Rationale for clinical trials of opiate antagonists in treating patients with personality disorders and self-injurious behavior

A subgroup of patients with personality disorders from the DSM-III-R (American Psychiatric Association 1987) "flamboyant" cluster is characterized by repetitive self-injurious behavior (SIB) apparently not motivated by suicidal intent. After describing the clinical and demographic characteristics of these patients, the clinical and preclinical evidence suggesting the involvement of endogenous opiate systems in this behavior is reviewed. Patients with personality disorders and SIB have been found to have elevated levels of plasma beta-endorphin. However, the available evidence is not sufficient to show whether this is a cause of or a consequence of SIB. Behavioral stereotypies resulting in self-injury in animals and SIB in mentally retarded patients have been shown to be abolished by opiate antagonist administration in a significant proportion of both groups. The available evidence suggests that clinical trials of oral opiate antagonist drugs should be undertaken because of the promise such drugs have in the treatment of this sometimes life-threatening disorder.     

Self-injurious behaviour, traumatic life events and alexithymia among treatment-seeking opiate addicts: prevalence, pattern and correlates

Objective

Aim of this study was to determine the prevalence and pattern of self-injurious behaviour (SIB) and identify the predictors of SIB among treatment-seeking opiate addicts.

Methods

Participants were 80 consecutively consenting opiate addicts admitted into community and inpatient treatment programmes of a large South London National Health Service (NHS) Mental Health Trust. Substance dependence was diagnosed with ICD-10. The following instruments were administered: self-injurious behaviour questionnaire, traumatic life events questionnaire, Toronto alexithymia scale and substance abuse assessment questionnaire.

Results

Lifetime SIB prevalence rate was 49% (95% CI = 37–60). There was no difference in lifetime SIB rates of male (50%) and female (46%) patients. The predominate function of SIB among opiate addicts was affect-regulation followed by self-punishment. Using a logistic regression, sexual harassment and difficulty identifying feelings were the only independent significant predictors of SIB, with the influence of age of first traumatic event and gender partialled out.

Conclusion

Given these findings, there is strong evidence to suggest that treatment of opiate addiction should involve routine screening for adult sexual trauma, deficits in emotional regulation and SIB. Where these problems are identified, appropriate psychological intervention should be integral to routine care for affected patients.     

Treatment of Amyotrophic Lateral Sclerosis: Lessons Learned from Many Failures

Amyotrophic lateral sclerosis (ALS) is one of the most complex neurodegenerative diseases, involving both cortical and spinal components of motor neuron circuitry and non-neuronal cells that support the motor neurons. There is no effective therapeutic for ALS, and compounds that have extended the lifespan of ALS mouse models have failed in clinical trials. This viewpoint discusses current information regarding the changing views about ALS and what the failures in clinical trials can teach us in the search for an effective treatment. Previous challenges and roadblocks in drug discovery for ALS are noted, and solutions to current limitations are discussed. Learning from the past and moving forward with a new mindset can translate into successful and effective treatment strategies in ALS and other related diseases.Amyotrophic lateral sclerosis (ALS), one of the most complex and unique diseases of the central nervous system, is characterized by the progressive degeneration of motor neuron circuitry, which includes neurons and cells that reside in the cortex, spinal cord, and the brainstem. Diminished motor function leads to muscle wasting, paralysis, and death, generally within 3–5 years of diagnosis. There is only one FDA-approved drug for the treatment of ALS, riluzole, which extends lifetime by only 2–3 months, without alleviating disease symptoms. ALS can have a genetic link or may sporadically occur in the patient. Although the symptoms of familial and sporadic ALS are indistinguishable, there are numerous pathways associated with disease etiology and pathology. Therefore, diagnosis and treatment offer many challenges.¹The past 10 years have witnessed an unprecedented pace of discoveries in ALS. Since the identification of mutations in the SOD1 gene, more than 25 genes have been directly linked, and 22 have been closely associated with ALS.² Although the function of the C9orf72 gene is not well understood, detection of its intron expansion in 80% of all ALS patients has been remarkable and has immense clinical implications.³ Developing insight from pathophysiological studies also began to provide information on how to treat ALS.⁴ It has become very clear that even though patients display similar pathologies, the underlying molecular and cellular causes are different, and that, like cancer and heart disease, one drug and one solution to ALS is not the direction medicinal chemists should be heading. This realization sets the stage for future clinical trials. Initially, inclusion criteria for clinical trials were based on gender, age, location of disease onset, and family history. However, we now appreciate the importance of heterogeneity among patients, and selection criteria for clinical trials need to focus on the cellular pathways that go wrong in specific individuals. Therefore, drug discovery should have the mindset that different molecules may be relevant only to select subsets of patient populations, and personalized medicine may be required based on the needs of the patient.⁵     

