Robert Lee Page

Potentiation of Warfarin by Dong Quai

Dong quai is a Chinese herbal supplement touted for treatment of menstrual cramping, irregular menses, and menopausal symptoms. Phytochemical analyses found it to consist of natural coumarin derivatives, as well as constituents possessing antithrombotic, antiarrhythmic, phototoxic, and carcinogenic effects. A 46‐year‐old African‐American woman with atrial fibrillation stabilized on warfarin experienced a greater than 2‐fold elevation in prothrombin time and international normalized ratio after taking dong quai concurrently for 4 weeks. No identifiable cause was ascertained for the increase except dong quai. The patients coagulation values returned to acceptable levels 1 month after discontinuing the herb. One animal study suggests a pharmacodynamic interaction between the product and warfarin, but the true mechanism remains unknown. Practitioners should be aware of the possibility of such an interaction and should inform patients of potential hazards of taking the two together.

Vitamin B12 Deficiency Associated with Histamine2-Receptor Antagonists and a Proton-Pump Inhibitor

OBJECTIVE: To report a case of vitamin B12 deficiency associated with long-term use (∼4½ y) of histamine2 (H2)-receptor antagonists and a proton-pump inhibitor (PPI) in a patient with gastroesophageal reflux. CASE SUMMARY: A 78-year-old nonvegetarian white woman with symptomatic gastroesophageal reflux (GER) was started on cimetidine 300 mg 4 × daily in February 1990 and took various other antisecretory medications over the course of the next 4½ years. She had a normal serum vitamin B12 concentration of 413 pg/mL in August 1992. In June 1994, her serum vitamin B12 concentration was found to be in the low normal range at 256 pg/mL. Biochemical markers of vitamin B12–dependent enzyme activity were measured at that time, and methylmalonic acid (MMA) and homocysteine (HCYS) were elevated at 757 nmol/L and 27.3 μmol/L, respectively. Serum folate was within the normal range at 4.9 ng/mL, and serum creatinine was slightly elevated at 1.4 mg/dL. MMA and HCYS concentrations decreased dramatically with oral replacement of vitamin B12 1000 μg/d, which confirmed vitamin B12 deficiency. Oral replacement also demonstrated that the woman was able to adequately absorb nonprotein—bound vitamin B12 from the gastrointestinal tract, suggesting that her deficiency was a result of food—cobalamin malabsorption. The accumulation of MMA and HCYS was not a consequence of renal dysfunction, since both metabolites dramatically decreased with vitamin B12 replacement. DISCUSSION: Malabsorption of dietary protein-bound vitamin B12 has been demonstrated with the use of H2-receptor antagonists and PPIs. One previous case report of vitamin B12 deficiency resulting from long-term use of omeprazole has been published. The malabsorption of dietary vitamin B12 is thought to be a result of its impaired release from food protein, which requires gastric acid and pepsin as the initial step in the absorption process. CONCLUSIONS: The use of H2-receptor antagonists and/or PPIs may impair the absorption of protein-bound dietary vitamin B12 and could contribute to the development of vitamin B12 deficiency with prolonged use. Patients taking these medications for extended periods of time, particularly >4 years, should be monitored for vitamin B12 status.

