Pharmacotherapy for alcohol use disorders - Unequal provision across sociodemographic factors and co-morbid conditions. A cohort study of the total population in Sweden.

BACKGROUND: Pharmacotherapy for alcohol use disorders (AUD) is effective. However, knowledge about utilization of, and patient characteristics associated with prescriptions is scarce. The aim is to investigate prescriptions of pharmacotherapy for AUD in Sweden across time, sociodemographics, domicile and comorbid conditions. METHOD: This is a national cohort study, comprising 132 733 adult patients with AUD diagnosis between 2007 and 2015. The exposure variables were age, sex, income, education, family constellation, domicile, origin, concurrent psychiatric and somatic co-morbid diagnoses. Logistic regression analyses were used to obtain odds ratios (OR) for any filled prescription of AUD pharmacotherapy; Acamprosate, Disulfiram, Naltrexone or Nalmefene during 12 months after AUD diagnosis. RESULTS: During the study period, the proportion of individuals who received pharmacotherapy ranged between 22.80 and 23.94 % (χ2(64) = 72.00, p = .23). Female sex, age 31-45, higher education and income, living in a big city, co-habiting and born in Sweden, bar Norway, Denmark and Iceland, were associated with higher odds of pharmacotherapy. Concurrent somatic diagnosis was associated with lower odds of pharmacotherapy but psychiatric diagnosis higher (aOR = 0.61 95 % CI 0.59-0.63 and aOR = 1.61 95 % CI 1.57-1.66 respectively). CONCLUSIONS: Pharmacotherapy for AUD is underutilized. The proportion of individuals with a prescription did not change between 2007 and 2015. Provision of treatment is unequal across different groups in society, where especially older age, lower income and education, and co-morbid somatic diagnosis were associated with lower odds of prescription. There is a need to develop treatment provision, particularly for individuals with co-morbid somatic conditions.

The potential of 1H-MRS in CNS drug development.

RATIONALE: Proton magnetic resonance spectroscopy (1H-MRS) is a cross-species neuroimaging technique that can measure concentrations of several brain metabolites, including glutamate and GABA. This non-invasive method has promise in developing centrally acting drugs, as it can be performed repeatedly within-subjects and be used to translate findings from the preclinical to clinical laboratory using the same imaging biomarker. OBJECTIVES: This review focuses on the utility of single-voxel 1H-MRS in developing novel glutamatergic or GABAergic drugs for the treatment of psychiatric disorders and includes research performed in rodent models, healthy volunteers and patient cohorts. RESULTS: Overall, these studies indicate that 1H-MRS is able to detect the predicted pharmacological effects of glutamatergic or GABAergic drugs on voxel glutamate or GABA concentrations, although there is a shortage of studies examining dose-related effects. Clinical studies have applied 1H-MRS to better understand drug therapeutic mechanisms, including the glutamatergic effects of ketamine in depression and of acamprosate in alcohol dependence. There is an emerging interest in identifying patient subgroups with 'high' or 'low' brain regional 1H-MRS glutamate levels for more targeted drug development, which may require ancillary biomarkers to improve the accuracy of subgroup discrimination. CONCLUSIONS: Considerations for future research include the sensitivity of single-voxel 1H-MRS in detecting drug effects, inter-site measurement reliability and the interpretation of drug-induced changes in 1H-MRS metabolites relative to the known pharmacological molecular mechanisms. On-going technological development, in single-voxel 1H-MRS and in related complementary techniques, will further support applications within CNS drug discovery.

Very Low Frequency of Drug Therapy of Alcohol Dependence in Germany - Analysis of Data of A Statutory Health Insurance.

