- Email: [email protected]
Safety of a Coleus forskohlii formulation in healthy volunteers
Personalized Medicine Universe 4 (2015) 63e65
Contents lists available at ScienceDirect
Personalized Medicine Universe journal homepage: www.elsevier.com/locate/pmu
Original article
Safety of a Coleus forskohlii formulation in healthy volunteers Seika Kamohara, MD, PhD a, b, *, Yoshiko Terasaki b, Itsuko Horikoshi b, Satoshi Sunayama, MD, PhD c a
Health Science University, Japan DHC Corporation, Japan c Suidoubashi Medical Clinic, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 January 2015 Accepted 13 January 2015
Coleus forskohlii (CF) is an Indian plant that has been used in Ayurvedic medicine. Several trials have reported the weight-loss effects of CF extract. We investigated the safety and efficacy of CF extract (Forskohlii, DHC Corporation) in healthy volunteers. A dose escalation study was performed to determine the type and frequency of adverse events. Twenty-nine healthy subjects were recruited in an open-label trial and were administered escalating doses from 250 to 1000 mg over a 4-week period. Patients were examined on a daily basis for adverse events. Blood, urine, and stool samples were obtained before and after supplementation in a subset of 10 subjects to assess the safety of the supplement. All 29 subjects completed the study. Intake of CF was associated with minor gastrointestinal adverse events such as soft stool and diarrhea, which appeared to be dose-related. There were no major adverse events. At each dose of CF, either 6 or 7 subjects reported minor GI events. C. forskohlii formulation appears to be well tolerated in daily oral doses up to 1000 mg, and warrants further investigation for its efficacy as a longterm anti-obesity intervention. This study was registered at http://www.umin.ac.jp, as UMIN000008224. Copyright © 2015, International Society of Personalized Medicine. Published by Elsevier B.V. All rights reserved.
Keywords: Coleus forskohlii Adverse events Safety Dietary supplements Obesity Ayurveda
1. Introduction Coleus forskohlii (CF) is an Indian plant that has been used in Ayurvedic medicine. The root contains the active constituent forskolin [1,2]. Forskolin is an adenylate cyclase activator. Adenylate cyclase is involved in production of cyclic adenosine monophosphate (cAMP), a significant biochemical agent in metabolic processes [3]. cAMP induces a variety of biochemical effects that trigger metabolic processes, diet-induced thermogenesis, and increased lean body mass. Loss of body fat is also stimulated by cAMP. Therefore, regular use of CF extract is one means of maintaining healthy body composition and lean body mass levels. So far, several small trials have reported the anti-obesity effect of the CF extract [4,5]. However, the safety of the extract is has not been well Abbreviations: BMI, body mass index; CF, Coleus forskohlii; cAMP, cyclic adenosine monophosphate; GI, gastrointestinal; TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine. * Corresponding author. Health Science University, Minami-azabu 2-8-12 NisseiBldg. 11Fl., DHC Laboratory, Tokyo 106-0047, Japan. Tel.: þ81 3 5442 3945; fax: þ81 3 5442 3947. E-mail address: [email protected] (S. Kamohara).
investigated. The purpose of this study is to investigate the safety and efficacy of CF extract in healthy volunteers. 2. Materials and methods 2.1. Subjects and study protocol Eligible participants were male and female volunteers, 20 years of age or older with normal organ function, who have never experienced psychological or critical diseases. After written informed consents were obtained, subjects were given CF every day for a total of 4 weeks. Additionally, dose levels were increased after each week; i.e. the oral intake was 250 mg per day in the 1st week, 500 mg per day in the 2nd week, 750 mg per day in the 3rd week, and 1000 mg per day 4th week. All subjects were examined on a daily basis to check for adverse events. Blood, urine, and stool samples were obtained in a subset of 10 subjects before and after the 4-week supplementation to assess the safety of CF use. Toxicities were graded based on the National Cancer Institute, Common Terminology Criteria for Adverse Events v3.0 (CTCAE).
http://dx.doi.org/10.1016/j.pmu.2015.01.001 2186-4950/Copyright © 2015, International Society of Personalized Medicine. Published by Elsevier B.V. All rights reserved.
