Naltrexone + Bupropion Combination for the Treatment of Binge-eating Disorder with Obesity: A Randomized, Controlled Pilot Study (2023)

Emerging work indicates divergence in the neurobiologies of binge-eating disorder (BED) and obesity despite their frequent co-occurrence. This review highlights specific distinguishing aspects of BED, including elevated impulsivity and compulsivity possibly involving the mesocorticolimbic dopamine system, and discusses implications for differential therapeutics for BED.

This narrative review describes epidemiologic, clinical, genetic, and preclinical differences between BED and obesity. Subsequently, this review discusses human neuroimaging work reporting differences in executive functioning, reward processing, and emotion reactivity in BED compared with obesity. Finally, on the basis of the neurobiology of BED, this review identifies existing and new therapeutic agents that may be most promising given their specific targets based on putative mechanisms of action relevant specifically to BED.

BED is characterized by elevated impulsivity and compulsivity compared with obesity, which is reflected in divergent neurobiological characteristics and effective pharmacotherapies. Therapeutic agents that influence both reward and executive function systems may be especially effective for BED.

Greater attention to impulsivity/compulsivity-related, reward-related, and emotion reactivity–related processes may enhance conceptualization and treatment approaches for patients with BED. Consideration of these distinguishing characteristics and processes could have implications for more targeted pharmacologic treatment research and interventions.

Vitamin D deficiency is highly prevalent in critically ill patients, and has been associated with more prolonged length of hospital stay and poor prognosis. Patients undergoing open-heart surgery are at higher risk due to the associated life-threatening postoperative complications. This study investigated the effect of alfacalcidol treatment on the length of hospital stay in patients undergoing valve-replacement surgery.

This single-center, randomized, open-label, controlled trial was conducted at El-Demerdash Cardiac Academy Hospital (Cairo, Egypt), from April 2017 to January 2018. This study included adult patients undergoing valve-replacement surgery who were randomized to the intervention group (n=47; alfacalcidol 2μg/d started 48h before surgery and continued throughout the hospital stay) or to the control group (n=42). The primary end points were lengths of stay (LOS) in the intensive care unit (ICU) and in the hospital. Secondary end points were the prevalence of postoperative hospital-acquired infections, cardiac complications, and in-hospital mortality.

A total of 86 patients were included in the final analysis, with 51 (59.3%) being vitamin D deficient on hospital admission. Treatment with alfacalcidol was associated with a statistically significant decrease in ICU LOS (hazard ratio=1.61; 95% CI, 1.77–2.81; P=0.041) and hospital LOS (hazard ratio=1.63; 95% CI, 1.04–2.55; P=0.034). Treated patients had a significantly lower postoperative infection rate than did the control group (35.5% vs 56.1%; P=0.017). The median epinephrinedose was lower in the intervention group compared to that in the control group (5.9 vs 8.2mg; P=0.019). The rate of in-hospital mortality was not significantly different between the 2 groups.

Early treatment with 2μg of alfacalcidol in patients undergoing valve-replacement surgery is promising and well tolerated. This effect may be attributed to its immunomodulatory and cardioprotective mechanisms. ClinicalTrials.gov identifier: NCT04085770.

A thorough QT study was conducted in healthy subjects to evaluate the effect of buprenorphine hydrochloride administered through a buccal soluble film under coverage of naltrexone to block confounding, secondary QT effects.

Healthy subjects were enrolled in a randomized, partially blinded, 4-way crossover designed study. Subjects received buprenorphine 3 mg with naltrexone, naltrexone alone (with placebo films), placebo (placebo films and placebo naltrexone), and open-label moxifloxacin 400 mg with placebo naltrexone in separate in-house treatment periods. Naltrexone treatment (50 mg) was initiated 12 hours before buprenorphine and was given every 12 hours for a total of 4 doses. ECG data were extracted from a continuous recording predose and serially after dosing on the treatment day. ECG intervals were measured at a central ECG laboratory by using the high-precision QT technique. The QT interval was corrected for heart rate with Fridericia’s formula (QTcF), and change-from-predose baseline QTcF (∆QTcF) was analyzed by using a mixed effect model.

Fifty-eight subjects (35 males) with a mean age of 32 were enrolled into the study. Treatment with buprenorphine 3 mg resulted in a small QT effect with the largest mean naltrexone-corrected ∆QTcF reaching 5.8 msec at 8 hours’ postdosing (upper bound of the 90% CI below 10 msec). Exposure response analysis with a linear model demonstrated a significant linear relationship between plasma levels and naltrexone-corrected ∆QTcF, with an estimated mean slope of 0.65 msec per nanogram/milliliter (90% CI, 0.22 to 1.08). Using the exposure response model, an effect on ∆QTcF of 4.5 msec (2.80 to 6.12) can be predicted at the observed geometric peak plasma level after administration of the 3-mg buprenorphine dose in this study (3.6 ng/mL [3.33 to 3.98]). Naltrexone alone did not have a relevant effect on the QTcF interval.

The present study showed that buprenorphine plasma levels up to 5 ng/mL had no effect on the QTc above the level of clinical concern.

This study aimed to determine the appropriate vancomycin dosage, considering patient size and organ maturation, by simulating the bacterial count and biomarker level for drug administration in pediatric patients with gram-positive bacterial (GPB) infections.

Natural language processing for n-gram analysis was used to detect appropriate pharmacodynamic (PD) markers in infectious disease patients. In addition, a mechanism-based model was established to describe the systemic exposure and evaluate the PD marker simultaneously in pediatric patients. A simulation study was then conducted by using a mechanism-based model to evaluate the optimal dose of vancomycin in pediatric patients.

