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Biomedical subjects

W Martin

Publications and source records attributed to W Martin.

At least 37 records · Page 2Linked to original sources
PubMed2002

The effect of food on the pharmacokinetics of nifedipine in two slow release formulations: pronounced lag-time after a high fat breakfast.

AIMS: The aim of this study was to investigate the effect of concomitant food intake on the bioavailability of two nifedipine containing modified release dosage forms for once daily administration. The clinical study was performed to investigate the in vivo relevance of pH-dependent differences in the in vitro release properties of the two dosage forms. METHODS: This was a randomized, open, 4-way crossover study in 24 healthy, male subjects. Following an overnight fast of 12 h single doses of Adalat OROS or Slofedipine XL were administered either in the fasted state or immediately after a high fat American breakfast. Nifedipine plasma concentrations in samples obtained until 48 h after drug administration were determined using a validated LC-MS/MS method. Calculation of pharmacokinetic parameters was conducted model-independently. The two dosage forms as well as the two administration conditions were compared by calculating point estimates and 90% confidence intervals for the relevant pharmacokinetic parameters. In vitro dissolution tests were performed using a paddle apparatus 3 acc. USP, a pharmacopoeial dissolution system consisting of reciprocating cylinders in flat-bottomed glass vessels, with various buffer systems covering the entire physiological pH-range of the gastrointestinal tract. RESULTS: After fasted administration the extent of bioavailability of nifedipine as characterized by AUC(0,infinity) was slightly lower for Slofedipine XL compared with Adalat OROS with a point estimate of 82.3% primarily resulting from pronounced differences in nifedipine concentrations during the first 15 h after administration. Accordingly, maximum plasma concentrations were lower after administration of Slofedipine XL compared with Adalat OROS (point estimate: 84.3%). Under fed conditions the differences in bioavailability between the two products as characterized by the pharmacokinetic parameters AUC(0,tn) and Cmax were greater than after fasting conditions with point estimates of 69.6% and 81.0%, respectively. However, most striking was a pronounced delay in nifedipine absorption observed under fed conditions after administration of Slofedipine XL which resulted in lag-times of more than 15 h in 15 out of 24 subjects. Owing to this lag-time under fed conditions the relative bioavailability of nifedipine from Slofedipine XL compared with Adalat OROS was only 28% over the intended dosing interval of 24 h. CONCLUSIONS: In this study a dosage form-dependent food interaction was observed which, under fed conditions, resulted in pronounced differences in the relative bioavailability of nifedipine between Slofedipine XL and Adalat OROS over the intended dosing interval of 24 h. The delay in nifedipine absorption when Slofedipine XL is administered after a high-fat breakfast may be explained by the formulation properties. Slofedipine XL is an erosive tablet with an acid resistant coating whereas Adalat OROS is designed with an osmotic push-pull system. Under fed conditions drug from the single unit enteric coated dosage form exhibits a delayed absorption probably due to an extensively prolonged gastric residence time which does not allow drug release, on the other hand the osmotically driven push-pull system is not sensitive to concomitant food intake. The observed phenomenon might be of therapeutic relevance. For example a change from taking Slofedipine XL in the fed to the fasted state might result in increased systemic concentrations of nifedipine.

Administration, Oral↗
PubMed2002

Inhibition of transforming growth factor (TGF)-beta1-induced extracellular matrix with a novel inhibitor of the TGF-beta type I receptor kinase activity: SB-431542.

