Larry W. Buie

The Role of Mannitol as a Nephroprotectant in Patients Receiving Cisplatin Therapy

Objective: To review the efficacy and safety of concomitant mannitol administration with cisplatin therapy to reduce the incidence of nephrotoxicity. Data Sources: A literature search was performed via MEDLINE, PubMed, and the Cochrane Library (1945-August 2011) using the terms mannitol, cisplatin, nephrotoxicity, and forced diuresis. Reference citations from the publications identified were also reviewed. Study Selection and Data Extraction: The search was limited to studies conducted in humans. All studies in which mannitol was used for forced diuresis with cisplatin therapy were evaluated. Data Synthesis: Cisplatin therapy can lead to transient and permanent renal impairment. Molecular and histologic changes occur in the renal tubules, which contribute to nephrotoxicity. The adverse effect profile of cisplatin is well documented, but the prevention strategies to alleviate renal impairment due to treatment are less understood. Mannitol plus hydration has been used for several years to alleviate toxicity associated with cisplatin therapy. However, the data for mannitol administration have not been convincing. When the use of mannitol and hydration is compared directly to hydration alone, mannitol shows no benefit. In some patients, not only was mannitol not protective, its administration was associated with worsening renal function. Conclusions: Although mannitol plus hydration is used to decrease cisplatin-induced nephrotoxicity, there are no compelling data that the addition of mannitol is more nephroprotective than the use of hydration alone. Appropriate hydration remains the most reasonable strategy to reduce the incidence of cisplatin-induced nephrotoxicity.

Rates of Renal Toxicity in Cancer Patients Receiving Cisplatin With and Without Mannitol

Background: Cisplatin is a widely used antineoplastic. One of the major complications of cisplatin use is dose-limiting nephrotoxicity. There are many strategies to prevent this toxicity, including the use of mannitol as a nephroprotectant in combination with hydration. Objective: We aimed to evaluate the rates of cisplatin-induced nephrotoxicity in cancer patients receiving single-agent cisplatin with and without mannitol. Methods: This single-center retrospective analysis was a quasi experiment created by the national mannitol shortage. Data were collected on adult cancer patients receiving single-agent cisplatin as an outpatient from January 2011 to September 2012. The primary outcome was acute kidney injury (AKI). Results: We evaluated 143 patients who received single-agent cisplatin; 97.2% of patients had head and neck cancer as their primary malignancy. Patients who did not receive mannitol were more likely to develop nephrotoxicity: odds ratio [OR] = 2.646 (95% CI = 1.008, 6.944; P = 0.048). Patients who received the 100 mg/m2 dosing and patients who had a history of hypertension also had a higher likelihood of developing nephrotoxicity: OR = 11.494 (95% CI = 4.149, 32.258; P < 0.0001) and OR = 3.219 (95% CI = 1.228, 8.439; P = 0.017), respectively. Conclusions: When limited quantities of mannitol are available, it should preferentially be given to patients at particularly high risk of nephrotoxicity. Our analysis suggests that those patients receiving the dosing schedule of 100 mg/m2 cisplatin every 3 weeks and those with hypertension are at the greatest risk of nephrotoxicity and would benefit from the addition of mannitol.

Allopurinol as Adjuvant Therapy in Poorly Responsive or Treatment Refractory Schizophrenia

Objective: To review the available literature evaluating the effectiveness of allopurinol for poorly responsive or treatment refractory schizophrenia. Data Sources: Searches of MEDLINE (1966–October 2006), the Cochrane Library, and International Pharmaceutical Abstracts (1970–October 2006) were conducted using the terms allopurinol and schizophrenia. Limits were set to select studies conducted in humans. Study Selection and Data Extraction: All articles identified from the data sources were evaluated. All case reports or clinical trials located were included in the review. Data Synthesis: Dopamine has been implicated for many years in the pathophysiology of schizophrenia, and the typical antipsychotics, via blockade of dopaminergic neurotransmission, have provided relief for patients with positive symptoms. However, because dopamine blockade does not relieve all symptoms of schizophrenia, it is now evident that many neurotransmitters may be involved in the pathogenesis of schizophrenia. Therefore, atypical antipsychotics, which target multiple neurotransmitters, have emerged as first-line therapies. An evolving body of evidence also supports a purinergic hypothesis for schizophrenia. Increased adenosinergic transmission is thought to reduce the affinity of dopamine agonists for dopamine receptors. Allopurinol, a xanthine oxidase inhibitor, may increase circulating pools of adenosine and may ultimately have antipsychotic and anxiolytic effects. Growing evidence for use of allopurinol as adjunctive therapy has been reported in both case reports and small clinical trials. Conclusions: Clinical trials show that adjuvant allopurinol may provide benefit to patients who are poorly responsive to current treatments for schizophrenia. Allopurinol is well tolerated by most patients. However, larger, randomized clinical trials need to be performed to determine the magnitude of this benefit, whether allopurinol should be routinely used as adjuvant therapy to antipsychotics, and which patient population is most likely to benefit from allopurinol use. For patients with limited options, allopurinol in doses of 300 mg once or twice daily may improve psychotic symptoms, especially refractory positive symptoms.

