The most widely used drug for iron chelation is deferoxamine (DFO) mesylate. While effective in promoting iron excretion, it requires prolonged daily infusions, often resulting in poor compliance. A clinical trial was conducted using starch-conjugated DFO (S-DFO; 40SD02), a high-molecular-weight iron chelator possessing prolonged vascular retention. Single doses of S-DFO were infused intravenously into groups of four transfusion-dependent patients with beta-thalassaemia at doses of 150, 300, 600 and 900 mg/kg. Urinary iron excretion and various pharmacologic parameters were evaluated for 1 week and safety for 3 weeks. No drug-related effects were observed on clinical chemistries, haematological and coagulation parameters, urinalyses, vital signs or electrocardiograms. Drug-related adverse events were limited to four urticarial reactions, none requiring termination of the infusion. The drug stimulated clinically significant urinary iron excretion, with the highest dose (900 mg/kg) inducing excretion of 1.31 mg of iron/kg (range 0.79-1.90 mg/kg) over 1 week, with residual iron-binding capacity present in the plasma for over 6 d. In summary, treatment with S-DFO, administered weekly, has the potential to achieve iron balance in the poorly compliant patient.

The release of free, reactive iron from cellular iron stores has been implicated as an important contributor to tissue damage in a variety of clinical situations, including ischemia and reperfusion injury, hemorrhagic shock, and burn injury. Deferoxamine mesylate (DFO), the only iron chelator currently approved for clinical use, is used for the treatment of iron overload, including acute iron poisoning and treatment of chronic iron overload in transfusion-dependent anemias such as beta-thalassemia. However, it is not suitable for acute care situations because of its toxicity, primarily hypotension when given at high intravenous doses, and its short plasma half-life. We have produced a high-molecular-weight iron chelator by chemically coupling DFO to hydroxyethyl starch. This novel chelator (HES-DFO) was administered to healthy male subjects by intravenous infusion over a 4-hour period. The drug was well tolerated, and signs of DFO acute toxicity were not observed. Maximum plasma chelator levels of approximately 3 mmol/L were achieved with HES-DFO, which is more than an order of magnitude higher than has been reported with injections of DFO. Drug residence time in plasma was markedly prolonged, with an initial half-life of 22 to 33 hours. Urinary iron excretion was 7.1 +/- 2.2 mg in 48 hours in the highest dose group, as compared with 0.06 +/- 0.15 mg in control subjects who received normal saline infusions. Intravenous infusion of HES-DFO is well tolerated, produces substantial and prolonged plasma chelator levels, and markedly stimulates urinary iron excretion.

Dragsten, Paul R.; Hanson, Gregory J.; Hallaway, Philip E.; Hedlund, Bo E. Author Information

The fluorescence and optical absorption of the membrane-staining dye merocyanine 540 (M-540) have been widely used to measure cellular transmembrane potentials. We have studied the molecular mechanisms of these optical changes by measuring the fluorescence polarization of M-540 and its response to membrane potential changes in hemispherical lipid bilayer membranes. The fluorescence responds to a potential step in two distinct time scales: a fast response with a rise time less than the instrumental capability of 6 micromilligram and a slow response with a time constant around 10(-1) s. Both response amplitudes are proportional to the amplitude of the membrane potential change and both require an asymmetrical distribution of M-540 across the membrane. The slow response is ascribed to a net change of the dye concentration in the membrane. The fast response appears to be dominated by a change in the distribution of orientations of the dye molecules in the membrane, with a concomitant perturbation of a monomer-dimer equilibrium, due to interaction of the applied electric field with the permanent molecular dipol moment of M-540. The amplitude of the fast fluorescence response is concentration dependent and can be modeled by including membrane saturation effects and the presence of a nonfluorescent dimer species in the membrane at high dye concentrations. Absorbance changes reported by other investigators are consistent with this model mechanism.

The large posterior tympanic membrane in intact field crickets vibrates up to several hundred. Angstroms in response to sounds of the same frequency and intensity as the cricket's calling song. The mechanical response is linear (Fig. 3), shows a peak near 5kHz (Figs. 2, 5), and the membrane vibrates in the same simple mode in response to tones from 4 to 20kHz (Fig. 4).

An interferometric optical heterodyne technique has been developed especially for vibrational amplitude and phase measurements on auditory organs of live animals. Laser light diffusely scattered from the vibrating structure is used for the measurement. Continuous calibration and feedback compensation systems were developed to cope with the problems of drift in interferometer alignment and small background movements. Vibrational amplitudes from below 0.1 Å to above 400 Å have been detected on the posterior tympanic membranes of live crickets. Subject Classification: [43]65.20; [43]40.60; [43]35.65.

The frequency response of the auditory organs of several species of field crickets (Gryllidae) was measured with a modified laser Michelson interferometer using light scattered directly from the tympanic membranes. The auditory organ consists of two tympanic membranes located on opposite sides of the leg external to an air-filled trachea. The trachea is divided lengthwise by a thin septum and hair cells (scolopidia) are attached to the side of the anterior tracheal branch. Tones were presented in free field and the resultant sound pressure level was monitored by a probe tube near the membrane under study. The mechanical sensitivity of the tympanic membranes does not reflect the bimodal frequency sensitivity of the auditory nervous system. This means that further frequency processing occurs beyond the initial reception of acoustic energy by the tympanic membranes. The peak displacement of the large membrane to a 5-kHz tone of intensity 45 dB SPL, which corresponds to the threshold for neural activity, is of the order of 1 Å. [Supported by NIH and NSF.]

We describe an optical technique for measurement of mechanical vibrations in the auditory organs of living animals. The technique uses light scattered from the vibrating structure and offers several new advantages. Better than 1 angstrom sensitivity, 10 micrometers spatial resolution, and > 70 decibels dynamic range are achieved. Illustrative measurements of the mechanical response of the tympanic membrane of crickets ( Gryllidae ) are reported.

A sensitive method for measurement of small vibrations at acoustical frequencies has been devised using optical heterodyne spectroscopy to detect the Doppler shifts of laser light diffusely scattered from the vibration object. Beginning with the geometry of a Michelson interferometer, we replace one mirror by the scatterer and mix the reference and scattered beam on a small-area photomultiplier cathode. With only simple optical alignment, acoustic vibration spectra can be measured without perturbations even on very small-size objects, since no attachment such as an interferometer mirror is required. Vibration amplitudes as low as 0.01 nm and up to ∼100 nm can be detected with a precision of a few percent in a few seconds averaging time by phase sensitive detection of the optical beat note at the excitation frequency. Application to mechanically unstable subjects such as the auditory organs of living biological specimens is facilitated by incorporation of low-frequency feedback control of the optical path length and provision for continuous amplitude calibration. The complete system has been used in measurements of tympanal membrane movements of acoustic receptor organs. [Supported by NSF and NIH].