Potent alpha 4 beta 1 peptide antagonists as potential anti-inflammatory agents

The migration, adhesion, and subsequent extravasation of leukocytes into inflamed tissues contribute to the pathogenesis of a variety of inflammatory diseases including asthma, rheumatoid arthritis, inflammatory bowel disease, and multiple sclerosis. The integrin adhesion receptor alpha 4 beta 1 expressed on leukocytes binds to the extracellular matrix protein fibronectin and to the cytokine inducible vascular cell adhesion molecule-1 (VCAM-1) at inflamed sites. Binding of alpha 4 beta 1 to VCAM-1 initiates firm adhesion of the leukocyte to the vascular endothelium followed by extravasation into the tissue. Monoclonal antibodies generated against either alpha 4 beta 1 or VCAM-1 can moderate this inflammatory response in a variety of animal models. Recently peptides containing a consensus LDV sequence based on the connecting segment-1 (CS-1) of fibronectin and cyclic peptides containing an RCD motif have shown promise in modulating leukocyte migration and inflammation presumably by blocking the interaction of alpha 4 beta 1 with VCAM-1. Here we describe novel, highly potent, cyclic peptides that competitively inhibit alpha 4 beta 1 binding to VCAM-1 and fibronectin at sub nanomolar concentrations. The structure of a representative analog was determined via NMR spectroscopy and used to facilitate optimization of peptide leads. The peptides discussed here utilize similar functional groups as the binding epitope of VCAM-1, inhibit lymphocyte migration in vivo, and are highly selective for alpha 4 beta 1. Furthermore the structure--activity relationships described here have provided a template for the structure-based design of small molecule antagonists of alpha 4 beta 1-mediated cell adhesion processes.     

Kinder therapy: Teachers as therapeutic agents.

The purpose of this article is to describe Kinder Therapy (from the German, kindergarten), a process that is based on the model of Filial Therapy developed by B. Guerney (1964) and the theoretical constructs of Individual Psychology. The authors developed and designed Kinder Therapy to train teachers to become therapeutic agents. This article presents a background on the development of Filial Therapy, an overview of the principles of Individual Psychology, and an explanation of Kinder Therapy. A case study illustrates the successful application of Kinder Therapy with a kindergarten child, the classroom teacher, and the school counselor. Also included are suggestions for variations on the Kinder Therapy approach, along with suggestions for future research. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

The potential of subtype-selective neuronal nicotinic acetylcholine receptor agonists as therapeutic agents

Neuronal nicotinic acetylcholine receptors (NAChRs) are pentameric ligand-gated ion channel receptors which exist as different functional subunit combinations which apparently subserve different physiological functions as indicated by molecular biological and pharmacological techniques. It is possible to design and synthesize novel compounds that have greater selective affinities and efficacies than nicotine for different NAChRs, which should translate into different behavioral profiles and therapeutic potentials. Examples of NAChR agonists studied are nicotine, SIB-1508Y, SIB-1553A and epibatidine. These compounds have different degrees of selectivity for human recombinant NAChRs, different neurotransmitter release profiles in vitro and in vivo and differential behavioral profiles. Preclinical studies suggest that SIB-1508Y is a candidate for the treatment of the motor and cognitive deficits of Parkinson's disease, whereas SIB-1553A appears to have potential as a candidate for the treatment of Alzheimer's disease. Epibatidine has a strong analgesic profile, however the ratio between pharmacological activity and undesirable effects is so low that it is difficult to envisage the use of this compound therapeutically. Nicotine has a broad profile of pharmacological activity, for instance demonstrating activity in models for cognition and analgesia. As for epibatidine, the adverse effects of nicotine severely limits its therapeutic use in humans. The discovery of subtype-selective NAChR agonists such as SIB-1508Y and SIB-1553A provides a new class of neuropsychopharmacological agents with better therapeutic ratios than nonspecific agents such as nicotine.     

Recombinant-DNA-derived insulin analogues as potentially useful therapeutic agents

Whilst insulin is a spectacularly successful drug for the management of diabetes mellitus, it remains difficult to mimic the physiological pattern of insulin secretion, even using the various quick-acting and insoluble formulations that are available. The introduction of recombinant-DNA technology to the manufacture of therapeutic insulin has made the rational design and production of insulin analogues with altered pharmacokinetic and pharmacological properties possible. Such analogues include 'monomeric' insulins, which do not form the insulin-zinc hexamer in solution and are absorbed more rapidly from the injection site, and long-acting insulins, which are absorbed very slowly at physiological pH. Many of these analogues are being tested clinically, and it is possible that the next generation of insulin therapy will be various combinations of rationally designed insulin analogues produced by industrial biotechnology.     

