An imaging approach for determining the mechanism of enhancement of intestinal absorption of an L-theanine supplement.

BACKGROUND & OBJECTIVE: Theanine (L-glutamylethylamide) contained in green tea is a functional food component that has been attracting attention due to its relaxation effect. It was shown that the ingredients added to the theanine formulations increased the absorption of theanine. If this mechanism can be elucidated, it would be possible to contribute to development of evidence-based formulations. In this study, we investigated the effect of ingredients in the formulations on the absorption of theanine in detail. MAIN METHODS: After oral administration of a mixture of theanine and additional components to Wistar rats the plasma concentration was determined by an HPLC and the pharmacokinetic parameters were calculated. In addition, a new system for evaluating intestinal blood flow was developed since the involvement of intestinal blood flow was considered as a factor that increased absorption of theanine. KEY FINDINGS: Plasma concentration of theanine increased significantly in the combined use group with eight ingredients containing piperine as compared with theanine only group. Piperine would increase theanine absorption by increased blood flow, not an inhibition of metabolism. We succeeded to develop a visual and quantitative system to evaluate the effect of these ingredients directly including piperine on the intestinal blood flow using indocyanine green while maintaining physiological conditions. SIGNIFICANCE: Increased intestinal blood flow by these ingredients including piperine enhanced the absorption of theanine. Other mechanisms may also be considered as the mechanism by which theanine absorption is increased in addition to increased blood flow.

L-Theanine regulates glutamine metabolism and immune function by binding to cannabinoid receptor 1.

l-Theanine is a characteristic amino acid in tea with various effects including antioxidant and anti-inflammatory effects. Previously, most studies had reported that l-theanine regulates the immune function in vivo by inhibiting the expression of the inflammatory factors, but how l-theanine regulates the inflammatory factors' pathway is not known. In this study, we innovatively found the binding target of l-theanine in vivo-cannabinoid receptor 1, and demonstrated that l-theanine regulated the immune function and glutamine metabolism by competitively binding cannabinoid receptor 1. Mechanistically, l-theanine competitively binds cannabinoid receptor 1, leading to inhibition of cannabinoid receptor 1 activity, and regulates glutamine metabolism and immune function in normal and E44813-stressed rats. In normal rats, l-theanine inhibits ERK1/2 phosphorylation through Gßy by antagonizing cannabinoid receptor 1, thus affecting GS expression. From the point of view of immune signaling, after LTA antagonizes the activity of cannabinoid receptor 1, it relieves the inhibition of cannabinoid receptor 1 on COX-2 expression, downregulates Pdcd4 expression and NFκB, and ultimately enhances the expression of the anti-inflammatory factor IL-10. In E44813-stressed rats, l-theanine promotes the nuclear translocation of p-ERK1/2 by inhibiting the activity of cannabinoid receptor 1, and finally acts on GS. At the same time, it decreases the expression of the pro-inflammatory factor TNF-α and increases the expression of the anti-inflammatory factor IL-10 in stressed rats through the COX2-Pdcd4-NFκB-IL10 and TNFα pathways. In summary, these results demonstrate that l-theanine regulates glutamine metabolism and immune function by competitively binding to cannabinoid receptor 1.

Enantiomers of 2-methylglutamate and 2-methylglutamine selectively impact mouse brain metabolism and behavior.

