LETTERS

Unresponsiveness to human recombinant erythropoietin in an epileptic dialysis patient secondary to valproic acid toxicity TO THE EDITOR: Several hematopoietic growth factors have been introduced intoclinicalpractice; hwnan recombinanterythropoietin (Hu-rEPO) is the one most widely used. The mechanisms of unresponsiveness to Hu-rEPO are difficult to predict and will be defined through continued clinical practice. We observed Hu-rEPO resistance in a hemodialysis patient with epilepsy. The underlying etiology of this resistance was concluded to be valproic acid toxicity. A 35-year-old woman wasaccepted to ourhemodialysis unitin 1987 because ofend-stage renal failure. Shehadbeen experiencing grand malseizures since she was 7 years oldandhadbeen treated with phenytoin. In 1990, when herseizures became uncontrollable despite phenytoin treatment, shewasswitched to valproic acid. Electroencephalogram recordings showed thatepileptic activity wascontrolled with a daily valproic acid dosage of 2500 mgpo(500 mg5 x Id). Atthebeginning of 1991, shebegan to receive Hu-rEPO together withoralironsupplementation as a partof herrenal replacement therapy, butshedid notrespond to Hu-rEPO 4000 units given 3 x Iwkiv.After three months of unresponsiveness, the route of administration was switched to subcutaneous injection. Thesame dosage of Hu-rEPO was maintained, butthepatient's hemoglobin andhematocrit concentrations remained unchanged at 78 gIL and0.24, respectively. InAugust 1991 she developed thrombocytopenia with mild bleeding tendency andleukopenia. A clinicalexamination wasunremarkable except for tremor andataxic gait.She was hospitalized andevaluated forthecause of herpancytopenia. Laboratory evaluationyielded the following results: hemoglobin 78 gIL, hematocrit 0.24, white blood cellcount 3.2 x lo"lL, platelet count 67 x lo"lL, mean corpuscular volume 105 fl., mean corpuscular hemoglobin 0.43fmol/cell, vitamin B12 concentration 405 pmol/L, andfolate 13.8 nmol/L. Bone marrow biopsy showed a normocellularbone marrow with slight erythroid hyperplasia; themarrow stained positively foriron stores. Serum trough valproic acidconcentration was measured andfound to be943mg/mL (toxic concentration >693). Thedosage of valproic acidwas reduced to 1000 mgbid; this wasfollowed bya prompt increase inhemoglobin and hematocrit values, which reached 98 gIL and 0.28,respectively. The patient's leukopenia andthrombocytopenia were alsocorrected. A control serum valproic acidtrough concentration measured at thistimewas498mg/mL. The patient is nowreceiving Hu-rEPO at a maintenance dosage of 4000units/wk sc andher hematologic parameters are within desired limits. Valproic acid, which is only slightly dialysable «5 percent), binds to plasma proteinsto a lesserdegree in uremia A dose reductionof approximately 25 percent is recommended for patients receiving hemodialysis treatment.P Ingestion of the drug before meals may further increase the risk of toxicity.' Bone marrow suppressionhas been reportedas one of the potentialtoxic effectsof this anticonvulsive drug and is dose dependent. 4 This case demonstrates that exogenously administered Hu-rEPO in dosages up to 12()()() units/wk cannot overcome the bone marrow suppression associated with valproic acid toxicity. CEM SUNGUR, M.D.

Nephrology Fellow Nephrology Unit DepartmentofInternalMedicine Hacettepe MedicalSchool 06100Sihhiye Ankara.Turkey ARZU SUNGUR, M.D.

AssistantProfessor DepartmentofPathology TEKIN AKPOLAT, M.D.

Nephrology Fellow UNAL YASAVUL, M.D.

AssociateProfessor CETIN TURGAN, M.D.

Professor

1156 • The Annals ofPharmacotherapy •

SAL) CAGLAR, M.D.

