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At least 1,369 records · Page 76Linked to original sources
PubMed1997

Interest of a therapeutic optimization strategy in severe ARDS.

STUDY OBJECTIVE: Evaluate the interest of the response to a therapeutic optimization as a predictor of prognosis in ARDS. DESIGN: Prospective study. SETTING: ICU of a University Hospital. PATIENTS: Thirty-six consecutive patients with severe ARDS addressed for extracorporeal carbon dioxide removal (ECCO2R). INTERVENTIONS: We studied the response during the first 2 days after arrival to the therapeutic optimization strategy consisting in a combination of the following: (1) decrease in extravascular lung water (diuretics or hemofiltration); (2) selection of the best ventilatory mode; (3) permissive hypercarbia; and (4) correction of hypoxemia by alveolar recruitment, additional continuous oxygen insufflation, body position changes (prone position), inhaled nitric oxide, enhancement of hypoxic pulmonary vasoconstriction with almitrine, and drainage of pleural or mediastinal effusions. In patients remaining severely hypoxemic despite these modalities, ECCO2R was then proposed. MEASUREMENTS AND RESULTS: Thirty-six patients were addressed after 8.3+/-5.5 days of mechanical ventilation. On arrival, mean simplified acute physiologic score was 46.8+/-14.2, multiple system organ failure score was 1.8+/-1.6, Murray score was 3.4+/-0.4, PaO2 was 75.3+/-31.3 (fraction of inspired oxygen [FIO2]=1) for a positive end-expiratory pressure level of 12.3+/-3.4 cm H2O. Nineteen of 36 patients improved their gas exchange within 2 days and their mortality was 21%. The seventeen remaining patients did not improve PaO2/FIO2; PaCO2 and airway pressures remained high and their mortality was 88%. This different response to therapeutic optimization appeared using stepwise logistic regression as the most predictive factor for mortality (p<0.05). CONCLUSIONS: In patients with severe ARDS, the response to an early performed therapeutic optimization used to improve hypoxemia appeared to be a highly discriminant factor distinguishing deceased from surviving patients.

Adolescent↗
PubMed2001

Delivery options and devices for aerosolized therapeutics.

Although inhalation is one of the oldest modes of drug delivery, it is currently receiving renewed attention. Prior to 1987, aerosolized therapeutics were delivered via systems that relied on chlorofluorocarbon propellant systems. The subsequent ban on all nonmedical uses of these inert gases stimulated pharmaceutical companies to investigate other propellant systems. Two hydrofluoroalkanes were effective. However, in some instances, the change in propellant required reformulation of the drugs to be delivered. In some cases, bioequivalence could be achieved at lower doses with reduced toxicity. Pressurized metered-dose inhalers (pMDIs) have been used to deliver many types of inhaled therapeutics since the 1960s. Their major limitation is that drug delivery and effectiveness are affected by patient factors, including coordination difficulties and problems related to breathing and breath holding in patients with airway disease. Dry-powder inhalers are being developed to deliver powdered formulations of drugs such as bronchodilators and anti-inflammatory drugs for the treatment of asthma and COPD, and, eventually, proteins, peptides, recombinant products, and gene therapeutics. These devices have been proven to be as efficient as pMDIs in clinical trials. In some cases, they deliver a greater amount of the drug to the lungs. Percentages of the emitted dose deposited in the lungs range from 15 to 40% with the current generation of these devices. Finally, metered-dose liquid inhalers also are under development. Drug deposition in the lung with devices that are currently being tested ranges from 30 to 80% of the emitted dose. The choice of delivery system depends on the effective dose, drug deposition, patient ability, patient acceptance, and cost. Patient education in the correct use of each device is essential to maximize the therapeutic benefit.

Administration, Inhalation↗
PubMed2004

Malignant pleural mesothelioma: update, current management, and newer therapeutic strategies.