Imbalance of excitatory and inhibitory neurotransmission is implicated in a wide range of psychiatric and neurologic disorders. Here we tested the hypothesis that insertion of a methyl group on the stereogenic alpha carbon of L-Glu or L-Gln would impact the γ-aminobutyric acid (GABA) shunt and the glutamate-glutamine cycle. (S)-2-methylglutamate, or (S)-2MeGlu, was efficiently transported into brain and synaptosomes where it was released by membrane depolarization in a manner equivalent to endogenous L-Glu. (R)-2MeGlu was transported less efficiently into brain and synaptosomes but was not released by membrane depolarization. Each enantiomer of 2MeGlu had limited activity across a panel of over 30 glutamate and GABA receptors. While neither enantiomer of 2MeGlu was metabolized along the GABA shunt, (S)-2MeGlu was selectively converted to (S)-2-methylglutamine, or (S)-2MeGln, which was subsequently slowly hydrolyzed back to (S)-2MeGlu in brain. rac-2MeGln was also transported into brain, with similar efficiency as (S)-2MeGlu. A battery of behavioral tests in young adult wild type mice showed safety with up to single 900 mg/kg dose of (R)-2MeGlu, (S)-2MeGlu, or rac-2MeGln, suppressed locomotor activity with single ≥ 100 mg/kg dose of (R)-2MeGlu or (S)-2MeGlu. No effect on anxiety or hippocampus-dependent learning was evident. Enantiomers of 2MeGlu and 2MeGln show promise as potential pharmacologic agents and imaging probes for cells that produce or transport L-Gln.

Potential effective inhibitory compounds against Prostate Specific Membrane Antigen (PSMA): A molecular docking and molecular dynamics study.

One of the most prevalent cancers in men is prostate cancer and could be managed with immunotoxins or antibody treatment. Because of the substantial rise of the Prostate-Specific Antigen and the Prostate-Specific Membrane Antigen (PSMA), cancer vaccination should be rendered with these antigens. Through pharmacodynamic experiments in a library of natural compounds from ZINC database, the current research sought to identify compounds that could suppress PSMA protein. To test the most productive compounds for further research, the Library has been scanned with Pharmacophore and ADMET analysis followed by molecular docking methods in the first phase. After selecting 15 ligands with the best pose related to docking results, to evaluate the stability of the ligand-protein bounds of the compounds, a molecular dynamics simulation considering the effect of the presence of zinc ions on the protein structure was performed. The measurement of ligand binding modes and free energy has shown that four compounds, including Z10, Z06, Z01, and Z03, have formed critical interactions with the active site's residues. Besides, multiple approaches were employed to determine their inhibition rating and describe the variables that facilitate the attachment of ligands to the protein active site. The results are obtained from the MMPBSA/GBSA analysis of four selected small molecules (Z10, Z06, Z01, and Z03), which are very close to the IC50 value of reference ligand (DCIBzl); they are -13.85 kcal/mol, -12.58 kcal/mol, -10.71 kcal/mol and -9.39 kcal/mol respectively. Finally, we evaluate the results obtained from selected ligands using hydrogen bond and decomposition analyzes. We have examined the effective interactions between ligands and S1/S1'pockets in protein. Our computational results illustrate the design of more efficient inhibitors of PSMA.

A chemical-specific adjustment factor for human interindividual differences in kinetics for glutamates (E620-625).

Use of a default methodology for establishment of a health-based guidance value (HBGV) resulted in a group acceptable daily intake (ADI) for glutamates (E620-625) below the normal dietary glutamate intake, and also lower than the intake of free glutamate by breast fed babies. Use of a chemical-specific adjustment factor (CSAF) may overcome this problem. The present study investigates the interindividual human variability in glutamate plasma and brain levels in order to define a CSAF for the interindividual variation in kinetics, a HKAF, for glutamates. Human clinical data on plasma glutamate levels available from different groups of subjects at Mitsui Memorial Hospital as well as literature data on plasma and brain-related glutamate levels were collected and analysed. The median HKAF value obtained amounted to 2.62-2.74 to 2.33-2.52 for plasma derived values and to 1.68-1.81 for brain derived values. Combining these values with the CSAF for the interspecies differences in kinetics of 1 and the default factors for interspecies and interindividual differences in dynamics of 2.5 and 3.16 results in an overall CSAF of 16-20. Using this CSAF will result in a HBGV for glutamate that is no longer below the acceptable range of oral intake (AROI).

N-(2-18F-fluoropropionyl)-l-glutamate as a potential oncology tracer for PET imaging of glioma.

