Cervical cap receives USFDA approval.
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Clinical pharmacology research in the pediatric patient: the challenge continues.
For most of the 20th century, most drugs labeled by the United States Food and Drug Administration (USFDA) have not been adequately studied in the pediatric population. This lack of data has necessitated the continued dependence of practitioners on sub-optimal prescribing data placing pediatric patients at great risk of serious therapeutic misadventures. Recently, the USFDA has enacted and begun to enforce the Final Rule of 1997 which became effective on 1 April 1999. This rule is the culmination of the persistent efforts of numerous professional organizations, clinicians, academicians, the USFDA and others, to ensure the ready availability of appropriate data for medications intended for or that will be used in children. Unlike the 1994 Rule which voluntarily required pharmaceutical manufacturers to submit pediatric data, the Final Rule mandates submission of such data and, most importantly, empowers the USFDA to afford incentives and penalties for non-compliance including possible removal of already marketed products. This overview addresses many of the important components which must be included in the performance of a comprehensive clinical pharmacologic evaluation serving as the foundation for optimal dosing across the broad age range encompassing pediatric practice. Furthermore, the possible risk and/or benefits of the study must be reasonably defined prior to undertaking the study and clearly shared with the patient's caregivers. Consent should always be obtained from the caregiver and, when appropriate, assent obtained from the underage child. To facilitate such clinical investigations and to foster collaborative efforts with innovators and clinical research programs, the National Institutes of Health through the National Institute of Child Health and Human Development of the NIH established a network of Pediatric Pharmacology Research Units. These units have worked closely together and with other pediatric research centers to facilitate USFDA labeling of a number of commonly used medications. All of these very positive efforts highlight the many challenges that remain for the pediatric investigator and practitioner while underscoring the very positive environment in support of these efforts.
Journal Article↗
Comparison of commercially available kits with standard methods for detection of Salmonella strains in foods.
Six commercial kits were compared with the U.S. Food and Drug Administration (USFDA) method and the Japanese standard method for Salmonella isolation in foods. When only Salmonella serovars were tested, many of the methods performed well; however, when foods were artificially inoculated, only the USFDA method and immunomagnetic separation coupled with the xylose-lysine-brilliant green agar method (MS-XLBG) could positively detect Salmonella serovars. All seven wild-type Salmonella serovars were detected by the USFDA method, and the MS-XLBG method detected salmonellae from six samples.
Bacterial Typing Techniques↗
Bioavailability of seven furosemide tablets in man.
A seven-way crossover study was conducted in 14 healthy male volunteers to evaluate the relative bioavailability of seven different marketed 40 mg furosemide tablets. Each dose was administered as a single tablet after an overnight fast, and blood samples were obtained for 16 hours. Plasma was assayed by HPLC. There were no statistically significant differences among the seven products for the mean peak concentration (1.01-1.29 micrograms/ml), mean time of peak (1.2-2.1 h) or mean area under the plasma concentration-time curves, which differed by less than 14 per cent. However, one product exhibited greater intersubject variability, and on this basis was considered inequivalent to the other six products. Furosemide is a potent and widely used diuretic. Currently the United States Food and Drug Administration (USFDA) has granted approval to at least twelve manufacturers of 40 mg furosemide tablets, based in part on bioavailability data obtained in human subjects. In addition, the USFDA has granted an 'AB' therapeutic equivalence evaluation to each of these products, which is understood by many to indicate the therapeutic equivalence and interchangeability of these products. The objective of the present investigation was to directly compare the bioavailability of seven 40 mg furosemide tablet products which had previously been approved by the Food and Drug Administration.
Adult↗
Transfer of lead from lead-glazed ceramics to food.