Acamprosate and naltrexone are medications of proven efficacy in the treatment of alcohol dependence. In order to investigate the prescription of these drugs in outpatient routine treatment in Germany (frequency of prescription, duration, medical specialty of prescribing physician), data of a large statutory health insurance were analyzed. Persons were included who were discharged from inpatient treatment with an alcohol-related disorder among their diagnoses during a one year observation period and with no diagnosed additional substance-related disorder (apart from nicotine- and cannabis-related disorders). Thus 12.958 patients were identified (mainly male, 77.9%; at average 51.4 years [+/-12.7] of age). 44.3% of these patients were treated in a psychiatric hospital, the remaining patients in hospitals of other specialties (e. g. 9.2% in departments of surgery). During an observation period of 6 months after discharge, acamprosate or naltrexone were prescribed at least once to 98 persons (0.76% of 12.958 patients; acamprosate n=80, 0.62%; naltrexone n=18, 0.14%). 16 (0.12%) patients were prescribed acamprosate or naltrexone for more than 3 months. Half of the prescriptions were issued by general practitioners. Possible reasons for this under-prescription are lack of knowledge about the drug treatment of alcohol dependence outside of addiction psychiatry, neglect of biological aspects (including medication) regarding etiology and treatment of substance-related disorders, and stigma of patients with substance-related disorders.

Acamprosate Protects Against Adjuvant-Induced Arthritis in Rats via Blocking the ERK/MAPK and NF-κB Signaling Pathway.

Osteoarthritis is a type of joint disease that results from the breakdown of joint cartilage and underlying bone and is believed to be caused by mechanical stress on the joint and low-grade inflammatory processes. Acamprosate significantly ameliorates the pathological features of experimental autoimmune encephalomyelitis due to its anti-inflammatory effect. The aims of the present study were to investigate the anti-arthritis activities of acamprosate and elucidate the underlying mechanisms. Adjuvant-induced arthritis (AIA) was induced by intradermal injection of complete Freund's adjuvant. Male Wistar rats were randomly divided into five groups: (1) sham control group, (2) AIA group, (3) acamprosate 10 mg/kg (AIA + ACA10), (4) acamprosate 30 mg/kg (AIA + ACA30), and (5) acamprosate 100 mg/kg (AIA + ACA100). Paw swelling and the arthritis index were measured, and the production of IL-1ß, IL-6, and TNF-α was detected by ELISA in serum. The expression of inflammation-related molecules, including c-Raf, ERK1/2, and NF-κB, was determined by Western blotting. We found that acamprosate significantly suppressed paw swelling and the arthritis index in AIA rats. Moreover, acamprosate also significantly suppressed the production of TNF-α, IL-1ß, and IL-6 in serum, which is elevated by AIA induction. Finally, acamprosate inhibited p-c-Raf and p-ERK1/2 and NF-κB activation after AIA treatment. These results indicate that acamprosate has an anti-inflammatory effect on adjuvant-induced arthritic rats via inhibiting the ERK/MAPK and NF-κB signaling pathways, and acamprosate may serve as a promising novel therapeutic agent for osteoarthritis.

Boosted Regeneration and Reduced Denervated Muscle Atrophy by NeuroHeal in a Pre-clinical Model of Lumbar Root Avulsion with Delayed Reimplantation.

The "gold standard" treatment of patients with spinal root injuries consists of delayed surgical reconnection of nerves. The sooner, the better, but problems such as injury-induced motor neuronal death and muscle atrophy due to long-term denervation mean that normal movement is not restored. Herein we describe a preclinical model of root avulsion with delayed reimplantation of lumbar roots that was used to establish a new adjuvant pharmacological treatment. Chronic treatment (up to 6 months) with NeuroHeal, a new combination drug therapy identified using a systems biology approach, exerted long-lasting neuroprotection, reduced gliosis and matrix proteoglycan content, accelerated nerve regeneration by activating the AKT pathway, promoted the formation of functional neuromuscular junctions, and reduced denervation-induced muscular atrophy. Thus, NeuroHeal is a promising treatment for spinal nerve root injuries and axonal regeneration after trauma.

Review article: pharmacotherapy for alcohol dependence - the why, the what and the wherefore.