Drug Therapy in the Heart Transplant Recipient Part IV: Drug–Drug Interactions

Received March 16, 2004; revision received July 23, 2004; accepted September 30, 2004. nnWith improving survival, the heart transplant recipient faces an increasing number of medical problems caused by both aging and the cumulative complications of immunosuppressive drugs.1 The availability of new drugs to treat infection, obesity, hypertension, hyperlipidemia, renal insufficiency, diabetes, osteoporosis, gout, and malignancies has resulted in the heart transplant recipient and their physicians facing an almost overwhelming number of important drug–drug interactions. In parts 1 through 3 of this series, we reviewed commonly used immunosuppressive drugs and their pharmacology, as well as the common medical problems faced by the heart transplant recipient. In this article, we provide an overview of the mechanisms of common and important potential drug–drug interactions and guidelines for avoiding these interactions.nnThe risk for drug–drug interactions is increased by advanced age, polypharmacy, medications with a narrow therapeutic index, or medications requiring intensive monitoring. All of these factors except advanced age are present in the heart transplant recipient. A 10-fold interpatient variability may exist in the magnitude of a drug interaction resulting from patient-related and drug-related factors.2nnPatient-related factors predisposing to drug interactions include concomitant diseases, genetics, diet, and environmental exposures. For example, commonly used immunosuppressants, antifungal agents, and lipid-lowering medications are metabolized through the cytochrome P450 (CYP450) enzyme system and effluxed from cells by the multiple drug resistance transporter protein p-glycoprotein (P-gp). Both systems are found in the liver and gastrointestinal tract and exhibit genetic polymorphism.2 The CYP450 enzymes belong to a superfamily of oxygenases; the primary purpose of these oxygenases is to add a functional group to a drug to increase its polarity and to promote its excretion from the body. If enzymes possess >40% homology, they are grouped together into families designated by an Arabic numeral (eg, the …

Posaconazole as salvage therapy in a patient with disseminated zygomycosis: case report and review of the literature.

Zygomycosis refers to any fungal infection originating from the class Zygomycetes and the order Mucorales. In immunocompromised patients, these fungi produce a relatively rapid, violently destructive, and highly fatal infection. Treatment approaches include both aggressive antifungal pharmacotherapy and surgical intervention. Unfortunately, even with optimal therapy, morbidity and mortality rates remain relatively high. As failure rates are elevated with commercial antifungals, new treatment options are needed. Posaconazole is an orally available, extended‐spectrum triazole antifungal being investigated in phase III clinical trials for the treatment and prevention of invasive fungal infections, including zygomycosis. We report the case of a 26‐year‐old Vietnamese man with a medical history of acute lymphocytic leukemia who had undergone consolidation chemotherapy and had neutropenic fever when he came to the emergency department. The patient was admitted to the hospital and treated with broad‐spectrum antibiotics and caspofungin. Two weeks into his admission, however, abscesses in the pelvis, prostate, and musculature surrounding the hip were detected radiographically; these abscesses eventually cultured for Mucor sp. Disseminated zygomycosis was diagnosed. Caspofungin was immediately discontinued, and high‐dose liposomal amphotericin B 10 mg/kg/day was begun. Over the next month, infection spread to the right lung, left kidney, middle thoracic spine, and epidural space. As a result, oral posaconazole 200 mg 4 times/day was added to the liposomal amphotericin B. Significant clinical, hematologic, mycologic, and radiologic improvements were demonstrated as early as 10 days after start of posaconazole therapy and continued through 41 days of inpatient treatment. Liposomal amphotericin B was discontinued after 3 weeks of posaconazole, and the patient was discharged on hospital day 92 receiving oral posaconazole, with no major adverse events reported. Five months after discharge, the patient had no evidence of fungal disease recurrence or progression. Posaconazole appears to be a well‐tolerated and effective salvage treatment for zygomycosis, including disseminated disease.

Potential Elevation of Tacrolimus Trough Concentrations with Concomitant Metronidazole Therapy

OBJECTIVE: To report the occurrence of a potential tacrolimus elevation in a renal transplant recipient after adding metronidazole to the medication regimen. CASE SUMMARY: A 24-year-old white man status post living-related renal transplant who had been stabilized on tacrolimus 4 mg twice daily (trough concentrations 7–10 ng/mL) for 2 months and prednisone 20 mg daily presented to the clinic with severe diarrhea. Stool cultures were positive for Clostridium difficile, and therapy with metronidazole 500 mg 4 times daily was initiated. Between days 4 and 14 of metronidazole therapy, the patients tacrolimus trough concentration and serum creatinine level increased to maximum levels of 26.3 ng/mL and 3.3 mg/dL (baseline 1.6–1.8 mg/dL), respectively. Tacrolimus was withheld for one dose and then decreased to 1 mg twice daily. Two days after metronidazole discontinuation, tacrolimus trough concentrations dropped to 9.4 ng/mL and serum creatinine to 2.3 mg/dL, warranting a tacrolimus dose increase to 3 mg daily. DISCUSSION: As of April 15, 2005, one other case has been reported documenting an elevation in tacrolimus concentrations with the addition of metronidazole. The possible mechanism may be related to metronidazoles weak inhibition of CYP3A4 and, possibly, P-glycoprotein. According to the Naranjo probability scale, metronidazole was the probable cause of this adverse reaction. CONCLUSIONS: Coadministration of tacrolimus with metronidazole may result in elevated tacrolimus concentrations, possibly leading to tacrolimus toxicity. Practitioners should be aware of this potential interaction and closely monitor tacrolimus concentrations and renal function.