The diagnosis and management of malignant pleural mesothelioma are major challenges that often frustrate both patient and clinician alike. Occupational asbestos exposure to crocidolite or amosite forms of the fiber is the most important known risk factor in North America and Western Europe. Other mineral fibers such as erionite, a naturally occurring fibrous zeolite crystal, are associated with mesothelioma in volcanic tuffs of the Cappadocia region of central Anatolia in Turkey. In addition, other possible factors such as the presence of simian virus 40 and genetic susceptibility have been associated recently with the development of mesothelioma in animal models. These latter findings are increasing our understanding of this disease. In addition, the discovery of elevated levels of various markers such as folic acid receptor alpha, cyclooxygenase 2, and multidrug resistance proteins 1 and 2 in mesothelioma tissue have opened up new areas of potential diagnostic and therapeutic importance. However, traditional treatment modalities--surgery, radiotherapy, and chemotherapy--have evolved slowly, and few gains in therapeutic efficacy have occurred. Recently, however, continuing research efforts have led to novel treatment strategies that are changing the way clinicians view a disease that has traditionally been managed with almost universal therapeutic nihilism. This review explores our current knowledge of this disease and presents current and novel therapeutic strategies.

Antimetabolites, Antineoplastic↗
PubMed2002

Tau therapeutics for Alzheimer's disease: the promise and the challenges.

The pathological diagnosis of Alzheimer's disease (AD) depends on the presence of plaques consisting of the beta-amyloid peptide as well as neurofibrillary tangles consisting of paired helical filaments (PHFs) of the tau (tau) protein. The role of each type of pathology in the pathogenesis and progression of AD remains unclear. Previous hypotheses suggested that these two processes were independent, whereas more recent data suggest that there may be a bidirectional interaction between these two pathological processes. The identification of the neurotoxic effects of beta-amyloid and the discovery of mutations responsible for early-onset Alzheimer's disease (EOAD) and their linkage to beta-amyloid overproduction, has made the amyloid hypothesis of AD the predominant influence for therapeutic targets. Several approaches have emerged from preclinical testing and have entered early phases of clinical developments. The recent identification of tau mutations and their linkage to progressive neurodegenerative disorders provides a counterbalancing influence on the search for therapeutic targets for AD. Therapeutic approaches that are targeted to either beta-amyloid or tau share certain features at the level of pharmacology and will face many of the same challenges as they progress through drug development paradigms. The aim of this article is to provide a brief overview of some of the commonalities and the challenges faced by tau-related therapeutic strategies. The issues discussed in this article are not exhaustively dealt with in either scope or detail.

Alzheimer Disease↗
PubMed2007

Development of new RNAi therapeutics.

RNAi-mediated gene inactivation has become a cornerstone of the present day gene function studies that are the foundation of mechanism and target based drug discovery and development, which could potentially shorten the otherwise long process of drug development. In particular, the coming of age of "RNAi drug" could provide new promising therapeutics bypassing traditional approaches. However, there are technological hurdles need to overcome and the biological limitations need to consider for achieving effective therapeutics. Major hurdles include the intrinsic poor pharmacokinetic property of siRNA and major biological restrictions include off-target effects, interferon response and the interference with endogenous miRNA. Recent innovations in nucleic acid chemistry, formulations and delivery methods have gradually rendered it possible to develop effective RNAi-based therapeutics. Careful design based on the newest RNAi/miRNA biology can also help to minimize the potential tissue toxicity. If successful with systemic application, RNAi drug will no doubt revolutionize the whole drug development process. This review attempts to describe the progress in this area, including applications in preclinical models and recent favorable experience in a number of human trials of local diseases, along with the discussion on the potential limitations of RNAi therapeutics.

Animals↗
PubMed2000

Intratumoral IL-12 gene transfer improves the therapeutic efficacy of IL-12 but not IL-19.

