Conditional nutrition (I): concerning zinc as a beneficial but variable regulator of inflammation and experimental arthritis.

This article extends the concept of conditional pharmacology (Whitehouse and Vernon-Roberts 1991; Whitehouse 1995) that considers how both internal factors/disease and external/environmental factors may alter the availability or efficacy of exogenous drugs. The same and other conditioning factors may also affect the utility and value of many nutriceuticals that may be clearly beneficial in the context of inflammation but sometimes showing quite variable pharmaco-activity. This is illustrated by considering some factors affecting the bioavailability and pharmaco-efficacy of dietary ionic zinc, Zn (II) an essential trace metal and a critical regulator of inflammation and tissue repair. With chronic zinc deficiency (zincopenia) due to diet, drugs and/or disease, we can usually survive-but may not necessarily thrive. Some strategies to minimise zincopenia are considered, based upon finding efficient means for (1) preventing its cause and/or (2) using parenteral delivery of zinc supplements to circumvent dietary and enteric impediments to zinc bio-availability.

Silver Pharmacology: Past, Present and Questions for the Future.

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 Seed and Related Extracts with Antiarthritic, Antiulcer, and Antimicrobial Activities.

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.

Effect of adjuvant-induced systemic inflammation in rats on hepatic disposition kinetics of taurocholate.

It has been reported that the adjuvant-induced inflammation could affect drug metabolism in liver. Here we further investigated the effect of inflammation on drug transport in liver using taurocholate as a model drug. The hepatic disposition kinetics of [(3)H]taurocholate in perfused normal and adjuvant-treated rat livers were investigated by the multiple indicator dilution technique and data were analyzed by a previously reported hepatobiliary taurocholate transport model. Real-time RT-PCR was also performed to determine the mRNA expression of liver bile salt transporters in normal and diseased livers. The uptake and biliary excretion of taurocholate were impaired in the adjuvant-treated rats as shown by decreased influx rate constant k(in) (0.65 ± 0.09 vs. 2.12 ± 0.30) and elimination rate constant k(be) (0.09 ± 0.02 vs. 0.17 ± 0.04) compared with control rat group, whereas the efflux rate constant k(out) was greatly increased (0.07 ± 0.02 vs. 0.02 ± 0.01). The changes of mRNA expression of liver bile salt transporters were found in adjuvant-treated rats. Hepatic taurocholate extraction ratio in adjuvant-treated rats (0.86 ± 0.05, n = 6) was significantly reduced compared with 0.93 ± 0.05 (n = 6) in normal rats. Hepatic extraction was well correlated with altered hepatic ATP content (r(2) = 0.90). In conclusion, systemic inflammation greatly affects hepatic ATP content/production and associated transporter activities and causes an impairment of transporter-mediated solute trafficking and pharmacokinetics.

Anti-inflammatory glucocorticoid drugs: reflections after 60 years.

This review considers the problem of the serious concomitant side effects of powerful anti-inflammatory drugs modelled upon the principal human glucocorticoid hormone, cortisol. The very nature of the original bio-assays to validate their cortisol-like hormonal and anti-inflammatory activities ensured that pleiotropic toxins were selected for clinical studies. Other complicating factors have been (1) considerable reliance on bio-assays conducted in laboratory animals that primarily secrete corticosterone, not cortisol, as their principal anti-inflammatory adrenal hormone; (2) some differences in the binding of xenobiotic cortisol analogues (vis á vis cortisol) to transport proteins, detoxifying enzymes and even some intra-cellular receptors; (3) the "rogue" properties of these hormonal xenobiotics, acting independently of--but still able to suppress--hormonal mechanisms regulating endogenous cortisol; and (4) problems of intrinsic/acquired "steroid resistance", diminishing their clinical efficacy, but not necessarily all their toxicities. The rather gloomy conclusion is that devising new drugs to reproduce the effect of multi-potent hormones may be a recipe for disaster, in contexts other than simply remedying an endocrine deficiency. Promising new developments include "designed" combination therapies that allow some reduction in total steroid doses (and hopefully their side effects); sharpening strategies to limit the actual duration of steroid administration; and resurgent interest in searching for more selective analogues (both steroidal and non-steroid) with less harmful side effects. Some oversights and neglected areas of research are also considered. Overall, it now seems timely to engage in some drastic rethinking about (retaining?) these "licensed toxins" as fundamental therapies for chronic inflammation.

Drugs to treat inflammation: a historical introduction.

Drugs to treat inflammation are discussed under the following headings: (1) random discoveries covering copper, salicylates, heterocyclic diones, ACTH, adrenal steroids and disease-modifying agents (DMARDs); these include Au(I)-thiolates, chloroquine, and hydroxychloroquine, minocycline, cyclosporin, salazopyrine, D-penicillamine and methotrexate; (2) programmed NSAID developments covering salicylates and fenamates, arylalkanoates, diones, non-acidic NSAIDs, clozic, lobenzarit and coxibs; (3) synthetic glucocorticosteroids; and (4) 'Biologicals' for neutralising pro-inflammatory cytokines. Clinical problems are highlighted, particularly unacceptable side-effects affecting the GI tract, skin, liver, etc. that caused many drugs to be withdrawn. Drug combinations may overcome some of these problems. The bibliography has selected reviews and monographs covering 50 years of publications.

