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Monday, September 1, 2014

September 2014

FDA approves new type of sleep drug, Suvorexant (Belsomra)

The U.S. Food and Drug Administration approved Belsomra (suvorexant) tablets for use as needed to treat difficulty in falling and staying asleep (insomnia).
Belsomra is an orexin receptor antagonist and is the first approved drug of this type. Orexins are chemicals that are involved in regulating the sleep-wake cycle and play a role in keeping people awake. Belsomra alters the signaling (action) of orexin in the brain.
Link: http://www.fda.gov/newsevents/newsroom/pressannouncements/ucm409950.htm

FDA Contrave (naltrexone hydrochloride and bupropion hydrochloride extended-release tablets) as treatment option for chronic weight management

The U.S. Food and Drug Administration today approved Contrave (naltrexone hydrochloride and bupropion hydrochloride extended-release tablets) as treatment option for chronic weight management in addition to a reduced-calorie diet and physical activity.
The drug is approved for use in adults with a body mass index (BMI) of 30 or greater (obesity) or adults with a BMI of 27 or greater (overweight) who have at least one weight-related condition such as high blood pressure (hypertension), type 2 diabetes, or high cholesterol (dyslipidemia).
BMI, which measures body fat based on an individual’s weight and height, is used to define the obesity and overweight categories. According to the Centers for Disease Control and Prevention, more than one-third of adults in the United States are obese.
“Obesity continues to be a major public health concern,” said Jean-Marc Guettier, M.D., director of the Division of Metabolism and Endocrinology Products in FDA’s Center for Drug Evaluation and Research. “When used as directed in combination with a healthy lifestyle that includes a reduced-calorie diet and exercise, Contrave provides another treatment option for chronic weight management for people who are obese or are overweight and have at least one weight-related health condition.”
Contrave is a combination of two FDA-approved drugs, naltrexone and bupropion, in an extended-release formulation. Naltrexone is approved to treat alcohol and opioid dependence.  Bupropion is approved to treat depression and seasonal affective disorder and as an aid to smoking cessation treatment.
The effectiveness of Contrave was evaluated in multiple clinical trials that included approximately 4,500 obese and overweight patients with and without significant weight-related conditions treated for one year. All patients received lifestyle modification that consisted of a reduced- calorie diet and regular physical activity.
Results from a clinical trial that enrolled patients without diabetes showed that patients had an average weight loss of 4.1 percent over treatment with placebo (inactive pill) at one year. In this trial, 42 percent of patients treated with Contrave lost at least 5 percent of their body weight compared with 17 percent of patients treated with placebo. Results from another clinical trial that enrolled patients with type 2 diabetes showed that patients had an average weight loss of 2 percent over treatment with placebo at one year. In this trial, 36 percent of patients treated with Contrave lost at least 5 percent of their body weight compared with 18 percent of patients treated with placebo.
Patients using Contrave at the maintenance dose should be evaluated after 12 weeks to determine if the treatment is working. If a patient has not lost at least 5 percent of baseline body weight, Contrave should be discontinued, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.
Because it contains bupropion, Contrave has a boxed warning to alert health care professionals and patients to the increased risk of suicidal thoughts and behaviors associated with antidepressant drugs. The warning also notes that serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation.
Contrave can cause seizures and must not be used in patients who have seizure disorders. The risk of seizure is dose-related. Contrave should be discontinued and not restarted in patients who experience a seizure while being treated with Contrave.
Contrave can also raise blood pressure and heart rate and must not be used in patients with uncontrolled high blood pressure. The clinical significance of the increases in blood pressure and heart rate observed with Contrave treatment is unclear, especially for patients with heart-related and cerebrovascular (blood vessel dysfunction impacting the brain) disease, since patients with a history of heart attack or stroke in the previous six months, life-threatening arrhythmias, or congestive heart failure were excluded from the clinical trials. Blood pressure and pulse should be measured prior to starting the drug and should be monitored at regular intervals, particularly among patients with controlled high blood pressure prior to treatment.
Other products containing bupropion should not be taken along with Contrave. The drug should not be used in patients who have eating disorders (bulimia or anorexia nervosa). Contrave should also not be taken by patients who are using opioids or treatments for opioid dependence, or who are experiencing acute opiate withdrawal. Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs should not take Contrave.  Women who are pregnant or trying to become pregnant should not take Contrave.
The most common adverse reactions reported with Contrave include nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, and diarrhea.
Link: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm413896.htm

Benzodiazepine use and risk of Alzheimer’s disease: case-control study

BMJ (British Medical Journal)
Abstract 
Objectives 
To investigate the relation between the risk of Alzheimer’s disease and exposure to benzodiazepines started at least five years before, considering both the dose-response relation and prodromes (anxiety, depression, insomnia) possibly linked with treatment.
Design
Case-control study.
Setting
The Quebec health insurance program database (RAMQ).
Participants
1796 people with a first diagnosis of Alzheimer’s disease and followed up for at least six years before were matched with 7184 controls on sex, age group, and duration of follow-up. Both groups were randomly sampled from older people (age >66) living in the community in 2000-09.
Main outcome measure 
The association between Alzheimer’s disease and benzodiazepine use started at least five years before diagnosis was assessed by using multivariable conditional logistic regression. Ever exposure to benzodiazepines was first considered and then categorised according to the cumulative dose expressed as prescribed daily doses (1-90, 91-180, >180) and the drug elimination half life.
Results 
Benzodiazepine ever use was associated with an increased risk of Alzheimer’s disease (adjusted odds ratio 1.51, 95% confidence interval 1.36 to 1.69; further adjustment on anxiety, depression, and insomnia did not markedly alter this result: 1.43, 1.28 to 1.60). No association was found for a cumulative dose <91 prescribed daily doses. The strength of association increased with exposure density (1.32 (1.01 to 1.74) for 91-180 prescribed daily doses and 1.84 (1.62 to 2.08) for >180 prescribed daily doses) and with the drug half life (1.43 (1.27 to 1.61) for short acting drugs and 1.70 (1.46 to 1.98) for long acting ones).
Conclusion 
Benzodiazepine use is associated with an increased risk of Alzheimer’s disease. The stronger association observed for long term exposures reinforces the suspicion of a possible direct association, even if benzodiazepine use might also be an early marker of a condition associated with an increased risk of dementia. Unwarranted long term use of these drugs should be considered as a public health concern.
Link: http://www.bmj.com/content/349/bmj.g5205

