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Letters to the Editor

Use of Cytochrome P450 and Prolonged Prothrombin Time

TO THE EDITOR: In the article written by Drs. Cupp and Tracy¹ on cytochrome P450 enzymes, the first illustrative case describes a patient who developed dry mouth, dizziness and prolongation of the prothrombin time after paroxetine and then fluoxetine were added to her medication regimen, which included amitriptyline and warfarin.

In Table 1, paroxetine is listed as an inhibitor and amitriptyline is listed as a substrate.¹ Warfarin is listed as a substrate in Tables 3 and 4¹; however, neither of these tables lists paroxetine or fluoxetine as a potential inhibitor.

Presumably the patient's dry mouth and dizziness were related to a drug interaction between paroxetine and amitriptyline; however, what was the reason for the prolonged International Normalized Ratio (INR)?

ARTHUR C. LIU, M.D.
Palo Alto Medical Clinic
Los Altos Center
370 Distel Circle
Los Altos, CA 94022

REFERENCE

1. Johns Cupp M, Tracy TS. Cytochrome P450: new nomenclature and clinical implications. Am Fam Physician 1998;57:107-16.

IN REPLY: We appreciate Dr. Liu's question concerning the cause of the prolonged International Normalized Ratio (INR) in the patient described in the illustrative case. A section of the text that would have explained this drug interaction was omitted from the final version of the manuscript at the suggestion of a reviewer who thought it would be "confusing to clinicians." However, we feel, as does Dr. Liu, that this interaction warrants an explanation.

Warfarin is a racemic mixture of R-warfarin and S-warfarin, which differ in potency and metabolic pathways.¹ R-warfarin is a less potent anticoagulant than is S-warfarin,¹ which is metabolized by CYP2C9.² CYP1A2 and CYP3A are the enzymes responsible for the metabolism of the less potent R-warfarin.

In the case presented in our article, the addition of fluoxetine, a CYP3A inhibitor, to the medication regimen of the patient was the likely cause of the increase in the INR. There is also limited information that suggests fluoxetine is a CYP2C9 inhibitor³; thus, it is an inhibitor of the more potent S-enantmer.

Despite case reports of a drug interaction between fluoxetine and warfarin,⁴ results of a pharmacokinetic study⁵ did not support a clinically significant interaction. Physicians may or may not see a change in the INR of a patient when a CYP3A inhibitor is added to warfarin therapy. The propensity for a clinically significant interaction might be influenced by interindividual activity of CYP3A, or by other medications taken by the patient that inhibit other warfarin metabolic pathways.

MELANIE JOHNS CUPP, PHARM.D.
TIMOTHY TRACY, PH.D.
West Virginia University School of Pharmacy
1124 HSN
P.O. Box 9550
Morgantown, WV 26506-9550

REFERENCES

1. Porter RS, Sawyer WT. Warfarin. In: Evans WE, Schentag JJ, Jusko WJ, eds. Applied pharmacokinetics: principles of therapeutic drug monitoring. 3d ed. Vancouver, Wash.: Applied Therapeutics, 1992:31.1-46.
2. Kaminsky LS, Zhang ZY. Human P450 metabolism of warfarin. Pharmacol Ther 1997;73:67-74.
3. Preskorn SH. Clinically relevant pharmacology of selective serotonin reuptake inhibitors. An overview with emphasis on pharmacokinetics and effects on oxidative drug metabolism. Clin Pharmacokinet 1997;32 Suppl 1:1-21.
4. Prozac (fluoxetine) prescribing information. Indianapolis, Ind.: Eli Lilly and Co., 1997.
5. Rowe H, Carmichael R, Lemberger L. The effect of fluoxetine on warfarin metabolism in the rat and man. Life Sci 1978;23:807-11.

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Occupational Lead Poisoning

TO THE EDITOR: The article by Drs. Staudinger and Roth on occupational lead poisoning¹ was timely and comprehensive. The authors' observation that a high index of suspicion is necessary to avoid missing the diagnosis cannot be emphasized enough.

One finding that should prompt consideration of occupational lead poisoning is unexplained basophilic stippling of the red cells on peripheral blood smear. The stippling seen in this condition is usually coarse, as opposed to the fine stippling seen in hemorrhage or hemolysis. A comprehensive occupational history, as well as the more specific studies listed in the article, should be pursued routinely as a follow-up to this important finding. It could save lives.²

LESLIE BENNETT, M.D.
Division of Hematology
Parkway Hospital
Queens, NY

ALLEN BENNETT, M.D.
Division of Hematology-Oncology
Beth Israel Medical Center
New York, NY

REFERENCES

1. Staudinger KC, Roth VS. Occupational lead poisoning. Am Fam Physician 1998;57:719-26.
2. Crosby WH. Lead-contaminated health food. JAMA 1977;237:2627-9.