BACKGROUND: The development of alcohol dependence is associated with significant morbidity and mortality. For the majority of affected people the most appropriate goal, in terms of drinking behaviour, is abstinence from alcohol. Psychosocial intervention is the mainstay of the treatment but adjuvant pharmacotherapy is also available and its use recommended. AIM: To provide an updated analysis of current and potential pharmacotherapeutic options for the management of alcohol dependence. In addition, factors predictive of therapeutic outcome, including compliance and pharmacogenetics, and the current barriers to treatment, including doctors' unwillingness to prescribe these agents, will be explored. METHODS: Relevant papers were selected for review following extensive, language- and date-unrestricted, electronic and manual searches of the literature. RESULTS: Acamprosate and naltrexone have a substantial evidence base for overall efficacy, safety and cost-effectiveness while the risks associated with the use of disulfiram are well-known and can be minimised with appropriate patient selection and supervision. Acamprosate can be used safely in patients with liver disease and in those with comorbid mental health issues and co-occurring drug-related problems. A number of other agents are being investigated for potential use for this indication including: baclofen, topiramate and metadoxine. CONCLUSION: Pharmacotherapy for alcohol dependence has been shown to be moderately efficacious with few safety concerns, but it is substantially underutilised. Concerted efforts must be made to remove the barriers to treatment in order to optimise the management of people with this condition.

Cannabis use during treatment for alcohol use disorders predicts alcohol treatment outcomes.

AIMS: To compare post-treatment alcohol use between those who use cannabis and those who abstain during treatment for alcohol use disorders (AUD); and to examine potential cannabis use thresholds by comparing post-treatment alcohol use between four frequency groups of cannabis users relative to abstainers. DESIGN: Secondary analyses of the Combined Pharmacotherapies and Behavioral Interventions (COMBINE) Study, a randomized control trial of AUD treatments. The current study compares longitudinal drinking data between those who used cannabis versus those who abstained during COMBINE treatment. SETTING: The COMBINE Study treatments were delivered on an out-patient basis for 16 weeks. The current analyses include 206 cannabis users and 999 cannabis abstainers. PARTICIPANTS: All participants met diagnosis of primary alcohol dependence (n = 1383). MEASUREMENTS: Primary exposures were any cannabis use and quartiles of cannabis use (Q1: 1-4 use days during treatment, Q2: 5-9 days, Q3: 10-44 days, Q4: 45-112 days). Outcomes were percentage of days abstinent from alcohol (PDA), drinks per drinking day (DPDD) and percentage of heavy drinking days (PHD), all measured at treatment end and 1 year post-treatment. FINDINGS: Compared with no cannabis use, any cannabis use during treatment was associated with 4.35% [95% confidence interval (CI) = -8.68, -0.02], or approximately 4 fewer alcohol abstinent days at the end of treatment. This association weakened by 1 year post-treatment (95% CI = -9.78, 0.54). Compared with no cannabis use, only those in the second quartile of cannabis use (those who used once or twice per month during treatment) had 8.81% (95% CI = -17.00, -0.63), or approximately 10 fewer days alcohol abstinent at end of treatment, and 11.82% (95% CI = -21.56, -2.07), or approximately 13 fewer alcohol abstinent days 1 year post-treatment. Neither any cannabis use nor quartiles were associated with DPDD or PHD at either time-point. CONCLUSIONS: Among individuals in alcohol treatment, any cannabis use (compared with none) is related to a significantly lower percentage of days abstinent from alcohol post-treatment, although only among those who used cannabis once or twice per month.

Factors Affecting Ethanol-Induced Conditioned Place Preference and Locomotor Sensitization in Mice.