Recent studies have shown a clear correlation between the use of lead-glazed ceramicware for cooking or food preparation and elevated blood lead levels. Two lots of lead-glazed ceramic bowls, each from a single manufacturing and firing lot were used to measure the sequential leaching of lead into salsa (an acidic food) and beans (a neutral food) stored or cooked in the bowls. The USFDA acetic acid extraction assay was also repeatedly performed on these bowls. The results of the USFDA extraction test were highly variable with levels ranging from 200 to more than 2,000 ppm (regulatory level for rejection is 2 ppm). The levels extracted declined rapidly but the rates were variable. Leaching of lead into salsa (pH = 4.8) was variable and ranged from 8 to greater than 500 ppm. Sequential extractions using salsa yielded variable but declining lead levels. Cooking beans with water in the bowls did not cause substantial leaching (levels between 3 and 8 ppm) and sequential cooking did not show any significant decline over 10 cycles. The results indicate substantial variability in leaching of lead into foods stored or cooked in lead-glazed ceramicware.
Acids↗
Validation of LC/MS electrospray ionisation method for the estimation of ursodiol in human plasma and its application in bioequivalence study.
A novel High Performance Liquid Chromatography-electrospray mass spectrometric method has been developed for the estimation of Ursodiol (Ursodeoxycholic acid)--a bile acid, in human plasma using Ornidazole as internal standard. The methodology involved solid phase extraction of the analyte from human plasma matrix. The chromatographic separation was achieved within seven minutes by an isocratic mobile phase containing 1.0 mM ammonium acetate and Acetonitrile (65:35, v/v), flowing through XTerra MS C18, 100 x 2.1, 3.5 microm analytical column, at a flow rate of 0.2 ml/min. Ion signals were measured in negative mode for Ursodiol and internal standard at m/z 391.3 and 278.1, respectively. A detailed validation of the method was performed as per USFDA guidelines and the standard curves were found to be linear in the range 50.0 ng/ml to 3000.0 ng/ml with the mean correlation coefficient more than 0.99. The absolute recovery was more than 54.90% for Ursodiol and 76.51% for internal standard. Ursodiol was stable for sixty-nine days at -70 degrees C and for eight hours at ambient temperature. After extraction from plasma, the reconstituted samples of Ursodiol were stable in autosampler at 10 degrees C for forty-eight hours. Upon subjecting to three freeze thaw cycles, there was no change in the recovery of the analyte. The integrity of the plasma samples remained unaffected even upon four-fold dilution with drug free human plasma. The method was simple, specific, sensitive, precise, accurate and suitable for bioequivalence and pharmacokinetic studies. It was successfully applied to the pilot bioequivalence study of Ursodiol in male human subjects.
Cholagogues and Choleretics↗
Validated HPLC method for the determination of fluconazole in human plasma.
A high-performance liquid chromatographic assay with UV detection was developed for the determination of fluconazole in human plasma. The method utilized solid-phase extraction for sample clean-up. The separation was performed on a C18 column by isocratic elution with a mobile phase of 10 mM acetate buffer at pH 5.0 and methanol and UV detection at 210 nm. Validation was performed according to the current recommendations of the USFDA bioanalytical method validation guidance. The method proved to be specific, accurate, precise and linear between 200 and 10,000 ng/mL with correlation coefficients greater than 0.999. The coefficient of variation was within 11% and relative deviation was less than 10%.
Antifungal Agents↗
Analysis of dichloroacetic acid in rat blood and tissues by hydrophilic interaction liquid chromatography with tandem mass spectrometry.
