A phase I study of RSR13, a radiation-enhancing hemoglobin modifier: tolerance of repeated intravenous doses and correlation of pharmacokinetics with pharmacodynamics.

PURPOSE: Preclinical studies indicate that RSR13 oxygenates and radiosensitizes hypoxic solid tumors by decreasing the oxygen (O(2))-binding affinity of hemoglobin (Hb). A Phase I open-label, multicenter dose and frequency escalation study was conducted to assess the safety, tolerance, pharmacokinetics, and pharmacodynamic effect of daily RSR13 administration to cancer patients receiving concurrent palliative radiotherapy (RT). METHODS AND MATERIALS: Eligibility criteria included the following: ECOG performance status < or =2; resting and exercise arterial oxygen saturation (SaO(2)) > or =90%; an indication for palliative RT, 20-40 Gy in 10-15 fractions. RSR13 was administered i.v. via central vein over 60 min immediately before RT. Patients received supplemental O(2) via nasal cannula at 4 L/min during RSR13 infusion and RT. Plasma, red blood cell (RBC), and urine RSR13 concentrations were assayed. The pharmacodynamic effect of RSR13 on Hb-O(2) binding affinity was quantified by multipoint tonometry and expressed as an increase in p50, defined as the partial pressure of O(2) that results in 50% SaO(2). The RSR13 dose in the first cohort was 75 mg/kg once a week for two doses; successive cohorts received higher, more frequent doses up to 100 mg/kg/day for 10 days during RT. RESULTS: Twenty patients were enrolled in the study. Repeated daily doses of RSR13 were generally well tolerated. Two adverse events of note occurred: (1) A patient with pre-existing restrictive lung disease had transient persistent hypoxemia after the sixth RSR13 dose; (2) a patient with a recurrent glioma receiving high-dose corticosteroids had edema after the seventh RSR13 dose, likely due to the daily high-volume fluid infusions. Both patients recovered to baseline status with conservative management. Maximum pharmacodynamic effect occurred at the end of RSR13 infusion and was proportional to the RBC RSR13 concentration. After an RSR13 dose of 100 mg/kg, the peak increase in p50 averaged 8.1 mm Hg, consistent with the targeted physiologic effect, and then diminished with a half-life of approximately 5 h. CONCLUSIONS: RSR13 was well tolerated in daily doses up to 100 mg/kg administered for 10 days during RT. The combined administration of RSR13 with 4 L/min supplemental O(2) yielded pharmacodynamic conditions in which hypoxic tumor radiosensitization can occur. Ongoing Phase II and Phase III studies are evaluating the combination of RT and RSR13 for selected indications, including primary brain tumors, brain metastases, and non-small-cell lung cancer.

Hearing results after primary cartilage tympanoplasty.

OBJECTIVES/HYPOTHESIS: Cartilage-perichondrium grafting of the tympanic membrane has been used in an effort to reduce recurrence or progression of middle ear disease. The rigidity of cartilage has obvious benefit in preventing tympanic membrane retraction, but concern has been raised regarding its sound conduction properties Few studies in the literature address hearing results after cartilage tympanoplasty. The purpose of this study was to investigate the hearing results after primary cartilage tympanoplasty and compare them with results after primary tympanoplasty with temporalis fascia. STUDY DESIGN: A retrospective review of all ear surgeries using cartilage between 1994 and 1999 was performed. METHODS: Only primary cases in which the ossicular chain was intact and no mastoid surgery was performed were included. Indications for surgery included tympanic membrane perforation, retraction, and cholesteatoma Pre- and postoperative speech reception thresholds and air-bone gaps at 500 Hz, 1,000 Hz, 2,000 Hz, and 4,000 Hz were compared. RESULTS: Eleven patients comprised the cartilage study group, and there were 11 age- and temporally matched control subjects. The mean improvement in speech reception threshold for both the study group and the control group was 10 dB. The majority of patients in both groups had ABG closure to within 10 dB at all frequencies examined. There were no statistically significant differences in speech reception threshold improvement or air-bone gap closures between the two groups. CONCLUSIONS: These results demonstrate that hearing results after cartilage tympanoplasty are comparable to those after temporalis fascia tympanoplasty. Therefore, when indicated, a cartilage-perichondrium graft can be used for prevention of disease recurrence or progression without fear of impairing hearing.

