Biotechnical development of genetic addiction risk score (GARS) and selective evidence for inclusion of polymorphic allelic risk in substance use disorder (SUD).

Research into the neurogenetic basis of addiction identified and characterized by Reward Deficiency Syndrome (RDS) includes all drug and non-drug addictive, obsessive and compulsive behaviors. We are proposing herein that a new model for the prevention and treatment of Substance Use Disorder (SUD) a subset of RDS behaviors, based on objective biologic evidence, should be given serious consideration in the face of a drug epidemic. The development of the Genetic Addiction Risk Score (GARS) followed seminal research in 1990, whereby, Blum's group identified the first genetic association with severe alcoholism published in JAMA. While it is true that no one to date has provided adequate RDS free controls there have been many studies using case -controls whereby SUD has been eliminated. We argue that this deficiency needs to be addressed in the field and if adopted appropriately many spurious results would be eliminated reducing confusion regarding the role of genetics in addiction. However, an estimation, based on these previous literature results provided herein, while not representative of all association studies known to date, this sampling of case- control studies displays significant associations between alcohol and drug risk. In fact, we present a total of 110,241 cases and 122,525 controls derived from the current literature. We strongly suggest that while we may take argument concerning many of these so-called controls (e.g. blood donors) it is quite remarkable that there are a plethora of case -control studies indicating selective association of these risk alleles ( measured in GARS) for the most part indicating a hypodopaminergia. The paper presents the detailed methodology of the GARS. Data collection procedures, instrumentation, and the analytical approach used to obtain GARS and subsequent research objectives are described. Can we combat SUD through early genetic risk screening in the addiction field enabling early intervention by the induction of dopamine homeostasis? It is envisaged that GARS type of screening will provide a novel opportunity to help identify causal pathways and associated mechanisms of genetic factors, psychological characteristics, and addictions awaiting additional scientific evidence including a future meta- analysis of all available data -a work in progress.

Understanding the Scientific Basis of Post-traumatic Stress Disorder (PTSD): Precision Behavioral Management Overrides Stigmatization.

Post-traumatic stress disorder (PTSD) is a severe polygenic disorder triggered by environmental factors. Many polymorphic genes, particularly the genetic determinants of hypodopaminergia (low dopamine function), associate with a predisposition to PTSD as well as substance use disorder. Support from the National Institutes of Health for neuroimaging research and molecular, genetic applied technologies has improved understanding of brain reward circuitry functions that have inspired the development of new innovative approaches to their early diagnosis and treatment of some PTSD symptomatology and addiction. This review presents psychosocial and genetic evidence that vulnerability or resilience to PTSD can theoretically be impacted by dopamine regulation. From a neuroscience perspective, dopamine is widely accepted as a major neurotransmitter. Questions about how to modulate dopamine clinically in order to treat and prevent PTSD and other types of reward deficiency disorders remain. Identification of genetic variations associated with the relevant genotype-phenotype relationships can be characterized using the Genetic Addiction Risk Score (GARS®) and psychosocial tools. Development of an advanced genetic panel is under study and will be based on a new array of genes linked to PTSD. However, for now, the recommendation is that enlistees for military duty be given the opportunity to voluntarily pre-test for risk of PTSD with GARS, before exposure to environmental triggers or upon return from deployment as part of PTSD management. Dopamine homeostasis may be achieved via customization of neuronutrient supplementation "Precision Behavioral Management" (PBM™) based on GARS test values and other pro-dopamine regulation interventions like exercise, mindfulness, biosensor tracking, and meditation.

Intravenous sodium valproate aborts migraine headaches rapidly.

OBJECTIVES: This preliminary study was designed to evaluate the efficacy and safety of intravenous sodium valproate in managing severe migraine headache. DESIGN/METHODS: In a preliminary prospective open-label study, we treated patients with severe migraine headache using intravenous sodium valproate, after obtaining written informed consent. Thirty-six patients, hospitalized with acute established migraine, were infused with sodium valproate. The diagnosis of migraine was based on the International Headache Society classification criteria. Severity of headache was reported on 10-point visual analog. Disability was assessed on a five-point scale. Primary and secondary endpoints were measured as sustained pain relief and symptoms improvement at 2 h, respectively. RESULTS: The study participants had a mean±SD age of 35.7±9.3 years. The loading dose of sodium valproate was 900-1200 mg, and the average time to best response for headache severity was 50 min. A reduction in pain from severe or moderate to mild or no pain in 60 min was reported in 75% of patients [OR=7.187 (95% confidence intervals: 1.32-38.95)]. After treatment with sodium valproate, headache severity was significantly decreased (P<0.0001). No serious adverse events were reported. CONCLUSIONS: Intravenous Sodium Valproate (iVPA) seems to be safe and rapidly effective for intractable migraine attack. Randomized, double-blinded, controlled studies are warranted.

Bioequivalence study of two fluoxetine capsule formulations in healthy Middle Eastern volunteers.

