A phase II trial evaluating the efficacy and safety of efavirenz in metastatic castration-resistant prostate cancer.

BACKGROUND: Preclinical studies demonstrated that non-nucleoside reverse transcriptase inhibitors used for the treatment of HIV could antagonize tumor development. This led us to assess the efficacy of efavirenz in patients with metastatic castration-resistant prostate cancer (mCRPC) in a multicenter phase II study. METHODS: We used a Simon two-stage design and a 3-month prostate-specific antigen (PSA) nonprogression rate of 40% as a primary objective. Patients received 600 mg efavirenz daily with the possibility of a dose increase in case of PSA progression. Exploratory analyses included pharmacokinetics of efavirenz plasma concentrations and correlations with clinical outcomes. RESULTS: Among 53 assessable patients, we observed 15 instances of PSA nonprogression at 3 months, corresponding to a nonprogression rate of 28.3% (95% confidence interval: 16.8%-42.3%). The exploratory analysis revealed that for the 7 patients in whom optimal plasma concentration of efavirenz was achieved, PSA progression was observed in only 28.6% compared with 81.8% of patients with suboptimal plasma concentrations of efavirenz. CONCLUSION: Although 600 mg efavirenz did not statistically improve the PSA nonprogression rate, our exploratory analysis suggests that higher plasma concentrations of this drug (i.e., use of increased dosages) may be of potential benefit for the treatment of mCRPC.

Prazosin and cyproheptadine in combination in the treatment of alcohol use disorder: A randomized, double-blind, placebo-controlled trial.

BACKGROUND AND AIMS: Pre-clinical studies suggest that the simultaneous blockade of the α1b and 5HT2A receptors may be effective in reducing alcohol consumption. This study aimed to assess the efficacy and safety of prazosin (α1b blocker) and cyproheptadine (5HT2A blocker) combination in decreasing total alcohol consumption (TAC) in alcohol use disorder (AUD). DESIGN, SETTING AND PARTICIPANTS: This was a double-blind, parallel group, placebo-controlled, Phase 2, randomized clinical trial conducted in 32 addiction treatment centres in France. A total of 108 men and 46 women with severe AUD took part. INTERVENTION: Participants were randomly assigned to one of the following 3-month treatments: (1) low-dose group (LDG) receiving 8 mg cyproheptadine and 5 mg prazosin extended-release (ER) formulation daily; (2) high-dose group (HDG) receiving 12 mg cyproheptadine and 10 mg prazosin ER daily; and (3) placebo group (PG) receiving placebo of cyproheptadine and prazosin ER. A total of 154 patients were randomized: 54 in the PG, 54 in the LDG and 46 in the HDG. MEASUREMENTS: The primary outcome was TAC change from baseline to month 3. FINDINGS: A significant main treatment effect in the change in TAC was found in the intent-to-treat population (P = 0.039). The HDG and LDG showed a benefit in the change in TAC from baseline to month 3 compared with PG: -23.6 g/day, P = 0.016, Cohen's d = -0.44; -18.4 g/day, P = 0.048 (Bonferroni correction P < 0.025), Cohen's d = -0.36. In a subgroup of very high-risk drinking-level participants (> 100 g/day of pure alcohol for men and > 60 g/day for women), the difference between the HDG and the PG in the primary outcome was -29.8 g/day (P = 0.031, Cohen's d = -0.51). The high and low doses were well-tolerated with a similar safety profile. CONCLUSIONS: A randomized controlled trial of treatment of severe alcohol use disorder with a cyproheptadine-prazosin combination for 3 months reduced drinking by more than 23 g per day compared with placebo. A higher dose combination was associated with a larger magnitude of drinking reduction than a lower dose combination while showing similar safety profile.

How to anticipate the assessment of the public health benefit of new medicines?