Professorand Head Nephrology Unit DepartmentofInternalMedicine REFERENCES

I. Maher JF. Principles of dialysisand dialysisof drugs. Am J Med 1977; 62:475-81. 2. Anthony IN. Nervous system. In: Daugirdas IT, Ing TS, eds. Handbook of dialysis. Boston: Little, Brown, 1988:524-34. 3. Glazko AJ. Antiepileptic drugs: biotransformation, metabolism and serumhalf-life. Epilepsia 1975;16:367-75. 4. Hooshmand H. Toxiceffects of anticonvulsants: general principles. Pediatrics1974;53:551-60. Treatment of viral hemorrhagic fevers with ribavirin TO THE EDITOR: Viral hemorrhagic fever (VHF) is a febrile illness caused by a variety of geographically restricted viruses.' Although the viruses causing VHF arise collectively from several taxonomic families and genera, 1 they are clinically united by the fact that hemorrhage and shock represent their most severe form of clinical presentation.t" These viral syndromes pose an important public health threat worldwide,'> including in the US where viral isolation in rodents 5,6 and in humans has been reported sporadically.' Although no cases of hwnan VHF have been confirmed in the US since 1976,2the large number of both civilian and military personnel moving in and around subsahara Africa and the Middle East where Crimean-Congo hemorrhagic fever (CCHF) is endemic, heightens the possibility that cases of this VHF may be imported in the future. The pathogenicmechanism by which hemorrhagic fever viruses cause disease is not well understood. CCHF is transmitted by ticks that are common on the region's domestic animals and livestock." Evidence strongly suggests that blood, urine, secretions,and excretions of infected animals and hwnans are possible sources of infection.' As with other forms of VHF, the patient's travel history, symptoms, and physical signs provide the strongestclues to early diagnosis. Following a 3- to 12-day incubation phase, the onset of CCHF begins with a sudden and severe headache frequently followed by rigors, chills, and fever. The fever pattern exhibits a double-peakedor "camelback" shape, with a brief 12- to 48-hour afebrile period occurring within the 7- to 9day febrile phase. Intense myalgias, persistent vomiting, sore throat, and photophobia may occur. Other signs and symptoms include diffuse abdominal pain accompanied by repeated vomiting"; upper body hyperemia encompassing the face, neck, chest, and hands; hepatomegaly and right upper-quadrantpain; and a petechial rash arising after 6 days of illness." The average case-fatality rate for untreated CCHF is estimated to range between 15 and 70 percent." No specific therapy currently exists for treating CCHF. Successful management relies heavily upon early diagnosis and prompt supportive care.' Because adult respiratorydistress syndrome,renal failure, seizures, and hemorrhage are frequent complicationsof VHF, the services provided by an intensivecare unit may be needed for severe cases. Hwnan immune convalescent serum has been used empirically in the management of Ebola hemorrhagic fever, Marburg hemorrhagic fever, and CCHF.2 With the exception of CCHF, where the results of two studies appear mixed, the serum's usefulness in the acute management of VHF remains unclear.P'" Heparin and corticosteroids also have been used empirically,but their value remains unproven and both may be contraindicated.' Ribavirin is a broad-spectrum antiviral drug currently approved for the treatment of respiratory syncytial viral infections in chil-

