Mark A Gales

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.

Angiotensin-Converting Enzyme Inhibitors and Angiotensin Receptor Blockers for the Prevention of Migraines

Objective: To evaluate the literature examining the efficacy of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for migraine prophylaxis. Data Sources: MEDLINE (1966–October 2009) and International Pharmaceutical Abstracts were searched using the terms migraine, headache, renina-ngiotensin system, angiotensin-converting enzyme inhibitor, angiotensin receptor blocker, aldosterone antagonist, and the individual agents in these classes. Study Selection and Data Extraction: English-language human clinical trials, case reports, and systematic reviews were evaluated for efficacy and safety data. The references of reviewed articles were examined to identify additional sources. Data Synthesis: Preventative trials evaluating ACE inhibitors consist of a case series, 2 open-label trials, and a placebo-controlled trial. Lisinopril reduced headache hours 20%, headache days 17%, and migraine days 21% versus placebo In the controlled trial (p < 0.06). Clinically significant (>50%) reductions in migraine measures were more common (52–66%) in open-label ACE inhibitor trials than in the controlled (32–36%) trial. Preventive trials evaluating ARBs consist of a meta-analysis, an open-label trial, and 2 placebo-controlled trials. Candesartan reduced headache hours 31%, headache days 26%, and migraine days 28% versus placebo in the first controlled trial (p ≤ 0.001). Telmisartan did not reduce any prespecified primary or secondary outcome measures in the second controlled trial. Clinically significant reductions (>50%) in migraine measures were more common (54–88%) in open-label ARB trials than in the controlled (26–38%) trials. A prescription database review found that ACE inhibitor or ARB therapy halved the use of abortive migraine agents compared to diuretic therapy. Conclusions: ACE inhibitors and ARBs have migraine prophylaxis activity similar to that of some currently utilized agents. Low-dose lisinopril or candesartan may be reasonable second- or third-line agents, particularly in patients with other indications for ACE inhibitor or ARB therapy. Further controlled clinical trials are needed to delineate the role of these agents in migraine prevention.

Oral Antihypertensives for Hypertensive Urgencies

OBJECTIVE: To review the data describing the use of oral antihypertensive agents in the treatment of hypertensive urgencies (HU). DATA SOURCES: A MEDLINE search of the English-language literature and fan searches of papers evaluating oral antihypertensives in HUs and emergencies were conducted. STUDY SELECTION: Controlled and uncontrolled studies in humans are reviewed. Emphasis was placed on recent trials evaluating individual agents and comparative trials. DATA SYNTHESIS: Comparative trials have demonstrated that four currently available oral agents can lower blood pressure rapidly and predictably. Nifedipine, the most extensively studied, and clonidine have served traditionally as the oral agents of choice for the treatment of HUs. All the agents can lower blood pressure effectively within the first few hours after dosing, but their use also has been associated with adverse effects. Nifedipine and captopril are the two agents with the most rapid onset, within 0.5–1 hour, and may treat hypertensive emergencies as well as urgencies. Clonidine and labetalol have maximal blood pressure lowering effects at 2–4 hours. CONCLUSIONS: Captopril, clonidine, labetalol, and nifedipine are all effective agents for the treatment of HUs. Agent selection should be based on the perceived need for urgent blood pressure control, the cause of HU, and concomitant conditions. A definite benefit from acute blood pressure lowering in HUs has yet to be demonstrated, especially in asymptomatic patients. More controlled trials with less aggressive dosing regimens and placebo controls need to be performed to assess the most appropriate treatments for HUs with the fewest adverse effects.

Sorbitol Compared with Xylitol in Prevention of Dental Caries

OBJECTIVE: To summarize published data on the comparative efficacy of sorbitol and xylitol for prevention of dental caries. DATA SOURCES: Published double-blind comparative trials, using sorbitol and xylitol products, identified by MEDLINE (January 1966–December 1998) and International Pharmaceutical Abstracts (January 1970–December 1998) searches. DATA SYNTHESIS: Clinical trials generally used sorbitol and xylitol gums, which patients chewed three to five times daily for 20–40 months. Xylitol was superior to sorbitol in two longer, secondary dentition trials (30–63% reductions), but not in two primary dentition trials. CONCLUSIONS: The data suggest that xylitol-containing gums may provide superior efficacy in reducing caries rates in high-risk populations.

