Jamie N. Brown

Modafinil for the Treatment of Multiple Sclerosis–Related Fatigue

Objective: To review the efficacy and safety of off-label use of modafinil in the treatment of multiple sclerosis (MS)–related fatigue. Data Sources: Literature was accessed via MEDLINE (1966–January 2010) and International Pharmaceutical Abstracts (1960–2010), using the medical subject heading terms modafinil, multiple sclerosis, and fatigue. Study Selection and Data Extraction: All English-language, peer reviewed publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 3 open-label trials, 1 single-blind trial, and 2 randomized placebo-controlled trials. Data Synthesis: Fatigue symptoms, assessed by a variety of self-reported symptom scales, improved in each of the uncontrolled studies reviewed when participants with MS received modafinil 200 mg or less daily for up to 12 weeks. These benefits were not maintained, however, in one uncontrolled study when modafinil was increased to 400 mg daily. Of the 2 randomized, controlled trials, 1 study found that modafinil 200 mg once daily resulted in a reduction in fatigue symptoms measured by the Fatigue Severity Scale at 8 weeks. The other study found no difference in the reduction of fatigue symptoms, measured by the Modified Fatigue Impact Scale at 5 weeks, between the placebo group and patients who received modafinil 100–200 mg twice daily. The most common adverse reactions associated with modafinil use in all studies included gastrointestinal and central nervous system effects. Conclusions: Based on the available data, use of modafinil for the treatment of MS-related fatigue has demonstrated benefit in all uncontrolled studies but has conflicting results from 2 controlled studies. Modafinil is a reasonable therapeutic option in this patient population, although larger, long-term, randomized controlled studies are necessary to further elucidate the appropriate dose of modafinil, its effects on MS-related fatigue, and adverse effects associated with its use.

Class Effect of Erythropoietin Therapy on Hemoglobin A1c in a Patient with Diabetes Mellitus and Chronic Kidney Disease Not Undergoing Hemodialysis

In patients with diabetes mellitus, hemoglobin A1c (A1C) is commonly interpreted as a measure of long‐term glycemic control, reflecting a mean glucose level over the previous 2–3 months. Although some reports suggest that treatment with recombinant erythropoietin may affect A1C values in patients undergoing hemodialysis, we know of no evidence to support this interaction in patients with chronic renal insufficiency who are not undergoing hemodialysis. In addition, we know of no evidence specific to the treatment effect of epoetin alfa and/or darbepoetin alfa on A1C. We describe a 64‐year‐old man with diabetes, chronic kidney disease, and anemia who was treated consecutively with epoetin alfa and darbepoetin alfa and experienced a temporal reduction in A1C level to a nadir of 4.4%. Throughout approximately 3 years of treatment with these erythropoietin analogs, the patients total daily dose of insulin was reduced in response to his decreasing A1C values, despite elevated blood glucose levels and the absence of patient‐reported hypoglycemic events. Five months after the patients erythropoietin therapy was discontinued, his A1C value increased to 8.8%, leading us to conclude that management of the insulin dose may have been different without the falsely lowered A1C levels. Use of the Naranjo adverse drug reaction probability scale indicated a probable association between this patients reduced A1C levels and erythropoietin therapy. This case demonstrates that both epoetin alfa and darbepoetin alfa may artificially lower A1C levels in a patient with diabetes who is not undergoing dialysis, and therefore this finding can be interpreted as a class effect. Clinicians should be aware of factors that affect A1C values, specifically erythrocyte life span. In patients receiving erythropoietin, therapeutic decisions should be based on A1C and glucose levels, as well as patient symptoms suggestive of hypo‐ or hyperglycemia, to avoid therapy changes that could complicate disease management.

The emerging role of tacrolimus in myasthenia gravis.