Comparison of Succinimidyl [125I]Iodobenzoate with Iodogen Iodination Methods to Study Pharmacokinetics and ADME of Biotherapeutics

Purpose

To assess the application of succinimidyl iodobenzoate (SIB) iodination method in labeling biotherapeutics to study their pharmacokinetics (PK) and biodistribution.

Method

An IgG molecule (protein-01) and a 40 KDa protein (protein-02) were evaluated. Pharmacokinetics (PK) and biodistribution of the radiolabeled IgG (¹²⁵I-protein-01) in mice compared parameters from SIB and Iodogen protein iodination labeling methods. In addition, PK of radiolabeled 40 KDa protein (¹²⁵I-protein-02) using SIB was compared with non-labeled protein-02 analyzed by ligand binding assay (LBA).

Results

Up to 72 h following a single IP injection to mice, the percentage of “free-label” determined by the soluble counts after TCA precipitation to total radioactivity in serum samples was 2.8–49.4% vs. <1.0% for ¹²⁵I-protein-01 iodinated via Iodogen or SIB methods, respectively, suggesting a higher in vivo stability of ¹²⁵I-protein-01 labeled via the SIB method. The serum exposure of ¹²⁵I-protein-01 was two-fold higher, and correspondingly, the tissue exposure was also higher (averaging 3.6 fold at 168 h) when using SIB protein labeling method than when using the Iodogen method. In addition, following subcutaneous (SC) administration to mice, the serum exposure of ¹²⁵I-protein-02 labeled via SIB method was similar to protein-02 measure by LBA.

Conclusion

In this study, iodination of proteins using SIB methodology has overcome the dehalogenation problem in vivo which is inherent in Iodogen method, and PK parameters of a protein iodinated via SIB were comparable to the un-labeled protein measured by LBA. The SIB iodination method is an improved labeling approach for biotherapeutics used in studying PK and biodistribution characteristics.     

How antipsychotics impact the different dimensions of Schizophrenia: A test of competing hypotheses

The clinical expression of schizophrenia is generally reported to be expressed by three to five different factors (i.e. positive, negative, disorganization, excitability, anxiety–depression symptoms). It is often claimed that antipsychotic medications are particularly helpful for positive symptoms, but not for the others, suggesting a differential efficacy for different aspects of the disorder. We formally tested this claim. Using Structural Equation Modeling in two large [1884 patients] clinical trials in schizophrenia, we compared the model of a common general effect of antipsychotics to models whereby the antipsychotics have multiple and differential effects on the different factors of the illness. We validated the generalizability of the model in further trials involving antipsychotics in chronic [1460 patients] and first-episode patients [1053 patients]. Across different populations, different trials and different antipsychotics – the best-fitting model suggests that symptom response in schizophrenia is underpinned by a single general effect with secondary and minor lower-order effects on specific symptom domains. This single-factor model explained nearly 80% of the variance, was superior to the assumption of unique efficacy for specific domains; and replicated across antipsychotics and illness stages. Despite theoretical and pharmacological claims the differential efficacy of antipsychotics on the various dimensions of schizophrenia is not supported in the prevailing data. The implication of this finding for the measurement of treatment response and our understanding of the neurobiology of antipsychotic action, for clinical practice and for future drug development are discussed.     

Sex selection bias in schizophrenia antipsychotic trials

The sex prevalence of schizophrenia is approximately equal, and yet clinical trials of new therapeutic drugs have been conducted, for the most part, with male participants. The authors reviewed the percentage of women in schizophrenia clinical trials of the new "atypical" antipsychotic medications. MEDLINE and Cochrane databases were searched for English-language randomized controlled trials involving risperidone, olanzapine, quetiapine, ziprasidone, and aripiprazole. Studies with a sample size of more than 50 and a subject diagnosis of schizophrenia, schizophrenia spectrum disorder, or broad psychosis were included for review. For each study, the following items were abstracted: source of support, pharmacotherapy, site location, treatment setting, patient phase, psychotic episode number, duration, number of men and women in the total sample, mean age of the sample, and the presence of women-specific inclusion/exclusion criteria. Sixty-seven published studies met criteria. The median percentage of women in the total sample was 33.3%, the minimum was 6.7%, and the maximum was 71.2%. A stepwise linear regression analysis showed that age (younger samples), center location (Unites States and Canada), treatment patient setting (inpatient), and ziprasidone trials were all associated with relatively lower percentages of women. Sex differences in antipsychotic pharmacokinetics and pharmacodynamics that may result in differential effectiveness and susceptibility to adverse effects cannot be ascertained when the percentage of women in clinical trials is as low as it is. The increasing shift toward outpatient rather than inpatient drug trials may help to increase the proportion of women.     