64
S. Kamohara et al. / Personalized Medicine Universe 4 (2015) 63e65
The study protocol and the comprehensive written informed consent used in this study were reviewed and approved by the DHC Corporation ethical committee and review board. This study was registered at UMIN Clinical Trials Registry (http://www.umin.ac.jp/ ctr/index.htm), as UMIN000008224, prior to its commencement. 2.2. Study drug Coleus forskohlii formulation was provided as a standardized powder extract in tablet form (Forskohlii™, DHC Corporation). It contains a 10% concentration of forskolin. 3. Results Twenty-nine participants gave informed consent for the study. All 29 subjects, 9 men with a mean age of 36.2 ± 2.3 years (range; 28e48) and 20 women with a mean age of 30.2 ± 0.8 years (range; 23e36), completed the trial and were eligible for analysis. Intake of CF was associated with minor gastrointestinal adverse events, such as soft stool and diarrhea, which appeared to be doserelated. No major adverse events were found. At each dose of CF, either 6 or 7 participants reported minor GI events, as summarized in Table 1. (Frequency of adverse GI events associated with intake of CF extract). During the 4-week study period, a total of 11 out of the 29 subjects reported adverse GI events, such as soft stool and diarrhea, at least once. There were no adverse events reported other than these GI events. No clinically significant changes were seen in metabolic markers, blood lipids, liver enzymes, electrolytes, hormones (insulin, TSH, T3, and T4), heart rate, or blood pressure (Table 2. Clinical outcomes for safety evaluation). 4. Discussion Coleus forskohlii (CF) is mainly cultivated for its root, which is commonly pickled and consumed as part of an ordinary diet [1]. The root has been also used in traditional Indian medicine, Ayurveda, for treating cardiovascular disorders, hypertension, abdominal pain, and constipation [6,7]. Based on the fact that it is commonly used in these traditional applications, CF root is generally regarded as safe. However, safety data in clinical trials are limited. More recently, CF root extract has been widely used as an ingredient of functional foods and dietary supplements for weight loss and weight management [4,5]. Several trials have reported the weight-loss effects of CF extract. An open-label 8-week trial reported that in 6 overweight, but otherwise healthy, women (BMI > 25), oral administration of CF extract (comprising 50 mg/day of forskolin) resulted in significant reduction of body weight and fat content [6]. In a randomized, double-blind, placebo-controlled study of 12 weeks duration, significant weight loss was observed in 30 overweight/obese men after an intake of CF extract (comprising 250 mg per day of forskolin) [8]. A randomized, double-blind, placebo-controlled 12-week clinical trial reported that
Table 2 Clinical outcomes of safety evaluation. Characteristics
Baseline
Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse rate (/min) AST (U/L) ALT (U/L) LDH (U/L) g-GTP (U/L) Amylase (U/L) Lipase (U/L) Creatinine (mg/dL) UA (mg/dL) BUN (mg/dL) FBS (mg/dL) HbA1c (%) TG (mg/dL) T-Cho (mg/dL) HDL (mg/dL) LDL (mg/dL) Na2þ (mEq/L) Kþ (mEq/L) Cl (mEq/L) Mg2þ (mg/L) Ca2þ (mg/L) P3 (mg/L) TSH (mIU/mL) Free T3 (pg/mL) Free T4 (ng/dL)
100.6 58.0 79.6 18.2 15.3 162.1 24.9 60.3 30.9 0.70 5.47 11.9 84.7 4.87 75.9 179.3 67.5 95.7 141.4 3.8 104.0 2.3 9.3 3.45 2.25 3.11 1.21
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
4 weeks 3.18 2.49 2.76 1.02 2.18 5.93 5.67 5.10 2.76 0.04 0.57 1.56 2.30 0.10 14.61 9.50 3.39 9.62 0.48 0.07 0.63 0.05 0.06 0.16 0.65 0.08 0.05
97.0 53.0 75.6 19.5 17.9 165.8 30.0 58.9 30.0 0.70 5.60 12.2 84.8 4.80 75.1 181.5 68.0 97.0 142.0 3.8 104.0 2.3 9.4 3.50 2.35 3.05 1.25
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
P Value 2.33 2.13 1.51 2.07 3.61 8.27 8.95 5.90 2.19 0.04 0.57 1.47 2.00 0.11 15.27 10.18 4.84 9.08 0.45 0.08 0.68 0.04 0.07 0.14 0.43 0.07 0.05
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
(n ¼ 10). Primary outcomes of the safety evaluation showed no significant differences before and after 4-week supplementation in a subset of 10 subjects.