The Public Health Benefit (PHB) of new medicines is a recent and French-specific criterion (October 1999 decree) which is often only partially documented in the transparency files due to a lack of timely information. At the time of the first reimbursement application for a new medicine to the "Transparency Committee", the file is exclusively based on data from randomised clinical trials. These data are generated from a global clinical development plan which was designed a long time before the new medicine's submission for reimbursement. And this plan does not systematically provide the data needed to assess the PHB. Thus, one easily understands the difficulty to anticipate and document this recent French criterion. In France, the PHB is both one of the necessary criteria for the reimbursement submission and an indicator for the national health policy management. Its assessment also helps to identify the needs and objectives of the post-registration studies (nowadays in the scope of responsibilities of the "Drug Economics Committee"). The assessment of the PHB criterion is carried through after the marketing authorization process and is an addition to it. To understand how to anticipate the assessment of the new medicines' PHB, one needs to consider how it differs from the preliminary step of the marketing authorization process. Whereas the evaluation for marketing authorization seeks to determine if the new medicine could be useful in a specific indication, the PHB assessment aims at quantifying the therapeutic benefit in a population, taking into account the reference treatments in this population. A new medicine receives a marketing authorization based on the data of the registration file which provides information on the clinical benefit of the new medicine in the populations of the trials and in the context of the trials. On the other side, the PHB looks at the effects of the new medicine at the scale of the general population, in real practice. The PHB components of a new medicine at first submission are the expected response of this new medicine to a public health need, the expected benefit on the health status of the population and ultimately the expected impact on the health care system. The benefit of a new medicine on the health status of a population is based on public health criteria which can be morbi-mortality or quality of life criteria. However, few registration files contain these public health criteria from the beginning and the predictive value of the surrogate criteria used in the trials is not always precisely assessed. It is, thus, difficult to quantify the expected benefit on these public health criteria. Moreover, the data that enable to quantify the new medicine's effects according to the various characteristics of the target population, are rarely available. Similarly, the French population epidemiological data related to the indication of the new medicine are often not available at the time of the assessment. Therefore it is difficult to evaluate the expected number of events that could be avoided if the new medicine reached the market. The authors suggest to adapt the clinical development plan for a better documentation of the PHB. They specifically recommend to integrate to the judgment criteria (endpoints) of the trials, criteria that are relevant in terms of public health, and to check for a good heterogeneity of the trial populations. They also suggest to start early enough collecting reliable national epidemiological data and the necessary elements for the assessment of the transposability of the trial results to the French population (ability to target the patients to be treated, adaptation of the healthcare system...). About the epidemiological data, the authors consider that the needs are covered in various ways depending on the diseases. To meet the needs of evaluation of the new medicines' target populations in specific indications, they recommend to use ad hoc studies as much as needed. In addition, epidemiological studies designed for market purpose with an acceptable methodology should not be systematically rejected but deserve to be presented. To be able to assess the importance of the expected theoretical benefit of a new medicine in a population, the authors underline the necessity to have access to study results with criteria related to this objective. They suggest to first define and list the criteria by disease. Regarding the representativity of the populations, it comes out that it would be advisable, but unrealistic to include in trials a population 100% representative of the population to be treated. Therefore the effect of the new medicine must be modelised (the "effect model") to be evaluated in the general population. Yet to obtain a reliable effect model, the study population must be sufficiently heterogeneous, which legitimates the demand to ensure a good population heterogeneity at the time of decision-making about trials methodology. When the criteria assessed during the development plan does not correspond to the PHB criteria, the only way to evaluate the number of events related to the PHB criterion is, again, to use modelisation. However, modelisation is only possible when the scientific literature has established a reliable correlation between the two types of criteria. In this case, the new model should be applied to a French target population to assess the expected benefit. As a conclusion, the possibilities to estimate the expected benefit of a new medicine on the health status of a specific population are currently limited. These limitations are regrettable because such an estimate is feasible without disrupting the development plans. The authors' general recommendations to update the development plans seem especially appropriate as the additions should not only be beneficial to France but to all the health authorities who would wish to assess the expected benefit of a new medicine on their territories. Anticipating the lack of clinical and epidemiological data and the lack of data that enable to evaluate the transposability of the trials results to real clinical practice is a sine qua none condition to improve the PHB assessment. The anticipation of these needs should be planned early enough by the pharmaceutical companies which could in this purpose meet the health authorities and the heads of the French public health policy in a consultation.Finally, because of the PHB's universal dimension, it is suggested that the necessary actions and publications be initiated so that the PHB can be acknowledged at the European level.