Transforming growth factor beta1 (TGF-beta1) is a potent fibrotic factor responsible for the synthesis of extracellular matrix. TGF-beta1 acts through the TGF-beta type I and type II receptors to activate intracellular mediators, such as Smad proteins, the p38 mitogen-activated protein kinase (MAPK), and the extracellular signal-regulated kinase pathway. We expressed the kinase domain of the TGF-beta type I receptor [activin receptor-like kinase (ALK)5] and the substrate, Smad3, and determined that SB-431542 is a selective inhibitor of Smad3 phosphorylation with an IC50 of 94 nM. It inhibited TGF-beta1-induced nuclear Smad3 localization. The p38 mitogen-activated protein kinase inhibitors SB-203580 and SB-202190 also inhibit phosphorylation of Smad3 by ALK5 with IC50 values of 6 and 3 microM, respectively. This suggests that these p38 MAPK inhibitors must be used at concentrations of less than 10 microM to selectively address p38 MAPK mechanisms. However, the p38 MAPK inhibitor SB-242235 did not inhibit ALK5. To evaluate the relative contribution of Smad signaling and p38 MAPK signaling in TGF-beta1-induced matrix production, the effect of SB-431542 was compared with that of SB-242235 in renal epithelial carcinoma A498 cells. All compounds inhibited TGF-beta1-induced fibronectin (FN) mRNA, indicating that FN synthesis is mediated in part via the p38 MAPK pathway. In contrast, SB-431542, but not the selective p38 MAPK inhibitor SB-242235, inhibited TGF-beta1-induced collagen Ialpha1 (col Ialpha1). These data indicate that some matrix markers that are stimulated by TGF-beta1 are mediated via the p38 MAPK pathway (i.e., FN), whereas others seem to be activated via ALK5 signaling independent of the p38 MAPK pathway (i.e., col Ialpha1).

Activin Receptors, Type I↗
PubMed2001

From genome to vaccine: in silico predictions, ex vivo verification.

Bioinformatics tools enable researchers to move rapidly from genome sequence to vaccine design. EpiMer and EpiMatrix are computer-driven pattern-matching algorithms that identify T cell epitopes. Conservatrix, BlastiMer, and Patent-Blast permit the analysis of protein sequences for highly conserved regions, for homology with other known proteins, and for homology with previously patented epitopes, respectively. Two applications of these tools to epitope-driven vaccine design are described in this review. Using Conservatrix and EpiMatrix, we analyzed more than 10000 HIV-1 sequences and identified peptides that were potentially immunostimulatory and highly conserved across HIV-1 clades. MHC binding assays and CTL assays have been carried out: 50 (69%) of the 72 candidate epitopes bound in assays with cell lines expressing the corresponding MHC molecule; 15 of the 24 B7 peptides (63%) stimulated gamma-interferon release in ELISpot assays. These results lend support to the bioinformatics approach to selecting novel, conserved, HIV-1 CTL epitopes. EpiMatrix was also applied to the entire 'proteome' derived from two Mycobacterium tuberculosis (Mtb) genomes. Using EpiMatrix, BlastiMer, and Patent-Blast, we narrowed the list of putative Mtb epitopes to be tested in vitro from 1600000 to 3000, a 99.8% reduction. The pace of vaccine design will accelerate when these and other bioinformatics tools are systematically applied to whole genomes and used in combination with in vitro methods for screening and confirming epitopes.

AIDS Vaccines↗
PubMed2001

Targeting drug delivery to radiation-induced neoantigens in tumor microvasculature.

Radiation can be used to guide drugs to specific sites such as neoplasms or aberrant blood vessels. When blood vessels are treated with ionizing radiation, they respond by expressing a number of cell adhesion molecules and receptors that participate in homeostasis. Examples of radiation-induced molecules in blood vessels include ICAM-1, E-selectin, P-selectin and the beta(3) integrin. We have observed that the endothelium and blood components respond to oxidative stress in a similar, if not identical manner in all tumor models. Although we have identified several other radiation-induced molecules within tumor blood vessels, the beta(3) target for drug delivery achieves the greatest site-specific peptide binding within irradiated tumor blood vessels. We have focused on peptides and antibodies that bind to integrin beta(3). beta(3)-binding proteins have been conjugated to fluorochromes and radionuclides to study the site specificity and microscopic distribution. We have found immunofluorescent and immunohistochemical staining of beta(3) within the lumen of blood vessels immediately following irradiation. To determine whether it is feasible to guide drug delivery to irradiated tumors, we studied ligands to alpha(2b)beta(3) (fibrinogen). Peptides within fibrinogen that bind to alpha(2b)beta(3) includes the dodecapeptide, HHLGGAKQAGDV and the RGD peptide. We utilized 131I conjugation to these ligands to study the biodistribution in tumor bearing mice. Our clinical trial consists of the RGD peptidomimetic, biapcitide, labeled with 99mTc. This study shows that it is feasible to guide drugs to human neoplasms by use of radiation-guided peptides. These studies have shown that peptides that bind to these integrins bind to tumors following exposure to ionizing radiation.

