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African Journal of Health Sciences
The Kenya Medical Research Institute (KEMRI)
ISSN: 1022-9272
Vol. 15, Num. 1-2, 2008, pp. 1-5
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African Journal of Health Sciences, Vol. 15, No. 1-2, Jan-Mar, 2007, pp. 1-5
Clinical aplications of Trioxolane
derivatives
Davy K. Koech
Kenya Medical Research Institute [KEMRI], P.O. Box 54840, Nairobi 00200, Kenya
Code Number: jh08002
Introduction and Product Description
Several laboratory, anecdotal and clinical studies have been performed using the patented derivatives of
1,2,4-Trioxolane during a period spanning over 20 years. Observations obtained
demonstrate the uniqueness of this product. The product, when properly
formulated can exhibit properties ranging from being a biological
response modifier, antirheumatic, immunomodulator, anti-inflammatory,
antiviral, and antimicrobial. These properties become handy in evaluating the
products potential in the clinical
management of various conditions such as infections and immune disorders [1].
Geraniol trioxolane, a trioxolane derivative
of a terpene, has been assessed on the basis of its direct biological activity
against certain target organisms in vitro. In Vivo assays have
similarly been undertaken to assess the product's toxicity, safety, and in
certain cases, efficacy. The studies have been conducted using the product
manufactured using a synthesis protocol, and synthesized strictly in accordance
with international guidelines and specifications, especially those issued by
United States Food and Drug Administration, United States Pharmacopoeia and
British Pharmacopoeia. The preparatory process met all requirements for the
Code of Good Manufacturing Practices (cGMP). In addition, the trioxolane derivative
of cis 3-hexene-1-ol, a non-terpene, was synthesized and compared with
geraniol trioxolane for the purposes of assessing its comparative activity.
Both geraniol Trioxolane and the trioxolane
derivative of cis 3-hexene-1-ol are colorless liquids. Geraniol trioxolane is more viscous and less stable than the trioxolane derivative of cis
3-hexene-1-ol.
After several trials, the
more user-friendly and stable version is a patented product that contains
methyl-5-octyl-1,2,4-trioxolane-3-(8-octanoate), a derivative of
1,2,4-trioxolane, as the active ingredient. This is a formulation manufactured
and conveniently dissolved in Squalane (2,6,10,15,19,23-hexamethyltetracosane),
as a carrier, using liquid preparation containing 200mg/ml of 1,2,4-trioxolane.
Studies so far conducted both in Mexico and Kenya have revealed that various
formulations of this product have a place in the clinical management of a
variety of conditions. Clinical trials have been done to assess the usefulness
of this product in the clinical management of HIV/AIDS, rheumatoid arthritis
and also in the improvement of blood circulation. No adverse effects were
observed in all the studies so far undertaken. Because of its wide window of
safety, two products have been developed and have received registration in Kenya: these are branded Alphamir for HIV/AIDS and Arthromir
for rheumatoid arthritis. Except for the initial experimental studies and
anecdotal observations, most of the clinical trials have been undertaken at the
Kenya Medical Research Institute (KEMRI).
HIV/AIDS
Recent studies were
undertaken at the Kenya Medical Research Institute (KEMRI), involving an open
label, randomized dose ranging clinical trial for efficacy, safety and
tolerability of the product in asymptomatic HIV-1 individuals with CD4 counts
of 100-500 cells/µl of whole blood.
In this study, 48 patients with proven HIV-1 status were recruited. The study
consisted of three arms at buccal (oropharyngeal) dose levels of 100mg, 200mg,
and 400mg daily for a period of 4 months. The patients CD4counts
were divided into low and medium, 100-250 cells/µl and 251-500 cells/µl of
whole blood respectively before random allocation to the 3-treatment dose
levels. Half of the patients at each dose level were between 100-250 cells/µl
and the other half between 251-500 cells/µl of blood. Efficacy parameters were
changes in the CD4, CD4/CD8 ratios and viral loads. Toxicity was assessed by
monitoring liver, renal and bone marrow functions. An extra 20 patients were recruited
on compassionate basis in an expanded study and studied under the same
protocol.