overweight women (BMI 25e35) taking CF extract (comprising 50 mg per day of forskolin) showed weight loss while the placebo group gained weight. Heart rate, blood pressure, and blood lipids were unaffected. No clinically significant side effects were observed [4]. In an open label trial of 8-week duration, 15 subjects who had oral administration of CF formulation (1000 mg per day, containing 100 mg of forskolin) showed significant weight-loss [5]. In Ayurvedic treatment, it was reported that CF extract administration led to mild improvements in both systolic and diastolic blood pressure in the hypertensive geriatric population [7]. Coleus forskohlii root has been used traditionally in Ayurvedic medicine for constipation. The contemporary use of dietary supplements containing CF extract for weight-loss have been associated with soft stool and diarrhea anecdotally. Therefore, we conducted this trial to investigate the safety and efficacy of a CF formulation, especially to assess the frequency and severity of adverse GI events. In this dose escalation study of 4 weeks duration, a CF formulation was associated with mild adverse GI events, which appeared to be dose-related. Forskolin, a major constituent of CF extract, activates adenylate cyclase and increases the production of cyclic adenosine monophosphate (cAMP). The mechanism of the GI events has not been fully elucidated, but one possibility is that they are caused by cAMP induced efflux of the Cl-ion from the intestinal membrane. We
Table 1 Frequency of adverse GI events associated with intake of CF extract.
Daily dose of CF extract Number of subjects (%) Mean % of days per subject per day
Week 1
Week 2
Week 3
Week 4
250 mg 6 (20.7%) 10.30%
500 mg 7 (24.1%) 12.30%
750 mg 6 (20.7%) 14.30%
1000 mg 6 (20.7%) 15.80%
(n ¼ 29). Patients were examined daily for adverse events. At each dose 6 to 7 subjects out of a total 29 reported adverse GI events. The mean percentages of subjects with GI events per day were calculated for each study week.
S. Kamohara et al. / Personalized Medicine Universe 4 (2015) 63e65
suggest the following causal mechanism for GI events in CF extract supplementation. Intestinal crypt cells secrete electrolytes that lead to water secretion. This contributes to the establishment of an osmotic gradient that pulls water into the intestinal lumen. The luminal membrane of crypt epithelial cells contains a cyclic AMPdependent chloride channel known also as the cystic fibrosis transmembrane conductance regulator or CFTR [9]. This channel is responsible for the secretion of water by the following steps: First, chloride ions enter the crypt epithelial cell by co-transport with sodium and potassium. Then, sodium is pumped back out via sodium pumps, and potassium is also exported via a number of channels. Activation of adenylyl cyclase by a number of so-called secretagogues leads to the generation of cAMP. Elevated intracellular concentrations of cAMP in crypt cells activate the CFTR, resulting in the secretion of chloride ions into the lumen. The accumulation of negatively charged chloride ions in the crypt creates an electrical potential that attracts sodium cations, pulling them into the lumen also, apparently across tight junctions. The net result is secretion of NaCl into the crypt. This creates an osmotic gradient across the tight junction that in turn draws water into the lumen. Theoretically, increased levels of cAMP in the intestine caused by CF extract could lead to the secretion of chloride ions into the lumen via the CFTR. This could in turn result in the secretion of water, which would be manifested as soft stool and diarrhea. To summarize, forskolin or CF extract may cause GI events by stimulating chloride ion channels. 5. Discussion In conclusion, the tolerance of our study participants for C. forskohlii formulation (Forskohlii™, DHC Corporation) in daily oral doses up to 1000 mg appeared to be excellent. This warrants further investigation of the formulation for its efficacy as a longterm anti-obesity intervention.