N-(2-18F-fluoropropionyl)-l-glutamate (18F-FPGLU), a new N-substituted 18F-labeling l-glutamate, is a potential amino acid tracer for oncology PET imaging with good tumor-to-background contrast in several tumor-bearing mice. Herein, we evaluated the potential value of 18F-FPGLU for PET imaging of glioma in orthotopic glioma-bearing SD rats. A series of competitive inhibition experiments with various types of inhibitors were conducted with C6 cells to investigate the transport mechanism of 18F-FPGLU in glioma. Establishment of orthotopic rat C6 glioma-bearing SD rats models was confirmed by MRI. Then PET imaging of 18F-FPGLU was performed on the orthotopic C6 glioma-bearing SD rats and compared with that of 18F-FDG. After the rats sacrificed, the whole brain was collected and immunofluorescence staining of glial fibrillary acidic protein (GFAP) and matrix metalloproteinase 2 (MMP2) were processed. Na+-dependent system XAG- and Na+-independent system XC- are the mainly transporters of 18F-FPGLU in C6 cells. N-methyl-d-aspartate (NMDA) receptor, which is associated with the invasiveness and proliferation of glioma cells, is also involved in the uptake of 18F-FPGLU. High uptake and retention of 18F-FPGLU was observerd in orthotopic glioma with good visualization and the tumor/background ratio reached 2.35 at 60 min post-injection, which was significantly higher than that of 18F-FDG (1.72) in small-animal PET images. High expression of MMP-2 and GFAP was observed in the immunofluorescence staining of glioma xerography slices. 18F-FPGLU seems to be a better potential PET tracer than 18F-FDG for brain glioma imaging with good visualization and ability to assess the tumor activity.

Fabrication of poly(D, L-lactic acid) nanoparticles as delivery system for sustained release of L-theanine.

L-theanine is present in tea as a unique, free, non-protein amino acid. Due to various beneficial effects on brain activity, it is widely used as a nutraceutical. After consumption, it is rapidly absorbed and metabolised followed by excretion through urine. Therefore, the authors developed an L-theanine delivery system by encapsulating into polymeric nanoparticles to release it slowly and make it available for a longer period of time. Poly(D, L-lactic acid) nanoparticle (PLANP) was fabricated by the double emulsion method and L-theanine was encapsulated into it (PLANP-T). Spherical nanoparticles with a hydrodynamic diameter of 247 and 278 nm and surface charge of -14.5 and -25.7 mV for PLANP and PLANP-T, respectively, were fabricated. The Fourier transform infrared spectroscopic data indicated encapsulation of L-theanine into PLANP. The PLANP showed high L-theanine encapsulation capacity (71.65%) with a sustained release character. The maximum release (66.3%) of L-theanine was recorded in pH 7.3 at 48 h. The release kinetics followed the Higuchi model and the release mechanism was determined as super case-II transport (erosion). This slow release will make it available to the target tissue for a longer period of time (sustain release effect) and will also avoid immediate metabolism and clearance from the circulation.

A Bivalent Inhibitor of Prostate Specific Membrane Antigen Radiolabeled with Copper-64 with High Tumor Uptake and Retention.

Molecules containing lysine-ureido-glutamate functional groups bind to the active site of prostate specific membrane antigen, which is overexpressed in prostate cancer. To prepare copper radiopharmaceuticals for the diagnosis and therapy of prostate cancer, macrobicyclic sarcophagine ligands tethered to either one or two lysine-ureido-glutamate functional groups through an appropriate linker have been prepared. Sarcophagine ligands can be readily radiolabeled with positron-emitting copper-64 at room temperature. The bivalent agent, in which two targeting groups are tethered to a single copper complex, dramatically outperforms the monomeric agent with respect to tumor uptake and retention. The high tumor uptake, low background, and prolonged tumor retention, even at 24 hours post injection, suggest the bivalent agent is a promising diagnostic for prostate cancer and could be used for prospective dosimetry for therapy with a copper-67 variant.

