Chapter 4

Apitherapy – Bee Venom Therapy

Christopher M.H. Kim

4.1 Introduction

Bee Venom Therapy (BVT) is a bio-therapeutic medical treatment that utilizes the
venom of the honeybee for the treatment of diseases.
Physicians dating back to Hippocrates used honeybee venom (HBV) to treat a
variety of illnesses. Today, physicians are still using HBV to treat patients world-
wide. Clinical trials and rigorous testing under certified licensed physicians have
proven that HBV is an effective treatment modality. The benefits of this drug have
proven to be remarkable all over the world from Russia to the United States.
The proponents of bee venom are extensive. In the case of chronic pain disorders
such as rheumatism and arthritis, bee venom is used to combat inflammation and the
degeneration of connective tissue. Neurological disorders such as migraine, periph-
eral neuritis and chronic back pain have also been treated successfully. In the case
of autoimmune disorders such as multiple sclerosis and lupus, it restores movement
and mobility by strengthening the body’s natural defense mechanism. In addition,
dermatological conditions such as eczema, psoriasis, herpes can be effectively
treated. Most recently, bee venom is being investigated for treatment of cancerous
tumors as well.
Bee venom therapy has been proven to be both safe and effective through exten-
sive regulation and standards set under federal guidelines. Formerly known as a
complementary alternative medicine (CAM), bee venom is gaining a larger audi-
ence in international scientific communities. As evidenced throughout medical his-
tory to be a traditional miracle treatment, bee venom is nature’s organic solution to
human affliction.

C.M.H. Kim, M.D. (*)

Graduate School of Integrated Medicine, CHA University,
Yatapdong, Bundanggu 222, 463-836 Seongnam, Gyeonggi-do, Korea
e-mail: [email protected]

M. Grassberger et al. (eds.), Biotherapy - History, Principles and Practice: 77

A Practical Guide to the Diagnosis and Treatment of Disease using Living Organisms,
DOI 10.1007/978-94-007-6585-6_4, © Springer Science+Business Media Dordrecht 2013
78 C.M.H. Kim

4.2 History of Bee Venom Use

From ancient times onwards it is recorded, that topical application of bee stings has
been used for a wide range of ailments and diseases, all through Africa, Asia,
Europe and the Americas. Hippocrates (ca. 460–370 BC), an ancient Greek physi-
cian and father of western medicine, was the first referring to apitherapy. According
to Galen (129 – ca. 200 AD), a prominent Roman physician as well as surgeon and
philosopher (of Greek ethnicity) apitherapy was understood as a common form of
medical treatment for the sick. Famous rulers such as Charlemagne (Carolus
Magnus, 747–814 AD) and Ivan the Terrible (1530–1584 AD) applied bee stings to
treat illnesses such as gout. The intrinsic benefits of bee venom is also referred to in
the Koran: “There proceeded from their bellies a liquor wherein is a medicine for
men” (Kim 1986).
In the late 1800s, scientific studies and articles were in progress in Western
Europe and Russia. The French physician Dr. Desjardins (1859) published his
experiments on treating rheumatism and skin cancer with bee stings in the journal
“Abeille Medical” (Medical Bee Journal). Dr. Langer (1897) reported his inspiring
progressive scientific studies. In Austria, Dr. Philip Terc (1904) developed the first
systematic application of bee stings with over 25 years of expertise and research in
rheumatic disorders.
In the 1900s, medical understanding of bee venom treatment progressed with Dr.
Rudolph Tertsch (1912) who published several research papers on the treatment of
rheumatic fevers and arthritis as well as a book (“Das Bienengift im Dienste der
Medizin”) describing his father’s research. Dr. Franz Kretsky (1928) from Austria
developed the first injectable form of bee venom. Studies performed by Neumann
et al. (1952) indicated that crude bee venom was a complex compound character-
ized by a unique biochemical composition. Decades later, in 2003, an American
physician Dr. Christopher Kim would patent the first standardized form of inject-
able honeybee venom branded as Apitoxin in South Korea. The apitherapy (Bee
Venom Therapy) timeline is summarized in Table 4.1.

4.2.1 Modern Bee Venom Therapy

Modern-day apitherapy is known as bee sting therapy (BST) or bee venom therapy
(BVT). BST utilizes the actual honeybee with its stinger, whereas BVT involves
injection of venom, which is extracted from honeybees in their hive environment
without any harm to their colony. BVT injections can treat a wide range of disorders
such as multiple sclerosis, lupus, chronic inflammation and pain, and as well as
rheumatoid arthritis, neurological disorders such as migraines and peripheral neuri-
tis. Furthermore, dermatological conditions such as eczema, psoriasis, herpes, urinary
tract infections, and other viral infections are combated as well (NIH 1995). In
South Korea, BVT injections are Korean FDA certified as a proven bio-therapeutic
drug, and in the United States, it is currently awaiting FDA approval.
4 Apitherapy – Bee Venom Therapy 79

Table 4.1 Brief history of apitherapy

460–370 BC Hippocrates utilized bee stings on his patients for treatment of disease
23–79 AD Pliny the Elder, Roman naturalist and Commander of the Roman Army and
Navy, prescribed bee venom and cited the beneficial uses of it in his
“Natural History”
129–199 AD Galen, the “Prince of Physicians” and also the “Father of Experimental
Physiology,” mentioned the uses of bee venom in his 500 treatises on
medicine
742–814 AD Charlemagne, the “King of Franks,” who built the largest empire in Western
Europe since Roman times was treated with bee stings. At this point in
time, bee stings were used to cure almost all maladies and illnesses
1530–1584 Ivan the Terrible, Ivan IV of Russia, who suffered from gout was cured with bee
stings
1600–1634 Monfat, another known naturalist, prescribed bee sting venom for reducing
kidney stones, as well as strengthening the urinary tract in treating infections
and other ailments
1859 Dr. Desjardins, a French physician, published the first scientific paper on the
successful treatment and curative properties of bee venom for rheumatic
diseases in the journal “Abeille Medical” (Medical Bee Journal). He also
reported to have cured two individual cases of skin cancer
1888 Dr. Philip Terc, an Austrian physician, one of the foremost pioneers of bee
venom therapy, applied over 39,000 bee stings to over 500 rheumatic
patients during a 25 year period. He was the first to apply bee stings
systematically and published his first article, “Report About a Peculiar
Connection Between the Bee Stings and Rheumatism” in the Vienna
Medical Press
1894 Dr. M.I. Lukomsky, a Russian professor at Saint-Petersburg Forestry, published
his successes of bee venom therapy in treating rheumatic fever, gout,
neuralgia, and other diseases
1897 Dr. Lyubarsky, a Russian military surgeon, concluded from his many years of
expertise with bee venom that it was a successful treatment and remedy for
rheumatic fever. He published these findings in his article entitled, “Bee
Venom As A Curative Agent”
1912 Viennese Dr. Rudolph Tertsch, the “Father of Modern Apitherapy,” published
scientific research studies and several publications on the treatment of
rheumatic fever with bee venom. Out of his 660 rheumatic arthritis patients,
his findings were staggering: 82 % were completely cured (544 persons);
15 % showed improvement (99 persons); and only 3 % (17 persons) failed
to show symptoms of recovery
1928 Dr. Franz Kretsky, an Austrian physician, was the first ever to invent an
injectable form of bee venom
1932 Yoannovoitch and Chahovitch both treated experimental cancerous tumors with
bee venom and published their findings in the Bulletin de l’Academie de
Medicine
1935 Dr. Bodog F. Beck, Hungarian-American physician, coined the phrase “bee
venom therapy” for the first time ever in history, and published his work on
the effects of bee venom entitled, “Bee Venom, Its Nature, and Its Effects on
Arthritis and Rheumatoid Conditions” in New York, USA
2003 Dr. Christopher Kim, Korean-American physician, patents the first standardized
and federal regulated injectable form of honeybee venom known as Apitoxin
(purified Apis mellifera toxin) in Korea; this bio-pharmaceutical drug is
awaiting United States FDA approval branded as Apitox
80 C.M.H. Kim

The list of renowned apitherapists in the United States include Bodog F. Beck,
M.D. (New York), Raymond Carey, M.D. (California), P.H. O’Connell, M.D.
(Connecticut), Joseph Broadman, M.D. (New York), L.A. Doyle, M.D. (Iowa),
Joseph Saine, M.D. (Montreal) and Charles Mraz, Master Beekeeper (Vermont).

4.2.2 American Apitherapy Society (AAS)

In 1977 the American Apitherapy Society was originally organized as the North
American Apitherapy Society (NAAS) in Washington, D.C., but was reconstituted
as the American Apitherapy Society (AAS) in 1988 as a non-profit organization
(Kim 2011). The Society is primarily responsible for informing the general public
and the medical profession in matters relating to apitherapy. They collect research
data and information on apitherapy approaches and methods, and also conduct sem-
inar workshops on a yearly basis.

