A maturity model for the scientific review of clinical trial designs and their informativeness.

BACKGROUND: Informativeness, in the context of clinical trials, defines whether a study's results definitively answer its research questions with meaningful next steps. Many clinical trials end uninformatively. Clinical trial protocols are required to go through reviews in regulatory and ethical domains: areas that focus on specifics outside of trial design, biostatistics, and research methods. Private foundations and government funders rarely require focused scientific design reviews for these areas. There are no documented standards and processes, or even best practices, toward a capability for funders to perform scientific design reviews after their peer review process prior to a funding commitment. MAIN BODY: Considering the investment in and standardization of ethical and regulatory reviews, and the prevalence of studies never finishing or failing to provide definitive results, it may be that scientific reviews of trial designs with a focus on informativeness offer the best chance for improved outcomes and return-on-investment in clinical trials. A maturity model is a helpful tool for knowledge transfer to help grow capabilities in a new area or for those looking to perform a self-assessment in an existing area. Such a model is offered for scientific design reviews of clinical trial protocols. This maturity model includes 11 process areas and 5 maturity levels. Each of the 55 process area levels is populated with descriptions on a continuum toward an optimal state to improve trial protocols in the areas of risk of failure or uninformativeness. CONCLUSION: This tool allows for prescriptive guidance on next investments to improve attributes of post-funding reviews of trials, with a focus on informativeness. Traditional pre-funding peer review has limited capacity for trial design review, especially for detailed biostatistical and methodological review. Select non-industry funders have begun to explore or invest in post-funding review programs of grantee protocols, based on exemplars of such programs. Funders with a desire to meet fiduciary responsibilities and mission goals can use the described model to enhance efforts supporting trial participant commitment and faster cures.

Bacillus cereus cellulitis from contaminated heroin.

Concern exists over recent unexplained deaths among intravenous drug users. This report describes a patient with crepitant cellulitis who was admitted complaining of severe pain in the right forearm. Ultrasonography demonstrated gas in the tissues and he was referred for early surgical debridement of the arm. He was treated with intravenous benzyl penicillin, gentamicin and metronidazole and made a full recovery. Aspirate samples grew Bacillus cereus, morphologically similar to the isolate obtained from a sample of the patient's own heroin. Antibiogram and API 50CHB profiles were also similar. Further typing included 'H' flagellar serotyping, which found both blood and heroin strains to be non-typable, and amplified fragment polymorphism analysis, which showed that the strains were indistinguishable. Genotyping of two selected genes from B. cereus confirmed almost certain identity between the two strains. This case illustrates the potential virulence of B. cereus when inoculated into tissues, and to our knowledge, is the first report to demonstrate a conclusive microbiological link between contaminated heroin and serious sepsis in a drug user due to B. cereus.

Potent synthetic inhibitors of tyrosyl tRNA synthetase derived from C-pyranosyl analogues of SB-219383.

Novel pyranosyl analogues of SB-219383 have been synthesised to elucidate the structure-activity relationships around the pyran ring. Analogues with highly potent stereoselective and bacterioselective inhibition of bacterial tyrosyl tRNA synthetase have been identified. A major reduction in the overall polarity of the molecule can be tolerated without loss of the nanomolar level of inhibition.

Synthesis and activity of analogues of SB-219383: novel potent inhibitors of bacterial tyrosyl tRNA synthetase.

SB-219383 is a naturally occurring antibiotic, which acts by inhibition of tyrosyl tRNA synthetase. Semi-synthetic derivatives of SB-219383 were prepared with the objective of elucidating the key features required for inhibition of tyrosyl tRNA synthetase in order to improve the antibacterial activity. Some ester and amide derivatives as well as monocyclic analogues exhibited sub-nanomolar inhibitory activity against tyrosyl tRNA synthetase.

ATP-Citrate lyase as a target for hypolipidemic intervention. 2. Synthesis and evaluation of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids and their gamma-lactone prodrugs as inhibitors of the enzyme in vitro and in vivo.