65
Trial identification This study is registered at http://www.umin.ac.jp/ctr/index.htm, as UMIN000008224. Competing interests Seika Kamohara is a research advisor for the DHC corporation laboratory. Yoshiko Terasaki and Itsuko Horikoshi are employees of the DHC Corporation. Acknowledgements The authors are grateful to Dr. L. Todd Landreneau and Mr. Somboon Noparatanawong for preparing this manuscript. References [1] de Souza NJ, Dohadwalla AN, Reden J. Forskolin: a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory, and adenylate cyclase activating properties. Med Res Rev 1983;3:201e19. [2] Ammon HP, Müller AB. Forskolin: from an ayurvedic remedy to a modern agent. Planta Med 1985;51:473e7. [3] Metzger H, Lindner E. The positive inotropic-acting forskolin, a potent adenylate cyclase activator. Arzneimittelforschung 1981;31:1248e50. [4] Henderson S, Magu B, Rasmussen C, et al. Effects of Coleus forskohlii supplementation on body composition and hematological profiles in mildly overweight women. J Int Soc Sports Nutr 2005;2:54e62. [5] Kamohara S, Noparatanawong SA. Coleus forskohlii extract improves body composition in healthy volunteers: an open-label trial. Pers Med Universe 2013;2:25e7. [6] Lieberman SA. A new potential weapon for fighting obesity. Forskolin - the active diterpene in Coleus. Altern Complement Ther 2004;10:330e3. [7] Jagtap M, Chandola HM, Ravishankar B. Clinical efficacy of Coleus forskohlii (Willd.) Briq. (Makandi) in hypertension of geriatric population. Ayu 2011;32:59e65. [8] Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res 2005;13:1335e43. [9] Thiagarajah JR, Verkman AS. CFTR pharmacology and its role in intestinal fluid secretion. Curr Opin Pharmacol 2003;3:594e9.
Contents lists available at ScienceDirect
Personalized Medicine Universe journal homepage: www.elsevier.com/locate/pmu
Original article
Safety of a Coleus forskohlii formulation in healthy volunteers Seika Kamohara, MD, PhD a, b, *, Yoshiko Terasaki b, Itsuko Horikoshi b, Satoshi Sunayama, MD, PhD c a
Health Science University, Japan DHC Corporation, Japan c Suidoubashi Medical Clinic, Japan b
a r t i c l e i n f o
a b s t r a c t
Article history: Received 5 January 2015 Accepted 13 January 2015
Coleus forskohlii (CF) is an Indian plant that has been used in Ayurvedic medicine. Several trials have reported the weight-loss effects of CF extract. We investigated the safety and efficacy of CF extract (Forskohlii, DHC Corporation) in healthy volunteers. A dose escalation study was performed to determine the type and frequency of adverse events. Twenty-nine healthy subjects were recruited in an open-label trial and were administered escalating doses from 250 to 1000 mg over a 4-week period. Patients were examined on a daily basis for adverse events. Blood, urine, and stool samples were obtained before and after supplementation in a subset of 10 subjects to assess the safety of the supplement. All 29 subjects completed the study. Intake of CF was associated with minor gastrointestinal adverse events such as soft stool and diarrhea, which appeared to be dose-related. There were no major adverse events. At each dose of CF, either 6 or 7 subjects reported minor GI events. C. forskohlii formulation appears to be well tolerated in daily oral doses up to 1000 mg, and warrants further investigation for its efficacy as a longterm anti-obesity intervention. This study was registered at http://www.umin.ac.jp, as UMIN000008224. Copyright © 2015, International Society of Personalized Medicine. Published by Elsevier B.V. All rights reserved.