4.3 Venom Source (Apis mellifera)

The genus Apis or the honeybee, has at least five separate species with several sub-
species. All species thrive in large colonies set up in their natural home environment
called the hive. Since honeybees are social insects, their hives are polymorphistic in
nature, where the inter-relationship and structural mechanism of the colony thrives
on the unique existential relationship between its queen, drones, and worker bees
(Fig. 4.1).
Larvae fed on royal jelly only will develop to future queens. The queen, upon
birth, must fight for the crown and for this purpose kill her sisters. The newly estab-
lished queen, which will live for a period up to 7 years, will be fed with the royal
food and will grow three times larger and twice her length to be able to oviposite
large numbers of eggs. She will lay about 1,000–2,000 fertilized eggs per day via
the ovipositor. The worker bees have a modified ovipositor called a stinger with
which they can sting to defend the hive against outside intruders.
The male bees are called drones and their primary function is to mate with the
queen in order to fertilize the eggs. Like the queen, drones cannot procure food and
are entirely dependent on the worker bees. The worker bees are females only, and
they take care of all the hive’s needs, e.g., collect nectar, pollen, and water, construct
combs, produce honey, and feed the brood. The worker bees also produce wax and
propolis and perform maintenance functions such as hive cleaning and ventilation
of the hive with the help of their wings and muscles in order to maintain the hive’s
temperature at a constant level.
When intruders such as wasps penetrate the hive, they can kill the bees and use
the different developmental stages of the bee as food. In such cases, the bees fight
back and use their stinger at the expense of their lives. If a worker bee uses her
4 Apitherapy – Bee Venom Therapy 81

Fig. 4.1 Honeybees: queen,

drone and worker

Table 4.2 Important honeybee species

Species name Description
Apis cerana This species is found in Asia and is known as the Indian honeybee. Bees of this
species are spread throughout most of the Asian continent
Apis dorsata This species is the largest among honeybees, and is known to have the most
powerful and strongest sting out of the five species
Apis florea This species (also called dwarf honeybee) is quite rare and the smallest of the
colony numbers. In Asia, the honey from this particular species commands
a premium price due to its rarity
Apis dorsata This species is the world largest honeybee and is morphologically quite close
laboriosa to Apis dorsata and is found only in the Himalayas
Apis mellifera This species of honeybee is worldwide the most commercially used one
and is used for Bee Sting Therapy and Bee Venom Therapy for approved
bio-therapeutic drugs such as Apitoxin/Apitox

stinger, she loses the entire sting apparatus, which is deadly to the bee. Hence, hon-
eybees only attack as a last resort and are usually not harmful, unless they are threat-
ened with annihilation.
It is important to note that throughout history, humans have cultivated honeybee
hives usually without danger. Despite the fact that honeybees have a powerful sting,
these bees only use it when they know they are being attacked. The history of api-
therapy, hive cultivation, and farm cultivation prove thast people and honeybees can
coexist together in harmonic balance and subsistence with one another in nature.
Important honeybee species are listed in Table 4.2.

4.4 Application Methods

4.4.1 Bee Venom Therapy (BVT)

Bee Venom Therapy (BVT) is the use of Apis mellifera toxin with the market name
Apitoxin and Apitox. This remedy is applied intradermally, and never intravenously.
Up to 2.0 mL of this solution can be injected subcutaneously, however the therapeutic
effects are less satisfactory than intradermal delivery. Only licensed medical doctors
and government approved acupuncture physicians can deliver bee venom injections,
82 C.M.H. Kim

Fig. 4.2 (a) samples of bee venom for injection; (b) injection site; (c) before injection; (d) after
several injections

since it must be regulated and monitored. BVT is used for the treatment of a variety
of autoimmune diseases, neurological disorders, chronic ailments and inflamma-
tions. Figure 4.2 shows samples of bee venom and the local reactions before and
after injection of bee venom.

4.4.2 Bee Sting Therapy (BST)

Bee Sting Therapy (BST) or Apipuncture is a method which is used by licensed prac-
titioners and licensed acupuncturists to treat ailments such as skin disease and arthritis
using the sting of a live bee. The treatment involves placing a live bee, held by twee-
zers, on the affected area of the body and simply allowing it to sting the patient.
Before the initiation of the treatment, the patient should be tested for allergies to
bee venom. The test is usually applied on the forearm by forcing a bee to sting the
skin and removing the stinger after a minute. Since most people have localized skin
reactions to bee venom, the practitioner will determine the level of severity depend-
ing on the patient’s condition. If the patient does not show any abnormal reactions
to the test after a period of 10–15 min, the treatment session can begin. The therapist
must record the patient’s history, symptoms, and the results of treatment. It is safe
to start with only 1–2 stings in the first session when the patient’s condition and
reaction time to sting is recorded.
The bee stings appear to work best when applied to so-called “trigger” points
that align with certain acupressure locations on the body. Once the point is identi-
fied and the sting applied, the initial effect will be minimal. However, as time goes
by, the area will redden, swell, and feel warm (Fig. 4.2d). The patient may also
experience localized pain. This indicates that an immune response has been triggered
4 Apitherapy – Bee Venom Therapy 83

Fig. 4.3 The two methods of bee sting therapy. (a-c) direct application; (d-f) indirect application

and potential healing processes are occurring. Over the next several weeks, the
patient will receive stings at regular intervals. As the treatment progresses, the
patient will become desensitized to the bee venom and will stop showing a swelling
when stung. At this point, the treatment is usually discontinued.
There are two ways to apply Bee Sting Therapy:
The direct application – catching a bee with tweezers or fine forceps, and grasp a
bee by the head or thorax, not the abdomen (Fig. 4.3a); put the bee at the spot on
the intended area (Fig. 4.3b); remove the stinger within 1 min (Fig. 4.3c) and
repeat steps a to c to treat different areas.
The indirect application – remove the sting using two tweezers or fine forceps
(Figs. 4.3d, e); put the stinger on the target point for only few seconds (Fig. 4.3f);
repeat step f, on up to ten different locations (using same stinger) and repeat steps
d to f when it is necessary.

4.4.3 Inhalation

This method is used in clinics and hospitals in Russia. The remedy is composed of
a unique blend of aromatized water and purified honeybee venom and it is applied
by inhalation with the help of a porcelain tube. Nowadays, this treatment modality
is being tested by physicians worldwide.

4.4.4 Iontophoresis

Iontophoresis (also called Electromotive Drug Administration, EMDA) is the introduc-

tion of drugs into the body by means of electrical current. This external application of
bee venom is yet to be scientifically validated, however it might be useful for patients
who cannot take injections.
84 C.M.H. Kim

4.4.5 Ointments

Ointments based on bee venom can easily be applied at home. However, this type of
delivery can produce lesions and irritations on large areas of the skin and it is much
less effective than intradermal injections.

4.5 Bee Venom Treatment (BVT) – Clinical Application

In case of BVT, the solution is administered intradermally using a 1.0 mL sterile

syringe with 0.1 mL graduations, 25–27 gauge, with a 1/2 in. or 1/4 – 5/8 in. needle.
A standard dose of 0.1 mL is given intradermally at each injection site. Prior to injec-
tion, the plunger should be retracted and to avoid intravascular injection. The injec-
tions are given in the painful or afflicted area first. It is considered more efficacious
if injections are given to the tender or trigger points. Later, injections to the spinal
area could be given according to the dermatome chart to achieve maximum effect.

4.5.1 Allergy Test

Like in bee sting therapy patients should always undergo an allergy test before ini-
tial treatments with honeybee venom (HBV). The test is conducted by injecting
1.0 mg/1.0 mL of bee venom on the flexor surface of the patient’s forearm. The test
area should be disinfected prior to injection and a sterile, disposable syringe should
be used. The needle should be introduced into the superficial skin layer until the
bevel of the needle is completely buried. 0.05 mL (one half of a standard single
treatment dose) is slowly injected to create a small hemispherical bleb.
A pinpoint sized blood spot usually appears on the area of needle insertion and
soon after a wheal with a diameter of 0.5–1.0 cm and a 2.5–4.0 cm large erythema-
tous area appear in the injection site. The severity of the reaction is monitored
according to the size of the wheal, size of erythema, and the appearance of any
irregular spreading or pseudo-pod like projections on the test area. A patient is con-
sidered negative to the test if he/she does not develop any of the systemic reactions
within 15–30 min after the intradermal injection of HBV.

4.5.2 Dosing Schedule

HBV is given in increments, depending on patient’s ability to tolerate honeybee

venom. Since sensitivity to venom differs in people, it is not possible to prescribe a
dosage schedule that is universal to all patients. For overly sensitive patients, an
individualized schedule should be employed.
4 Apitherapy – Bee Venom Therapy 85

In general, two sessions per week or treatments at 3 days interval are recommended.
The doses of the venom should be increased with each succession, e.g. 3×, 5×, 7×
and up to 20 injections, at one session. The total number of injections might be
higher than 20 (2.0 mg/2.0 mL) depending physician’s expertise and experience.

4.5.3 Treatment Duration

To achieve maximum results, it is necessary that patients receive an average of

12–20 sessions for most chronic inflammatory diseases. Chronic disabling condi-
tions such as rheumatoid arthritis and multiple sclerosis may require longer treat-
ment periods.

4.5.4 Instruction for Patients

For optimal treatment results patients should be instructed to adhere to the follow-
ing recommendations during BVT:
1. Alcohol is strictly forbidden during treatment.
2. If a local reaction in form of swelling and/or itching appears, ice packs could be
applied to the site.
3. It is recommended to take 2.000–3.000 mg of Vitamin C daily.
4. If fever and chills occur, acetaminophen could be taken (650 mg every 3–4 h as
needed).
5. In case of severe itching an anti-histaminic drug might be prescribed.
6. If any serious reactions occur, the caring physician should be contacted
immediately.