Possible heart failure exacerbation associated with rosiglitazone: case report and literature review.

Increasing evidence suggests that neurohumoral manifestations of heart failure may lead to insulin resistance, predisposing patients with heart failure to the development of glucose intolerance or worsening of existing diabetes. Theoretically, insulin‐sensitizing thiazolidinediones (TZDs) should be beneficial in this patient population. A 74‐year‐old man with well‐compensated systolic dysfunction and longstanding type 2 diabetes mellitus treated with glyburide began therapy with rosiglitazone 4 mg/day, which was increased to 8 mg/day after 1 month. Two weeks later he was seen with a 5‐kg weight gain, shortness of breath, bibasilar rales, +S3 gallop, and increased jugular venous distention. Twelve days later symptoms worsened, with pulmonary edema on chest radiograph, continued weight gain, and +4 pitting edema resistant to oral diuretics. The patient was admitted to the hospital for exacerbation of heart failure. Five days after discharge he was readmitted for similar symptoms, including an 11.8‐kg weight gain. He reported adherence to drug therapy and diet. Rosiglitazone was immediately discontinued and 11 days later the mans weight stabilized to 79 kg and remained between 79 and 80 kg 2 and 3 months after discharge. This case demonstrates that TZDs may precipitate weight gain and pulmonary and peripheral edema in patients with stable heart failure. Earlier reports documented similar symptoms in patients without a history of heart failure. Although current recommendations state that TZDs should not be administered to patients with New York Heart Association class III or IV disease, practitioners should be aware that these adverse effects also may occur in patients with milder forms heart failure as well as those without heart failure.

Possible Interaction Between Intravenous Azithromycin and Oral Cyclosporine

A 42‐year‐old man who had received a cadaveric kidney transplant 9 years earlier was admitted to the hospital with pneumonia. His oral cyclosporine dosage for the past 2 years was stabilized at 100 mg twice/day; his cyclosporine whole blood trough levels 15 days earlier and on the day he was admitted were both 178 ng/ml. The patient was treated with intravenous ceftriaxone and intravenous azithromycin and continued to receive the same dosage of oral cyclosporine. On hospital day 3, his cyclosporine trough level rose to 400 ng/ml and his dosage was reduced by 50%. Trough levels were 181 ng/ml and 175 ng/ml on hospital days 6 and 9, respectively. On hospital day 9, the patient stopped receiving azithromycin. On hospital day 14, his cyclosporine trough level dropped to 76 ng/ml, and his cyclosporine dosage was increased back to 100 mg twice/day. The dosage produced trough levels consistent with those before he had been admitted. The patient was discharged on day 20, and a follow‐up cyclosporine trough level determined 3 weeks later was 175 ng/ml. Administration of azithromycin may have caused the increased cyclosporine concentrations in this patient through p‐glycoprotein inhibition and/or competition for biliary excretion. Azithromycins interference may be inferred by the increase in cyclosporine levels after administration of this drug and the decrease in cyclosporine levels after its discontinuation—‐both consistent with the pharmacokinetic properties of cyclosporine. Ceftriaxone and acute‐phase reactant activation during infection, however, also may have interfered with the patients cyclosporine elimination. Azithromycin generally is considered unlikely to interact with cyclosporine. Nonetheless, practitioners should be aware of this possibility and should monitor cyclosporine levels closely, especially in critically ill patients who have other complications.