Pyridostigmine in the Treatment of Orthostatic Intolerance

Objective: To review the efficacy of pyridostigmine bromide for the treatment of orthostatic intolerance. Data Sources: MEDLINE and International Pharmaceutical Abstracts were searched (1966–December 2006) using the terms pyridostigmine, acetylcholinesterase inhibitor, orthostatic intolerance, orthostatic hypotension, neurogenic orthostatic hypotension, postural tachycardia syndrome, tachycardia, and orthostatic tachycardia. Study Selection and Data Extraction: Pertinent English-language human clinical trials, case reports, and background material were evaluated for safety and efficacy data. The references of reviewed articles were reviewed and used to identify additional sources. Data Synthesis: Pyridostigmine bromide has been associated with improved baroreceptor sensitivity and presents a novel approach to treatment of orthostatic intolerance. Four single-dose trials and a follow-up survey encompassing a total of 106 patients were identified. One open-label and one placebo-controlled single-dose trial in patients with neurogenic orthostatic hypotension (NOH) found statistically significant improvement in standing diastolic blood pressures (DBP). Absolute improvements in standing DBP were 3.7 and 6.4 mm Hg in the open-label and controlled trials, respectively. Long-term data consist of a single survey of patients receiving open-label pyridostigmine bromide. Twenty-nine percent of patients who initiated maintenance pyridostigmine bromide discontinued therapy. Concomitant NOH medications were taken by 75% of patients, and 85% of patients reported receiving benefit from pyridostigmine bromide. When evaluated for postural tachycardia syndrome, pyridostigmine bromide significantly reduced standing heart rate (10%). Pyridostigmine bromide significantly reduced symptom scores when compared with baseline but not placebo. The majority of patients included in these trials did not have supine hypertension. Conclusions: Single doses of pyridostigmine bromide produced modest but statistically significant improvements in hemodynamic measurements. At this time, long-term data are insufficient to support recommending the routine use of pyridostigmine bromide for treatment of orthostatic intolerance.

Phosphodiesterase-5 Inhibitors for Lower Urinary Tract Symptoms in Men

Objective: To review the efficacy of phosphodiesterase-5 (PDE-5) inhibitors for the treatment of lower urinary tract symptoms in men. Data Sources: MEDLINE and International Pharmaceutical Abstracts were searched (1970–August 2007) using the terms phosphodiesterase inhibitor, sildenafil, vardenafil, tadalafil, tower urinary tract symptoms, and benign prostatic hypertrophy. Study Selection and Data Extraction: English-language clinical trials, case reports, and background material were evaluated for safety and efficacy data. References of reviewed articles were examined and used to identify additional sources. Data Synthesis: Erectile dysfunction (ED) and lower urinary tract symptoms have numerous shared risk factors and are common in aging men. PDE-5 inhibitors may relax urinary tract smooth muscle tissue, which has led to interest in their utility for lower urinary tract symptoms. Six 12 week clinical trials were identified. Three uncontrolled trials (N = 158) examined the effects of on-demand sildenafil ED dosing on lower urinary tract symptoms. The 2 largest trials found that, the greater the ED response, the larger the reduction in lower urinary tract symptoms. A single prospective placebo-controlled trial (N = 369) studied sildenafil 100 mg daily in men with ED and lower urinary tract symptoms. Lower urinary tract symptoms improved significantly in the sildenafil group; patents with the worst lower urinary tract symptoms experienced the greatest benefits. An open-label trial (N = 62) compared daily sildenafil 25 mg, alfuzosin 10 mg, or sildenafil 25 mg plus alfuzosin 10 mg on ED and tower urinary tract symptoms. Combination therapy resulted in greater improvements in ED and lower urinary tract symptoms and urinary flow than did either drug alone. The effects of daily tadalafil 20 mg were studied in 281 men with lower urinary tract symptoms independent of ED. Tadalafil produced statistically significant but clinically modest improvements in tower urinary tract symptoms when compared with placebo. Conclusions: PDE-5 inhibitors consistently produced modest reductions in lower urinary tract symptoms. Further studies are needed to fully elucidate the efficacy, cost effectiveness, safety, and appropriate place in therapy of PDE-5 inhibitors. At this time, data are insufficient to routinely recommend chronic use of PDE-5 Inhibitors for tower urinary tract symptoms in men.