4.5.5 Cautions

Vyatchannikov and Sinka (1973) reported bee venom neurotoxicity is not severe or
dangerous when administered correctly. Adolapin (a newly isolated analgetic and
anti-inflammatory polypeptide from bee venom) has an analgesic effect in which
central mechanisms may also be involved. This is suggested by the fact that
Naloxone, a blocker of the opiate receptors eliminates this analgesic effect. Injection
of Apamin (a neurotoxin found in bee venom) in the spinal cord causes an increase
in monosysnaptic extensor reflex potentials and also in polysynaptic potentials due
to flexor afferents. MCD-Peptide and Phospholipase A2 may decrease blood pres-
sure if administered incorrectly. Apamin may also induce an anti-arrhythmic or
cardiac effect if administered improperly. Therefore it is important to note, that
Honeybee Venom (HBV) must be administered by licensed physicians or by gov-
ernment approved practitioners.
86 C.M.H. Kim

All physicians and licensed practitioners must be thoroughly aware of potential

adverse reactions before administering honeybee venom such as Apitoxin/Apitox to
prevent over-dosage and adverse reactions during pregnancy. HBV must only be
administered by physicians who are experienced with BVT to provide efficient and
maximum tolerated dose levels. Due to the possibility of severe systemic reactions,
the patient must always be fully informed with precautionary recommendations and
must be under constant direct supervision by their physicians. In case of emergency
the patient must be given an injection of subcutaneous epinephrine (adrenaline)
immediately, and must be transferred to hospital.

4.6 Biochemical Properties

The honeybee contains 0.1–0.3 mg of venom in its poison glands. The venom con-
centration is transparent, aromatically pungent, and bitter in taste. Its specific grav-
ity is 1.1313, and its pH 5.2–5.5. The venom is very resistant to heat and can
withstand temperatures of up to 100 °C or 212 °F. Dehydration of the venom takes
approximately 10-days and does not affect the potency of the venom. The venom is
also very resistant to cold, moreover, the toxicity is not reduced in freezing condi-
tions. Desiccated venom, if protected from moisture, can retain its potency for sev-
eral years. Figure 4.4 shows samples of dry bee venom.

Fig. 4.4 (a) samples of dried bee venom (raw); (b) sample of dried Apitox
4 Apitherapy – Bee Venom Therapy 87

Table 4.3 General composition of honeybee venom

Components Mol. wt. % (dry)
Peptides Melittin 2,840 40–50
Apamin 2,036 2–3
MCD-Peptide (Peptide 401) 2,588 2–3
Adolapin 11,500 1.0
Protease inhibitor 9,000 <0.8
Secarpin 0.5
Tertiapin 0.1
Melittin F 0.01
Procamine A, B 1.4
Minimine 6,000 2–3
Enzymes Hyaluronidase 38,000 1.5–2
Phospholipase A2 19,000 10–12
-D-Glucosidase 170,000 0.6
Acid phosphomonoesterase 55,000 1.0
Lysophospholipase 22,000 1.0
Active amines Histamine 0.6–1.6
Dopamine 0.13–1.0
Norepinephrine 0.1–0.7
Glucose & fructose (carbs) <2.0
6 Phospholipids (lipids) 4–5
r-aminobutyric acid (amino <0.5
acids)
b-aminoisobutyric acid <0.01
Adapted from Kim (1992)

There are numerous studies regarding the biochemical composition of honeybee

venom (Tu 1977; O’Connor and Peck 1978; Shipolini 1984; Meier and White
1995). It is important to note that semi-purified fractions and purified concentra-
tions of HBV are being produced, which should be even more effective in the treat-
ment of patients (see Table 4.3).

4.7 Pharmacology

The pharmacologic profile of HBV has been determined with the aid of in-vitro
analysis and research in animals and humans (Minton 1974; Tu 1977; O’Connor
and Peck 1978; Habermehl 1981; Shipolini 1984; Meier and White 1995). The dif-
ferent ingredients of HBV are discussed below briefly.

4.7.1 Melittin

Melittin has anti-inflammatory properties that stimulate the pituitary-adrenal system

which releases cortisol (Vick and Shipman 1972; Vick et al. 1972; Knepel and
88 C.M.H. Kim

Gerhards 1987). It is known to be 100 times more potent than hydrocortisone as

evidenced in animal models (Vick et al. 1972). Melittin is also known to stabilize
lysosome cell membranes and it is involved in the specific mechanisms that control
against inflammation (Dufourcq 1986).
Melittin is known for its anti-bacterial, anti-fungal, and anti-viral properties
(Dorman and Markey 1971; Fennell et al. 1968) as well as protection from
X-irradiation by increasing resistance against irradiation (Shipman 1967; Ginsberg
et al. 1968; Shipman and Cole 1968; Kanno et al. 1970). Furthermore, it has an anti-
nociceptive effect (Son et al. 2007) and is known for its antitumor activities (Orsolic
et al. 2003; Liu et al. 2008).

4.7.2 Apamin

Apamin stimulates the pituitary-adrenal system which releases cortisol (Vick and
Shipman 1972). It reduces inflammation caused by dextran and serotonin induced
inflammation. Additionally, it inhibits the complement system component C3,
which is known to cause inflammation (Gencheva and Shkenderov 1986).
Habermann and Cheng-Raude (1975) reaffirmed this by stating that the neuro-
toxic and postsynaptic effects (efferent system) of apamin blocks inhibition from α,
not from β adreno-receptors. Furthermore, apamin is known to antagonize
neurotensin-induced relaxation, while blocking most of the hyperpolarizing inhibi-
tory effects (invertebrate smooth muscle) including: α-adrenergic, cholinergic, puri-
nergic, and neurotensin-induced relaxations, and not β-adrenergic relaxation.
Apamin is a selective blocker of the Ca-dependent K+ channels that are present
in cell membranes (Hugues et al. 1982a). It also supports neural functional ability
as concluded by with rat brain synaptosomes (Hugues et al. 1982b).

4.7.3 Mast-Cell Degranulating (MCD) Peptide (Peptide 401)

MCD peptide was originally named due to its biological action of causing release of
histamine from mast cells (Jasani et al. 1979; Banks et al. 1990). MCD Peptide is
known to block arachidonic acid and inhibits prostaglandin synthesis (Hanson et al.
1974). It has the property of inhibition of epilepsy and inhibiting a voltage-dependent
potassium channel in brain membranes (Gandolfo et al. 1989).

4.7.4 Adolapin

Adolapin inhibits the microsomal cyclooxygenase and is 70 times stronger than

indomethacin as shown in animal models. Moreover, adolapin inhibits platelet
4 Apitherapy – Bee Venom Therapy 89

lipoxygenase, which includes hydroperoxy-eicosotetranonic acid (HPETE) and

leukotriens, as well as thromboxane (TXA2) and prostacycline (PGI2), which are
activated during inflammation. Additionally adolapin has anti-nociceptive and anti-
inflammatory properties through inhibition of cyclooxygenase activity (Shkenderov
and Koburova 1982). Adolapin has an analgesic effect (Koburova et al. 1985) and
antipyretic properties (Koburova et al. 1984), in which central mechanism may also
be involved.

4.7.5 Protease Inhibitor

The protease inhibitor is known to prevent infections and viruses by inhibiting pros-
taglandin E1-, bradykinin- and histamine-induced inflammation. It’s also known to
inhibit chymotrypsin and leucine-aminopeptidase (Shkenderov 1986).

4.7.6 Phospholipase A2 (PLA2)

Phospholipase A2 has inflammatory, nociceptive (Hartman et al. 1991; Landucci

et al. 2000) and antigenic and allergenic effects (Minton 1974; Habermehl 1981;
Shipolini 1984). PLA2 is involved in nerve regeneration (Edstrom et al. 1996), facil-
itates neurotransmitter release (Yue et al. 2005), and delayed neurotoxic effects
in vitro and in vivo (Clapp et al. 1995). PLA2 shows complex interactions with
melittin that can result in potentiation of secretory PLA2 effects or in inhibition
depending on the peptide/phospholipid ratio (Koumanov et al. 2003).

4.7.7 Hyaluronidase

Hyaluronidase break down hyaluronic acid in tissues such as in synovial bursa of

rheumatoid arthritis patients (Barker et al. 1964). Hyaluronidase is very sensitive to
heat and light so that it is a good indicator of the stability of bee venom (Kim 2012).

4.8 Clinical Studies

Studies over the past 25 years evaluating the safety and efficacy of Apitoxin/Apitox
have been conducted in patients with chronic pain and inflammation such as rheu-
matoid arthritis, osteoarthritis, fibromyositis, peripheral neuritis, multiple sclerosis,
and a multitude of other diseases. These studies are discussed below according to
the disease or disorder type.
90 C.M.H. Kim

