Human studies recovery

The positions, numbers, and types of sugars on the anthocyanin molecule influence its bioaccessibility. Indeed, a recent human study reported that the acylation of anthocyaifins resulted in a sigififlcant decrease of anthocyanin recoveries in plasma and urine. In addition, anthocyanins form linkages with aromatic acids, aliphatic acids, and methyl ester derivatives, which can also affect their passage through the intestinal barrier. 

No human studies of sufficient exposure duration with measured concentrations producing irreversible or life-threatening effects were located in the available literature. However, the data of Barcroft (1931), a 1.5-min exposure at 500-625 ppm, and Bonsall (1984), a 6-min exposure at approximately 450 ppm, with recovery from symptoms and effects, can be considered short-term upper limits for healthy adults. 

The usual GLP 30- or 60-day repeat-dose toxicology study with a recovery group offers an opportunity to perform a more systematic investigation of the more subtle pharmacodynamic or toxicologic effects of biopharmaceuticals than those endpoints usually incorporated into such protocols. Some of these demand tissue samples, but many involve noninvasive biomarkers that can be carried forward into early phase human studies. These might include CNS assessments, inflammation and immune activation or suppression, cell proliferation or apoptosis in tissue samples, and end-organ toxicities. 

The assay has been validated and the results of validation demonstrate that the standard curve is linear over the concentration range of 100-2000 ng/mL. The assay is reproducible and accurate, with recovery of the analyte and internal standard in the range of 80-90 %. The analysis requires 0.5 mL of plasma and has a limit of quantification of 70 ng/mL. The stability of plasma samples stored at -20 °C has been demonstrated for up to 12 weeks. Autoinjector stability has been demonstrated for over 13 h and freeze-thaw stability has been demonstrated for 3 freeze-thaw cycles. The procedure has a sample throughput of at least 30 specimens per day. The assay meets the guidelines for bioanalytical methods validation for human studies (Shah et al. 1991). 

A conventional mass spectrometer was used to measure ion abtmdance ratios of the diligand fragments [Fe(6511702)2] which were formed during electron-impact ionization. Sample isotopic enrichment levels were obtained from standard curves that related ion abundance ratios to enrichment levels. Tracer concentration was calculated from the values for total iron content and enrichment level. The relative standard deviation for the ion abundance measurement was less than 2%. Recovery of tracers from spiked fecal samples ranged from 90% to 104%. The method was used to analyze samples collected from a human study. Iron availability from breakfast meals was determined in 6 yo mg women by giving 7 mg of in apple juice on one... 

Interferon - This continued to be an extremely active area both in the laboratory and in human studies. The role played by Interferon in the course of natural varicella infection was studied in human patients with and without impairment of host-defense mechanisms. In infected patients with normal defense mechanisms, interferon titres present in cutaneous vesicles were initially high, and appeared to prevent virus dissemination and allow rapid recovery. On the other hand, in patients with Hodgkins disease, lymphomas and leukemias where there is an Impairment of host-defense mechanisms, low titres of cutaneous interferon were initially present, and viral dissemination was rapid and in some cases led to death. In those cases which were resolved favorably the remission followed the late appearance of high interferon titres. 

Recovery nd Purifica.tion. The production of EH Lilly s human insulin requires 31 principal processing steps of which 27 are associated with product recovery and purification (13). The production process for human insulin, based on a fermentation which yields proinsulin, provides an instmctive case study on the range of unit operations which must be considered in the recovery and purification of a recombinant product from a bacterial fermentation. Whereas the exact sequence has not been pubUshed, the principle steps in the purification scheme are outlined in Figure la. 

Based on tests with laboratory animals, aniline may cause cancer. The National Cancer Institute (NCI) and the Chemical Industry Institute of Toxicology (CUT) conducted lifetime rodent feeding studies, and both studies found tumors of the spleen at high dosage (100 —300 mg/kg pet day of aniline chloride). CUT found no tumors at the 10—30 mg/kg per day feeding rates. The latter value is equivalent to a human 8-h inhalation level of 17—50 ppm aniline vapor. In a short term (10-d) inhalation toxicity test by Du Pont, a no-effect level of 17 ppm aniline vapor was found for rats. At high levels (47—87 ppm), there were blood-related effects which were largely reversible within a 13-d recovery period (70). 