Double-blind, randomized, placebo-controlled study of trofinetide in pediatric Rett syndrome.

OBJECTIVE: To determine safety, tolerability, and pharmacokinetics of trofinetide and evaluate its efficacy in female children/adolescents with Rett syndrome (RTT), a debilitating neurodevelopmental condition for which no pharmacotherapies directed at core features are available. METHODS: This was a phase 2, multicenter, double-blind, placebo-controlled, parallel-group study, in which safety/tolerability, pharmacokinetics, and clinical response to trofinetide were characterized in 82 children/adolescents with RTT, aged 5 to 15 years. Sixty-two participants were randomized 1:1:1:1 to receive placebo twice a day (bid) for 14 days, followed by placebo, 50, 100, or 200 mg/kg bid of trofinetide for 42 days. Following blinded safety data review, 20 additional participants were randomized 1:1 to the 200 mg/kg or placebo bid groups. Safety assessments included adverse events, clinical laboratory tests, physical examinations, and concomitant medications. Clinician- and caregiver-based efficacy measurements assessed clinically relevant, phenotypic dimensions of impairment of RTT. RESULTS: All dose levels were well tolerated and generally safe. Trofinetide at 200 mg/kg bid showed statistically significant and clinically relevant improvements relative to placebo on the Rett Syndrome Behaviour Questionnaire, RTT-Clinician Domain Specific Concerns-Visual Analog Scale, and Clinical Global Impression Scale-Improvement. Exploratory analyses suggested that observed changes correlated with trofinetide exposure. CONCLUSION: These results, together with those from a previous adolescent/adult trial, indicate trofinetide's potential for treating core RTT symptoms and support further trials. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children/adolescents with RTT, trofinetide was safe, well-tolerated, and demonstrated improvement over placebo at 200 mg/kg bid in functionally important dimensions of RTT.

Theanine: the unique amino acid in the tea plant as an oral hepatoprotective agent.

For thousands of years, humans have consumed tea made from leaves of Camellia sinensis, first as a medicinal herb and then as a widely popular beverage. In the past 10 years, theanine, a tea-derived, unique, nonproteinic amino acid, has been extensively studied for its health benefits. Recently, multiple lines of evidence have proven its beneficial effects on hepatic and immune functions. One possible mechanism for its biological activity involves the downregulation of the inflammatory response through the induction of nitric oxide production and glutathione synthesis. In this review, we summarize published results describing the potential mechanisms for these beneficial health effects and provide new insight into how theanine can be therapeutic for liver injury and chronic liver disease.

Preliminary evaluation of prostate-targeted radiotherapy using (131) I-MIP-1095 in combination with radiosensitising chemotherapeutic drugs.

OBJECTIVES: Despite recent advances in the treatment of metastatic prostate cancer, survival rates are low and treatment options are limited to chemotherapy and hormonal therapy. (131) I-MIP-1095 is a recently developed prostate-specific membrane antigen (PSMA)-targeting, small molecular weight radiopharmaceutical which has anti-tumour activity as a single agent. Our purpose was to determine in vitro the potential benefit to be gained by combining (131) I-MIP-1095 with cytotoxic drug treatments. METHODS: Various cytotoxic agents were evaluated in combination with (131) I-MIP-1095 for their capacity to delay the growth of LNCaP cells cultured as multicellular tumour spheroids. Two end-points were used to assess treatment efficacy: (i) the time required for doubling of spheroid volume and (ii) the area under the volume-time growth curves. KEY FINDINGS: The PARP-1 inhibitor olaparib, the topoisomerase I inhibitor topotecan, the proteasome inhibitor bortezomib, the inhibitor of the P53-MDM2 interaction nutlin-3 and the copper-chelated form of the oxidising agent disulfiram (DSF:Cu) all significantly enhanced the inhibition of the growth of spheroids induced by (131) I-MIP-1095. However, the Chk1 inhibitor AZD7762 failed to potentiate the effect of (131) I-MIP-1095. CONCLUSIONS: These results indicate that targeted radiotherapy of prostate cancer may be optimised by combining its administration with chemotherapy.