We have compared the therapeutic activity of IL-12 and IL-18 in mice carrying IL-2 gene-transduced syngeneic sarcoma Mc12. The IL-2 gene-transduced sarcoma has previously been utilized as an irradiated, genetically modified tumour vaccine. Murine recombinant IL-12 was capable of suppressing growth of the IL-2 gene-modified sarcoma Mc12 in syngeneic mice more efficiently than growth of the parental Mc12 sarcoma. In contrast, murine recombinant IL-18 could neither inhibit growth of the parental Mc12 sarcoma, nor suppress growth of its IL-2 gene-modified transfectant. These results suggest that although both of these cytokines are functionally related and participate in the induction of IFN gamma production as well as in cell-mediated immune cytotoxicity, in the murine sarcoma system only IL-12 is therapeutically active and exerts its therapeutic effect in concert with the IL-2 gene. Thus, intratumoral IL-2 gene transfer improves the therapeutic efficacy of IL-12; administration of recombinant IL-12 should therefore be considered as adjuvant in IL-2 gene therapy with irradiated, genetically modified tumour vaccines.

Animals↗
PubMed2003

Rethinking therapeutic action.

Like other core psychoanalytic constructs, the theory of therapeutic action is currently in flux, as theorists of differing persuasions propose different mechanisms. In this article, the authors attempt to integrate developments within and without psychoanalysis to provide a working model of the multifaceted processes involved in producing change in psychoanalysis and psychoanalytic psychotherapy. A theory of therapeutic action must describe both what changes (the aims of treatment) and what strategies are likely to be useful in facilitating those changes (technique). The authors believe that single-mechanism theories of therapeutic action, no matter how complex, are unlikely to prove useful at this point because of the variety of targets of change and the variety of methods useful in effecting change in those targets (such as techniques aimed at altering different kinds of conscious and unconscious processes). Interventions that facilitate change may be classified into one of three categories: those that foster insight, those that make use of various mutative aspects of the treatment relationship and a variety of secondary strategies that can be of tremendous importance. They propose that, in all forms of psychoanalytic treatment, we would be more accurate to speak of the therapeutic actions, rather than action.

Affect↗
PubMed2005

Nitric oxide donor drugs: an update on pathophysiology and therapeutic potential.

The discovery of the multiple physiological and pathophysiological processes in which nitric oxide (NO) is involved has promoted a great number of pharmacological researches to develop new drugs that are capable of influencing NO production directly and/or indirectly for therapeutic purposes (i.e, NO-releasing drugs, NO-inhibiting drugs, and phosphodiesterase V inhibitors). In particular, the so-called NO donor drugs could actually have an important therapeutic effect in the treatment of many diseases such as arteriopathies (atherosclerosis and its sequelae, arterial hypertension and some forms of male sexual impotence), various acute and chronic inflammatory conditions (colitis, rheumatoid arthritis and tissue remodelling), and several degenerative diseases (Alzheimer's disease and cancer). The old organic nitrates show some well-known pitfalls including the induction of tolerance and acute side effects related to abrupt vasodilation such as cephalea and hypotension, which limit their therapeutic indications. A low therapeutic index (i.e., peroxynitrite toxicity) has always characterised the sydnonimines class. A series of interesting new classes of NO donors are under intense pharmacological investigation and scrutiny (S-nitrosothiols, diazeniumdiolates and NO hybrid drugs), each characterised by a particular pharmacokinetic and pharmacodynamic profile. The most important obstacle in the field of NO donor drugs is represented by the difficulty in targeting NO release, and thereby its effects, to a particular tissue.

Cardiovascular Diseases↗
PubMed2006

Therapeutic use of the high-density lipoprotein protein and peptides.