Acetaminophen for Patent Ductus Arteriosus

Objective: To evaluate the literature describing acetaminophen use in treatment of patent ductus arteriosus (PDA). Data Sources: Searches were conducted in MEDLINE with full text (EBSCOhost; 1946 to September 2014) using the search terms acetaminophen, paracetamol, and patent ductus arteriosus. The references of identified articles were reviewed to identify other relevant articles. Study Selection and Data Extraction: Human clinical trials and case reports limited to the English language were reviewed. In all, 12 case reports and 2 randomized, controlled clinical trials explored the use of acetaminophen in treating PDA. Data Synthesis: The case reports described the use of oral or intravenous acetaminophen in patients with contraindications to or who had previously failed nonsteroidal anti-inflammatory drug therapy for PDA. More than 76% of patients achieved successful PDA closure in reported cases. The clinical trials compared the efficacy of oral acetaminophen versus oral ibuprofen in preterm infants. Acetaminophen was noninferior to ibuprofen, with closure rates from 72.5% to 81.2%. The acetaminophen dose used in most case series and trials was 15 mg/kg dose every 6 hours for 3 days. Acetaminophen therapy was well tolerated, with only a few incidents of elevated liver enzymes being reported. Conclusion: Oral acetaminophen is an alternative to PDA therapy in preterm infants when indomethacin/ibuprofen is not effective or is contraindicated, and it may be considered before surgical ligation.

Octreotide or vasopressin for bleeding esophageal varices

Acute bleeding due to esophageal varices continues to be a life-threatening complication of liver disease. Despite the availability of improved therapy, mortality continues to be high. Octreotide has been shown to be at least as effective as vasopressin in the treatment of bleeding varices, with fewer and less severe systemic adverse effects. In addition, octreotide has also been consistently associated with a decreased need for transfusions. Octreotide has been used safely in patients without serious cardiovascular disease when administered as a continuous intravenous infusion of 25 micrograms/h for 24 hours with or without an initial 100-micrograms bolus dose. Since these trials have used small numbers of patients, the ability to detect small but clinically important differences has been limited. Additional controlled trials comparing octreotide with the combination of vasopressin and nitroglycerin are needed to more clearly determine the efficacy and cost-effectiveness of therapy. Furthermore, the optimal dosage, duration, and route of administration of octreotide in the treatment of bleeding esophageal varices has yet to be determined.

Granulocyte-Colony Stimulating Factor for Sulfasalazine-Induced Agranulocytosis

OBJECTIVE: To report a case of sulfasalazine-induced agranulocytosis that was successfully treated with granulocyte-colony stimulating factor (G-CSF). CASE SUMMARY: An 82-year-old woman developed agranulocytosis within two months of initiating sulfasalazine therapy. She was hospitalized, empiric antibiotics and antifungal agents were prescribed, and sulfasalazine therapy was stopped. The patient received G-CSF 600 μg/d subcutaneously for six consecutive days, starting on hospital day 5. Agranulocytosis resolved on day 5 and leukopenia on day 6 of G-CSF therapy. No adverse reactions were attributed to administration of this agent and the patient was discharged on hospital day 13. DISCUSSION: Numerous agents, including sulfasalazine, have been associated with agranulocytosis. Agranulocytic patients frequently experience life-threatening bacterial and fungal infections. Administration of colony stimulating factors may reduce the duration of agranulocytosis and incidence of life-threatening infections. CONCLUSIONS: G-CSF administration appears to have decreased the duration of this elderly patients agranulocytosis and hospitalization.

Is Rectally Administered Cisapride an Effective Prokinetic Agent

OBJECTIVE: To summarize the published data on the efficacy of rectally administered cisapride. DATA SOURCES: Published double-blind, placebo-controlled trials on rectally administered cisapride identified by MEDLINE (January 1966–December 1998) and International Pharmaceutical Abstracts (January 1970–December 1998) searches. DATA SYNTHESIS: Cisapride is an oral prokinetic agent that increases lower esophageal sphincter tone, accelerates gastric emptying, and increases small-bowel motility. Clinical trials of rectal cisapride have used both single- and multiple-dosing regimens. Typically, patients received one or two 30-mg suppositories (provided by the manufacturer). Rectal cisapride was effective in enhancing gastric emptying of solid or semisolid meals in healthy patients or patients with chronic gastric emptying disorders. Rectal cisapride was not effective in antagonizing the gastrointestinal effects of narcotic analgesics or promoting the return of small-bowel activity in adults with postoperative ileus. Mixed results were seen when rectal cisapride was used to promote enteral feedings in patients with persistent ileus. CONCLUSIONS: The use of rectal cisapride cannot be recommended at this time. Rectal cisapride was effective only in patients who could have otherwise taken either cisapride tablets or suspension but it was not effective in patients who are physically unable to swallow or restricted from ingesting anything orally following surgical procedures. Considering the varied patient populations and evaluation methods used in these studies, the lack of a commercially available cisapride suppository, and absence of studies involving extemporaneously prepared cisapride suppositories, the use of suppositories should be limited to investigational trials.