Liposomes and Nanoparticles in the Treatment of Intracellular Bacterial Infections

The treatment of infections caused by obligate or facultative intracellular microorganisms is difficult because most of the available antibiotics have either poor intracellular diffusion and retention or reduced activity at the acidic pH of the lysosomes. The need for antibiotics with greater intracellular efficacy led to the development of endocytosable drug carriers, such as liposomes and nanoparticles, which mimic the entry path of the bacteria by penetrating the cells into phagosomes or lysosomes. This Review assesses the potential of liposomes and nanoparticles in the targeted antibiotic therapy of intracellular bacterial infections and diseases and the pharmaceutical advantages and limitations of these submicron delivery systems.     

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients

Summary Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of <500/l that lasted for > 14 days or thrombocytopenia of <25,000/l that lasted for > 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m². Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.Supported in part by U.S. Public Health Service grant P01CA-38493 and by a grant from the Mather's Foundation. Two of the authors (J. P. E. and A. D. E.) are recipients of Career Development awards from the American Cancer Society, and one (T. C. S.) is a recipient of a Faculty Development Award from the Pharmaceutical Manufacturer's Association Foundation     

Accelerated fractionation in esophageal cancers: A multivariate analysis on 88 patients

: Accelerated fractionation was used to shorten overall treatment time to increase locoregional control and cause-specific survival.

: Eighty-eight patients with cancer of the esophagus ineligible for surgery were entered in the study between 1986 and 1993. Neoadjuvant chemotherapy was given to 64% of patients. Accelerated radiotherapy using the concomitant boost technique delivered a median dose of 65 Gy in a median overall treatment time of 32 days.

: The 3-year acturial local control rate in patients with T1, T2, and T3 tumors was 71%, 42%,and 33%, respectively. The 3-year cause-specific survival rates were 40%, 22%, and 6%, respectively. Sixteen percent of patients experienced Grafe 3 esophagitis. Late toxicity included esophageal stenosis and pulmonary fibrosis in 8% and 9% of the patients, respectively. Multivariate analysis demonstrated that T stage and overall treatment time were prognostic factors for cause-specific survival. T stage and neoadjuvant chemotherapy were independent prognostic factors for locoregional control.

: These findings suggest that accelerated giben in an overall treatment time of <35 days might be beneficial for easy-stage cancer of the esophagus. Neoadjuvant chemotherapy is not recommended, as it was a significant adverse prognostic factor in the multivariate analysis for local control. Accelerated fractionation can be carried out with modeate acure and late toxicity.     

Hepatic arterial oxaliplatin infusion plus intravenous chemotherapy in colorectal cancer with inoperable hepatic metastases: a trial of the gastrointestinal group of the Federation Nationale des Centres de Lutte Contre le Cancer.

PURPOSE: Isolated hepatic metastases of colorectal cancer constitute a frequent and serious therapeutic problem that has led to the evaluation of hepatic arterial infusion (HAI) of different drugs. Oxaliplatin combined with fluorouracil (FU) and leucovorin is effective in the treatment of colorectal cancer. In this context, a phase II study was conducted to evaluate concomitant administration of oxaliplatin by HAI and intravenous (IV) FU plus leucovorin according to the LV5FU2 protocol (leucovorin 200 mg/m(2), FU 400 mg/m(2) IV bolus, FU 600 mg/m(2) 22-hour continuous infusion on days 1 and 2 every 2 weeks). PATIENTS AND METHODS: Patients had metastatic colorectal cancer that was restricted to the liver and inoperable. The patients were not to have previously received oxaliplatin. After surgical insertion of a catheter in the hepatic artery, patients were treated with oxaliplatin 100 mg/m(2) HAI combined with FU + leucovorin IV according to the LV5FU2 protocol. Treatment was continued until disease progression or toxicity. Response was evaluated every 2 months. RESULTS: Twenty-eight patients were included, and 26 patients were treated. Two hundred courses of therapy were administered, and the median number of courses received was eight courses (range, zero to 20 courses). The most frequent toxicity consisted of neutropenia. The main toxicity related to HAI was pain. The intent-to-treat objective response rate was 64% (95% CI, 44% to 81%; 18 of 28 patients). With a median follow-up of 23 months, the median overall and disease-free survival times were 27 and 27 months, respectively. CONCLUSION: The combination of oxaliplatin HAI and FU + leucovorin according to the LV5FU2 protocol is feasible and effective in patients presenting with isolated hepatic metastases of colorectal cancer.     

Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.

PURPOSE: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. DESIGN: Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. RESULTS: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. CONCLUSION: The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.     

Polymer colon drug delivery systems and their application to peptides, proteins, and nucleic acids

Most therapeutic peptides and proteins are administered via the parenteral route, which presents numerous drawbacks and limitations. To overcome these drawbacks, alternative administration routes, such as oral or mucosal routes, have been investigated. The oral route presents a series of attractive advantages for the administration of therapeutic compounds, such as the avoidance of the pain and discomfort associated with injections, good patient compliance, and being less expensive to produce. However, oral administration of peptides, proteins, or nucleic acids also presents several difficulties because of their instability in the upper gastrointestinal (GI) tract and their poor transport across biologic membranes. Among the various approaches developed to improve the oral delivery of peptides, proteins, or nucleic acids, specific delivery to the colon has attracted a lot of interest because of its potential for the local treatment of colonic diseases, systemic delivery of poorly absorbed drugs, and vaccine delivery. Numerous pharmaceutical approaches described in this review have been exploited for the development of colon-targeted drug delivery systems using various concepts, such as pH-dependent, time-dependent, pressure-controlled, or bacterially triggered delivery systems. The action of the pH-dependent delivery systems is based on pH differences between the stomach and the ileum. Time-dependent delivery systems are based on the transit time of pharmaceutical dosage forms in the GI tract, drug release being delayed until they reach the colon. A combination of pH- and time-dependent delivery systems has also been described to avoid the drawbacks of both strategies. The pressure-controlled delivery concept exploits the physiologic luminal pressure of the colon as the driving force for site-specific delivery of drugs. Finally, bacterially triggered delivery systems exploit the enormous diversity of enzymatic activity associated with the colonic microflora. Bacterially triggered delivery systems are generally composed of polymers, which are specifically degraded by colonic enzymes of microbial origin. These polymers have been used to form prodrugs with the drug moiety, as coating materials for the drug core, or as embedding media to entrap the drug into matrix or hydrogel systems. Each of these concepts has advantages and limitations. They present varied colonic specificity and, among them, bacterially triggered delivery systems in particular show the greatest potential for colonic delivery of peptides, proteins, and nucleic acids.