Dichloroacetic acid (DCA) is a compound found in chlorinated drinking water. In addition, the compound is a metabolite of several halogenated solvents, including trichloroethylene (TCE) and perchloroethylene (PCE). Exposure to DCA is of concern because high doses of the compound have been shown to cause cancer in laboratory animals. Dosages of TCE administered to animals in cancer studies are designed to elicit maximal DCA formation in vivo, whereas levels of DCA to which individuals are exposed in drinking water are very low. Analysis of DCA in biological samples has been quite challenging. Derivatizing reagents commonly used to convert DCA into a more volatile form for analysis by gas chromatography (GC) have been found to convert trichloroacetic acid (TCA), a major metabolite of TCE and PCE, into DCA. High-performance liquid chromatography (HPLC) analysis does not require derivatization of DCA and can thus avoid this problem. However, the most popular stationary phases in HPLC columns do not retain small, polar compounds such as DCA well. The liquid chromatography/tandem mass spectrometry (LC/MS/MS) method described in this paper uses hydrophilic interaction liquid chromatography (HILIC), a type of chromatography that is able to retain these small, polar compounds. Method validation was performed using the United States Food and Drug Administration (USFDA) and International Conference on Harmonziation (ICH) Guidance for Industry: Bioanalytical Method Validation as a guide. Levels of DCA found in rats dosed with 2 g/kg TCE were 17.2 ng/mL (liver), 262.4 ng/mL (kidney), 175.1 ng/mL (lung), and 39.5 ng/mL (blood).
Animals↗
Food preservation using ionizing radiation.
Irradiation processing has been researched extensively and is now in use worldwide for many food commodities. Irradiation has been successfully used to reduce pathogenic bacteria, eliminate parasites, decrease postharvest sprouting, and extend the shelf life of fresh perishable foods. Although food irradiation is widely accepted in world food markets, U.S. markets have been slower to accept the idea of irradiated food products. For fruits and vegetables, irradiation is not a cure for shelf life problems; cost and quality problems damage preclude its general use. It appears that the most likely use of irradiation in fruits and vegetables is as an insect control in those commodities for which there is no effective alternative method. For grains such as rice and wheat, irradiation has been used primarily to control insect infestation when insects have been shown to develop resistance to the traditional fumigation methods. Treatment of spices with irradiation doses of 10 kGy has proved to extend shelf life without causing significant changes in sensory or chemical quality. Higher doses that effectively sterilize spices, however, may cause undesirable chemical and sensorial changes. For meat, especially red meat, irradiation is considered a viable alternative in the effort to improve the safety of meat products. With time, the authors believe that economic realities and the technical superiority of irradiation for specific poultry products will lead to public acceptance of the process. Irradiation of seafood products is still being considered for approval by the USFDA, although it is currently used in Asian and European markets, especially for shrimp. It is our belief that scientifically based research in food irradiation and the positive results thereof will also prove economical in the twenty-first century. As we move to a more peaceful world with reduced threat of nuclear holocaust, these valid opinions will prevail and will overshadow the distortions and misinformation generated by the opponents of irradiation.
Animals↗
Chemistry and fate of fenvalerate and esfenvalerate.
Fenvalerate is listed under Class IV of the U.S. Food and Drug Administration (USFDA) Surveillance Index Classification, indicating a low hazard potential to humans from both exposure and toxicological standpoints; thus, minimal monitoring is required (Reed 1981; Eisler 1992). To date, monitoring efforts have been of limited value in evaluating concentrations of fenvalerate and its subsequent risk to the environment. Few regulations currently exist for protection of sensitive natural resources against fenvalerate or esfenvalerate, although current application rates may be lethal to many nontarget species, including bees, fish, and aquatic invertebrates. Additional monitoring is recommended to measure residues in the environment and evaluate risks associated with use. It is clear that both fenvalerate and esfenvalerate are considerably less harmful to the environment and most nontarget organisms than most other insecticides. They are considerably less persistent and more selective in their toxicity, except for their high degree of toxicity to fish and aquatic invertebrates. However, they are moderately persistent in soils and, because of low water solubilities, high octanol-water partition coefficients (Kow), and moderate persistence, both fenvalerate and esfenvalerate have been identified as having the potential to accumulate in aquatic sediments and biota (Nowell et al. 1999). Numerous studies of fenvalerate dynamics in soils indicate that it is relatively immobile and readily degraded. In almost all cases, the degradation products formed are