[Show abstract][Hide abstract] ABSTRACT: Microdosing provides a tool to enhance drug development by initiating human studies prior to Phase I studies. The purpose is to assist in the go versus no-go decision-making process and to eliminate early ineffective compounds from the drug pipeline. Selection of multiple potential leads can be performed at the clinical stage instead of in preclinical studies. The microdosing approach can be easily used for a molecularly targeted potential drug compound with a known mechanism of action. It provides useful data regarding accessibility and biodistribution that can be used in many estimations benefiting the development of the molecule. In addition, steady state and genetic investigations are becoming possible. Microdosing has a sparing effect on timelines and costs, however, the real importance is not yet known because, although it is known to be widely performed, only a few original reports have been published.
[Show abstract][Hide abstract] ABSTRACT: Purpose: Multidrug resistance (MDR) is a significant obstacle to successful chemotherapy and a major prognostic factor in osteosarcoma
(OS). We have previously observed that the chemosensitivity of OS cell lines to doxorubicin depends on P-glycoprotein (Pgp)
and can be predicted based on functional assays using 99mTc-Sestamibi (MIBI). These results prompted us to develop an orthotopic
model of OS for in vivo imaging of MDR and pharmacological inhibition with MIBI.
Methods: Sensitive (143B) and resistant (MNNG) OS cell lines expressing different levels of Pgp and carrying a luciferase reporter
gene were inoculated into the tibia of nude mice. Local tumor growth was monitored weekly by bioluminescence imaging and X-ray.
After primary tumor growth, the animals were imaged with MIBI during 60 min. A group of animals were pre-treated with a Pgp
inhibitor (PSC833). Images were analyzed for calculation of MIBI washout half-life (t1/2) and T/NT uptake ratios.
Results: A progressively increasing bioluminescent signal was detected at 1-2 weeks after cells inoculation. The t1/2 of MIBI in drug resistant MNNG-tumors (t1/2 = 87.3±15.7 min) was significantly (pt1/2 = 161.0±47.4 min). Administration of PSC833 increased significantly the retention of MIBI in MNNG-tumors (t1/2 = 173.0±24.5 min) and had no significant effects in 143Btumors. The T/NT ratio was significantly (p
[Show abstract][Hide abstract] ABSTRACT: Cardiovascular disease is the major cause of death worldwide. Apart from the traditional risk factors of smoking, hypertension and diabetes, high homocysteine plasma concentrations have also been suggested as a factor causing atherosclerosis. It has been shown that this amino acid is able to activate the immune system in such a way that monocyte chemotaxis to the injured vessel wall (a major feature of atherosclerosis) is enhanced. In addition, high homocysteine levels may induce highly reactive oxygen species that inactivate nitric oxide (NO), an important vascular relaxing factor. High homocysteine levels have also been associated with altered lipid metabolism and increased uptake of modified low-density lipoprotein (LDL) by macrophages in the vessel wall. Numerous observational studies have demonstrated high homocysteine levels in patients with atherosclerotic disease, including myocardial infarction and cerebral stroke. However, over the past two decades, various highly powered, large, randomized, controlled and population-based studies have failed to show a relationship between homocysteine levels and the risk of vascular diseases, with the exception of stroke, calling into question whether high homocysteine levels represent a risk factor or merely a risk indicator. Furthermore, folic acid treatment alters the methylation potential, which may induce carcinogenesis. A number of well-designed epidemiological studies are still under way and at present it seems best to adhere to a wait-and-see policy. Copyright 2008 Prous Science, S.A.U. or its licensors. All rights reserved.
Drugs of the Future 05/2008; 33(5). DOI:10.1358/dof.2008.033.05.1191555 · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Tetrahydrofolate is derived from folate and serves as a backbone for single-carbon transfer reactions. The donation of one-carbon units, such as methyl and methylene, is crucial for nucleotide synthesis and consequently for proper DNA formation and gene regulation. The biochemical pathways of dietary methionine produce S-adenosylmethionine, which is the universal methyl donor and a precursor for homocysteine. To save methionine for the body, homocysteine can be converted to methionine. This bioreaction shares the reaction process with the folate bioreaction cycle. Thus, dietary folate and methionine are biochemically linked and folate intake may reduce homocysteine levels. This explains why homocysteine is a sensitive marker for folate deficiency and reduced biomethylation. The results of various epidemiological studies suggest a link between low folate intake and an increased risk of various malignancies, such as cancer of the breast, ovary, esophagus, pancreas, lung, cervix and, notably, colorectal cancer. There is ample preclinical evidence that folate depletion induces hypomethylation in essential coding regions, which may result in dysfunctional tumor suppressor genes and DNA repair mechanisms. In addition to hypomethylation, hypermethylation is also frequently associated with cancer, which suggests that aberrant methylation creates suitable conditions for malignant cells to proliferate. This brings about a valid concern that both folate deficiency and excessive use of folic acid supplementation may increase the risk of cancer. This article reviews the present knowledge on the relationship between folate intake and the risk of cancer.
