FAIR reporting of clinical trials for public health practice.

The number of clinical trials is rapidly growing, and automation of literature processing is becoming desirable but unresolved. Our purpose was to assess and increase the readiness of clinical trial reports for supporting automated retrieval and implementation in public health practice. We searched the Medline database for a random sample of clinical trials of HIV/AIDS management with likely relevance to public health in Africa. Five authors assessed trial reports for inclusion, extracted data, and assessed quality based on the FAIR principles of scientific data management (findable, accessible, interoperable, and reusable). Subsequently, we categorized reported results in terms of outcomes and essentials of implementation. A sample of 96 trial reports was selected. Information about the tested intervention that is essential for practical implementation was largely missing, including personnel resources needed 32·3% (.95 CI: 22·9-41·6); material/supplies needed 33·3% (.95 CI: 23·9-42·8); major equipment/building investment 42·8% (CI: 33·8-53·7); methods of educating providers 53·1% (CI: 43·1-63·4); and methods of educating the community 27·1% (CI: 18·2-36·0). Overall, 65% of studies measured health/biologic outcomes, among them, only a fraction showed any positive effects. Several specific design elements were identified that frequently make clinical trials unreal and their results unusable. To sort and interpret clinical trial results easier and faster, a new reporting structure, a practice- and retrieval-oriented trial outline with numeric outcomes (PROTON) table was developed and illustrated. Many clinical trials are either inconsequential by design or report incomprehensible results. According to the latest expectations of FAIR scientific data management, all clinical trial reports should include a consistent and practical impact-oriented table of clinical trial results.

Toxicological safety evaluation of gadobenate dimeglumine 0.5 M solution for injection (MultiHance), a new magnetic resonance imaging contrast medium.

OBJECTIVE: To support the clinical use of gadobenate dimeglumine for injection as an intravascular magnetic resonance imaging contrast medium through an extensive battery of toxicological safety studies. METHODS: Single and multiple dose toxicity, reproduction and mutagenicity assessments were carried out in rodents and non-rodents. RESULTS: Initial adverse clinical signs in monkeys were associated with a systemic exposure 34 times higher than that found in humans after 0.1 mmol/kg gadobenate dimeglumine. Good systemic tolerance was observed in repeated dose toxicity studies. Reproductive performance and physical and behavioral development of offspring were unaffected at doses corresponding to 20 times the human dose. Mutagenicity tests excluded any genotoxic potential of gadobenate dimeglumine. CONCLUSION: Based on the wide margins of safety demonstrated in different species, particularly in primates, gadobenate dimeglumine can be considered as safe in the range of clinical doses recommended for magnetic resonance imaging.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (1)--single dose intravenous and intracisternal toxicity study in rats].

Gadobenate dimeglumine formulation (E7155) was evaluated for its general toxicity potential following a single intravenous and intracisternal administration to rats. Dosage levels tested were 3.3, 4.5, 6.0 and 8.0 mmol/kg at the injection rate of 6 ml/min and 7.50, 8.89, 10.54 and 12.50 mmol/kg at 1 ml/min for the intravenous administration route, and 0.15, 0.21, 0.29 and 0.40 mmol/kg for the intracisternal administration route. Parameters measured during the 14-day observation period were mortality, clinical signs and macroscopic examination. After intravenous administration at the injection rate of 6 ml/min, twitches, respiratory blocking and prostration were observed at 6.0 mmol/kg, and dyspnoea and sedation at 3.3 and 4.5 mmol/kg. Deaths occurred within 1 min after administration at 6.0 mmol/kg and above. LD50 values were 7.97 mmol/kg in males and 6.22 mmol/kg in females. After intravenous administration at the injection rate of 1 ml/min, shallow breathing, twitches and sedation were observed at 7.50 mmol/kg and above and respiratory arrest at 8.89 mmol/kg. Deaths occurred within 1 min after administration at 8.89 mmol/kg and above. LD50 values were 9.0 mmol/kg in males and 9.7 mmol/kg in females. After intracisternal administration, symptoms consisted of sedation, staggering gait, dyspnoea, twitches and ataxia at 0.15 mmol/kg and above, prostration, paralysis of forelimbs, and/or hind limbs and chromodacryorrhea at 0.21 mmol/kg, and convulsions at 0.29 mmol/kg and above. Deaths occurred within 7 days after administration at 0.21 mmol/kg and within 5 min at 0.29 mmol/kg and above. LD50 values were 0.42 mmol/kg in males and 0.25 mmol/kg in females.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (2)--Single dose intravenous toxicity study in dogs].

