A method for the evaluation of dose-toxicity relationships in clinical trials

This paper considers a proportional hazards model that describes the relationship between time-dependent cumulative dose of drug and development of toxicity. We estimate probabilities of developing toxicity in both the presence and the absence of competing risks and provide variances for the latter case. Mitoxantrone data collected in Southwest Oncology Group studies illustrate the methods.     

Effect of the aldose reductase inhibitor, ponalrestat, on diabetic neuropathy

The effect of treatment with the aldose reductase inhibitor, Ponalrestat*, was studied in 30 diabetic patients with established peripheral and autonomic neuropathy. After a 4-week placebo run-in phase, patients were randomised to 16 weeks active or placebo treatment in a double-blind, parallel-group trial. Changes in neuropathy were assessed using vibration perception thresholds, heart rate responses to deep breathing, pulse and blood pressure changes on standing and the patients' subjective scoring of peripheral and autonomic neuropathic symptoms. In addition, circulating neuropeptides and the responses of circulating gut peptides to an oral glucose tolerance test were studied. There was a significant improvement in the mean vibration perception threshold over the four sites studied in the ponalrestat treated group. There were no significant changes in the other indices of neuropathy, including heart rate variability, blood pressure responses to standing or symptom scores, though there were trends towards improvement. There were no significant changes in the levels of the circulating neuropeptides or in the responses of the circulating gut peptides to oral glucose tolerance test. No clinically important side-effects attributable to ponalrestat were observed. We conclude that ponalrestat improves some of the parameters of diabetic neuropathy and is likely to be of value in the treatment of this condition.     

Reduction-mediated technetium-99m labeling of monoclonal antibodies

A simple and generally applicable method for labeling antibodies with technetium-99m (99mTc) is described. Following reduction of intrinsic disulphide bonds, the antibody is labeled with 99mTc in the presence of a weak competing ligand methylene diphosphonate. High labeling efficiencies (greater than 97%), in a final labeling step taking only a few minutes, can be routinely obtained with high in-vitro stability over 24 hr. No effect upon antibody reactivity is seen.     

Concurrent Borrelia burgdorferi and Babesia microti infection in nymphal Ixodes dammini.

Ixodes dammini nymphs were examined for evidence of concurrent infection with Borrelia burgdorferi and Babesia microti. A total of 19 nymphs (18.6%) from Nantucket Island were simultaneously infected, as were 24 nymphs (8.2%) from Naushon Island. These observations are consistent with a common reservoir host for both I. dammini-transmitted pathogens.     

Radioimmunoscintigraphy of orbital metastases from ovarian carcinoma

Radioimmunoscintigraphy with I-123 labeled monoclonal antibody HMFG1 has been used for imaging primary and metastatic ovarian neoplasms. Uptake of I-123 labeled HMFG1 is reported in a patient with an orbital metastasis from a primary ovarian adenocarcinoma. Radioimmunoscintigraphy may have a role to play in imaging metastatic orbital neoplasms.     

Insulin resistance in maturity onset diabetes of the young

Insulin resistance was assessed by euglycaemic clamp studies in matched groups of MODY, classical NIDDM patients and non-diabetic control subjects. The MODY patients metabolised less glucose (4.8 +/- 0.3 mg/Kg/min) than the classical NIDDM patients (7.0 +/- 0.5 mg/Kg/min) at an insulin infusion rate of 1.0 mU/Kg/min (p less than 0.05). At an insulin infusion rate 10 mU/Kg/min the differences between the MODY and the classical NIDDM patients were not significant. At both infusion rates the two diabetic groups metabolised less glucose than the control subjects. The results indicate that despite their younger age, the patients with MODY are more insulin resistant than the patients with classical NIDDM.     

West Nile virus in blood: stability,distribution, and susceptibility to PEN110 inactivation

BACKGROUND: The outbreak of West Nile virus (WNV) is the most recent reminder that the blood supply continues to be vulnerable to emerging and reemerging pathogens. A potentially prospective approach to reducing the risk of transfusion-transmitted infections of a known or newly emerging microbe is implementation of a broad-spectrum pathogen reduction technology. The purpose of this study was to evaluate the susceptibility of WNV to PEN110 inactivation in RBCs and to characterize the WNV interaction with blood, including the stability of WNV in RBCs stored at 1 to 6 degrees C, its distribution and infectivity, and its ability to infect WBCs. STUDY DESIGN AND METHODS: Inactivation was performed with three WNV isolates spiked into WBC-reduced RBCs. The stability of the virus was evaluated by spiking two viral loads into RBCs followed by storing at 1 to 6 degrees C for up to 42 days. The distribution of the virus in plasma, RBCs, and PBMCs was evaluated with whole blood from infected hamsters. Finally, in vitro propagation of WNV was evaluated with the THP-1 cell line and primary monocytes. RESULTS: The kinetics of PEN110 inactivation of WNV isolates RI-44, NJ-176, and 99-3494031 were fast and complete within 24 hours with reduction factors of 5 to 7 log plaque-forming units per mL. WNV remained infectious for up to 42 days at 1 to 6 degrees C. The WNV titers in whole blood, plasma, RBCs, and PBMC fractions were equally distributed and ranged from 2 to 3 log tissue culture infectious dose 50 percent per mL. Productive infection of stimulated monocytes and THP-1 cells was also demonstrated. CONCLUSIONS: These studies demonstrated that PEN110 efficiently inactivated WNV in RBCs and whole blood from infected hamsters to the limit of detection. WNV survived in RBCs stored at 1 to 6 degrees C with a gradual loss of titer but infectivity could still be observed for up to 42 days. In addition, it was observed that WNV was equally distributed in all blood fractions including PBMCs and it was possible to establish productive infection of a human monocytic cell line and stimulated human monocytes.