Self-injurious behaviour: a comparison of caffeine and pemoline models in rats

Self-injurious behaviour (SIB) is a debilitating behaviour disorder that can have life-threatening consequences. It is often exhibited in intellectually handicapped and autistic populations, and it has been modeled with pharmacological manipulations in animals. We have characterized the induction of SIB using high doses of caffeine and pemoline in rats. Caffeine only produced very mild SIB in a small proportion of the rats, when administered repeatedly at very high doses (140-185 mg/kg/day). All the caffeine-treated rats showed profound signs of caffeine-toxicity at these doses, and lower doses did not induce any self-injury. On the other hand, pemoline was effective across a range of doses (100-300 mg/kg/day), including doses that did not produce overt signs of toxicity (100-200 mg/kg/day). The topography of the tissue injury sites (tail vs. paws and ventrum) differed between caffeine and pemoline treatments, and across doses of pemoline. The speed of onset, the incidence, and the severity of SIB occurred in a dose-orderly manner across the pemoline doses, and there was substantial individual variability in the induction of SIB when a moderately high dose (200 mg/kg/day) was used. These individual differences in vulnerability to self-injure are reminiscent of the fact that some humans with specific neurobiological disorders express SIB and some individuals with those same disorders do not. Accordingly, the pemoline model of SIB may be useful to investigate the neurobiological basis of factors that contribute to etiology of SIB.     

Reasons that prevent the inclusion of Alzheimer's disease patients in clinical trials

Aim

To assess reasons that prevent Alzheimer''s disease (AD) patients from being included in clinical trials.

Methods

In 2009, we reviewed the Lille Memory Clinic''s case database to identify patients suitable for inclusion in four AD clinical trials. An initial selection was made on the basis of four criteria: (i) a diagnosis of AD (with or without white matter lesions [WML]), (ii) age, (iii) mini mental state examination (MMSE) score and (iv) symptomatic treatment of AD (cholinesterase inhibitors/memantine). Next, data on patients fulfilling these criteria were reviewed against all the inclusion/exclusion criteria for four clinical trials performed in 2009 at the Memory Clinic. Reasons for non-inclusion were analyzed.

Results

Two hundred and five patients were selected according to the four initial criteria. Reasons for subsequently not including some of patients in clinical trials were abnormalities on MRI (56.9%, 88.9% of which were WML), unauthorized medication (37.3%), the lack of a study partner/informant (37.1%), the presence of a non-authorized disease (24.4%), contraindication to MRI (9%), a change in diagnosis over time (3.9%), visual/auditory impairments (2.9%), alcohol abuse (2%) and an insufficient educational level (1%).

Conclusion

A high proportion of AD patients presented with vascular abnormalities on MRI. This was not unexpected, since the patients were selected from the database and, as shown in epidemiologic studies, cerebrovascular diseases are frequently associated with AD. The presence of a study partner is essential for enabling a patient to participate in clinical trials because of the need to record reliably primary and secondary outcomes.     

Reversal of a vigilance decrement in the aged rat by subtype-selective nicotinic ligands.