Denosumab for the Management of Hypercalcemia of Malignancy in Patients With Multiple Myeloma and Renal Dysfunction

Hypercalcemia and renal dysfunction are common sequelae associated with multiple myeloma and portend poor outcomes. Resistance to bisphosphonates and uncertainty regarding dosing in the setting of renal dysfunction could limit the utility of these agents. Weight-based denosumab dosing might be a reasonable alternative for patients with multiple myeloma in the setting of recalcitrant hypercalcemia and renal dysfunction; such a strategy might minimize the risk of profound and prolonged hypocalcemia. The serum calcium levels should be routinely monitored in all patients receiving denosumab for hypercalcemia of malignancy.

Management of menorrhagia associated with chemotherapy-induced thrombocytopenia in women with hematologic malignancy.

Abnormal uterine bleeding in women with a blood dyscrasia, such as leukemia, or who experience thrombocytopenia secondary to myelosuppressive chemotherapy is a clinical condition associated with significant morbidity. Consequently, effective management is necessary to prevent adverse outcomes. Prevention of menorrhagia, defined as heavy regular menstrual cycles with more than 80 ml of blood loss/cycle or a cycle duration longer than 7 days, in this patient population is the goal of therapy. Gonadotropin‐releasing hormone analogs (e.g., leuprolide) are promising therapies that have been shown to decrease vaginal bleeding during periods of thrombocytopenia and to have minimal adverse effects other than those associated with gonadal inhibition. In patients who experience menorrhagia despite preventive therapies, or in patients who have thrombocytopenia and menorrhagia at diagnosis, treatment is indicated. For these women, treatment options may include platelet transfusions, antifibrinolytic therapy (e.g., tranexamic acid), continuous high‐dose oral contraceptives, cyclic progestins, or other therapies for more refractory patients such as danazol, desmopressin, and recombinant factor VIIa. Hormonal therapies are often the mainstay of therapy in women with menorrhagia secondary to thrombocytopenia, but data for these agents are sparse. The most robust data for the treatment of menorrhagia are for tranexamic acid. Most women receiving tranexamic acid in randomized trials experienced meaningful reductions in menstrual bleeding, and this translated into improved quality of life; however, these trials were not performed in patients with cancer. Further clinical trials are warranted to evaluate both preventive and therapeutic agents for menorrhagia in premenopausal women with cancer who are receiving myelosuppressive chemotherapy.

Successful Use of Intrathecal Carboxypeptidase G2 for Intrathecal Methotrexate Overdose: A Case Study and Review of the Literature

Clinical Practice Points Intrathecal (IT) methotrexate (MTX) overdose is a medical emergency. Available interventions include cerebrospinal fluid (CSF) drainage and ventriculolumbar perfusion, which are limited by timing and/or availability. Carboxypeptidase G2 hydrolyzes MTX into inactive metabolites and represents a promising agent for the treatment of IT MTX overdose. We set out to compile and review available animal data and human case reports using carboxypeptidase G2 by the IT route in the setting of IT MTX overdose. A review of the literature reveals promising results with IT carboxypeptidase G2, including a nearly 2-log reduction in CSF MTX levels and excellent neurologic outcomes in patients receiving 155 to 600 mg of IT MTX. Additionally, we have included a new report of a 66-year-old woman with primary CNS lymphoma who inadvertently received a 150-mg dose of IT MTX. Immediate treatment consisted of CSF drainage and intravenous dexamethasone and leucovorin. She subsequently received 2000 U of IT carboxypeptidase G2 11 hours after the overdose along with continued supportive care. CSF MTX levels promptly decreased and the patient was discharged with no residual neurologic deficits. IT carboxypeptidase G2 leads to rapid reduction of CSF MTX levels in patients with IT MTX overdose and is associated with excellent neurologic outcomes. Further studies are needed to clarify the role of this intervention in the context of existing drainage techniques.

