Design and implementation of clinical trials of antimicrobial drugs and devices used in periodontal disease treatment

The design and implementation of clinical trials (CTs) carried out to evaluate antimicrobial and anti-infective drugs and devices are one of the most difficult challenges in contemporary periodontal research and product development. The overwhelming amount of evidence which has established a microbial etiology for periodontitis is the basis for developing and testing antimicrobial treatments. Well-designed antimicrobial CTs start with a carefully crafted hypothesis and a protocol which explicitly integrates the requirements of the patient, the clinician, the sponsor, and regulatory authorities. Surrogate variables for effectiveness must be clinically relevant, scientifically sound, and statistically valid. Currently, clinical attachment level measurements and alveolar bone assessments are accepted as proof of effectiveness. Indication and claim support of the antimicrobial product guide the design and implementation of the CT. Adverse microbiologic consequences, such as lack of antimicrobial susceptibility, wrong spectrum, incorrect dosage, non-compliance, and drug interference, must be monitored. Successful CTs balance a large group of variables used to screen, randomize, and assign subjects to experimental and control groups to ensure that prognostic and risk factors are properly accounted for.     

Phase I study of mitoxantrone plus etoposide with multidrug blockade by SDZ PSC-833 in relapsed or refractory acute myelogenous leukemia

PURPOSE: Expression of the multidrug resistance gene (MDR1) p170 protein is frequent in leukemic blasts from patients with relapsed acute myelogenous leukemia (AML). A phase I study using the nonimmunosuppressive MDR1 blocker SDZ PSC-833 (PSC) in combination with mitoxantrone (MITO) and etoposide (VP) was performed. PATIENTS AND METHODS: Starting doses (LVL0) of MITO (3.25 mg/m2/d on days 1 and 3 to 6) and VP (210 mg/m2/d on days 1 and 3 to 5) were 40% of the maximal-tolerated dose (MTD) from a prior study. A 1.5-mg/kg loading dose of PSC was followed by a 120-hour continuous infusion of 10 mg/kg/d on days 2 to 6. Blood samples for PSC, MITO, and VP pharmacokinetics (PK) were taken on days 1 and 3, and samples for MDR1 expression were taken on day 0. RESULTS: Severe mucositis developed in all patients at LVL0; therefore, MITO and VP doses were reduced to 2.5 and 170 mg/m2 (LVL-1) for the next seven patients, and this dose proved to be MTD. All LVL0 and three LVL-1 patients had transient elevations in the serum bilirubin level to > or = 4 mg/dL. Serum creatinine level increased to greater than 2 mg/dL in one case. There were no other grade 3 or 4 nonhematologic toxicities observed. The peripheral blood was cleared of leukemia in three LVL0 and four LVL-1 patients. The marrow was cleared of leukemic cells in one LVL0 and five LVL-1 patients, and a significant reduction in marrow leukemic infiltrate was observed in eight of 10. No patient achieved complete remission (CR), and all died of progressive disease (n = 8) or infection (n = 2). MDR1 expression was detected by fluorescent-activated cell sorter (FACS) analysis in five of seven cases. An elevated MDR1 mRNA level was detected by quantitative polymerase chain reaction (Q-PCR) in six of eight cases studied. Clearing of leukemia cells from the marrow occurred in four of six MDR1-positive and one of three MDR1-negative patients. Despite the fact that LVL0 doses had to be reduced due to toxicity, coadministration of PSC did not produce a consistent effect on MITO PK; however, it did repeatedly lead to increased levels of VP in the serum. CONCLUSION: We conclude that PSC-MITO-VP is a tolerable regimen with antileukemic activity. Addition of PSC necessitated a 66% reduction in MITO and VP doses from a prior study without PSC.     

VRCTC-310--a novel compound of purified animal toxins separates antitumor efficacy from neurotoxicity

Two purified animal venom toxins, crotoxin and cardiotoxin, have been combined to produce a unique natural product (VRCTC-310) currently under investigation as an antitumor agent by the National Cancer Institute. In vitro, it has demonstrated cytotoxic disease specificity and a unique mechanism of action when submitted to COMPARE analysis. In vivo, tolerance was developed to the neurotoxic properties of crotoxin which allowed comparison of several schedules of fixed and escalating daily i.m. doses to mice bearing s.c. Lewis Lung carcinoma. An 83% inhibition of tumor growth was achieved using an escalating dose schedule starting at 1.8 mg/kg and reaching 6.3 mg/kg/day on day 20. Although some irritation around the sites of i.m. injection was noted, animal weight loss was negligible and there were no other signs of adverse toxicity. This natural product represents a new, membrane interactive anticancer agent which produces a unique spectrum of cytotoxicity in vitro and which has demonstrated interesting in vivo antitumor efficacy.     

Intravitreal tolerance of a new perfluorocarbon vitreous replacement, Multifluor APF-144

OBJECTIVE: To evaluate the intravitreal tolerance of a new perfluorocarbon vitreous replacement, Multifluor APF-144 (perfluorotetramethylcyclohexane). DESIGN: Ten New Zealand albino rabbits (one eye from each) underwent vitrectomy. The vitreous was replaced in five eyes with Multifluor APF-144 and in five eyes with saline (control group). OUTCOME MEASURES: Appearance on indirect ophthalmoscopy, electroretinography recordings before and 2, 4 and 8 weeks after vitrectomy, findings on electron and light microscopy at 8 weeks. RESULTS: Endophthalmitis did not develop in any of the eyes. There was no significant change in electroretinography values for the experimental eyes after vitrectomy. No evidence of retinal toxicity was found on light or electron microscopic examination. CONCLUSIONS: Multifluor APF-144 shows promise as a short-term postoperative retinal tamponading agent.     

Variability in the proliferative responsiveness of cultured human vascular smooth muscle cells to alpha-thrombin

alpha-Thrombin, a key enzyme of the coagulation cascade, is also a potent mitogen for many cell types. In the present study, the responsiveness to alpha-thrombin of cultured human vascular smooth muscle cells (HVSMC) derived from either vein or normal and atherosclerotic arteries was investigated. All HVSMC populations examined responded mitogenically to alpha-thrombin. However, the extent of this response varied between different cell populations. No significant differences were observed between HVSMC derived from vein versus artery or atherosclerotic versus normal tissues. The responsiveness of a specific HVSMC culture to alpha-thrombin was not affected by cell density and remained constant over several passages. Unlike platelet-derived growth factor BB (PDGF-BB), alpha-thrombin did not exhibit any significant chemotactic effects on HVSMC or induce their anchorage independent growth in semi-solid medium. The hypothesis that the observed variability in HVSMC responsiveness to alpha-thrombin is due to the heterogeneity of cultured HVSMC is raised and discussed.     

Space-domain method of moments solution for a strip on a dielectricslab

This paper presents a space-domain method of moments (MoM) solution to the problem of a strip dipole on a dielectric slab. The solution involves the use of a special junction basis function which models the nearly singular polarization currents in the vicinity of the strip/dielectric junction