A series of (3R,5S)-omega-substituted-3-carboxy-3, 5-dihydroxyalkanoic acids have been synthesized and evaluated as inhibitors of the recombinant human form of ATP-citrate lyase. The best of these have Ki's in the 200-1000 nM range. As the corresponding thermodynamically favored gamma-lactone prodrugs, a number of compounds are able to inhibit cholesterol and fatty acid synthesis in HepG2 cells and reduce plasma triglyceride levels in vivo. The best of these, compound 77, is able to induce clear hypocholesterolemic and hypotriglyceridaemic responses when administered orally to rat and dog. These results provide evidence to support the hypothesis that compounds which inhibit ATP-citrate lyase have the potential to be a novel class of hypolipidemic agent, which possess combined hypocholesterolemic and hypotriglyceridemic activities.

ATP-citrate lyase as a target for hypolipidemic intervention. Design and synthesis of 2-substituted butanedioic acids as novel, potent inhibitors of the enzyme.

ATP-citrate lyase is the primary enzyme responsible for the synthesis of cytosolic acetyl-CoA in many tissues. Inhibitors of the enzyme represent a potentially novel class of hypolipidemic agent, which are anticipated to have combined hypocholesterolemic and hypotriglyceridemic properties. A series of 2-substituted butanedioic acids have been designed and synthesized as inhibitors of the enzyme. The best compounds, 58, 68, 71, 74 have reversible Ki's in the 1-3 microM range against the isolated rat enzyme. As representative of this compound class, 58, has been shown to exert its inhibitory action through a mainly competitive mechanism with respect to citrate and a noncompetitive one with respect to CoA. None of the inhibitors were able to inhibit cholesterol and/or fatty acid synthesis in HepG2 cells. This has been attributed to the adverse physicochemical properties of the molecules leading to a lack of cell penetration. Despite this, a lead structural class of compound has been identified with the potential for modification into potent, cell-penetrant, and efficacious inhibitors of ATP-citrate lyase.

Feasibility of pharmacotherapy in HIV-related affective spectrum disorders: an open trial with fluvoxamine.

Among HIV patients treated for AIDS-related adjustment, major depressive disorders and other affective disorders, we assessed in an open study the feasibility of using a serotonergic antidepressant (fluvoxamine). Thirty-five seropositive patients with the above conditions (22 men and 13 women) were followed over a minimum period of four weeks. At the end of the treatment, a large number of patients (77%) showed marked improvement. "Nuclear" depressive and anxiety symptoms remitted, while the "somatic" ones seemed less sensitive to treatment. Treatment had to be terminated prematurely due to side effects in only two patients (6%).

Perceptual and conceptual information processing in schizophrenia and depression.

Schizophrenic patients (n = 20), depressive patients (n = 20), and normal adults (n = 20) were compared on global vs local analyses of perceptual information using tachistoscopic tasks and on top-down vs bottom-up conceptual processing using card-sort tasks. The schizophrenic group performed more poorly on tasks requiring either global analyses (counting lines when distracting circles were present) or top-down conceptual processing (rule learning) than they did on tasks requiring local analyses (counting heterogeneous lines) or bottom-up processing (attribute identification). The schizophrenic group appeared not to use conceptually guided processing. Normal adults showed the reverse pattern. The depressive group performed similarly to the schizophrenic group on perceptual tasks but closer to the normal group on conceptual tasks, thereby appearing to be less dependent on a particular information-processing strategy. These deficits in organizational strategy may be related to the use of available processing resources as well as the allocation of attention.

Discern--an integrated prospective decision support system.

We present a new integrated decision support tool, called Discern, for prospective case management within a comprehensive Healthcare Network Architecture (HNA). Discern is an event-driven, expert system tightly integrated into this architecture. It can perform a variety of actions including generating alerts, ordering tests, and entering results. Over 100 institutions use Discern to automate care processes. Discern was designed to meet the demanding requirements for effective decision support.

Drug abuse treatment programs as centers for HIV-related research and treatment.