OBJECTIVE: To assess the bioequivalence of two fluoxetine hydrochloride capsule (20 mg) formulations (Fluoxicare capsule from Pharmacare Ltd., Chemicals and Cosmetics, Ramallah, Palestine, as test formulation, and Prozac from Eli Lilly Ltd., Basingstoke, UK, as reference formulation). DESIGN AND METHODS: The study was conducted open with a randomized 2-period crossover design and a 6-week washout period. Participants were 24 healthy male volunteers aged 18-28 years, divided into 2 groups of 12 subjects. One group was given the originator drug (reference formulation), and the other was given the test formulation. Blood samples were obtained at baseline and at 14 time points during the interval 0-96 hours after drug administration. The concentrations of the samples were assayed spectrophotometrically at 220 nm using a Shimadzu 160 A UV-visible spectrometer. We calculated the plasma concentration-time curve (AUC), maximum plasma concentration (Cmax), and time of maximum plasma concentration (tmax) for each subject. Logarithmic transformation of the AUC and Cmax was used for the statistical analyses and to assess the bioavailability of the two formulations, using analyses of variance (ANOVA) and Satherwait t-tests for unequal variances. The ANOVA performed of tmax in Cmax, and in AUC provided the appropriate intra-subject variance estimates to evaluate the 90% confidence intervals for the differences between study variables after administration of the test and reference formulations. Statistical analyses were conducted on AUC 0-4 as the extrapolated part of the AUC, a truncated area approach was adapted. RESULTS: The mean pharmacokinetic parameters for both of the drugs under study were as follows: Cmax = 61.24 (+/- 12.96) ng/ml for the test formulation, and for the reference formulation Cmax = 61.39 (+/- 14.1) ng/ml, the effects were statistically equivalent. The tmax for the test formulation was 8.25 (+/- 1.7) and 7.33 (+/- 0.96) for the reference formulation. The area under the curve to infinity (AUC 0-infinity (ng, day/ml)) for the test formulation and for the reference formulation were 293.02 (+/- 52.69) and 296.15 (+/- 61.69), respectively. CONCLUSIONS: The two formulations had equivalent pharmacokinetic parameters, were well-tolerated, and their relative bioavailability was 98.94%.

Plasma homocysteine, vitamin B12 and folate in Alzheimer's patients and healthy Arabs in Israel.

High plasma homocysteine (tHcy) is a risk factor for cardiovascular disease and stroke and Alzheimer's disease (AD). An inverse relationship has been reported between tHcy and plasma B12 and folate levels. Seventy-nine AD patients and 156 controls from three Arab villages in northern Israel participated. Plasma tHcy, B12 and folate levels were determined. Data were analyzed using univariate statistical tests and logistical regression with confounders. tHcy was significantly higher in AD patients (20.6+/-8.7 micromol/l) than in controls (16.4+/-6.5 micromol/l) (p=0.03) after correction for year of birth, gender and smoking status. Plasma B12 (322.9+/-136.0/350.5+/-175.3 pmol/l) and plasma folate (4.5+/-3.8/4.9+/-2.6 nmol/l) levels did not differ significantly between AD patients and controls. Subjects in the highest tHcy tertile or in the lowest B12 and folate tertiles did not have greater risk to develop AD. In this population residing in Arab villages in northern Israel, tHcy levels were significantly higher among AD patients than in controls. Plasma B12 and folate levels were lower among cases but were not significant. There was not a significant association between plasma tHcy, B12 and folate levels in controls or AD patients. High levels of tHcy may suggest the need for folate and vitamin B12 supplementation in this population.

Prevalence of Alzheimer's type dementia in an elderly Arab population.

The aim of this study was to estimate the prevalence of dementia of the Alzheimer type (DAT) in an Arab Israeli community. Epidemiological studies of dementia have rarely been reported in Arab populations. The target population, aged 60 years or older, comprised 821 persons (362 males) who, on 1 October 1995, were residents of the rural area of Wadi Ara. These persons were examined for symptoms of dementia (DSM-IV criteria), using a semistructured questionnaire for collection of demographic and medical data. Age, gender, and education-specific prevalence rates were calculated for this population and compared to those obtained in other studies. DAT was diagnosed in 20.5% of this population. Its prevalence increased steeply with age, from 8% among those younger than 70 years to 33% among those aged 70-79 and 51% among those 80 years or older. Illiteracy was very common in this population, and strongly associated with higher prevalence of DAT (27% vs. 4%, P < 0.001). DAT was more prevalent among females than males (25% vs. 15%, P < 0.001). However, illiteracy was also significantly more frequent among women (96% vs. 42%, P < 0.001). After correction for illiteracy, the gender difference lost statistical significance. Few women smoked, but among men, the prevalence of DAT in those who smoked was lower as compared to non-smokers (14% vs. 23%, a non-significant difference). These results were confirmed by logistic regression wherein DAT was included as the dependent variable and age, illiteracy, gender and smoking as independent variables (OR=2.8, 2.8, 1.2 and 0.7, respectively; P < 0.005 for each, except for smoking). Our findings suggest that this population is unique because of extremely high rates of dementia. While the results support a protective effect of schooling against the development of dementia, other factors (e.g. genetic) must be sought to explain this high frequency.