less toxic than the parent insecticide. However, some degradation products from fenvalerate may demonstrate elevated toxicity, and more research into and increased monitoring of abiotic degradation may be warranted. Results from environmental monitoring are minimal at best and do not adequately support research done in the laboratory. These results are critical for accurately determining the risk these insecticides pose to the environment. The pyrethroids are poised to fill the gap left in the insecticide market with the impending suspension of many of the organophosphates and possibly at least some carbamates. One agent, chlorpyrifos, has already been heavily restricted by the U.S. Environmental Protection Agency (USEPA), and one manufacturer has ceased production. The environmental risk posed by both fenvalerate and esfenvalerate can change significantly with increased application, and current information is not sufficient to adequately assess the risk that a dramatic rise in use would pose. Future efforts should focus on increased environmental monitoring and research on esfenvalerate fate with increased and repeated application. Pyrethroids, including fenvalerate and esfenvalerate, have also recently been linked to endocrine disruption (Garey and Wolff 1998; Go et al. 1999). Endocrine disruption is an emerging field, and more research is essential in documenting and managing these types of effects. Research into the bioavailability and dynamics of esfenvalerate at the sediment-water interface is also of key importance. Current information indicates that resuspension or desorption from soils should be minimal, but this is not equivalent to the fraction of sediment-sorbed esfenvalerate that may be bioavailable to sensitive aquatic species. In terms of risk, fenvalerate and esfenvalerate are significant improvements over many of their predecessors, but it is clear that more information is needed to fully support this conclusion.
Animals↗
Specific cell-signal targets for cancer chemotherapy.
Attempts to develop drugs, specific for cancer cells, are dealt here according to the intended cell-target. While many target specific drugs were developed, they reach only moderate successes in clinics for reasons, such as, delivery problem, lack of in vivo efficacy or toxicity. However, recent efforts focusing on the diversity of tyrosine kinases, participating in cell-signal transduction, brought fruit. The firs such drug, Givec, approved by the USFDA recently, is used in clinics with great success to threat CML. The drug inhibits tyrosin kinase of bcr-abl, c-abl and v-abl. Work is progressing on other tyrosin kinase inhibitors and on other type of specific cancer cell signal protein inhibitors. These efforts are hoped to yield better cures for cancer in the near future.
Alkyl and Aryl Transferases↗
Mercury toxicology as assessed through fish scales.
Increasing pollution in water bodies is directly or indirectly related to increasing urbanization and indiscriminate disposal of agrochemical & industrial effluents. Heavy metals are one of the important categories of such pollutants and are causing serious hazards to non target species (Mwachiro and Druve1997). Their salts constitute a serious type of pollution in fresh water and being stable compounds; they are not readily removed by oxidation, precipitation or other processes and affect the activity in recipient animal (Jagadeesan and Vijayalakshmi 1998). Increase in the concentration of heavy metals has been reported in water of Vasai Creek, Maharastra and surface as well as groundwater of Delhi (Lokhande and Kelker 1999; Dixit et al. 2003). Recently, Food and Drug Adminstration (USFDA) and Environmental Protection Agency (USEPA) (2004) in their combined report recommended that pregnant women and lactating mothers should not eat shark, sword fish and king Mackerel as these fishes contain high levels of mercury.
Animals↗
Haemophilus influenzae type B epiglottitis after immunization with HbOC conjugate vaccine.
INTRODUCTION: US Food and Drug Administration (USFDA) has licensed four Haemophilus influenzae type B (Hib) vaccines for use in children. Haemophilus influenzae type B is by far the most common pathogen in childhood epiglottitis and it is hoped that with the introduction of the Hib vaccine that a corresponding decrease in epiglottitis cases will be appreciated. MATERIALS AND METHODS: A retrospective study of all children admitted with the diagnosis of epiglottitis for the 11-year period of 1982 to 1992 was conducted in order to determine the incidence of epiglottitis and Hib vaccine failure. Fifty-nine cases were included in the study by documentation of an inflamed epiglottis. The case of Hib epiglottitis in a 4-year-old child immunized with HbOC conjugate vaccine at 18 months of age is detailed. RESULTS: A statistically significant decrease was found in the incidence of epiglottitis since introduction of the vaccines; however, the overall trend in decrease for the 11-year period was not statistically significant. Vaccination status was difficult to accurately document with only two cases of vaccine failure identified. CONCLUSION: The incidence of Haemophilus influenzae type B epiglottitis at our regional Children's hospital has decreased since the introduction of the Hib vaccine. Reasons for vaccine failure are postulated.