Gadobenate dimeglumine formulation (E7155) was given by single intravenous injection to 4-5 month-old beagle dogs at doses of 2 or 6 mmol/kg. Treatment was followed by a 14-day observation period in order to evaluate the test article's toxicity. The male and female dogs at 6 mmol/kg vomited and showed reddened gums and ears as clinical signs. One male dog at 6 mmol/kg was euthanized approximately 23 hr after administration due to its very poor clinical condition, which included an unwillingness to move, pale gums and weak pulse. Body weight was decreased at 6 mmol/kg, and also slightly at 2 mmol/kg. Decreased food consumption was noted both at 2 and 6 mmol/kg. Hematology for the euthanized male at 6 mmol/kg showed increases in the total white blood cell count, packed cell volume, hemoglobin and red cell count and a decrease in the platelet count. Biochemistry showed a dose-related increase in alkaline phosphatase, GPT and GOT at 2 and 6 mmol/kg. Males and females at 6 mmol/kg showed increases in bilirubin, calcium and urea, and a reduction in glucose. Females at 6 mmol/kg also showed a reduction in total protein. Urinalysis showed an increase in pH at 2 mmol/kg and above. For females at 6 mmol/kg, an increase in urine volume and a decrease in specific gravity and osmolality were noted. An increase in relative liver and kidney weights was recorded for males and females dosed at 6 mmol/kg. For the euthanized male at 6 mmol/kg, postmortem examination revealed a pale liver with rounded edges and an accentuated lobular pattern, and dark material on the gastro-intestinal mucosal surface. In macroscopic pathology, the male at 6 mmol/kg revealed single liver cell necrosis, minimal early hyperplasia in small biliary ductules, inflammatory cells in the sinusoidal and portal tracts, centrilobular inflammatory cells, diffuse vacuolation of the hepatocytes and sinusoidal dilatation in the liver, and cortical tubular vacuolation in the kidneys. In the female dog treated at 6 mmol/kg, hyperplasia in the small biliary ductules, inflammatory cells in the portal tracts, diffuse vacuolation of hepatocytes and sinusoidal dilatation were seen in the liver, and increases in the severity of cortical tubular basophilia, cortical tubular dilatation and cortical tubular casts were detected in the kidney. Based on these results, the lethal dose of E7155 was set at 6 mmol/kg. It is also concluded that a dose of 2 mmol/kg was tolerated in the beagle dog after a single injection followed by a 14-day observation period.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (3)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in rats].