Exploratory Clinical Investigation of (4S)-4-(3-18F-Fluoropropyl)-L-Glutamate PET of Inflammatory and Infectious Lesions.

UNLABELLED: We explored system [Formula: see text] transporter activity and the detection of inflammatory or infectious lesions using (4S)-4-(3-(18)F-fluoropropyl)-l-glutamate ((18)F-FSPG) PET. METHODS: In 10 patients with various inflammatory or infectious diseases, as many as 5 of the largest lesions were selected as reference lesions. (18)F-FSPG images were assessed visually and quantitatively. Expression levels of xCT, CD44, and surface markers of inflammatory cells were evaluated by immunohistochemistry. RESULTS: (18)F-FSPG PET detected all reference lesions. (18)F-FSPG uptake in sarcoidosis was significantly higher than that in nonsarcoidosis. The lesion-to-blood-pool SUV ratio for (18)F-FSPG was comparable to that for (18)F-FDG in sarcoidosis. In nonsarcoidosis, however, it was significantly lower. In 5 patients with available tissue samples, the SUVmax for (18)F-FSPG and CD163 were negatively correlated (ρ = -0.872, P = 0.054). CONCLUSION: (18)F-FSPG PET may detect inflammatory lesions when activated macrophages or monocytes are present, such as in sarcoidosis.

Effects of melatonin and theanine administration on pentylenetetrazole-induced seizures and brain tissue oxidative damage in ovariectomized rats.

BACKGROUND/AIM: The effects of coadministration of melatonin and theanine (Mel/Thea) on pentylenetetrazole (PTZ)-induced seizures and brain tissue oxidative damage were investigated in ovariectomized (OVX) and sham-operated rats. MATERIALS AND METHODS: The rats were divided into the following groups: 1) sham, 2) ovariectomized (OVX), 3) sham-PTZ, 4) OVX- PTZ, 5) sham-Mel/Thea-PTZ, and 6) OVX-Mel/Thea-PTZ. Groups 1-4 received saline, while groups 5 and 6 received a combination of Mel/Thea for 6 weeks. All animals except for those in groups 1 and 2 received a single injection of PTZ. RESULTS: The OVX-PTZ group had higher generalized tonic-clonic seizure (GTCS) latency compared to the sham-PTZ group. Administration of Mel/Thea increased minimal clonic seizure and GTCS latencies in both the sham-Mel/Thea-PTZ and OVX-Mel/Thea-PTZ groups compared to the controls. Additionally, PTZ exposure increased malondialdehyde levels and reduced thiol concentrations in brain tissues of both the sham-PTZ and OVX-PTZ groups. Mel/Thea pretreatment resulted in MDA reduction and thiol increase in brain tissues. CONCLUSION: The results of this study demonstrated the antioxidant and anticonvulsant activities of Mel/Thea despite the presence or absence of ovarian hormones.

Colonic delivery of celecoxib is a potential pharmaceutical strategy for repositioning the selective COX-2 inhibitor as an anti-colitic agent.