The rewarding effects of alcohol can lead to progressively heavier and more frequent drinking. Since studies of reward have mainly focused on responses to higher alcohol doses, the relations between reward and moderate/sustained alcohol exposure remain unknown. Our objective was to evaluate factors affecting the reward value of low alcohol doses and risk factors for increasing alcohol doses due to reward progression caused by alcohol exposure patterns. We thus performed conditioned place preference (CPP) and ethanol (EtOH)-induced locomotor sensitization tests in mice. Low-dose EtOH (0.5 or 1 g/kg twice/week)-induced CPP was stronger than that produced by saline control treatment, but the effect decreased with increasing numbers of conditioning trials. Moderate-dose/long-term EtOH exposure induced a weaker CPP than high-dose/short-term EtOH (2 g/kg twice/week) exposure with the same total EtOH dose (8 g/kg/experiment). Acamprosate calcium, an anti-relapse drug, preclusively reduced EtOH-induced CPP. EtOH induced CPP and locomotor sensitization in black but not white chamber, although the initial preference and the basal locomotion in each chamber were equal. Therefore the brightness of the chamber had an effect on EtOH-induced sensitization. Moreover, additional studies indicated that EtOH-induced locomotor sensitization also depends on the dose but not the administration interval. Paired associative learning with EtOH exposure is a potent factor influencing the level of reward produced by EtOH. Moreover, exposure to high doses of alcohol, even on an intermittent schedule, carries a higher risk of addiction than exposure to moderate doses over longer periods.

The indirect NMDAR antagonist acamprosate induces postischemic neurologic recovery associated with sustained neuroprotection and neuroregeneration.

Cerebral ischemia stimulates N-methyl-d-aspartate receptors (NMDARs) resulting in increased calcium concentration and excitotoxicity. Yet, deactivation of NMDAR failed in clinical studies due to poor preclinical study designs or toxicity of NMDAR antagonists. Acamprosate is an indirect NMDAR antagonist used for patients with chronic alcohol dependence. We herein analyzed the therapeutic potential of acamprosate on brain injury, neurologic recovery and their underlying mechanisms. Mice were exposed to cerebral ischemia, treated with intraperitoneal injections of acamprosate or saline (controls), and allowed to survive until 3 months. Acamprosate yielded sustained neuroprotection and increased neurologic recovery when given no later than 12 hours after stroke. The latter was associated with increased postischemic angioneurogenesis, albeit acamprosate did not stimulate angioneurogenesis itself. Rather, increased angioneurogenesis was due to inhibition of calpain-mediated pro-injurious signaling cascades. As such, acamprosate-mediated reduction of calpain activity resulted in decreased degradation of p35, increased abundance of the pro-survival factor STAT6, and reduced N-terminal-Jun-kinase activation. Inhibition of calpain was associated with enhanced stability of the blood-brain barrier, reduction of oxidative stress and cerebral leukocyte infiltration. Taken into account its excellent tolerability, its sustained effects on neurologic recovery, brain tissue survival, and neural remodeling, acamprosate is an intriguing candidate for adjuvant future stroke treatment.

The development of acamprosate as a treatment against alcohol relapse.

INTRODUCTION: Globally, alcohol abuse and dependence are significant contributors to chronic disease and injury and are responsible for nearly 4% of all deaths annually. Acamprosate (Campral), one of only three pharmacological treatments approved for the treatment of alcohol dependence, has shown mixed efficacy in clinical trials in maintaining abstinence of detoxified alcoholics since studies began in the 1980s. Yielding inconsistent results, these studies have prompted skepticism. AREAS COVERED: Herein, the authors review the preclinical studies which have assessed the efficacy of acamprosate in various animal models of alcohol dependence and discuss the disparate findings from the major clinical trials. Moreover, the authors discuss the major limitations of these preclinical and clinical studies and offer explanations for the often-contradictory findings. The article also looks at the importance of the calcium moiety that accompanies the salt form of acamprosate and its relevance to its activity. EXPERT OPINION: The recent discovery that large doses of calcium largely duplicate the effects of acamprosate in animal models has introduced a serious challenge to the widely held functional association between this drug and the glutamate neurotransmission system. Future research on acamprosate or newer pharmacotherapeutics should consider assessing plasma and/or brain levels of calcium as a correlate or mediating factor in anti-relapse efficacy. Further, preclinical research on acamprosate has thus far lacked animal models of chemical dependence on alcohol, and the testing of rodents with histories of alcohol intoxication and withdrawal is suggested.