Objective: To describe and evaluate the available evidence assessing the role of tacrolimus in the management of patients with myasthenia gravis (MG). Data sources: A literature search of MEDLINE (1946 to September 2014) and EMBASE (1947 to September 2014) was performed using the terms ‘tacrolimus’ and ‘myasthenia gravis’. Citations of retrieved articles were examined for relevance. Study selection and data extraction: The search was limited to prospective clinical trials focused on clinical outcomes in patients with generalized MG. Case reports, retrospective evaluations and non-English articles were excluded. Data synthesis: A total of 12 studies met inclusion criteria, of which seven articles evaluated tacrolimus in steroid-dependent patients and two examined the utility of tacrolimus in patients failing corticosteroids and cyclosporine. Other studies evaluated early initiation of tacrolimus after thymectomy, effectiveness of tacrolimus in de novo MG and the effectiveness of tacrolimus post-thymectomy in thymoma patients versus nonthymoma. A total of eight trials showed statistically significant improvements in quantitative MG score (QMGS) and postintervention status criteria – Myasthenia Gravis Foundation of America (PSC-MGFA). Of the trials examining steroid reduction with tacrolimus, two reported high rates of complete withdrawal; however, the most robust trial was unable to detect a difference in mean steroid dose. Long-term effects of tacrolimus (up to 5 years) were assessed in eight trials, which consistently showed positive effects on QMGS or reduction in adjunct therapies. Conclusions: There is limited yet promising information to suggest a beneficial role for tacrolimus in reducing QMGS and corticosteroid burden in patients with refractory symptoms or new-onset MG. Long-term use appears to be safe in this population.

Clomiphene for the treatment of male infertility.

Male infertility is a relatively common condition caused by low sperm production, immobile sperm, or blockages that prevent the delivery of sperm. This condition can be caused by a variety of illnesses, injuries, chronic health problems, lifestyle choices, other factors, or idiopathic, in which abnormal semen parameters occur without an identifiable cause. Medical management traditionally focuses on correcting endocrine abnormalities related to hormone deficiencies. Clomiphene citrate is an antiestrogen thought to increase sperm parameters in males attempting to conceive. The objective of this review was to evaluate the efficacy and safety of clomiphene citrate in the treatment of male patients with infertility. A literature search of MEDLINE (1966-June 2012) and EMBASE (1980-June 2012) was conducted using the medical terms clomiphene and male infertility and 9 clinical studies were identified. Overall, only 1 study detected a statistically significant benefit on the pregnancy rate in the clomiphene group; however, the majority of the studies demonstrated a statistically significant increase in sperm concentrations. At doses used to treat male infertility, clomiphene was well tolerated with no identified serious adverse effects. Based on the reviewed studies there is insufficient evidence to indicate that clomiphene is effective for the treatment of male infertility.

Use of gabapentin in patients experiencing hot flashes.

Hot flashes occur frequently in menopausal women and in women with breast cancer, diminishing their quality of life. A report from the Womens Health Initiative published in 2002 raised concerns about the long‐term safety of estrogen therapy. As a result, nonhormonal alternatives have emerged as preferred treatments. Gabapentin is an anticonvulsant that the United States Food and Drug Administration approved as an adjunct therapy for partial seizures and postherpetic neuralgia. Somnolence, dizziness, ataxia, fatigue, nystagmus, and peripheral edema are adverse effects commonly associated with gabapentin in the treatment of epilepsy and postherpetic neuralgia. The North American Menopause Society and the American College of Obstetricians and Gynecologists recommend the use of gabapentin as an option for managing hot flashes in women who are unwilling to take estrogen‐containing supplements. To evaluate the efficacy and safety of gabapentin for the treatment of hot flashes in women with menopause and/or breast cancer, we performed a search of the MEDLINE database (1966‐March 2008) and International Pharmaceutical Abstracts, as well as manually searching reference articles for relevant articles and abstracts; 10 clinical studies were identified. Although the studies were few, all showed gabapentin to be safe and effective in the treatment of hot flashes. At doses used to control hot flashes, gabapentin was well tolerated, with drowsiness as its most reported adverse effect. Gabapentin can be considered effective in the treatment of hot flashes and should be considered a reasonable alternative when estrogen therapy is not desired.