Celecoxib is a selective cyclooxygenase-2 inhibitor applied to the treatment of arthritis. Repositioning the anti-inflammatory drug as an anti-inflammatory bowel disease drug has obstacles such as controversial anti-colitic efficacy and potential side effects. We examined whether colonic delivery of celecoxib could circumvent the therapeutic limitations. N-succinylglutam-1-yl celecoxib (SG1C), a colon-specific prodrug of celecoxib), was administered orally to rats with colitis and the anti-inflammatory activity and pharmacologic mechanisms were investigated. SG1C alleviated the colonic injury and lowered myeloperoxidase activity in the inflamed colonic tissues much more effectively than conventional celecoxib. While suppressing expression of pro-inflammatory nuclear factor kappaB gene products including cyclooxygenase-2, SG1C elevated an anti-inflammatory nuclear factor-erythroid 2 p45 (NF-E2)-related factor 2 (Nrf2) and its target gene product heme oxygenase (HO)-1 in the inflamed colon. In contrast, no significant molecular effects were observed with conventional celecoxib. Unlike conventional celecoxib, SG1C did not lower the serum level of 6-keto-PGF1α, an inverse indicator of cardiovascular adverse effects. Collectively, colonic delivery of celecoxib, likely improving therapeutic and toxicological properties of celecoxib, may be a feasible pharmaceutical strategy to therapeutically switch celecoxib to an anti-colitic drug.

[Pemetrexed nephrotoxicity]. / Néphrotoxicité du pemetrexed.

Pemetrexed belongs to a new generation of multitargeted antifolate cytotoxic agents. It is increasingly used as first-line treatment in combination with cisplatin, and as second-line treatment or maintenance monotherapy mainly in metastatic non-small cell lung cancer and in malignant mesothelioma. It is increasingly used as first-line treatment in combination with cisplatin in lung adenocarcinoma, and as second-line treatment or maintenance monotherapy in patients mainly controlled by the first-line to progression or poor tolerance. In mesothelioma, pemetrexed is indicated only in first-line with a platinum salt. The main side effect of pemetrexed is myelosuppression, which may be prevented by folinic acid supplementation. This review focuses on the progressive and cumulative emerging renal toxicity of pemetrexed, affecting five to ten percent of "long-term" pemetrexed-treated patients.

Prediction of renal transporter mediated drug-drug interactions for pemetrexed using physiologically based pharmacokinetic modeling.

Pemetrexed, an anionic anticancer drug with a narrow therapeutic index, is eliminated mainly by active renal tubular secretion. The in vitro to in vivo extrapolation approach used in this work was developed to predict possible drug-drug interactions (DDIs) that may occur after coadministration of pemetrexed and nonsteroidal anti-inflammatory drugs (NSAIDs), and it included in vitro assays, risk assessment models, and physiologically based pharmacokinetic (PBPK) models. The pemetrexed transport and its inhibition parameters by several NSAIDs were quantified using HEK-PEAK cells expressing organic anion transporter (OAT) 3 or OAT4. The NSAIDs were ranked according to their DDI index, calculated as the ratio of their maximum unbound concentration in plasma over the concentration inhibiting 50% (IC50) of active pemetrexed transport. A PBPK model for ibuprofen, the NSAID with the highest DDI index, was built incorporating active renal secretion in Simcyp Simulator. The bottom-up model for pemetrexed underpredicted the clearance by 2-fold. The model we built using a scaling factor of 5.3 for the maximal uptake rate (Vmax) of OAT3, which estimated using plasma concentration profiles from patients given a 10-minute infusion of 500 mg/m(2) of pemetrexed supplemented with folic acid and vitamin B12, recovered the clinical data adequately. The observed/predicted increases in Cmax and the area under the plasma-concentration time curve (AUC0-inf) of pemetrexed when ibuprofen was coadministered were 1.1 and 1.0, respectively. The coadministration of all other NSAIDs was predicted to have no significant impact on the AUC0-inf based on their DDI indexes. The PBPK model reasonably reproduced pemetrexed concentration time profiles in cancer patients and its interaction with ibuprofen.

A phase I, dose-escalation trial of continuous- and pulsed-dose afatinib combined with pemetrexed in patients with advanced solid tumors.

