Progress in drug research. Fortschritte der Arzneimittelforschung. Progres des recherches pharmaceutiques最新文献

Silver pharmacology is at the cross-roads. It has a long history as a chemosterilent but is currently denigrated by some vested interests and other 'knowledge monopolies'. It deserves better--particularly in these critical times of ever mounting incidence of antibiotic resistance. This reappraisal outlines some approaches to a dispassionate debate as to why we should, or should not, be reconsidering silver as an addition to (not a substitute for) other antibiotics at the front line of medicine. This will require more understanding about (i) the chemistry of silver in a biological environment; (ii) the different physical and bio-reactive properties of ionised silver (Ag(I)) and nanoparticulate metallic silver (Ag(o)); (iii) the antibiotic potential of both Ag(I) and Ag(o); and (iv) establishing objective Quality Controls for potential silver therapies. Six appendices (A-F) provide some technical data and focus further upon the need to clearly define (a) procedures for manufacturing nanoparticulate metallic silver (NMS); and (b) the purity and properties of NMS preparations--especially stability, antibiotic efficacy and safety of products offered for clinical evaluation. A further appendix (G) deals with some political considerations currently impeding impartial clinical research on silver therapeutics.

Celery preparations have been used extensively for several millennia as natural therapies for acute and chronic painful or inflammatory conditions. This chapter reviews some of the biological and chemical properties of various celery preparations that have been used as natural remedies. Many of these have varying activities and product qualities. A fully standardized celery preparation has been prepared known as an alcoholic extract of the seeds of a plant source derived from northern India. This is termed, Celery Seed Extract (CSE) and has been found to be at least as effective as aspirin, ibuprofen, and naproxen in suppressing arthritis in a model of polyarthritis. CSE can also reduce existing inflammation in rats. CSE has also been shown to provide analgesia in two model systems. CSE, in addition to acting as an analgesic and inflammatory agent, has been shown to protect against and/or reduce gastric irritation caused by NSAIDs, as well as act synergistically with them to reduce inflammation. The CSE was fractionated by organic solvent extractions, then subjected to column chromatography followed by HPLC and was characterized by mass spectrometry. This yielded a purified component that had specific inhibitory effects on Helicobacter pylori but was not active against Campylobacter jejuni or Escherichia coli. Additionally, toxicology studies did not reveal any clear signs of toxicity at doses relevant to human use. Also, unlike many dietary supplements, the available data suggest that CSE does not significantly affect the p450 enzyme systems and thus is less likely to alter the metabolism of drugs the individual may be taking. CSE may be a prototype of a natural product that can be used therapeutically to treat arthritis and other inflammatory diseases.

Bacteria represent the earliest form of independent life on this planet. Bacterial development has included cooperative symbiosis with plants (e.g., Leguminosae family and nitrogen fixing bacteria in soil) and animals (e.g., the gut microbiome). It is generally agreed upon that the fusion of two prokaryotes evolutionarily gave rise to the eukaryotic cell in which mitochondria may be envisaged as a genetically functional mosaic, a relic from one of the prokaryotes. This is expressed by the appearance of mitochondria in eukaryotic cells (an alpha-proteobacteria input), a significant endosymbiotic evolutionary event. As such, the evolution of human life has been complexly connected to bacterial activities. Hence, microbial colonization of mammals has been a progressively driven process. The interactions between the human host and the microbiome inhabiting the gastrointestinal tract (GIT) for example, afford the human host the necessary cues for the development of regulated signals that in part are induced by reactive oxygen species (ROS). This regulated activity then promotes immunological tolerance and metabolic regulation and stability, which then helps establish control of local and extraintestinal end-organ (e.g., kidneys) physiology. Pharmacobiotics, the targeted administration of live probiotic cultures, is an advancing area of potential therapeutics, either directly or as adjuvants. Hence the continued scientific understanding of the human microbiome in health and disease may further lead to fine tuning the targeted delivery of probiotics for a therapeutic gain.

Perna canaliculus (Green-Lippped Mussel) is found only in New Zealand waters and is cultivated and manufactured for both the food and nutraceutical industry world-wide. P. canaliculus has traditionally been used as a therapeutic to treat various arthralgias in both humans and animals; however, clinical research reports provide conflicting results. Numerous in vitro studies have reported anti-inflammatory activity of the mussel under various conditions and also demonstrated a synergistic effect with pharmaceutical medications such as non-steroidal anti-inflammatory drugs (NSAIDs) with P. canaliculus protecting the gastrointestinal mucosal lining against such medications. It is proposed that the anti-inflammatory activity demonstrated by P. canaliculus is predominantly due to the lipid fraction, however, among the major classes of compounds found in mussel meat, proteins and peptides are the largest with isolates demonstrating various anti-microbial, anti-inflammatory, anti-oxidant, bioadhesive and anti-hypertensive activities. A review of the bioactive components, their function and therapeutic application is outlined in this chapter. Furthermore, we hypothesise and provide supportive evidence that the gastrointestinal microbiota play an important role in disease processes such as Rheumatoid arthritis and Osteoarthritis and also in the efficacy of P. canaliculus in chronic inflammatory conditions. The metabolic capacity of intestinal microbiota can modify bioactive food components altering the hosts' exposure to these components, potentially enhancing or diminishing their health effects. Understanding the interaction of the bioactive compounds in P. canaliculus with commensal and pathogenic bacteria may facilitate the development of novel interventions to control intestinal and extraintestinal inflammation.

