PHYTO-LARIA

1
PHYTO-LARIA A PROMISING HERBAL ANTIMALARIAL
FROM GHANA THE HERBAL DIVISION OF
PHYTO-RIKER PHARMACEUTICALS
Diane Winn
2
In Ghana, Artesunate has become
the treatment of choice, but it has proven to be
in short supply, its hard to obtain, prices are
high, and several patients on Artesunate-Amodiaqui
n therapy have recently died.
3
The African continent abounds
with other plants that reportedly have
anti-malarial activity which could be further
studied and exploited.
4
Herbal Products for Phyto-Riker
have been developed by a team of individual
scientists and collaborating institutions,
building on the work of Dr. Oku Ampofo, a western
trained Ghanaian physician who incorporated
herbal medicines into his practice of western
medicine for nearly 40 years.
5
The main plant that Dr.
Ampofo recommended for the treatment of malaria
was Cryptolepis sanguinolenta. The root is
bright yellow when it is cut and the root is the
main source of its anti-malarial activity.
6

Folklore indicates that
Cryptolepis was used by the Fulanis for jaundice
and hepatitis, in Zaire and Senegal for stomach
and intestinal disorders, in the Congo for
amoebiasis, and among various tribes in Ghana
for fevers, infectious diseases, venereal
diseases and especially for malaria.
7
Cryptolepis sanguinolenta
8
(No Transcript)
9
THE PLANT

• Anecdotal evidence of efficacy of root and root
  bark decoction of a plant used by traditional
  medical practitioners to treat a number of
  diseases including malaria.
• Name of plant Cryptolepis sanguinolenta a.k.a.
  Pergularia sanguinolenta or Cryptolepis
  triangularis.
• Indigenous to Africa.
• Local name is Nibima.
• Grows wild as a thin-stemmed twining and
  scrambling shrub along the west coast of Africa.

10
WHAT IS KNOWN

• A number of scientific studies on preparations of
  C. sanguinolenta available, indicating that the
  plant is
• Anti-plasmodial, i.e., works against the malaria
  parasite Plasmodium falciparum outside the body.
• Anti-microbial, i.e., works against small or
  micro organisms (germs, bacteria)
• Anti-hyperglycaemic, i.e., against diabetes.

11
The root decoction of Cryptolepis, a plant that
is indigenous to Ghana, has been traditionally
used for the treatment of malaria. The
anti-malarial effect of the decoction has been
studied by the Faculty of Pharmacy, Kwame Nkrumah
University of Science and Technology in Kumasi
and the Centre for Scientific Research into Plant
Medicine.
12
The Noguchi Memorial Institute for Medical
Research has carried out extensive studies on the
safety and toxicity of the tea bag formulation.
The faculty of Pharmacy of KNUST has
standardized the tea bag formulation and
Phyto-Riker manufactured it and put it on the
market as PHYTO-LARIA.
13
In a teabag formulation clinical trial conducted
by Boye et al in 2000, Phyto-Laria completely
eliminated parasitaemia within 3 to 5 days in
over 90 of patients, with no observable side
effects. Fever was reduced within the first 24
hours, thus obviating the need for a separate
anti-pyretic medication.
14

• This trial is important, in that
• there has been only one publication on
  clinical efficacy of the plant, in spite of
  many anecdotal claims of efficacy in treating
  malaria.
• the results indicated that efficacy of
  Cryptolepis is comparable to that of
  chloroquine.
• the Current evaluation is another one on
  clinical efficacy.
• the study shows that there is no need for a
  separate anti-pyretic medication.

15

• RESULTS
• an overall cure rate of 93.5.
• two cases of late recrudescence on Days 21
  and 28 could be due to re- infection
• values of parasite clearance time (82.3h) and
  fever clearance time (25.2h) comparable to
  those obtained in the reported clinical study
  when the Cryptolepis aqueous extract was
  compared with chloroquine, (80h and 36h
  respectively).
• shorter fever clearance time when compared
  to chloroquine.

16

• RESULTS
• Presenting symptoms with very high
  incidence (gt90) could be regarded as the
  ones characteristic of falciparum malaria.
• These were
• Bodyache - Chills
• Fever - Headache
• Weakness - Nausea
• Of these, chills, fever, nausea and vomiting
  cleared rapidly and were completely resolved
  by Day 7 when the blood was cleared of
  parasites.

17

• CONCLUSION
• Evaluated on evidence of fever clearance and
  disappearance of parasitaemia by Day 7,
  according to the modified WHO criteria,
• PHYTO-LARIA has been shown to be highly
  effective in the treatment of acute
  uncomplicated malaria.