Bacterial Proteins↗
Human serum butyrylcholinesterase: in vitro and in vivo stability, pharmacokinetics, and safety in mice.
The use of exogenously administered cholinesterases (ChEs) as bioscavengers of highly toxic organophosphate (OP) nerve agents is now sufficiently well documented to make them a highly viable prophylactic treatment against this potential threat. Of the ChEs evaluated so far, human serum butyrylcholinesterase (HuBChE) is most suitable for human use. A dose of 200 mg (3 mg/kg) of HuBChE is envisioned as a prophylactic treatment in humans that can protect from an exposure of up to 2 x LD50 of soman. In addition to its use as a prophylactic for a variety of wartime scenarios, including covert actions, it also has potential use for first responders (civilians) reacting to terrorist nerve gas release. We recently, developed a procedure for the large-scale purification of HuBChE, which yielded approximately 6 g of highly purified enzyme from 120 kg of Cohn fraction IV-4. The enzyme had a specific activity of 700-750 U/mg and migrated as a single band on SDS-PAGE. To provide data for initiating an investigational new drug (IND) application for the use of this enzyme as a bioscavenger in humans, we established its pharmacokinetic properties, examined its safety in mice, and evaluated its shelf life at various temperatures. In mice administered various doses up to 90 mg/kg, enzyme activity reached peak levels in circulation at 10 and 24 h following i.p. and i.m. injections, respectively. The enzyme displayed a mean residence time (MRT) of 40-50 h, regardless of the route of administration or dose of injected enzyme. Mice were euthanized 2 weeks following enzyme administration and tissues were examined grossly or microscopically for possible toxic effects. Results suggest that HuBChE does not exhibit any toxicity in mice as measured by general observation, serum chemistry, hematology, gross or histologic tissue changes. The shelf life of this enzyme stored at 4, 25, 37, and 45 degrees C was determined in lyophilized form. The enzyme was found to be stable when stored in lyophilized form at -20, 4, 25, or 37 degrees C to date (2 years), as measured by specific activity and SDS polyacrylamide gel electrophoresis. The effect of storage on circulatory stability was determined by measuring MRT in mice; there was no change in the MRT of lyophilized enzyme stored at -20 degrees C to date (2 years). These results provide convincing data that HuBChE is a safe bioscavenger that can provide protection against all OP nerve agents. Efforts are now underway to prepare the required documentation for submission of an IND application to the United States Food and Drug Administration (USFDA).
Animals↗
Estimation of acceptable mercury intake from fish in Taiwan.
The US Food and Drug Administration (USFDA) and Environmental Protection Agency (USEPA) are advising women and young children to avoid eating fish that contain high levels of mercury (Hg). However in Taiwan, the annual Black Fin Tuna Festival encourages the public to consume fish. The aim of this study was to assess fish intake in relation to the health risks of mercury exposure and calculate the acceptable and safe intake of fish in children and women of childbearing age. From the Monte Carlo simulation, based on USEPA's reference dose (0.1 microgkg(-1)d(-1)), we found that 21.6%-24.3% and 45.6%-57.4% of the daily mercury dose estimates exceeded the reference dose for typical and high-seafood consumers. The acceptable ingestion rates are <50 g d(-1) (children) and 90.8 +/- 15.7 g d(-1) (women of childbearing). Sensitivity analysis suggests that Hg concentration in fish may be a key parameter to aid governments as they offer guidance for risk management.