The Observational Data Base (ODB) is a multicenter, longitudinal effort of the Community Programs for Clinical Research in AIDS (CPCRA) designed to collect HIV-related data on a large number of HIV-infected patients receiving primary care from community based physicians and health care groups. Over 400 patients from the Addiction Research and Treatment Corporation have enrolled in the ODB. Compared to the remainder of the CPCRA, ARTC ODB enrollees are more likely to be female, African American or Hispanic and to have injectable drug use and heterosexual contact with an injectable drug user as risk factors. The ARTC ODB patient profile closely resembles the fastest growing segments of the AIDS epidemic.

ATP-citrate lyase as a target for hypolipidemic intervention. Sulfoximine and 3-hydroxy-beta-lactam containing analogues of citric acid as potential tight-binding inhibitors.

Citric acid analogues (+/-)-12a,b and (+/-)-17a,b, where one of the primary carboxylates has been replaced by a sulfoximinoyl and a 3-(3-hydroxy-beta-lactamyl) moiety, respectively, have been synthesized and evaluated as inhibitors of ATP-citrate lyase. The design of these inhibitors was based on methionine sulfoximine and tabtoxinine beta-lactam, potent, tight-binding inhibitors of glutamine synthetase. Both ATP-citrate lyase and glutamine synthetase employ phosphate-carboxylate anhydrides as a method for carboxylate activation during catalysis. Only one diastereomer, (+/-)-12a, displayed weak, reversible inhibition, while the remaining citrate analogues (+/-)-12b and (+/-)-17a,b were inactive against the lyase. No time-dependent inactivation of the enzyme was observed.

Treatment of generalized anxiety disorder: preliminary clinical experience with buspirone.

The authors reviewed pharmacologic treatment of generalized anxiety disorder (GAD), particularly treatment with benzodiazepine agents, and compared the antianxiety effects and dependence risks of these agents with those of nonGABAergic compounds such as buspirone--a new psychotropic drug--in the treatment of chronic anxiety. Forty outpatients who met DSM-III criteria for GAD were randomly assigned to double-blind treatment with buspirone or lorazepam. After 8 weeks, treatment was abruptly stopped and withdrawal reactions were evaluated at Weeks 9 and 10. After 3 to 4 weeks, buspirone's efficacy in treating GAD symptomatology was found to be comparable with lorazepam's, except for sleep disturbances, which were minimally affected by buspirone. After treatment was discontinued, buspirone-treated patients were free from withdrawal symptoms, while the symptoms of lorazepam-treated patients worsened at Week 9.

Panic disorder: review of the empirical and rational basis of pharmacological treatment.

The increasing interest in and clinical research on the nature and treatment of panic disorder and agoraphobia have produced and should continue to produce rapid progress in the accumulation of scientific knowledge in this field. This article reviews some basic aspects of the effective pharmacotherapeutic management of panic-agoraphobic patients. Research results with different drug classes are reviewed and their implications for effective treatment discussed. The final section deals with special issues of case management, such as choice of specific drug, length of treatment, and probability and frequency of relapse.

Differential changes in areas of social adjustment from depressive episodes through recovery.

The findings of the present short-term prospective study of 99 depressed outpatients further support previous cross-sectional observations to the effect that the course of depressive illness is often complicated by fluctuating social disturbances manifested by uneasiness in the work area, by disagreements with colleagues, and by difficulty in maintaining conflict-free relationships with significant others. By contrast, the incapacity to enjoy and use leisure time appeared less related to the symptomatologic variation in depression. Although we favor the hypothesis that impairment in leisure activity may represent a trait marker of depression, the hypothesis of it being a residual complication of repeated depressive episodes cannot be ruled out in view of short follow-up.

Clomipramine for panic disorder: I. The first 10 weeks of a long-term comparison with imipramine.

Clomipramine and imipramine treatments were compared in a sample of 152 panic disorders. Diagnosis was according to the positive criteria of DSM-III-R, but without exclusion of comorbid affective or personality disorders. The 2-year design provides non-blind treatment under typical clinical practice conditions, and it includes random assignment, periodic assessment with standardized measures, and comparable, flexible drug dosages. Findings on six outcome measures in the first 59 cases to complete 10 weeks showed both tricyclics to be markedly and equally effective for blocking panic attacks, alleviating phobic avoidance, and reducing nonspecific aspects of anxiety. Clomipramine's predominantly serotonergic action seemed not to determine a different action spectrum. During the first 2 weeks, clomipramine was significantly and unexpectedly superior to imipramine in both antipanic and antiphobic actions. These results require replication under double-blind conditions.