Profiles of a healthful diet and its relationship to biomarkers in a population sample from Mediterranean southern France.

OBJECTIVES: The failure of single-nutrient supplementation to prevent disease in intervention studies underlines the necessity to develop a holistic view of food intake. The objectives of this study were to devise a diet quality index (DQI) and identify biomarkers of multidimensional dietary behavior. DESIGN: A nutrition survey was conducted in Mediterranean southern France by means of a food frequency questionnaire. The DQI was based on current dietary recommendations for prevention of diet-related diseases such as cardiovascular disease and some cancers. A second DQI included tobacco use. STATISTICAL ANALYSES: performed Spearman rank correlations, cross-classifications and intraclass correlations were computed between the DQI and biomarkers. RESULTS: Of the 146 subjects, 10 had a healthful diet and 18 had a poor diet. Erythrocyte omega-3 fatty acids-eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)-beta carotene, and vitamin E concentrations were lower and cholesterol concentrations were higher in the poor diet; the difference was significant for EPA and DHA and borderline significant for vitamin E. Significant correlation was found between the DQI and vitamin E (-0.12), EPA (-0.30), and DHA (-0.28), and beta carotene (-0.17) when tobacco use was considered, but not between the DQI and cholesterol. The correlation coefficient reached 0.58 (P0.01) for a composite index based on all biomarkers except cholesterol. CONCLUSIONS: Subjects with a beta carotene levels greater thanl micromol/L, vitamin E greater than 30 micromol/L and EPA greater than 0.65% and DHA greater than 4% of fatty acids in erythrocytes were likely to have a healthful diet. Each biomarker indicated the quality of diet, but correlation was higher with a composite index.

Evidence for an across-frequency, between-channel process in asymptotic monaural temporal gap detection.

Monaurally measured temporal gap detection (TGD) thresholds characteristically increase as the frequency difference is increased over a range of about half an octave to an octave between two sinusoids that mark the onset and offset of the silent gap. For greater sinusoidal frequency separations, the TGD thresholds often become asymptotic. This pattern probably reflects two different processes. The first process likely reflects within-channel processing within a single auditory filter or channel. The second process is less certain, but may reflect between-channel processing of the silent gap stimulus across two or more independent frequency channels. To evaluate the hypothesis that asymptotic monaural gap detection can be explained by a simple between-channel process, TGD thresholds were measured as a function of frequency separation between a pregap sinusoid presented to the left ear (channel 1) and a postgap sinusoid, of higher frequency, presented to the right ear (channel 2). The rationale for dichotic presentation of the sinusoidal markers and gap signal followed from the fact that the gap detection task must be performed between two independent channels by combining the outputs from each channel (ear) and recovering the gap information centrally. The resulting TGD thresholds for pregap sinusoids from 250 to 4000 Hz were relatively invariant and increased only slightly with increasing marker frequency separation. The average TGD thresholds for four listeners were in the range of 30 to 40 ms, which corresponded closely with their asymptotic TGD thresholds for the same set of stimulus conditions measured monaurally. This correspondence of the two data sets supports an across-frequency, between-channel process for asymptotic monaural gap detection at marker frequency separations greater than about half an octave.

The rationale for, and effects of oxygen delivery enhancement to ischemic brain in a feline model of human stroke.