4.8.1 Arthritis, Chronic Pain, and Inflammation

Zaitsev and Poriadin (1961) reported that of 150 patients stricken with ankylosing
spondylitis and polyarthritic deformity, symptomatic relief was obtained in 117
cases (78 %), satisfactory results in 30 cases (20 %), no change in two cases, and
allergic reaction in one case.
A controlled clinical study was conducted by Steigerwaldt and Mathies (1966)
comparing 50 cases treated with a standardized preparation of bee venom against 11
cases treated with a placebo (injection of physiologic sodium chloride solution).
The results showed beneficial effects in 84 % of the cases and 55 % in those using
a placebo. After elimination of the cases that showed only weak improvement, the
proportion of patients showing beneficial effects was 66 % of those treated with
venom and 27 % of those who had been given a placebo.
Hurkov (1971) studied the use of venom in 180 patients suffering from osteoar-
thritis. Ninety-four showed a significant improvement and no adverse reaction was
observed. Nokolova (1973) reported a success rate of 94 % of his patients stricken
with rheumatoid arthritis who had been treated without success by conventional
treatments. Serban (1981) compared indomethacine (100 mg/day) with purified bee
venom (Forapin) in two groups of 50 patients. The groups consisted of 20 cases of
gonarthrosis, 10 cases of coxarthrosis, and 20 cases of spondylitis. After 24 days the
bee venom treatment produced better responses than indomethacine. Feldsher et al.
(1981) reported that bee venom therapy is highly effective for the treatment of
chronic low back pain and lumbosacral radiculitis.
Mund-Hoym (1982) described the therapeutic results of 211 patients who suf-
fered from mesenchymal diseases of the hip and knee joints. After 6 weeks of treat-
ment, 70 % of patients showed marked improvement.
Forestier and Palmer (1983) reported that among 1.600 cases that were treated
with bee venom, an 80 % success rate was obtained in the following cases: pain in
the knee before the arthritis was advanced; chronic periarthritis of the shoulder and
epicondylitis of the elbow that resisted the injections of cortisone; relief of pain at
the base of the toes. In case of rheumatoid polyarthritis, positive results were noticed
at the beginning, but effectiveness gradually diminished. There was a minimal effect
observed in patients with coxarthrosis, ankylosing spondylitis, and vertebral osteo-
porosis of menopausal women. The authors finally conclude that an increasing dose
of bee venom could end the intense pain of severe rheumatism, which has existed
for months or even years.
Lonauer et al. (1985) presented results of 30 patients suffering from rheumatoid
arthritis in stages I-III. The use of corticosteroid was excluded, and most of the
patients did not use any non-steroidal anti-inflammatory drugs (NSAIDs). A marked
improvement of articular joint pain was observed in 74 % of the cases, a moderate
improvement in 9 % of the cases and no improvement in 17 %. Joint mobility was
improved in 65 % of the cases and swelling diminished in 56.5 % of the cases. The
use of NSAIDs could be reduced considerably and apitherapy constituted an effi-
cient treatment and was well tolerated.
4 Apitherapy – Bee Venom Therapy 91

Kim (1989) conducted a study of bee venom therapy and a positive correlation
of effectiveness between arthritic inflammation and bee venom was established.
Kim (1991) conducted another study comprising with 180 randomized patients
received injections of Apitox (purified Apis mellifera toxin) for over a period of
6 weeks (also known as Apitoxin in Korea). The injection dosage in this case was set
at 1.0 mg/mL of honeybee venom, while the 50 % of each group (the control indi-
viduals) received 1.0 mL of histamine phosphate 0.275 mg/mL. The number of
injections increased with each subsequent visit (e.g. 3, 6, 9, 12, 15, 18, and up to 20
injections per session); with a continuous dosage schedule of 20 injections/sessions
for the remaining period of the study. Initially, the injections were administered
directly to the area of pain. After the fifth session, when the number of injections
increased gradually, injections were also administered to the corresponding derma-
tome area of the spine. A visual analogue scale (VAS) and a McGill Pain
Questionnaire (MPQ) were used to assess the level of pain. Thermographic evalua-
tions and physical examinations (to evaluate swelling, tenderness, and range of
motion limitations) were also performed. Both groups experienced a reductions in
pain (good or moderate scores) following treatment with Apitox. It was also shown
that the Apitox treatment group demonstrated a greater improvement in their pain
reduction scores compare to the control group. Scores after treatment with Apitox
were established at 18 (pain level), while the control group scored at 57. After a
period of 6 months, there was yet another significant difference in scores between
the control and the Apitox treatment group. In this case, pain reduction scores were
significantly higher, as the Apitox treatment group scored an average of 29, whereas
the control group scored at 83. Overall, the Apitox treatment group demonstrated a
remarkable improvement with their physical examinations as well as reduced
inflammation in their computerized infrared thermographic readings.
Klinghardt (1990) reported anecdotally that among 128 patients with a wide
spectrum of illnesses, all but 11 appeared to improve (90 % improvement). This
report is typical of anecdotal apitherapy results that begin with stories of beekeepers
recounting various health improvements after receiving accidental multiple stings
from their bees. The patients had diagnoses of gout, rheumatoid arthritis, fibromy-
algia, spinal strain (injury to either a muscle or tendon) or sprain (stretching or tear-
ing of a ligament), spinal disc injuries, post-laminectomy pain, bunion (hallux
valgus), postherpetic neuralgia (PHN), incomplete healing of fractured bone, intrac-
table pain from large burn wounds, osteoarthritis, ankylosing spondylitis, vertigo,
and multiple sclerosis.

4.8.2 Korean FDA, Phase I Clinical Study

Kang and Kim (1993) performed the toxicity study on human. The total 20 (10 male,
10 female) subjects between the ages of 23 and 45 years of age were enrolled and
15 completed the study. Five subjects dropped out of study because of failure to
keep study appointments, not following study directions, or due to consumption of
92 C.M.H. Kim

alcohol during the study. Each subject received an initial test dose of 0.05 mL and
then 12 doses of Apitox, starting with 0.1 mL with the first intradermal injection and
increasing to 0.2 mL (second injection), 0.25 mL (third injection), 0.3–0.7 mL
(fourth through twelfth injections). Injections were administered 2–3 times per
week over a period of 4–6 weeks. Physical examination, blood and urine laboratory
evaluations, and vital sign measurements were performed.
There were no significant changes pre- and post-test of the hematology, blood
chemistry, urinalysis, and vital signs after injection with Apitoxin. Also, there were
no significant physiological changes in the clinical evaluations. Localized itching
was the most common adverse experience (11/15). Edema (5/15), pain at injection
site (2/15), and blister at injection site (1/15) were also reported, but no serious
adverse experiences were reported. Thus, it was concluded that Apitox can be safely
administered to humans when applied in therapeutic doses (Kim 1987).

4.8.3 Korean FDA, Phase II Clinical Study

This study was evaluated by the Korean FDA, labeled as Phase II Clinical Study,
and was an active-controlled study. One hundred one randomized subjects with
osteoarthritis of the knee or spine were given injections of Apitoxin. Maximum dose
levels and schedules were set at: 0.7 mg twice a week for Group A; 1.5 mg for
Group B; 2.0 mg for Group C, and 1,000 mg per os of Nabumetone (a non-steroidal
anti-inflammatory drug) for Group D (control group) once daily for over a period of
6 weeks. A four-point Likert-like symptom severity rating scale was used to assess
pain, disability, and physical mobility. In addition, a 5-point self-evaluation scale
and assessment form was given to the research subjects. Overall, 81 out of the 101
subjects completed the study. Safety of the treatment was assessed through observa-
tions of adverse reactions or experience as well as through the assessment of blood
and urine laboratory test.
There were no significant changes in vital signs or results of laboratory examina-
tions of any patient in this clinical trial. Localized itching was experienced by all
patients who received Apitox injections. Itching at the injection site generally lasted
for 2–3 weeks; several patients had this reaction for a longer period. Chills and
generalized body ache were reported by 81.7 % of Apitox-treated patients, and 60 %
experienced pain at injection sites. One patient complained of nausea and abdominal
pain after Apitox treatment, but it was not clearly due to the bee venom injection and
the patient completed the trial. One patient dropped out the study because of blister
formation at injection site; the blister was cured with local wound care. One patient
developed urticaria following treatment but symptoms resolved after 1 week.
The results of this study demonstrate overall efficacy rates of 85 and 90 % in the
moderate-dose and high-dose groups, respectively. The clinical study proved that
the Apitoxin treatment group demonstrated significantly greater improvements than
those in the Nabumetone group (p <0.01). Within the Apitoxin groups, Groups B and
C demonstrated greater improvements than Group A (p <0.01) (Won et al. 1999).
4 Apitherapy – Bee Venom Therapy 93

4.8.4 Korean FDA, Phase III Clinical Study

The purpose of this clinical study was to compare efficacy and safety of Apitoxin
and Nabumetone when the patients with osteoarthritis were given injection of
Apitoxin and Nabumetone during 6 weeks. The clinical study was conducted with
patients from four Korean University Medical Centers. The study was designed as
randomized, active-controlled trial in which 405 subjects with osteoarthritis of the
knee or spine were given intradermal injections of Apitoxin twice a week with maxi-
mum doses of 1.5 mg, while the control group received an oral dose of 1,000 mg
Nabumetone once daily for a period of 8 weeks. Out of 405 participants 310 com-
pleted the study.
There were no significant changes in vital signs or results of laboratory examina-
tions of any patient in this clinical trial. The adverse reactions were a little higher in
the Apitoxin group, but there was no statistical significance. Adverse reactions
caused by the medicine to study were similar in the two groups. No significant side
effects were reported during this study.
Comparing the ratios of subjects who showed more than 20 % improvement in
the total point of efficacy evaluation items during the 6th week of trial, the apitoxin
group showed a better improvement compared to the Nabumetone group (69.69 vs.
46.15 %).
Furthermore, the improvement rate during the 2nd week after completion of the
study of the Apitoxin group was 58.44 % while 42.95 % of the Nabumetone group
improved. This tells us that the Apitoxin group showed a better sustained improve-
ment rate in statistical significance than the Nabumetone group. The rate and sever-
ity of adverse reactions were similar in both groups. Muscle pain of the
musculoskeletal system was more frequent in the Apitoxin group, while gastrointes-
tinal pain was most common in the Nabumetone group. The authors concluded that
Apitoxin was significantly more effective than the control drug Nabumetone in the
treatment of pain and inflammation for osteoarthritis patients. Reduction of disability
and physical progress was greater in the Apitoxin group than in the control group.