Follow-up was
done every two weeks. At each follow-up all toxicity and efficacy assessments
were done and the viral loads were done every month. At the end of the study
period, a total of 48 individuals had been recruited into the formal study. The
first and second follow up had been done in all of them. Thirty-seven have had
the third follow up while sixteen had the fourth follow up. During the period,
there have been four dropouts. One was due to relocation of his work place
following posting by his employer; another was due to the frequent travels in
and out of the country that could not offer sufficient time for regular
follow-up and visits. The reasons for the dropout of the other two were not
related to use of the drug.
Before data
analysis was done, all the study patients, except the drop-outs, had completed
the scheduled follow-ups. Those with previous weight loss had gained an average
of 1.2kg (2.6lb) by the fourth week and this rate of weight gain was maintained
during the period of study or until it reached the expected weight. At the end
of the follow-up period in all patients, the results indicated that the maximum
reduction of log -0.3 or more in viral load was achieved in those patients on
200mg daily dose. Those on 100mg registered log -0.19 while those on 400mg
registered log -0.13.
The CD4 levels
have shown appreciable increase over the base line in those on daily doses of
200mg. The levels reached a plateau during the third month of treatment at an
average of 30% increase over the baseline. The increase was significant. More
than 70% of patients had an increase of more than 20% of their CD4 counts over
the baseline while only 20% of those on 100mg daily dose had a similar
increase. Less than 20% of those on 400mg had more than 20% increases in their
CD4 counts. In summary, those patients on 200mg daily dose did better in terms
their CD4 counts than those on either 100mg or 400mg daily dose. Observation on
whether the high levels of CD4 can be sustained. Due to constraints in
resources, observations on this parameter were done in selected, but random
samples. CD4 levels were have been sustained in samples tested. Further studies
on this product are underway.
Rheumatoid
Arthritis
This was an open label
study to determine efficacy and safety of the product (Arthromir) in the
management of patients with rheumatoid arthritis (RA). The study was conducted
under and in accordance with approved protocols. In the expanded study, 50
patients with a clinical diagnosis of rheumatoid arthritis were enrolled after
fulfilling the prescribed inclusion criteria. Trioxolane at 200mg given in
four divided doses daily was given sublingually for 12 weeks. Efficacy and
safety was assessed as defined in the protocol. The patients were followed up
for a total of two months after completion of therapy. A similar number of
patients were enrolled purely on compassionate basis, but outside the approved study,
and followed up together with those on the study.
This approved study
involved a two-week hospitalization. In this regard, the choice of the dates
for the patients to check in was dependent largely on the individual patients
work schedules or programs.
The patients completed
three-month follow-up and there has never been any recurrence of the clinical
disease during the period under study. In all patients, there has been
consistent response: alleviation of pain within one week of hospitalization and
commencement of therapy and sharp reduction of inflammation at the affected
areas.
On admission, the
major majority of patients presented themselves with chronic active painful
joints associated with swellings in the joints. The majority of them were
unable to move the joints and edema cleared by week 1 after commencement of
medication. Pain had subsided and they were able to move the joints. Pain was
virtually gone by week 4. So far, subsequent follow-ups have shown that they
were able to sustain pain free status, except one case whose pain recurred and
required additional round of medication. After the second round of medication,
the patient recovered and has since remained symptom free.
The preliminary data
obtained so far have strongly suggested that Arthromir is a product that has
great potential in the clinical management of rheumatoid arthritis. Its
mechanism of action is novel and provides an insight into the understanding of
the pathology associated with the disease. On the basis of the properties of
Arthromir, there are new pieces of information which strongly suggest that the
pathogenesis of arthritis needs to be looked at afresh.
