Poor Drug Penetration Research Articles

Signal transduction as a therapeutic target.

Cancer therapy is entering a critical period. Conventional approaches for cancer treatment, such as chemotherapy, radiotherapy, or surgery, have obtained results only in lymphoproliferative neoplasms and in a small percentage of solid tumors. The cause of this limited success can be ascribed to several factors, including the poor penetration of drug into tumor masses, biological heterogeneity of cancer cells in primary neoplasms and secondary foci, development of drug resistance, and the ability of malignant cells to invade and metastasize early in the tumorigenic process, often long before the primary tumor is detectable.

Amorolfine nail lacquer: a novel formulation

Onychomycosis is difficult to treat. Systemic therapy with the potent oral azoles may be restricted by their potential side-effects; an attractive alternative is topical application of an antifungal directly to the nail. Several such formulations have been developed, including creams and lotions which are largely ineffective due to poor drug penetration into and through the nail structure. Nail keratin is thick and compact; its permeability is low. Transungual drug diffusion depends on the characteristics of the nail (especially degree of hydration) and the properties of the chemical (molecular weight and size, and lipophilic/hydrophilic profile). A nail lacquer containing 5% amorolfine was recently introduced; the volatile vehicle evaporates, leaving an occlusive film on the surface of the nail. The film acts as a drug depot, while at the same time increasing the hydration of the nail and the thermodynamic activity of the drug, thereby enhancing diffusion, particularly of hydrophilic compounds. Amorolfine has been shown to penetrate human nail from the film at clinically effective concentrations. In addition, the effect is long lasting: a single application of lacquer provides protection for 1 week. Release and rate of diffusion can be optimized by selecting the components of the lacquer formulation (solvent, polymer, plasticizer). Transungual drug delivery via nail lacquer is a major addition in the dermatologist's therapeutic arsenal.

Prophylaxis of Endophthalmitis

Prophylactic antibiotics can be administered by various routes to prevent endophthalmitis. Topical application is simple and minimally invasive, but it provides relatively poor penetration into the vitreous. Collagen shields are effective in delivering therapeutic levels of antibiotics to the cornea and aqueous but not to the vitreous cavity. Systemic administration for prophylaxis is questionable because of the poor ocular penetration of most drugs (however, some antibiotics, such as imipenem, pefloxacin, and ciprofloxacin, may provide therapeutic levels to the vitreous). Subconjunctival injection may provide significant drug levels in the aqueous for 4 to 6 hours. However, we found subconjunctival gentamicin ineffective in experimentally induced Pseudomonas aeruginosa endophthalmitis in postoperative aphakic eyes. We recommend the use of antibiotics in infusion fluid. In cases of trauma, we inject 48 micrograms gentamicin and 54 micrograms clindamycin intracamerally or intravitreally.

Vancomycin penetration into biofilm covering infected prostheses and effect on bacteria.

To evaluate the adequacy of penetration of antibiotics into biofilm, a novel in vitro model for prosthesis-related infection was developed. Sterile stainless steel orthopedic nuts were incubated with slime-producing Staphylococcus epidermidis. Biofilm-covered nuts were exposed to varying concentrations of vancomycin; then biofilms were harvested. Vancomycin levels in biofilm, as measured by fluorescent polarization immunoassay, far exceeded the MIC and MBC of vancomycin for the organism. Bacterial growth in biofilm was inversely related to vancomycin concentration in biofilm, but even extremely high drug concentrations did not eradicate bacteria embedded in biofilm. The MICs and MBCs for bacteria recovered from biofilm did not differ from those for incubating organisms. Thus, failure of glycopeptide antibiotics to cure prosthesis-related infection is not due to poor penetration of drugs into biofilm but likely due to diminished antimicrobial effect on bacteria in the biofilm environment.

Uptake and retention of estramustine and the presence of estramustine binding protein in malignant brain tumours in humans.

Estraumustine phosphate (EMP), a cytotoxic drug used in the treatment of prostatic carcinoma, has been shown to exert cytotoxic effects on glioma cells in vitro. The drug uptake is assumed to depend on a specific estramustine binding protein (EMBP). One of the main difficulties in achieving cytotoxic effect in malignant brain tumours is believed to be due to the poor penetration of cytotoxic drugs into tumour tissue. In patients with malignant supratentorial brain tumours we have analysed the uptake of EMP metabolites in tumour tissue after oral administration and demonstrated EMBP in the same tissue specimens. Sixteen patients were given 280 mg EMP orally 14 h prior to surgery. Specimens from brain tumour tissue, cystic fluid, and serum were collected during surgery. Using gas chromatography the metabolites of EMP, estramustine (EaM) and estromustine (EoM), were quantified, EMBP was demonstrated by immunohistochemistry. The mean concentrations of EaM and EoM, expressed in ng g-1, were 60.3 and 38.4 in tumour tissue and 3.5 and 56.3 in serum, respectively. An accumulation of EaM in tumour tissue was found with a mean concentration gradient of 16.1 versus serum, while the gradient for EoM was 0.76. EMBP was demonstrated with a high degree of staining in all but one tumour. The high concentrations of EaM and EoM found in malignant brain tumour tissue correspond to potentially cytotoxic levels. The present results as well as the earlier in vitro demonstrated cytotoxic effects on glioma cells strengthen the possibility of a therapeutic effect of EMP in the treatment of malignant brain tumours.

