Evaluation of potential antirheumatic drugs <i>in vitro</i> using lymphocytes and epithelial cells. The selective action of indoxole, methyl glyoxal and chloroquine

Mw, Whitehouse

doi:10.1111/j.2042-7158.1967.tb09594.x

Cited by 23 publications

(8 citation statements)

References 14 publications

(2 reference statements)

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“…(4) Non-specific physicochemical interactions with biomembranes: plasma (Norman et al 2004), mitochondrial (Whitehouse 1964), lysosomal, (Weissmann and Thomas 1963), intact lymphocytes (Morita and Munck 1964;Whitehouse 1967) or developing tissues (Whitehouse and Lash 1961). They are readily demonstrated in vitro using non-physiological doses of steroids.…”

Section: Mechanisms Of Action As Mainly Defined/understood For Cortisolmentioning

confidence: 99%

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Whitehouse

2010

Inflammopharmacol

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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.

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Section: Mechanisms Of Action As Mainly Defined/understood For Cortisolmentioning

confidence: 99%

Anti-inflammatory glucocorticoid drugs: reflections after 60 years

Whitehouse

2010

Inflammopharmacol

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“…Table 1 shows that in a protein-free medium the primary alcohols were all more potent in depressing thymidine incorporation into thymocytes than the corresponding NSAI acids. The sole exception was salicyl alcohol, inactive at 2 raM; at which concentration salicylate inhibits DNA synthesis in lymphocytes [3,6]. By contrast, two aliphatic alcohols (n-octanol and n-dodecanol) were no more potent as inhibitors of thymidine incorporation than solutions of the corresponding acids.…”

Section: :Experimentalmentioning

confidence: 81%

“…The incorporation of thymidine-6-3H into the acid insoluble fraction of twice washed rabbit thymocytes incubated in phosphate buffered Hanks' medium, was determined as described elsewhere [3].…”

Section: :Experimentalmentioning

confidence: 99%

Concerning the pharmacological activity of non-steroid anti-inflammatory drugs: Is the acidic function essential?

Whitehouse

Famaey

1973

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There are scattered reports, mainly in the patent literature, indicating that certain primary alcohols, amines and other nonacidic derivatives of nonsteroidal anti-inflammatory (NSAI) acidic drugs display anti-inflammatory activity (see for example [1,2]). This is of more than academic interest for, besides expanding the structure-:'action relationships, these reports may indicate a possible means of improving the therapeutic: ulcerogenic index of effective NSAI agetats.The assumption that these particular nonacidic agents must owe their in vivo activity to bioeffective acidic metabolites, has not been rigorously questioned. This communication presents evidence that a variety of NSAI car~boxylic acids and their corresponding primary alcohols have very similar effects on cellular metabolism. In fact, these particular alcohols are rather more potent than the acids under in vitro conditions which preclude their rapid conversion to the related acids. :ExperimentalDrugs and carbinols were added to incubations of lymphocytes and various radioactive ions or metabolites, from solutions in DMSO or DMF yielding a final concentration of organic solvent never exceeding 2 % v/v DMF or 1% v/v DMSO. The incorporation of thymidine-6-3H 1) Present Address:

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“…There is a plethora of names in the literature to describe the ring system (3) or its derivatives. The name most often used is benzofurazan (prefixed by the site and name of the substituent) for the benzofurazan and benzoiuroxan systems, and Nbf-C1* (or NBD-CI) for 4-nitro-7-chlorobenzofurazan.…”

Section: Nomenclature and Structurementioning

confidence: 99%