The following article was taken from the Fall 2000 Issue, Vol. 7, No. 3
Efficacy of Apitox (Bee Venom) for Osteoarthritis: A Randomized Active-Controlled Trail
Choong-Hee Won, M.D. , Seong-Sun Hong, Ph.D. , Christopher M-H Kim, M.D.
INVESTIGATORS:
Chong-Hee Won, Seung-Back Kang, D-Hoon Lee, Young-Do Ko, Bong-Soon
Chang, You-Young Lee,
Department of Orthopedic Surgery, Chung Buk National University Medical Center-
Korea, Seong-Sun Hong,
Graduate School of Pharmacy, Sookmyung Women's University-Korea, Christopher
M-H Kin, International Pain Institute - USA
Part 1 Summary, Introduction, and Methods
This trial covered the period from December 1, 1995 to March 31, 1997. The study was an injectable bee venom (Apitox, IND) containing 10mg of dried honeybee venom in 10ml of saline solution. For the control drug, Nabumetone (Ralafen, Smith Kline Beecham, USA) 500mg, a non-steroidal anti-inflammatory drug (NSAID) was chosen because it is commonly used for osteoarthritic patients and has fewer gastrointestinal side-effects than other similar agents.
Introduction
Background
The venom of Apis mellifera (honeybee) has been used
for arthritis for over 2,000 years, and many identified components
of bee venom contain strong anti-inflammatory properties (Broadman,
1962; Kim, 1992, 1997; Yorish, 1977). Most recently China, Japan, Korea,
Germany, Russia, South America and others have used bee venom to treat
various chronic inflammatory diseases, but there are no scientific
guidelines for using this substance. Therefore, this trial is an attempt
to evaluate the efficacy and safety of honeybee venom in a well-designed
clinical study.
Bee venom is composed of 30 different components, the main anti-inflammatory
pharmacological components are peptides: melittin, apamin, peptide 401, adolapin,
and protease inhibitors. Melittin stimulates the hypophyseal-adrenal system
and produces cortisone. It is 100 times more potent than hydrocortisone
(Couch, 1972; Knepel et al., 1987; Vick et al., 1972, 1975). Melittin
also stabilizes the lysosome cell membrane to protect against inflammation
(Shkenderov et al., 1986). Apamin works like melittin to produce cortisone
(Vick and Shipman, 1972), and inhibits the complement system, C3, which
is involved in inflammation (Gencheva et al., 1986). Peptide 401, or MDC peptide,
blocks the arachidonic acid and inhibits prostaglandin synthesis (Hanson et
al., 1974; Neubould, 1963; Surfer et al., 1973). Adolapin inhibits the
microsomal cyclooxygenase. It is 70 times stronger than Indomethacin in
animal models (Shkenderov et al., 1986). It also inhibits platelet lipoxygenase,
which involves hydroperoxyeicotetranonic acid (HPETE) and leukotriens
(Koburova et al., 1985), as well as inhibiting thromboxane (TXA2) and
prostacycline (PGI2), which are activated during inflammation (Shkenderov
et al, 1986). Protease inhibitors inhibit carrageenin, prostaglandin E1,
bradykinin, and histamine induced inflammations; they also inhibit chymotrypsin
and leucine-aminopeptidase (Shkenderov, 1986). Schmidt-Lange (1941), Ortel
(1955), and Fennell et al. (1968) reported that bee venom has a strong anti-bacterial and
anti-fungal effect as well as a radioprotection effect (Ginsberg et al., 1968;
Kanno et al., 1970; Shipman et al, 1967, 1968).
It has been reported that bee venom has a strong anti-inflammatory effect,
as mentioned above. It has also been proven that bee venom is a strong
immunological agent and stimulates the body's protective mechanisms against
disease, but there are only a few reports on this substance for clinical
use. Therefore, the International Pain Institute produced a formula of
pure bee venom solution (Apitox) and applied it to animals and to human
volunteers to study it for toxicity and safety. Apitox contains 1.0mg pure
dried bee venom in 1.0ml solute. The result of these studies very clearly
show that bee venom is very safe to use in therapeutic doses (Hwang et
al., 1994; Kang and Kim, 1993; Kim, 1989, 1992, 1994). The next step was
to perform a clinical study in the efficacy and safety of Apitox in osteoarthritis
patients.
Purpose of the Study
Apitox (honeybee venom) has a variety of strong anti-inflammatory actions and immunological
effects leading to its wide use for degenerative disorders, as well as arthritis
and related diseases. Presently, the safety of Apitox has been confirmed after completion
of Pre-Clinical Animal Studies and Phase I Human Studies. Therefore, the main
purpose of this trial was to investigate the efficacy and safety of Apitox
in different dosing schedules. Thus, this clinical trial was a Phase II
Study performed on degenerative osteoarthritis patients. The main objective
goal was to investigate safety as it related to different dosing schedules
and to determine the minimum effective dosage.
Osteoarthritis is the most common disease affecting joints (Dieppe, 1994).
Heine (1926) reported that the damage of the joint cartilage was quite
common after the age of 65. There is more than 80 percent radiological
evidence of osteoarthritis after age 75 (Cooper, 1994). The management
of osteoarthritis depends mainly on pharmacological approaches. Recently,
the development of a prosthesis has helped to improve the quality of life
in victims of advanced disease, but it is an important medical need to develop
a new drug with high efficacy and few side effects. Bee venom has the
dual major properties of encouraging strong immune responses and anti-inflammatory
effects with relatively few side reactions. Therefore, it is important
to investigate the efficacy of Apitox.