Adult↗
A 13-week dietary toxicity and toxicokinetic study with l-theanine in rats.
This study was conducted to evaluate the safety of l-theanine (Suntheanine) when administered as a dietary admixture to male and female Crl:CD (SD)GS BR rats at concentrations providing doses of 0, 1500, 3000 or 4000 mg/kg bw/day for 13 weeks. The study design was consistent with OECD Guideline 408 and USFDA Redbook II (1993) and GLP. There were no consistent, statistically significant treatment-related adverse effects on behavior, morbidity, mortality, body weight, food consumption and efficiency, clinical chemistry, hematology, or urinalysis. There were no consistent treatment-related adverse effects in gross pathology, organ weights or ratios or histopathology. The increased incidence of renal tubular cell adenomas in high-dose females only were not consistent with the characteristics of a renal carcinogen (due to early onset and low number of animals affected) but were more consistent with a genetic predisposition than with direct organ toxicity. The no-observed-adverse-effect-level (NOAEL) was 4000 mg/kg bw/day, the highest dose tested.
Animals↗
Liquid chromatography--electrospray ionisation mass spectrometry method for the determination of escitalopram in human plasma and its application in bioequivalence study.
A novel liquid chromatographic--electrospray ionisation mass spectrometric (LC--ESI-MS) method has been developed for the determination of escitalopram, an antidepressant in human plasma using paroxetine as internal standard. The method involved liquid--liquid extraction of the analyte from human plasma with a mixture of diethyl ether and dichloromethane (70:30, v/v). The chromatographic separation was achieved within 7.0 min by using 2.0 mM ammonium acetate (pH 5.0)--acetonitrile (54:46, v/v) as mobile phase and a ODS YMCAQ 150 mm x 4.6 mm analytical column; the flow-rate was 1.0 ml/min. Ion signals m/z 325.0 and 330.0 for escitalopram and internal standard, were measured in the positive mode. A detailed validation of the method was performed as per USFDA guidelines and the standard curves were found to be linear in the range of 1.0-200 ng/ml with a mean correlation coefficient more than 0.99. The absolute recovery was more than 75% for both escitalopram and internal standard. The method was simple, sensitive, precise, accurate and was successfully applied to the bioequivalence study of escitalopram in healthy, male, human subjects.
Chromatography, Liquid↗
Direct injection, column switching-liquid chromatographic technique for the estimation of rabeprazole in bioequivalence study.
A rapid, simple and sensitive high-performance liquid chromatography-ultra violet (HPLC-UV) method with column switching between sample pre-treatment column and analytical column was developed for the quantitation of rabeprazole in human plasma; on a Bio-Sample Analysis system (Co-sense for BA) from Shimadzu Corporation, Kyoto, Japan. Zaleplon was used as an internal standard. The method was validated as per USFDA guidelines for the concentration range of 20.0-1200.0 ng/mL and the correlation coefficient were found to be better than 0.999. Recovery of rabeprazole as well as the internal standard from human plasma was more than 90.0%. Rabeprazole was stable in human plasma for 4 months at -70 +/- 5 degrees C and for 20.0 h at ambient temperature. In the auto sampler, the drug was stable for 24.0 h at 4 degrees C. The method was specific as there were no interfering peaks in the human plasma eluting at the retention times of the rabeprazole and the internal standard. The frozen plasma samples containing rabeprazole were stable to three freeze thaw cycles. The bioanalytical method was rugged in terms of inter- and intra-day accuracy and precision. The method was simple, specific, sensitive, precise, accurate and suitable for bioequivalence and pharmacokinetic studies. It was successfully applied to the pilot bioequivalence study of 20mg rabeprazole tablet of German Remedies Ltd. (A division of Cadila Healthcare Ltd.), India versus Pariet tablet of Eisai Ltd. & Janssen-Cilag Ltd., Japan in male human subjects.
2-Pyridinylmethylsulfinylbenzimidazoles↗