Amino Acid Sequence↗
PubMed2001

A randomized, controlled trial of remacemide for motor fluctuations in Parkinson's disease.

BACKGROUND: Preclinical studies suggest that glutamate antagonists help ameliorate motor fluctuations in patients with PD treated with levodopa. METHODS: In a multicenter, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study, the authors assessed the safety, tolerability, and efficacy of the glutamate receptor blocker remacemide hydrochloride in 279 patients with motor fluctuations treated with levodopa. The primary objective was to assess the short-term tolerability and safety of four dosage levels of remacemide during 7 weeks of treatment. Patients were also monitored with home diaries and the Unified PD Rating Scale (UPDRS) to collect preliminary data on treatment efficacy. RESULTS: Remacemide was well tolerated up to a dosage of 300 mg/d on a twice daily schedule and 600 mg/d on a four times daily schedule. The most common dosage-related adverse events were dizziness and nausea, as observed in previous studies of remacemide. The percent "on" time and motor UPDRS scores showed trends toward improvement in the patients treated with 150 and 300 mg/d remacemide compared with placebo-treated patients, although these improvements were not significant. CONCLUSION: Remacemide is a safe and tolerable adjunct to dopaminergic therapy for patients with PD and motor fluctuations. Although this study had limited power to detect therapeutic effects, the observed improvement is consistent with studies of non-human primates with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonian signs and symptoms. Additional studies are warranted to confirm these results over an extended period of observation, and to explore the potential neuroprotective effects of remacemide in slowing the progression of PD.

Acetamides↗
PubMed2001

Role of copper ions and cytochrome P450 in the vasodilator actions of the nitroxyl anion generator, Angeli's salt, on rat aorta.

Since copper ions catalyse the oxidation of nitroxyl anion to nitric oxide, we investigated whether this might explain the vasodilator actions of the nitroxyl generator, Angeli's salt, in rat aorta. Parallel studies were conducted with S-nitroso-N-acetyl-D,L-penicillamine (SNAP), since Cu ions catalyse the liberation of nitric oxide from this compound. Copper sulphate enhanced relaxation to Angeli's salt and SNAP but this resulted from reduced destruction of nitric oxide by superoxide rather than from enhanced generation of nitric oxide, since it was mimicked by superoxide dismutase and by the superoxide dismutase mimetic, MnCl2. Results with the selective Cu2+ chelators, neocuproine and bathocuproine disulfonate, and the Cu2+ chelators, EDTA, cuprizone and diethyldithiocarbamate, confirmed an important role for endogenous copper in mediating relaxation to SNAP but suggested only a minor role for Angeli's salt. Relaxation to Angeli's salt was, however, powerfully blocked by proadifen, suggesting an important role for cytochrome P450.

Animals↗
PubMed2001

How many genes in Arabidopsis come from cyanobacteria? An estimate from 386 protein phylogenies.

It is well known that chloroplasts and mitochondria donated many genes to nuclear chromosomes during evolution - but how many is "many"? A sample of 3961 Arabidopsis nuclear protein-coding genes was compared with the complete set of proteins from yeast and 17 reference prokaryotic genomes, including one cyanobacterium (the lineage from which plastids arose). The analysis of 386 phylogenetic trees distilled from these data suggests that between approximately 400 (1.6%) and approximately 2200 (9.2%) of Arabidopsis nuclear genes stem from cyanobacteria. The degree of conservation preserved in protein sequences in addition to lateral gene transfer between free-living prokaryotes pose substantial challenges to genome phylogenetics.