A Study of layered learning in oncology

Objective. To explore use of pharmacy learners as a means to expand pharmacy services in a layered learning practice model (LLPM), to examine whether an LLPM environment precludes achievement of knowledge-based learning objectives, and to explore learner perception of the experience. Design. An acute care oncology pharmacy practice experience was redesigned to support the LLPM. Specifically, the redesign focused on micro discussion, standardized feedback (eg, rubrics), and cooperative learning to enhance educational gain through performing clinical activities. Assessment. Posttest scores evaluating knowledge-based learning objectives increased in mean percentage compared to pretest values. Learners viewed the newly designed practice experience positively with respect to perceived knowledge attainment, improved clinical time management skills, contributions to patient care, and development of clinical and self-management skills. A fifth theme among students, comfort with learning, was also noted. Conclusion. Layered learning in an oncology practice experience was well-received by pharmacy learners. Data suggest a practice experience in the LLPM environment does not preclude achieving knowledge-based learning objectives and supports further studies of the LLPM.

Neutropenia-Associated Outcomes in Adults with Acute Myeloid Leukemia Receiving Cytarabine Consolidation Chemotherapy with or without Granulocyte Colony-Stimulating Factor

To determine whether granulocyte colony‐stimulating factor (G‐CSF) prophylaxis after consolidation with high‐ or intermediate‐dose cytarabine (H/IDAC) for treatment of acute myeloid leukemia (AML) reduces the frequency of neutropenia‐associated complications.

Impact of a new assay for measuring serum creatinine levels on carboplatin dosing

PURPOSE The impact of converting to the isotope dilution mass spectrometry (IDMS)-traceable serum creatinine (SCr) assay for determining the calculated and delivered dose of carboplatin was studied. METHODS A single-center, retrospective, observational chart review of adult patients who received a dose of carboplatin within one month before and after implementation of the IDMS-traceable SCr assay was conducted using information available in medical records and chemotherapy orders. Patient-specific data were collected and used to calculate a carboplatin dose before and after the SCr assay change using the Cockcroft-Gault equation, with the Calvert et al. formula used to calculate the carboplatin dose based on the target area under the concentration-time curve in the chemotherapy order forms. The primary outcome was the difference in calculated carboplatin dose, assessed as the percent difference between the mean carboplatin dose before and after the assay change. Results Fifty-six patients were included in the data analysis. The mean calculated carboplatin dose was 9.6% greater when the IDMS-traceable assay was used compared with the previous institutional standard enzymatic assay. This difference was statistically significant (p < 0.005). Nearly 50% of patients received a dose of carboplatin that was increased by >10% compared with the dose received before conversion to the IDMS-traceable assay for SCr measurement. CONCLUSION After implementation of the IDMS-traceable assay, the mean calculated carboplatin dose was 9.6% larger than before implementation, and nearly 50% of patients received a dose of carboplatin that was increased by greater than 10% compared with the dose received before the assay change.

Vemurafenib-associated pancreatitis: case report.

Vemurafenib is a novel BRAF kinase inhibitor indicated in metastatic melanoma patients with V600E mutation. We report the first case of vemurafenib‐associated pancreatitis. Two weeks after initiation of vemurafenib, a patient presented to the emergency department with severe epigastric pain and a serum lipase of 1544 units/L. Drug‐induced pancreatitis was diagnosed on exclusion of all other potential causes. Vemurafenib was rechallenged at half the daily dose and the patient subsequently developed exacerbated symptoms of pancreatitis after two doses. The strong temporal relationship between drug exposure and toxicity, along with the positive results from a rechallenge study, strongly support a conclusion of causality. To our knowledge, this is the first report of vemurafenib‐induced pancreatitis.