Alcohol use disorders and current pharmacological therapies: the role of GABA(A) receptors.

Alcohol use disorders (AUD) are defined as alcohol abuse and alcohol dependence, which create large problems both for society and for the drinkers themselves. To date, no therapeutic can effectively solve these problems. Understanding the underlying mechanisms leading to AUD is critically important for developing effective and safe pharmacological therapies. Benzodiazepines (BZs) are used to reduce the symptoms of alcohol withdrawal syndrome. However, frequent use of BZs causes cross-tolerance, dependence, and cross-addiction to alcohol. The FDA-approved naltrexone and acamprosate have shown mixed results in clinical trials. Naltrexone is effective to treat alcohol dependence (decreased length and frequency of drinking bouts), but its severe side effects, including withdrawal symptoms, are difficult to overcome. Acamprosate showed efficacy for treating alcohol dependence in European trials, but two large US trials have failed to confirm the efficacy. Another FDA-approved medication, disulfiram, does not diminish craving, and it causes a peripheral neuropathy. Kudzu is the only natural medication mentioned by the National Institute on Alcohol Abuse and Alcoholism, but its mechanisms of action are not yet established. It has been recently shown that dihydromyricetin, a flavonoid purified from Hovenia, has unique effects on GABAA receptors and blocks ethanol intoxication and withdrawal in alcoholic animal models. In this article, we review the role of GABAA receptors in the treatment of AUD and currently available and potentially novel pharmacological agents.

[Electrophysiological study of acamprosate effects on frontal cortical neurons in rats].

The effect of drug for alcoholism treatment acamprosate (campral) on spontaneous electrical activity of frontal cortical neurons was studied in rats. Acamprosate after acute intraperitoneal administration (600 mg/kg) and microiontophoretic application reduced the frequency of spike activity in about 30 % of cells studied. The agent didn't change the magnitude and form of action potentials. Microiontophoretically applied acamprosate reduced the excitatory responses to ethanol electroosmotically applied to neurons at "small doses" (ejected current < 50 nA) and increased the value of neuronal depression induced by ethanol at the "large doses" (ejected current 50 nA). Effects of acamprosate were dose independent. It is suggested that acamprosate has no interaction with specific postsynaptic receptors and its action is determined by presynaptic mechanisms.

Alcohol dependence: analysis of factors associated with retention of patients in outpatient treatment.

AIMS: To identify factors associated with retention in treatment of alcohol-dependent individuals and to compare treatment retention between men and women. METHODS: Analysis of the treatment attendance records and baseline characteristics of 833 men and 218 women who undertook to attend follow-up treatment in an alcoholism treatment centre. RESULTS: Retention after 4 weeks of treatment is more likely to occur among those using adjuvant medication (the most frequent of which was disulfiram), those presenting severe alcoholism and those who are older and tend to be frequent drinkers. There was no gender difference regarding treatment retention. CONCLUSION: Such results suggest possibilities for developing specific strategies to reduce the risk of early dropout from treatment.

Medical treatment of alcohol dependence: a systematic review.

OBJECTIVE: To summarize published data on pharmacologic treatments for alcohol dependence alone and in combination with brief psychosocial therapies that may be feasible for primary care and specialty medical settings. METHODS: We conducted electronic searches of published original research articles and reviews in MEDLINE, SCOPUS, CINAHL, Embase, and PsychINFO. In addition, hand searches of reference lists of review articles, supplemental searches of internet references and contacts with experts in the field were conducted. Randomized controlled studies published between January 1960 and August 2010 that met our inclusion/exclusion criteria were included. RESULTS: A total of 85 studies, representing 18,937 subjects, met our criteria for inclusion. The evidence base for oral naltrexone (6% more days abstinent than placebo in the largest study) and topiramate (prescribed off-label) (e.g., 26.2% more days abstinent than placebo in a recent study) is positive but modest. Acamprosate shows modest efficacy with recently abstinent patients, with European studies showing better results than U.S. ones. The evidence-base for disulfiram is equivocal. Depot naltrexone shows efficacy (25% greater reduction in rate of heavy drinking vs. placebo, in one of the largest studies) in a limited number of studies. Some studies suggest that patients do better with extensive psychosocial treatments added to medications while others show that brief support can be equally effective. CONCLUSIONS: Although treatment effects are modest, medications for alcohol dependence, in conjunction with either brief support or more extensive psychosocial therapy, can be effective in primary and specialty care medical settings.