Arabidopsis↗
PubMed2001

How do mitochondrial genes get into the nucleus?

It is well known that genes from chloroplasts and mitochondria were transferred to the nucleus many times during plant evolution. But in what form do the transferred genes physically make that intracellular journey--as RNA, as cDNA, as pieces of organelle DNA, or as whole organelle chromosomes? Current views focus upon cDNA as the vehicle, based upon some examples from plants. But other mechanisms, involving direct transfer of DNA from organelle chromosomes, could also account for the available data. Direct DNA transfer, rather than cDNA-mediated transfer, does occur today, and it probably prevailed during the early phases of organelle evolution.

Cell Nucleus↗
PubMed2001

Validation of an echocardiographic wall motion index in heart failure due to ischaemic heart disease.

AIMS: The echocardiographic assessment of left ventricular ejection fraction (LVEF) by geometric methods is limited in many patients because of inadequate views and also in the presence of regional wall motion abnormalities due to ischaemic heart disease (IHD). This study aimed to examine the application of a wall motion index (WMI) method, using a nine-segment LV model in patients with chronic heart failure (CHF) due to IHD. METHODS AND RESULTS: Echocardiography was performed in 71 consecutive subjects with CHF due to IHD. WMI could be derived in 70 subjects (99%). The inter-observer variability (repeatability coefficient) of WMI was 0.66, i.e. LVEF+/-20%. In 66 subjects, LVEF was measured, within 4 weeks, using radionuclide ventriculography (RNV-EF). The inter-observer variability of RNV-EF was +/-3.1%. Using the mean of two observations for each method, the Bland-Altman range of agreement for LVEF was 26% (+/-13%). CONCLUSION: WMI is a widely applicable echocardiographic method for assessing LV systolic function and has moderate agreement with RNV-EF. Unlike RNV-EF, however, WMI is not likely to be a suitable method for the measurement of small, but prognostically important, changes in LV function that may occur in CHF.

Aged↗
PubMed2001

Formation of nitric oxide from nitroxyl anion: role of quinones and ferricytochrome c.

1. Our previous finding that copper ions oxidize nitroxyl anion released from Angeli's salt to nitric oxide prompted us to examine if copper-containing enzymes shared this property. 2. The copper-containing enzyme, tyrosinase, which catalyses the hydroxylation of monophenols to diphenols and the subsequent oxidation of these to the respective unstable quinone, failed to generate nitric oxide from Angeli's salt by itself, but did so in the presence of tyrosine. 3. L-DOPA, the initial product of the reaction of tyrosinase with tyrosine, was not the active species, since it failed to generate nitric oxide from Angeli's salt. Nevertheless, L-DOPA and two other substrates, namely, catechol and tyramine did produce nitric oxide from Angeli's salt in the presence of tyrosinase, suggesting involvement of the respective unstable quinones. In support, we found that 1,4-benzoquinone produced a powerful nitric oxide signal from Angeli's salt. 4. Coenzyme Q(o), an analogue of ubiquinone, failed to generate nitric oxide from Angeli's salt by itself, but produced a powerful signal in the presence of its mitochondrial complex III cofactor, ferricytochrome c. 5. Experiments conducted on rat aortic rings with the mitochondrial complex III inhibitor, myxothiazol, to determine if this pathway was responsible for the vascular conversion of nitroxyl to nitric oxide were equivocal: relaxation to Angeli's salt was inhibited but so too was that to unrelated relaxants. 6. Thus, certain quinones oxidize nitroxyl to nitric oxide. Further work is required to determine if endogenous quinones contribute to the relaxant actions of nitroxyl donors such as Angeli's salt.

