The current concept tries to analyse four old drugs as essential parts of a treatment towards the progression of MS and possibly remyelinization to a certain degree. For the patient of today, recognitions of separate drugs, made by expensive, ethically doubtful, prolonged and little predictive research techniques is, at best, to considered as research for future patients. With a certain despair, patients with a progressive disease may feel forced to adapt to alternative treatments which are not supported by large studies and still try to keep away from other miraculous suggestions, to which the MS-patient is so excessively exposed from well-meaning friends. Is it possible to find a pathway between the controlled study and whichcraft?
If it is, the therapeutic goal must be adjusted to realities: not complete recovery, but stabilization and slight improval is attempted. After all, expensive therapies offer no more hope to victims of progressive disease (whereas pure RR-MS still offers the hope of complete recovery). The therapy must include dietary precautions and occupational measures, a tablet alone will not do.
Recently, Summer 2004, I have been aware of various studies concerning four old drugs, which appear promising in the therapy. Rather than discussing them singularly, I want to consider them here together. I am aware that my review is more superficial than the ones, I have performed here over the years. Even if these substances are rather harmless in singular, it is at least principially possible that they may cause undesirable interaction in the combination – although a favourable synergism seems more likely to expect. The drugs are comparatively cheap, having lost patency protection decades ago. For that reason, no drug firm will ever back expensive studies. Two of the substances are actually won on a herbal basis, but the chemically active substances have been identified and many drugs can be trailed to exotic or even rather unspectacular plants.
It is time to let the cat out of the sack: I am talking about minocycline, a tetracycline (here not used for its antibiotic properties), silymarin, curcumin and phosphatidylcholin (lecithin). Again, I must excuse a superficial review, which I hope to improve later, but I did not want to delay publication of this “cure.”
The amount of literature for its neuroprotective properties of minocycline is overwhelming, but searching for MS and minocycline in September 2004 only provided 6 hits. Minocycline has an effect completely different from its antibiotic one it reduces production of matrix metalloproteinase 9 (MMP-9, also called Gelatinase B) and inhibits activity of what is left. Moreover, it has been shown to decrease migration of T-lymphocytes []. Tetracyclines varies greatly concerning that effect [], so the vainful use of some other drug for the hypothesis of chlamydia-infection can offer no indication of the possible effect of minocyclin. Since MMP-9 cleaves Interferon-beta (IFN-beta) [], minocycline appears a reasonable addition to IFN-beta-therapy (when this has proven unsuccessful) but the drug has been reported success in both experimental [] and clinical [] demyelinating disease. To that, a warning of too explosive enthusiasm should also be referred: “minocycline has clearly been shown to have variable and even contradictory (beneficial or detrimental) effects in different species and models of neurological disorders, and its"neuroprotective" mechanisms remain to be clarified” [].
Minocycline is an old drug, used predominantly for long-term (years) treatment of destructive bacterial skin diseases (acne and rosacea). Even here, minocycline is not necessarily meant to kill the bacteria, just to keep them off from producing connective tissue destructing enzymes. That implies that there is an exceptional experience with the long-term toxicology and other adverse effects, and the drug is cheap, available from competing generic firms. Rare properties for MS-drugs!
Like other tetracyclines, it is banned for use in children due to dental deposits, causing discoloration of the teath. In children below 8 years, more serious bone malacies have been described. Then there are the general adverse effects to antibiotic therapy, reminding us that we must live with the microbes without attempting to kill them all, since there will always come some others to fill the empty spaces – in this case possibly soars and other fungal diseases. Allergic and anaphylactic conditions are rare, compared to other antibiotics. Pigmental disorders of skin and nails have been seen after long-term, high-dose use of the drug.
Of bigger importance to me (and my morning coffee) is that minocycline should be given with a distance of at least two hours to the ingestion of milk products. It is not a dangerous interaction, thee drug is simply bound in the bowel by calcium complexes (the affinity responsible for tooth and bone malacies). So it is a vaste of drug, and it seems that a split dosage over the day (2 X 50 mg) is reasonable.
The interactions may be relevant: minoclin augments the effect, and thereby the toxicity, of methotrexat and cyclosporin, as well as some anticoagulant drugs. Contraceptives, on the other hand, loose effect while their absorption from the bowel is diminished. A rarely used drug (Isotretionin, for acne) should not be used together with minocyclin (the interaction resulting in increased intracranial pressure).
Silymarin (Silibinin), a plant flavonoid from milk thistle (Silybum marianum) is a natural acknowledged hepatoprotector which for decades has been wildly used in humans for its antihepatotoxic properties. It has strong antioxidant properties, of possible therapeutic concequences []. Recent studies have revealed that it induces recovery of pancreatic function experimentally [] and has an effect against the spread of malignant cells, possibly of use in breast cancer [], prostatic cancer [,] and metastatic spread in lung cancer []. Qi et al. [] suggested that an effect upon epidermal growth factor receptor, a key regulator in cell signaling pathways, is responsible for its antiprolifative effects. Concerning the cerebral effects, Wang et al. [] found an inhibition of microglia and the production of inflammatory mediators, such as tumour necrosis factor-alpha and
nitric oxide. Moreover, silymarin could effectively reduce superoxide generation and nuclear factor kappaB activation. The authors suggested that the latter was responsible for the drugs inhibitory effect upon microglia activation.
I am always suspecting drugs claimed to have universal beneficial properties. This one has not even been tested in MS. In connection with the other substances suggested here, there may be a weak indication for letting it join the cocktail, so to speak as an antiinflammative drug.
Curcurim is another herbal ‘anti-inflammatory’ substance, and this one has shown favourable properties in EAE [] – as have hundred of other of drugs, which were never shown any effect in human MS. Also curcumin has been shown effects against various cancer forms [,,] and has strong antioxidant properties [,,]. It has been demonstrated to cause a moderate increase in interleukin-4 production, considered favourable in autoimmune diseases.
Phosphatidylcholine (lecithine) is a naturally occurring (human) phospholipid with properties suggesting an effect upon remyelinization [] but otherwise, antiphospholipid antibodies have also been measured in some patients with multiple sclerosis [] and studies have found reduced levels in some MS patients []. If such an imbalance can be favourably influenced by exogenic addition is unproven. In fact, such therapy was favoured many decades ago, without causing any proven benefit. It caused no harm either.
In summary, there are considerable reasons to adapt minocline in a therapy attempt of progressive demyelinating diseases when other attempts fail or are excluded. Whether the other substances add any benefit remains to be proven – with the possibility that such a proof may indeed appear, but not necessarily in your lifetime. Theoretical considerations, added to the long experience with these drugs without serious adverse effects and the low price all help to include them in a cure, in which also beneficial interactions may play a role.
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