Reduced brain tissue oxygenation is frequently seen in severe head injury and after subarachnoid hemorrhage, and this is considered a major cause of secondary ischemic brain injury. In fact, in a previous study, we found a tight correlation between low brain tissue oxygen tension and poor outcome. Therefore, we tested the hypothesis that an allosteric modifier of hemoglobin, which improves oxygen transport to tissue, could reduce the size of an acute infarct in a feline model of human stroke. This compound produces a shift in the hemoglobin dissociation curve to the right and therefore facilitates the unloading of oxygen during low oxygen tension. Seventeen adult cats were studied. Ischemic stroke was induced through a transorbital, permanent, middle cerebral artery occlusion. Seven animals received saline, and 10 received the allosteric Hb modifier RSR-13. Three different endpoints were used to determine the effect of the allosteric modifier. Delta p50 values were measured in the arterial blood; the intra-infarct oxygen tension was measured, and finally, the volume of the infarct was assessed using TTC staining. Mean delta p50 changes varied from 10.4 +/- 9.2 mmHg up to 15.0 +/- 6.8 mmHg. Mean intra-infarct oxygen tension was 27 +/- 6 mmHg for the control group and 33 +/- 7 mmHg for the drug-treated animals. The mean infarct size (measured as percentage of hemisphere volume) in the control group was 32 +/- 9% and for the RSR-13 animals 22 +/- 10% (p < 0.05). A definitive trend towards improvement in brain oxygen tension was seen, such that animals pretreated with RSR-13 showed a higher infarct oxygen tension. Infarct size was significantly reduced in the drug group. Therefore, RSR-13 is potentially beneficial in the treatment of brain ischemia. Since human studies with this compound are already completed, and other compounds which increase oxygen delivery, such as perfluorocarbons, are already being evaluated, it is likely that oxygen delivery enhancement will rapidly become the first 'neuroprotective' modality, employed in patients with severe brain injury, stroke and subarachnoid hemorrhage.

Measurement of background urban nitrogen dioxide pollution levels with passive samplers in Montpellier, France.

Background nitrogen dioxide (NO2) pollution levels in Montpellier were measured in the context of an assessment operation carried out by the local monitoring network (AMPADI-LR), using Palmes passive samplers. The equipment was validated by continuous measurement with automatic chemiluminescence analyzers. Measurements from representative background pollution sites and the ensuing cartographic representation provide information about local pollution data, a description of seasonal evolution and an assessment of the influence of various sources. The study may be used to define parameters for establishing an exposure index, taking into account roads with heavy traffic, which affects the distribution of NO2 over Montpellier, and meteorological factors. This is a pilot study which will subsequently be used for a more precise assessment measuring the personal exposure of inhabitants, for the purposes of a study on effects on health.

Timing of magnesium therapy affects experimental infarct size.

BACKGROUND: Controversy exists regarding the use of magnesium in the treatment of acute myocardial infarction (AMI) because of apparent conflicting results from clinical trials. One hypothesis to explain the various clinical observations proposes that the timing of magnesium administration significantly influences its therapeutic effect; ie, supraphysiological levels of Mg2+ must be present at the time of reperfusion for magnesium to produce clinical benefit. METHODS AND RESULTS: These experiments evaluated the effect of varying the timing of magnesium administration during AMI. Female Yorkshire swine (34 to 42 kg) underwent thoracotomy and 50 minutes of left anterior descending coronary artery (LAD) occlusion, followed by 3 hours of reperfusion. In the first group, MgSO4 (250 mg of magnesium diluted in 60 cm3 saline) was infused into the LAD over 12 minutes, beginning immediately with the onset of reperfusion (n = 6, Mg-early group). In the second group, MgSO4 was given after 1 hour of reperfusion (n = 6, Mg-late group). Six pigs received saline instead of magnesium and served as the control group. Lethal arrhythmias were significantly reduced in the Mg-early group. Infarct size was determined by vital staining. Infarct size was 0.16 +/- 0.05 g/kg body wt (Mg-early), 0.35 +/- 0.08 g/kg (Mg-late), and 0.42 +/- 0.04 g/kg for the control group. Compared with the control group, significant (P = .029) reduction in infarct size occurred in the Mg-early group but not in the Mg-late group. CONCLUSIONS: We conclude that intracoronary MgSO4 delivered during reperfusion can significantly diminish infarct size in swine, but the timing of administration is critical.

Regional localization of chromosome 3-specific DNA fragments by using a hybrid cell deletion mapping panel.