Keywords: Coleus forskohlii Adverse events Safety Dietary supplements Obesity Ayurveda
1. Introduction Coleus forskohlii (CF) is an Indian plant that has been used in Ayurvedic medicine. The root contains the active constituent forskolin [1,2]. Forskolin is an adenylate cyclase activator. Adenylate cyclase is involved in production of cyclic adenosine monophosphate (cAMP), a significant biochemical agent in metabolic processes [3]. cAMP induces a variety of biochemical effects that trigger metabolic processes, diet-induced thermogenesis, and increased lean body mass. Loss of body fat is also stimulated by cAMP. Therefore, regular use of CF extract is one means of maintaining healthy body composition and lean body mass levels. So far, several small trials have reported the anti-obesity effect of the CF extract [4,5]. However, the safety of the extract is has not been well Abbreviations: BMI, body mass index; CF, Coleus forskohlii; cAMP, cyclic adenosine monophosphate; GI, gastrointestinal; TSH, thyroid stimulating hormone; T3, triiodothyronine; T4, thyroxine. * Corresponding author. Health Science University, Minami-azabu 2-8-12 NisseiBldg. 11Fl., DHC Laboratory, Tokyo 106-0047, Japan. Tel.: þ81 3 5442 3945; fax: þ81 3 5442 3947. E-mail address: [email protected] (S. Kamohara).
investigated. The purpose of this study is to investigate the safety and efficacy of CF extract in healthy volunteers. 2. Materials and methods 2.1. Subjects and study protocol Eligible participants were male and female volunteers, 20 years of age or older with normal organ function, who have never experienced psychological or critical diseases. After written informed consents were obtained, subjects were given CF every day for a total of 4 weeks. Additionally, dose levels were increased after each week; i.e. the oral intake was 250 mg per day in the 1st week, 500 mg per day in the 2nd week, 750 mg per day in the 3rd week, and 1000 mg per day 4th week. All subjects were examined on a daily basis to check for adverse events. Blood, urine, and stool samples were obtained in a subset of 10 subjects before and after the 4-week supplementation to assess the safety of CF use. Toxicities were graded based on the National Cancer Institute, Common Terminology Criteria for Adverse Events v3.0 (CTCAE).
http://dx.doi.org/10.1016/j.pmu.2015.01.001 2186-4950/Copyright © 2015, International Society of Personalized Medicine. Published by Elsevier B.V. All rights reserved.
64
S. Kamohara et al. / Personalized Medicine Universe 4 (2015) 63e65
The study protocol and the comprehensive written informed consent used in this study were reviewed and approved by the DHC Corporation ethical committee and review board. This study was registered at UMIN Clinical Trials Registry (http://www.umin.ac.jp/ ctr/index.htm), as UMIN000008224, prior to its commencement. 2.2. Study drug Coleus forskohlii formulation was provided as a standardized powder extract in tablet form (Forskohlii™, DHC Corporation). It contains a 10% concentration of forskolin. 3. Results Twenty-nine participants gave informed consent for the study. All 29 subjects, 9 men with a mean age of 36.2 ± 2.3 years (range; 28e48) and 20 women with a mean age of 30.2 ± 0.8 years (range; 23e36), completed the trial and were eligible for analysis. Intake of CF was associated with minor gastrointestinal adverse events, such as soft stool and diarrhea, which appeared to be doserelated. No major adverse events were found. At each dose of CF, either 6 or 7 participants reported minor GI events, as summarized in Table 1. (Frequency of adverse GI events associated with intake of CF extract). During the 4-week study period, a total of 11 out of the 29 subjects reported adverse GI events, such as soft stool and diarrhea, at least once. There were no adverse events reported other than these GI events. No clinically significant changes were seen in metabolic markers, blood lipids, liver enzymes, electrolytes, hormones (insulin, TSH, T3, and T4), heart rate, or blood pressure (Table 2. Clinical outcomes for safety evaluation). 