Phosphodiesterase Type 5 Inhibitors as Adjunctive Therapy in the Management of Systolic Heart Failure

Objective: To review the efficacy and safety of phosphodiesterase-5 (PDE5) inhibitors in the treatment of patients with chronic systolic heart failure (HF). Data Sources: Literature was retrieved through MEDLINE (1966-September 2011) and EMBASE (1980-September 2011), using the medical subject heading terms heart failure and phosphodiesterase-5 Inhibitors, sildenafil, tadalafil, and vardenafil. Focus was placed on multidose trials of patients with systolic HF, because of these trials’ greater strength of clinical evidence. Study Selection and Data Extraction: All English-language, peer-reviewed publications were analyzed for relevance. Studies appropriate to the objective were evaluated, including 4 multidose trials investigating the effect of sildenafil on cardiovascular function. Data Synthesis: In patients with New York Heart Association class II or III HF, treatment with sildenafil was associated with improvements in cardiac index, right ventricular ejection fraction, and other markers of cardiovascular function, as well as reduced pulmonary arterial pressure. Study durations ranged from 4 weeks to 1 year, and the studies used varying doses of sildenafil, ranging from 75 to 225 mg/day, in divided doses. The most common adverse effects associated with sildenafil therapy were headache and flushing. Conclusions: Based on current studies, sildenafil appears to be well tolerated and can improve markers of cardiovascular and pulmonary function in patients with HF. PDE5 inhibitors may be a therapeutic option for patients who cannot tolerate standard therapy for HF or who remain symptomatic with standard therapy. Larger long-term trials are necessary to better understand the role of PDE5 inhibitors in HF.

Use of Risperidone as Augmentation Treatment for Major Depressive Disorder

Objective To review the efficacy and safety of risperidone for augmentation treatment In patients with major depressive disorder who fail to achieve adequate response to antidepressant monotherapy. Data Sources: A search of MEDLINE (1966-August 2010) and EMBASE (1980-August 2010) was conducted, using the terms risperidone and major depressive disorder. In addition, a manual search of the references cited in each publication identified from the database search was conducted to identify relevant articles. Study Selection And Data Extraction: All English-language, peer-reviewed publications identified from the data sources were evaluated. Four clinical trials and 1 subanalysis of a clinical trial were included for analysis. Data Synthesis: Risperidone is an atypical antipsychotic that displays antidepressant properties due to its activity at various serotonergic and dopaminergic receptors. Studies have demonstrated that risperidone augmentation may be effective and safe when used at low doses. Although several of the studies identified had limited sample sizes, all studies demonstrated improvement on various standardized depressive symptom assessment scales. Study durations ranged from 4 to 24 weeks, with doses ranging from 0.25 to 2 mg/day. The most common adverse effects associated with risperidone therapy were headache, dry mouth, and increased appetite. Conclusions: Clinical evidence suggests that the use of risperidone as adjunctive therapy for treatment-resistant depression may improve rates of response and remission, but long-term effectiveness and safety cannot be determined at this time. Therefore, an adequate trial of first-line agents from different classes and/or a combination of agents from different classes would be recommended prior to initiation of risperidone. If the decision is made to start risperidone, health-care providers should ensure that patients are educated regarding the potential benefits and adverse effects before initiating risperidone.