4.8.5 Korean FDA, Phase IV Clinical Study

In 2003 the Korean FDA issued a final report on the effects of bee venom injection
treatment branded as Apitoxin. This drug became the first federally regulated bio-
pharmaceutical medicine in the world (Guju and Apimeds 2003).
Following approval of Apitoxin in Korea a post-marketing survey (PMS) was
conducted between the years 2003 and 2009 upon the conclusion of the 6-year study
involving a total of 3,194 patients who voluntarily received Apitoxin treatment. The
exit surveys concerned personal details, present illnesses, past history, present med-
ication use, treatment dates for 12 or more sessions, dosage amounts, and any
adverse reactions or experiences. A complete blood count was performed before the
first and after the last treatment. The participants’ physicians and Korean FDA were
94 C.M.H. Kim

instructed to contact the acting pharmaceutical company involved to report any

negative feedback or reactions. According to the survey no major adverse reactions
were reported (Guju and Apimeds 2009).
The Pain Center at PC University Medical Center in Korea has documented the
use of Apitoxin with over 6,132 patients with intractable medical conditions and
autoimmune diseases between the years of 2003 and 2009. Minor adverse reactions
included itching (injection site), swelling (injection site), slight pain, low-grade
fever, flushing, headache, and diarrhea (Kim 2009).

4.8.6 Future Studies in the United States

Currently in the United States, Apitox is in Phase III for clinical study and is also in
progress for United States FDA approval at the Center for Biologics Evaluation and
Research (CBER). The study was labeled as a “Multi-Center, Randomized, Double-
Blind, Active-Controlled, Phase III Parallel Group Clinical Study to Evaluate the
Safety and Efficacy of Apitox vs. Histamine in Subjects with Refractory Osteoarthritic
Pain and Inflammation”. Twenty-six clinical centers in the US and India have been
selected and the study might be completed by the end of 2013 (NIH 2010).
Kim (2012) reported the stability study of Apitox to the CBER, FDA. It is very
safe and stable up to 36 months.

4.9 Case Studies and Research

There are hundreds of scientific case studies evaluating the effects of bee venom on
both human and animal models. During a period of 50 years, scientists and physicians
validated the restorative properties of honeybee venom as a treatment for many dis-
eases and afflictions. The studies cited below are arranged according to disease type.

4.9.1 Arthritis and Rheumatoid Arthritis

Lorenzetti et al. (1972) conducted studies on the use of bee venom prophylactically
and therapeutically to reverse adjuvant-induced arthritis in rats. Bee venom was
injected three times a week for a period of 4 weeks subcutaneously. The researchers
were able to prevent arthritic syndromes such as foot edema, secondary lesions, and
reduction in inflammation. In this case, the experimenters proved that bee venom is
effective as a therapeutic and as a prophylactic treatment producing immediate results.
Weissmann et al. (1973) found that the effects of daily injections of three indi-
vidual bee venom components (melittin, apamin, and phospholipase A2), along with
the effects of daily injections of whole bee venom, prevented adjuvant arthritis from
developing in rats.
4 Apitherapy – Bee Venom Therapy 95

Chang and Bliven (1979) administered bee venom for adjuvant-induced arthritis
in rats. The sub-cutaneous injection dose was between 0.01 and 1.0 mL daily over a
period of 17 days. It was shown that honeybee venom suppressed the development
of adjuvant arthritis in a dose dependent manner. Single administration of bee
venom also proved to suppress the development of carrageenan-induced paw edema.
Moreover, bee venom was shown to effectively suppress the development of poly-
arthritis. This suppressive effect would decrease progressively over time as dosing
was delayed. Bee venom was found to be most effective when mixed and injected
together with CFA (complete Freund’s adjuvant), the disease-inducing agent.
Similarly, bee venom mixed with egg albumin and CFA injected into the hind paw
prevented the development of arthritis. These results suggest that at least two mech-
anisms are involved in the anti-arthritic action of bee venom; one involving the
alteration of immune response (most likely via antigen competition), and the second
being the anti-inflammatory action and property of bee venom.
Eiseman et al. (1982) showed that the therapeutic effect of bee venom on arthritis
was completely dependent on the site of administration. In particular, local injection
of bee venom near the site of inflammation was more effective in inhibiting the
development of adjuvant-induced arthritis.
Kim (1997) stated that according to TCM (traditional Chinese medicine) arthritis
originates from a deficiency in the circulation of the blood and lymph inside tissue
joints, which results in an accumulation of lactic acid where bacteria can multiply.
He contended that the vasodilatatory effect of bee venom therapy can increase local
circulation, which corrects deficient circulation and also works against the spread of
irritation.
Kwon et al. (2001a) conducted a study to evaluate the anti-nociceptive effect of
bee venom injections into a specific acupoint (Zusanli, Stomach point 36) as com-
pared to a non-acupoint in a rat model with chronic arthritis. Subcutaneous injec-
tions of bee venom (1.0 mg/kg per day) were found to dramatically inhibit paw
edema caused by CFA injection. It was also shown that this treatment modality
significantly reduced arthritis-induced nociceptive behaviors such as the nocicep-
tive scores for mechanical hyperalgesia and thermal hyperalgesia. The anti-
nociceptive and the anti-inflammatory effects of bee venom were observed for a
period of 12–21 days post treatment. In addition, bee venom significantly sup-
pressed the adjuvant-induced Fos-gene expression in the lumbar spinal cord at the
3rd week post-adjuvant injection. Finally, injection of bee venom into the Zusanli
acupoint resulted in a significantly greater analgesic effect on arthritic pain as com-
pared with bee venom injection into a more distant non-acupoint. The study has
further demonstrated that bee venom injection into the Zusanli acupoint had both
anti-inflammatory and anti-nociceptive effects on CFA-induced arthritis in rats.
Altogether, these findings suggest that bee venom acupuncture is an effective ther-
apy treatment for rheumatoid arthritis.
Kwon et al. (2001b) conducted a study with bee venom treatment for osteoarthritis.
This was a 4-week comparison trial involving a total of 60 volunteers. The treatment
group (n = 30) received honeybee venom acupuncture (bee venom injection at acu-
puncture points), while the control group (n = 30) received traditional acupuncture
96 C.M.H. Kim

treatment. It was observed that bee venom acupuncture produced maximum effective
results for chronic pain relief rather than acupuncture treatment alone. Bee venom
acupuncture showed a significant improvement (82.5 %) and almost all patients
reported relief from pain and chronic ailments, while their computerized infrared
thermograph readings were at normal levels.
Kang et al. (2002) effectively assessed the clinico-therapeutic effect of bee
venom by administrating venom to 90 rats with adjuvant-induced arthritis rats.
Clinical findings of lameness score, edema volume, hematological values, and
histo-pathology (the interphalangeal joint of the right hind paw) were observed dur-
ing the treatment period. In the treatment groups, the development of inflammatory
edema and polyarthritis were suppressed effectively through bee venom treatment.
In addition, the authors found that there were no significant changes regarding the
hind paw edema volume and lameness score between the prednisolone and the
venom treatment groups. Red blood cell count, hematocrit, and hemoglobin counts
were not different between the groups; although significant leucocytosis was
observed in the control group (p <0.01). Moreover, bee venom was found to effec-
tively suppress erosions of articular cartilage and inflammatory cell infiltrations into
the interphalangeal joints. The researchers concluded that honeybee venom
successfully suppresses arthritic inflammation in rats.
Park et al. (2004) investigated the molecular mechanisms of the anti-inflammatory
effects of bee venom using rat models. The rats suffered from carrageenan-induced
acute edema in their paws and chronic adjuvant-induced arthritis. Bee venom was
administered daily at 0.8 and 1.6 µg/kg into their hind paws. The results were con-
sistent with the in vitro results, which showed an inhibitory effect of bee venom set
between 0.5, 1.0, and 5.0 µg/mL per treatment. The study also showed that melittin
(a major component in bee venom) applied at 5.0 and 10.0 µg/mL had an anti-
inflammatory effect in rats with arthritis.
Yin et al. (2005) used HTB-94 human chondrosarcoma cells to establish the gene
expression profiles of bee venom treatment. Out of the 344 genes profiled, 35 were
down-regulated by bee venom; 16 were up regulated, whereas seven were down
regulated by lipopolysaccharide (LPS). Furthermore, 32 were down regulated by
LPS mixed with bee venom. The bee venom proved to reverse the upregulation
caused by LPS for some genes, such as the IL-6 receptor, matrix metalloproteinase-
15 (MMP-15), tumor necrosis factor, superfamily-10, caspase-6, and tissue inhibitor
of metalloproteinase-1 (TIMP-1). The researchers effectively established the phar-
macologic activity of bee venom in the treatment of arthritis.

