John S. Patton

Absorption of recombinant methionyl-human growth hormone (Met-hGH) from rat nasal mucosa

Abstract The absorption of recombinant methionyl human growth hormone (Met-hGH) from the nasal mucosa into the systemic circulation was studied in anesthetized rats. Met-hGH was administered intranasally (i.n.), intramuscularly (i.m.) and intravenously (i.v.) to determine the relative and absolute bioavailability of an intranasal Met-hGH formulation. In the absence of detergent enhancers, the absolute bioavailability of meth hGH was

Convergence in biomedical technology

An entrepreneur and a pioneer in innovative technologies trade views with an industry veteran on the likely importance of convergent technology in health care.

Recombinant Tumor Necrosis Factor-α Chronically Administered in Rats: Lack of Cachectic Effect

Abstract Recombinant human tumor necrosis factor-α (rHuTNF) was injected into rats to test its reported cachectic effects. Rats were subcutaneously injected daily at 1730 hr with either saline or rHuTNF (0.25 mg/kg body wt) for either 5 or 14 days. Daily food intakes were significantly depressed only for the first day and first two days of rHuTNF injection in animals treated for 5 days and 14 days, respectively. There were no significant differences in daily body weights among the groups. Analysis of carcass composition revealed no significant differences in percentage of lipid or protein. Liver and inguinal pad weights were not significantly different. In vitro determination of lipogenesis showed it was enhanced in the inguinal pad and depressed in the liver only after 14 days of treatment. These results demonstrate that although in vivo rHuTNF may specifically alter tissue metabolism, it does not, by itself, result in a sustained cachectic effect.

The pattern of lung injury induced after pulmonary exposure to tumor necrosis factor-α depends on the route of administration

TNF-alpha is a protein elaborated by monocytes and macrophages in response to endotoxin. The in vivo consequences of TNF-alpha elaboration have been examined extensively after intravenous administration of TNF-alpha. Substantially less is known about the effects of TNF-alpha that may be generated locally by resident tissue phagocytes. We investigated the direct effects of TNF-alpha on lung tissue by administering large amounts of human TNF-alpha directly to the lung, either as an aerosol or as an intratracheal bolus. Rats were exposed to an aerosol containing several concentrations of TNF-alpha, resulting in retention of significant quantities of TNF-alpha. The histologic response to inhaled TNF-alpha was characterized by adherence of leukocytes to venular endothelium, endothelial cell disruption, and bronchovascular edema. After aerosol administration, however, there was no evidence of alveolar inflammation or edema. In contrast, intravenous administration of large amounts of human TNF-alpha, at a dose that produced a lung content of TNF-alpha similar to that produced after high-concentration aerosol exposure, resulted in severe alveolar injury and edema. Intravenous administration of TNF-alpha did not result in the bronchovascular changes seen after inhalation. To ensure that sufficient quantities of TNF-alpha were being delivered to the lung, TNF-alpha was given as an intratracheal bolus to rats. This led to measurable absorption, but the spectrum and severity of lung injury was similar to the group that received TNF-alpha as an aerosol. We conclude that in rats, the pulmonary response to the injurious effects of TNF-alpha differ, depending on whether the TNF-alpha is delivered to the air or blood side of the alveolar capillary barrier.

Cellular Pathways in the Movement of Lipophilic Xenobiotics from GI Tract to Breast Milk

Throughout the world human breast milk is contaminated with fat soluble (log octanol/water partition coefficient >5) organic molecules that have originated from industrial synthesis or the pyrolysis of organic matter (lipophilic xenobiotics = LXs). There have been numerous measurements of contaminant levels in human milk (for a review see Jensen 1983) most of which have focused on the lipophilic xenobiotics. On a whole milk basis the concentrations are usually in the parts per billion (ppb) or parts per trillion (ppt) range, which seems miniscule; however, if one adds up the molecules, 100 ml of milk contaminated with 1 ppb DDT contains approximately 17,000,000,000,000 molecules of the pesticide. Although there are many kinds of lipophilic xenobiotics, DDT and PCB contaminants have been the most studied (the use of both is banned in the U.S.A.). PCBs, which have primarily urban and industrial applications, are found in highest levels (ppms) in human milk in urban and industrial areas (Jensen 1983). In contrast, the highest levels of DDT in human milk (ppms) are found in rural agriculture areas where its use as an insecticide is still approved (Campos and Olszyna-Marzys, 1979).

A historical perspective on convergence technology.

VOLUME 24 NUMBER 3 MARCH 2006 NATURE BIOTECHNOLOGY has interpreted primary mode of action based on the ‘intended function’ or ‘purpose’ of the combined product. A proposed reinterpretation, although not yet defined explicitly by the US Congress or FDA, seems to rely on the ‘relative contribution of each component’ of a combined product. A third source of uncertainly is a complex product-development path. The integration of research-stage combination technologies into a product development program is always risky and tends to entail higher development and manufacturing costs. In addition, adding components from disciplines that are not part of the core business requires a more complex management structure and collaboration with unfamiliar business partners. This complexity, combined with the higher costs of regulatory compliance, slows the introduction and increases the entry costs of novel technologies. A final concern is patient compliance. The drug-eluting stent, a metal scaffold used to treat occluded blood vessels, provides an instructive example. Up to 40% of patients who receive stents without an antiproliferative drug coating have an occlusion of the vessel within 6 months, whereas the long-term restenosis rates for drug-eluting stents from Johnson & Johnson and Boston Scientific are in the low single digits, leading to very rapid adoption of this technology. However, current drug-eluting stent treatments require long-term anti-platelet therapy—an off-label use for drug manufacturers. The result may be problems with patient compliance and an increased risk of heart attacks. It should thus be emphasized that the adoption of convergent technologies and the benefits that accrue will be accompanied by the emergence of new risks. Healthcare providers have a responsibility to their patients to exercise caution in making the transition to this new paradigm. Convergence is about improving the ability of a provider to deliver a service or product; if rushed, it could undermine the ability to function and potentially increase costs.