1992 September, Volume26

dren." It also inhibits many Bunyaviridae viruses, including the one responsible for CCHF.IS During an outbreak of CCHF in Cape Town, South Africa, ribavirin was used prophylactically in healthcare workers exposed to the contaminated blood. I6-18 Only one person who received ribavirin developed mild symptoms, and two of three nontreated, exposed workers developed severe disease. However, the large number of exposed workers who received no treatment yet remained asymptomatic makes it impossible to evaluate the therapeutic value of ribavirin in the treatment of CCHF. Ribavirin's usefulness remains unconfirmed; at present, however, it appears to be the best therapeutic option available for the treatment of diagnosed or suspected CCHF. Current Centers for Disease Control treatment guidelines recommend that ribavirin be given to suspected cases as a 30-mg/kg iv loading dose, followed by 16 mg/kg iv q6h for four days, then 8 mg/kg iv q8h for six additional days.' As in the case of other types of VHF, initiating ribavirin therapy early after fever onset may improve clinical outcome. Convalescent patients and people who come in contact with them should be wamed that as with most VHFs, the causative agents may continue to be shed for several weeks.' Close contacts, such as family members, medical staff, or those handling laboratory specimens of the index case within three weeks of disease onset, should be placed under surveillance. High-risk people, such as those having mucous membrane contact, should also be placed under surveillance and considered for ribavirin prophylaxis. These cases should receive ribavirin 500 mg po q6h for seven days.' Institutions requiring more information on the treatment of CCHF are encouraged to contact Susan Fisher-Hock, M.D., Centers for Disease Control, (404) 639-1115, extension 3308. Additional information on the current ribavirin dosing guidelines for CCHF or other VHF should contact J.W. Huggins, Ph.D., USAMRIID, Ft Detrick, MD, (301) 665-7494. Oral and parenteral ribavirin is not commercially available. Access to these formulations is on an investigational or compassionate-use basis. Ribavirin can be obtained from ICN Pharmaceuticals, Costa Mesa, California, (800) 548-5100. Inquiries should be directed to Hemberto Fernandez, M.D., Medical Director. CPT JEFFREY T. MOSS, MS Instructor Pharmacy Branch Medicine/Surgery Division Academy ofHealth Sciences Fort Sam Houston, Texas 78234

LTC JAMES P. WILSON, MS Pharmacy Consultant Office ofthe Surgeon General Headquarters. Department ofthe Army Falls Church. Virginia The opinions or assertions conlained herein are the private views of the au!hors and are nol to be construed as official or reflecting the views of the US Department of the Army or the Department of Defense.

REFERENCES

I. Johnson KM. Epidemic hemorrhagic fevers. In: Hoeprich PO, Jordan MC, eds. Infectious diseases. Vol.4. Philadelphia: 18 Lippincott, 1989: 909-15. 2. Management of patientswith suspected viral hemorrhagic fever. MMWR 1988;37(suppl S-3):1-15. 3. Lee HW. Hemorrhagic feverwithrenalsyndrome (HFRS). ScandJ Infect Dis (suppl) 1982;36:82-5. 4. McKee KT, Le Due JW, MacDonald C, Peters CJ. Hemorrhagic fever withrenalsyndrome--a clinical perspective. MilitMed 1985; 150:640-7. 5. Lee P-W, Yanagihara R, Franko MC, Amyx HL, Gibbs CJ, Gajdusek DC. Preliminary evidencethat Hantaanor a closelyrelatedvirus is enzootic in domestic rodents. N Engl J Med 1982;307:624-5. 6. Le Due JW, Smith GA, Johnson KM. Hantaan-like viruses fromdomestic rats captured in theUnited States. Am J TropMedHyg 1984;33:992-8. 7. Yanagihara R, Gajdusek DC, Gibbs CJ, Traub R. ProspectHill virus: serologic evidence for infection in mammalogists. N Engl J Med 1984; 310:1325-6. 8. Tantawi HH, Shony MO, AI-Tikriti SK. Antibodies to Crimean-Congo hemorrhagic fever virus in domesticanimals in Iraq: a seroepidemiologicsurvey. J Trop Med Hyg 1981;84:117-20.

