Safety and Efficacy of Engineered Toxin Body MT-3724 in Relapsed or Refractory B-cell Non-Hodgkin's Lymphomas and Diffuse Large B-cell Lymphoma.

Unlabelled: MT-3724, a novel engineered toxin body comprised of an anti-CD20 single-chain variable fragment genetically fused to Shiga-like Toxin A subunit, is capable of binding to and internalizing against CD20, inducing cell killing via permanent ribosomal inactivation. This study evaluated MT-3724 in patients with relapsed/refractory B-cell non-Hodgkin lymphoma (r/rNHL). This open-label, multiple-dose phase Ia/b trial included a dose escalation in patients with r/rNHL according to a standard 3+3 design.

Combinatorial Efficacy and Toxicity of an Engineered Toxin Body MT-3724 with Gemcitabine and Oxaliplatin in Relapsed or Refractory Diffuse Large B Cell Lymphoma.

MT-3724 is an engineered direct-kill immunotoxin comprised of a CD20-specific scFv fused to a Shiga-like toxin subunit. In this phase IIa study, eight patients with relapsed diffuse large B-cell lymphoma were treated with MT-3724 combined with gemcitabine and oxaliplatin (GEMOX). The objective response rate was 85.

Phase 1 Study of High-Specific-Activity I-131 MIBG for Metastatic and/or Recurrent Pheochromocytoma or Paraganglioma.

Context: No therapies are approved for the treatment of metastatic and/or recurrent pheochromocytoma or paraganglioma (PPGL) in the United States.

Objective: To determine the maximum tolerated dose (MTD) of high-specific-activity I-131 meta-iodobenzylguanidine (MIBG) for the treatment of metastatic and/or recurrent PPGL.

Design: Phase 1, dose-escalating study to determine the MTD via a standard 3 + 3 design, escalating by 37 MBq/kg starting at 222 MBq/kg.

Phase 2 Study of Tc-Trofolastat SPECT/CT to Identify and Localize Prostate Cancer in Intermediate- and High-Risk Patients Undergoing Radical Prostatectomy and Extended Pelvic LN Dissection.

Tc-trofolastat (Tc-MIP-1404), a small-molecule inhibitor of prostate-specific membrane antigen, shows high potential to detect prostate cancer (PCa) noninvasively using SPECT. We therefore wanted to assess the performance of Tc-trofolastat SPECT/CT in a phase 2 multicenter, multireader prospective study in patients with intermediate- and high-grade PCa, before radical prostatectomy and extended pelvic lymph node (LN) dissection, with histopathology as the gold standard. PCa patients ( = 105) with an increased risk of LN involvement (LNI) underwent pelvic Tc-trofolastat SPECT/CT before radical prostatectomy with extended pelvic LN dissection.

The pharmacokinetics of alternative insulin delivery systems.

Limited progress has been made toward developing safer and more acceptable methods for the administration of insulin treatment, despite several attempts to replace subcutaneous injection with alternate routes of administration. Attempts to develop methods for pulmonary administration have demonstrated promise, but have been met with little patient acceptance thus far, while potentially more attractive routes, such as nasal, oral or transdermal administration, have been mainly unsuccessful in providing sufficiently favorable pharmacokinetics and bioavailability for clinical use. The use of enhancers and/or enzyme inhibitors transiently increases absorption across the epithelia of the oral and nasal cavities and the mucosa of the gastrointestinal tract; however, absorption appears to be highly variable, overall bioavailability remains low, causing the cost of goods to be high, and the long-term safety of additives and insulin as a potential local growth factor is not well characterized.

Synthesis and characterization of rhenium and technetium-99m labeled insulin.

A (99m)Tc-labeled insulin analogue was synthesized through a direct labeling method in which the [(99m)Tc(CO)(3)](+) core was combined with a protected insulin derivative (9) bearing a M(I) chelate linked to the first amino acid of the B-chain (B1). Regioselective labeling was achieved by careful control over the pH and the reaction time. Following a TFA-anisole mediated deprotection step (decay-corrected yield of 30 +/- 11%, n = 4), the identity of the final (99m)Tc-labeled product was confirmed by HPLC.

Real-world effectiveness of new medicines should be evaluated by appropriately designed clinical trials.

Objectives: Health care providers, policy makers, and importantly patients themselves are increasingly interested in the outcomes of clinical trials yet often expect different questions to be addressed than those commonly asked in conventional phase 3 trials.

Study Design And Setting: Review of methodological articles.

Results: Conventional randomized controlled trials (RCTs) emphasize internal validity through standardization and control but by design reduce external validity, that is, generalizability of results and conclusions.

Glycemic exposure is affected favorably by inhaled human insulin (Exubera) as compared with subcutaneous insulin glargine (Lantus) in patients with type 2 diabetes.

Background: The objective was to compare the effects on glycemia of adding either inhaled human insulin (Exubera [EXU] [insulin human (recombinant DNA origin) inhalational powder]) or subcutaneous insulin glargine (GLA) to the treatment regimens of patients with type 2 diabetes uncontrolled with oral antidiabetic drugs.

