Therapeutic Activity and Safety of Vitamin K 2-7 in Muscle Cramps: An Interventional Case-Series

Abstract

Objective To study, the safety, tolerability and therapeutic activity of Vitamin K 2-7(MK7) in a series of patients with idiopathic muscle cramps-systremma Material and Method An open-labelled ambulant trial was conducted in 19 patients presenting with muscle cramps. Vitamin K 2-7 (100µg/Capsule/ Day) was given orally for 3 months. Patients on regular anti-coagulant treatment were excluded from the study. Patients kept the record of frequency, duration and intensity of their cramps during the baseline period of 7 days and throughout the study. They were divided in two groups A and B as per the frequency of cramps. The intensity of cramps was assessed with a Visual Analogue Scale (VAS). They were followed up in the fourth month for recurrence of any cramps. Blood biochemistry and organ function tests were studied at the baseline and at the end of therapy for safety. Prior to the study EC permission and informed consent from patients were obtained. Results Patients from Group A (n=9) had 1-2 cramps/day to 5 /day with severity of 2-9 on the VAS and duration of 1min to 10 min. Patients from Group B (n=10) had lesser frequency of 2-4/wk to at least once a week. Duration of cramps varied from less than 1 min to 10 min with a severity of 2-8 on the VAS. Patients from both the groups experienced a reduction in the frequency. In the Group A, it reduced from 1-2 cramps/day and 5 /day to no cramps or 2-3/ month and in the Group B, from 2-4/wk the frequency reduced to no cramps-1/month. There was also a reduction in the duration as well as severity recorded as 0-3 on VAS as compared to the baseline 2-9 in the Group A. Intensity of cramps was also reduced in the group B from 2-8 VAS decreasing to 0-2 score. Vitamin K 2-7 was well tolerated clinically and found to be safe on the organ function in all the patients. No severe adverse events were reported during the period of therapy. Conclusion Vitamin K 2-7 at a dose of 100 µg /day for 3 months was found to be well tolerated and safe with a therapeutic relief of muscle cramps. The therapeutic activity needs to be evaluated in a larger sample size, with a placebo-randomized cross-over double blind trial to ascertain the efficacy. (The Ind. Pract. 2010; 63(5):287-291)

Full text

May 2010 q Vol. 63 No. 5 The Indian Practitioner q 287
Original Article
Therapeutic Activity and Safety of Vitamin K 2-7 in
Muscle Cramps: An Interventional Case- Series
Mehta DS*, Vaidya RA**#, Dound YA*, Nabar NS**, Pandey SN**#, Vaidya ADB**#
ABSTRACT
Objective
To study, the safety, tolerability and therapeutic activity of Vitamin K 2-7(MK7) in a series of
patients with idiopathic muscle cramps- systremma
Material and Method
An open-labelled ambulant trial was conducted in 19 patients presenting with muscle
cramps. Vitamin K 2-7 (100µg/Capsule/ Day) was given orally for 3 months. Patients on
regular anti-coagulant treatment were excluded from the study. Patients kept the record of
frequency, duration and intensity of their cramps during the baseline period of 7 days and
throughout the study. They were divided in two groups A and B as per the frequency of cramps.
The intensity of cramps was assessed with a Visual Analogue Scale (VAS). They were followed
up in the fourth month for recurrence of any cramps. Blood biochemistry and organ function
tests were studied at the baseline and at the end of therapy for safety. Prior to the study EC
permission and informed consent from patients were obtained.
Results
Patients from Group A (n=9) had 1-2 cramps/day to 5 /day with severity of 2-9 on the VAS
and duration of 1min to 10 min. Patients from Group B (n=10) had lesser frequency of 2-4/wk
to at least once a week. Duration of cramps varied from less than 1 min to 10 min with a
severity of 2-8 on the VAS. Patients from both the groups experienced a reduction in the
frequency. In the Group A, it reduced from 1-2 cramps/day and 5 /day to no cramps or 2-3/
month and in the Group B, from 2-4/wk the frequency reduced to no cramps - 1/month. There
was also a reduction in the duration as well as severity recorded as 0-3 on VAS as compared to
the baseline 2-9 in the Group A. Intensity of cramps was also reduced in the group B from 2-8
VAS decreasing to 0-2 score. Vitamin K 2-7 was well tolerated clinically and found to be safe on
the organ function in all the patients. No severe adverse events were reported during the
period of therapy.
Conclusion
Vitamin K 2-7 at a dose of 100 µg /day for 3 months was found to be well tolerated and safe
with a therapeutic relief of muscle cramps. The therapeutic activity needs to be evaluated in
a larger sample size, with a placebo - randomized cross-over double blind trial to ascertain the
efficacy. (The Ind. Pract. 2010; 63(5):287-291)
*Viridis Biopharma Pvt.Ltd., V.N. Purav Marg, Mumbai-400022
**ICMR Advance Centre of Reverse Pharmacology in Traditional Medicine, Medical Research Center-
Kasturba Health society, 17 Khandubhai Desai Road, Mumbai - 400056
Brahmakumaris, #BSES M.G. Hospital, Global Hospital and Research Centre, S.V. Road, Mumbai-400058
Correspondence: Dr. Ashok D.B. Vaidya, Research Director, MRC-KHS, 17. K Desai Road, Vile Parle (w),
Mumbai: 400 056 E-mail: mmrckhs@gmail.com

