JIP3 links lysosome transport to regulation of multiple components of the axonal cytoskeleton.

Lysosome axonal transport is important for the clearance of cargoes sequestered by the endocytic and autophagic pathways. Building on observations that mutations in the JIP3 (MAPK8IP3) gene result in lysosome-filled axonal swellings, we analyzed the impact of JIP3 depletion on the cytoskeleton of human neurons. Dynamic focal lysosome accumulations were accompanied by disruption of the axonal periodic scaffold (spectrin, F-actin and myosin II) throughout each affected axon. Additionally, axonal microtubule organization was locally disrupted at each lysosome-filled swelling. This local axonal microtubule disorganization was accompanied by accumulations of both F-actin and myosin II. These results indicate that transport of axonal lysosomes is functionally interconnected with mechanisms that control the organization and maintenance of the axonal cytoskeleton. They have potential relevance to human neurological disease arising from JIP3 mutations as well as for neurodegenerative diseases associated with the focal accumulations of lysosomes within axonal swellings such as Alzheimer's disease.

Spontaneous pneumomediastinum. An unusual cause of a sore throat.

Sore throat, usually related to pharyngitis, is a common presenting symptom in the primary care setting. Drs Frenkel and Lyons describe a case showing that physicians need to be aware of another, puzzling cause--spontaneous pneumo-mediastinum.

Plasma levels following single and repeated doses of erythromycin estolate and erythromycin stearate.

The pharmacokinetics of erythromycin and erythromycin 2'-propanoate were studied in healthy male volunteers following single and repeated doses of erythromycin stearate tablets, erythromycin estolate capsules, and a suspension. Estolate dosages gave rise to higher plasma levels of total drug than the stearate. However, the stearate yielded higher plasma levels of erythromycin base. Absorption of all dosage forms, except the suspension, was delayed, and pharmacokinetic interpretation of both single- and multiple-dose data required incorporation of an absorption lag time. The absorption of erythromycin stearate was inhibited by food and also by low fluid volumes in fasted subjects. Absorption of erythromycin estolate was increased in the presence of food and was not greatly affected by fluid volume. Although single-dose data poorly predicted circulating levels of erythromycin following repeated doses, trends observed after single doses were maintained during chronic treatment.

Bioavailability of erythromycin stearate: influence of food and fluid volume.

The influence of various test meals and coadministered water volumes on erythromycin stearate bioavailability from orally dosed film-coated tablets was studied in healthy human subjects. Serum erythromycin levels were uniformly reduced by all test meals, with the reduction in mean peak serum levels varying from 47 to 60%. Serum erythromycin levels also were reduced significantly in fasted individuals when the accompanying water volume was reduced from 250 to 20 ml. The apparent drug absorption rate constant was not influenced by treatments. This result is probably due to rapid degradation of solubilized, unabsorbed drug in the GI tract. Higher and more uniform serum erythromycin levels are obtained when erythromycin stearate tablets are given on an empty stomach together with an adequate water volume.

Pharmacokinetics of alcohol following single low doses to fasted and nonfasted subjects.

The absorption and elimination characteristics of alcohol have been studied in healthy fasted and nonfasted human volunteers using low single doses. In non-fasted subjects, carbohydrate reduced overall alcohol bioavailability by about 96 percent, compared to 90 per cent for fat and 75 per cent for protein. Inhibition of absorption in nonfasted subjects appeared to be due to less alcohol being available for absorption rather than a reduced absorption rate. Serum alcohol levels in fasted subjects were interpreted in terms of both first-order and zero-order absorption followed by first-order elimination. Of the two proposed models, that utilizing zero-order absorption provided a marginally better fit to observed data.

Propoxyphene and norpropoxyphene: influence of diet and fluid on plasma levels.

The influence of various test meals and ingested fluid volumes on the bioavailability and pharmacokinetics of propoxyphene and its major metabolite norporpoxyphene has been studied in healthy human subjects. The absorption of drug was delayed by all test meals, but the overall efficiency of absorption was either not affected or was slightly increased. Increased fluid volume intake decreased propoxyphene bioavailability. Plasma levels of metabolite correlated well with levels of unchanged drug, particularly in the first 2 hr after dosing, but were not markedly influenced by treatments.

Influence of diet and fluid on bioavailability of theophylline.

The influence of various test meals, and of fluid volumes, on the bioavailability of theophylline from a solid dosage form has been studied in healthy male volunteers. Absorption of a drug was faster after dosing immediately following a high protein meal than after a high fat or a high carbohydrate meal. Absorption from a solution was faster than from a solid dosage form in all treatments; areas under serum level time curves after dosing were also significantly higher up to 12 hr. Areas up to 12 hr after dosing also tended to be higher after the high protein meal and after dosing with 500 ml water on an empty stomach than after other solid dose treatments.