In humans, nicotine has been demonstrated to improve both normal and disordered attention, suggesting potential clinical utility for nicotinic ligands. However, attempts to replicate these findings in the rodent have met with some difficulty, thus hampering the search for specific receptor mechanisms underlying these effects. In the present studies, we sought to characterize the effects of nicotine and subtype-selective ligands in a group of aged rats, which show consistent deficits in sustained attention over prolonged sessions of responding in the five-choice serial reaction time task (5-CSRTT). Following the establishment of a replicable performance improvement with nicotine (0.4 mg/kg), we assessed the effects of both SIB 1765F (1-5 mg/kg) and AR-R17779 (20 mg/kg), agonist ligands with selective affinities for the alpha(4)beta(2) and alpha(7) receptor sites, respectively. We then attempted to block this effect of nicotine using the high affinity, competitive nicotinic antagonist DHbetaE (3 mg/kg). Finally, in an attempt to determine whether the psychostimulant profile of nicotinic agonists could be dissociated from their effects on attention, we compared the (R)- and (S)-enantiomers of SIB 1765F in the 5-CSRTT, and in their ability to increase locomotor activity. Reversal of a within-session decline in performance speed and accuracy by nicotine was mimicked by SIB 1765F, but not by AR-R17779, whereas DHbetaE antagonized all of the performance changes induced by nicotine. Finally, the (S)- but not the (R)-enantiomer increased locomotor activity and improved performance in the 5-CSRTT. These results support a critical involvement for the alpha(4)beta(2) nicotinic receptor in mediating the attention-enhancing properties of nicotine.     

From older toxic natural products to current drugs and drug candidates

Currently, and ignoring marine-sourced fatty acids/esters, there are 8 approved drugs(US FDA and Australia) that can be traced back to marine natural products initially isolated from a variety of sources. Six are directed towards cancers of man, one is for pain relief and one is an anti-HIV agent. These have come from the approximately 25,000 compounds currently reported from marine sources from approximately 1965. However,there are a substantial number of "toxic" agents that are either in clinical trials(as the initial compound or a derivative) or are potential "warheads" to be used with specific monoclonal antibodies. The 8 approved agents will be noted with brief comments, but the majority of the available time will be devoted to discussing agents from a variety of marine sources, that are either candidates for warheads, and/or have proceeded to PhaseⅡand Ⅲ trials in man against various cancers. The influence of older compounds that can be modified chemically to provide "interesting leads" will be one of the fundamental areas noted.     

Evaluation of drug treatment outcome in epilepsy: a clinical perspectiv

This article provides a comprehensive discussion of clinical outcome measures used in trials aimed at assessing the efficacy and safety of antiepileptic drugs. For efficacy, assessment still relies on careful documentation of changes in ictal activity as determined by seizure counts based on patients recall, direct clinical observation and (for absence seizures) EEG monitoring. In selected cases, assessment of seizure severity may also be indicated. The precise choice of outcome measures is largerly dependent upon the specific trial design. In shortterm regulatory trials, parameters such as time to nth seizure after randomization (or after achievement of target dosage) may be used as an index of antiepileptic efficacy, but the clinical relevance of such measures is questionable. In addon trials in refractory patients, changes in seizure counts and proportion of patients achieving 50%, 75% and 100% reduction in seizure frequency may be appropriate. For longterm monotherapy trials in newly diagnosed patients, proportion of patients achieving prolonged remission (1year or longer) usually represents the most clinically meaningful efficacy outcome. Retention of patients on the allocated treatment over time is also a valuable measure, but it should be regarded as a composite endpoint because decision to continue treatment is dependent on both efficacy and tolerability. At present, there is no universally accepted method for evaluating side effects, particularly those which can not be documented objectively. Spontaneous reports of symptoms or use of specific checklists have advantages and disadvantages. Studies aimed at ensuring greater standardization in safety assesment should be encouraged, especially with respect to need of obtaining quantitative estimates, and information on both prevalence and incidence of side effects should be reported in all trials.     

Intent-to-randomize corrections for missing data resulting from run-in selection bias in clinical trials for chronic conditions

In many clinical trials for chronic conditions a run-in period is used prior to randomization. Often, only those participants who meet certain criteria during the run-in phase go on to get randomized. The others, along with the information that they might have provided, are excluded from the study. This exclusion of the relevant response data from any subsequent study analysis can be considered as resulting in missing data; although quite common in practice, this approach has expectedly been shown to create a bias in favor of the active treatment when this active treatment is used during the run-in. Hence, many randomized clinical trials report overly optimistic results, with the extent of the bias depending in large part on how many otherwise eligible subjects were excluded due to the use of the run-in. If these biased trials are to contribute valid information to medical decision making, then the biases need to be corrected, and this involves accounting for all participants who were intended to be randomized. We propose specific imputation methods for doing so.     