Medication adherence in combat veterans with traumatic brain injury

PURPOSE Medication adherence in combat veterans with traumatic brain injury (TBI) was evaluated. METHODS Patients with a diagnosis of TBI were identified by a computer search of veterans enrolled in the Operation Enduring Freedom/Operation Iraqi Freedom or TBI/polytrauma clinics at Durham Veterans Affairs Medical Center (VAMC) between September 15, 2007, and September 15, 2008. Patients were included if they were at least 18 years old, received medical care and medications at the VAMC for at least 12 continuous months, and were taking at least one maintenance medication. A randomly selected age-matched comparator group without TBI was obtained through a computer-generated convenience sample. A composite adherence score for each patient was calculated using the medication possession ratio (MPR). The most commonly prescribed medications and indicators of increased adherence among the TBI group were also identified. RESULTS The composite MPR did not significantly differ between groups. The most commonly prescribed medications were selective serotonin-reuptake inhibitors and serotonin-norepinephrine-reuptake inhibitors and other antidepressants; however, these classes were associated with the lowest adherence rates. Factors associated with increased adherence included taking more than five maintenance medications (78%), living with a spouse or significant other (77%), owning a memory-assistance device (74%), and comorbid diagnosis of posttraumatic stress disorder (PTSD) (74%). CONCLUSION Medication adherence rates were similar among combat veterans with a diagnosis of TBI and an age-matched comparator group. Factors associated with increased adherence included taking more than five maintenance medications, living with a spouse or significant other, owning a memory-assistance device, and a comorbid diagnosis of PTSD.

The effect of angiotensin II receptor blockers on hyperuricemia.

The objective of this review was to explore the efficacy of angiotensin II receptor blockers (ARBs) for the treatment of hyperuricemia in individuals diagnosed with gout or hyperuricemia defined as ⩾7 mg/dl at baseline. A literature search of MEDLINE (1946 to June 2015) and EMBASE (1947 to June 2015) was conducted. The following search terms were used: ‘uric acid’, ‘urate transporter’, ‘gout’, ‘angiotensin II receptor blockers’, ‘hyperuricemia’ and the names for individual ARBs, as well as any combinations of these terms. Studies were excluded that did not explore fractional excretion or serum uric acid as an endpoint, if patients did not have a diagnosis of gout or hyperuricemia at baseline, or if they were non-English language. A total of eight studies met the inclusion criteria. Of the eight studies identified, six explored ARB monotherapy and two studies investigated ARBs as adjunct therapy. Losartan demonstrated statistically significant reductions in serum uric acid levels or increases in fractional excretion of uric acid in all studies, whereas no other ARB reached statistical benefit. The effect of ARBs on the occurrence of gout attacks or other clinical outcomes were not represented. Four studies evaluated safety effects of these agents indicating abnormalities such as minor changes in lab values. In conclusion, losartan is the only ARB that has consistently demonstrated a significant reduction in serum uric acid levels, although the significance of impacting clinical outcomes remains unknown. Losartan appears to be a safe and efficacious agent to lower serum uric acid levels in patients with hyperuricemia.

Inhaler misuse in an older adult population.

OBJECTIVE To determine the prevalence of inhaler misuse in an older adult population. DESIGN Prospective observational study. SETTING Two primary care outpatient clinics in a Veterans Affairs Medical Center in North Carolina. PARTICIPANTS Male veterans 65 years of age and older (N = 24) prescribed a pressurized metered dose inhaler (pMDI) or a dry powder inhaler (DPI). MEASUREMENTS Inhaler technique was evaluated using placebo inhaler devices and a standardized technique assessment form that included critical steps. Potential risk factors for misuse were obtained from the medical record, and the time for technique evaluation was collected. MAIN RESULTS Study participants yielded 44 unique device observations. Patients were male with an average age of 82 years. All patients made at least one error, with a mean error rate of 2.5 errors/patient/inhaler, while 20 of 24 (83%) patients made at least one critical error with a mean error rate of 1.2 critical errors/patient/inhaler. Assessment of inhaler technique required 2.3 minutes/inhaler. Critical errors were made during 15 of 19 (79%) pMDI observations and 22 of 25 (88%) DPI observations. Patients with multiple inhalers or a history of stroke committed errors more often, although no risk factors demonstrated meaningful differences in error rates. CONCLUSIONS Inhaler misuse in older adults is common, including committing critical errors that have been shown to reduce drug delivery. The time necessary for technique evaluation is relatively small. The high rate of misuse observed should serve as motivation for increased vigilance, individualized technique education, and routine re-assessment in the highly heterogeneous older adult population.