288 q The Indian Practitioner May 2010 q Vol. 63 No. 5
and open-labelled for evaluation of clinical
safety, organ function and tolerability and
therapeutic activity of Vitamin K 2-7 in
patients with muscle cramps. The study was
conducted at the ICMR Advance Centre of
Reverse Pharmacology in Traditional
Medicine of the Medical Research Center,
Kasturba Health Society (MRC-KHS),
Mumbai.
Subjects
Prior to the study, the permission from
the Intersystem Biomedical Ethics
Committee (ISBEC) was obtained. Twenty
one patients of age 18-81 yrs were screened.
A written informed consent (approved by
ISBEC) was taken from all the patients prior
to their enrollment. They served as their
own baseline control. Patients who had
muscle cramps associated with endocrine
and metabolic disorders were also screened
for the study. After a detailed history and a
physical examination, patients were
instructed to keep a daily record of muscle
cramps for seven days prior to their
inclusion in the study. Patients who were on
regular anti-coagulants treatment were
excluded from the study. Out of 21 patients
screened, one did not have any cramp
during pre-enrollment period and thus was
not included and one was not willing to
initiate the treatment. The remaining 19
patients (female 13 and male 6) were divided
into 2 groups Group A (n=9) and Group B
(N=10) depending upon the frequency of
cramps viz, cramps every day in group A and
2-3 cramps every week in group B
The study procedure and assessments
Twenty one patients after a proper
history, examination and investigations
were enrolled as per the selection criteria
for idiopathic cramps. Nineteen of the
enrolled patients were given 100µg/day of
Vitamin K2-7 (Viridis BioPharma Pvt. Ltd),
in the form of capsule for 3 months. The
severity of cramps was assessed with Visual
Analogue Scale-VAS from 0 to 10 (nil to
unbearable) before and after the therapy.
Patients were also followed up in the 4th
month for any recurrence of the muscle
cramps. Blood investigations viz. complete
blood counts with ESR, liver function tests,
KEY WORDS
Vitamin K 2-7, Muscle Cramps, Reverse
Pharmacology, Serendipity
INTRODUCTION
Systremma or muscle cramps are sudden
involuntary and painful contractions of the
skeletal muscles. Muscle cramps are more
common in the old age.1,2 These commonly
occur during sleep and exposure to cold.
Cramps occurring without obvious diseases
or due to drugs known to cause muscle
cramps are termed as idiopathic cramps.
Prevalence of these simple cramps in older
individual above the age of 60 has varied from
26% in men and 52% in women.3 Quinine
sulphate was the most widely used drug in
the treatment of muscle cramps.4,5 However,
quinine has many side effects and some of
these can be severe. This makes its use
questionable for a benign but highly painful
condition of idiopathic muscle cramps. Other
drugs used are nifedipine, gabapentine6 etc.
These drugs also have side effects and are
even known to cause muscle cramps. There
is thus an unmet medical need for filling up
this therapeutic gap.
One of the authors (DSM), took vitamin K 2-
7 in a dose of 100 microgram/day as a food
supplement. He observed that his painful
muscle cramps had ceased. The cramps did
recur on discontinuation of the vitamin K 2-7
and again subsided on restarting it. This
serendipitous finding on the cramp was
confirmed by the other author (ABV) in a
challenge, dechallenge and rechallenge
cycles on himself . Hence it was decided to
carry out an experiential interventional study
in a case series as per reverse pharmacology
path to detect the activity and sefaty.
In the present article we report the
outcome of this observational study of
Vitamin K 2-7 (MK-7) in 19 patients with
muscle cramps. Appropriate permission from
Ethics Committee (EC) was obtained prior to
the study and signed written informed
consents were taken.
MATERIAL AND METHOD
Study Design
This case-series study was observational