Theophylline derivatives as potential histamine H3-receptor antagonists

Previous results of histamine H3-receptors investigations allowed to formulate a general structure of H3-receptor antagonists. According to this model a series of compounds were obtained. As heterocycles they contained a theophylline moiety connected with a polar group (amine, ester, amide, and thiourea function) via an alkyl chain linked by a spacer to a lipophilic residue. The common distance between xanthine moiety and lipophilic rest was a six-link-chain. Selected compounds did not show significant H3-receptor antagonist activity and were weak antagonists at histamine H1-receptors.     

Quaternary pilocarpine derivatives as potential acetylcholine antagonists. 2. Alterations in the lactone and imidazole moieties

In order to investigate the chemical behavior of pilocarpine, as well as the factors which determine its pharmacological activity, systematic and specific structural changes involving the lactone and imidazole moieties have been performed. Series of model compounds with cyclic or open-chain structures and a variety of N-3 bonded chains obtained from previously prepared anticholinergic derivatives of pilocarpine have been synthesized. The changes included N-3 chains of different lengths with an acetylcholine-like structure, the introduction of nucleophilic groups such as ketoxime, hydroxamic, or both at the side chain, or following hydroxylaminolysis of the lactone, respectively. Specific structural alterations could be obtained by reacting with free hydroxylamine under carefully controlled conditions, and the existence of syn and anti isomers was disclosed in certain cases. The new groups in the pilocarpine derivatives influenced their degree of antagonism to acetylcholine. Several compounds displayed some antidotal activity.     

Hydroxyphthalocyanines as potential photodynamic agents for cancer therapy

A series of benzyl-substituted phthalonitriles, substituted at the 3-, 4-, and 4,5-positions, underwent varied condensations with phthalonitrile to give a series of protected (monohydroxy- and polyhydroxyphthalocyaninato)zinc(II) derivatives which were readily cleaved to give several hydroxyphthalocyanines (ZnPc) (phthalocyanine phenol analogues). Their efficacy as sensitizers for the photodynamic therapy (PDT) of cancer was evaluated on the EMT-6 mammary tumor cell line. In vitro, the 2-hydroxy ZnPc (32) was the most active, followed by the 2,3- and 2,9-dihydroxy ZnPc (39 and 45), with the 2,9,16-trihydroxy ZnPc (33) exhibiting the least activity. In vivo, the monohydroxy derivative 32 and the 2,3-dihydroxy derivative 39 were both efficient in inducing tumor necrosis at 1 micromol kg-1, but complete tumor regression was poor, even at 2 micromol/kg. In contrast, the 2,9-dihydroxy isomer 45, at 2 micromol kg-1, induced tumor necrosis in all animals treated, with 75% complete regression. These results underline the importance of the position of the substituents on the Pc macrocycle to optimize tumor response and confirm the PDT potential of the unsymmetrical Pcs bearing functional groups on adjacent benzene rings.     

Alpha-glucosidase inhibitors as potential broad based anti-viral agents

Fusion proteins were constructed between the porcine alpha2A-adrenoceptor and either wild-type (Cys351) or a pertussis toxin-resistant (Gly351) form of the G protein Gi1alpha. Addition of adrenaline to membranes expressing the fusion proteins resulted in concentration-dependent stimulation of their high affinity GTPase activity. The alpha2A-adrenoceptor-wild type Gi1alpha fusion protein produced substantially higher maximal stimulation of GTPase activity in response to adrenaline than that containing Gly351 Gi1alpha. Treatment of the fusion proteins as agonist-regulated enzymes allowed measurement of Vmax and turnover number for adrenaline-stimulation of the GTPase activity of each fusion construct. The turnover number of the alpha2A-adrenoceptor-Cys351 Gly Gi1alpha fusion protein was only 44'S, of that for the alpha2A-adrenoceptor-wild type Gi1alpha fusion protein. These data provide the first direct quantitative evaluation of the effects of a mutation of a G protein on the capacity of an agonist-occupied receptor to activate the mutant.     

3-Benzisothiazolylpiperazine derivatives as potential atypical antipsychotic agents

90K is a tumor-associated antigen. Using myelomonocytic cell line THP-1 we determined neopterin production and tryptophan degradation after exposure of cells to 90K in the presence and the absence of interferon-gamma. Interferon-gamma is a well known stimulus for THP-1 cells inducing e.g. neopterin production and tryptophan degradation. Treatment of cells with 50 micrograms/ml 90K induced significant neopterin formation, and the exposure of cells to 90K in addition to 100 U/ml interferon-gamma amplified neopterin production compared to the sole effect of interferon-gamma. In parallel, a significant degradation of tryptophan was observed in culture supernatants leading to the formation of kynurenine. When the cells were treated with the combination of 90K and interferon-gamma the degradation of tryptophan was further enhanced. The data demonstrate that tumor-associated antigen 90K interferes with immunocompetent target cells and is able to induce a biochemical response in monocytic cells.     

