This review addresses recent developments in amyloid β (Aβ), total tau (t-tau) and phosporylated tau (p-tau) protein analysis, in cerebrospinal fluid (CSF) and plasma as biomarkers for dementia. Recent research focused on the progression of patients with mild cognitive impairment (MCI) into dementia and the differential diagnosis of Alzheimer´s Disease (AD).

A combination of Aβ42 and t-tau in CSF can discriminate between patients with stable MCI and patients with progressive MCI into AD or other types of dementia with a sufficient sensitivity and specificity. Regression analyses demonstrated that pathological CSF (with decreased Aβ42 and increased tau levels) is a very strong predictor for the progression of MCI into AD.

Furthermore, CSF measurements of p-tau and Aβ42 can assist in diagnosing vascular dementia or frontotemporal dementia in the differential diagnosis of AD indicated by a reasonable sensitivity and specificity. Whether tau in combination with Aβ42 or in combination with the Aβ37/Aβ42 or Aβ38/Aß42 ratio aids in the discrimination between AD and Lewy Body dementia remains to be elucidated.

Cross-sectional research could not demonstrate significant differences for Aβ40 and Aβ42 in plasma between AD and controls. However, a recently published longitudinal study showed high baseline Aβ40 levels, especially when combined with low baseline Aβ42 levels, is a strong risk factor for the development of dementia. This emphasises the importance of performing longitudinal studies in addition to cross-sectional ones. The origin of plasma Aβ and its transport between CSF and plasma, however, needs further clarification.

In conclusion, progress has been made regarding Aβ and tau as biomarkers for dementia both for differentiation between stable MCI and progressive MCI patients and for the differential diagnosis of AD. Future research should aim to validate these recently published results, preferably in pathologically confirmed AD patients. In addition, it is important to standardise research in terms of study design (longitudinal, minimal follow-up period of 5 years), type of researched parameters (total or p-tau, type of Aβ peptides), type of matrix (CSF and plasma) and data analysis (establishment of predefined cut-off values, type of ratio, type of marker combination).


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The Molecular Basis of Class Side Effects Due to Treatment with Inhibitors of the VEGF/VEGFR Pathway
Jeanine M. Roodhart, Marlies H. Langenberg, Els Witteveen and Emile E. Voest

Vascular Endothelial Growth Factor (VEGF) is considered to be one of the most important regulators of angiogenesis and a new key target in anti-cancer treatment. Various clinical trials have validated the clinical importance of anti-VEGF or anti-VEGF receptor (VEGFR) therapy. Currently the humanized monoclonal antibody bevacizumab (blocks VEGF-A), and the tyrosine kinase inhibitors sunitinib and sorafenib (inhibit VEGFRs) are approved for patients with various malignancies and several others are expected in the coming years. Unfortunately, anti-VEGF/VEGFR treatment is not void of side effects. An array of unexpected side effects is now seen in clinical practice. Management of these side effects is extremely important in the development of the various anti-VEGF/VEGFR therapies and their optimal use. This review provides an overview of the toxicity profile of this class of agents, the molecular basis behind these side effects and indicates potential options for management.

VEGF and its receptors play an important role in normal tissues and are widely expressed. It is likely that interference with this pathway induces an array of side effects due to the lack of normal function of VEGF. A consistent pattern of side effects is now emerging. Hypertension, gastro-intestinal toxicity, hypothyroidism, proteinuria, coagulation disorders and neurotoxicity are side effects observed with both anti-VEGF and anti-VEGFR inhibitors. For these side effects the role of VEGF/VEGFR pathway in normal tissue was reviewed in order to provide a molecular mechanism that linked side effect with physiological activity of VEGF/VEGFR. Insight into the molecular basis may aid specific supportive care measures to ensure optimal use of this class of agents.

Conclusion: Inhibiting the VEGF/VEGFR pathway is an effective approach to treat cancer. It has also provided new insight into the physiological role of this pathway in various organs. Integrating the knowledge in daily oncological practice will be a challenge for the future.