A 4-week repeated dose toxicity study of gadobenate dimeglumine formulation (E7155) was conducted in Sprague-Dawley rats to assess its non-clinical safety. E7155 was administered intravenously at doses of 0.3, 1.0 and 3.0 mmol/kg/day to male and female rats once a day during 4 weeks. The reversibility of toxicity was evaluated during a 4-week recovery period at 3.0 mmol/kg/day. At 0.3 mmol/kg/day and higher, vacuolation of the cortical epithelium was seen in the kidneys and an increase in the incidence of local damage at the injection sites. In the 1.0 and 3.0 mmol/kg/day male and female groups, scabbing/ulceration of the tail at the injection sites, macroscopic pale/thickened fundic mucosa in the stomachs, vacuolation of the urinary bladder, and mucosal mineralization with epithelial hyperplasia of the glandular stomach were found. In the 1.0 and 3.0 mmol/kg/day male group and 3.0 mmol/kg/day female group, increases of water consumption and urinary potassium excretion, increased kidney weight and enlargement of the kidneys were observed. In the 3.0 mmol/kg/day male and female group, hepatocyte necrosis with inflammatory cells in the liver and epithelial degranulation in the interlobular ducts of the salivary glands were found. In addition, in the 3.0 mmol/kg/day male group, increases in plasma sodium and decreases of urinary sodium and chloride excretion, and degenerative changes in the testes and epididymides were observed. After the 4-week recovery period, except for an increase in urinary potassium excretion, increased kidney weights and changes in the testes and epididymides, all of the above findings had complete or partial recovery. Vacuolation of renal tubular cells was common, expected, and known as an adaptive change of treatment with hypertonic solutions, and an increase in the incidence of local damage at the injection sites was due to irritation by repeated intravenous dosing with hypertonic solutions. Therefore, these changes were not toxic changes. In conclusion, the dose level of 0.3 mmol/kg/day should be regarded as the No Observed Adverse Effect Level (NOAEL) after repeated administration of E7155 in rats.

[General toxicity study of gadobenate dimeglumine formulation (E7155) (4)--4-week repeated dose intravenous toxicity study followed by 4-week recovery period in dogs].

Gadobenate dimeglumine formulation (E7155), at doses of 0 (physiological saline), 0.25, 0.5, 1 and 2 mmol/kg/day of body weight, was administered intravenously to male and female beagle dogs once daily for 4 consecutive weeks in order to evaluate the subacute toxicity of the test article. Reversibility of toxicity was evaluated during a 4-week recovery period at 1 and 2 mmol/kg/day. No toxicologically significant changes were observed at 0.25 and 0.5 mmol/kg/day. In animals receiving 1 or 2 mmol/kg/day, transient swelling and redness of the facial and eye areas, lethargy, decreased activity, emesis, retching, watery or unformed stool, decreased body weight or body weight gain, decreased food consumption, decreased hematocrit and hemoglobin concentration, increased APTT, increases in plasma ALP, GPT or gamma-GT, decreased plasma inorganic phosphorus, total protein or albumin, increased liver or kidney weight, subacute inflammatory infiltrates, loss of centrilobular hepatocytes or hepatocellular cytoplamic vacuolation in the liver, vacuoles in the epithelial cells of the renal tubles and/or hypocellularity in the bone marrow were seen. The results of toxicokinetic analysis showed that systemic exposure was similar in males and females, and there was no accumulation of the test material over the treatment period, although AUC tended to be enhanced by slightly more than the proportionate dose increase. These effects were recovered or tended to be reversed after a post-dosing period for 4 weeks. In conclusion, the No Observed Adverse Effect Level (NOAEL) was 0.5 mmol/kg/day.

[Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (1)--Fertility study in male rats by intravenous administration].

The influence of gadobenate dimeglumine formulation (E7155) on general reproductive performance and fertility in male rats of the Sprague-Dawley strain was assessed in this study. E7155 was administered by intravenous injection at a dosage of 0.3, 1.0, or 2.0 mmol/kg/day to groups of 22 male rats for 13 weeks. Control animals received 0.9% sterile physiological saline throughout the same period. After four weeks of treatment, each male was paired with an untreated female of the same strain. Each male was paired again after 10 weeks of treatment with another untreated female of the same strain. All females were killed on Day 14 of gestation for examination of pregnancy status. No significant toxicological signs associated with systemic exposure to E7155 were observed. There were no effects of treatment with E7155 on body weight gain, food consumption, macroscopic findings, reproductive organ weights and sperm count or sperm motility in male rats. Mating performance after pairing at Weeks 4 and 10 of treatment as well as litter size and number of survival embryos on Day 14 of gestation were not affected by paternal treatment with E7155. From these results, the No Observed Adverse Effect Level (NOAEL) of E7155 was 2.0 mmol/kg/day for general and reproductive toxicity parameters in male rats treated with E7155 and for development in their embryos.

[Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (2)--Combined study of effects on fertility and embryo-fetal toxicity in female rats by intravenous administration].

The influence of gadobenate dimeglumine formulation (E7155) on fertility and general reproductive performance and embryo-fetal development was assessed in female Sprague-Dawley rats. E7155 was administered by intravenous injection at a dose of 0.3, 1.0 or 2.0 mmol/kg/day to groups of 22 female rats for 15 days before pairing. Treatment was continued throughout mating and up to Day 17 of gestation. Control animals received 0.9% sterile physiological saline throughout the same period. All females were killed on Day 20 of gestation for examination of their uterine contents. There were no toxic clinical signs of treatment. The body weight and food consumption of females before pairing and during gestation were not affected by treatment. Estrous cycles, mating performance, litter size and fetal weight, survival and development were also not affected by treatment. Based on the above results, the No Observed Adverse Effect Level (NOAEL) of E7155 was 2.0 mmol/kg/day for general toxicologic effects and reproduction of female rats and the development of their fetuses.

[Mutagenicity study of gadobenate dimeglumine formulation (E7155) (1)--Reverse mutation assays in S. typhimurium and E. coli tester strains].

The ability of gadobenate dimeglumine formulation (E7155) to cause gene mutations was assessed in five strains of Salmonella typhimurium (TA100, TA1535, TA98, TA1538, and TA1537) and a strain of Escherichia coli (CM891; WP2, uvrA-, pKM101) using the Ames test (agar plate assay). The results suggest that E7155 is non-mutagenic towards these bacterial tester strains.

[Reproductive and developmental toxicity study of gadobenate dimeglumine formulation (E7155) (3)--Study of embryo-fetal toxicity in rabbits by intravenous administration].

Gadobenate dimeglumine formulation (E7155) was daily administered by intravenous injection at 0.3, 0.9 or 2.0 mmol/kg/day to mated NZW female rabbits (20/group) to assess the effect on embryo-fetal development. Treatment with 2.0 mmol/kg/day caused initial, notable loss of body weight and reduction in food consumption. Slightly reduced body weight gain and food intake were recorded at 0.9 mmol/kg/day. There were no obvious adverse effects in dams given E7155 at 0.3 mmol/kg/day. There was a slightly higher incidence of early intrauterine deaths at 0.9 and 2.0 mmol/kg/day. Morphological examination of fetuses at 2.0 mmol/kg/day revealed small eye/microphthalmia and/or retinal irregularities in three fetuses from three separate litters. There was also an increase in the incidence of additional and/or fused sternebral centres and 20-thoracolumbar vertebrae at this dosage. From these results, the No Observed Adverse Effect Level (NOAEL) for general toxicity of dams and embryo-fetal development was 0.3 mmol/kg/day.

[Mutagenicity study of gadobenate dimeglumine formulation (E7155) (2)--Chromosome aberration test with human lymphocytes in culture].

The mutagenic potential of gadobenate dimeglumine formulation (E7155) was studied by the chromosome aberration test in cultured human lymphocytes. Human lymphocytes were exposed to E7155 at 0.078-10 mM both in the presence and absence of S9 mix derived from rat livers. Three dose levels (2.5-10 mM) were selected for the metaphase analysis. E7155 induced no increase in the incidence of aberrant cells or polyploid cells in any treatments both in the presence and absence of metabolic activation. Thus, it is concluded that E7155 has shown no evidence of clastogenic or polyploidy-inducing activity under these experimental conditions.

[Mutagenicity study of gadobenate dimeglumine formulation (E7155) (3)--Micronucleus test in rat bone marrow cells].

The mutagenic potential of gadobenate dimeglumine formulation (E7155) was studied by the micronucleus test in rats. Single intraperitoneal injection of E7155 to Sprague Dawley rats at the dose of 5295.2 mg/kg (5 mmol/kg) did not induce any statistically significant increase in the frequency of micronucleate cells in the bone marrow sampled after 18, 42 and 66 hr from time of administration.

[Muscular irritation study of gadobenate dimeglumine formulation (E7155) in rabbits].