: C-reactive protein (CRP) was selected as a PD marker from an analysis of ~270,000 abstracts in PubMed. In addition, clinical results, including the vancomycin plasma concentrations and CRP levels of pediatric patients (n=93), were collected from electronic medical records. The vancomycin pharmacokinetic model with allometric scaling and a maturation function was built as a one-compartment model, with an additional compartment for bacteria. Both the effects of vancomycin plasma concentrations on the destruction of bacteria and those of bacteria on CRP production rates were represented by using a maximum achievable effect model (E_max model). Simulation for dose optimization was conducted not only by using the final model but also by exploring the possibility of therapeutic failure based on the MICs of vancomycin for GPB. Clinical cure was defined as when the CRP level fell below the upper limit of the normal range. Our dose optimization simulations suggested a vancomycin dosage of 10mg/kg every 8h as the optimal maintenance dose for pediatric patients with a postconceptual age <30 weeks and 10mg/kg every 6h for older children, aged up to 12 years. In addition, the MIC of 3μg/mL was assessed as the upper concentration limit associated with successful vancomycin treatment of GPB infections.

This study confirmed that the changes in bacterial counts and CRP levels were well described with mechanistic exposure–response modeling of vancomycin. This model can be used to determine optimal empiric doses of vancomycin and to improve therapeutic outcomes in pediatric patients with GPB.

Critical limb ischemia (CLI) has been identified as being connected to rates of cardiovascular mortality and lower extremity amputation (LEA). This prospective study investigated the effects of percutaneous coronary intervention (PCI), pharmacologic treatment, and predisposing factors on clinical outcomes in patients with and without type 2 diabetes mellitus (DM) along with CLI after endovascular intervention.

249 consecutive patients with CLI (Fontaine stages III–IV) received pharmacologic treatment after successful endovascular intervention. Their primary patency rates of infrapopliteal lesions and cardiovascular and amputation events during a 36-month follow-up period were assessed.

Patients with DM were more likely to be younger (P=0.026); 50% (n=63), 42.9% (n=54), 52.4% (n=66), and 77% (n=97) of DM patients had arterial calcification, end-stage renal disease, diabetic neuropathy, and Fontaine stage IV (P<0.001, P<0.001, P<0.001, and P=0.019, respectively). The primary patency rates were 61%, 48.8%, and 42.3% at 12, 24, and 36 months, in the patients without DM (P=0.034, P=0.013, and P=0.005). Patients with DM had higher risks of 36-month coronary artery disease, cerebrovascular accident, mortality, and LEA (P=0.005, P=0.042, P=0.042, and P<0.001). Patients with CLI receiving long-term cilostazol treatment had a better primary patency and amputation-free survival, and a lower risk of mortality at 36 months (P<0.001, P<0.001, and P=0.001). Statin use was associated with 36-month amputation-free survival but not with primary patency (P=0.032 and P=0.088). Subgroup multivariate Cox analyses showed that primary patency was independently associated with long-term cilostazol treatment, PCI in the first postoperative year, and direct revascularization in the DM group, whereas in the control group, long-term cilostazol treatment was the main independent factor. The risk of amputation was independently associated with a high high-sensitivity chronic reactive protein level, diabetic neuropathy, sole use of an oral hypoglycemic agent, and lack of supervised exercise.

Long-term cilostazol treatment, aggressive management of dyslipidemia, and meticulous assessment and prevention of postoperative unstable coronary artery disease should be considered in CLI patients with and without DM to maximize clinical outcomes. PCI in the first postoperative year may be a predisposing factor for patency failure in patients with CLI, especially those with DM. A large-scale prospective randomized trial should be conducted to confirm these findings (TVGH IRB No. 2013-08-020B).

The diphtheria-tetanus-pertussis vaccine (DTP) and oral polio vaccine (OPV) were introduced in children 3 of 5 months of age in 1981–1983 in Bandim, in the capital of Guinea-Bissau. Because DTP has been linked to deleterious nonspecific effects (NSEs) and OPV to beneficial NSEs, we followed up this cohort to 3 years of age and examined the effects of DTP with OPV on all-cause mortality and the interactions of DTP and OPV with the measles vaccine (MV).

DTP and OPV were offered at 3 monthly community weighing sessions. Vaccination groups were defined by the last vaccine received. We compared overall mortality for different groups in Cox proportional hazards regression models, reporting hazards ratios (HRs) with 95% CIs.

The study cohort included 1491 children born in Bandim from December 1980 to December 1983. From 3 to 35 months of age, with censoring for MV, children vaccinated with DTP and/or OPV had higher mortality than both unvaccinated children (HR=l.66; 95% CI, 1.03–2.69) and OPV-only vaccinated children (HR=2.81; 95% CI, 1.02–7.69); DTP-only vaccinated children had higher mortality than OPV-only vaccinated children (HR=3.38; 95% CI, 1.15-–9.93). In the age group of 3–8 months, before MV is administered, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR=3.38; 95% CI, 1.59–7.20). Between 9 and 35 months of age, when MV is given, DTP-vaccinated and MV-unvaccinated children had higher mortality (HR=2.76; 95% CI, 1.36–5.59) than children who had received MV after DTP, and among children who received DTP with MV or after MV, DTP-only vaccination was associated with a higher mortality than DTP with OPV (HR=6.25; 95% CI, 2.55–15.37).

Because the 2 vaccines had differential effects and the healthiest children were vaccinated first, selection biases are unlikely to explain the estimated impact on child survival. OPV had beneficial NSEs, and administration of OPV with DTP may have reduced the negative effects of DTP.