A proposed new approach to the clinical subclassification of depressive illness.

This paper focuses on the classification of mood disorders. Data are reported from 227 outpatients who met DSM-III-R criteria for Major Depressive Episode. Each patient was evaluated by the Semistructured Interview for Depression (SID), which was developed and organized according to a decision tree model. The SID was used both to identify the sample with major depressive disorders and, then, to subclassify them into five subtypes. Three bipolar types (I, II, III) and two unipolar types (recurrent and single episode) were distinguished, and comparisons among the subtypes are presented. Therapeutic implications of the classification are discussed in relation to recent advances in targeting short and long-term treatments for specific subtypes.

Tricyclic treatment of generalized anxiety disorder.

While tricyclic antidepressants (TCAs) have now long been used in treatment for depressive and panic-phobic disorders, we reviewed and reported on their efficacy in generalized anxiety states. These ill-defined states usually have admixtures of anxiety and depression. While there is no neat diagnostic categorization to fit this wasteland of yet-to-be-defined disorders, they show surprising responsiveness to imipramine. The onset of efficacy appears to begin at about 2 weeks or later and is probably superior to at least one well-known benzodiazepine, chlordiazepoxide, well beyond that time. It is not possible to dismiss these observed antianxiety effects as secondary to antidepressant effects or as attributable to the unintended inclusion of a peculiarly sensitive subset of individuals such as panic-phobic patients. These findings indicate that affect regulation by TCAs applies to so-called generalized anxiety as well as to depression and panic-phobic disorder. Brief reminders and guidelines are outlined for the possible clinical use of TCAs in anxiety disorders, but there remain more questions than answers. Several replication studies concerning the results reviewed here are now under way.

Corneal blood staining. An animal model.

Corneal blood staining was established in the rabbit cornea by injecting autologous, citrate-buffered blood in the anterior chamber. Increased intraocular pressure was maintained above 30 mm of Hg by self-sealing trans-limbal injections repeated every 12 hours. Typically, corneal edema developed in 3 days, followed several days later by a red discoloration that turned brown about 2 days later. Histopathologically, the edematous cornea disclosed endothelial swelling and attenuation with marked stromal edema. Histochemically, the red-stained cornea disclosed only extracellular hemoglobin particles; the brown-stained corneas showed extracellular and intracellular hemoglobin particles as well as intracellular hemosiderin in keratocytes. Spectrophotometric analysis of the keratectomy specimens suggested the presence of porphyrins in all stages of blood staining, including the edematous cornea. Oxyhemoglobin was found in red-stained corneas, while methemoglobin was present in the brown-stained corneas. It was concluded that endothelial degeneration uniformly accompanied corneal blood staining in this model and that keratocytes are actively involved in hemoglobin degradation.

Imipramine and chlordiazepoxide in depressive and anxiety disorders. I. Efficacy in depressed outpatients.

We randomly assigned 425 outpatients, independently classified as primarily depressed by two trained psychiatrists, to double-blind treatment with Imipramine hydrochloride, chlordiazepoxide hydrochloride, or placebo. Those patients who remained at least moderately depressed (following a two-week placebo washout period) were treated for an additional eight weeks. An endpoint analysis of 387 patients who completed two or more weeks of medication disclosed early therapeutic advantages of chlordiazepoxide. By week 4 of treatment, however, imipramine produced more improvement than did placebo and chlordiazepoxide. By six and eight weeks a general, marked therapeutic advantage was found for imipramine relative to placebo and to chlordiazepoxide on measures of depression, anxiety, anger-hostility, interpersonal sensitivity, and global improvement. Chlordiazepoxide-treated patients generally did significantly better on sleep difficulty but significantly worse on anger-hostility and interpersonal sensitivity than did imipramine- or placebo-treated patients.