TO THE EDITOR: We congratulate Drs. Staudinger and Roth on an excellent review of occupational lead poisoning, which includes user-friendly resource lists.¹ As physicians at the Occupational Safety and Health Administration (OSHA), we have encountered problems if lead screening guidelines are provided in rote fashion based solely on the levels of lead permitted by OSHA's lead standard. We have encountered the following situations:

• who clear patients to work with lead because their blood lead levels have not reached the mandatory cut-off level, despite significantly elevated levels of zinc protoporphyrin and mild anemia.
• levels of zinc protoporphyrin, with or without declines in hematocrit levels, that have not been followed up to rule out possible iron deficiency.
• lead levels in young patients that have risen from less than 5 µg per dL (0.25 µmol per L) to over 30 µg per dL (1.45 µmol per L) without comment from the examining physician.
• in which there is almost no communication between the safety officer and the examining physician, or in which the examining physician provides the entire medical examination report to a nonmedical safety officer.

Measurement of whole blood lead levels is an extremely accurate method of evaluating current exposure to lead. The levels permitted by the OSHA standard resulted from a great deal of compromise and have not been revised since the publication of the standard in 1978. The level at which overt toxicity occurs remains controversial, and the levels that are in the OSHA standard do not guarantee the absence of lead toxicity.²

The most serious concern about long-term lead toxicity in the range experienced by current employees (i.e., generally less than 40 µg per dL [1.95 µmol per L]) is the potential for nephrotoxicity. For this reason, efforts should be made to identify individuals at risk for renal damage from other occupational exposures (such as cadmium) and from nonoccupational causes (such as diabetes or hypertension), and to cautiously monitor their lead exposure. The physician may wish to contact the environmental safety manager at the plant to find out if additional industrial hygiene measures may be useful. For example, powered air purifying respirators provide additional protection compared with the usual negative pressure respirators used by most employees, and their use may be warranted in these individuals. While making any recommendation, it is important to maintain medical confidentiality, including the nature of medical conditions that are non­work-related. The information to be shared with the employer is that the individual is being cleared for work, with certain specific restrictions.

Another area of significant concern is reproductive toxicity due to exposure to lead. Under the OSHA standard, medical examination or consultation may be requested by an employee who desires information about reproduction and exposure to lead. For men, we generally recommend a three-month medical removal from lead exposure before conception is attempted. We recommend medical removal protection for women throughout pregnancy since the fetus is more susceptible than the general pediatric population, for whom the level of concern is a blood lead level of 10 µg per dL (0.5 µmol per L), and it is difficult to achieve these levels in many industrial and construction settings. Medical removal protection maintains job security and income for up to 18 months while individuals are transferred to jobs without exposure to lead.

Please bear in mind that the level of lead in the general population now averages 2.8 µg per dL (0.15 µmol per L).³ When the level of lead in a new employee increases by four or five times, the physician may wish to identify the source of the problem, even if the level remains below 40 µg per dL (1.95 µmol per L).

Finally, we would like to encourage all physicians who conduct any occupational medical surveillance to make use of the environmental safety managers. The goal of medical surveillance is to provide a feedback loop for engineers, industrial hygienists and safety managers to recognize that a breakdown in true primary prevention has occurred, and to identify and correct the problem.

ROSEMARY K. SOKAS, M.D., M.O.H.
EUGENE SCHWARTZ, M.D., M.P.H.
JAMES C. WESDOCK, M.D., M.P.H.
Office of Occupational Medicine, Room N3653
U.S. Department of Labor
Occupational Health and Safety Administration
200 Constitution Ave.
Washington, D.C. 20210

REFERENCES

1. Staudinger KC, Roth VS. Occupational lead poisoning. Am Fam Physician 1998;57:719-26.
2. al-Saleh IA. The biochemical and clinical consequences of lead poisoning. Med Res Rev 1994; 14:415-86.
3. Pirkle JL, Brody DJ, Gunter EW, Kramer RA, Paschal DC, Flegal KM, et al. The decline in blood lead levels in the United States. The National Health and Nutrition Examination Surveys (NHANES). JAMA 1994;272:284-91.

IN REPLY: We wish to thank Drs. Bennett for their insightful observation regarding the finding of basophilic stippling and its possible etiology related to lead. Such a finding may indeed provide the impetus for further questioning regarding occupational exposure to lead, thereby permitting earlier detection of lead poisoning in workers who are at risk and the subsequent institution of protective measures before employees experience adverse clinical effects. As previously stated in our article,¹ the diagnosis of clinical effects related to lead requires a high index of suspicion on the part of the examiner and any clues that suggest potential poisoning should be used.