Solubility of ( ± )-Ibuprofen and S ( + )-Ibuprofen in the Presence of Cosolvents and Cyclodextrins

Aqueous solubility is an important parameter for the development of liquid formulations and in the determination of bioavailability of oral dosage forms. Ibuprofen (IB), a nonsteroidal anti-inflammatory drug, is a chiral molecule and is currently used clinically as a racemate (racIB). However, the S form of ibuprofen or S(+)-ibuprofen (SIB) is the biologically active isomer and is primarily responsible for the anti-inflammatory activity. Phase solubility studies were carried out to compare the saturation solubilities of racIB and SIB in the presence of common pharmaceutical solvents such as glycerol, sorbitol solution, propylene glycol (PG), and polyethylene glycol (PEG 300) over the range of 20% to 80% v/v in aqueous based systems. The solubilities of the two compounds were also compared in the presence of cyclodextrins such as beta cyclodextrin (CD), hydroxypropyl beta cyclodextrin (HPCD), and beta cyclodextrin sulfobutyl ether sodium salt (CDSB) over the range of 5% to 25% w/v. Solubility determinations were carried at 25°C and 37°C. Cosolvents exponentially increased the solubility of both SIB and racIB, especially in the presence of PG and PEG 300. Glycerol was not very effective in increasing the aqueous solubilities of both compounds, whereas sorbitol solution had a minimal effect on their solubility. PG and PEG 300 increased the solubility of SIB by 400-fold and 1500-fold, respectively, whereas the rise in solubility for racIB was 193-fold and 700-fold, respectively, at 25°C for the highest concentration of the cosolvents used (80% v/v). Of the two compounds studied, higher equilibrium solubilities were observed for SIB as compared with racIB. The derivatized cyclodextrins increased the aqueous solubility of racIB and SIB in a concentration-dependent manner giving A_L type of phase diagrams. The phase solubility diagrams indicated the formation of soluble inclusion complexes between the drugs and HPCD and CDSB, which was of 1:1 stoichiometry. The addition of underivatized CD reduced the solubility of racIB and SIB via the formation of an insoluble complex. The S form formed more stable complexes with HPCD and CDSB as compared with racIB. The solubilization process is discussed in terms of solvent polarity and differential solid-state structure of racIB and SIB. The thermodynamic parameters for the solubilization process are presented.     

Acute ischaemic stroke in patients aged 80 years and older: focus on the tolerability of thrombolytic agents

Ischaemic stroke is a devastating disease in the elderly with 30-50% 90-day mortality. Thrombolysis for stroke is potentially life saving and disability sparing in this group but the number of elderly patients studied in clinical trials, particularly those aged > or = 80 years, has been small. Indeed, < 50 patients aged > 80 years have been treated in clinical thrombolytic trials of ischaemic stroke. However, there is no evidence of a differential treatment effect by age. Multiple cohort studies have suggested that the risk of symptomatic intracerebral haemorrhage among octogenarians is no different from that in younger patients. Thrombolysis can be safely offered to acute ischaemic stroke patients aged > or = 80 years, although robust data from randomized clinical trials are relatively scarce.     

Is selective reporting of clinical research unethical as well as unscientific?

BACKGROUND: Studies that do not confirm their prior hypotheses, otherwise called "negative" studies, receive less interest from different parties including authors, editors and sponsors, and so, not to publish such studies is a common phenomenon. Opinions differ on whether or not this phenomenon introduces imprecision into the assessment of health research and care. OBJECTIVE: The current paper gives arguments against and in favor of publishing "negative" trials, and tries to give suggestions for a more balanced approach to this problem. RESULTS: Arguments against publishing "negative" trials include: we need not publish erroneously "negative" trials; we need not publish a "negative" study out of worry that the favored treatment is inferior; full-length reports of "negative" trials devaluate the quality of literature, because the data are usually not so important, and generally receive little interest from readers, and so, not to publish them is a more or less "natural" matter of course. Arguments in favor of publishing "negative" trials include: no report reduces the flow of information because "negative" trials provide at least some evidence and balance against the overwhelming power of positive data readily accepted for publication; no report violates the promise to patient participants; studies that do not confirm prior hypotheses are especially important; not-publishing leads to unnecessary repetition of research. Initially, trials were frequently "negative" not only due to lack of power but also due to inappropriate hypotheses and poor designs. Currently, this is less so, and the issue of selective reporting, therefore, needs to be reassessed. Suggestions for a more balanced approach to the problem of selective reporting might include: careful planning before the trial begins, reduces the chance of biased and erroneously "negative" trials; any trial, "positive" or "negative", provides probabilities rather than truths; this notion does not explain away publication bias but does make it less of a problem; "negative" trials may not be appropriate for general journals but very relevant to specialist journals as well as other organs of specialist groups; ethical committees and trial review boards should address the issue of publishing as part of their function. CONCLUSION: Data from properly executed trials should routinely be made available. However, we should not forget that the empirical observations provided by clinical trials, are statistically tested, and that statistics are based merely on probabilities. It means that we must consider a more philosophical attitude to clinical trial evidence in terms of acceptance that scientific truths are rarely absolute.     