Plants of the genus Aloe have perhaps the longest recorded history of medicinal usage and are amongst the most widely used plants for traditional medicinal purposes worldwide. Aloe vera, Aloe ferox, Aloe arborescens and Aloe perryi are the best known and most widely used, but many other species are also used for their therapeutic properties. The Aloes have been used since ancient times, particularly for the treatment of microbial infections, gastrointestinal disorders and inflammatory conditions. In addition to their myriad uses in traditional therapeutics, the Aloes have also been used as components of cosmetic formulations, and in the food and beverage industries. Despite their wide acceptance, studies from different laboratories often report wide variations in the therapeutic bioactivities from within the same Aloe species, even when the same extraction procedures are used. Furthermore, leaves from individual Aloe plants within the same species may have widely varying levels of the bioactive phytochemicals. Phytochemical analyses have shown that many Aloe species contain various carbohydrate polymers (notably glucomannans) and a range of other low molecular weight phenolic compounds including alkaloids, anthraquinones, anthrones, benzene and furan derivatives, chromones, coumarins, flavonoids, phytosterols, pyrans and pyrones. There has been a wealth of information published about the phytochemistry and therapeutic potential of the Aloes (especially Aloe vera). Much of this has been contradictory. Intra- and interspecies differences in the redox state of the individual Aloe components and in the ratios of these components may occur between individual plants. These factors may all affect the physiological properties of Aloe extracts. Due to the structure and chemical nature of many of the Aloe phytochemicals, it is likely that many of the reported medicinal properties are due to antioxidant or prooxidant effects. The antioxidant/prooxidant activities of many Aloe phytochemicals depend not only on their individual levels, but also on the ratios between the various components and their individual redox states. Therefore, discrepancies between bioactivity studies are likely when using different crude mixtures. This report aims to summarise the phytochemistry of the Aloes and (a) examine how their constituents may be responsible for their medicinal properties and (b) some possible reasons for the wide variations reported for their medicinal properties and (c) their therapeutic mechanisms. Some future areas of research into the medicinal activities of this important genus are also highlighted.

Calcitonin gene-related peptide (CGRP), a 37 aminoacid-residue peptide, is a marker of afferent fibers in the upper gastrointestinal tract, being almost completely depleted following treatment with the selective neurotoxin capsaicin that targets these fibers via transient receptor potential vanilloid type-1 (TRPV-1). It is widely distributed in the peripheral nervous system of mammals where it is present as alpha isoform, while intrinsic neurons of the enteric nervous systems express predominantly CGRP-beta. Many gastrointestinal functions involve CGRP-containing afferent fibers of the enteric nervous system such as defense against irritants, intestinal nociception, modulation of gastrointestinal motility and secretion, and healing of gastric ulcers. The main effects on stomach homeostasis rely on local vasodilator actions during increased acid-back diffusion. In humans, release of CGRP through the activation of TRPV-1 has been shown to protect from gastric damage induced by several stimuli and to be involved in gastritis. In both dyspepsia and irritable bowel syndrome the repeated stimulation of TRPV-1 induced an improvement in epigastric pain of these patients. The TRPV-1/CGRP pathway might be a novel target for therapeutics in gastric mucosal injury and visceral sensitivity.

Genetic manipulation of the kallikrein-kinin system (KKS) in mice, with either gain or loss of function, and study of human genetic variability in KKS components which has been well documented at the phenotypic and genomic level, have allowed recognizing the physiological role of KKS in health and in disease. This role has been especially documented in the cardiovascular system and the kidney. Kinins are produced at slow rate in most organs in resting condition and/or inactivated quickly. Yet the KKS is involved in arterial function and in renal tubular function. In several pathological situations, kinin production increases, kinin receptor synthesis is upregulated, and kinins play an important role, whether beneficial or detrimental, in disease outcome. In the setting of ischemic, diabetic or hemodynamic aggression, kinin release by tissue kallikrein protects against organ damage, through B2 and/or B1 bradykinin receptor activation, depending on organ and disease. This has been well documented for the ischemic or diabetic heart, kidney and skeletal muscle, where KKS activity reduces oxidative stress, limits necrosis or fibrosis and promotes angiogenesis. On the other hand, in some pathological situations where plasma prekallikrein is inappropriately activated, excess kinin release in local or systemic circulation is detrimental, through oedema or hypotension. Putative therapeutic application of these clinical and experimental findings through current pharmacological development is discussed in the chapter.

Cardiovascular diseases are the most common causes of mortality worldwide. Hypertension and diabetes are the two major risk factors in the development of cardiac hypertrophy, ischemic heart disease, and cardiac failure. In Kuwait, high rate of prevalence of hypertension and diabetes has been documented. Previous studies have indicated altered activities of the BK-generating components in hypertension and diabetes. Bradykinin is pharmacologically active polypeptide that can promote both cardiovascular and renal function, for example, vasodilation, natriuresis, diuresis, and release of nitric oxide (NO). In addition, B2 kinin receptors are present in the cardiac endothelial cells which may enhance the biosynthesis and release of NO. It has been demonstrated that reduced urinary (renal) kallikrein levels may be associated with the development of high blood pressure in humans and spontaneously hypertensive and diabetic rats. The BK may produce its pharmacological effects via NO and cyclic GMP release. Furthermore, it is established that the BK has cardioprotective actions in myocardial ischemia and can prevent left ventricular hypertrophy. Also, transgenic mice carrying tissue kallikrein gene and overexpressing tissue kallikrein had reduced blood pressure. NO synthase and renal tissue kallikrein are both involved in blood pressure regulation. The ability of kallikrein gene delivery and the use of kinin B2 receptor agonists to produce a wide spectrum of beneficial effects make it a powerful candidate in treating hypertension, cardiovascular, and renal diseases. Strategies that activate kinin receptors might be applicable to the treatment of cardiovascular disease. Increased plasma prekallikrein levels in diabetic patients may serve as an indicator of developing hypertension and renal damage. Also high plasma and urine concentrations of tissue kallikrein may cause higher glucose levels in the blood.