Micro-capillary
Circulation
This short pilot and
anecdotal study was done in the United States and Kenya. Wet freshly drawn whole blood from clinically
normal individuals exhibit a general cellular stickiness with massive red cell
agglutination, irregular cell size and shape, and extraneous intracellular
debris that includes pleomorphic granules, especially in the extremities.
However, when the product is administered as prescribed, and blood drawn in
about 20 minutes and examined, marked and obvious changes were seen. Within 20
minutes, the red cells had plumped up and showed more homogenous size and
shape. They had "lost" the previously seen "stickiness" and
now appeared less viscous and "teflonized" and moved more freely
without any evidence of agglutination. Capillary perfusion showed marked
improvement.
The undiluted freshly drawn fingertip blood was found to be sticking together
in a rosette manner. It was, however, too close to each other to observe any
changes. This necessitated the dilution of blood by 30 percent with normal
saline. This dilution factor was applied in all pre- and post- treatment
samples.
We
have overcome the problem of dilution. The pre-treatment samples revealed that
most of the cells (more than 90 percent) were sticky and floating together in a
chain form. After 15 minutes following drug administration, the stickiness had
reduced to 60 percent and little debris was seen floating. At 30 minutes, the
stickiness had reduced to less than 40 percent and the debris eliminated. It is
believed that scavenger cells had eliminated the floating debris that had been
released following the de-clumping of red cells. Maximum teflonization of cells
was achieved at around 30 minutes post-treatment and this condition was
maintained for two hours, the longest time the observation was made.
We
are currently assessing the level of activity of phagocytic cells by looking at
the levels of peroxidase activity at different time intervals, and the
possibility of nitric oxide involvement.
Further
studies notwithstanding, the present observations strongly places the product
as a very good candidate in the prevention and management of stroke and heart
attack, and in the prevention of debilitating complications associated with
diabetes. Studies on this front are being contemplated.
1,2,4-Trioxolane Derivative as a Drug
From
the foregoing, the studies on trioxolane derivatives have led to the
development of two drugs which have received registration in Kenya for use in
the clinical management of HIV/AIDS and rheumatoid arthritis. These drugs bear
the trade names Alphamir (for HIV/AIDS) and Arthromir (for rheumatoid
arthritis). Because of its properties, the trioxolane derivative has been
described as a biological response modifier, antirheumatic, immunomodulator,
anti-inflammatory, antiviral, and antimicrobial.
Composition and
presentation
The drugs contain
methyl-5-octyl-1,2,4-trioxolane-3-(8-octanoate), a derivative of
1,2,4-trioxolane, as the active ingredient. This is a formulation manufactured
and conveniently dissolved in Squalane (2,6,10,15,19,23-Hexamethyltetracosane),
as a carrier, using liquid preparation containing 200mg/ml of 1,2,4-trioxolane.
Indications
Arthromiris used in the treatment of acute and chronic rheumatoid arthritis,
osteoarthritis, inflammatory polyarthritis and other forms of arthropathies;
systemic lupus erythematosus; and is also used in promoting micro-capillary
blood circulation. Alphamir is used in the treatment of HIV/AIDS.
Dosage and
administration
Arthromir is for both
oropharyngeal and topical use depending on the condition for which it is
applied. Alphamir is primarily for oropharyngeal use.
For oropharyngeal use, the
drug should be administered as a buccal (sublingual) dose of 50mg contained in
250ul (or 10 drops containing a total of 50mg of 1,2,4-trioxolane), four times
a day. Retain the drug within the oropharyngeal area for at least five minutes
after which it may be swallowed. Avoid taking anything else by mouth for at
least 30 minutes following administration. Because one of the principal modes
of action of Arthromir is through receptor activation at the oropharyngeal
area, the dosage is not directly related to body weight but, rather, to surface
area on which the drug is acting. Hence, the adult dose is similar to that of
children above the age of five years.