Methods: Forty patients were randomized to receive either EXU three times daily prior to meals or subcutaneous GLA once daily in a crossover design. Interstitial glucose concentrations were monitored using a continuous glucose monitoring system (CGMS) for the final 72-h period of 8 treatment days.

Assessing the impact of a new delivery method of insulin on glycemic control using a novel trial design.

Objective: The purpose of the trial was to examine the impact of inhaled human insulin (INH) on patient or physician willingness to adopt insulin after oral diabetes agent failure.

Research Design And Methods: The EXPERIENCE trial was a one-year randomized controlled trial conducted at primary, secondary and tertiary care facilities in Europe and North America. The primary study endpoint was difference in glycated hemoglobin (A(1c)) between randomized groups at 26 weeks, and results from that phase have been reported previously.

Inhaled insulin is associated with prolonged enhancement of glucose disposal in muscle and liver in the canine.

Diabetic patients treated with inhaled insulin exhibit reduced fasting plasma glucose levels. In dogs, insulin action in muscle is enhanced for as long as 3 h after insulin inhalation. This study was designed to determine whether this effect lasts for a prolonged duration such that it could explain the effect observed in diabetic patients.

Imaging as a tool in drug development.

Medical imaging has experienced a huge increase in exploratory technologies over the past 20 to 30 years. From drug discovery to drug development to routine clinical practice, the advent of functional imaging is about to revolutionize both medicine and pharmaceutical drug development. Currently, a number of technologies are in competition.

Inhalation of human insulin (exubera) augments the efficiency of muscle glucose uptake in vivo.

This study assessed the site of increased glucose uptake resulting from insulin inhalation, quantified its effect under steady-state glucose concentrations, and identified the time to onset of effect. Human insulin was administered to 13 beagles via inhalation (Exubera [insulin human (rDNA origin)] Inhalation Powder; n = 7) or infusion into the inferior vena cava (Humulin R; n = 6) using an algorithm to match plasma insulin levels and kinetics for both groups. Somatostatin and glucagon were infused.

Inhalation of human insulin is associated with improved insulin action compared with subcutaneous injection and endogenous secretion in dogs.

This study compared the effects of endogenous (portal) insulin secretion versus peripheral insulin administration with subcutaneous or inhaled human insulin [INH; Exubera, insulin human (rDNA origin) inhalation powder] on glucose disposal in fasted dogs. In the control group, glucose was infused into the portal vein (Endo; n = 6). In two other groups, glucose was infused portally, whereas insulin was administered peripherally by inhalation (n = 13) or s.

Will availability of inhaled human insulin (Exubera) improve management of type 2 diabetes? The design of the Real World trial.

Background: Common deterrents to insulin therapy for both physicians and patients are the complexity and burden of daily injections. In January 2006, the first inhaled human insulin (INH, Exubera (insulinhuman [rDNA origin])InhalationPowder) was approved for use in adult patients with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) in the United States and European Union. Results from the INH clinical trial program have shown comparable efficacy of INH to subcutaneous (s.

Inhaled human insulin.

The benefit of subcutaneous insulin therapy in patients with diabetes is frequently limited due to difficulty in convincing patients of the importance of multiple daily insulin injections to cope effectively with meal-associated glycemic changes. Thus, the aim of achieving tight glycemic control, which is critical for reducing the risk of long-term diabetes-related complications, frequently remains elusive. The successful development of an inhalable insulin as a noninvasive alternative promises to change the management of diabetes.

Synthesis and in vitro evaluation of 18F- and 19F-labeled insulin: a new radiotracer for PET-based molecular imaging studies.

A new and regioselective strategy was developed for the preparation of fluorine-18-labeled insulin as a novel positron emission tomography (PET) tracer. [18F]-4-Fluorobenzoic acid (4-18FBA), which was produced in 83 +/- 8% yield (n = 10), through the use of succinimidyl [18F]-4-fluorobenzoate (4-(18)FSB), was conjugated through a short spacer (6-aminohexanoic acid, AHx) to the PheB1 residue of a protected form of insulin. 18FB-AHx-insulin (8b) was repeatedly prepared in practical quantities (10-20 mCi, 370-740 MBq) in good radiochemical yield (9 +/- 5%, n = 9) and in a specific activity of 7.

Inhalation of insulin (Exubera) is associated with augmented disposal of portally infused glucose in dogs.

The results of the present study, using the conscious beagle dog, demonstrate that inhaled insulin (INH; Exubera) provides better glycemic control during an intraportal glucose load than identical insulin levels induced by insulin (Humulin) infusion into the inferior vena cava (IVC). In the INH group (n = 13), portal glucose infusion caused arterial plasma glucose to rise transiently (152 +/- 9 mg/dl), before it returned to baseline (65 min) for the next 2 h. Net hepatic glucose uptake was minimal, whereas nonhepatic uptake rose to 12.

Inhalation of insulin in dogs: assessment of insulin levels and comparison to subcutaneous injection.

Pulmonary insulin delivery is being developed as a more acceptable alternative to conventional subcutaneous administration. In 15 healthy Beagle dogs (average weight 9.3 kg), we compared insulin distribution in arterial, deep venous, and hepatic portal circulation.