[State of unmet medical needs in France in 2006: necessity of reinforcing research effort]. / Besoins médicaux non couverts en France en 2006: l'effort de recherche doit être poursuivi.

Leem (French Pharmaceutical Companies) realized an inventory of unmet medical needs in 2006 in France for 12 pathologies. All of them are considered as national public health priorities by the law of August 9th, 2004. Allied to the epidemiological projections, analyses concerned various stages and/or pathology forms, impact of guidelines in clinical practice, therapeutic strategies, marketed therapeutics and pharmacological products in an advanced phase of clinical development. With more than 100 products listed in clinical phase III or pre-registration/marketed for those pathologies, French Pharmaceutical Companies contribute, quasi exclusively, to the development of innovative pharmaceutical products to answer unmet medical needs. This study illustrates the necessity of French Government to support therapeutic innovation led by Pharmaceutical Companies in France.

The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg) and cyproheptadine (1 mg/kg) (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively) blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v) and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France) and cyproheptadine (1 mg/kg) could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

Serum thyroid-stimulating-hormone concentration as an index of severity of major depression.

Alterations in thyroid axis are common in depression and subclinical hypothyroidism may predispose to recurrent depressive episodes and resistance to antidepressants. The same normal reference ranges are used in both depressive and non-psychiatric patients to detect hypothyroidism. We hypothesized that in depressive patients, serum TSH (thyrotropin) elevation within the normal reference range (>/= upper 25th percentile) may be related to patients' characteristics reflecting the severity of the depressive illness. We analysed, in a cross-sectional study, the relationship between serum TSH and serum-free thyroxine (T4) concentrations and different demographic and psychiatric characteristics in 94 depressive in-patients with DSM-III-R criteria for major depression. The frequency of subclinical hypothyroidism (normal serum T4, higher than normal serum TSH) was 5.3 %. In univariate analyses patients who had serum TSH concentrations >/= upper 25th percentile of the normal range were more likely to have recurrent depression, longer disease duration, higher number of episodes of major depression, higher number of previous suicide attempts and higher body mass index than those patients who had serum TSH concentrations < upper 25th percentile of the normal range (age-adjusted p<0.05). Stepwise logistic regression analysis showed that serum TSH >/= upper 25th percentile of the normal range was positively associated with recurrent depression (p=0.0001), presence of somatic disease condition (p=0.04), marital status (p=0.06) and number of suicide attempt (p=0.1). On the other hand, significantly higher serum TSH concentrations were observed in patients with recurrent depression, melancholia and associated somatic disease conditions. Correspondence analysis showed that serum TSH in the higher 25th percentile of the normal reference range projected together with the presence of melancholia, psychiatric and somatic disease conditions, severe major depressive episodes, recurrence of depressive episodes, prescription of at least two antidepressants or non-response to two antidepressants, and previous suicide attempts. Our study suggests that serum TSH concentration in the upper 25th percentile of the normal reference range may be associated with characteristics of severe major depression. Further prospective studies are needed to establish whether serum TSH concentration in the upper 25th percentile of the normal reference range is a contributory causal factor or a consequence of the severity of major depression.

Dopaminergic drug response and the genotype (Taq IA polymorphism) of the dopamine D2 receptor.