We also thank Dr. Sokas and colleagues for their comments in regard to occupational lead poisoning and the OSHA lead standard. They succinctly define the renal and reproductive concerns, highlighting individuals at potential risk with blood lead levels that are lower than the stated standard. Importantly, they point out that the standard cannot assure the absence of adverse health effects, even if held strictly to its stated blood levels.

From an occupational physician's standpoint, failure to reach the mandatory cut-off levels of blood lead levels does not preclude the need for continued medical surveillance and initiation of proper control measures. Gradually increasing blood lead levels in a worker, with or without overt health effects, require further investigation of both the worker and the work environment. Timely intervention before the attainment of mandatory cut-off levels could provide the controls needed before clinical effects manifest and/or other workers are noted with increased blood lead levels. Importantly, Dr. Sokas and colleagues relate how critical the relationship is between the examining physician and the safety officer for the implementation of proper control measures, both administrative and engineering. This relationship is the key to primary prevention efforts and long-term avoidance of further exposure.

VICTOR S. ROTH, M.D., M.P.H.
University of Alabama at Birmingham School of Medicine
Division of Occupational and Environmental Medicine
121 CHSB
930 20th St. S.
Birmingham, AL 35205

KEVIN C. STAUDINGER, M.D., M.P.H.
Baptist Health Centers, Inc.
Birmingham, AL

REFERENCE

1. Staudinger KC, Roth VS. Occupational lead poisoning. Am Fam Physician 1998;57:719-26.

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TABLE 4 Summary of Guidelines for Antiretroviral Therapy for HIV Infection Preferred initial regimen Two nucleoside analogs + a highly active protease inhibitor, such as ritonavir (Norvir), indinavir (Crixivan), nelfinavir (Viracept) or saquinavir (Fortovase) Alternative initial regimens Two nucleoside analogs + a nonnucleoside reverse transcriptase inhibitor Two nucleoside analogs + saquinavir Two nucleoside analogs (although not generally recommended) Regimens not recommended Monotherapy Stavudine (Zerit) + zidovudine (Retrovir) Zalcitabine (Hivid) + didanosine (Videx) Zalcitabine + stavudine Zalcitabine + lamivudine (Epivir) Suggested regimens for patients who fail to respond to initial therapy If initial regimen was two nucleoside analogs and a protease inhibitor, change to one of the following: Two different nucleoside analogs + a different protease inhibitor Two different nucleoside analogs + a protease inhibitor combination Two different nucleoside analogs + a protease inhibitor + a nonnucleoside reverse transcriptase inhibitor If initial regimen was two nucleoside analogs and a nonnucleoside reverse transcriptase inhibitor, change to the following: Two different nucleoside analogs + a protease inhibitor If initial regimen was two nucleoside analogs, change to the following: Two different nucleoside analogs + a protease inhibitor If initial regimen was one nucleoside analog, change to one of the following: Two different nucleoside analogs + a protease inhibitor Two different nucleoside analogs + a nonnucleoside reverse transcriptase inhibitor NOTE: Recommended nucleoside analog combinations are as follows: zidovudine + lamivudine; zidovudine + didanosine; zidovudine + zalcitabine; stavudine + lamivudine; or didanosine + stavudine. Information from references 11 and 12.

Correction

Table 1 of the article "Combination Antiretroviral Therapy for HIV Infection" (June 1998, p. 2791) contained an editing error. Dosing recommendations for zalcitabine (ddC: Hivid) would only include a dose reduction for weight under 60 kg in patients who have developed peripheral neuropathy attributed to zalcitabine therapy. Table 4 of the same article also contained an error. The Invirase formulation of saquinavir should not have been included. The corrected table is reprinted above.

The editors of AFP welcome input concerning topics of current medical interest and feedback in response to articles and other material published in AFP. Send letters to Jay Siwek, M.D., Editor, American Family Physician, 8880 Ward Pkwy., Kansas City, MO 64114; fax: 816-333-0303; e-mail: afplet@aafp.org. Please include your complete address, telephone number and fax number. Letters should be double-spaced, fewer than 500 words and limited to one table or figure and six references. Letters submitted for publication in AFP must not be submitted to any other publication. Letters pertaining to AFP subject matter must be received within two months of publication. Any financial associations or other possible conflicts of interest must be disclosed at time of submission. Submission of a letter constitutes transfer of copyright to the American Academy of Family Physicians. The editors reserve the right to edit correspondence to meet style and space requirements.

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