The "Statins": Lovastatin, Mevastatin, Pravastatin,
Simvastatin (HMG CoA Reductase Inhibitors)
Walker (1992) has recently reviewed the worldwide experience of the beneficial use of this interesting group of antifungal antibiotics in the treatment of hyperlipidemia and atherosclerosis. La Ville et al (1989), Oogushi (1991) and Zhu et al (1992) have documented the ability of these antibiotics to prevent atherosclerosis in animals.
Kuo et al (1989) found that lovastatin administered for a period of one year was highly effective in treating the hypercholesterolemia which is a common complication of cardiac transplantation appears to play a role in the accelerated rate of coronary atherosclerosis seen following the procedure. They found that lovastatin was uniformly well tolerated and when given in modest dosages, lovastatin appears to be a safe and effective therapy for hypercholesterolemia in cardiac transplant recipients.
Mevastatin (originally called compactin) is a Penicillium-derived antibiotic which was isolated in Japan in 1976 by Endo et al. It was found to reduce LDL cholesterol levels in humans.
In 1978, Brown et al determined that cholesterol synthesis was inhibited in human cell cultures. Several years later. a structurally-related antibiotic, lovastatin (mevinolin) was isolated from cultures of Aspergillus and Monascus species. Chemically modified versions, pravastatin and simvastatin were subsequently developed.
The mechanism of action in lowering cholesterol was the finding that these drugs, often referred to as "the statins", competitively inhibited HMG CoA reductase, the rate controlling enzyme in the biosynthetic pathway for cholesterol. This finding led to the statins becoming known as the HMG CoA reductase inhibitors. Discovering such inhibitors of cholesterol synthesis has given the proponents of the cholesterol etiology concept of atherogenesis more than sufficient reason to advance that postulate. The only problem, is that in humans, there is now recognized an interesting cholesterol synthesis-protecting mechanism which dramatically compensate for the HMG CoA reductase inhibiting effect of these drugs; humans simply make more of the enzyme which overcomes the inhibiting effect! This phenomena was suggested by the work of Grundy and Bilheimer (1984) who found no correlation between the magnitude of change in rate of production of cholesterol synthesis and the decrease in the levels of plasma LDL.
Obviously, something is very wrong with the generally accepted concept of HMG CoA reductase inhibitors lowering cholesterol and thereby preventing atherosclerosis. Considerable research into other possible biochemical mechanisms to explain the fall of LDL in patients treated with these antibiotics have failed to fully explain how these antibiotics actually work. The missing piece of the puzzle is that the mechanism of action is the antifungal nature of these antibiotics in a disease process which has a fungal etiology.
Each of these fungal-derived antibiotics is composed of a naphthalene ring system, a molecule well known to possess antifungal activity.
Antifungal Activity of the Statins
Engstrom et al (1989) have reported the antifungal effects of two inhibitors of 3 hydroxy 3 methyl glutaryl coenzyme A reductase tunicamycin and lovastatin on nuclear division in the myxomycete Physarum polycephalum. They found that lovastatin exerts its inhibitory effects on Physarum nuclear division by decreasing the activity of HMG CoA reductase.
Lorenz and Parks (1990) found that lovastatin to be very effective in
lowering the sterol levels of Saccharomyces cerevisiae resulting in inhibiting
the growth of the organism.
Equally provocative was their finding that lovastatin increased the effect of three azole antifungal drugs (ketoconazole, clotrimazole, and miconazole) from 6 to 32 fold when lovastatin was added to the culture media.
Ikeura et al (1988) Documented the growth inhibition effect of yeast by compactin analogues.
Bard et al (1988) found that lovastatin resistant mutants of Saccharomyces cerevisiae were found to be also somewhat resistant to another antifungal antibiotic, nystatin. This finding suggests that some similarity may exist in the mode of action of lovastatin and the antifungal antibiotic nystatin.
