ABSTRACT
Preclinical evidence suggests that pharmacotherapy for obesity using combinations of agents targeted at distinct regulatory pathways may produce robust additive or synergistic effects on weight loss. This randomized placebo-controlled trial examined the safety and efficacy of the amylin analogue pramlintide alone or in combination with either phentermine or sibutramine. All patients also received lifestyle intervention. Following a 1-week placebo lead-in, 244 obese or overweight, nondiabetic subjects (88% female; 41 +/- 11 years; BMI 37.7 +/- 5.4 kg/m(2); weight 103 +/- 19 kg; mean +/- s.d.) received placebo subcutaneously (sc) t.i.d., pramlintide sc (120 microg t.i.d.), pramlintide sc (120 microg t.i.d.) + oral sibutramine (10 mg q.a.m.), or pramlintide sc (120 microg t.i.d.) + oral phentermine (37.5 mg q.a.m.) for 24 weeks. Treatment was single-blind for subjects receiving subcutaneous medication only and open-label for subjects in the combination arms. Weight loss achieved at week 24 with either combination treatment was greater than with pramlintide alone or placebo (P < 0.001; 11.1 +/- 1.1% with pramlintide + sibutramine, 11.3 +/- 0.9% with pramlintide + phentermine, -3.7 +/- 0.7% with pramlintide; -2.2 +/- 0.7% with placebo; mean +/- s.e.). Elevations from baseline in heart rate and diastolic blood pressure were demonstrated with both pramlintide + sibutramine (3.1 +/- 1.2 beats/min, P < 0.05; 2.7 +/- 0.9 mm Hg, P < 0.01) and pramlintide + phentermine (4.5 +/- 1.3 beats/min, P < 0.01; 3.5 +/- 1.2 mm Hg, P < 0.001) using 24-h ambulatory monitoring. However, the majority of subjects receiving these treatments remained within normal blood pressure ranges. These results support the potential of pramlintide-containing combination treatments for obesity.
Subject(s)
Appetite Depressants/therapeutic use , Cyclobutanes/therapeutic use , Hypoglycemic Agents/therapeutic use , Islet Amyloid Polypeptide/therapeutic use , Obesity/drug therapy , Phentermine/therapeutic use , Weight Loss/drug effects , Adolescent , Adult , Appetite Depressants/administration & dosage , Appetite Depressants/pharmacology , Blood Pressure/drug effects , Cyclobutanes/administration & dosage , Cyclobutanes/pharmacology , Drug Therapy, Combination , Female , Heart Rate/drug effects , Humans , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/pharmacology , Islet Amyloid Polypeptide/administration & dosage , Islet Amyloid Polypeptide/pharmacology , Male , Middle Aged , Phentermine/administration & dosage , Phentermine/pharmacology , Single-Blind Method , Young AdultABSTRACT
OBJECTIVE: To assess long-term weight loss efficacy and safety of pramlintide used at different dosing regimens and in conjunction with lifestyle intervention (LSI). RESEARCH DESIGN AND METHODS: In a 4-month, double-blind, placebo-controlled, dose-ranging study, 411 obese subjects were randomized to receive pramlintide (six arms: 120, 240, and 360 microg b.i.d. and t.i.d.) or placebo in conjunction with a structured LSI program geared toward weight loss. Of the 4-month evaluable subjects (n = 270), 77% opted to continue preexisting treatment during an 8-month single-blind extension (LSI geared toward weight maintenance). RESULTS: At month 4, mean weight loss from baseline in the pramlintide arms ranged from 3.8 +/- 0.7 to 6.1 +/- 0.8 kg (2.8 +/- 0.8 kg with placebo). By month 12, initial 4-month weight loss was regained in the placebo group but was maintained in all but the 120-microg b.i.d. group. Placebo-corrected weight loss with 120 microg t.i.d. and 360 microg b.i.d. averaged 3.2 +/- 1.2 kg (3.1 +/- 1.1% body wt) and 3.3 +/- 1.1 kg (3.1 +/- 1.0% body wt), respectively, at month 4 (both P < 0.01; 4-month evaluable n = 270) and 6.1 +/- 2.1 kg (5.6 +/- 2.1% body wt) and 7.2 +/- 2.3 kg (6.8 +/- 2.3% body wt), respectively, at month 12 (both P < 0.01; 12-month evaluable n = 146). At month 12, 40 and 43% of subjects treated with 120 microg t.i.d. and 360 microg b.i.d., respectively, achieved >or=10% weight loss (vs. 12% for placebo). Nausea, the most common adverse event with pramlintide in the 4-month study (9-29% pramlintide vs. 2% placebo), was generally mild to moderate and occurred in <10% of subjects during the extension. CONCLUSIONS: When used over 12 months as an adjunct to LSI, pramlintide treatment, with low-dose three-times-daily or higher-dose two-times-daily regimens, helped obese subjects achieve greater initial weight loss and enhanced long-term maintenance of weight loss.
Subject(s)
Amyloid/therapeutic use , Hypoglycemic Agents/therapeutic use , Life Style , Weight Loss/drug effects , Adult , Body Mass Index , Body Size , Double-Blind Method , Female , Follow-Up Studies , Humans , Islet Amyloid Polypeptide , Male , Middle Aged , Placebos , Single-Blind Method , Time FactorsABSTRACT
BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a bilateral optic neuropathy of mitochondrial inheritance that produces significant painless, central vision loss and dyschromatopsia. LHON usually occurs in young males between the ages of 15 and 30 years and manifests an episode of subacute or acute vision loss in one eye, with the opposite eye becoming involved weeks to months later. Approximately 80% to 90% of all LHON patients are male. While the disease usually presents itself around the third decade of life, its onset ranges anywhere from 5 to 80 years. CASE REPORT: We report a case of an uncooperative 12-year-old Hispanic boy who was brought to our group practice following referral from an outside optometrist for amblyopia therapy. Following the workup by the binocular vision clinician, a neuro-ophthalmic consultation was obtained, eventually leading to the diagnosis and confirmation of LHON. CONCLUSION: Leber's hereditary optic neuropathy may manifest signs and symptoms that mimic common ophthalmic entities. Teenage males often are reluctant to report its subtle clinical findings, making its discovery even more challenging. LHON should be kept in mind as a possibility for anyone who manifests unexplained visual loss.
