Looking through some patent materials which Chuck Stratton sent on to us at www.CPn Help.org
(not yet posted there) I extracted the following from a patent application for "ADJUNCTIVE PHYSIOCHEMICAL AGENTS THAT INACTIVATE THE INFECTIVITY OF CHLAMYDIAL ELEMENTARY BODIES"
The inventors have discovered that EBs infect host cells by attaching to and entering secretory vesicles from regulated exocytosis when these vesicles transiently fuse with the plasma membrane in order to release their secretory proteins. When these vesicles are recycled to the trans-Golgi apparatus, the acellular infectious EBs enter along with them.
Acellular infectious EBs must await the availability of these specific receptor sites involved in regulated exocytosis before they can enter host cells. The result of this delayed infection is the accumulation of infectious acellular EBs. Although the existence and importance of the acellular HIV-1 load has recently become recognized (70-74) a similar acellular EB load in chronic and/or systemic chlamydial infections is not recognized in the current teachings and practice of medicine. In contrast, the inventors have discovered that infectious EBs of Chlamydia pneumoniae are readily recovered from blood cultures of many adults suggesting that this pathogen does indeed cause a chronic infection of arteries and veins, thus creating an acellular EB load.
The phenomenon of acellular load already has been found to be important in HIV infections and will clearly be of great clinical importance in chlamydial infections. This is because these metabolically-inactive, non-replicating infectious acellular EBs escape the action of currently used antichlamydial agents. The presence of these infectious acellular EBs after the completion of short courses of antimicrobial therapy for chlamydial infections has been discovered by the inventors to result in relapse and the continuation of chronic infections. Thus, the duration of antimicrobial therapy required for eradication of systemic chlamydial infections is, in part, dictated by the acellular load of EBs.
Inactivation of Chlamydial EBs.
The inventors have discovered a unique class of physiochemical agents that can be specifically used to inactivate infectious acellular EBs. Unless acellular EBs are inactivated, antichlamydial therapy for these chronic infections must be continued until the acellular EB load are eliminated. Currently, this means that these acellular elements have infected human cells. This clearly is undesirable as it prolongs the therapy of chronic chlamydial infections which increases the opportunity for resistance to occur (91).
The inventors have discovered that infectious acellular EBs can be inactivated by the use of thiol-containing compounds and seek a patent for this use. Specific thiol-containing compounds that the inventors have discovered to be effective include meso-2,3-dimercaptosuccinic acid (meso-DMSA), an oral chelating agent currently used to treat lead poisoning (92). Meso-DMSA is a weak acid with four ionizable hydrogens. Moreover, meso-DMSA has two highly charged carboxyl groups which prevent its passage through human cell membranes. Meso-DMSA thus remains in the extracellular fluid where it readily can encounter acellular EBs. The two thiol (sulfhydryl) groups on the succimer molecule are able to dissolve disulfide bonds in the outer membranes of acellular EBs.
The disruption of these outer membranes of acellular EBs results in physiological effects . The dissolution of the outer membrane initiates the transition of the EB form to the RB form. When this occurs in the acellular milieu where there is no available energy source for the chlamydial ATPase, the nascent RB perishes.
The inventors also have discovered that other thiol-containing compounds can inactivate the infectivity of acellular EBs. One compound is penicillamine (93,94) which is used in low doses (250-500 mg per day). Penicillamine, D/L-ß, ß-dimethlcysteine, is a sulfhydryl amino acid which was first isolated in 1953 from the urine of patients with chronic liver disease who were receiving parenteral penicillin. Its use to inactivate infectious acellular EBs, however, is somewhat curtailed by a variety of undesirable side effects (94) which do not appear to be problems with meso-DMSA.
However, the inventors have discovered an alternative method of providing the release of penicillamine or penicillamine-like agents under physiologic conditions that avoids the issue of side effects. This methhod is simply to use oral ß-lactam agents which, in part, appear to be metabolized in humans to sulfhydryl-containing molecules such as N-formylpenacillamine or penicillamine (95).
...Indeed, the inventors have discovered that oral penicillins such as amoxicillin can be used as a low-cost alternative to meso-DMSA and penicillamine. The in-vivo production of penicillamine or other degredation products containing sulfhydryl groups from this in-vivo degradation of penicillins undoubtedly accounts for the known in-vitro ability of penicillins to reduce or prevent the development of infectious chlamydial EBs in cell cultures (89-94). Moreover, a murine model was used to evaluate the effects of oral treatment with oxytetracycline, ampicillin, and amoxicillin against an otherwise lethal intranasal infection with Chlamydia trachomatis. These investigators found that amoxicillin had the lowest mean protective dose for both seven and fourteen days of therapy.