Animals↗
PubMed2001

Dominant role of an endothelium-derived hyperpolarizing factor (EDHF)-like vasodilator in the ciliary vascular bed of the bovine isolated perfused eye.

1. The roles of the endothelium-derived nitric oxide, prostacyclin and endothelium-derived hyperpolarizing factor (EDHF) in mediating vasodilator responses to acetylcholine and bradykinin were assessed in the ciliary vascular bed of the bovine isolated perfused eye preparation. 2. Vasodilatation to acetylcholine or bradykinin was unaffected by the nitric oxide synthase inhibitor, L-NAME (100 microM), or the cyclo-oxygenase inhibitor, flurbiprofen (30 microM), but was virtually abolished following treatment with a high concentration of KCl (30 mM), or by damaging the endothelium with the detergent, CHAPS (0.3%, 2 min). 3. Acetylcholine-induced vasodilatation was unaffected by glibenclamide (10 microM), an inhibitor of ATP-sensitive K(+) channels (K(+)(ATP)), but was significantly attenuated by TEA (10 mM), a non-selective inhibitor of K(+) channels. 4. The small conductance calcium-sensitive K(+) channel (SK(+)(Ca)) inhibitor, apamin (100 nM), and the large conductance calcium-sensitive K(+) channel (BK(+)(Ca)) inhibitor, iberiotoxin (50 nM), had no significant effect on acetylcholine-induced vasodilatation. In contrast, the intermediate (IK(+)(Ca))/large conductance calcium-sensitive K(+) channel inhibitor, charybdotoxin (50 nM), powerfully blocked these vasodilator responses, and uncovered a vasoconstrictor response. 5. The combination of apamin (100 nM) with a sub-threshold concentration of charybdotoxin (10 nM) significantly attenuated acetylcholine-induced vasodilatation, but the combination of apamin (100 nM) with iberiotoxin (50 nM) had no effect. 6. In conclusion, blockade by a high concentration of KCl, by charybdotoxin, or by the combination of apamin with a sub-threshold concentration of charybdotoxin, strongly suggests that vasodilatation in the bovine isolated perfused eye is mediated by an EDHF.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed2001

Purification and cloning of chloroplast 6-phosphogluconate dehydrogenase from spinach. Cyanobacterial genes for chloroplast and cytosolic isoenzymes encoded in eukaryotic chromosomes.

Previous attempts to purify chloroplast 6-phosphogluconate dehydrogenase (cp6PGDH), a key enzyme of the oxidative pentose phosphate pathway, have been unsuccessful due to rapid activity loss. An efficient purification protocol was developed and the enzyme from spinach leaves was purified 1000-fold to apparent homogeneity with a specific activity of 60 U.mg-1. The enzyme is a homodimer with subunits of 50 kDa. Antibodies raised against the purified cp6PGDH detected a 53-kDa protein from a crude extract, indicating alterations during purification. Purified cp6PGDH was microsequenced and the corresponding spinach cDNA was cloned using PCR techniques and degenerate primers. The cDNA for cytosolic 6PGDH from spinach was cloned for comparison. Phylogenetic analysis in the context of available homologues from eukaryotes and eubacteria revealed that animal and fungal cytosolic 6PGDH sequences are more similar to their homologues from gamma-proteobacteria, whereas plant 6PGDH is more similar to its cyanobacterial homologues. The ancestral gene for higher plant 6PGDH was acquired from the antecedent of plastids through endosymbiosis and gene transfer to the nucleus. A subsequent gene duplication gave rise to higher plant cytosolic 6PGDH, which assumed the function of its pre-existing cytosolic homologue through endosymbiotic gene replacement. The protein phylogeny of both 6PGDH and of the first enzyme of the oxidative pentose phosphate pathway, glucose-6-phosphate dehydrogenase, indicate a surprisingly close relationship between the plant and Trypanosoma brucei lineages, suggesting that T. brucei (a relative of Euglena gracilis) may be secondarily nonphotosynthetic.