Methods
Design of the Study
There were three Study Drug Groups (A, B, and C) divided according to injection dosages.
This trial compared those three groups to a Control Group (D). A participant who
fit the inclusion criteria was given a preset number and randomly assigned
to a group. Each participant went through six weeks of treatment, with
a follow-up visit four weeks after the last treatment. The complete trial
period for each participant was 11 weeks including a one week wash-out
period. Therefore, this trial was a randomized controlled study comparing
four groups.
This trial was not a double blind study because there is no substance that
provokes a similar skin reaction to that provoked by bee venom that is
safe for humans. We tested the possibility of using Histamine phosphate
on three volunteers, but the tests failed. We concluded that histamine
cannot be used as a control drug for a double blind study, and we could
not find any other substance to provoke a reaction similar to that of the study drug.
Another issue was one of ethical consideration, that of using a placebo as
a control drug for 11 weeks for patients suffering from a painful disease.
We therefore designed a comparison study using one of the nonsteroidal
anti-inflammatory drugs, Nabumetone, as the control drug.
Subject Diseases
The diseases studied were degenerative osteoarthritis affecting the knee joint
and spine, based on radiological findings and physical examinations. Participants
were chosen according to the selection criteria found in Table 1-1.
Table 1-1 Patient Selection
Criteria |
Study Groups and Control Group
The following therapeutic course has been used at the International Pain Institute,
USA. Treatment is given twice weekly for 12 sessions (6 weeks). Initial
dose is 0.3ml with the dose increasing gradually at each subsequent visit;
the maximum dose is 2.0ml. The three groups were (A) minimum dose group,
up to 0.7ml which was given in our Phase I Trial; (B) medium dose group,
up to 1.5ml in one session; and (C) maximum dose group, up to 2.0ml in
one session. In the control group (D), the participants were given a 500mg Nabumetone
tablet twice daily for 6 weeks (Table 1-2).
Table 1-2 Dosing Schedule
of the Study Group and the Control Group
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Reducing Dose Criteria
The total doses in the study drug could be reduced only under the following
conditions; injection site reaction is more than ++; the participant complains
that the treatment is too irritable to tolerate; the investigator sees
that a reduced dosage will be of more benefit to the participant. In these
instances, the dosing schedule could be reduced one level, ie., C to B,
B to A, A to Drop-out. In this study, no participant's dose was reduced.
Agreement of the Participants
All participants included in this study were volunteers who signed consent
forms. All of them fully understood and were well informed about all conditions
related to this study.
Randomization
There were 100 preset numbered tags written, 25 each for A, B, C, and D. These
tags were kept in a black bag to maintain blindness. When a participant
entered the trial, one random tag was removed from the bag, and the participant
was assigned to a group according to the tag. 60 more preset tags were
kept in reserve. The total number of participants was 101: A, 25; B, 26;
C, 25; D, 25. The total assigned number was 104 because the investigator
mistakenly skipped three slots.
Skin Test
We initially excluded five volunteers because of a history of hypersensitivity
to bee venom. Subjects of all injection groups (A, B, and C) were given
skin tests before treatment was initiated. Injections were given intradermally.
Skin tests were performed in two steps. First, Apitox was diluted 1:1,000 with
injectable normal saline (1µg/ml) and 0.05ml was injected intradermally
in the flexor surface of the forearm. Local reactions were observed for
15 minutes. Then Apitox (1mg/ml) 0.05ml was injected. All participants
were observed carefully for systemic reactions for 20 minutes to check
for local reactions such as the size of the weal, the size and shape of erythematous
spreading, development of pseudopod, etc. Systemic reactions were generalized
itching, rashes, dizziness, shortness of breath, chills, fever and possible anaphylactic
response. None of the participants of this trial developed allergic reactions.
Criteria for local reactions is described in Table 1-3. If any of the systemic
signs
developed during the observation, we declared the subject as positive, i.e.
sensitive to bee venom, and excluded the subject from participation in
the study. None developed allergic reactions.
Table 1-3 Criteria for
Local Reaction
|
Collection of the Analysis Data
Once a participant was selected, we confirmed the wash-out period of seven
days and the patient was randomly assigned as described above. All participants
were treated for six weeks and laboratory tests were performed on three
separate occasions: before treatment, after two weeks and after completion
of treatment (six weeks). Efficacy analyses were conducted on five separate
occasions: before treatment, after two weeks after six weeks, after eight
weeks, and after ten weeks (four weeks after completion of treatment).
(The presentation of this study will continue in the Winter 2000 issue
of Bee Informed.)
This study was sponsored by the International Pain Institute, USA and Guju
Pharmaceutical Co., Ltd., Korea
Choong-Hee Won, MD, Principal Investigator, is affiliated with the Department
of Orthopedic Surgery, College of Medicine, Chung Buk National University,
Korea.Seong-Sun Hong, Ph.D. is affiliated with the Graduate School of Pharmacy,
Sookmyung Women's University, Korea.Christopher M-H Kim, MD is affiliated
with the International Pain Institute, USA