May 2010 q Vol. 63 No. 5 The Indian Practitioner q 289
serum creatinine, fasting and post prandial
plasma glucose, serum TSH and LDH were
done at base line and at the end of the
intervention. Bleeding time and clotting
time were also investigated. The patients
were serially followed up on 7th day, 30th
day, 60th day, 90th day, and 120th day. A
detailed physical (general and systemic)
examination was done at the baseline and
at every follow up visits. A predesigned Case
Record Form which included a page of
adverse events was used. Safety was
assessed by clinical tolerability, adverse
events and by organ function tests,
therapeutic activity was assessed by noting
the difference in the frequency, severity and
duration of the cramps as compared to the
baseline. Any other effect during the
therapy - beneficial or adverse - or carry over
activity of the vitamin K2-7 after the
discontinuation were also recorded.
Methods for organ function tests
Complete blood counts were done by the
cell counter (ERMA-PCE210), liver function
tests (SGOT/PT) were done by autoanalyser
and the Merck kit. Serum creatinine was
assayed by autoanalyser and Spinreact kit.
Fasting and post prandial plasma glucose
was estimated by GOD-POD method. Serum
TSH and LDH was done by ERBA kit.
Interventional drug, dosage and
compliance
Vitamin K 2-7 was supplied by Viridis
BioPharma Pvt. Ltd, in the form of capsules
(100 µg) packed - 60 capsules per bottle. Drug
was dispensed in bottles to patients at the
time of the enrollment and at the end of 2nd
month. Patient ingested a 100 µg capsule
every morning, after breakfast for three
months. The drug compliance was judged by
counting the medicine in the bottles at the
follow-up visits. Patient was said to be
compliant if he had consumed minimum
80% of the total dispensed medications.
RESULTS
Patients from the Group A (n=9) had 1-2
cramps/day to 5 /day with severity of 2-9 of
VAS and duration of 1 min to 10 min.
Patients from the Group B (n=10) had lesser
frequency of 2-4/wk to at least once a week.
Duration of cramps varied from less than 1
min 10 min with severity of 2-8 of VAS.
Patients from both the groups experienced a
reduction in the frequency except one from
the Group B. In the Group A, muscle cramps
reduced from 1-2 cramps/day (n=8) to 5 /day
(n=1) at base line to 0 cramps (n=8) to 2-3/
month (n=1) during therapy. In patients
from the Group B, cramps 2-4/wk at
baseline were reduced to 0 - 1/month during
the therapy. There was also a reduction in
the duration and severity recorded as 0-3 on
VAS as compared to the baseline 2-9 in
Group A. Intensity of cramps were also
reduced in group B from 2-8 on VAS score
decreasing to 0-2 score as shown in the
Figure 1.
At the end of the 3rd month of the
therapy, all the patients of the group B had
no cramps, while in the Group A occasional
cramps (1-2/ month) were still noticed in 5/
9 patients. There was a decrease in
frequency, severity as well as duration.
There was a reappearance of cramps with
reduced frequency and severity in both the
groups by the 3rd week after the
discontinuation of the therapy.
Tolerability and Safety
Vitamin K 2-7 capsules were clinically
tolerated well by all the patients.
Occasionally patients complained of mild
constipation. Biochemical investigations
and the organ function tests were in normal
limits at baseline and at the end of the
therapy of three months.
Compliance
Monitoring of the drug intake during 3
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290 q The Indian Practitioner May 2010 q Vol. 63 No. 5
months of trial indicated that drug intake
was only forgotten on when the patient had
travelled out of the station for a few days.
Recurrence of milder cramps was also
noticed when the drug was missed on 3-4
consecutive days.
The study has shown a good therapeutic
activity of vitamin K 2-7 for idiopathic
muscle cramps as a response was observed
in most of the patients. This open labelled
experiential study indicates that Vitamin K
2-7 has shown the potential of a safe and
active candidate for further studies in relief
of patients with idiopathic muscle cramps.
DISCUSSION
Muscle cramps are a common and quite
distressing problem in old age. Its prevalence
increases in the elderly age, affecting 30% of >
60 year olds and 50% over the age of 80.1,2
Underlying pathophysiology of muscle cramps
still remains less understood. The conditions
known to trigger the muscle cramps are
sports, pregnancy, sleep, cold, limb positions
etc. They are frequently observed in patients
with endocrine/ metabolic disorders.
Overexertion, dehydration and electrolyte loss
during prolonged sun-exposure etc., can
precipitate muscle cramps.7 Certain drugs
are also known to cause muscle cramps.8
However when they tend to occur without any
obvious underlying cause, they are known as
'idiopathic muscle cramps'.
Treatment modalities for muscle cramps
vary based often on the diversity of causes.
Several treatment modalities are currently in
clinical practice with varying degree of
success in relieving the symptoms.9 These
modalities include quinine sulphate.4,5
calcium channel blockers10, magnesium,11
gabapentin,6 botulinum toxin,12 phenytoin,13
Vitamin E,14 carisoprodol and orphenadrine.15
In a meta analysis of trials on 659 patients
with idiopathic cramps treated with quinine,
it was found that there was 24 to 31%
reduction in muscle cramps within a period of
4 weeks.16 However quinine has many side
effects such as tinnitus, headache, nausea,
tremor, hypotension and gastrointestinal
upset. Occasionally fatal hypersensitivity
reactions and thrombocytopenia can occur.
Quinine amblyopia was reported in a patient
who was suffering from benign nocturnal
cramps. There are also side effects like,
neurological symptoms, haemolysis, acute
renal failure, and arrhythmias. Serious side
effects of quinine make its use questionable
for a benign but painful condition like
nocturnal leg cramps.16-18 Because of its
potential severe toxicity US FDA has banned
over- the-counter use of quinine based
products.
A serendipitous observation of relief of
cramps made by two of the authors (DSM and
ABV) of the study strongly emphasizes that the
safe vitamin K 2-7 can be studied in an open
labelled, observational study for its activity.
Complementary and Alternative system of
the medicine provides the description of the
similar clinical condition and treatment
modalities for the muscle cramps. In
Ayurveda, a cramp is described as
Pindicodweshtan under the Vatavyadhi. Use
of Dashamool (Roots of ten medicinal plants) is
the choice of medicine in Vatavyadhi.19 In the
case of Homoeopathy system of medicine,
treatment for muscle cramps is mentioned
along with various other literatures. Kent
repertory of homoeopathic materia medica20
in the chapter on extremity mentions the use
of Magnesium phosphoricum, Chamomila,
Natrum Muriaticum, etc. for the treatment of
muscle cramps.
In the current study we have observed that
a daily administration of vitamin K 2-7 in a
dose of 100 µg not only relieved the existing
occurrence of muscle cramps but also
prevented its recurrence for a while from 4
days to 2 weeks after its discontinuation.
Schurgers et al,21 have shown that the half life
of vitamin K 2-7 is 72 hrs. So a cumulative
presence of vitamin K 2-7 in the body can
explain its longer duration of activity.
It is of great interest to review a subsequent
case of a female of 59 years. The patient with
severe muscle cramps was referred to MRC-
KHS by a haematologist. The severity of the
cramps was reaching 9-10 VAS score. Cramps
occurred during any time of the day or night.
Her jaw will go in to titanic cramps
precipitated by a yawn. Her hand muscles
went of into cramps while she brushed her
teeth. She obtained 70% relief from muscle