Synergistic Interaction of Natural Human Tumor Necrosis Factor-α/Natural Human Interferon-α Mixture Alone and in Combination with Cisplatin Against Head and Neck Laryngeal Squamous Carcinoma Multicellular Tumor Spheroids

We evaluated the effects of each component, natural human tumor necrosis factor-alpha (nHuTNF-alpha) and natural human interferon-alpha (nHu-IFN-alpha), and the combined nHuTNF-alpha/nHuIFN-alpha preparation with or without cisplatin (DDP) at tumor mass level. Multicellular tumor spheroids (MTS) of approximately 500 microns in diameter were produced from HEp-2 laryngeal squamous carcinoma cell line by liquid overlay culture technique. Cell kill effects of 72 hr exposure to nHuTNF-alpha, nHuIFN-alpha, or nHuTNF-alpha/nHuIFN-alpha against cells in MTS were 2-3-fold less than those in monolayer. In MTS, does response curves become progressively flat at high drug concentrations, indicative of poor drug penetration into the MTS core. Combination nHuTNF-alpha/nHuIFN-alpha produced synergistic cell kill for both MTS and monolayers. For monolayer cells exposure to nHuTNF-alpha/nHuIFN-alpha first (72 hr) followed by DDP (1 hr) after 1 hr rest period was synergistic with combination index (CI) of approximately 0.8 at LD50. Simultaneous (72 hr in nHuTNF-alpha/nHuIFN-alpha with DDP in last 1 hr) or reverse order of exposure were antagonistic. In contrast, for MTS, DDP followed by nHuTNF-alpha/nHuIFN-alpha was most synergistic with CI of approximately 0.2. Simultaneous exposure or nHuTNF-alpha/nHuIFN-alpha followed by DDP showed synergism with CI of approximately 0.5 and 0.8, respectively. The improved efficacy of DDP followed by nHuTNF-alpha/nHuIFN-alpha sequence for MTS cells appears to be due to increased nHuTNF-alpha/nHuIFN-alpha penetration into the MTS core aided by DDP.

Current Pharmacological Treatment Approaches to Central Nervous System Leukaemia

Significant advances in the treatment and prevention of meningeal leukaemia have been made in the past 3 decades. This progress has resulted from the development of innovative approaches to treatment as well as a better understanding of the pharmacokinetics and pharmacodynamics of the commonly used antileukaemic agents. Intrathecal therapy, via the intralumbar or intraventricular route, is a form of regional therapy that results in the delivery of very high drug concentrations to the principle target tumour site (the meninges) using a relatively small drug dose, thereby minimising both systemic drug exposure and systemic toxicity. The dosage and schedules, clinical pharmacology and toxicities of the commonly used intrathecal agents, methotrexate and cytarabine (cytosine arabinoside; Ara-C) are discussed in detail. Another approach which has been used to overcome the poor penetration of antileukaemic drugs into the CNS has been the use of high-dose systemic therapy. This strategy has been successfully applied in the treatment of meningeal leukaemia using both high-dose methotrexate and high-dose cytarabine. The clinical pharmacology, toxicities, and potential limitations of this approach are outlined. Finally, new agents that are currently undergoing clinical evaluation and future directions for research are also discussed.

Prevention of experimental corneal allograft rejection in rabbits using cyclosporin-collagen shields

Topical administration of cyclosporin A, a highly hydrophobic cyclic undecapeptide, has been relatively ineffective in preventing corneal allograft rejections due to poor drug penetration. Therefore, we investigated a new continuous-delivery system for cyclosporin A using collagen bandage shields fabricated from porcine scleral tissue. Collagen bandage shields containing 4 mg cyclosporin A were used for the treatment of four corneal allografts embedded in prevascularized rabbit corneas. Four controls were treated with shields containing no cyclosporin A. The shields were changed every 2nd day and signs of rejection were recorded. All controls were rejected by the end of the experiment. Treatment with collagen shields containing cyclosporin A effectively prevented such rejection. The clinical examinations were also confirmed with histopathological analysis. The results indicate that collagen shields can slowly release cyclosporin A and increase the penetration time for the drug. Thus, they are excellent delivery systems for hydrophobic drugs with poor penetration properties.