4. Discussion Coleus forskohlii (CF) is mainly cultivated for its root, which is commonly pickled and consumed as part of an ordinary diet [1]. The root has been also used in traditional Indian medicine, Ayurveda, for treating cardiovascular disorders, hypertension, abdominal pain, and constipation [6,7]. Based on the fact that it is commonly used in these traditional applications, CF root is generally regarded as safe. However, safety data in clinical trials are limited. More recently, CF root extract has been widely used as an ingredient of functional foods and dietary supplements for weight loss and weight management [4,5]. Several trials have reported the weight-loss effects of CF extract. An open-label 8-week trial reported that in 6 overweight, but otherwise healthy, women (BMI > 25), oral administration of CF extract (comprising 50 mg/day of forskolin) resulted in significant reduction of body weight and fat content [6]. In a randomized, double-blind, placebo-controlled study of 12 weeks duration, significant weight loss was observed in 30 overweight/obese men after an intake of CF extract (comprising 250 mg per day of forskolin) [8]. A randomized, double-blind, placebo-controlled 12-week clinical trial reported that
Table 2 Clinical outcomes of safety evaluation. Characteristics
Baseline
Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse rate (/min) AST (U/L) ALT (U/L) LDH (U/L) g-GTP (U/L) Amylase (U/L) Lipase (U/L) Creatinine (mg/dL) UA (mg/dL) BUN (mg/dL) FBS (mg/dL) HbA1c (%) TG (mg/dL) T-Cho (mg/dL) HDL (mg/dL) LDL (mg/dL) Na2þ (mEq/L) Kþ (mEq/L) Cl (mEq/L) Mg2þ (mg/L) Ca2þ (mg/L) P3 (mg/L) TSH (mIU/mL) Free T3 (pg/mL) Free T4 (ng/dL)
100.6 58.0 79.6 18.2 15.3 162.1 24.9 60.3 30.9 0.70 5.47 11.9 84.7 4.87 75.9 179.3 67.5 95.7 141.4 3.8 104.0 2.3 9.3 3.45 2.25 3.11 1.21
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
4 weeks 3.18 2.49 2.76 1.02 2.18 5.93 5.67 5.10 2.76 0.04 0.57 1.56 2.30 0.10 14.61 9.50 3.39 9.62 0.48 0.07 0.63 0.05 0.06 0.16 0.65 0.08 0.05
97.0 53.0 75.6 19.5 17.9 165.8 30.0 58.9 30.0 0.70 5.60 12.2 84.8 4.80 75.1 181.5 68.0 97.0 142.0 3.8 104.0 2.3 9.4 3.50 2.35 3.05 1.25
± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
P Value 2.33 2.13 1.51 2.07 3.61 8.27 8.95 5.90 2.19 0.04 0.57 1.47 2.00 0.11 15.27 10.18 4.84 9.08 0.45 0.08 0.68 0.04 0.07 0.14 0.43 0.07 0.05
n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s. n.s.
(n ¼ 10). Primary outcomes of the safety evaluation showed no significant differences before and after 4-week supplementation in a subset of 10 subjects.
overweight women (BMI 25e35) taking CF extract (comprising 50 mg per day of forskolin) showed weight loss while the placebo group gained weight. Heart rate, blood pressure, and blood lipids were unaffected. No clinically significant side effects were observed [4]. In an open label trial of 8-week duration, 15 subjects who had oral administration of CF formulation (1000 mg per day, containing 100 mg of forskolin) showed significant weight-loss [5]. In Ayurvedic treatment, it was reported that CF extract administration led to mild improvements in both systolic and diastolic blood pressure in the hypertensive geriatric population [7]. Coleus forskohlii root has been used traditionally in Ayurvedic medicine for constipation. The contemporary use of dietary supplements containing CF extract for weight-loss have been associated with soft stool and diarrhea anecdotally. Therefore, we conducted this trial to investigate the safety and efficacy of a CF formulation, especially to assess the frequency and severity of adverse GI events. In this dose escalation study of 4 weeks duration, a CF formulation was associated with mild adverse GI events, which appeared to be dose-related. Forskolin, a major constituent of CF extract, activates adenylate cyclase and increases the production of cyclic adenosine monophosphate (cAMP). The mechanism of the GI events has not been fully elucidated, but one possibility is that they are caused by cAMP induced efflux of the Cl-ion from the intestinal membrane. We
Table 1 Frequency of adverse GI events associated with intake of CF extract.
Daily dose of CF extract Number of subjects (%) Mean % of days per subject per day
Week 1
Week 2
Week 3
Week 4
250 mg 6 (20.7%) 10.30%
500 mg 7 (24.1%) 12.30%
750 mg 6 (20.7%) 14.30%
1000 mg 6 (20.7%) 15.80%
(n ¼ 29). Patients were examined daily for adverse events. At each dose 6 to 7 subjects out of a total 29 reported adverse GI events. The mean percentages of subjects with GI events per day were calculated for each study week.