Amino Acid Sequence↗
PubMed2001

The role of myocardial perfusion scanning, heart rate variability and D-dimers in predicting the risk of perioperative cardiac complications after peripheral vascular surgery.

OBJECTIVES: To study the value of a number of proposed prognostic factors in prediction of the risk of perioperative cardiac events after vascular surgery. DESIGN AND METHODS: Two hundred and ninety-seven patients undergoing peripheral vascular surgery were prospectively studied. Patients underwent preoperative 24 h ambulatory electrocardiography, measurement of haemostatic variables, myocardial assessment of perfusion by dipyridamole-thallium scintigraphy and radionuclide ventriculography. The primary endpoint was cardiac death or nonfatal myocardial infarction within 30 days of surgery. A combined endpoint included the primary endpoint plus occurrence of cardiac failure, unstable angina or serious arrhythmias. RESULTS: The primary endpoint occurred in 21 (7%), and the combined endpoint in 41 (14%) of patients. On multivariate analysis, increased age, previous myocardial infarction, aortic surgery, impaired heart rate variability and a positive thallium scan were independent predictors of primary end-points. Preoperative atrial fibrillation and increased fibrin D-dimer were additional predictors of the combined endpoint. Construction of receiver-operator characteristic curves to examine the incremental value of predictive models showed that sensitivity and specificity of clinical data alone for primary endpoints was 71% and 72% respectively, while for the full model (incorporating heart rate variability and thallium data) this rose to 84% and 80% (p=0.0001). CONCLUSIONS: Preliminary screening using clinical data has limited value in risk assessment prior to vascular surgery but preoperative heart rate variability, D-dimers and thallium scanning provide modest incremental predictive value.

Aged↗
PubMed2001

Are ejection fractions from gated SPECT perfusion studies clinically useful? A comparison with radionuclide ventriculography.

Gated SPECT (GSPECT) was evaluated for the measurement of left ventricular ejection fraction (LVEF) by comparing with equilibrium gated radionuclide ventriculography (RNVG). A total of 99 subjects underwent GSPECT and RNVG imaging. All studies were acquired in list mode with GSPECT studies processed to give 16- and 8-frames per R-R interval, and RNVG studies 24 frames per R-R interval. The Cedars-Sinai QGS software was used to calculate ejection fraction from GSPECT studies. RNVG studies were processed using a manually drawn single region of interest technique. Comparison of LVEF from GSPECT with RNVG yielded correlation coefficients of 0.82 and 0.81 for 16- and 8-frame GSPECT studies respectively. The mean 95% prediction interval was 33 +/- 11 percentage points for both 16- and 8-frame studies, indicating a great disparity between predicted ejection fraction values from GSPECT and actual RNVG values. Subgroup analysis of 29 patients with pathological Q-wave evidence of myocardial infarction demonstrated a poorer correlation coefficient of r = 0.69. Subgroup analysis of 32 patients with end-diastolic volumes < 100 ml demonstrated a poorer correlation coefficient of r = 0.32. Ejection fractions calculated from 16- and 8-frame studies showed a correlation of 0.99 with a mean 95% prediction interval of 8.7 +/- 0.04 percentage points. The 8-frame studies underestimated LVEF by 3.6 +/- 2.3% compared to the 16-frame studies. In conclusion, left ventricular ejection fractions calculated using the QGS algorithm from GSPECT studies are inadequate for use in clinical practice.

Adult↗
PubMed2001

Pyruvate : NADP+ oxidoreductase from the mitochondrion of Euglena gracilis and from the apicomplexan Cryptosporidium parvum: a biochemical relic linking pyruvate metabolism in mitochondriate and amitochondriate protists.

