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In a structure-activity correlation study, a number of N-substituted derivatives of rolipram (52) were prepared and evaluated [146]. A carbamate ester of rolipram was found to be approximately 10-fold more potent than rolipram itself at inhibiting human PDE IV. A methyl ketone derivate of rolipram shows more potent inhibition of PDE IV compared to rolipram or its carbamate ester. Based on proton NMR spectroscopy and computer modeling studies, a pharmacophore model of the methyl ketone derivative was proposed [147]. This model showed that the ketone carbonyl oxygen atom is involved in an important interaction within the PDE IV active site. Sodium orthovanadate, a phosphotyrosine phosphate inhibitor, exhibits dose- and time-dependent suppression of Lewis lung carcinoma A11 cells spreading. Protein tyrosine phosphorylation levels in A11 cells was elevated after treatment with orthovanadate; this increase was partially deminished by the tyrosine kinase inhibitor ST 638, concomitantly with restoration of the suppressed cell spreading, as well as invasive and metastatic ability [148]. These results suggest tyrosine phosphorylation influences adhesion of cancer cells to lung surface endothelia and that a valid approach in treating cancer is inhibition of phosphotyrosine phosphatase.

Activity in the lung is known to be reduced by multiple diseases and by exposure to drugs and medical procedures, because of reversible endothelial damage [150]. Thus, the ideal carrier would be a nonpharmacological substrate (or inhibitor) with a broad spectrum affinity substrate for membrane-bound epithelial enzymes.

For such an approach to drug targeting to be effective, it is assumed that the drug and carrier are able to become internalized by transport across the contralumenal membrane and passage into the basement membrane tissues. In this respect, the use of macromolecule carriers such as dextran (see later discussion) that can conjugate both drug and multiple-binding molecules may be an advantage. This approach can also be considered a viable strategy for the transendothelial route in the lung because several different peptidases are known to be bound to the endothelial membrane [151 -153] (Table 1).

Another strategy for obtaining an enhancement in pulmonary clearance of drugs is to conjugate the drug molecule to a chemical entity that binds to one or more surface receptors on endothelial or epithelial cells. Examples of the receptor agonists serotonin and norepinephrine have already been mentioned. However, there are examples of lung targeting that have used other pulmonary receptor substrates as targeting vectors.

Human pulmonary carcinomas have been shown to contain high levels of opioid peptides and their corresponding membrane-bound receptors [154]. Rigaudy et al. [154] targeted drugs to these receptors using modified metabolically stable enkephalins linked to cytotoxic drugs. These conjugates were expected to specifically internalize within opiate receptor-baring cells. Cell culture studies with NG 108-15 mouse tumor cells indicated that the peptide -ellipticinium conjugates 53a and 53b were internalized and were intracellularly stable but showed much lower cytotoxicity than their parent drug toward the opioid receptor-bearing cells. Nevertheless, the study did indicate that enkephalin-derived peptides could be used as specific carriers to target cytotoxic agents toward opioid receptor-rich cells. A similar approach for targeting pulmonary epithelial membrane-bound enkephalinase (Table 1) may also be valid, using enkephalin drug or enkephalinase inhibitor-drug conjugates. One potential problem with the drug-targeting strategy is the likelihood that in disease states membrane receptor populations may not be maintained. In this respect, an approach that uses a carrier capable of binding to multiple types of receptors may be more successful.

A cell-based drug delivery system for lung targeting has been investigated. Doxorubicin was loaded into B16-F10 murine melanoma cells [a drug-loaded tumor cell (DLTC)]. The amount and rate of drug released from the DLTC mainly depended on the drug loading and carrier cell concentration. After a bolus injection of 30 mg doxorubicin either in the DLTC form or in free solution into the mice tail veins, drug deposit ion in the lung from DLTC was 3.6-fold greater than that achieved by free drug solution. This DLTC system demonstrated a lung-targeting activity that may be due to specific surface characteristics [155,156].

Some recent studies [157] indicate that insulin is efficiently absorbed from the lung when administered either by intratracheal instillation in the rat or by aerosol inhalation in the rabbit. Because insulin is also actively cleared from the systemic circulation [158] and has a lower potential for acute pharmacological effects, the conjugation of appropriate drug molecules to this polypeptide may also be a useful strategy for lung targeting.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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