Raafat Maher Fahmy, Ph.D. 

Center for Veterinary Medicine
Division of Manufacturing Technology
Rockville, MD

Background:

FDA Experience - 9 years

Research Interests:

Achieve quality by design for tablet dosage form product by developing scientific understanding to the material attributes and critical manufacturing process which impact the critical quality attribute of tablet drug products. Monitoring and controlling all the critical material and process attributes using Near Infrared with chemometric modeling. Study Design Space methodology, define the best practice for Design Space applications and develop specific examples of Design Space methodology that can be used for the educational purposes.

Proposed Research Project for FDA Fellow:

The fellow will help in the formulation, manufacturing and the analytical work for this project. The fellow will have the opportunity to work with state of the art technology at the University of Maryland, School of Pharmacy facility.

The fellow will be exposed to all the prefromulation development, formulation development, and manufacturing processes. Will learn how to define variables and critical manufacturing parameters and how to monitor and control them, working with on/at line monitoring system such as NIR and chemometric modeling to achieve feedback/feed forward during manufacturing and predict the quality from upstream for solid oral dosage forms.

Selected Recent Publications:

1. Quality by Design, Part I: Application of NIR Spectroscopy to Monitor Manufacturing Process for Orbifloxacin Tablets. Simin Hassannejad Tabasi, Raafat Fahmy, Charles O’Brien, Dennis Bensley, and Stephen Hoag. Journal of pharmaceutical Science. 2008
2. Quality by Design Part II: Application of NIR Spectroscopy in Tablet Coating Process and Dissolution Testing for Blends of Polyacrylates. Simin Hassannejad Tabasi, Raafat Fahmy, Charles O’Brien, Dennis Bensley, and Stephen Hoag. Journal of pharmaceutical Science. 2008
3. Quality by Design Part III: Prediction of Curing Endpoint for Pharmaceutical Sustained Release Products Using NIR Spectroscopy and Multi Variant Analysis. Simin Hassannejad Tabasi, Raafat Fahmy, Charles O’Brien, Dennis Bensley, and Stephen Hoag. Journal of pharmaceutical Science. 2008
4. Fahmy, Bensley, Marnane, Hollenbeck, Dissolution test development for complex veterinary dosage forms: oral boluses, American Association for Pharmaceutical Scientists journal “Special Veterinary Volume,” October 2002.
5. Fahmy, Bensley, Marnane, Hollenbeck, Dissolution testing of sulfa boluses, Journal of Dissolution Technologies; 8(1), 2001.
6. Fahmy, Bensley, Marnane, Hollenbeck, Dissolution testing of aspirin boluses, Journal of Dissolution Technologies; 8(1), 2001.
7. Fahmy, Bensley, Marnane, Hollenbeck, Dissolution Testing of Tetracycline Boluses, Journal of Dissolution Technologies; 8(1), 2001.
8. Fahmy, Steber, Bensley, Zupan, Marnane, Hollenbeck, Determine the effect of selected formulation, equipment and process changes on the physical characteristics and performance attributes of sulfamethazine boluses, Pharmaceutical Technology, 27(9), 2003.
9. Martinez, Kawalek, Howard, Ward, Marroum, Marnane, Bensley , Pelsor, Hoag, Tatavarti, Xie, and Fahmy, Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles. J Vet Pharmacol Ther. 29(6), 2006.
10. Aditya Tatavarti, Raafat Fahmy, Dennis Bensley , William Marnane , Ajaz Hussein, Gary Hollenbeck and Stephen W. Hoag. Assessment of the NIR Technique for Process Analytical Testing of Physicochemical Properties of Sulfamethazine Boluses. AAPS Pharmsci.

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Joseph C. Kawalek, Ph.D. 

Division of Animal Research
Office of Research
Center for Veterinary Medicine
Laurel, MD

Background: 
B.S., St. Francis College
Ph.D., University of Pittsburgh

Research Interests:

Dr. Joseph C. Kawalek, Research Chemist investigates drug metabolism and disposition in veterinary animals. His research addresses factors that affect drug metabolism, e.g., age, gender, diet/nutrition, physiological states, and disease. He has published several articles on the maturation of hepatic drug metabolizing enzyme activities in several species (sheep, dogs, cattle, and chickens). His current research activities are in support of the Agency’s Critical Path Initiatives in the area of Process Analytical Technology (in vitro in vivo correlations) and species bioavailability comparisons in support of developing guidelines for drug approvals under CVM’s Minor Use Minor Species Program.

