Dennis F. Thompson

Dexrazoxane in the Prevention of Doxorubicin-Induced Cardiotoxicity

OBJECTIVE: To review doxorubicin-induced cardiotoxicity and to evaluate the use of dexrazoxane in its prevention. DATA SOURCES: All animal and human reports involving doxorubicin-induced cardiac adverse effects were searched using MEDLINE combined with a fan search of relevant papers. DATA EXTRACTION: Animal, in vitro cellular, and human data are thoroughly reviewed with particular emphasis on doxorubicin-induced cardiotoxicity, including clinical manifestations, risk factors, and mechanisms of toxicity. The role of dexrazoxane in the prevention of doxorubicin-induced cardiotoxicity is reviewed, including mechanism of effect, animal data, and human trials. DATA SYNTHESIS: Anthracyclines are associated with a cumulative, dose-dependent, irreversible cardiomyopathy that can lead to congestive heart failure and death. The incidence of cardiotoxicity rises sharply at a total lifetime dose of more than 550 mg/m2. Through its semiquinone metabolite, doxorubicin appears to generate superoxide anion and superhydroxide free radicals with iron as a cofactor. Because of poor myocardial concentrations of superoxide dismutase, catalase, and glutathione peroxidase, these free radicals cause extensive lipid peroxidation and mitochondrial destruction. CONCLUSIONS: Dexrazoxane is hydrolyzed to its active form intracellularly and binds iron to prevent the formation of superhydroxide radicals, thus preventing mitochondrial destruction. The effect of dexrazoxane on the prevention of doxorubicin-induced cardiotoxicity is impressive in both animal and human studies. Further research is needed to clearly demonstrate the effect dexrazoxane has on the antitumor effects of combination chemotherapy while defining optimal dosing strategies to minimize myelosuppression and maximize cardioprotection.

Fibrin Glue: A Review of its Preparation, Efficacy, and Adverse Effects as a Topical Hemostat

Fibrin glue is composed of two separate solutions of fibrinogen and thrombin. When mixed together, these agents mimic the last stages of the clotting cascade to form a fibrin clot. Fibrin glue is available in Europe but is not commercially available in the U.S.; therefore, investigators have extemporaneously compounded their own fibrin glue. Fibrinogen can be obtained from pooled, single-donor, and autologous blood donors and is usually isolated by the process of cryoprecipitation. The thrombin component is generally derived from commercial bovine sources. Some investigators have added calcium chloride and/or antifibrinolytics (i.e., aminocaproic acid, aprotinin) to their preparations. Fibrin glue can be applied using a double-barrel syringe or by spray application. Although fibrin glue has been used in a variety of surgical procedures, it has been especially useful in heparinized patients undergoing cardiovascular procedures requiring extracorporeal circulation, as it does not require an intact hemostatic system to be effective. Fibrin glue also has been evaluated in presealing woven or knitted Dacron vascular grafts. The major drawback to its use is the risk of transmitted serological disease from pooled and single-donor blood donors. The safest preparations use the patients own blood to prepare fibrin glue. Overall, fibrin glue is a useful adjunct to other methods to control bleeding in selected surgical patients.

Retinoic acid syndrome: a review

The retinoic acid syndrome (RAS) is an unpredictable but frequent complication which may develop after administration of all‐trans retinoic acid (ATRA) most commonly in patients with acute promyelocytic leukaemia (APL). In this review, we describe the incidence, predictive factors, clinical course, outcome and treatment of RAS in patients with APL treated with ATRA. The incidence of RAS in patients receiving ATRA is about 14–16%, with an associated mortality of about 2%. Initial high white blood cell (WBC) count, rapidly increasing WBC count and/or the presence of the CD 13 expression on leukaemic cells may help in identifying patients likely to develop RAS. Concurrent chemotherapy will probably decrease the risk of developing RAS but often exacerbates bleeding, leading to leucocytosis, thrombocytopenia, disseminated intravascular coagulation and fibrinolysis. Prophylactic steroids are not recommended but prompt administration of steroids at the first sign of unexplained dyspnea, fever, weight gain or pulmonary infiltrate, is critical. Liposomal ATRA is being investigated to induce haematological cure in APL without chemotherapy and to reduce the incidence of RAS but further validation of its usefulness is necessary.

Drug-Induced Nightmares:

OBJECTIVE: To compile and assess the English-language literature on drug-induced nightmares, excluding nightmares secondary to drug withdrawal or drug-associated night terrors. DATA SOURCES: Published articles, letters, case reports, and abstracts in English were identified by MEDLINE (1966–May 1998) searches using the search term nightmares, chemically induced. Additional articles were obtained from bibliographies of retrieved articles. DATA EXTRACTION: All case reports of drug-induced nightmares were evaluated using the Naranjo algorithm for causality. Clinical studies of drugs that reported nightmares as an adverse effect were assessed for frequency of occurrence. DATA SYNTHESIS: Nightmares, defined as nocturnal episodes of intense anxiety and fear associated with a vivid, emotionally charged dream experience, are generally classified as a parasomnia. Possible pharmacologic mechanisms for drug-induced nightmares, such as REM suppression and dopamine receptor stimulation, are reviewed. However, the vast majority of therapeutic agents implicated in causing nightmares have no obvious pharmacologic mechanism. CONCLUSIONS: Assessing causality with an event such as a nightmare is difficult because of the high incidence of nightmares in the healthy population. Using qualitative, quantitative, and possible pharmacologic mechanism criteria, it appears that sedative/hypnotics, β-blockers, and amphetamines are the therapeutic modalities most frequently associated with nightmares. These drug classes have a plausible pharmacologic mechanism to explain this effect. Dopamine agonists also have evidence of causality, with dopamine receptor stimulation as a possible pharmacologic mechanism.