The antibiotic neomycin is long known for its unexplained dramatic beneficial effect upon hyperlipidemia (Hoeg et al 1984) (Gurakar et al 1985).
An interesting and most provocative finding is that neomycin is effective only when administered orally and not when given by system routes. The postulated explanation for this finding is that perhaps neomycin forms insoluble complexes with bile acids in the gut similar to the postulated explanation to that posed for the sequestrants of bile acids.
In 1967, Samuel and associates noted that the ingestion of small amounts of neomycin was very effective in lowering the plasma cholesterol.
Only neomycin and nicotinic acid (niacin) are shown to lower plasma Lp(a) levels therapeutically, although anabolic steroid medication causes lower plasma Lp(a) concentrations (Doetsch et al 1991).
Antifungal Activity of Neomycin
Neomycin is an aminoglycoside antibiotic which is considered to be non-absorbable and effective against only bacteria. However, the scientific literature is not silent regarding the antifungal activity of neomycin. Koshinsky et (1988) reported the sensitivity of Saccharomyces cerversiae to neomycin.
The fact that neomycin is not absorbed from the gut and is ineffective in lowering plasma lipoproteins when given systemically supports the concept that it is the neomycin-sensitive fungal population of the gut, including mycotoxin-producing fungi colonizing the intestinal stream gut which is the source of the hyperlipidemia. This same type of opposite effects of oral versus systemic administration of a lipid lowering agent was also documented in the case of colchicine, oral colchicine (which is absorbed) lowered plasma lipids, injected colchicine did not.
Aspirin (Acetyl Salicylic Acid)
The universal use of aspirin to prevent atherosclerosis and its complications is well documented (Waters and Lesperance 1991).
The Antifungal Activity of Salicylic Acid
Phenol (carbolic acid) is the parent of salicylic acid, the active chemical structure of all of the salicylates. Salicylic acid was first synthesized and manufactured from phenol by Kolbe and Lautemann in 1860. Phenol is one of the most potent of all of the known antiseptic agents. Phenol is bactericidal at a concentration of 1% and fungicidal at a concentration above 1.3%. GG ref here. Quite predictably, salicylic acid also possess significant antifungal activity. The fact of the matter is that salicylic acid was actually classified as a germicide in the older literature. Since all of the salicylates act by virtue of their content of salicylic acid, each maintains its salicylic acid mediated antifungal activity. This singularly important mode of action of the salicylates has neither recognized nor appreciated in the pertinent current literature.
The antifungal property of salicylic acid was noted by Crowdy and Davis (1952). Heng et al (1990) have reported the antifungal effects of saliclyates on Pityosporum ovale. Khadikar et al (1986) documented the antifungal activity of the salicylate, 5 sulphosalicylic acid. Goudard et al (1987) reported the excellent antifungal effects of the salicylate epicarine, 3 (2 hydroxy 1 naphthylmethyl) salicylic acid upon 221 pathogenic strains belonging to 23 different species which included dermatophytes, yeasts and moulds.
Aspirin Inhibition of the Arachidonic Acid Cascade in Yeast cells
van Dyk and his coworkers (1991) elucidated the nature of novel arachidonic acid metabolite 3 hydroxy 5,8,11,14 eicosatetraenoic acid 3 HETE from the yeast Dipodascopsis uninucleata. When arachidonic acid is added to the yeast culture they found the existence of the arachidonic cascade in these fungal cells. van Dyke also noted that "strikingly, the formation of this new metabolite was found to be inhibited by aspirin".
The Antifungal Activity of Other Cardiotherapeutic Salicylates
Para-Amino Salicylic Acid
Barter et al (1974) reported the lowering of serum cholesterol and triglyceride by para-amino salicylic acid in hyperlipoproteinemia.
Para-aminosalicylic acid is a structural analogue of para-amino benzoic
acid and its mode of action is very similar to that of the sulfonamides.
The antimicrobial action of para-amino salicylic acid was well documented
by its beneficial application in the treatment of tuberculosis (Lehmann