18
Compliance was a bit of a problem because of
the bitter taste of the tea. An encapsulated
extract has now been developed that has overcome
the bitter taste and the capsules willbe tested
in double blind clinical trials to confirm the
efficacy found in the teabag formulation.
19
The root extract comprises multiple active
compounds, several of which are anti-malarial,
would have syner- gistic activity and, unlike
Artesunate, is predicted make parasite
resistance to it evolve much more slowly. It
could also be formulated in combination with
other anti-malarial drugs to further delay the
emergence of resistance.
20
Approval from the Ghanaian Food and Drugs
Board has been granted to enable the Noguchi
Institute to conduct dose-finding as well as
efficacy studies on the capsule formulation. This
latter study has received funding from theWHO
Africa Regional Office.
21

A publicprivate partnership called
PHYTOSEARCH has been formed to seek financial
assistance to carry out further clinical trials
and other relevant studies that will result in a
scientifically developed indigenous herbal
medicine for the treatment of malaria that will
be internationally recognized.
22

Plans also includes cultivation of the plant
on a large scaleas a raw material source and
will thus provide employment for Ghanaian
farmers.
23
NEXT STEPS FOR CRYPTOLEPIS THERAPY
DEVELOPMENT
24
1. The dose finding study, funded by WHO Africa,
is currently underway at the Noguchi Institute,
using the capsule formulation, to determine the
optimal dose. Pharmacokinetic activity may be a
determining factor.
25
2.  A summary of what has been done to date, as
part of an initial Investigators Brochure, will
be prepared by the Director of Noguchi for an
initial submission to WHO, as well as proposals
and protocols for subsequent studies, with
detailed budget figures and timelines attached.

26
3. Additional studies to determine the best
technique to yield the highest quality extract,
and development of improved assays for
standardizing the extract have to be done. Apart
from Cryptolepine, other indoloquinoline
alkaloids, which are isomers and dimers of
cryptolepine, also have anti-malarial activity.

27
4. The objective is to standardize the
extract against the content of all the
indoloquinoline alkaloids, for an improved
standardization method. Toxicology studies will
also have to be done to confirm the safety of
the newly formulated product, as well as
bioavailability and pharmacokinetic studies.
28
5. It will be important to publish the results
of the clinical trials and encourage multi-center
trials to confirm the results. This would most
likely involve randomized controlled trials of
Cryptolepis versus the current first-line
treatment for malaria in patients at the primary
health care level with presumed uncomplicated
malaria .
29
6. Cost effectiveness will be a primary outcome
measure of the trials, after which the
Investigators Brochure will be completed and
presented to WHO, along with an appeal to WHO to
recognize and recommend the product for use on
the African continent.
30
7. We must begin to expand the cultivation of
the plant by outgrower farming networks.
Cryptolepis is a plant indigenous to Ghana and
is a climber which grows better in the
rainforest areas than on the plains. Growing in
different areas must be compared, to ensure
uniformity in quality of the final product.
31
8. Work with agricultural partners for large
scale growing of Cryptolepis. And, an efficient
tracking system must be put in place to ensure
consistency from seed to capsule
32
9. It will be important to develop an
alternative formulation for infants and young
children, whether it is syrup, a suppository or
a sub-lingual spray. It will then be important to
conduct a dose finding study and a clinical trial
to confirm its efficacy in infants and young
children.
33
10. The last step is to launch these products
into the market, with marketing studies and an
effective promotional and advertising campaign,
including post marketing surveillance. We should
also appeal to governments and to the NGO
communities to make them available to those who
are most vulnerable to malaria.
34
WHY THIS STUDY?

• Only one publication on clinical efficacy of the
  plant, in spite of many anecdotal claims of
  efficacy in treating malaria.
• Results indicated that efficacy of C.
  sanguinolenta is comparable to that of
  chloroquine.
• Current evaluation is another one on clinical
  efficacy.

35
RATIONALE FOR THIS STUDY

• Tea-bag formulation to avoid preservation with
  chemicals including CHCl3.
• Necessity of confirming the clinical efficacy of
  C. sanguinolenta in the new tea-bag formulation
  and in the dose prescribed.
• Overall aim of the study
• to evaluate the clinical efficacy and safety of
  PHYTO-LARIA as prescribed in the treatment of
  symptomatic uncomplicated malaria in semi-immune
  patients.

