Oral Prednisolone for Acute Gout
Source: Janssens H, et al. Lancet. 2008;371:1854-1860.
There have been no major therapeutic steps added for the management of acute gouty arthritis (AGA) for over 30 years. Although extensive experience with NSAIDs and colchicine attests to their efficacy, recent recognition of important toxicities with both has stimulated interest in alternative interventions.
Corticosteroids (CTS)—oral, parenteral, or intra-articular—have shown efficacy in AGA. However, the comparative efficacy of CTS vs NSAIDs or colchicines is unknown, and was the subject of investigation by Nanssens, et al.
In a randomized controlled trial, 120 AGA subjects (confirmed by identification of urate crystals) were assigned to either 5 days of naproxen 500 mg bid (NAP) or prednisolone 35 mg qd (PRED); to make blinding secure, a double-dummy design, wherein PRED recipients received a matching placebo to provide bid dosing for both groups, was employed.
Four days into treatment, the results for pain reduction were essentially equivalent for PRED and NAP. There were no major adverse effects reported by either treatment group. Prednisolone 35 mg/d may be a reasonable alternative therapy for gout, especially when concerns about NSAID or colchicine toxicity are present
Adding Aliskiren to Losartan for Diabetic Nephropathy
Source: Parving HH, et al. N Engl J Med. 2008;358:2433-2446.
Treatment with angiotensin receptor blockers (ARBs) reduces levels of proteinuria in diabetics, and forestalls endstage renal disease. Unfortunately, despite full therapeutic doses of either ARB or angiotensin converting enzyme inhibitors (ACEi), not all patients enjoy equal success in reducing renal protein losses. Combination therapies for proteinuria, such as ACEi + ARB or ACEi + spironolactone, offer promise in this regard, but the combination of the direct renin inhibitor aliskiren (ALIS) with ARB has not been previously investigated.
A population of type 2 diabetics with nephropathy (24 hr urine protein > 300 mg) was randomized to stabilization on losartan 100 mg/d to either aliskiren titrated to 300 mg/d or placebo. Patients with nephrotic syndrome or severe chronic kidney disease (GFR <30) were excluded.
At six months, ALIS treatment produced a 20% greater reduction in the urinary albumin-to-creatinine ratio than placebo. Although BP reduction is also associated with reduced renal protein loss, correction for the modest BP effect of adding ALIS to ARB (2/1 mm Hg) still indicated a statistically significant, BP-independent impact. Adverse effects were similar in both treatment groups. Simultaneous modulation of the renin-angiotensin-aldosterone system by more than one mechanism provides additional benefit for reduction of proteinuria.
Early Aggressive Therapy in Type 2 Diabetes Pays Off
Source: Weng J, et al. Lancet. 2008;371:1753-1760.
Using current criteria for the diagnosis of type 2 diabetes (DM2), approximately 50% of beta-cell function has been lost at the time of initial diagnosis. DM2 has been characterized as a disease of progressive decline in beta cell function; the UKPDS trial showed that all treatment regimens (sulfonylurea, metformin, insulin) were associated with progressive decline in control of A1c.
Because pancreatic beta cells become dysfunctional when subjected to persistent supraphysiologic glucose levels (perhaps as low as 140 mg/dL, sustained), investigators have opined that prompt intensive control of glucose might rejuvenate dysfunctional beta cells; limited data supports this concept.
Weng, et al performed a clinical trial on DM2 patients (n=382) comparing intensive insulin regimens (IIR) to oral hypoglycemic agents. Intensive insulin was either multiple daily insulin injections (basal insulin plus thrice daily insulin analog injections) or continuous subcutaneous insulin infusion.
Most IIR patients achieved glycemic control within 6 days, compared to 9.3 days using oral agents. All regimens were continued for 2 weeks once control was attained, and then discontinued, after which subjects used diet and exercise to try and maintain control for 1 year.
At one year, remission rates for IIR groups (45-50%) were statistically greater than oral agent rates (27%). First phase insulin response was improved only by IIR. Early intensive treatment produces durable improvements in beta cell function.
Sublingual Immunotherapy
Source: Frew, AJ. N Engl J Med. 2008;358:2259-2264.