Proposed Research Project for FDA Fellow:

The fellow would have the opportunity to participate in the minor use/minor species comparison study of the pharmacokinetics of anti-parasitical drugs in ruminants. To date results indicate some differences in bioavailability and metabolism which could be explained by differences in hepatic and/or intestinal drug-metabolizing enzyme activities. An interspecies comparison of these enzymatic activities could provide valuable insight in explaining the observed pharmacokinetic differences. A clinically-trained individual would be exposed to in vitro drug metabolism techniques which would broaden their appreciation for drug metabolism/disposition in the whole animal.

Selected Recent Publications:

1. Myers, MJ, and Kawalek, JC, 1995. Effect of cytokines on drug-metabolizing enzymes in Cytokines in Animal Health and Disease (Myers MJ and Murtaugh MP, eds) pp235-259, Marcel-Dekker, New York.
2. Myers, M.J., Farrell, D.E., Howard, K.D., and Kawalek, JC, 2001. Identification of multiple constitutive and inducible hepatic cytochrome P450 enzymes in market weight swine, Drug Metabolism and Disposition, 29:908-915.
3. Kawalek, JC, Howard, K.D., Myers, M.J., Derr, J., Farrell, D.E., Cope, C.V., and Jackson, J.E. (2003). Effect of oral administration of low doses of pentobarbital on the induction of cytochrome P450 isoforms and cytochrome P450-mediated reactions in immature Beagles. Am. J. Vet. Res. 64: 1167 - 1175.
4. Kawalek, JC, Myers, M.J., Howard, K.D., Farrell, D.E. and Shaikh B, 2006. Hepatic CYP Isoforms and drug-metabolizing enzyme activities in broiler chicks. Int. J. of Poultry Science, 5:104-111.
5. Martinez, MN, Kawalek, JC, Howard, HD, Ward, JL, Marroum, P, Marnane, W., Bensley, D, Pelsor, FR, Hoag, S, Tatavarti, AS, Xie, L, and Fahmy, R, 2006. Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles. J. vet Pharmacol Therap. 29:459-467.

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Marylyn N. Martinez, Ph.D. 

Center for Veterinary Medicine
Division Of Therapeutic Drugs For Food Animals
Rockville, Maryland
marilyn.martinez@fda.hhs.gov

Background:

Ph.D., Georgetown School of Medicine
FDA Experience - 24 years

Research Interests:

Pharmacokinetics and biopharmaceutics. One of the challenges encountered within the Division of Therapeutic Drugs for Food Animals is the problem of assessing the blood concentrations of drugs when administered to animals in feed or drinking water. Oftentimes, sponsors wish to use blood level studies to bridge to existing clinical safety or effectiveness information. In these cases, differences in systemic drug exposure can be due to differences in drug intake in water versus feed (an animal behavior question) or due to formulation differences (a biopharmaceutics question). While the latter can be addressed via assessing blood concentration-time profiles after gavage dosing the two formulations (a relative bioavailability study), exposure differences due to food versus water consumption cannot be easily obtained. In particular, efforts to capture blood levels during such investigations interfere with normal animal behavior. Therefore, we are often left with little option but to conduct additional studies.

Proposed Research Project for FDA Fellow:

In this proposed project, the Fellow would be responsible for generating a pharmacokinetic model that can be used to convert gavage dose blood levels and feed consumption information into predictions of drug concentration/time profiles under conditions of use. This would involve not only literature research into normal eating and drinking patterns (e.g., of pigs), but also how such information can be combined with intake information (from palatability studies) and pharmacokinetic model parameters. Working with the PK group and statisticians, population predictions would be generated. Testing of the model predications would be based upon existing literature information. Sensitivity analysis would help to define the critical model parameters.