Anesthetics. Ethyl amiaobenzoate [94-09-7] (benzocaiae), C2H22NO2, is the only anesthetic candidate that might allow spawned-out broodstock carcasses to be used for pet or human food. Studies are still required to determine which residues remain ia the carcasses (9). Electronarcosis is an alternative to chemical anesthesia that uses varying electrical frequencies to rapidly anesthetize fishes and allow gentie recovery. Electronarcosis has been used effectively on tilapia (Oreochromis sp.) and the common carp Cyprinus carpid) and the technique is being tested with other fishes (23,24). 

An opportimity for error recovery would have been to implement a checking stage by a supervisor or independent worker, since this was a critical maintenance operation. However, this had not been done. Another aspect of the unforgiving environment was the vulnerability of the system to a single human error. The fact that the critical water jacket flow was dependent upon a single pump was a poor design that would have been detected if a hazard identification technique such as a hazard and operability study (HAZOP) had been used to assess the design. 

During the PHEA stage, the analyst has to identify likely human errors and possible ways of error detection and recovery. The PHEA prompts the analyst to examine the main performance-influencing factors (PIFs) (see Chapter 3) which can contribute to critical errors. All the task steps at the bottom level of the HTA are analyzed in turn to identify likely error modes, their potential for recovery, their safety or quality consequences, and the main performance-influencing factors (PIFs) which can give rise to these errors. In this case study, credible errors were found for the majority of the task steps and each error had multiple causes. An analysis of two operations from the HTA is presented to illustrate the outputs of the PHEA. Figure 7.12 shows a PHEA of the two following tasks Receive instructions to pump and Reset system. 

Despite their potential health-promoting effects as dietary antioxidants, the fate of betalains in humans has been poorly studied. Betalain bioavailability was first demonstrated in humans by the appearance of betacyanins in urines after ingestion of beetroot extract" and red beet juice," indicating that these compounds are indeed absorbed. Although intact betacyanins (betanin and isobetaiun) appeared rapidly in human urine with a maximum excretion rate observed within 2.5 to 8 hr," betacy-anin recoveries in human urine were usually low (< 1% of the dose) over 24 hr postdose, suggesting that either the bioavailabifity of betacyaiuns from red beetroot is low or that renal clearance is a minor excretion route for these compounds. 

Studies on workers in an occupational setting showed a dose-response relationship between the concentration of acrylonitrile of inspired air and the recovery of metabolites in the urine (Houthuijs et al. 1982 Sakurai et al. 1978). In a controlled study using human volunteers, urinary metabolite data suggested that the elimination of acrylonitrile followed first-order kinetics, with a half- life of seven to eight hours (Jakubowski et al. 1987). 

In humans, severe cases of acrylonitrile poisoning have resulted in low grade anemia (Wilson 1944 Wilson et al. 1948), but complete recovery was reported. Chronic occupational exposure to low levels of acrylonitrile has not resulted in detectable effects on the hematological system (Sakurai et al. 1978). In intermediate and chronic studies in animals, decreased red cell count, hemoglobin concentration and hematocyte were observed (Bio/dynamics 1980a, 1980b, 1980c Quast et al. 

Human toxicity data are limited to secondary citations. Because these citations provided no experimental details, they cannot be considered reliable. Deaths have occurred from aniline ingestion and skin absorption, but doses were unknown. Reviews of the older literature indicate that a concentration of 5 ppm was considered safe for daily exposures, concentrations of 7 to 53 ppm produced slight symptoms after several hours, a concentration of 40 to 53 ppm was tolerated for 6 h without distinct symptoms, a concentration of 130 ppm may be tolerated for 0.5 to 1 h without immediate or late sequalae, and 100 to 160 ppm was the maximum concentration that could be inhaled for 1 h without serious disturbance. In studies of accidents with unknown exposure concentrations, methemoglobin levels of up to 72% were measured. Recoveries occurred with a minimum of medical intervention following cessation of exposure. 

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