To examine the local muscular irritation potency of gadobenate dimeglumine formulation (E7155), E7155 was injected into the right vastus lateralis muscle of male Kbl:JW rabbits, and saline as the negative control was injected into the left muscle. Half of the animals were subjected to necropsy at 2 or 14 days after administration. The muscles were examined macroscopically and histopathologically. Also, 0.425 w/v% and 1.7 w/v% acetic acid solutions were used as a positive control. In macroscopic observation, hemorrhage with white or brown coloration was seen in the muscles treated with E7155 at 2 days after administration, and white coloration was seen in one case at 14 days after administration. In histopathological examination, slight or moderate hemorrhage, edema, cellular infiltration, degeneration of muscle fibers and necrosis of muscle fibers were seen in the muscles treated with E7155 at 2 days after administration, and very slight to slight cellular infiltration, degeneration of muscle fibers, fibrosis, calcification of muscle fibers and foreign body giant cells were seen in the muscles treated with E7155 at 14 days after administration. The changes in the muscle caused by E7155 were definitely less than those caused by the 1.7 w/v% acetic acid solution at both 2 and 14 days, and slightly less and definitely less than those caused by the 0.425 w/v% acetic acid solution at 2 days and 14 days after administration, respectively. The changes caused by E7155 were more severe than those caused by saline. It was concluded that the local muscular irritation potency of E7155 could be classified at Grade 2.

Neurotolerability of nonionic X-ray contrast media. The role of chemotoxicity.

RATIONALE AND OBJECTIVES: Because small quantities of x-ray contrast agents can cross the blood-brain barrier, the authors evaluate the properties that contribute to neurotoxicity. METHODS: The acute toxicity of various monomer and dimer contrast media was assessed after intracerebroventricular (ICV) injection to mice and intracisternal (ICI) injection to rats. RESULTS: In mice, median lethal dose (LD50) values for monomer contrast media apart from iohexol were higher than those for dimer contrast media. In rats, iopentol and iopromide were more neurotoxic than all other contrast media. The signs of toxicity for all contrast media included convulsions, dyspnea, hypoactivity, and sedation. Hypertonic D-mannitol solution was tolerated as well as artificial cerebrospinal fluid. Neither the hydrophilicity of the molecules nor the physicochemical properties of their solutions explain the toxicities satisfactorily. CONCLUSIONS: Neurotoxicity of monomer or dimer contrast media depends more on chemical structure characteristics other than hydrophilicity than on the physicochemical characteristics of their solutions.

Comparison of esophageal, tracheal, and mouth occlusion pressure in patients with chronic obstructive pulmonary disease during acute respiratory failure.

In 14 acutely ill patients with chronic obstructive pulmonary disease who were either intubated or breathed via a tracheostomy, we measured the pressures generated in the esophagus and trachea during the first 0.1 s of spontaneous inspiratory efforts against closed airway (P0.1). No significant difference was found between P0.1 in the trachea and esophagus, where it was measured at 2 balloon levels (distance from balloon tip to nares: 35 and 45 cm). In 4 of the patients we also compared esophageal and mouth occlusion pressures during mouth breathing, the orifice of tracheostomy being temporarily obstructed. Mouth P0.1 in the 4 patients averaged approximately 47% of the esophageal occlusion pressure (4.4 +/- 1.7 versus 8.9 +/- 3.1 cm H2O, respectively). Because in patients with COPD with upper airways bypassed (tracheostomized or intubated) the changes in esophageal and tracheal pressure during occluded respiratory efforts were similar, it is concluded that the difference between esophageal and mouth occlusion pressure is due to the tissue compliance of the oropharynx.

Effects of airway anesthesia on pattern of breathing and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure.