The genotype of the receptor with which a particular drug interacts may be a between- subject factor that modifies the pharmacodynamic and consequently the therapeutic response to drugs. Subjects with A1 allele (Taq IA restriction fragment length polymorphism) of the gene encoding for the dopamine D2 receptor (DRD2) seem to express lower number of DRD2 compared to subjects who do not have this allele. We investigated whether subjects homozygous for the A1 allele of the DRD2 gene have decreased response to DRD2 stimulation by apomorphine when compared with those homozygous for the A2 allele. Two hundred and two Caucasian subjects were genotyped for DRD2 Taq IA polymorphism, 6.9 % had the genotype A1A1 and 65% A2A2. Nine homozygous subjects/group were selected for the apomorphine study. Five, 10 and 20 &mgr;g/kg of apomorphine were administered subcutaneously according to a randomized crossover design. The main pharmacodynamic criterion was the plasma growth hormone increase induced by apomorphine. Secondarily, we measured oral temperature responses and yawns in response to apomorphine. Plasma apomorphine concentrations were similar for the two matched and only genotypically different groups. Apomorphine dose-dependently increased serum growth hormone concentration, and significant effect of time, dose by time interaction but no effect of genotype or genotype by dose interaction was shown. Apomorphine decreased body temperature, significant effect of dose, time, dose by time interaction but no effect of genotype or genotype by dose interaction were observed. The number of apomorphine-induced yawns increased dose-dependently but no significant difference between groups occurred. Thus, in this study apomorphine-induced responses were not modified by DRD2 Taq IA polymorphism although the power of the study could be insufficient to detect subtle differences.

Dose-related effects of amisulpride on five dimensions of psychopathology in patients with acute exacerbation of schizophrenia.

The present analysis investigated symptom-specific dose-response relationships of the atypical antipsychotic amisulpride (AMI) in schizophrenic patients. The effects of different AMI doses on five different symptom dimensions of the Brief Psychiatric Rating Scale (BPRS) were analyzed. Results on global efficacy and safety parameters have been previously published. Four AMI doses (100 mg/day [AMI100], 400 mg/day [AMI400], 800 mg/day [AMI800], 1200 mg/day) were compared with 16 mg haloperidol (HAL16) in a multicenter, double-blind, randomized, parallel-group, 4-week trial. A total of 319 patients with acute exacerbation of schizophrenia (DSM-III-R) were included. AMI100 was compared with the other AMI doses, and HAL16 was compared with all AMI dosage groups. Response on BPRS factors defined as > or = 40% improvement and ORs were computed. An optimal AMI dose was calculated for each BPRS factor based on linear and quadratic regression. For all BPRS factors, inverted u-shaped dose-response curves emerged (r2 > 95%). The estimated AMI dose optimum for the BPRS factors activation/ agitation (760 mg), thought disturbances (716 mg), and hostility/suspiciousness (694 mg) was higher than that for anergia/negative symptoms (584 mg) and depression/anxiety (672 mg). Significant differences (p < 0.05) were found for AMI400/800 versus AMI100 (thought disturbances, hostility/ suspiciousness), for AMI400/800 versus HAL16 (depression/anxiety, thought disturbances, hostility/suspiciousness), and for AMI400 versus HAL16 (anergia/negative symptoms). ORs for response of the BPRS factors depression/anxiety, anergia/negative symptoms, and hostility/suspiciousness were highest under treatment with AMI400 compared to AMI100 and HAL16. For the BPRS factors thought disturbances and activation/agitation, the highest response chance emerged under AMI800 compared to AMI100 or HAL16. AMI seems to show the best clinical efficacy in acutely schizophrenic patients in a moderate dose (400-800 mg/day), with a somewhat lower dose optimum for negative than for positive symptoms. The present finding of distinct dose-response relationships of AMI regarding the BPRS dimensions is in accordance with studies on the mechanism of action of AMI and provides a useful rationale for the clinical treatment of schizophrenic patients with AMI.