Acamprosate for alcohol dependence.

BACKGROUND: Alcohol dependence is among the main leading health risk factors in most developed and developing countries. Therapeutic success of psychosocial programs for relapse prevention is moderate, but could potentially be increased by an adjuvant treatment with the glutamate antagonist acamprosate. OBJECTIVES: To determine the effectiveness and tolerability of acamprosate in comparison to placebo and other pharmacological agents. SEARCH STRATEGY: We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE and CINAHL in January 2009 and inquired manufacturers and researchers for unpublished trials. SELECTION CRITERIA: All double-blind randomised controlled trials (RCTs) which compare the effects of acamprosate with placebo or active control on drinking-related outcomes. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data. Trial quality was assessed by one author and cross-checked by a second author. Individual patient data (IPD) meta-analyses were used to verify the primary effectiveness outcomes. MAIN RESULTS: 24 RCTs with 6915 participants fulfilled the criteria of inclusion and were included in the review. Compared to placebo, acamprosate was shown to significantly reduce the risk of any drinking RR 0.86 (95% CI 0.81 to 0.91); NNT 9.09 (95% CI 6.66 to 14.28) and to significantly increase the cumulative abstinence duration MD 10.94 (95% CI 5.08 to 16.81), while secondary outcomes (gamma-glutamyltransferase, heavy drinking) did not reach statistical significance. Diarrhea was the only side effect that was more frequently reported under acamprosate than placebo RD 0.11 (95% 0.09 to 0.13); NNTB 9.09 (95% CI 7.69 to 11.11). Effects of industry-sponsored trials RR 0.88 (95% 0.80 to 0.97) did not significantly differ from those of non-profit funded trials RR 0.88 (95% CI 0.81 to 0.96). In addition, the linear regression test did not indicate a significant risk of publication bias (p = 0.861). AUTHORS' CONCLUSIONS: Acamprosate appears to be an effective and safe treatment strategy for supporting continuous abstinence after detoxification in alcohol dependent patients. Even though the sizes of treatment effects appear to be rather moderate in their magnitude, they should be valued against the background of the relapsing nature of alcoholism and the limited therapeutic options currently available for its treatment.

Alcohol and opioid dependence medications: prescription trends, overall and by physician specialty.

Over the past decade, advances in addiction neurobiology have led to the approval of new medications to treat alcohol and opioid dependence. This study examined data from the IMS National Prescription Audit (NPA) Plus database of retail pharmacy transactions to evaluate trends in U.S. retail sales and prescriptions of FDA-approved medications to treat substance use disorders. Data reveal that prescriptions for alcoholism medications grew from 393,000 in 2003 ($30 million in sales) to an estimated 720,000 ($78 million in sales) in 2007. The growth was largely driven by the introduction of acamprosate in 2005, which soon became the market leader ($35 million in sales). Prescriptions for the two buprenorphine formulations increased from 48,000 prescriptions ($5 million in sales) in the year of their introduction (2003) to 1.9 million prescriptions ($327 million in sales) in 2007. While acamprosate and buprenorphine grew rapidly after market entry, overall substance abuse retail medication sales remain small relative to the size of the population that could benefit from treatment and relative to sales for other medications, such as antidepressants. The extent to which substance dependence medications will be adopted by physicians and patients, and marketed by industry, remains uncertain.