INTRODUCTION: Afatinib, an irreversible ErbB family blocker, demonstrated synergistic inhibition of epidermal growth factor receptor-mutant cell growth with pemetrexed. This phase I study investigated the maximum tolerated dose (MTD), safety, pharmacokinetics, and antitumor activity of afatinib plus pemetrexed in patients with advanced solid tumors. METHODS: In a 3 + 3 dose-escalation design, patients were given intravenous pemetrexed (500 mg/m(2)) on day 1 of a 21-day cycle (maximum 6 cycles), combined with continuous daily oral afatinib (schedule A [SA]; starting dose 30 mg, escalation to 50 mg) or pulsed-dose daily oral afatinib (schedule B [SB]; starting dose 50 mg, escalation to 70 mg) on days 1-6 of each 21-day cycle. Primary endpoint was determination of MTD based on dose-limiting toxicities (DLTs) in cycle 1. RESULTS: Fifty-three patients were treated (SA: n = 23; SB: n = 30). Eight patients had DLTs in SA, 11 patients in SB; diarrhea and fatigue were the most common. MTD of afatinib was 30 mg in SA and 50 mg in SB. Six patients in SA and eight in SB completed 6 treatment cycles. One patient in each schedule had confirmed objective response; 18/53 patients had disease control (SA: n = 7; SB: n = 11). Most frequent drug-related adverse events were diarrhea, rash, fatigue, and stomatitis. No relevant pharmacokinetic interactions were observed. CONCLUSIONS: Continuous- or pulsed-dose afatinib combined with pemetrexed exhibited a manageable safety profile. Pulsed dosing conferred no apparent safety or dose advantage. Continuous-dose afatinib 30 mg/day with pemetrexed is recommended for phase II studies.

Preclinical analyses and phase I evaluation of LY2603618 administered in combination with pemetrexed and cisplatin in patients with advanced cancer.

LY2603618 is an inhibitor of checkpoint kinase 1 (CHK1), an important regulator of the DNA damage checkpoints. Preclinical experiments analyzed NCI-H2122 and NCI-H441 NSCLC cell lines and in vitro/in vivo models treated with pemetrexed and LY2603618 to provide rationale for evaluating this combination in a clinical setting. Combination treatment of LY2603618 with pemetrexed arrested DNA synthesis following initiation of S-phase in cells. Experiments with tumor-bearing mice administered the combination of LY2603618 and pemetrexed demonstrated a significant increase of growth inhibition of NCI-H2122 (H2122) and NCI-H441 (H441) xenograft tumors. These data informed the clinical assessment of LY2603618 in a seamless phase I/II study, which administered pemetrexed (500 mg/m(2)) and cisplatin (75 mg/m(2)) and escalating doses of LY2603618: 130-275 mg. Patients were assessed for safety, toxicity, and pharmacokinetics. In phase I, 14 patients were enrolled, and the most frequently reported adverse events included fatigue, nausea, pyrexia, neutropenia, and vomiting. No DLTs were reported at the tested doses. The systemic exposure of LY2603618 increased in a dose-dependent manner. Pharmacokinetic parameters that correlate with the maximal pharmacodynamic effect in nonclinical xenograft models were achieved at doses ≥240 mg. The pharmacokinetics of LY2603618, pemetrexed, and cisplatin were not altered when used in combination. Two patients achieved a confirmed partial response (both non-small cell lung cancer), and 8 patients had stable disease. LY2603618 administered in combination with pemetrexed and cisplatin demonstrated an acceptable safety profile. The recommended phase II dose of LY2603618 was 275 mg.

Radiation dosimetry and first therapy results with a (124)I/ (131)I-labeled small molecule (MIP-1095) targeting PSMA for prostate cancer therapy.

