Clinical pharmacology and therapeutics of benzodiazepines.

Benzodiazepines are among the most commonly prescribed drugs in the world. In contrast to their extensive use, the therapeutic indications and potential of benzodiazepines are limited. All benzodiazepine derivatives available in Canada are similar structurally and in their pharmacologic actions. Few have specific advantages over any others. For example, no benzodiazepine has been shown to be superior to chlordiazepoxide in the treatment of acute anxiety, chronic anxiety neurosis or insomnia. Barbiturates should not be prescribed for these problems since benzodiazepines are just as effective and are safer. Persons more than 70 years old should receive initial doses of benzodiazepines 50% less than those prescribed for younger persons, and individuals with cirrhosis should receive chlordiazepoxide or diazepam in one third the usual dose; oxazepam or lorazepam should be considered for these two groups of patients. Diazepam and chlordiazepoxide should not be given intramuscularly. Benzodiazepines should be prescribed only when clearly indicated and only for the necessary length of time.     

Benzodiazepineverslaving; een stille verslaving onder ouderen

Benzodiazepines are frequently prescribed for a longer period of time for anxiety disorders and insomnia in spite of the many guidelines to prescribe these drugs only short-term. These guidelines are based on the risk-benefit balance between long-term effectiveness and side effects like addiction, anterograde amnesia, and increased risk on falling (resulting in hip fractures), traffic accidents and even mortality. Also low-dose benzodiazepine use can lead to benzodiazepine dependence. Although initially most attention has been paid to the physical withdrawal syndrome, psychological aspects of benzodiazepine dependence have received more and more attention in the past decades. Recently, a relationship between the brain-reward system, involved in addiction, and benzodiazepine use, was demonstrated. When long-term benzodiazepine use is recognised as problematic by both physician and patient, different treatment modalities are available to support patients in achieving abstinence. One of every four patients is able to stop by themselves with the aid of a minimal intervention providing psychoeducation and encouragement. Two out of three long-term uses are able to stop their usage with the aid of systematic tapering protocols guided by a physician or psychologist. In case of an underlying insomnia or anxiety disorder, cognitive-behavioural therapy should be added to the tapering protocol. In contrast to the general opinion, advanced old age has no negative impact on the treatment response.     

Alternative hypotheses for the effects of drugs in small-scale clinical studies

New drugs that will be investigated in the future are expected to deal with chronic diseases, where the number of patients available for controlled clinical trials will be small and where the long-term sequelae that it is hoped will be ameliorated take a long time to occur. Thus, it would be useful to construct powerful tests of hypotheses that can be used to compare subtle intermediate measures of change in condition. This paper examines the probabilistic characteristics of these measures and the changes in them that might be expected from drug therapy.     

Alcohol addiction; problems in treatment

Of about five million problem drinkers in the United States, at least 750,000 are chronic alcoholics, a sixth of whom are in California. Seven phases of drinking patterns are described, from nondependent or "social" drinking, to the last two phases, when blackouts become more frequent and severe, "benders" fade into each other and serious organic diseases appear. General principles of treatment, after medical diagnosis and psychosocial evaluation, include hospitalization for acute episodes and physical disabilities, use of Antabuse (disulfiram) in suitable cases, psychotherapy, and the use of social aids such as Alcoholics Anonymous. The problem requires all resources available in the community, since chronic alcoholics are never cured and need support for long periods. A cooperative patient can finally readjust himself and get along without alcohol. Physicians must recognize the seriousness of alcohol addiction and help patients to accept treatment.     

Nitrosyl-cobinamide, a new and direct nitric oxide releasing drug effective in vivo

A limited number of nitric oxide (NO)-generating drugs are available for clinical use for acute and chronic conditions. Most of these agents are organic nitrates, which do not directly release NO; tolerance to the drugs develops, in part, as a consequence of their conversion to NO. We synthesized nitrosyl-cobinamide (NO-Cbi) from cobinamide, a structural analog of cobalamin (vitamin B12). NO-Cbi is a direct NO-releasing agent that we found was stable in water, but under physiologic conditions, it released NO with a half-life of 30 mins to 1 h. We show in five different biological systems that NO-Cbi is an effective NO-releasing drug. First, in cultured rat vascular smooth muscle cells, NO-Cbi induced phosphorylation of vasodilator-stimulated phosphoprotein, a downstream target of cGMP and cGMP-dependent protein kinase. Second, in isolated Drosophila melanogaster Malpighian tubules, NO-Cbi-stimulated fluid secretion was similar to that stimulated by Deta-NONOate and a cGMP analog. Third, in isolated mouse hearts, NO-Cbi increased coronary flow much more potently than nitroglycerin. Fourth, in contracted mouse aortic rings, NO-Cbi induced relaxation, albeit to a lesser extent than sodium nitroprusside. Fifth, in intact mice, a single NO-Cbi injection rapidly reduced blood pressure, and blood pressure returned to normal after 45 mins; repeated NO-Cbi injections induced the expected fall in blood pressure. These studies indicate that NO-Cbi is a useful NO donor that can be used experimentally in the laboratory; moreover, it could be developed into a vasodilating drug for treating hypertension and potentially other diseases such as angina and congestive heart failure.     