High-density lipoprotein (HDL) therapy is a novel and emerging area of therapeutic development in the cardiovascular field. It attempts to supplement and improve the vascular benefit exerted by other agents that are active on lipid metabolism, for example, hypolipidaemic drugs. Furthermore, it takes advantage of the novel techniques of coronary evaluation. A number of reports have examined the potential therapeutic properties of the synthetic HDLs prepared by complexing recombinant apolipoprotein (apo) A-I(Milano), a variant form of native apoA-I, with phospholipids. The availability of synthetic HDL complexes containing recombinant apoA-I(Milano) has opened up a new era of therapeutic management for coronary disease. HDL formulations of recombinant apoA-I(Milano)-phospholipid complexes have clearly shown rapid regression of a focal carotid atheroma as well as powerful protection from myocardial infarction in a rabbit model. In a pilot study, ETC-216 showed a significant reduction in coronary plaque burden after five weekly treatments, assessed by intravascular ultrasound in patients with acute coronary syndrome. Other therapeutic options of HDL therapy have recently became available.

Animals↗
PubMed1997

Recent advances in the identification of alpha1- and alpha2-adrenoceptor subtypes: therapeutic implications.

The cloning of multiple subtypes of both alpha1- and alpha2-adrenoceptors has renewed interest in the therapeutic application of agents interacting with these receptors. Effort has primarily been directed towards the design of uroselective alpha1-adrenoceptor antagonists for the treatment of benign prostatic hyperplasia (BPH). Evidence is accumulating for the involvement of a novel alpha1-adrenoceptor, designated as alpha1L-adrenoceptor, in alpha1-adrenoceptor-mediated smooth muscle contraction in prostatic and other urogenital tissues. While several antagonists showing a high degree of uroselectivity in animal models have been identified, their clinical superiority over the currently available alpha1-adrenoceptor antagonists has not yet been demonstrated. It is possible that the interaction with alpha1-adrenoceptors, as yet uncharacterised subtypes, at non-prostatic sites contributes to the therapeutic activity of this drug class in BPH. The alpha1-adrenoceptor subtypes involved in the control of vascular tone are currently being evaluated, and the profile of interaction with the various alpha1-adrenoceptor subtypes may play a key role in the efficacy of cardiovascular drugs such as carvedilol. Alpha2-adrenoceptor agonists are now being employed for a variety of therapeutic applications, most involving actions on receptors within the central nervous system (CNS). These agents are useful in the treatment of hypertension, glaucoma, opiate withdrawal and attention deficit hyperactivity disorder (ADHD), and as analgesics and adjuncts to general anaesthesia. While subtype selectivity has not yet been applied to the design of new alpha2-adrenoceptor agonists for these applications, recent gene mutation/knock-out experiments have identified the alpha2-subtypes involved in some of these actions, and optimisation of a therapeutic profile may be possible. Furthermore, the design of agents combining affinities for multiple adrenoceptor subtypes, or the combination of a specific adrenoceptor affinity profile with another pharmacological action, may offer advantages over molecules selective for an individual adrenoceptor subtype.

Journal Article↗
PubMed2000

Therapeutic and chemical developments of cholecystokinin receptor ligands.

Cholecystokinin (CCK) is an important 'brain-gut' hormone located both in the gastrointestinal (GI) system and in the CNS. At least two different G-coupled high affinity receptors have been identified: the CCK-A and the CCK-B receptors. Although the complex biological role of CCK is, as yet, not fully understood, its connection with many different physiological processes both at the GI level and at the CNS level is now well established. There is much potential for therapeutic use of CCK receptor ligands, however, clear investigations have yet to be completed. Several chemical families have been investigated over the last 20 years to find potent, subtype selective and stable CCK receptor agonists and antagonists. The main goal was to discover new therapeutic drugs acting on GI and/or on CNS diseases and also, to obtain powerful pharmacological tools that could permit a better understanding of the biological role of CCK. Despite promising results from investigations into medicinal chemistry of CCK receptor ligands, the therapeutical applications of these ligands still remains to be defined. This article reviews the main biological role of CCK, the therapeutic potential of CCK-A and CCK-B receptor agonists and antagonists and the common compounds from the different families of ligands.

Animals↗
PubMed2006

Antimicrobial peptides: therapeutic potential.