4.9.2 Osteoarthritis and Chronic Pain

Vick et al. (1976) found a positive correlation between the effects of bee venom on
cortisol levels related to increase of the activity of dogs that had hip dysplasia. Out
of 24 dogs, 16 were normal and eight had severe hip dysplasia. The two groups were
sub-divided into four treatment groups. Groups I and II included eight normal dogs
each whereas Groups III and IV contained four dogs each with hip dysplasia.
4 Apitherapy – Bee Venom Therapy 97

Groups II and IV received 1.0 mg (about 0.067 mg/kg) of bee venom subcutaneously
on days 30, 37, 50, and 60, and were crossed over to receive saline control treatment on
days 90, 97, 110, and 120. Groups I and III first received a saline solution and later
were crossed over to receive bee venom treatment. On day 90, treatment would be
crossed-over again. The dogs receiving bee venom had an increase in plasma cortisol
levels, and their physical activity increased inside the cages. The results showed that
bee venom treatment stimulated the production of cortisol, which had anti-inflammatory
properties, thus enhancing the mobility of dogs with hip dysplasia related arthritis.
Short et al. (1979) reported the results of treating 17 dogs that had been diag-
nosed as arthritic. Following bee venom therapy, 14 of 17 dogs improved signifi-
cantly, returning to normal or near-normal movement. Four of five dogs treated for
joint complications (hip displasia and arthritic joints) showed improved movement;
four of six dogs treated for poor surgical recovery responded well and all dogs suf-
fering from disc complications returned to normal or near-normal conditions after a
series of bee venom injections administered at the sites of pain and stiffness. From
the results of this study, the authors concluded that bee venom therapy may be
highly beneficial in alleviating certain arthritic conditions in dogs.
Von Bredow et al. (1981) conducted a study in which he observed the effects of
bee venom injections on eight arthritic horses, ranging in age from 8 to 17 years. Six
of the eight horses showed significant improvement, with three of these six demon-
strating a complete recovery.
Lee et al. (2001) examined the anti-nociceptive and anti-inflammatory effects of
bee venom pretreatment on carrageenan-induced inflammation in rats. The experi-
ments were designed to evaluate the effect of BV pretreatment on carrageenan
(CR)-induced acute paw edema and thermal hyperalgesia. In addition, spinal cord
Fos-gene expression induced by peripheral inflammation was quantitatively ana-
lyzed. In normal animals subcutaneous BV injection into the hindlimb was found to
slightly increase Fos expression in the spinal cord without producing detectable
nociceptive behaviors or hyperalgesia. In contrast pretreatment with BV (0.8 mg/
kg) 30 min prior to CR injection suppressed both the paw edema and thermal hyper-
algesia evoked by CR. In addition, there was a positive correlation between the
percent change in paw volume and the expression of Fos positive neurons in the
spinal cord. These results indicate that BV pretreatment has both antinociceptive
and anti-inflammatory effects in CR-induced inflammatory pain. These data also
suggest that BV administration may be useful in the treatment of the pain and edema
associated with chronic inflammatory diseases.

4.9.3 Vascular System

Forster (1950) studied the pharmacological effects of bee venom based upon all its
components, in particular the effect upon the blood circulation, the permeability of
biological membranes, and the organic exchanges. Administration of venom results
in vasodilation, accompanied by an increase of permeability of blood vessel caused
by hyaluronidase. He also describes a hypophyseal effect demonstrated by the
98 C.M.H. Kim

absence of an effect upon hypophysectomised animals. This effect upon the hypoph-
ysis brings about a discharge of cortisol from the adrenal glands.
Zaitsev and Poriadin (1973) studied 415 patients: 77 were suffering from endar-
teriitis obliterance (a form of vasculitis with unknown etiology), 138 had arterio-
sclerosis of the peripheral blood vessels, 65 Bechterew’s disease (ankylosing
spondylitis), 50 spondylarthritis deformans, 85 polyarthritis deformans. He reported
a good result (80 %) of the arterial diseases of the extremities and satisfactory result
(67 %) of the spine and the joint diseases.
Hanson et al. (1974) have shown that the intradermal injection of peptide 401 (mast
cell degranulating peptide, a component of honeybee venom), substantially inhibited
the edema provoked by subplantar injection of carrageenan or an intra-articular
injection of turpentine in rats. Peptide 401 also suppressed the increased vascular
permeability due to intradermal injection of various smooth muscle spasmogens
(histamine, bradykinin, 5-hydroxytryptamine and prostaglandins). These results
demonstrate that peptide 401 is a potent anti-inflammatory agent in the rat. Its effec-
tiveness has proven superior to that of indomethacine, salicylate, and phenylbutazone.
Lee et al. (2010) studied the influence of bee venom on the expression of cellular
adhesion molecules in the vascular endothelium. A great amount of information
exists concerning the effects of an atherogenic diet on atherosclerotic changes in the
aorta, but little is known about the molecular mechanisms and the levels of gene
regulation involved in the anti-inflammatory process induced by BV. The experi-
mental atherosclerosis was induced in mice by a lipopolysaccharide (LPS) injection
and an atherogenic diet. The animals were divided into three groups, the NC groups
of animals that were fed with a normal diet, the LPS/fat group was fed with the
atherogenic diet and received intraperitoneal injections of LPS, and the LPS/
fat + BV group was given LPS, an atherogenic diet and intraperitoneal BV injec-
tions. At the end of each treatment period, the LPS/fat + BV group had decreased
levels of total cholesterol (TC) and tri-glyceride (TG) in their serum, compared to
the LPS/fat group. The LPS/fat group had significant expression of tumor necrosis
factor (TNF)-α and interleukin (IL)-1α in the serum, compared with the NC group
(p <0.05). The amount of cytokines was consistently reduced in the BV treatment
groups compared with those in LPS/fat group. BV significantly reduced the amount
of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1
(VCAM-1), transforming growth factor-α1 (TGF-α1) and fibronectin in the aorta,
compared with the LPS/fat group (p <0.05). A similar pattern was also observed in
the heart. In conclusion, BV has anti-atherogenic properties via its lipid-lowering
and anti-inflammatory mechanisms.
Kim et al. (2011) investigated the effects of melittin (a major component of bee
venom) regulated athero-sclerotic changes in an animal model of atherosclerosis.
The results showed that melittin decreased the total cholesterol and triglyceride
levels in atherosclerotic mice. In addition, melittin decreased the expression levels
of tumor necrosis factor (TNF)-ß, interleukin (IL)-1ß, vascular cell adhesion molecule
(VCAM)-1, intercellular adhesion molecule (ICAM)-1, fibronectin and transforming
growth factor (TGF)-ß1 in atherosclerotic mice. In vitro, melittin decreased
lipopolysaccharide (LPS)-induced THP-1 cells-derived macro-phases TNF-α and
4 Apitherapy – Bee Venom Therapy 99

IL-1ß expression level and nuclear factor (NF)-κB signal pathway. The authors con-
cluded that melittin has an anti-atherogenic effect by suppression of pro-inflammatory
cytokines and adhesion molecules.

4.9.4 Immune System and Disease

Hyre and Smith (1986) conducted a study on the immunological effects of honey-
bee venom in mice. The authors state that mice injected with bee venom prior to,
and following, an injection of sheep red blood cells produced significantly more
direct IgM plaques than the sham-injected group. The results of this study indicate
that bee venom can effects both T and B lymphocyte functions.
Hadjipetrou-Kourounakis and Yiangou (1988) conducted a study in order to deter-
mine whether the in-vivo effects of bee venom may be mediated by alterations in
lymphokine production. With dosage schedules set at 0.5 mg/kg a day, bee venom was
administered intramuscularly (IM) in rats for over a period of 17 days, which caused a
reduction in interleukin (IL) production by splenocytes (white blood cell types purified
from splenic tissue). Moreover, in vitro addition of IL-1 or IL-2 to the cultures resulted
in an increase in normal response levels, suggesting that bee venom can affect the
production of IL-1 by macrophages. These findings also indicate that bee venom can
modify inflammatory responses by interfering with inflammatory cell functions.
Defendini et al. (1988) studies on adjuvant-induced symptoms in which a positive
correlation between lymphokine production and the anti-inflammatory response of
bee venom was demonstrated.
Rekka et al. (1990) showed that honeybee venom is able to inhibit significantly
nonenzymatic lipid peroxidation. It also possesses a considerable hydroxyl radical
scavenging activity, evaluated by its competition with dimethyl sulfoxide for HO
(hydroxyl radicals). These results, in relation to the in vitro suppression mainly of
interleukin-1 production offered by honey bee venom, may further support that anti-
oxidant activity is involved in the anti-inflammatory activity of honey bee venom.

4.9.5 Anti-fungal, Anti-bacterial, and Anti-viral Properties

Schmidt-Lange (1941) wrote about the anti-bacterial properties of bee venom as

an effective germicide. These findings were confirmed by Fennell et al. (1968) in
their studies on the anti-bacterial action of melittin, which is an important compo-
nent of honeybee venom. Furthermore, these researchers showed that honeybee
venom and a polypeptide fraction of melittin, had an antibacterial property against
a penicillin-resistant strain of Staphylococcus aureus (Strain 80). Both, whole bee
venom and melittin inhibited the growth of 20 out of 30 different bacterial strains.
Fennell and his team found that 86 % of the Gram-positive and 46 % of the Gram-
negative bacteria were sensitive to bee venom and to melittin. Among the
100 C.M.H. Kim

Gram-positive micro-organisms, the antibacterial effect of 1.0 mg melittin was equal

to that of 0.1–93 units of penicillin. Other studies by Dorman and Markey (1971)
substantiated the anti-bacterial qualities of HBV.
Rauen et al. (1972) studied the anti-fungal properties of melittin and apamin on
a variety fungi, while Hadjipetrou-Kourounakis and Yiangou (1984) showed that
bee venom also had anti-viral properties.
Han et al. (2007) examined the antibacterial activity of bee venom against the
most contagious agents of bovine mastitis. The results showed bee venom has
significant antibacterial effects against seven major bacterial mastitis pathogens.
The minimal inhibitory concentrations (MIC) against Staphylococcus aureus, meth-
icillin resistant Staphylococcus aureus (MRSA) and Escherichia coli had a stronger
effect as compared with standard drugs. The study indicates that bee venom has
potential antibacterial effects, and provides justification for the evaluation of bee
venom as an alternative to antibiotics for the treatment of bovine mastitis.