The project would entail:

1. The generation of the model.
2. The development of a protocol for a study at the CVM’s Office of Research that would generate the data necessary to test the validity of the model.
   Hopefully, the person would have the opportunity to participate in study experiments and data analysis.

Selected Recent Publications:

1. J Pharm Sci. 2008 Jul 25.Factors influencing the gastric residence of dosage forms in dogs. Martinez MN, Papich MG.
2. J Vet Pharmacol Ther. 2008 Aug;31(4):285-300. The pharmacogenomics of P-glycoprotein and its role in veterinary medicine. Martinez M, Modric S, Sharkey M, Troutman L, Walker L, Mealey K.
3. J Control Release. 2008 Jul 14;129(2):79-87. In vitro and in vivo considerations associated with parenteral sustained release products: a review based upon information presented and points expressed at the 2007 Controlled Release Society Annual Meeting. Martinez M, Rathbone M, Burgess D, Huynh M.
4. J Vet Pharmacol Ther. 2008 Jun;31(3):281-4. Prediction of xenobiotic clearance in avian species using mammalian or avian data: how accurate is the prediction? Hunter RP, Mahmood I, Martinez MN.
5. AAPS J. 2008;10(1):110-9. Epub 2008 Feb 15. Pharmacogenetic and metabolic differences between dog breeds: their impact on canine medicine and the use of the dog as a preclinical animal model. Fleischer S, Sharkey M, Mealey K, Ostrander EA, Martinez M.
6. J. Antimicrob Chemother. 2007 Dec;60(6):1185-8. AUC/MIC: a PK/PD index for antibiotics with a time dimension or simply a dimensionless scoring factor? Toutain PL, Bousquet-Mélou A, Martinez M.
7. J Vet Pharmacol Ther. 2006 Dec;29(6):459-67. Comparison of bovine in vivo bioavailability of two sulfamethazine oral boluses exhibiting different in vitro dissolution profiles. Martinez MN, Kawalek JC, Howard KD, Ward JL, Marroum P, Marnane W, Bensley D, Pelsor FR, Hoag S, Tatavarti AS, Xie L, Fahmy R.
8. J Vet Pharmacol Ther. 2006 Oct;29(5):425-32. Interspecies allometric scaling: prediction of clearance in large animal species: part II: mathematical considerations. Martinez M, Mahmood I, Hunter RP.
9. J Vet Pharmacol Ther. 2006 Oct;29(5):415-23. Interspecies allometric scaling. Part I: prediction of clearance in large animals. Mahmood I, Martinez M, Hunter RP.
10. Vet J. 2006 Jul;172(1):10-28.Pharmacology of the fluoroquinolones: a perspective for the use in domestic animals. Martinez M, McDermott P, Walker R.

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Jennifer Matysczak, V.M.D. 

Center for Veterinary Medicine
Division of Therapeutic Drugs for Food Animals
Rockville, Maryland

Background:

V.M.D., University of Pennsylvania School of Veterinary Medicine
FDA Experience - 4 years

Research Interests:

Fish (aquaculture, aquarium, public policy)

Proposed Research Project for FDA Fellow:

Extrapolating study design guidelines which have been used to demonstrate drug safety and effectiveness in terrestrial food and companion animals to fish (finfish and shellfish) has proved to be challenging. Quantification of physiological effects or enumeration of pathogens such as external parasites has not been standardized for fish in many cases. The Fellow would identify public data within Investigational New Animal Drug files and from external sources that can be used to inform design of studies of the effectiveness of anesthetic, antiparasitic, and other types of drugs for fish, while benefiting from training on the FDA and the New Animal Drug Application process.

Selected Recent Publications:

1. J Matysczak. “FDA/CVM and Aquaculture Drugs.” USDA/APHIS Field Veterinary Medical Officer Aquaculture Training, Madison, WI, September 2007.
2. J Matysczak. “An Overview of the Drug Approval Process and Answers to questions you might never think to ask.” Aquaculture Drug Approval Coordination Workshop, LaCrosse, WI, August 2006.
3. J Matysczak. “Overview on Drugs Approved for Use in Aquaculture.” International Conference on Recirculating Aquaculture, Roanoke, VA, July 2006.
4. J Matysczak, T Clauss, H Krum, T Nietfeld, RPE Yanong, A Dove “Unusual Trematode ‘Egg Nests’ In the Stomach Tissues of Goggle-Eyed Scad, Selar crumenophthalmus (Bloch, 1793).” 31st Eastern Fish Health Workshop, Charleston, SC, 2006.
5. J Matysczak. “Mysteries of the Gas bladder.” University of Florida’s Advanced Fish Medicine Course, Gainesville, FL, November 2005.
6. J Matysczak, RPE Yanong, IK Berzins, S Coats. “Diagnostics Involved in the Certification of Aquacultured Corals.” 36th Annual IAAAM Conference, Seward, AK, May 2005.
7. J Matysczak, I Berzins. “Post-Mortem Evaluation of a Sharp-Tail Mola, Masturus lanceolatus” (Poster). 36th Annual IAAAM Conference, Seward, AK, 2005.

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Lynn O. Post, D.V.M., Ph.D., DABVT 

Center for Veterinary Medicine
Office of Surveillance and Compliance
Division of Surveillance
Rockville, MD

Background:

B.S., Animal Science, Cornell University
B.S., Veterinary Science, Texas A&M University
M.S., Veterinary Toxicology, Texas A&M University
D.V.M., Veterinary Medicine, Texas A&M University
Ph.D., Toxicology and Pharmacology, Louisiana State University
Board Certified, American Board of Veterinary Toxicology

Research Interests:

Toxicology and Pharmacology: Drug interactions, adverse drug events, pharmacogenomics and toxic plants.

Proposed Research Project for FDA Fellow:

Pharmacogenomics: Adverse Event Detection and Analysis

Project Title: Impact of Solanum eleagnifolium (Silverleaf Nightshade) in Ivermectin Toxicity in Horses: Rabbit Model to Determine Mechanism of Enhanced Toxicity of Ivermectin.

Objective: Use a rabbit model to study which of the following alternative hypotheses best explains how Solanum causes ivermectin-induced CNS toxicity:

Hypothesis 1: Solanum elaeagnifolium causes a toxic interaction with ivermectin by altering the blood brain barrier. (Note: The toxic principle in unknown).

Hypothesis 2: Solanum alters the normal functionality of the drug transport proteins, causing either an increase in the transport of ivermectin into the brain, or decreasing the efflux of ivermectin.

Background: In 1989 the first cases of ivermectin toxicity in horses were identified that were also exposed to Silverleaf nightshade (Solanum). Eight horses confined to stalls and given hay contaminated with Solanum developed signs of CNS toxicity. Six horses in a pasture containing Solanum did not exhibit signs of ivermectin toxicity. One of the eight horses subsequently died from the ivermectin toxicity, and upon necropsy, it was discovered that they had brain concentrations of ivermectin of 115 ppb. A second case also witnessed a horse dying from the ivermectin toxicity. This animal was also fed hay containing Solanum and had a brain concentration of 672 ppb of ivermectin. A third case that same year a group of horses being given ivermectin paste every 2 weeks while housed in a pasture containing Solanum developed the signs of ivermectin CNS toxicity. All the animals recovered within 5 months after being given clean hay and discontinuing ivermectin treatment. There have been additional published reports of Solanum mediated ivermectin CNS toxicity, along with ADE reports to CVM, the most of which was reported in March of 2008.

The exact mechanism responsible for inducing the ivermectin CNS toxicities is unknown. A rabbit model has been developed by Garland and colleagues (Texas A & M) that can mimic these toxicities, but to date this model has not been used to understand the molecular mechanisms for this phenomena. There are two plausible hypothesis to explain these observations. The first would have Solanum somehow alter the functionality or concentration of P-glycoprotein. P-glycoprotein (P-gp) is a member of the drug transporter protein family and is responsible for the removal of ivermectin from tissues such as brain. A genetic defect in herding dogs such as collies is responsible for the ivermectin-induced CNS toxicities in dogs; this results in elevated ivermectin levels in their brain. A second possibility is that Solanum alters the blood brain barrier, resulting in the influx of higher than expected levels of ivermectin.

Using this rabbit model, we will begin studies designed to elicit which of these two alternative hypotheses best explains how Solanum causes ivermectin-induced CNS toxicity.