Vaccine development and therapeutic design for 2019-nCoV/SARS-CoV-2: Challenges and chances

The ongoing outbreak of the recently emerged 2019 novel coronavirus (nCoV), which has seriously threatened global health security, is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with high morbidity and mortality. Despite the burden of the disease worldwide, still, no licensed vaccine or any specific drug against 2019-nCoV is available. Data from several countries show that few repurposed drugs using existing antiviral drugs have not (so far) been satisfactory and more recently were proven to be even highly toxic. These findings underline an urgent need for preventative and therapeutic interventions designed to target specific aspects of 2019-nCoV. Again the major factor in this urgency is that the process of data acquisition by physical experiment is time-consuming and expensive to obtain. Scientific simulations and more in-depth data analysis permit to validate or refute drug repurposing opportunities predicted via target similarity profiling to speed up the development of a new more effective anti-2019-nCoV therapy especially where in vitro and/or in vivo data are not yet available. In addition, several research programs are being developed, aiming at the exploration of vaccines to prevent and treat the 2019-nCoV. Computational-based technology has given us the tools to explore and identify potentially effective drug and/or vaccine candidates which can effectively shorten the time and reduce the operating cost. The aim of the present review is to address the available information on molecular determinants in disease pathobiology modules and define the computational approaches employed in systematic drug repositioning and vaccine development settings for SARS-CoV-2.     

Short and Long Term Measures of Anxiety Exhibit Opposite Results

Animal models of human diseases of the central nervous system, generalized anxiety disorder included, are essential for the study of the brain-behavior interface and obligatory for drug development; yet, these models fail to yield new insights and efficacious drugs. By increasing testing duration hundredfold and arena size tenfold, and comparing the behavior of the common animal model to that of wild mice, we raise concerns that chronic anxiety might have been measured at the wrong time, for the wrong duration, and in the wrong animal. Furthermore, the mice start the experimental session with a short period of transient adaptation to the novel environment (habituation period) and a long period reflecting the respective trait of the mice. Using common measures of anxiety reveals that mice exhibit opposite results during these periods suggesting that chronic anxiety should be measured during the post-habituation period. We recommend tools for measuring the transient period, and provide suggestions for characterizing the post habituation period.     

Drug use among Croatian students

The subject of this study was to determine the frequency of drug use and attitudes toward drug use in Croatian high school students. The study was carried out in a middle-class high school in Zagreb. Out of 273 students who participated in an anonymous, self-report, 23-item questionnaire, 69 reported that they had at least once used drugs. The most frequently used drug was cannabis. While one third of students have been offered drugs, even 41% of the students would have take the drug if it becomes available. It can be concluded that the drugs appear to be highly available among Croatian students. According to our results, even more stronger increase in the number of drug users in Croatia could be expected.     

Should the Same Safety Scrutiny of Antiobesity Medications be Applied to Other Chronic Usage Drugs?

Obesity treatment is highly stigmatized, mainly because of the stigma of obesity itself. The frequent withdrawal of medications, lorcaserin being the last example, contributes to this stigma, but it is also probably a reflection of it, as data suggest that the threshold for a withdrawal is lower than with other classes of drugs. Safety should always be an absolute priority for every new medication, especially when used on a chronic basis; however, the safety scrutiny given to antiobesity medications is not given for other medications, such as postmenopausal hormone therapy and central nervous system drugs for psychiatric use. The withdrawal of medications for obesity can also impact future research in the area, so we need transparency and equality. Transparency in knowing exactly what reason led to a drug being discontinued and equality in long‐term safety should be a concern with any medication prescribed for chronic diseases.     