Drugs of the Future 04/2008; 33(4). DOI:10.1358/dof.2008.033.04.1185671 · 0.17 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Skeletal infection continues to be a common and difficult condition in clinical practice and early accurate diagnosis is very challenging. Clinical and laboratory features of skeletal infections are not always present, may be confusing, and are nonspecific for bone infection in its early stages, therefore, several imaging modalities are used for early detection of osteomyelitis. Plain films should always be the first step in the imaging assessment of osteomyelitis, however, the sensitivity for X-ray radiography has been reported to range from 43% to 75%, and the specificity from 75% to 83%. Over years, scintigraphic procedures have become an essential part of the diagnostic procedure for osteomyelitis. The standard approach for bone scintigraphy with tech 99mTc labeled methylene diphosphonate to assess for osteomyelitis is to perform a three-phase procedure. The positive uptake on all three phases is highly sensitive for osteomyelitis (sensitivity 73% to 100%). 67Ga citrate gained more attention for the more specific diagnosis of osteomyelitis due to its known capacity to localize in cases of active infection and pus. The reported specificity for 67Ga scintigraphy in osteomyelitis is around 67-70% and the specificity is much higher (92%) when 67Ga single photon emission tomography was obtained. Labeled white blood cell (WBC) imaging has become the procedure of choice to diagnose most cases of skeletal infections except for those of the spine. Labeling of leucocytes can be done either by 111In or 99mTc labeled hexamethylpropylene amineoxime. The sensitivity and specificity for labeled WBCs are in the high range of 80% to 90%. [18F]fluorodeoxyglucose positron emission tomography (PET) has been found to accumulate non-specifically at sites of infection and inflammation. Investigational studies showed that PET is particularly valuable in the evaluation of chronic osteomyelitis and infected prostheses. Other imaging modalities include sonography, computed tomography (CT) and magnetic resonance imaging (MRI). The sensitivity and specificity of CT for the diagnosis of osteomyelitis has not been established clearly and are in the range of 65% to 75%. The sensitivity of MRI for osteomyelitis has been generally reported as being between 82% and 100%, and specificity between 75% and 96%. Cases of osteomyelitis commonly referred to diagnostic imaging departments include chronic osteomyelitis, diabetic foot infections, vertebral osteomyelitis, joint prostheses and patients with suspected reinfection. These specific entities need special attention and careful selection of the correct tracer or combination of imaging modalities that is best suited for the proper therapeutic management protocols.
The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.. 10/2006; 50(3):167-92. · 2.03 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The outcome of antifungal therapy depends on the progression of the infection at the start of therapy. Unfortunately, most patients are diagnosed once the fungal infection has progressed considerably as a result of the non-specific clinical signs of fungal infections in immunocompromised patients and the poor sensitivity of current mycological diagnostic tests. This review will highlight current fungal diagnostic techniques and will focus on scintigraphic methods for the specific detection of fungal infections in mice. For this purpose, antifungal components (e.g. fluconazole and antifungal peptides) are radiolabeled e.g. with technetium-99m ((99m)Tc) and their in vivo distribution is monitored in infected mice. It has been demonstrated that (99m)Tc-fluconazole is an excellent tracer to detect Candida albicans infections in mice as it distinguishes these infections from bacterial infections and sterile inflammations. However, this radiopharmaceutical only poorly detects infections with Aspergillus fumigatus in mice. (99m)Tc-peptides derived from antifungal peptides/proteins, such as human ubiquicidin and lactoferrin, can distinguish C. albicans and A. fumigatus infections from sterile inflammations, but not from bacterial infections, in mice. Furthermore, the efficacy of fluconazole in C. albicans-infected mice could be successfully monitored using (99m)Tc-ubiquicidin. In conclusion, neither (99m)Tc-fluconazole nor the (99m)Tc-peptides tested are optimal tracers for fungal infections. Nonetheless, since early initiation of antifungal therapy for candidemia reduces its high mortality rate, a positive result with (99m)Tc-fluconazole scintigraphy is of clinical relevance. Finally, the possibility that other (radiolabeled) antifungal agents, e.g. voriconazole, caspofungin, antifungal plant or insect defensins, can be useful for detection of fungal infections should be considered.
Current Drug Targets 01/2006; 6(8):945-54. DOI:10.2174/138945005774912753 · 3.02 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Glomerular function of all long-term survivors who underwent hemopoietic stem cell transplantation (HSCT) from 1991 to 1998 (study I, n=121) was studied retrospectively. In addition, we prospectively analyzed glomerular and tubular function of all long-term surviving children who received an HSCT between 1998 and 2000 (study II, n=41). We found a lower prevalence of children with chronic renal failure (CRF) post-HSCT in our more recent cohort (study II: 10%) as compared to the older cohort (study I: 24%) 5.0 (0.7 s.d.) and 7.6 (2.4 s.d.) year's post-HSCT, respectively. Furthermore, it seems that renal function may stabilize after 1-year post-HSCT. None of the patients required dialysis or antihypertensive medication at long-term follow-up. The sole predictor of CRF in our study was high serum creatinine pre-HSCT (P=0.007), while acute renal failure within 3 months after HSCT (P=0.08) only showed a trend towards predicting CRF. We could not confirm a relation of conditioning with irradiation with CRF post-HSCT, as was shown in several other pediatric and adult studies. Proximal and distal tubular dysfunction only occurred in a minority of long-time survivors of HSCT (3-12 and 9-13%, respectively) and had no clinical consequences.
Bone Marrow Transplantation 11/2005; 36(7):605-10. DOI:10.1038/sj.bmt.1705110 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Technetium-99m (Tc-99m) is the radionuclide of choice for nuclear medicine imaging. However, some radiotracers are still labeled with radioiodine, which has various detrimental characteristics. Among these agents is the radioiodine-labeled guanethidine analogue MIBG (metaiodobenzylguanidine), which is used for the study of cardiac innervation. This scintigraphic depiction of the innervation patterns is of clinical importance to evaluate the function of the cardiac sympathetic nervous system. This paper reviews the possibilities of developing a Tc-99m-labeled radiotracer that has adrenergic specificity. This search has resulted in four agents which, with some effort, can be labeled with 99mTc and have the potential to be used for diagnostic purposes: epinephrine, metahydroxyepinephrine, desipramine and atomoxetine. In order to avoid pharmacological effects, the final product after labeling should be (nearly) carrier-free.
Drugs of the Future 10/2005; 30(10). DOI:10.1358/dof.2005.030.10.927378 · 0.17 Impact Factor