Selected Recent Publications:

1. Post, LO, Reporting an adverse drug reaction to FDA, in Kirk’s Veterinary Therapy XIV, ed. Bonagura, Elsevier Science, 2008
2. Post, LO, Regulatory considerations in veterinary toxicolgy, in Veterinary Toxicology: Basic and Clincal Practices, ed. Gupta, 2007
3. Post, LO, Baker, J, Farrell D, Cope, CV, Myers, MJ, Influence of porcine Actinobacillus Pleuropneumoniae (APP) infection and dexamethasone on the pharmacokinetic parameters of enrofloxacin. Journal of Pharmacology and Experimental Therapeutics. 301:1-6, 2002.
4. Post, LO, Baker, J, Farrell D, Cope, CV, Myers, MJ, The Effect of Endotoxin and Dexamethasone on Enrofloxacin Pharmacokinetic Parameters in Swine. Journal of Pharmacology and Experimental Therapeutics. February 1, 2003.
5. Post, LO, Keller, WC, An update on antidote availability in veterinary medicine. Veterinary and Human Toxicology, 41 (Aug), 258-61 1999.
6. Lovell, R, Post, LO, Guidance for Industry: Fumonisin Levels in Human Foods and Animal Feeds; Availability that was published in the Federal Register, November 9, 2001.
7. Post, LO, Keller, WC (1999), Current status of food-animal antidotes. Veterinary Clinics of North America, Food Animal Practice, Fall 2000

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Larisa Rudenko, Ph.D., DABT 

Senior Advisor, Biotechnology
Center for Veterinary Medicine
Office of New Animal Drug Evaluation
Rockville, MD

Background:

Ph.D., Cellular and Molecular Pharmacology
Diplomate of the American Board of Toxicology
FDA Experience - 8 years

Research Interests:

The focus of our group is providing science-based direction via guidances and regulations towards the safe and effective use of genetically engineered (GE) animals. Ensuring consumer safety and confidence in GE therapeutics, food or animals, relies on a consistent, rigorous, transparent, science-based approval process. The Animal Biotechnology group at the Center for Veterinary Medicine is the first government agency to implement pre-market mandatory approval for GE animals. Towards this end we have proposed draft guidance for the regulation of GE animals containing heritable rDNA constructs as a first step towards assisting sponsors involved in this process as well as educating consumers of safety issues. We are interested in ensuring animal welfare, food safety, human health and environmental safety through the continuing promulgation of guidances and regulations and discussions with industry, scientific researchers and consumers.

Proposed Research Project for FDA Fellow:

The FDA Fellow will work closely with members of the Animal Biotechnology team to determine areas of the GE animal industry that require guidances or regulations to address current and future needs. Fellows will also assist with formulating and finalizing these guidances and regulations as well as addressing the FDA’s position with regard to this technology through journal articles and other public venues.

Selected Recent Publications:

1. Animal cloning and the FDA--the risk assessment paradigm under public scrutiny, Nature Biotechnology, January 2007, Volume 25 Number 1, pages 39-43
2. Animal Cloning: A Risk Assessment, January 2008, available at http://www.fda.gov/cvm/cloning.htm
3. Draft Guidance for Industry #187 - Regulation of Genetically Engineered Animals Containing Heritable rDNA Constructs, September 2008, available at http://www.fda.gov/cvm/GEAnimals.htm

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Ruby Singh, Ph.D. 

Office of New Animal Drug Evaluation
Center for Veterinary Medicine
Rockville, MD

Background:

Ph.D., University of Maryland Baltimore
FDA Experience – 7 years

Research Interests:

Antimicrobial resistance development among bacteria of public health concern in or on food-producing animals, following their treatment with (or exposure to) antimicrobial drugs (or compounds with antimicrobial activities).

Proposed Research Project for FDA Fellow:

Antimicrobial agents have been used in food-producing animals to treat and prevent disease for nearly as long as they have been used in human medicine.  Regarding food-producing animals, antimicrobial agents have been used as therapy and prophylaxis for bacterial agents. Antimicrobial agents are also used in animal production as non-therapeutic agents, to promote growth by enhancing feed efficiency and increasing weight gain.