A significant component of the innate immune system of a wide variety of animals and plants is arbitrated by cationic host defence peptides. In man, these peptides, in addition to exhibiting a direct antimicrobial activity, seems to provide a range of non-antimicrobial bioactivities related to defence, inflammation and wound healing. Despite the fact that such peptides have so far failed to reach the market, there are continued initiatives to advance such potential therapeutics to, and through, the clinic. The reasons behind such initiatives include: reduced manufacturing costs for peptides; allowing entry into therapeutic areas previously inaccessible due to cost; the continued identification of previously unknown bioactivities of such peptides; and the resurgence of interest in peptide therapeutics. As a result, clinical programmes based on cationic host defence peptides exist in the areas of infection, dermatology, cancer and inflammation. The probability of clinical success for host defence peptide-based therapeutics is on the rise as options for a wider range of clinical indications emerge.

Animals↗
PubMed2003

Emerging technologies that overcome biological barriers for therapeutic protein delivery.

In the past decade, genomic research and the nascent field of proteomics have exponentially increased the number of potential protein therapeutic molecules for treating medical needs that were previously unmet. To realise the full clinical potential of many of the novel protein drug entities arising from these intense research efforts, emerging protein delivery technologies may be required. Advanced delivery technologies may offer the ability to overcome biochemical and anatomical barriers to protein drug transport, without incurring adverse events, to deliver the agent(s) at a certain desired rate and duration, to protect therapeutic macromolecules from in situ or systemic degradation, as well as increase their therapeutic index by targeting the drug action to a specific site. This review will cover a myriad of novel and emerging technologies that are directed at bypassing biological barriers and that have shown promise in advancing the therapeutic potential of protein drugs.

Administration, Cutaneous↗
PubMed2003

Antibodies as therapeutic agents: vive la renaissance!

Until recently, the concept of antibodies as in vivo therapeutics was still considered to be an exceedingly ambitious goal. However, in 2003, the situation has been completely transformed, with 14 FDA-approved monclonal antibodies (mAbs), 70 in late stage clinical (Phase II+) trials and > 1000 in preclinical development. The driving force behind this reversal in fortune has been advances in antibody engineering and the emergence of novel discovery techniques which overcame stability and immunogenicity issues that had blighted previous clinical trials of murine antibodies. For indications as diverse as inflammation, cancer and infectious disease, it is clear that unique properties of antibodies make them safe, effective and versatile therapeutics. These drugs can be used to neutralise pathogens, toxins and endogenous mediators of pathology. As cell targeting reagents, antibodies can be used to modulate cytoplasmic cascades or to 'tag' specific cells for complement- or effector-mediated lysis. Antibodies can also be modified to deliver toxic or modulatory payloads (small molecules, radionuclides and enzymes) and engineered to bind multiple epitopes (bispecifics) or even to have novel catalytic activity (abzymes). The modular structure of immunoglobulins and the availability of antibody fragment libraries also make it possible to produce variable-domain therapeutics (Fab, single-chain and domain antibodies). Although exhibiting less favourable kinetics in vivo, these fragments are simple to express and have an increased tissue penetration, making them especially useful as neutralising agents or in the delivery of payload. The number of approved antibodies is expected to increase arithmetically in the near term, as the platform is adopted as a valid alternative to small molecule discovery. This review provides an introduction to the antibody discovery process and discusses the past, present and future applications of therapeutic antibodies, with reference to several FDA-approved precedents.

Animals↗
PubMed2004

Therapeutic potential of retroviral RNAi vectors.