INTRODUCTION: Since the prostate-specific membrane antigen (PSMA) is frequently over-expressed in prostate cancer (PCa) several PSMA-targeting molecules are under development to detect and treat metastatic castration resistant prostate cancer (mCRPC). We investigated the tissue kinetics of a small molecule inhibitor of PSMA ((S)-2-(3-((S)-1-carboxy-5-(3-(4-[(124)I]iodophenyl)ureido)pentyl)ureido)pentanedioicacid; MIP-1095) using PET/CT to estimate radiation dosimetry for the potential therapeutic use of (131)I-MIP-1095 in men with mCRPC. We also report preliminary safety and efficacy of the first 28 consecutive patients treated under a compassionate-use protocol with a single cycle of (131)I-MIP-1095. METHODS: Sixteen patients with known prostate cancer underwent PET/CT imaging after i.v. administration of (124)I-MIP-1095 (mean activity: 67.4 MBq). Each patient was scanned using PET/CT up to five times at 1, 4, 24, 48 and 72 h post injection. Volumes of interest were defined for tumor lesions and normal organs at each time point followed by dose calculations using the OLINDA/EXM software. Twenty-eight men with mCRPC were treated with a single cycle of (131)I-MIP-1095 (mean activity: 4.8 GBq, range 2 to 7.2 GBq) and followed for safety and efficacy. Baseline and follow up examinations included a complete blood count, liver and kidney function tests, and measurement of serum PSA. RESULTS: I-124-MIP-1095 PET/CT images showed excellent tumor uptake and moderate uptake in liver, proximal intestine and within a few hours post-injection also in the kidneys. High uptake values were observed only in salivary and lacrimal glands. Dosimetry estimates for I-131-MIP-1095 revealed that the highest absorbed doses were delivered to the salivary glands (3.8 mSv/MBq, liver (1.7 mSv/MBq) and kidneys (1.4 mSv/MBq). The absorbed dose calculated for the red marrow was 0.37 mSv/MBq. PSA values decreased by >50 % in 60.7 % of the men treated. Of men with bone pain, 84.6 % showed complete or moderate reduction in pain. Hematological toxicities were mild. Of men treated, 25 % had a transient slight to moderate dry mouth. No adverse effects on renal function were observed. CONCLUSION: Based on the biodistribution and dose calculations of the PSMA-targeted small molecule (124)I-MIP-1095 therapy with the authentic analog (131)I-MIP-1095 enables a targeted tumor therapy with unprecedented doses delivered to the tumor lesions. Involved lymph node and bone metastases were exposed to estimated absorbed doses upwards of 300 Gy.

Biodistribution and radiation dosimetry in healthy volunteers of a novel tumour-specific probe for PET/CT imaging: BAY 85-8050.

PURPOSE: Novel tracers for the diagnosis of malignant disease with PET and PET/CT are being developed as the most commonly used (18)F deoxyglucose (FDG) tracer shows certain limitations. Employing radioactively labelled glutamate derivatives for specific imaging of the truncated citrate cycle potentially allows more specific tumour imaging. Radiation dosimetry of the novel tracer BAY 85-8050, a glutamate derivative, was calculated and the effective dose (ED) was compared with that of FDG. METHODS: Five healthy volunteers were included in the study. Attenuation-corrected whole-body PET/CT scans were performed from 0 to 90 min, at 120 and at 240 min after injection of 305.0 ± 17.6 MBq of BAY 85-8050. Organs with moderate to high uptake at any of the imaging time points were used as source organs. Total activity in each organ at each time point was measured. Time-activity curves (TAC) were determined for the whole body and all source organs. The resulting TACs were fitted to exponential equations and accumulated activities were determined. OLINDA/EXM software was used to calculate individual organ doses and the whole-body ED from the acquired data. RESULTS: Uptake of the tracer was highest in the kidneys due to renal excretion of the tracer, followed by the pancreas, heart wall and osteogenic cells. The mean organ doses were: kidneys 38.4 ± 11.2 µSv/MBq, pancreas 23.2 ± 3.8 µSv/MBq, heart wall 17.4 ± 4.1 µSv/MBq, and osteogenic cells 13.6 ± 3.5 µSv/MBq. The calculated ED was 8.9 ± 1.5 µSv/MBq. CONCLUSION: Based on the distribution and dose estimates, the calculated radiation dose of BAY 85-8050 is 2.67 ± 0.45 mSv at a patient dose of 300 MBq, which compares favourably with the radiation dose of FDG (5.7 mSv).