Congress approved an amendment in 2001 that appropriated funding for work at FDA/CVM on antimicrobial resistance.  CVM began work to review the safety of previously approved antimicrobial products, specifically beginning with the non-therapeutic uses of tetracyclines and macrolides. In order to have the appropriate background and context for assessing the conclusions of the drug application reviews, it is essential to obtain a comprehensive literature search, review, analysis, synthesis, and report from an author recognized as an expert in the area of antimicrobial resistance and public health.

In this proposed project, the Fellow would be responsible for conducting a literature search and review, to assess the following: the potential contribution of the use of antimicrobial products in food animals to bacterial resistance to tetracyclines and macrolides, if there is any evidence suggesting that populations of resistant bacteria are maintained in or on the animal or in the environment (chicken house, barnyard, feed lot, etc.) after antibiotic use is discontinued, what evidence exists for transmission of resistant bacteria, and whether there is evidence of a relationship between the use of these antibiotics in animals and the subsequent increase in antibacterial resistance in animal and human isolates.  The review would also include an assessment of the public health impact resulting from any evidence linking the non-therapeutic use of antibiotics in animals to the subsequent development of antimicrobial resistance in organisms of public health concern.

Upon completion of this project, the Fellow would be expected to:

1. Provide a review of the literature to CVM with copies of all relevant articles and any necessary translations of said articles into English.
2. Provide CVM with a report that answers (to CVM’s satisfaction) the following questions:
   • What is currently known about bacterial antibiotic resistance to tetracyclines and macrolides?
   • Is there any evidence suggesting that populations of resistant bacteria are maintained in or on the animal or in the environment after antibiotic use is discontinued?
   • What is the evidence for transmission of resistant bacteria?
   • Is there any evidence of a relationship between the use of antibiotics in animals and the increase in antibacterial resistance to the antibiotic in animal or human isolates?
   • What is the public health impact of the non-therapeutic use of antibiotics in animals and the subsequent increase in antibacterial resistance to the antibiotic in organisms of public health concern?

Selected Recent Publications:

1. Gilbert, J.M., White, D.G., and McDermott, P.F. The U.S. National Antimicrobial Resistance Monitoring System. Future Microbiol. 2: 493-500, 2007.
2. Zhao, S., P.F. McDermott, S. Friedman, S. Qaiyumi, J. Abbott, C. Kiessling, S. Ayers, R. Singh, S. Hubert, J. Sofos, and D.G. White. Characterization of antimicrobial resistant Salmonella from imported foods. J. Food Protection, 2006, Pages 500–507.
3. Singh, R. C.M. Schroeder, J. Meng, D.G. White, P.F. McDermott, D.D. Wagner, H. Yang, S. Simjee, C. DebRoy, R.D. Walker, and S. Zhao. 2005. Identification of antimicrobial resistance and class 1 integrons in shiga toxin-producing Escherichia coli recovered from humans and food Animals. J. Antimicrob. Chemother. 56:216-219.
4. Batz MB, Doyle MP, Morris JG Jr, Painter J, Singh R, Tauxe RV et al. Attributing illness to food. Emerging Infectious Disease. 2005 July, vol 11 No. 7.
5. White, D. G.; S. Zhao; R. Singh, P. F. McDermott, Antimicrobial resistance among Gram-negative foodborne bacterial pathogens, Foodborne Pathogens & Disease, 1: 137-152, 2004.
6. Yan, S.S., and Gilbert, J.M. Antimicrobial drug delivery in food animals and microbial food safety concerns: an overview of in vitro and in vivo factors potentially affecting the animal gut microflora. Adv. Drug Delivery Rev. Adv. Drug Delivery Rev. 56: 1497-1521, 2004.
7. Zhao,S., S.Qaiyumi, S. Friedman, R. Singh, S.L. Foley, D. G. White, P. F. McDermott, T.Donkar, C. Bolin, S. Munro, E. J. Baron, and R. D. Walker. 2003. Characterization of Salmonella enterica Serotype Newport isolated from human and food animals. Journal of Clinical Microbiology. 41: 5366-5371, 2003.

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