Effects of Baseline Problematic Alcohol and Drug Use on Internet-Based Cognitive Behavioral Therapy Outcomes for Depression,Panic Disorder and Social Anxiety Disorder

Purpose

Patients’ problematic substance use prevalence and effects were explored in relation to internet-based cognitive behavioral therapy (ICBT) outcomes for depression, panic disorder and social anxiety disorder.

Methods

At baseline and treatment conclusion, 1601 ICBT patients were assessed with self-rated measures for alcohol and drug use (AUDIT/DUDIT), depressive symptoms (MADRS-S), panic disorder symptoms (PDSS-SR) and social anxiety symptoms (LSAS-SR).

Results

Problematic substance use (AUDIT ≥8 for men, ≥6 for women; DUDIT ≥1) occurred among 32.4% of the patients; 24.1% only alcohol, 4.6% only drugs, and 3.7% combined alcohol and drug use. Hazardous alcohol use and probable alcohol dependence negatively affected panic disorder outcomes, and hazardous drug use led to worse social anxiety outcomes. Depression outcomes were not affected by substance use. Treatment adherence was negatively affected by problematic drug use among men and 25–34 year olds; combined substance use negatively affected adherence for women and 35–64 year olds.

Conclusion

Problematic substance use does not preclude ICBT treatment but can worsen outcomes, particularly problematic alcohol use for panic disorder patients and hazardous drug use for social anxiety patients. ICBT clinicians should exercise particular caution when treating men and younger patients with problematic drug use, and women or older patients with combined substance use.     

Combination of Two but Not Three Current Targeted Drugs Can Improve Therapy of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a cancer of the hematopoietic system and has been treated with the drug Imatinib relatively successfully. Drug resistance, acquired by mutations, is an obstacle to success. Two additional drugs are now considered and could be combined with Imatinib to prevent resistance, Dasatinib and Nilotinib. While most mutations conferring resistance to one drug do not confer resistance to the other drugs, there is one mutation (T315I) that induces resistance against all three drugs. Using computational methods, the combination of two drugs is found to increase the probability of treatment success despite this cross-resistance. Combining more than two drugs, however, does not provide further advantages. We also explore possible combination therapies using drugs currently under development. We conclude that among the targeted drugs currently available for the treamtent of CML, only the two most effective ones should be used in combination for the prevention of drug resistance.     

Alterations in cerebral diazepam binding inhibitor expression in drug dependence: a possible biochemical alteration common to drug dependence

Mechanisms for formation of drug dependence and expression of withdrawal syndrome have not fully clarified despite of huge accumulation of experimental and clinical data at present. Several clinical features of withdrawal syndrome are considered to be common among patients with drug dependence induced by different drugs of abuse. One of them is anxiety. Recent investigations have revealed that diazepam binding inhibitor (DBI), a peptide consisting of 87 amino acids with molecular weight of about 10 kDa, serves as an inverse agonist for benzodiazepine (BZD) receptors with endogenously anxiogenic potential. These lines of data suggest that cerebral DBI expression in brain may participates in formation of drug dependence and/or emergence of withdrawal syndrome. Based on this working hypothesis, we have examined DBI expression in the brain derived from mice depended on alcohol (ethanol), nicotine, and morphine to investigate functional relationship between cerebral DBI expression and drug dependence. Cerebral DBI expression significantly increases in animals with drug dependence induced by these drugs, and in the cases of nicotine- and morphine-dependent mice concomitant administration of antagonists for nicotinic acetylcholine and opioid receptors, respectively, abolished the increase. Abrupt cessation of administration of drugs facilitated further increase in DBI expression. Therefore, these alterations in DBI expression have close relationship with formation of drug dependence and/or emergence of withdrawal syndrome, and are considered to be a common biochemical process in drug dependence induced by different drugs of abuse. Finding and elucidation of mechanisms for common biochemical alterations among drug dependence may provide a clue to clarify mechanisms for formation of drug dependence and/or emergence of withdrawal syndrome.     

The chemical and pharmacological importance of morphine analogues

The object of this review is to summarize the efforts which resulted in the discovery of therapeutically useful morphine-like drugs. The search for new analgesics can be divided into three stages: (a) search for analgesics with high efficacy and reduced unwanted side-effects; (b) understanding of structure-activity relationships; (c) studies on the mechanism of pain perception and its alleviation by investigation of the pharmacology of opioids. An immense body of literature has been produced on the syntheses of thousands of new compounds which resulted in the development of detailed structure-activity relationships. The physical and psychologic dependence of opioid analgesics also facilitated investigators to solve the problem of the separation of strong analgesia from addiction liability. In the past decades more mixed agonist-antagonist analgesics, pure antagonists devoid of agonist action and potent opioids like the 6,14-ethenomorphinan derivatives were developed. Naloxone, Naltrexone, Buprenorphine and Pentazocine are the outstanding representatives which are introduced into clinical therapy.     