Evaluation of some acylamide derivatives as potential hypoglycemic agents

A series of new acylamide derivatives with piperidine, pyrrolidinyl and alanyl have been tested for their hypoglycemic activities. 2-(Pyrrolidynyl)-N-(3-chlorophenyl) acetamide and 2-(Piperazinyl)-N-(4-methoxy phenyl) acetamide were found most active hypoglycemic compounds. Probably the amides have mode of action similar to sulphonylureas.     

Vaccination against malaria. Disappointments and hopes

After the first in vitro cultivation of Plasmodium falciparum 21 years ago, the prospect of anti-malarial vaccination arose many hopes, but, in the end, it so far has mainly given rise to doubts and disappointments. Technically, the problem is particularly difficult. Plasmodium falciparum has a very complex antigenic structure with several hundreds, if not several thousands, of different epitopes for each of the four main evolutive stages of the parasite (sporozoites, merozoites, gametocytes, ookinetes) which correspond to different phase of the infection and could be a target for vaccination. Many of these epitopes are stage-specific and some of them vary from one strain to another. Adjuvants also play a major role and can qualitatively modify the type of immune response. The immune mechanisms also differ according to the final goal: anti-Plasmodium infection or anti-disease vaccine. Over the last few years, the first clinical assays have been carried out with the Spf66 vaccine, a synthetic complex protein directed against sporozoites and merozoites. In adults and children, the first results in South America and in East Africa were modest but encouraging. Unfortunately they were not confirmed by further studies in West Africa and South-East Asia. Two new types of vaccines are under preliminary clinical evaluation. One is directed against ookinetes of Plasmodium falciparum (Pfs25 and Pfs28) and can stop the transmission from the mosquito. The other is an anti-sporozoite vaccine with a new immunogen (RTS,S) in which the circumsporozoite protein is fused to the hepatitis B surface antigen and can protect against infestation. New prospects and improvements are offered by the technique of DNA vaccines and will probably also result from better knowledge of cellular and molecular biology of the parasite which is being extensively studied (genomic structure). If new promising perspectives exist, it is particularly important to be careful to avoid such disappointments as those caused, in the past, by a too-optimistic and over-publicized presentation of some preliminary results. It is now certain that one or several malaria-vaccines will be available, but no one can seriously say when, for whom and how. In any case, it is unrealistic to hope that vaccine(s) alone will be able to eradicate such an epidemiologically complex disease as malaria. It is probable that only the coordinated use of all the techniques available (anti-vectorial protection and fight, chemoprophylaxis and chemotherapy, vaccination) will lead to success.     

The taxoids. Comparative clinical pharmacology and therapeutic potential

Paclitaxel and docetaxel are 2 compounds from the new taxoid class of anti-cancer agents. Both drugs are very similar in preclinical activity, mechanism of action and spectrum of clinical activity. Some subtle differences in the intracellular retention of docetaxel may account for its lack of schedule-related myelosuppression and greater potency, and may be relevant to the skin toxicity and oedema which it produces. Early data suggest that there may be differing behaviour of anthracycline/taxoid combinations with respect to cardiotoxicity. Paclitaxel has been studied in several first-line combination therapy trials in ovarian cancer. Here, paclitaxel in combination with a platinum compound seems to have proven itself as a standard regimen. It is uncertain if docetaxel will be evaluated in this context. An abundance of clinical data is available for both analogues in the advanced, metastatic setting of breast cancer. Both also have been compared as single agents with doxorubicin with the results suggesting paclitaxel in a 3-hour infusion is inferior to the anthracycline (in terms of response rate), and those of docetaxel suggesting it is superior to the same dose of doxorubicin. This indirect comparison favours the activity of docetaxel; however, it is clear that in the dose/schedules studied, the taxoid compounds are not equitoxic. Either agent by itself, in the treatment of metastatic breast cancer, remains appropriate; however, lack of cumulative toxicity may make paclitaxel more attractive in some situations where prolonged administration is foreseen. Lung cancer trials have also confirmed the activity of both agents, although docetaxel appears to have slightly more promising activity in previously treated patients than paclitaxel. Paclitaxel in combination with cisplatin has been evaluated in randomised trials as first-line treatment of non-small-cell lung cancer (NSCLC). The results of these trials taken together suggest that this combination has an impact on survival similar to other new regimens now considered 'standard' in the front-line setting in this disease. Unfortunately, despite all the phase II data generated in numerous tumour types, little else can be said about the role of either taxoid in the 'standard' management of malignant disease. It will be some years yet before taxoid-based combinations have been evaluated sufficiently in randomised trials such that the impact of this novel class can be adequately assessed in terms of survival and cure rates.