Elevated Maternal C-Reactive Protein and Increased Risk of Schizophrenia in a National Birth Cohort

The American Journal of Psychiatry
Abstract 
Objective
The objective of the present study was to investigate an association between early gestational C-reactive protein, an established inflammatory biomarker, prospectively assayed in maternal sera, and schizophrenia in a large, national birth cohort with an extensive serum biobank.
Method  
A nested case-control design from the Finnish Prenatal Study of Schizophrenia cohort was utilized. A total of 777 schizophrenia cases (schizophrenia, N=630; schizoaffective disorder, N=147) with maternal sera available for C-reactive protein testing were identified and matched to 777 control subjects in the analysis. Maternal C-reactive protein levels were assessed using a latex immunoassay from archived maternal serum specimens.
Results  
Increasing maternal C-reactive protein levels, classified as a continuous variable, were significantly associated with schizophrenia in offspring (adjusted odds ratio=1.31, 95% confidence interval=1.10–1.56). This finding remained significant after adjusting for potential confounders, including maternal and parental history of psychiatric disorders, twin/singleton birth, urbanicity, province of birth, and maternal socioeconomic status.
Conclusions  
This finding provides the most robust evidence to date that maternal inflammation may play a significant role in schizophrenia, with possible implications for identifying preventive strategies and pathogenic mechanisms in schizophrenia and other neurodevelopmental disorders.
Link: http://ajp.psychiatryonline.org/Article.aspx?ArticleID=1885777

The Potential Therapeutic Effects of THC on Alzheimer's Disease

Journal of Alzheimer's Disease
Abstract 
The purpose of this study was to investigate the potential therapeutic qualities of Δ9-tetrahydrocannabinol (THC) with respect to slowing or halting the hallmark characteristics of Alzheimer's disease. N2a-variant amyloid-β protein precursor (AβPP) cells were incubated with THC and assayed for amyloid-β (Aβ) levels at the 6-, 24-, and 48-hour time marks. THC was also tested for synergy with caffeine, in respect to the reduction of the Aβ level in N2a/AβPPswe cells. THC was also tested to determine if multiple treatments were beneficial. The MTT assay was performed to test the toxicity of THC. Thioflavin T assays and western blots were performed to test the direct anti-Aβ aggregation significance of THC. Lastly, THC was tested to determine its effects on glycogen synthase kinase-3β (GSK-3β) and related signaling pathways. From the results, we have discovered THC to be effective at lowering Aβ levels in N2a/AβPPswe cells at extremely low concentrations in a dose-dependent manner. However, no additive effect was found by combining caffeine and THC together. We did discover that THC directly interacts with Aβ peptide, thereby inhibiting aggregation. Furthermore, THC was effective at lowering both total GSK-3β levels and phosphorylated GSK-3β in a dose-dependent manner at low concentrations. At the treatment concentrations, no toxicity was observed and the CB1 receptor was not significantly upregulated. Additionally, low doses of THC can enhance mitochondria function and does not inhibit melatonin's enhancement of mitochondria function. These sets of data strongly suggest that THC could be a potential therapeutic treatment option for Alzheimer's disease through multiple functions and pathways.
Link: http://iospress.metapress.com/content/8421pvx80144t354/

Is eating behavior manipulated by the gastrointestinal microbiota? Evolutionary pressures and potential mechanisms

Journal: BioEssays
Abstract 
Microbes in the gastrointestinal tract are under selective pressure to manipulate host eating behavior to increase their fitness, sometimes at the expense of host fitness. Microbes may do this through two potential strategies: (i) generating cravings for foods that they specialize on or foods that suppress their competitors, or (ii) inducing dysphoria until we eat foods that enhance their fitness. We review several potential mechanisms for microbial control over eating behavior including microbial influence on reward and satiety pathways, production of toxins that alter mood, changes to receptors including taste receptors, and hijacking of the vagus nerve, the neural axis between the gut and the brain. We also review the evidence for alternative explanations for cravings and unhealthy eating behavior. Because microbiota are easily manipulatable by prebiotics, probiotics, antibiotics, fecal transplants, and dietary changes, altering our microbiota offers a tractable approach to otherwise intractable problems of obesity and unhealthy eating.
Link: http://onlinelibrary.wiley.com/doi/10.1002/bies.201400071/abstract

Course of psychiatric symptoms and global cognition in early Parkinson Disease

Journal: Neurology
Abstract Conclusion
Multiple NPS (NeuroPsychiatric Symptoms) are more common in de novo, untreated patients with PD (Parkinson Disease) compared with the general population, but they also remain relatively stable in early disease, while global cognition slightly deteriorates. In contrast, initiation of DRT (Dopamine Replacement Therapy) is associated with increasing frequency of several other NPS.
Link: http://www.neurology.org/content/early/2014/08/14/WNL.0000000000000801.short



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