To assess the role played by airway receptors in the genesis of rapid and shallow breathing of patients with chronic obstructive pulmonary disease (COPD), we studied the effects of airway anesthesia in 14 patients with COPD during acute respiratory failure. Airway anesthesia was performed by fiberoptic xylocaine administration from the larynx to the subsegmental bronchi, all patients being intubated or tracheostomized. A small decrease in minute ventilation of 6 +/- 1% of the control values occurred after airway anesthesia. This was due to a decrease (p less than 0.01) in respiratory frequency (f) (14.5 +/- 1%). The latter resulted from an increase (p less than 0.0005) in the expiratory time, whereas the inspiratory time did not change significantly. On the other hand, tidal volume increased (p less than 0.02) by 10.1 +/- 0.6%. In all patients, these modifications were accompanied by arterial blood gas deterioration, mean PaO2 and PaCO2 of 42 +/- 3 mmHg and 62 +/- 3 mmHg, respectively, 15 min after xylocaine administration, as compared with 48 +/- 2 mmHg and 54 +/- 2 mmHg, respectively, during the control period. No correlation was found between the changes in minute ventilation and PaO2 or PaCO2. We conclude that (1) activation of airway receptors are involved in the determination of the rapid and shallow breathing observed in patients with COPD during acute respiratory failure, and (2) airway xylocaine anesthesia that worsens arterial blood gases is contraindicated in these patients.

[Effect of sleep on respiration]. / Influence du sommeil sur la respiration.

Physiologists as well as chest physicians are both interested in respiratory control and disturbances during sleep. Many studies have demonstrated episodic falls in oxygen saturation in lung disease during sleep related to episodic alveolar hypoventilation and/or apneas. A better understanding of these sleep-induced disorders has been possible since the use of electroencephalo-and oculogram (EEG-EOG) to separate the two stages of sleep i.e rapid eye movement sleep (REM sleep) and slow wave sleep (non-REM sleep), and of non invasive methods in assessment of respiratory parameters. Several mechanisms may explain respiratory disturbances during sleep: --a failure of respiratory control systems which differ between the two stages of sleep (central apnea); --a decrease in activity of all upper airway muscles, mainly during REM sleep (occlusive apnea); --a worsening in ventilation-perfusion inhomogeneities which may occur independently of the apnea periods. The detection of such falls in oxygen saturation in pulmonary patients, especially in hypoxemic ones appear to be very important to avoid the adverse effects of hypoxemia on pulmonary circulation. This could be realized by: --an evaluation of respiratory disorders during sleep; --a better assessment of the respiratory control systems in cold patients; --suppression of predisposing factors of occlusive apnea. These different investigations would lead us to a more logical management of respiratory disturbances during sleep, especially in patients suffering from chronic respiratory insufficiency.

[Assessment of chemoprophylaxis with intermittent tetracycline in chronic bronchitis. A functional follow-up for 3 years (author's transl)]. / Essai d'une antibiothérapie prophylactique discontinue dans la bronchite chronique. Surveillance fonctionnelle pendant trois ans.

This study is a reappraisal for the value of intermittent tetracycline therapy in the reduction of the rate of pulmonary function alteration in patients with chronic obstructive lung disease. Two groups of patients with chronic bronchitis were randomly divided and followed up for three years. No significant differences in pulmonary function were observed between these two groups.

[Interest of helium-oxygen flow volume and isoflow volume curves in chronic obstructive lung disease (author's transl)]. / Intérêt des courbes débit-volume en air et en mélange hélium-oxygène dans les bronchopathies chroniques obstructives.

We have compared changes in maximal flows induced by breathing gases of different density in 54 patients suffering from emphysema and chronic bronchitis. We considered as positive responders those subjects displaying an increase by at least 20% of maximal expiratory flows while breathing gases of lower density. Such a response was demonstrated in 21 cases, the remainder (33 cases) being non-responders. Hence, in such patients, airways obstruction may primarily be localised in central or peripheral airways. There was no correlation between the nature of this response and the clinical diagnosis, but non-responders, in general, were those in whom respiratory insufficiency was more severe. There seemed to be no additional information gained by measuring isoflow-volume (iso V vol.) in comparison with measuring differences in maximal flows at 50% of vital capacity.