36
PATIENTS

• 11 to 50 years old with clinical features of
  uncomplicated malaria, recruited from three
  outpatient clinic sites.
• Patients with large number of parasites in the
  blood (between 1000 and 100,000 P. falciparum per
  8000 white blood cells).
• Exclusion criteria
• Patients with complicated malaria, (severe
  anaemia or cerebral malaria)
• Pregnant and lactating women
• Patients who had taken therapeutic doses of
  chloroquine within the previous 14 days, or
  sulfadoxine/pyremethamine within 28 days.
• Consent obtained from all participating patients.

37
TEST DRUG

• PHYTO-LARIA a teabag formulation of C.
  sanguinolenta root powder.
• Each teabag contained 2.5g of the root powder,
  plus flavourings primarily to cover up the bitter
  taste.
• Dose one teabag three times a day, morning noon
  and night, for five days of treatment.

38
STUDY PLAN

• Days of examination 0 - 7, 14, 21, 28.
• Patients medical history Day 0.
• Days of treatment days 1 5.
• Physical examination for presenting symptoms all
  days of examination.
• Thick and thin blood films prepared and used to
  count the number of parasites.
• Blood obtained for haematological indices and
  blood chemistry on days 0, 3, 7, 14, 21 and 28.

39
PRESENTING SYMPTOMS

• Abdominal Pains
• Body ache
• Chills
• Diarrhoea
• Dizziness
• FeverHallucinations
• Headache
• Nausea
• Skin itching
• Vomiting
• Weakness.

40
PARAMETERS TO BE OBTAINED

• Parasite clearance time
• Fever clearance time
• Recurrence within the 28 days follow up.
• Treatment considered curative if all parasites
  cleared from the blood by Day 7 and no recurrence
  during the 28-day follow up period.

41
PATIENTS

• 23 males and 21 females (44 patients) entered the
  study.
• Mean age 25.2 years, mean body weight 60.1kg.
• Thirty-one patients completed the study.
• All patients in the study had symptoms of malaria
  and a significant number of parasites in the blood

42
RESULTS

• Patients mean initial temperature was 38.430C.
• Mean fever clearance time was 25.2 hours.
• Mean parasite clearance time was 82.3 hours
• More than 50 of patients were cleared of
  para-sites in their blood by the end of the third
  day.
• All patients cleared of parasites by Day 7 and,
  except for two, remained so throughout the rest
  of the 28 days.
• There were 2 cases of recurrence, one occurring
  on Day 21 and the other on Day 28, but they may
  have been re-infected.

43
RESULTS contd

• Mean haemoglobin levels lower during treatment,
  compared to pre-treatment values, but started to
  rise by Day 14, approaching pre-treatment levels
  by Day 28.
• Total WBC count dropped from the pre-treatment
  level and remained low throughout the 28-day
  study period although the post-treatment values
  were higher than the values during treatment.
• Platelet count increased progressively with
  treatment, from a low pre-treatment value to
  upper normal values and began to decline after
  Day 14.
• ESR, haematocrit and reticulocyte counts showed
  little change from the pre-treatment values with
  treatment.

44
RESULTS contd

• Biochemical parameters not significantly modified
  following treatment
• Creatinine
• Urea were within the range considered normal.
• Both total and direct bilirubin appeared elevated
  compared to pre-treatment values but the levels
  were all within the range considered normal.
• No significant differences in the two
  aminotransferases measured (ASAT and ALAT),
  although the values were generally higher during
  and after treatment.
• Level of total protein and glucose did not change
  significantly with treatment.

45
INFERENCE

• Overall cure rate of 93.5.
• Two cases of late recrudescence on Days 21 and 28
  could be due to re-infection as this was an
  out-patient study.
• Values of parasite clearance time (82.3h) and
  fever clearance time (25.2h) comparable to those
  obtained in the reported clinical study when C.
  sanguinolenta aqueous extract was compared with
  chloroquine, (80h and 36h respectively).
• Shorter fever clearance time for PHYTO-LARIA
  compared to chloroquine. Therefore, more
  evidence of anti-pyretic effect reported for C.
  sanguinolenta provided.

46
INFERENCE

• Evidence of chloroquine resistance in Ghana.
• C. sanguinolenta has been shown to be effective
  against chloroquine-resistant strains of the
  parasite.
• Therefore, although chloroquine resistance was
  not part of the study, the high cure rate
  reported suggests that PHYTO-LARIA could be used
  for the treatment of malaria caused by
  chloroquine-resistant strain of P. falciparum.

47
CONCLUSION

• Evaluated on evidence of fever clearance and
  disappearance of parasitaemia by Day 7, according
  to the modified WHO criteria, PHYTO-LARIA has
  been shown to be highly effective in the
  treatment of acute uncomplicated malaria.