The Comorbidity Conundrum: A Focus on the Role of Noncardiovascular Chronic Conditions in the Heart Failure Patient

The rapid aging of the US population combined with improvements in modern medicine has created a new public health concern of comorbidity, a chronic condition that co-exists with a primary illness. Over 141 million Americans suffer from one or more comorbid conditions. In the heart failure (HF) patient, this comorbidity burden is particularly high, with over 40% of patients having five or more chronic conditions. These comorbidities can vary from being a risk factor to a cause of HF progression or even a precipitating factor for decompensation. Comorbidities, particularly the noncardiovascular conditions, have been associated with greater health resource utilization, poor health outcomes, and increased mortality. To minimize the negative impact that these comorbidities have on patient outcomes, appropriate attention should be paid to identifying, prioritizing, and managing each condition; minimizing medication complexity and polypharmacy; and improving overall coordination of care between providers and patients.

Should β-Blockers Be Used in the Treatment of Cocaine-Associated Acute Coronary Syndrome?

Objective: To critically evaluate the 30 year debate of β-blocker use in cocaine-induced acute coronary syndrome (CIACS). Data Sources: An Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, and Ovid MEDLINE (1966–August 21, 2007) search of the medical literature was conducted using the key terms cocaine, myocardial infarction, acute coronary syndrome, and adrenergic β-antagonists. Study Selection and Data Extraction: All clinical trials, case reports, national cardiovascular guidelines, and reviews published in English were evaluated. Case reports were included based on whether (1) acute coronary syndrome was suspected, (2) a β-blocker was used during the treatment course, and (3) objective and subjective patient-specific information was documented. Data Synthesis: Three case reports and 2 placebo-controlled trials were identified that used 4 β-blockers (atenolol, labetalol, metoprolol, propranolol). Three national guidelines addressed β-blocker use. Although published data are limited, propranolol and labetalol exert minimal to no effect on alleviating cocaine-induced coronary vasoconstriction. None of the evaluated national guidelines recommends β-blockers as first-line agents in CIACS management. Conclusion: β-Blockers should not be considered first-line agents for controlling chest pain in patients with documented CIACS. If long-term β-blockade is warranted, its benefits should be weighed against recurrent use of cocaine and possible exacerbation of acute coronary syndrome. Given that carvedilol exhibits ancillary pharmacologic proprieties beneficial in CIACS, and post-myocardial infarction mortality data are available regarding its use, this agent could be considered to be appropriate therapy.

Intractable Epistaxis Associated with Topiramate Administration

Objective: To report a case of a patient who experienced serious, intractable epistaxis warranting emergency department (ED) visits and hospital admission after initiation of topiramate therapy. Case Summary: A 61-year-old woman with significant cardiovascular disease was started on topiramate 25 mg daily for lower extremity neuropathy. After 7 days of treatment, she began to experience severe, intractable epistaxis that lasted 8 days, warranting an ED visit. The epistaxis resolved 1 week after topiramate discontinuation. Topiramate was restarted 3 months later, and the patient again developed intractable epistaxis. After 2 days of epistaxis, she returned to the ED with significant anginal pain and was admitted to the hospital, where she received 2 units of packed red blood cells. One week after stopping topiramate, the epistaxis stopped. At the time of writing, she had exhibited no epistaxis for 6 months. According to the Naranjo probability scale, topiramate was the probable cause of epistaxis. Discussion: Topiramate is a neuromodulatory compound approved for management of migraines, as well as partial and generalized tonic–clonic seizures. Over the past decade, its use has expanded to include many other neuropathic conditions. Currently, epistaxis has been reported in only 1–4% of patients receiving topiramate in clinical trials; however, these data were derived from a young study population. Like topiramate, calcium-channel blockers (CCBs) modulate voltage-gated L type calcium ion channels. These specific channels are located on vascular smooth muscle and non-contractile tissues such as platelets. Due to their possible antiplatelet effects, CCBs have been associated with an increased risk of hemorrhage, epistaxis, and prolonged bleeding time. The same may hold true for topiramate. Conclusions: Topiramate, particularly in combination with antiplatelet medications, may be associated with severe, intractable epistaxis. Intractable epistaxis should be added to the list of potentially serious adverse reactions that are monitored when topiramate is administered.