Selective serotonin re-uptake inhibitors in the treatment of self-injurious behaviour in adults with mental retardation

Self-injurious behaviour (SIB) amongst people with learning disabilities is very common and is often difficult to treat. This study supports the theory that serotonin is involved in the development of SIB in these individuals. Twelve patients suffering from mild to severe mental retardation were treated with either fluoxetine or fluvoxamine. Ten of them showed marked improvement of their SIB, clinically as well as objectively (according to scores on the adaptive behaviour scale). The treatment had to be discontinued in the other two patients because of the development of severe adverse effects to the medication. The results of this study are therefore in line with previous studies showing the effectivity of Selective Serotonin Re-uptake Inhibitors in the treatment of SIB in mentally retarded individuals. © 1998 John Wiley & Sons, Ltd.     

Active specific immunotherapy with autologous tumor cell vaccines for stage II colon cancer: logistics, efficacy, safety and immunological Pharmacodynamics

In the area of cancer treatment, immunotherapy with vaccines has suffered in the last five years, due to many clinical trial failures. One must keep in mind however, that many of the clinical trials conducted in the past decade were performed without the benefit of sound regulatory guidance or validated and compliant manufacturing processes. This has clearly been the case for patient specific, tumor cell vaccine therapy. The safety concerns that emanated within the regulatory agencies from the Somatic Cell Therapy concepts, translated to active specific immunotherapy with vaccines. Fortunately, in the past five years advances in understanding the immune system, improved design of clinical trials, improvement and compliance of manufacturing processes provided opportunities to significantly improve efficacy and safety. Clearly, the vaccine research establishment has learned the importance of not just selecting antigens but the requirement of tumor associated immunogens that can stimulate a functional immune response. Also, it has become clear that immunotherapy works best in situations of minimal residual disease. Finally, more realistic endpoints in clinical trials have been recognized and accepted by oversight review committees. This commentary describes the "trials and tribulations" of developing a patient specific, autologous tumor cell vaccine for therapy of Stage II colon cancer.     

Early rheumatoid arthritis: pitfalls in diagnosis and review of recent clinical trials

The treatment of rheumatoid arthritis (RA) has changed dramatically in the past decade as advancements in the understanding of the pathobiology of the disease have led to novel therapeutic agents. The recognition that early diagnosis and treatment leads to improvements in morbidity and mortality has altered the therapeutic strategy such that early therapy is now considered the standard of care.This review focuses on the challenges in making the diagnosis of early RA, including a broad differential diagnosis for inflammatory polyarthritis, poor performance of the standard classification criteria, difficulty in clinical assessment of synovitis, absence of absolute laboratory tests, inability of conventional radiography to detect bony changes early, and barriers to rheumatology care. Additionally, the pathogenesis of RA is highlighted, with particular emphasis on cytokine biology as it relates to therapeutic regimens. Relevant clinical trials in early RA are reviewed and discussed, including trials of combination disease-modifying antirheumatic drugs and biological therapy. The role of induction therapy as a novel therapeutic approach is highlighted. The search for predictors of response is reviewed and the external validity of the trials is analysed. Finally, the trials in early RA therapy suggest that swift intervention with combinations of medications is required for patients with severe RA. However, further research is needed to determine which regimen is appropriate for the individual patient with RA.     

Present and future drug treatments for chronic kidney diseases: evolving targets in renoprotection

At present, there are no specific cures for most of the acquired chronic kidney diseases, and renal transplantation is limited by organ shortage, therefore present efforts are concentrated on the prevention of progression of renal diseases. There is robust experimental and clinical evidence that progression of chronic nephropathies is multifactorial; however, intraglomerular haemodynamic changes and proteinuria play a key role in this process. With a focus on renoprotection, we first examine more established therapies--such as those that modulate the renin-angiotensin-aldosterone system--that can be used for the treatment of proteinuric renal diseases. We then discuss examples of novel drugs and biologics that might be used to target the inflammatory and profibrotic process, and glomerular injury, highlighting results from recent clinical trials.