The ability of small interfering RNA (siRNA) to mediate gene-specific post-transcriptional silencing in mammalian cells will undoubtedly revolutionise functional genomics, as well as drug target identification and validation. Furthermore, there is widespread excitement that siRNA itself might prove useful in the clinical setting. For those wishing to develop siRNA as a therapeutic agent, the most difficult obstacle to overcome will be delivery. Recently, several breakthroughs have highlighted viruses as excellent vehicles for siRNA delivery. Retroviruses, the transgene-delivery vector of choice for many experimental gene therapy studies, have been engineered to deliver and stably express therapeutic siRNA within cells, both in vitro and in vivo. These findings are important milestones for the development of siRNA as a gene therapy for treatment of viral infections, cancer, autoimmune syndromes and numerous genetic disorders. This review describes the development of retroviral siRNA vectors, highlights proof-of-concept experiments demonstrating their therapeutic efficacy and explores therapeutic targets particularly suitable for retroviral-mediated gene silencing.

Animals↗
PubMed2007

Strategies to achieve systemic delivery of therapeutic cells and microbes to tumors.

In order to more effectively treat cancer, targeted delivery of therapeutic agents will be needed. The creation of delivery vehicles capable of locating and entering tumors before delivering a therapeutic payload will, therefore, enable the design of more beneficial and less toxic treatment platforms. Although nanoparticles, microbubbles and liposomes may also partially address these issues, the use of biological agents as delivery vehicles presently holds much promise. Through the hijacking of natural pathogen or cell trafficking pathways it is possible to actively target such agents to the tumor; they are then capable of selective replication (multiplying their therapeutic potential) and may be directly cytolytic themselves and/or may be utilized to deliver therapeutic genes. These agents, such as oncolytic viruses, attenuated bacteria and eukaryotic cells (cellular immunotherapeutics and progenitor and stem cells) will be discussed along with the mechanisms employed to deliver them systemically to tumors, including disseminated disease and micrometsastases.

Animals↗
PubMed2001

A therapeutic area review of oncology products and players.

This article reviews the dynamics of the oncology market and treatment trends and provides strategic guidance to those concerned with new product discovery and development. Cancer is the therapeutic area of highest potential, with an annual market value expected to be in excess of US 40 billion dollars in 2020. The global incidence of cancer cases is forecast to more than double over the next 20 years. Investments in research and development will keep pace with the growing demand for effective treatments, aiming to fulfil the many and often discrete unmet medical needs. Recent breakthroughs promise more successful outcomes, particularly with the advent of more selective chemotherapy and novel therapeutic approaches. Among the latter, a number of angiogenesis inhibitors and monoclonal antibodies (mAbs) should show encouraging levels of efficacy by 2004. Oncology is a complex and high-risk therapeutic area that offers high rewards. It is appropriate for only the stronger or more focused serious players within the pharmaceutical industry. The winners will be the companies with a long-term strategic intent, a credible portfolio and engagement in appropriate alliances, particularly in discovery. The future presents ethical, clinical and commercial challenges, given the wide disparity of therapeutic outcomes among cancer patients around the world. The real success will thus be to treat cancer in innovative ways that benefit everyone and are, in volume and across the life cycle, commercially attractive to the treatment provider.

Journal Article↗
PubMed2003

Emerging therapeutic targets in chronic heart failure: part II.

Chronic heart failure is characterised by functional deficiencies of the myocardium. Structural abnormalities of the left ventricular wall occur in many cases as a consequence of myocardial infarction (MI). The overburdened postMI heart is characterised by an active reorganisation of the remaining myocardium. Increased expression and activity of matrix metalloproteinases lead to altered composition and arrangement of the extracellular matrix, which is accompanied by eccentric hypertrophy of cardiomyocytes. The altered geometry of the heart muscle fosters biomechanical stress, driving the heart into a dead-end situation. Clearly, novel therapeutic concepts must be developed to reverse this process. Part II of the current review will focus on emerging therapeutic targets for small molecule therapeutics in the fields of cardiac remodelling and impaired survival of cardiomyocytes in the diseased heart. Finally, innovative therapeutic concepts for heart gene therapy and replacement options for destroyed post-MI myocardium using embryonic and adult stem cells are described.

Apoptosis↗