Most eukaryotes perform the oxidative decarboxylation of pyruvate in mitochondria using pyruvate dehydrogenase (PDH). Eukaryotes that lack mitochondria also lack PDH, using instead the O(2)-sensitive enzyme pyruvate : ferredoxin oxidoreductase (PFO), which is localized either in the cytosol or in hydrogenosomes. The facultatively anaerobic mitochondria of the photosynthetic protist Euglena gracilis constitute a hitherto unique exception in that these mitochondria oxidize pyruvate with the O(2)-sensitive enzyme pyruvate : NADP oxidoreductase (PNO). Cloning and analysis of Euglena PNO revealed that the cDNA encodes a mitochondrial transit peptide followed by an N-terminal PFO domain that is fused to a C-terminal NADPH-cytochrome P450 reductase (CPR) domain. Two independent 5.8-kb full-size cDNAs for Euglena mitochondrial PNO were isolated; the gene was expressed in cultures supplied with 2% CO(2) in air and with 2% CO(2) in N(2). The apicomplexan Cryptosporidium parvum was also shown to encode and express the same PFO-CPR fusion, except that, unlike E. gracilis, no mitochondrial transit peptide for C. parvum PNO was found. Recombination-derived remnants of PNO are conserved in the genomes of Saccharomyces cerevisiae and Schizosaccharomyces pombe as proteins involved in sulfite reduction. Notably, Trypanosoma brucei was found to encode homologs of both PFO and all four PDH subunits. Gene organization and phylogeny revealed that eukaryotic nuclear genes for mitochondrial, hydrogenosomal, and cytosolic PFO trace to a single eubacterial acquisition. These findings suggest a common ancestry of PFO in amitochondriate protists with Euglena mitochondrial PNO and Cryptosporidium PNO. They are also consistent with the view that eukaryotic PFO domains are biochemical relics inherited from a facultatively anaerobic, eubacterial ancestor of mitochondria and hydrogenosomes.

Amino Acid Sequence↗
PubMed2001

Radiation-mediated control of drug delivery.

Clinical trials of radiotherapy to control drug delivery were initiated in 1999 at Vanderbilt University. The initial studies exploited the findings that platelets are activated in tumor blood vessels after high-dose irradiation as used in radiosurgery and high-dose-rate brachytherapy. Platelets labeled with 111In showed binding in tumor blood vessels. However, the platelet labeling process caused platelets to also accumulate in the spleen. That clinical trial was closed, and subsequent clinical trials targeted protein activation in irradiated tumor blood vessels. Preclinical studies showed that peptide libraries that bind within irradiated tumor blood vessels contained the peptide sequence Arg-Gln-Asp (RGD). RGD binds to integrin receptors (e.g., receptors for fibrinogen, fibronectin, and vitronectin). We found that the fibrinogen receptor (GPIIb/IIIa, alpha2bbeta3) is activated within irradiated tumor blood vessels. RGD peptidemimetics currently in clinical trials include GPIIb/IIIa antagonists and the platelet-imaging agent biapcitide. Biapcitide is an RGD mimetic that is labeled with 99Tc to allow gamma camera imaging of the biodistribution of the GPIIb/IIIa receptor in neoplasms of patients treated with radiosurgery. This study has shown that the schedule of administration of the RGD mimetic is crucial. The peptide mimetic must be administered immediately before irradiation, whereas the natural ligands to the receptor compete for biapcitide binding if biapcitide is administered after irradiation. The authors currently are conducting a dose deescalation study to determine the threshold dosage required for RGD mimetic binding to radiation activated receptor. Radiation-guided clinical trials have been initiated by use of high-dose-rate brachytherapy. In a separate trial, the pharmacokinetics of radiation-inducible gene therapy are being investigated. In this trial, the radiation-activated promoter Egr-1 regulates expression of the tumor necrosis factor alpha gene, which is administered by use of the attenuated adenovirus vector. The Ad.Egr-TNF (ADGV) gene is administered by intratumoral injection of vector followed by irradiation in patients with soft-tissue sarcomas. This review highlights recent findings in these phase I pharmacokinetic studies of radiation-controlled drug delivery systems.

Animals↗