A series of human chromosome 3-specific DNA fragments isolated and characterized from a lamda phage genomic library were regionally localized on human chromosome 3. This was accomplished using filter hybridization blot analysis of a human chromosome 3 hybrid cell deletion mapping panel. Twenty-three new anonymous DNA fragments were assigned to one of four physical regions of chromosome 3. Seventeen DNA fragments were mapped to the long arm of chromosome 3, including one DNA fragment that demonstrated a restriction fragment length polymorphism (RFLP). Five DNA fragments were assigned to 3p14.2----pter, including one highly polymorphic fragment sublocalized at 3p25----pter by in situ hybridization. This DNA fragment is the second reported distal 3p polymorphic probe. One DNA fragment was localized to 3p14----p14.2. In addition, three fragments previously assigned to chromosome 3 were confirmed. Polymorphic DNA probes DNF15S2 (formerly D1S1) and D3S2 were mapped to 3p14.2----pter. The previous 3p25 in situ localization of the c-raf-1 oncogene was supported by deletion panel mapping. The physical localization of these twenty-three new DNA fragments has more than doubled the number of cloned DNA fragments assigned to chromosome 3. These and future regional assignments of DNA fragment probes will facilitate construction of both a physical and genetic linkage map of chromosome 3. They may also be useful in characterizing the chromosomal and molecular aberrations involved in small-cell lung cancer (SCLC), renal cell carcinoma, other malignancies, and the 3p14.2 common fragile site.

The effect of topical ophthalmic instillation of timolol and betaxolol on lung function in asthmatic subjects.

The propensity of systemic beta-adrenergic blockers to cause bronchoconstriction in patients with reactive airway disease is well recognized. A study was carried out to determine the prevalence of sensitivity to ophthalmic timolol in 24 asthmatic subjects at our institution and to determine the effect of ophthalmic betaxolol, a cardioselective beta-blocker efficacious in the treatment of glaucoma, in 8 subjects who were timolol-sensitive. Subjects received topical timolol 0.5%; ventilatory function, blood pressure, and heart rate were monitored over a 90-min period. The mean FEV1 fell from 2.47 to 1.93 L by 30 min after drug treatment to a minimal value of 1.86 L (-27.8%). There was a corresponding fall in FVC from 3.68 to 3.09 L by 30 min with a minimal value of 3.00 L(-20.7%). FEV1/FVC ratio also fell from 66.9 to 61.0% by 30 min, reaching a minimum of 60.0%. In 14 subjects (58.3%), the fall in FEV1 was greater than or equal to 20%, with a mean fall of 38.7% by 30 min and a maximal fall of 44.9%. The severity of timolol-sensitivity correlated with the extent of reduction in baseline percent predicted FEV1 and FVC and with exercise-induced bronchospasm. In addition, the administration of timolol reduced the bronchodilator response to below the pretimolol value. In 8 of the timolol-sensitive patients who underwent a double-blind crossover challenge with ocular instillation of betaxolol 1% and saline, betaxolol was well-tolerated and did not affect ventilatory function over a 4-h observation period. In addition, it did not prevent the FEV1 response to inhaled bronchodilator.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional assignment of the polymorphic probe D3S3 to 3p14 by molecular hybridization.

The polymorphic DNA probe D3S3 was assigned to 3p14 by molecular hybridization using a human chromosome 3/hamster somatic cell hybrid deletion panel. This is the first regional assignment of a polymorphic probe to the short arm of chromosome 3. This probe appears to be proximal to the chromosome 3 fragile site and, therefore, may prove useful in characterizing the 3p chromosomal aberrations that occur in various malignant diseases.

Verbal factors in visual recognition memory of poor readers.

This study examined the role of verbal factors in visual learning and recognition of 36 good and 36 poor readers of normal intelligence. These second and third grade boys studied 3 sets of paired-associates in which pictorial stimuli were paired with letters, geometric designs, or abstract shapes. Recognition memory was assessed. Verbal factors measured were knowledge of names of letters and shapes, latency to label production, and verbal mediational strategies. Poor readers did not differ from good readers on any of the measures of verbal processing. Letters, geometric designs, and abstract shapes differed from one another on latency to production of labels or verbal codability. Poor readers performed significantly more poorly than good readers on the recognition task regardless of the codability of the stimuli. These findings are consistent with a perceptual deficit view of visual recognition problems of young boys who are poor readers.