May 2010 q Vol. 63 No. 5 The Indian Practitioner q 291
cramps after she had already received
Vitamin K 2-7 in a dose of 50 µg per day for
the past 9 months. The therapeutic activity
was noted within a fortnight after she had
started Vitamin K 2-7. On discontinuation
of the vitamin in between, she had
experienced a morbid relapse. This
additional case reinforces that even smaller
dose could be active therapeutically. An
appropriate dose-searching, dose-finding
and dose-optimizing study for kinetic-
dynamics needs to precede a large scale
controlled clinical trial.
CONCLUSION
Vitamin K 2-7 at a dose of 100 µg /day for 3
months was found to be well tolerated and
safe with a therapeutic activity of relief of
muscle cramps. A proper dose escalation
and a fixed-flexible dosage and a closely
monitored compliance with kinetic
monitoring, is required with vitamin K 2-7
in muscle cramp. Meanwhile as vitamin K
2-7 is safe and the product is available in a
low dosage form of 45 µg, astute clinician
can evaluate its effects in clinical settings
for systremma - benign but very painful
conditions.
ACKNOWLEDGEMENTS
We thank Sri Dhiru Mehta, President and Dr
Pratibha Narang Secretary of Kasturba Health
Society for encouraging the study. We deeply
appreciate the guidance and technical expertise of
Dr. Anselm de'Souza, the Technical Director,
Viridis BioPharma Pvt. Ltd, Mumbai. We thank Dr
S.C. Talwalkar and Mrs Shubhada Agashe for the
laboratory evaluation of organ function tests. We
thank Dr Deepak Dave, Medical Director, MRC-KHS
for the use of the clinical facilities.
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