Experimental chemotherapy and concepts related to the cell cycle.

Scheduling of chemotherapy is limited by damage to normal tissues, and tolerated schedules are dependent on normal tissue recovery. Most anticancer drugs are more toxic to proliferating cells and the fall and recovery of granulocyte counts after chemotherapy may be explained by the effect of drugs on rapidly proliferating precursor cells in the bone marrow. It is argued that serious toxicity due to myelosuppression most often occurs because of damage to proliferating precursors that may be recognized in bone marrow rather than to stem cells. In contrast, therapy that is aimed at producing cure or long-term remission of tumours must be directed at killing tumour stem cells. The evidence that tumours contain a limited population of cells which can repopulate the tumour after treatment (and are therefore tumour stem cells) is reviewed critically. While there is quite strong evidence for a limited population of target cells, evidence from studies on metastases suggests that the tumour cells which may express this stem cell property may change with time. The stem cell concept has major implications for predictive assays. Although colony-forming assays appear to have a sound biological background for predicting tumour response, technical problems prevent them from being used routinely in patient management. Cells in tumours are known to be heterogeneous and at least three types of heterogeneity may influence tumour response to drug treatment: the development of subclones with differing properties including drug resistance; variation in cellular properties due to differentiation during clonal expansion; and variation in properties due to nutritional status and micro-anatomy. Heterogeneity in drug distribution within solid tumours may occur because of limited drug penetration from blood vessels, and nutrient-deprived cells in solid tumours may be expected to escape the toxicity of some anticancer drugs as well as being resistant to radiation because of hypoxia. This may occur both because nutrient-deprived cells have a low rate of cell proliferation, and also because of poor drug penetration to them. There is a need for improved understanding of the mechanisms that lead to cell death in tumours. If these mechanisms were understood, it might be possible to simulate them by therapeutic manoeuvres. Recent research from our laboratory suggests that the combination of low extracellular pH and hypoxia may be very toxic to cells in nutrient-deprived regions. Drugs which limit the cell's ability to survive in regions of acid pH may provide strategy for therapy of nutrient-deprived cells.

Hyperthermic potentiation of doxorubicin and 4′-epi-doxorubicin in a transplantable neurogenic rat tumor (BT 4A) in BD IX rats

The combined effect of hyperthermis and doxorubicin on the neurogenic rat cell line BT 4C was found to be synergistic in vitro. The present investigation was initiated to study if this synergistic effect also could be obtained in vivo. An enhanced effect occurred when doxorubicin and 4′-epi-doxorubicin 7 mg/kg body weight were given 30 minutes prior to local water bath hypertbermia (one hour at 44.0 °C). The local side effects of the combined treatment did not increase above that of bypertbermia alone. Therefore, local byperthermia may become a useful modality for enhancement of the effect of anthracyclines on tumors with marginal drug sensitivity or bulky tumors with poor drug penetration.

Failure of single doses of cefazolin and cefamandole to penetrate experimental chronic Escherichia coli abdominal abscesses.

Four perforated capsules were implanted into the abdominal cavity of each of three rabbits. After 4 to 5 weeks, single doses of cefazolin (30 mg/kg) or cefamandole (90 mg/kg) were administered intramuscularly. Peak levels of the respective drugs in serum were 104 +/- 10 and 127 +/- 5 micrograms/ml (mean +/- standard error); corresponding peak levels in capsule fluid were 6.3 +/- 2.3 micrograms/ml. Sixteen weeks after implantation, 2 X 10(6) colony-forming units of a strain of Escherichia coli susceptible to cefazolin (minimum inhibitory concentration, 1.0 microgram/ml) and cefamandole (minimum inhibitory concentration, less than 0.125 microgram/ml) was introduced into each of the 12 capsules. Chronic infection was established in seven of the capsules. At 4 to 6 weeks after infection, cefazolin and cefamandole were again administered. Peak serum concentrations were 102 +/- 3.3 micrograms/ml for cefazolin and 148 +/- 6.7 micrograms/ml for cefamandole. Peak concentrations in noninfected capsules were 7.5 +/- 3.4 and 12.1 +/- 2.1 micrograms/ml, respectively, not statistically different from the first study (P greater than 0.2). However, peak concentrations in infected capsules (less than 0.3 microgram/ml) were strikingly lower than in uninfected capsules (P less than 0.002). In keeping with the latter finding, quantitative cultures of E. coli in the infected capsules remained unchanged. Administration of [14C]cefamandole indicated that low drug levels were a result of poor drug penetration rather than drug inactivation or binding. Lack of vascularity and capsule wall necrosis may be responsible for poor drug penetration.