In cases of
topical manifestations as well as systemic conditions, it is possible to use
both the topical preparation in the affected areas and the oropharyngeal
preparation simultaneously, without inducing toxicity or overdose, and without
loss of efficacy. The drug is well tolerated.
In cases of localized
topical manifestations or swellings, it is possible to apply the topical
preparation on the affected areas and use oropharyngeal preparation
simultaneously without inducing toxicity or overdose, and without loss of
efficacy.
Contraindications and
special precautions
There are no known
hypersensitivity reactions to the active substance or to any of the excipients.
Unlike other non-steroidal anti-inflammatory drugs (NSAIDs), both drugs are
safe for use in patients with allergies. In case itching or any other
undesirable effect occurs, drug may be withdrawn temporarily (for about 2 days)
and thereafter, resumption of treatment can begin.
Overdose
The window of safety for
Arthromir is wide; hence, there is little likelihood of the drug inadvertently
causing recognized toxicity due to overdose. However, caution should be taken
(by taking the recommended dose) in order to limit loss of efficacy that may
occur as a result of higher doses than recommended.
Pharmacodynamics and
pharmacokinetics
1,2,4-Trioxolane is an
endoperoxide derivative of an unsaturated fatty acid. It is metabolized in
vivo by cleavage of the endoperoxide ring followed by beta-oxidation of the
resulting short chain aliphatic molecules. The molecule is sufficiently
lipophilic to be able to cross cell membranes. But due to its ready
inactivation in tissues, its site of action is near the site of administration,
i.e. the oropharyngeal areas (the buccal cavity) or the skin. The relative ease
of inactivation of the molecule confers on it the unique safety margin during
its use in therapy. The therapeutic regimen of 1,2,4-trioxolane represents a
special concept in pharmacodynamics whereby small amounts of the agent is
administered to initiate a biological response modification which then develops
a cascade of reactions through molecular signaling [2, 3]. The pharmacokinetic
behaviour of such an agent would not be expected to provide significant levels
of the compound and its metabolites in body fluids for detection and especially
due to its rapid rate of metabolism and its non-parenteral mode of
administration. This is a novel concept in modern pharmacotherapy.
Storage requirements
The product is stable at
ambient temperatures (15°C-30°C). However, the activity
progressively reduces as ambient temperatures increase. It is, therefore,
recommended to keep the drug in a cool dry place, and it is better if
refrigerated. It should not be frozen. Keep free from moisture.
Acknowledgements
I
wish to thank Dr Zack H. Haddad, Professor and Director, Allergy/Immunology,
USC, USA; Dr Illiana Gonzalez, Center for Pharmaceutical Chemistry, Mexico; Dr
Carmen L. Garcia, Center for Research and Development of Medicines (CIDEM),
Mexico; Dr Juana I. Tillan Capo, Chief of Biological Control Laboratory, CIDEM.
[Since some of the studies were done several years ago, some of the
individuals mentioned may no longer be holding the positions they had at the
time of the study]. I also thank Stephen D. Herman and James Herman for use
of their data on product analyses. My thanks also go to several of my
colleagues in KEMRI for all their contributions in some aspects of the study
and for allowing some portions of unpublished data to appear in this article. I
thank Molecular Technologies Limited for sponsoring some of the studies. This
article is published with the permission of the Director, KEMRI.
References
- Koech DK, Herman JA, Kofi-Tsekpo MW and Herman SD.
Trioxolanes: A new generation of compounds with wide ranging activities. African
Journal of Health Sciences. 1994; 1:147-150.
- Young AS and Koech DK. Biological response modifiers:
cytokines in health and disease and their possible therapeutic value. African
Journal of Health Sciences. 1994; 1:
6-12.
- Young AS and Koech DK. Cytokines
in health and disease and their possible therapeutic value. 15th African
Health Sciences Congress. 7-11 February 1994. Nairobi, Kenya
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