4.9.6 Anti-inflammatory Properties

There are numerous scientific articles that present sound evidence of the anti-
inflammatory properties of bee venom.
Vick et al. (1972) studied the effect of whole bee venom on plasma cortisol levels
in a monkey model. Subcutaneous injections of bee venom (1.0–100.0 mg), and
melittin (1.0–10.0 mg) caused a marked and sustained elevation in plasma cortisol
levels. This increase occurred approximately an hour after injection and lasted for
2–4 days. This effect appeared to be dose-related as higher doses of bee venom or
melittin resulted in the production of the quickest and highest plasma cortisol levels.
In an additional monkey subject, bee venom (1.0 mg) and melittin (0.1 mg) were
administered each at 72–96 h respectively. This resulted in an immediate and
sustained rise in cortisol which lasted for 20–30 days. Melittin alone appeared to be
ten times more potent than whole bee venom. Necropsy conducted on the four mon-
keys that received the highest dosages of bee venom or melittin revealed no signifi-
cant tissue damages. Overall, this study indicates that bee venom and its isolated
component melittin stimulates the production of cortisol from the adrenal gland.
Banks et al. (1976) reported on the prostaglandins, which are implicated during
the ‘secondary inflammation’ phase. The non-steroidal anti-inflammatory drugs
(NSAIDs), such as aspirin and indomethacine, are inhibitors of the synthesis of the
prostaglandins in vivo and in vitro. They have shown that peptide 401 is also an
inhibitor in the conversion of arachidonic acid to prostaglandin E in vitro.
Menander-Huber (1980) demonstrated that melittin binds with calmodulin, and
Jones et al. (1982) demonstrated that NADPH-oxidase contained in the membrane
fraction of the activated leukocytes (which are responsible for the production of
superoxide anions) depends on calmodulin. It could be that bee venom works via a
similar mechanism. The principal fraction of venom, melittin, shows a great affinity
to calmodulin, and is the only fraction of bee venom which has this characteristic.
4 Apitherapy – Bee Venom Therapy 101

Somerfield et al. (1986) explained the mechanism of bee venom’s anti-inflammatory

action by investigating its effect on neutrophil O2-production. It is well established
that oxygen radicals and their metabolites play a role in chronic inflammations and
tissue destruction. Using human peripheral blood leukocytes, the polymorphonuclear
fraction was isolated and used for in vitro assessments on the ability of melittin and
other bee venom peptides on the production of reactive oxygen species (ROS). The
results showed that melittin but not other bee venom fractions, inhibited ROS produc-
tion both pre- and post-stimulation, suggesting that melittin may have a role in the
in vivo regulation of radical production.
Dufourcq (1986) showed that melittin strongly disturbs the membrane structure
of the liposomes into which it penetrates. It is not selective about the phospholipids,
and it increases the permeability of all kinds of cells, like mastocytes and cytoplasmic
bacterial membranes.
Gencheva and Shkenderov (1986) reported that the low molecular fraction of bee
venom injected into rats in a daily dose of 100 µg/kg over a 3-week period reduced
the activity of the complement system by 45 %.

4.9.7 Lyme’s Disease

Tests measuring melittin’s inhibitory actions against Lyme’s Disease were carried
out at the U.S. National Institute of Allergy and Infectious Diseases in Hamilton,
Montana, Rocky Mountain Laboratories Microscopy Branch. Thorough research on
Borrelia burgdorferi (the bacterial agent of Lyme disease) demonstrated that bee
venom effectively resisted in vitro effects of powerful eukaryotic and prokaryotic
metabolic inhibitors. Moreover, treatment of laboratory cultures of B. burgdorferi in
Barbour-Stoenner-Kelly medium with melittin, showed immediate and profound inhi-
bitory effects monitored with dark-field microscopy and optical density measurements.
Furthermore, melittin concentrations as low as 100 mg/ml, ceased virtually all
spirochete motility within seconds. The examination of the spirochetes under the
electron microscope, which could reveal obvious alterations on the surface envelope
of the spirochetes showed an extraordinary sensitivity of B. burgdorferi to melittin
providing both a research tool in the study of selective permeability in micro-
organisms and also important clues for the development of new and effective drugs
against Lyme disease with melittin and honeybee venom (Lubke and Garon 1997).

4.9.8 Radioprotective Effects

Shipman (1967) investigated the resistance of bee venom treated mice to irradiation
with X-rays. The response of animals to whole-body irradiation with a lethal dose
was modified by changes in their physiological state induced before exposure.
The ability of bee venom in producing a degree of physiological stress in animals,
102 C.M.H. Kim

eliciting a neuroendocrine response (pituitary-adrenal stimulation), increased the

resistance of mice to radiation. In these experiments, pre-treatment with bee venom
(IP dose range: 1.1–1.24 µg; SC dose range: 4.3–5.6 µg) resulted in greater survival
rates as compared to saline control animals. Bee venom administered subcutane-
ously resulted in the greatest protection (70–80 % survival rate in a 30-day period)
from irradiation. Only 7 % of the rats, which had 5.4 µg of melittin administered
subcutaneously survived for a 30-day period. Based on these results, it was pro-
posed that at least three mechanisms of action were attributed regarding the radio-
protective effect of bee venom in mice. First, a stressor-like action that elicits an
“adaptation syndrome”; second, the production of changes in the hematopoietic
system; and third, the antibacterial properties of the venom.
Ginsberg et al. (1968) deduced that melittin provided a significant protection
from x-irradiation in mice that received an SC injection dose of 60 mg/kg bee
venom 24 h prior to irradiation.
Shipman and Cole (1968) came to the same conclusions, wherein mice were
injected 1 day prior to radiation, as did Kanno et al. (1970) who reported similar
results on the radio-protective action of bee venom.

4.9.9 Cancer

Bee sting therapy was used by Dr. Desjardins (1859) to treat skin tumors, and
Yoannovoitch and Chahovitch (1932) to treat experimental cancerous tumors. They
produced experimental cancers on the ears of rabbits and then treated them with bee
venom. The tumors became soft, their bases diminished and parts fell off, followed
by scar formation. The most noteworthy fact was that bee venom had an effect even
on the tumors of the other ear, providing that it had not only local but also remote
application and therefore systemic action.
Belliveau (1992) conducted research on colon cancer of rats induced by injection
of adjuvant. He reported that bee venom is effective in treating an animal model of
colon cancer.
Yun et al. (2000) reviewed the study on bee venom related to cancer in the
PubMed database. He found 38 related articles published: leukemia (10), nonspecific
tumor (5), neuroblastoma (4), lung cancer (3), pituitary tumor (3), pheochromocytoma
(3), astrocytoma (2), glioma (2), lymphoma (2), bladder cancer (1), breast carcinoma
(1), pancreatic carcinoma (1), and squamous cell carcinoma (1).
Jang et al. (2003) demonstrated that cells of the human lung cancer line NCI-
H1299 treated with bee venom exhibit several features of apoptosis. In addition,
reverse transcription-polymerase chain reaction and prostaglandin E2 immunoassay
were performed to verify whether BV possesses an inhibitory effect on the
expression of cyclo-oxygenase (COX) and prostaglandin E2 (PGE2) synthesis.
Expression of COX2 mRNA and synthesis of PGE2 were inhibited by BV. These
results suggest the possibility that BV may exert an anti-tumor effect on human
lung cancer cells in vitro.
4 Apitherapy – Bee Venom Therapy 103

Yin et al. (2005) also investigated cancer concentrating on gene expression and
chondrosarcoma cells. The HTB-94 human chondrosarcoma cells were treated with
BV, lipopolysaccharide (LPS), or both. Of the 344 genes profiled in this study, with
a cut-off level of fourfold change in the expression, (1) 35 were down regulated
following BV treatment, (2) 16 were up regulated and 7 down regulated following
LPS treatment, and (3) 32 were down regulated following co-stimulation of BV and
LPS. The results of this study shows that treatment with BV reversed the LPS-
induced up regulation of such genes as interleukin-6 (IL-6) receptor, matrix metal-
loproteinase 15 (MMP-15), tumor necrosis factor (ligand) superfamily-10, caspase-6
and tissue inhibitor of metalloproteinase-1 (TIMP-1).
Kim et al. (2005) studied the effect of bee venom on the bone function in human
osteoblastic cells. To provide insights into the effect of bee venom on aromatase
activity in bone-derived cells, they examined the human leukemic cell line FLG29.1,
which is induced to differentiate toward the osteoblastic phenotype by TPA and
TGF-beta 1, and the primary first-passage osteoblastic cells (hOB). The authors
demonstrated that cells of the osteoblastic lineage synthesize aromatase in vitro by
the local cytokine of TGF-beta 1 and bee venom.
More recently, BVT was also considered as a potential cancer treatment (Hu
et al. 2006a, b; Liu et al. 2008; Orsolic et al. 2003; Putz et al. 2006; Ip et al. 2012;
Jo et al. 2012; Orsolic 2012).

4.9.10 Peripheral Nerve Paralysis

Kim et al. (2007a, b) administered Apitoxin/Apitox to dogs with hind limb paraly-
sis, which resulted in favorable therapeutic responses. However, more studies are
needed to prove the therapeutic effect of bee venom in cases of canine hind limb
paralysis as well as of paralysis of the face.