Surfactant protein expression in human skin: evidence and implications.

The presence of surfactant proteins (SPs), critical to local barrier and defense functions and usually associated with the lung, was revealed in adult and fetal human skin complementary deoxyribonucleic acid, in skin samples from three adult female donors and also in cultured fibroblasts, keratinocytes, and melanocytes. Using reverse transcription-PCR, SP-A, SP-B, SP-C, and SP-D messenger ribonucleic acid expression was detected to varying extents in the different skin sources. The stronger expression of SP-C in fetal skin, compared to adult skin, suggested that the role of this protein alters with age. Immunohistochemical studies showed variable distribution of SPs in human epidermis and dermis, confirming that these proteins are indeed translated and expressed in skin tissue. In vitro studies showed that the surface tension of SP-deficient artificial sebum is (a) lowered by skin-extracted SP-B and (b) further reduced to a level comparable to normal sebum by the additional presence of skin-extracted SP-A and SP-D, consistent with their surface tension-lowering capabilities in lung. The possible roles of SPs in skin, based on their known functions in the lung are discussed. However, their potential as therapeutic targets or diagnostic markers of skin disease remains to be elucidated.

Hepatic pharmacokinetics of propranolol in rats with adjuvant-induced systemic inflammation.

Systemic inflammation is known to affect drug disposition in the liver. This study sought to relate and quantitate changes in hepatic pharmacokinetics of propranolol with changes in hepatic architecture and physiology in adjuvant-treated rats. Transmission electron microscopy was used to assess morphological changes in mitochondria and lysosomes of adjuvant-treated rat livers. The disposition of propranolol was assessed in the perfused rat liver using the multiple indicator dilution technique. Hepatic extraction and mean transit time were determined from outflow-concentration profiles using a nonparametric method. Kinetic parameters were derived from a two-phase physiologically based organ pharmacokinetic model. Possible relationships were then explored between the changes in hepatic drug disposition and cytochrome P-450 activity and iron concentration. Adjuvant treatment induced the appearance of mitochondrial inclusions/tubularization and irregularly shaped lysosomes in rat livers. Livers from adjuvant-treated rats had (relative to normal) significantly higher alpha(1)-acid glycoprotein (orosomucoid) and iron tissue concentrations but lower cytochrome P-450 content. The hepatic extraction, metabolism, and ion trapping of propranolol were significantly impaired in adjuvant-treated rats and could be correlated with altered iron store and cytochrome P-450 activity. It is concluded that adjuvant-induced systemic inflammation alters hepatocellular morphology and biochemistry and consequently influences hepatic disposition of propranolol.

Prostanoids as friends, not foes: further evidence from the interference by cycloxygenase-inhibitory drugs when inducing tolerance to experimental arthritigens in rats.

Pharmacologists have generally been prejudiced against prostanoids, uncritically accepting their suppression as desirable therapy, especially for 'quick-fix' analgesia. This myopic perception for a long time ignored (a) the essentiality of prostanoid precursors in nutrition, (b) the physiological protective functions of natural prostaglandins (PGs) (vasculature, stomach, kidney), (c) resolution of inflammation after the expression of COX-2 and (d) increasing therapeutic use of either synthetic PGs (for erectile dysfunction, ophthalmic disorders, inducing parturition, etc) or their natural precursors, e.g., omega3-rich polyunsaturated oils, to treat arthritis. Experimental studies in rats have indicated that prostaglandins (E series) are (i) useful, perhaps auto-regulators of established immunoreactivity and (ii) able to amplify (or even induce) anti-inflammatory activity with other agents. Furthermore, anti-prostanoid therapy (APT) can be arthritigenic!!, interfering with the acquisition of tolerance to some arthritigens. For patients with rheumatoid arthritis this additional side-effect of APT, barely recognised to date, may actually perpetuate their arthritis by impairing prostanoid-mediated remission processes. Hopefully, recent adverse publicity about COX-2 inhibitory drugs might stimulate serious re-assessment of some traditional anti-inflammatory therapies with low APT activity for the management of both acute pain (non-addictive cannabinoids, celery seed, etc.) and chronic inflammation, e.g., Lyprinol (a mussel lipid extract).

D-Tyrosine as a chiral precusor to potent inhibitors of human nonpancreatic secretory phospholipase A2 (IIa) with antiinflammatory activity.

Few reported inhibitors of secretory phospholipase A(2) enzymes truly inhibit the IIa human isoform (hnpsPLA(2)-IIa) noncovalently at submicromolar concentrations. Herein, the simple chiral precursor D-tyrosine was derivatised to give a series of potent new inhibitors of hnpsPLA(2)-IIa. A 2.2-A crystal structure shows an inhibitor bound in the active site of the enzyme, chelated to a Ca(2+) ion through carboxylate and amide oxygen atoms, H-bonded through an amide NH group to His48, with multiple hydrophobic contacts and a T-shaped aromatic-group-His6 interaction. Antiinflammatory activity is also demonstrated for two compounds administered orally to rats.