PROPER USE OF ANTIBIOTICS IN TREATMENT OF ACUTE OTITIS MEDIA

The problem of preventing loss of hearing following acute otitis media has been made more complex by the use of penicillin and other antibiotic agents which may apparently cure yet leave dangerous residual disease. The causes of loss of hearing must be recognized early if remedial treatment is to be effective. In children particularly, loss of hearing may go unnoticed for some time.Physicians who treat otitis media should feel the responsibility not only of bringing an acutely ill child back to health but of preserving the function of the hearing mechanism. Careful examination of the ear after apparent subsidence of infection is mandatory. It is of the utmost importance to be able to recognize the ear drum in its normal state and its various pathological states and to be alert to the early signs of changes associated with loss of hearing. Antibiotics should not be expected to do more than help combat the acute infection in otitis media. Adequate follow-up demands strong suspicion of residual pathologic process in the ear. The prevention of loss of hearing still requires knowledge of the established clinical facts and therapeutic procedures and the application of this knowledge to treatment of acute infections of the middle ear.     

Withdrawal from long-term benzodiazepine treatment.

Long-term, normal-dose benzodiazepine treatment was discontinued in 16 patients who were suspected of being dependent on their medication. The withdrawal was gradual, placebo-controlled, and double-blind. All the patients experienced some form of withdrawal reaction, which ranged from anxiety and dysphoria to moderate affective and perceptual changes. Symptom ratings rose as the drugs were discontinued, but usually subsided to prewithdrawal levels over the next two to four weeks. Other features of the withdrawal included disturbance of sleep and appetite and noticeable weight loss. Electroencephalography showed appreciable reduction in fast-wave activity as the drugs were withdrawn, and an improvement in psychological performance was recorded by the Digit Symbol Substitution Test. Because of the risk of dependence on benzodiazepines these agents should probably not be given as regular daily treatment for chronic anxiety.     

Inhibition of stress- or anxiogenic-drug-induced increases in dopamine release in the rat prefrontal cortex by long-term treatment with antidepressant drugs

The effects of long-term treatment with imipramine or mirtazapine, two antidepressant drugs with different mechanisms of action, on the response of cortical dopaminergic neurons to foot-shock stress or to the anxiogenic drug FG7142 were evaluated in freely moving rats. As expected, foot shock induced a marked increase (+ 90%) in the extracellular concentration of dopamine in the prefrontal cortex of control rats. Chronic treatment with imipramine or mirtazapine inhibited or prevented, respectively, the effect of foot-shock stress on cortical dopamine output. Whereas acute administration of the anxiogenic drug FG7142 induced a significant increase (+ 60%) in cortical dopamine output in control rats, chronic treatment with imipramine or mirtazapine completely inhibited this effect. In contrast, the administration of a single dose of either antidepressant 40 min before foot shock, had no effect on the response of the cortical dopaminergic innervation to stress. These results show that long-term treatment with imipramine or mirtazapine inhibits the neurochemical changes elicited by stress or an anxiogenic drug with an efficacy similar to that of acute treatment with benzodiazepines. Given that episodes of anxiety or depression are often preceded by stressful events, modulation by antidepressants of the dopaminergic response to stress might be related to the anxiolytic and antidepressant effects of these drugs.     

Protein kinase C isozymes and addiction

Protein kinase C (PKC) has long been recognized an important family of enzymes that regulate numerous aspects of neuronal signal transduction, neurotransmitter synthesis, release and reuptake, receptor and ion channel function, neuronal excitability, development, and gene expression. Much evidence has implicated PKCs in the effects of several drugs of abuse, and in behavioral responses to these drugs. The present review summarizes the effects of both acute and chronic exposure to various drugs of abuse on individual PKC isozymes in the brain. In addition, we summarize recent studies utilizing mice with targeted deletions of the genes for PKCγ and PKCɛ. These studies suggest that individual PKC isozymes play a role in the development of drug dependence and addiction.     

Review. Neurobiological mechanisms for opponent motivational processes in addiction

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.