A microdialysis study of extracellular levels of acamprosate and naltrexone in the rat brain following acute and repeated administration.

Acamprosate and naltrexone are widely used in the treatment of alcoholism. However, numerous studies in rodents have shown differential effects of these compounds on alcohol consumption and/or relapse-like behavior following acute versus repeated administration. In order to determine if these differential behavioral effects could be attributable to changes in extracellular levels of these compounds, we used in vivo microdialysis to monitor extracellular levels of acamprosate and naltrexone in the rat medial prefrontal cortex following acute and repeated intraperitoneal administration. For acute treatment, animals received a single administration of acamprosate (100 or 300 mg/kg) or naltrexone (1 or 3 mg/kg). For repeated treatment, animals received once daily treatment with saline, acamprosate (300 mg/kg) or naltrexone (3 mg/kg) for 10 days before a subsequent challenge with the compound according to their respective pretreatment group. Dialysate levels of acamprosate and naltrexone were analyzed by liquid chromatography-tandem mass spectrometry and high performance liquid chromatography, respectively. Following acute administration, peak dialysate concentrations of each compound were dose-dependent, observed within 1 hour of administration, and were found to be in the low micromolar range for acamprosate and in the low to mid-nanomolar range for naltrexone. Pretreatment with acamprosate, but not naltrexone, for 10 days resulted in higher dialysate concentrations of the compound relative to saline-pretreated controls. Thus, repeated administration of acamprosate, but not naltrexone, results in augmented extracellular levels of the compound in the brain relative to saline-pretreated controls, which may explain the need for repeated administration of acamprosate in order to observe effects on alcohol consumption and/or relapse.

What's new in clinical pharmacology and therapeutics.

The US Food and Drug Administration (FDA) has approved several new drugs in the last few years. We have summarized a few of these that should be of interest to a primary care physician. These belong to either a new class of drugs or have a better drug profile in terms of ease of administration, prolonged duration of action, or fewer side effects. Daptomycin is a cyclic lipopeptide, active against methycillin resistant Staphylococcus aureus (MRSA). Telithromycin is a ketolide that can be used in place of macrolide antibiotics. Rifaximin is a semi-synthetic derivative of rifampin approved by the FDA for treatment of traveller's diarrhea. Pramlintide is an injectable synthetic amylin useful in treating type 1 and 2 diabetes. Tiotropium is an anti-cholinergic bronchodilator that can be taken once a day for treatment of chronic obstructive pulmonary disease. Lanthanum Carbonate is useful in treatment of hyperphosphatemia in patients with end stage renal disease. Flumist is an intranasal influenza vaccine. Eszopiclone is a new hypnotic that has fewer side effects. Memantine is in a new class of drugs useful in the treatment of Alzheimer's disease. Ibandronate is a new bisphosphonate approved for once a month use for osteoporosis in postmenopausal women. Acamprosate is approved for treatment of alcohol dependence.

Can experimental paradigms and animal models be used to discover clinically effective medications for alcoholism?

Evaluating medications in animal laboratory paradigms can reveal whether the compound is effective in an established alcoholism model, at clinically relevant doses and exposure conditions, when administered orally (or transdermally) and without serious limiting side effects. Positive outcomes constitute a possible discovery for relevance to alcoholism and, under favorable marketing conditions, encourage further development. Medication testing using animal models of alcoholism might also guide clinical testing by discriminating clinically effective from clinically ineffective compounds. This ability rests on whether there are tests or, more reasonably, batteries of tests having this discriminative ability. The present paper examines this possibility. Effects of naltrexone and acamprosate in animal paradigms which model behavioral aspects of alcoholism are reviewed and compared with the effects of compounds which have limited effects in alcoholics. It is not clear at present whether any single paradigm or combination of paradigms differentiates clinically effective from clinically limited compounds. Steps are suggested to improve the use of preclinical laboratory tests to predict which compounds are likely to be effective medications for reducing drinking and sustaining abstinence in human alcoholics.