A phase II study of sulofenur,a novel sulfonylurea,in recurrent epithelial ovarian cancer

Summary A total of 16 patients with recurrent epithelial ovarian cancer were treated with sulofenur (LY 186641), a novel oral sulfonylurea. All subjects had received previous chemotherapy. Anaemia occurred in all 16 patients, 14 of whom required a blood transfusion, and 2/16 patients received methylene blue for breathlessness due to methaemaglobinaemia. Treatment was discontinued in 2/16 cases due to rising liver enzyme values, which reverted to normal on cessation of the drug. There was no nausea or alopecia. Only two minor responses were seen. Plasma drug levels were insufficient to result in antitumour activity as extrapolated from animal data. Further studies that attempt to increase the bioavailability and improve the therapeutic index are warranted.     

Muscle lactate transport studied in sarcolemmal giant vesicles: dependence on fibre type and age.

Lactate transport was studied in sarcolemmal giant vesicles obtained from rat or rabbit skeletal muscle. With this technique it is possible to obtain quantitative information on sarcolemmal transport characteristics. In equilibrium exchange experiments with 10, 30 and 60 mM lactate, vesicles from 'red' rat muscles had a 50% higher lactate transport capacity than vesicles from 'white' muscles. Giant vesicles made from rabbit red muscles had a 39% higher lactate transport capacity than vesicles from white muscles. These differences probably reflect a different number of lactate transporters, whereas the lactate affinity in red and white muscles are identical. Lactate transport capacity decreased with age. Sarcolemmal giant vesicles made from 22-month-old rats had a 28% lower transport capacity than vesicles from 2-month old rats. In absolute terms, the initial exchange flux with 30 mM lactate was 92 and 127 pmol cm-2 sec-1 for old and young rats, respectively. In supplementary studies in which microelectrode measurements were made in single mouse muscle fibers, it was shown that the cellular acidification rate due to lactate incubation, was 38% lower in fibres from 18-month old mice than in fibres from 2-month old mice.     

Expression, distribution and ultrastructural localization of the synapse-organizing molecule agrin in the mature avian retina

At the vertebrate neuromuscular junction the extracellular matrix molecule agrin is responsible for the formation, maintenance and regeneration of most if not all postsynaptic specializations. Several agrin isoforms are generated by alternative splicing which differ in their function and which are all expressed in the CNS. To analyse the role of agrin in the CNS, we investigated the expression and ultrastructural localization of agrin in the posthatched chick retina. In situ hybridization revealed the presence of agrin mRNA in all cellular layers of the mature retina, indicating that most if not all major retinal cell types synthesize agrin. Pan-specific as well as isoform-specific antiagrin antisera stained the optic fibre layer and the outer plexiform layer. However, only the pan-specific antiserum additionally stained the inner limiting membrane. Immunoelectron microscopy showed that in the optic fibre layer agrin was associated with ganglion cell axons and that at least part of this agrin corresponds to a neuronal isoform of agrin. In the outer plexiform layer, agrin was localized in the cleft between the photoreceptor terminals and the invaginating horizontal and bipolar cell dendrites. In the synapse-containing inner plexiform layer both antisera revealed punctate immunoreactivity. This staining corresponded to agrin concentrated in the synaptic cleft of conventional synapses as determined by preembedding immunoelectron microscopy. Agrin is thus concentrated at mature interneuronal synapses as it is at the neuromuscular junction, consistent with a role of agrin during formation and/or maintenance of synapses in the CNS.     

Corneal ulcers and the use of topical fluoroquinolones.

PURPOSE: To determine whether the widespread use of topical fluoroquinolones has changed the spectrum of ulcerative keratitis, and to determine how it has affected practice patterns in the treatment of corneal ulcers. METHODS: We retrospectively reviewed the charts of 48 consecutive patients with infectious corneal ulcers from 7/1/91 to 12/31/91 and 47 consecutive patients from 7/1/94 to 12/31/94. Patients were treated with intensive topical antibiotics (either standard fortified antibiotics or topical fluoroquinolones) at a frequency of at least every hour while awake. Some patients were admitted to the hospital, and some underwent scraping for smears and cultures. RESULTS: Ulcers which were seen in 1994 appear to have been more severe than those seen in 1991 as judged by the presence of more ulcers associated with hypopyons, (P< 0.05) but not with regard to the size of the infiltrate or epithelial defect. More ulcers in 1994 were treated on an outpatient basis (P< 0.02) and fewer ulcers were scraped and cultured than in 1991 (P< 0.001). Culture results from the 1991 and 1994 groups were similar. The most frequently isolated organisms were coagulase-negative Staphylococcus, Pseudomonas, Staphylococcus aureus, and Streptococcus spp. CONCLUSION: The spectrum of ulcerative keratitis at a tertiary referral center may be showing a trend towards more severe ulcers, but the causative agents responsible for the infection are unchanged.     

Charged amino acids as spectroscopic determinants for chlorophyll in vivo

In this paper we propose that the large spectroscopic red shifts observed for chlorophyll (Chl) and bacteriochlorophyll (BChl) in vivo may be due to charged amino acids in the binding site. Molecular orbital calculations of the transition energies of Chl in the field of external charges are carried out. The calculated wavelength shifts induced by these charges are comparable in magnitude to those observed in vivo. Moreover the size of the shifts increases in the order BChl b > BChl a > Chl a, which is the observed trend. The ability of the calculations to account for both the absolute and relative magnitudes of the wavelength shifts argues for the validity of the model. Further indirect support comes from the recent demonstration that charged amino acids are responsible for the colors of visual pigments and bacteriorhodopsin. In addition to their effects on spectra the presence of external charges induces large changes in the ionization potential of Chl molecules and thus might explain the in vivo alteration of the oxidation potentials in reaction centers.