Vancomycin Therapeutic Drug Monitoring: Is it Necessary?

OBJECTIVE: To review the literature and assess the validity of obtaining vancomycin serum drug concentrations in patients. DATA SOURCES: A MEDLINE search of the English literature and a bibliographic review of articles pertaining to vancomycin serum concentrations, their use, and the rationale of cited therapeutic ranges. STUDY SELECTION AND DATA EXTRACTION: Studies pertaining to the use of vancomycin concentrations in the clinical setting, methods for predicting these concentrations, and studies that reported efficacy or toxicity associated with vancomycin use and possible correlation of serum concentrations. DATA SYNTHESIS: The usefulness of vancomycin serum concentrations, the determination of a therapeutic range of values, and their correlation to antibacterial efficacy and drug toxicity in the clinical setting are controversial. Old reports of toxicities need to be critically examined due to lack of information and the actual frequency of toxic reactions. The efficacy of vancomycins antibacterial effect and its correlation with reported therapeutic ranges may advocate obtaining a vancomycin trough concentration in certain groups of patients. CONCLUSIONS: Determination of serum vancomycin concentrations in the clinical setting and their usefulness in patient care is questionable and unnecessary in the majority of patients.

Drug-Induced Sweet's Syndrome

Objective: To systematically review the pertinent literature on drug-induced Sweets syndrome (SS). Data Sources: MEDLINE (1966–December 2006), International Pharmaceutical Abstracts (1970–December 2006), Science Citation Index (1945–December 2006), and EMBASE (1980–December 2006) were searched using the key terms Sweets syndrome, drug-induced, and acute neutrophilic dermatitis. Study Selection and Data Extraction: All case reports of drug-induced SS located using the above databases were collected for causality assessment. In addition, relevant articles regarding the various causes and presentations of SS were selected to provide background information. Bibliographies of all relevant articles were reviewed for additional citations. Data Synthesis: All case reports of drug-induced SS were evaluated against an expanded Naranjo scale with specific criteria for SS. Tables were developed listing key criteria for evaluating the case reports for causality. Data were evaluated by quantity and quality of evidence, and an assessment was made as to whether there was a feasible pharmacologic mechanism to explain causality. Conclusions: Granulocyte colony-stimulating factor (G-CSF), all-trans retinoic acid (ATRA), and vaccines met 2 of 3 criteria for an association with SS. There are sufficient data and a plausible pharmacologic mechanism for G-CSF and ATRA. Vaccines meet the qualitative criteria and also have a plausible pharmacologic mechanism. The evidence regarding minocycline is of high quality; however, the quantity of evidence and a reasonable pharmacologic mechanism are lacking. A host of miscellaneous drugs have also been implicated in causing the disorder, all without sufficient evidence.

Drug‐Induced Lichen Planus

Lichen planus is a relatively common skin disorder of unknown etiology. A wide variety of drugs have been implicated in its cause. Using five or more cases of drug‐induced lichen planus reported in at least three separate reports with at least one case of probable cause by the scale of Naranjo et al as criteria, sufficient evidence exists that β‐blockers, methyldopa, penicillamine, quinidine, and quinine play a role in this disorder. Evidence is insufficient for angiotensin‐converting enzyme inhibitors, sulfonylurea agents, carbamazepine, gold, lithium, and a host of miscellaneous drugs. Given available epidemiologic evidence, nonsteroidal antiinflammatory agents probably should also be considered causative. Differentiating drug‐induced lichen planus from the idiopathic disorder is difficult; most evidence is based on the dechallenge and rechallenge with the drug when these data are available.

Drug-Induced Pure Red Cell Aplasia

Pure red cell aplasia (PRCA) is an uncommon hematologic disorder characterized by the absence of erythroblasts in otherwise normal bone marrow. It is commonly an autoimmune disorder sometimes associated with a congenital error. It may also be acquired in association with thymomas, hematologic malignancies, human parvovirus B19 infection, drugs, and other disease states. Thirty drugs have been implicated as causative in PRCA, but most literature reports describe only one or two patients. Data evaluating possible mechanisms of drug‐induced PRCA are extremely limited, with conflicting results from different investigators. The criteria we used were at least five patients reported, reports from at least three separate investigators, and a minimum of one case of probable causality or better using a published assessment scale. With these criteria, phenytoin, azathioprine, and isoniazid had sufficient evidence of causality. All three are documented causes of PRCA and should be considered in any case of selective erythrocyte aplasia.

Drug-induced hiccups

Drugs are rarely the cause but should be screened for in cases of persistent hiccups.

A review of methotrexate-induced accelerated nodulosis.

Objective. To review the English‐language literature on methotrexate‐induced accelerated nodulosis, compile case reports of its occurrences, and make recommendations on the clinical management of patients.