S. Kamohara et al. / Personalized Medicine Universe 4 (2015) 63e65
suggest the following causal mechanism for GI events in CF extract supplementation. Intestinal crypt cells secrete electrolytes that lead to water secretion. This contributes to the establishment of an osmotic gradient that pulls water into the intestinal lumen. The luminal membrane of crypt epithelial cells contains a cyclic AMPdependent chloride channel known also as the cystic fibrosis transmembrane conductance regulator or CFTR [9]. This channel is responsible for the secretion of water by the following steps: First, chloride ions enter the crypt epithelial cell by co-transport with sodium and potassium. Then, sodium is pumped back out via sodium pumps, and potassium is also exported via a number of channels. Activation of adenylyl cyclase by a number of so-called secretagogues leads to the generation of cAMP. Elevated intracellular concentrations of cAMP in crypt cells activate the CFTR, resulting in the secretion of chloride ions into the lumen. The accumulation of negatively charged chloride ions in the crypt creates an electrical potential that attracts sodium cations, pulling them into the lumen also, apparently across tight junctions. The net result is secretion of NaCl into the crypt. This creates an osmotic gradient across the tight junction that in turn draws water into the lumen. Theoretically, increased levels of cAMP in the intestine caused by CF extract could lead to the secretion of chloride ions into the lumen via the CFTR. This could in turn result in the secretion of water, which would be manifested as soft stool and diarrhea. To summarize, forskolin or CF extract may cause GI events by stimulating chloride ion channels. 5. Discussion In conclusion, the tolerance of our study participants for C. forskohlii formulation (Forskohlii™, DHC Corporation) in daily oral doses up to 1000 mg appeared to be excellent. This warrants further investigation of the formulation for its efficacy as a longterm anti-obesity intervention.
65
Trial identification This study is registered at http://www.umin.ac.jp/ctr/index.htm, as UMIN000008224. Competing interests Seika Kamohara is a research advisor for the DHC corporation laboratory. Yoshiko Terasaki and Itsuko Horikoshi are employees of the DHC Corporation. Acknowledgements The authors are grateful to Dr. L. Todd Landreneau and Mr. Somboon Noparatanawong for preparing this manuscript. References [1] de Souza NJ, Dohadwalla AN, Reden J. Forskolin: a labdane diterpenoid with antihypertensive, positive inotropic, platelet aggregation inhibitory, and adenylate cyclase activating properties. Med Res Rev 1983;3:201e19. [2] Ammon HP, Müller AB. Forskolin: from an ayurvedic remedy to a modern agent. Planta Med 1985;51:473e7. [3] Metzger H, Lindner E. The positive inotropic-acting forskolin, a potent adenylate cyclase activator. Arzneimittelforschung 1981;31:1248e50. [4] Henderson S, Magu B, Rasmussen C, et al. Effects of Coleus forskohlii supplementation on body composition and hematological profiles in mildly overweight women. J Int Soc Sports Nutr 2005;2:54e62. [5] Kamohara S, Noparatanawong SA. Coleus forskohlii extract improves body composition in healthy volunteers: an open-label trial. Pers Med Universe 2013;2:25e7. [6] Lieberman SA. A new potential weapon for fighting obesity. Forskolin - the active diterpene in Coleus. Altern Complement Ther 2004;10:330e3. [7] Jagtap M, Chandola HM, Ravishankar B. Clinical efficacy of Coleus forskohlii (Willd.) Briq. (Makandi) in hypertension of geriatric population. Ayu 2011;32:59e65. [8] Godard MP, Johnson BA, Richmond SR. Body composition and hormonal adaptations associated with forskolin consumption in overweight and obese men. Obes Res 2005;13:1335e43. [9] Thiagarajah JR, Verkman AS. CFTR pharmacology and its role in intestinal fluid secretion. Curr Opin Pharmacol 2003;3:594e9.