Iontophoretic delivery of model inorganic and drug ions.

The in vitro delivery of the inorganic ions Li+, Na+, K+, Mg2+, and Ca2+, and the model organic ions pyridostigmine and propranolol through various types of excised skin was investigated using a constant current iontophoretic system. The drug delivery rate was found to be linearly dependent on current for each ion. The slope of this linear dependence is defined as the iontophoretic flux and was used to calculate the efficiency of drug delivery which was found to be virtually independent of the type of skin employed. However, the efficiency of drug delivery was affected by the anode material and drug counterion employed in the iontophoretic system. In addition, the efficiency of delivery for divalent magnesium and calcium ions was found to be less than half that observed for the monovalent sodium and potassium ions. The in vivo iontophoretic delivery of pyridostigmine using the domestic weanling pig is also reported. The in vivo results were found to be similar to those observed in vitro.

The prevention of elastase-induced emphysema in hamsters by the intratracheal administration of a synthetic elastase inhibitor bound to albumin microspheres.

The peptide, succinyl-alanyl-alanyl-prolyl-valine chloromethylketone (SPCK), a synthetic inhibitor of elastase, was covalently attached to human albumin microspheres (HAM) and administered intratracheally to hamsters 15 min and 8 h prior to the instillation of porcine pancreatic elastase. Pressure-volume relationships and histologic examination of excised lungs after 4 wk showed complete protection from emphysema when SPCK-HAM was administered either 15 min or 8 h before elastase exposure. Concurrent experiments with free SPCK showed that protection was achieved only if elastase was administered within 15 min after the instillation of SPCK. Extending this period to 8 h not only led to a failure of free SPCK to prevent emphysema but actually resulted in more extensive air-space enlargement. The prolonged effectiveness conferred by the attachment of SPCK to a biodegradable carrier should reduce the frequency with which it would have to be administered for the therapeutic intervention of emphysema and should minimize any toxic side reactions.

Protection against pulmonary oxygen toxicity in rats by the intratracheal administration of liposome-encapsulated superoxide dismutase or catalase.

To test the feasibility of using liposomes to deliver therapeutic agents to the lungs, the effect of liposome-encapsulated superoxide dismutase (SOD) or catalase on pulmonary oxygen toxicity was studied in rats. The SOD or catalase was encapsulated in negatively changed multilamellar liposomes and administered directly into the trachea of adult rats, which were subsequently exposed to hyperoxia (greater than 95% O2). Response to hyperoxia was examined by studying lung SOD and catalase activities, survival rates, and lung morphology. Rats receiving liposome-encapsulated SOD or catalase showed increased levels of enzyme activities in the lung homogenates compared with those in the control groups after 24 to 72 h of hyperoxic exposure. Elevated enzyme levels in the lungs of rats treated with liposome-encapsulated SOD or catalase were accompanied by a significant improvement in survival rates after 72 h of hyperoxic exposure and less lung injury than in the other control groups.

The nucleotide sequence of the right-hand terminal SmaI-K fragment of adenovirus type 2 DNA.

The primary structure of the SmaI-K fragment of adenovirus type 2 (Ad2) DNA has been determined. This region includes one of the origins of DNA replication (Winnacker, 1978; Sussenbach and Kuijk, 1978). A leader sequence for an early mRNA in region 4 (Berk and Sharp, 1977; 1978) has also been mapped in this region. The comparison of the primary structure of this region in Ad2 DNA with the corresponding region in Ad5 DNA shows a remarkable homology which may be significant in view of the fact that Ad2 and Ad5 DNAs can interchangeably function in the in vitro replication system of Challberg and Kelly (1979).

Isolation and characterization of a homogeneous DNA-protein complex from adenovirus type 2 virion.

Adenovirus DNA-protein complex purified by sedimentation on a sucrose gradient containing 4 M-guanidine hydrochloride was found to contain other virion proteins in addition to the terminal protein of mol. wt. 55000. In this report, we describe a simple and rapid method for the isolation of a homogeneous DNA-protein complex. The procedure involves gel electrophoresis of the complex on agarose in the presence of sodium dodecyl sulphate. DNA was found to migrate into the gel with a single protein of mol. wt. 55000 tightly attached to it. Restriction enzyme cleavage analysis of the DNA-protein complex shows that the protein is associated with the two terminal fragments.