4.9.11 Multiple Sclerosis

Hauser et al. (2001) proposed that BVT as an alternative therapy for the treatment
of multiple sclerosis (MS). A study was made to evaluate the efficacy of bee venom
injections to halt or reverse the course of MS. Fifty-one patients with clinically
documented MS were first tested to ensure safety of participation before they receive
higher doses of venom. The venom was administered one to three times per week,
consisting of an average of 11 intradermal injections (0.1 mL) per session. The
patients’ clinical responses were evaluated every 3 months for a year. A positive
correlation between BVT and the improvement of MS symptoms was shown. Fifty-
eight percent of the participants experienced positive results; 29.8 % experienced no
benefits, and only one patient reported a worsening of his condition. BVT was effec-
tive against fatigue and showed a 42–44 % improvement in the overall condition.
104 C.M.H. Kim

Significant improvements were also seen in bowel control (32.2 %) and body
coordination (31.4 %). After only 12 months of treatment, average scores for the
Related Observable Symptoms Scale (ROSS) survey went up from 36.1 to 48.6.
Overall, 68 % of the patients enrolled in the study experienced positive and long-
lasting effects from bee venom treatment.
Wesselius et al. (2005) performed a randomized crossover study of bee sting
therapy for multiple sclerosis (MS). A total of 26 patients with relapsing-remitting
or relapsing secondary progressive MS was enrolled, and assigned to 24 weeks of
bee sting therapy or 24 weeks of no treatment. Live bees (up to a maximum of 20)
were used three times a week. The results showed that there was no significant
reduction in the cumulative numbers of new gadolinium-enhancing lesions. The
T2-weighted lesion load further progressed, and there was no significant reduc-
tion in relapse rate. There was no improvement of symptoms of MS. Bee sting
therapy was well tolerated, and there were no serious adverse events. The authors
concluded that the treatment with live bee sting in patients with relapsing MS
did not reduce disease activity, disability, or fatigue and did not improve the
quality of life.
Castro et al. (2005) evaluated the safety of bee venom extract as a possible treat-
ment for patients with progressive forms of multiple sclerosis (MS). A total of nine
patients (with no history of bee venom allergy) with progressive forms of MS, who
were 21–55 years of age with no other illnesses, were entered into four groups on a
structured 1-year immunization schedule. Although no serious adverse allergic
reactions were observed in any of nine subjects, four experienced worsening of
symptoms, necessitating their termination of the study; this could not be ascribed to
side effects of the therapy. Of remaining five subjects, three felt that the therapy had
subjective amelioration of symptoms and two showed objective improvement.
Although this study suggests safety, because of the small numbers studied, there
was no definite conclusion regarding efficacy. Larger and more carefully conducted
multicenter studies will be required to establish efficacy.

4.10 Case Reports

4.10.1 Multiple Sclerosis (MS)

SR is a 47-year old female suffering from MS for the last 15 years. Despite multiple
conventional treatments, her quality of life was worsening progressively. She con-
tinuously felt tingling and numbness in her legs, lost 40 % of bladder control, lost
strength in her extremities, and she was only walking with the help of a cane or
walker. After a total 28 treatment sessions, a marked improvement was observed in
her condition (Table 4.4). Accordingly, she regained 100 % control over her bladder
and she did no longer need a cane or walker. Today, she only comes for follow-up
visits every 3–4 weeks to monitor progress.
4 Apitherapy – Bee Venom Therapy 105

Table 4.4 Clinical evaluation Before treatment After treatment

of patient SR before and after
Muscle weakness ++++ +
treatment of MS
Spasticity +++++ ++
Bladder control +++ +++++
Balance Poor Good
Using a cane or walker + −
Legend: (+) 20 %, (++) 40 %, (+++) 60 %, (++++) 80 %,
(+++++) 100 %

Table 4.5 Clinical evaluation before and after treatment, RA

Before treatment After treatment
RA titer (<20 = negative) 268 18
ESR (normal:0–10) 49 7
Range of motion (Flexion: 0–70) Wrists – right:15, left:10 Wrists – right:55, left:60
Tenderness and swelling +++++ +
Visual analog scale 98 15
Legend: (+) 20 %, (++) 40 %, (+++) 60 %, (++++) 80 %, (+++++) 100 %

Table 4.6 Clinical Before treatment After treatment

evaluation before and after
Tenderness and swelling +++++ +
treatment, Ankylosing
Spondylitis Visual analog scale 95 20
Legend: (+) 20 %, (++) 40 %, (+++) 60 %, (++++) 80 %,
(+++++) 100 %

4.10.2 Rheumatoid Arthritis (RA)

NG, a 39-year old female was suffering from RA for the last 19 years. Previously,
she was treated with a large variety of prescriptions, including a new cancer drug to
help her condition. The pain and swelling of her hands and wrists were unbearable
and she became disabled. She underwent 24 sessions of BVT with a 95 % improve-
ment rating (Table 4.5). Her condition stabilized and she reported that she no longer
suffered from pain and swelling.

4.10.3 Ankylosing Spondylitis

MO, a 53-year old male had long-standing lower back problems, along with multiple
operations with fusions. He underwent 18-months of rehabilitation therapy without
relief. After 26 treatments with BVT, he showed excellent improvement of symp-
toms (Table 4.6). Medication was no longer needed, thus, only monthly follow-up
visits were required.
106 C.M.H. Kim

Table 4.7 Clinical Before treatment After treatment

evaluation before and after
Tenderness and swelling +++++ +
treatment, Ankylosing
Spondylitis Visual analog scale 92 14
Legend: (+) 20 %, (++) 40 %, (+++) 60 %, (++++) 80 %,
(+++++) 100 %

Table 4.8 The treatment Concentration Total dose

sessions, concentration of Treatment per injection (mg)
each bee venom injections,
1st 1 × 0.07 0.07
and dosing schedule
2nd 1 × 0.07 + 0.05 0.12
3rd 2 × 0.07 0.14
4th 2 × 0.07 + 0.05 0.19
5th 3 × 0.07 0.21
6th 3 × 0.07 + 0.05 0.26
7th 4 × 0.07 0.28
8th 4 × 0.07 + 0.05 0.33
9th 5 × 0.07 0.35
10th 5 × 0.07 0.35
11th 5 × 0.07 0.35
12th 5 × 0.07 0.35
13th 5 × 0.07 0.35

4.10.4 Chronic Surgical Inflammation and Pain

BC, a 49-year old male had more than ten abdominal surgeries due to bleeding
ulcers, alcoholic liver cirrhosis, and intestinal obstructions. Due to a phantom gall-
bladder pain and general surgical pain, he was heavily addicted to multiple medica-
tions. After 28 sessions with BVT concentrating at his surgical scars, relief was
rated at nearly 100 % (Table 4.7).

4.10.5 Report Index for Healthy Normal Human Volunteers

Fourteen healthy volunteers (10 males and 4 females) between 26 and 52 years were
enrolled in this study. They were given injections twice a week subcutaneously with
each dose being dependent upon the tolerance level of the previous dose. All sub-
jects were administered a maximum dose of 0.07 mg of bee venom which were
continued for a week, before changing to an arthritic injection schedule. Each sub-
ject received 13 doses of bee venom according to the following schedule (Table 4.8)
All were administered skin tests, vital sign measurements, blood and urine labo-
ratory analyses. One subject who became ill was subsequently hospitalized and was
diagnosed with an adenovirus infection. Another subject had a delayed local reac-
tion (the subject developed a 4+ wheal with a very large flare, 18 h after the injec-
tion). All other subjects who received the same dosage schedule did not show any
4 Apitherapy – Bee Venom Therapy 107

delayed local reaction or systemic reaction. The volunteers reported that they did
not notice any changes in their vital signs. None of the subjects reported any signifi-
cant pain or adverse reaction.
In a similar study, 20 subjects (10 males and 10 females) between the ages of 23
and 45 years were enrolled. Five subjects dropped out due to failure of keeping
appointments, failure to adhere to research instructions, and/or to consumption of
alcohol during the study. Each subject received an initial test dose of 0.05 mL, as
well as 12 doses of Apitoxin throughout the course of the study. The injections
began at 0.1 mL for the first intradermal injection; later increasing to 0.2 mL for the
second injection; 0.25 mL for the third injection, and last, anywhere from 0.3 to
0.7 mL (through the fourth up to the twelfth injection). These injections were
administered 2–3 times per week over a period of 4–6 weeks. A physical examina-
tion along with blood and urinary laboratory analyses were conducted. No signifi-
cant changes or major adverse reactions were noted. Minor reactions included
localized itching as the most common adverse effect for 11 out of the 15 participants,
followed by edema (5/15), pain felt at injection site (2/15), and blister formation at
injection site (1/15). To conclude, there were no serious adverse experiences or
complications reported. The results above confirm that bee venom can be safely
administered to humans when applied in therapeutic doses (Kim 1987).

4.11 Conclusions

In some ways, apitherapy is a classic alternative therapy. It has ancient roots, wide-
spread worldwide use and, although discarded by mainstream medicine, has sur-
vived in folk medicine. Bee sting therapy, consisting of a series of honeybee stings
at regular intervals, is often administered by private beekeepers and other non-
medically qualified practitioners and entails a risk of fatal allergic reactions.
The first injectable bee venom to treat human patients with bee venom therapy
was approved by the Korean Food and Drug Administration in 2003 (Guju Pharma,
Apimeds 2003), but its efficacy and safety have not yet been approved by the U.S.
FDA (NIH 2010). Thus, it still remains a challenge for physician to accept bee
venom therapy as mainstream therapy.

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