Allergic rhinitis is often treated successfully with antihistamines and local corticosteroids, but because of inadequate symptom control, patient preference, or both, sometimes allergen desensitization becomes preferable. Most of our knowledge about desensitization comes from studies using parenteral allergens, but other routes for desensitization have been suggested. Sublingual immunotherapy (SIT) has been recently demonstrated in large double-blind, placebo controlled trials to be effective in reducing allergic rhinitis symptoms and need for rescue medication.
The exact mechanism by which parenteral immunotherapy produces its beneficial effects is still controversial, since treatment induces T regulatory cells that blunt the late-phase reaction, generates IgG "blocking" antibodies to offending antigens, and decreases the IgE response to antigens. Because SIT provides antigen in sufficient magnitude that some is absorbed through the oral vasculature, stimulation of regional lymph nodes to produce allergen-specific IgG has been demonstrated.
Advantages of SIT include that desensitization may be initiated at a full maintenance dose (as compared to injections, which must be very gradually titrated), the very low likelihood of anaphylaxis (as demonstrated by trial data to date), and lack of necessity for injections, which may be preferred by some patients, especially children.
Disadvantages of SIT include limitations of approved antigens (thus far, grass allergens are the only ones commercially available, and none are yet FDA approved), limited data-base compared with injection immunotherapy, and especially the uncertainty surrounding durability of SIT, since long term trials of SIT (beyond 2 years) are lacking.
For patients with compelling reasons to seek SIT instead of injection, SIT is available in England.
Methylnaltrexone for Opioid-Induced Constipation
Source: Thomas J, et al. N Engl J Med. 2008;358:2332-2343.
In the adverse effects induced by opioid therapy, constipation is singular in its persistence. Opioid-induced bowel dysfunction (OBD) is felt to result primarily from action of opioids upon the mu receptor in the colonic myenteric plexus, resulting in lack of contractility of the longitudinal muscle fibers, and hence a loss of peristalsis. Traditional laxative tools for constipation are generally employed with some success. Bulk forming laxatives (eg, fiber), should be avoided in OBD, since they may actually worsen symptoms or even lead to full obstruction in a non-motile colon.
Methylnaltrexone (MTX) is a mu-receptor antagonist which, because it is a quaternary amine compound, does not induce withdrawal symptoms in persons on chronic opioid therapy. Small pilot trials have supported the utility of both oral and parenteral MTX for prompt relief of constipation.
Thomas, et al studied a population of subjects on opioid therapy (n=133) who had not achieved relief of constipation with "traditional" laxatives. MTX subcutaneous was administered every other day for two weeks. Within 4 hours of the first dose, almost half of subjects had a spontaneous bowel movement (ie, without the use of a "rescue" laxative). Pain scores were not adversely affected, and there were no signs of opioid withdrawal. No serious adverse events attributable to MTX were seen.
Prucalopride for Severe Constipation
Source: Camilleri M, et al. N Engl J Med. 2008;358:2344-2354.
Chronic constipation sufferers have few FDA-approved therapeutic choices since the removal of tegaserod from the market due to CV toxicity. Mechanistically similar to tegaserod, prucalopride (PRU) is a 5-HT4 receptor agonist; dissimilar to tegaserod, PRU does NOT interact with receptors putatively associated with cardiovascular risk.
A double-blind trial of PRU in severe constipation randomized patients to 2-4 mg/d of oral PRU x 12 weeks or placebo (n=620). Entry criteria included having < 2 spontaneous bowel movements (SBM) per week; indeed, 75% of study subjects had < 1 bowel movement per week.
Thirty-one percent of PRU-treated subjects (2 mg dose) reported three or more SBM per week, vs 12% of the placebo group. Other problematic attributes of constipation (eg, straining at stool, consistency of SBM) were statistically improved also. Treatment was rated as quite-extremely effective in 33.3% of PRU 2 mg subjects (vs 17% placebo).
No serious adverse effects were seen. Diarrhea was seen in 13.5% of patients at the 2 mg dose (vs 5.3% placebo). PRU shows promise as a treatment for chronic severe constipation.
Oral Prednisolone for Acute Gout; Adding Aliskiren to Losartan for Diabetic Nephropathy; Early Aggressive Therapy in Type 2 Diabetes Pays Off; Sublingual Immunotherapy; Methylnaltrexone for Opioid-Induced Constipation; Prucalopride for Severe ConstipationYou have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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