9. Oldfield EC, Wallace MR, Hyams KC, Yousif AA, Lewis DE, Beougeois AL. Endemic infectiousdiseases in the middle east. Rev Infect Dis 1991;13(suppI3):SI97-217. 10. Swanepoel R, Gill DE, Shephard AJ, Leman PA, Mynhardt JH, Harvey S. The clinical pathology of Crimean-Congo hemorrhagic fever. Rev InfectDis 1989; II (suppl 4):S794-8OO. II. Centers for Disease Control. Viral hemorrhagic fever: initialmanagementof suspected and confirmed cases. MMWR 1983;32:27S-39S. 12. Vassilenko SM, Vassilev TL, Bozadjiev LG, Bineva IL, Kazarov GZ. Specific intravenous immunoglobulin for Crimean-Congo hemorrhagicfever. Lancet 1990;335:791-2. 13. Ribavirin. In: McEvoy OK, ed. AHFS Drug Information '91. Bethesda, MD: American Societyof Hospital Pharmacists, 1991 :391-9. 14. Sidwell RW, Robin RK, Hillard IW. Ribavirin: an antiviral agent. PharmacolTher 1979;6: 123-46. 15. Huggins JW. Prospects for treatmentof viral hemorrhagic fevers with ribavirin,a broadspectrum antiviral drug. Rev InfectDis 1989; I I(suppl 4):S750-61. 16. Van Eeden PJ, Joulert JR, Van de Wal BW, King JB, De Kock A, Groenewald JH. A nosocomialoutbreakof Crimean-Congo hemorrhagicfever in Tygerberg Hospital. Part I. Clinicalfeatures. S Afr Med J 1985;68:711-7. 17. Van Eeden PJ, Van Eeden SF, Joulert JR, King JB, Van de Wal BW, Michell WI. A nosocomial outbreakof Crimean-Congo hemorrhagicfever at Tygerberg Hospital. Part II. Management of patients. S AfrMedJ 1985;68:718-28. 18. Van de Wal BW, Joulert JR, Van Eeden PJ, King JB. A nosocomial outbreakof Crimean-Congo hemorrhagic feverat Tygerberg Hospital. Part Ill. Prevention and prophylactic measures. S Afr Med J 1985;68: 729-32. Comment: cecal vitamin bezoar formation inducing abdominal discomfort TO THE EDITOR: The case report by Hunt-Fugate and Schmidt (Ann

Pharmacother 1992;26:485-7) discusses the treatment of phytobezoars, including enzymatic therapy with cellulase. Proteolytic enzyme therapy with papain also has been successful in the management of phytobezoars. Early reports described papain therapy using Papase tablets, which contain proteolytic enzymes extracted from Carica papaya.I This product is no longer available in the US. The only other available source of papain is Adolph's Meat Tenderizer (AMT). Successful treatment regimens that have been reported include one teaspoonful of AMT dissolved in 200--250 mL of water and administered orally three to four times daily for two to seven days.P Adverse effects reported with papain include hypernatrernia,' gastric ulceration," and esophageal perforation! Successful treatment of phytobezoars has been reported with a cellulase-containing enzyme preparation,' as well as with cellulase alone. Gastroenterase tablets (pepsin, pancreatic enzyme mixture, dehydrocholic acid, and cellulase) have been reported to have a 100 percent success rate in the treatment of phytobezoars, as well as no associated adverse effects.' Cellulase 3-5 g dissolved in 300--500mL of water and administered orally for two to five days has been reported to have an identical success rate and adverse effect profile," Because of the unavailability of these products. over the past several years clinicians have been required to choose less attractive alternative therapies for the management of phytobezoars. Our institution has discovered that cellulase is once again available in the US. We have successfully treated one patient who had both a postoperative gastric and small intestinal phytobezoar with cellulase 4 g (4000 units I g) dissolved in 300 mL of sterile water and administered orally for five days. This preparation was obtained from Solvay Enzyme, Elkhart, IN; 1-800/3422097. PAMELAB. WALKER,Phann.D.

Clinical Specialist Pulmanary and Critical Care Medicine Department ofPharmacy Services Medical University ofSouth Carolina 171 Ashley Avenue Charleston, South Carolina 29425

JON V. TRANKINA, M.D. Gastroenterology Fellow Department ofGastroenterology

The Annals ofPharmacotherapy • 1992 September, Volume 26 • 1157