Archived Comments for:
Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain
Comment on ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’
Rutger Kriek, JP Russell Sci Ltd.
27 October 2014
R. Kriek, on behalf of JP Russell Science Ltd (30 Chytron Street/Office A32, 1075 Nicosia, Cyprus; E: rutger.kriek@equationcs.com T: +35722257129)
Sir,
The recently published paper ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’ by Impellizzeri D, Bruschetta G, Cordaro M, Crupi R, Siracusa R, Esposito E and Cuzzocrea S contains some strong statements in favor of patented micronized and ultramicronized palmitoylethanolamide (PEA) formulations, based on clear mistakes in assessments and in selective reporting of literature, without reporting a conflict of interest. We will bring forward a number of important flaws and shortcomings of this paper.
1. Conflict of interest
Professor Salvatore Cuzzocrea is inventor of patent WO 2013121449 A1: Compositions and methods for the modulation of specific amidases for n-acylethanolamines for use in the therapy of inflammatory diseases, together with senior management of Epitech Group Srl, Dr. Francesco Della Valle, en Dr. Maria Federica Della Valle, the patent holders of a number of patents on micronized and ultramicronized PEA. In the aforementioned patent PEA defines a number of claims, such as: “A further object of the invention is a compound of formula (I) for the use defined above in combination with one or more different compounds of formula (I) or with palmitoylethanolamide, for a combined, separate or sequential administration.”
It is interesting to note that since the submission date of the patent in 2012 the group of Dr Cuzzocrea suddenly started publishing a sprawl of papers on ultramicronized PEA formulations patented by Epitech Group Srl. In some of these publications data gathered with non-micronized PEA have been misrepresented as if the data were based on ultramicronized PEA. (Kriek 2014). (1) Surprisingly, in all these papers, and in the recent papers published in the Journal of Neuroinflammation, however ‘no conflict of interest’ was reported by professor Cuzzocrea. (2)
2. Selective reporting of literature (selection bias): ignoring of efficacy data with nonmicronized oral PEA
In the paper ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’ the authors do not discuss a number of important and relevant articles supporting the oral efficacy of unmicronized PEA in various paradigms and its dose-dependency. It was a research group under the guidance of the Nobel laureate professor Rita Levi-Montalcini who already in 1996 used the same paradigm of inflammatory pain in the rat as used in the article by Cuzzocrea et al. for the analysis of PEA’s mechanism of action. They described a clear and significant oral dose-response curve for PEA (at that time explored under the code name of the company LifeGroup Spa LG 2110/1 and under its chemical name: N-(2-Hydroxyethyl) hexadecanamide). (3) The conclusion of the experiments from the group of Levi-Montalcini was clear: These results indicate that orally administered N-(2-hydroxy- ethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. Furthermore, the authors demonstrated that 10 mg PEA/kg taken orally could also reduce mechanical hyperalgesia comparable to indomethacine.
Instead of referring to this article while discussing the carrageenan-induced paw edema model, the group of Cuzzocrea at al refers to a different paper, also published in 1996, where PEA was not mentioned.(4) In the same model professor Barbara Costa’s group in 2002 also documented efficacy of oral, unmicronized PEA.(5) PEA (1, 3, 5, 10 mg kg−1) was compared to indomethacin (5 mg kg−1). PEA (10 mg kg−1), like indomethacin, reduced COX activity down to the same value as in non-inflamed tissues. Furthermore PEA had a curative effect on inflammation, inhibiting the carrageenan-induced edema in a dose- and time-dependent manner over days. These findings were replicated in other experiments.(6)
In a different rat model used by a different research group, the rat forced swimming test for analyzing antidepressant activity, nonmicronized PEA in a dose of 10 mg/kg was far superior to the golden standard fluoxetine in a dose of 20 mg/kg.(7)
The biological effects of oral nonmicronized PEA are already known since 1973 and shown in a number of studies.(8-10) In some studies PEA was given orally during a prolonged period of time, with clear therapeutic efficacy in the models used. Never did anyone question the validity of these data or suggested that oral nonmicronized PEA has no biological effect. A discussion of the results from these papers is missing in the paper of Impellizzeri et al. and this clearly demonstrates selective literature reporting.
The results of a number of these publications centering around the oral bioactivity of nonmicronized PEA even found its way into authorative textbooks, as well milestone review articles. (12-13)
In the light of the remarkably deviant results of Impellizzeri et al., it is remarkable that there is no discussion whatsoever of those positive results. Selective use of literature and data is a technique that is frequently used by companies to give an unrealistically positive picture of products. In this framework, one also wonders why there is so much emphasis in the article on the commercial sources of the different products tested, and why the conflict of interest of professor Cuzzocrea is not reported.
3. Unlikely results for purity
In the paper the authors claim to have assessed the purity of various PEA formulations, including PeaPure and PeaVera. JP Russell Science only accepts PEA for its PeaPure and PeaVera after two different, independent laboratories, using state of the art HPLC methods, have provided results for purity of any batch. In the batches used by the authors purity has been documented by these laboratories as 99,8% and 100,1% . It is therefore highly improbable to find purity of 87-88% for PeaPure and PeaVera.
4. Abundant clinical proof of efficacy for non-micronized PEA and absence of proof for (ultra-)micronized PEA formulations
Last but not least it is important to note that all double blind, placebo controlled clinical studies of sufficient power supporting PEA’s efficacy and safety in over 3000 patients have been conducted with low-tech non-micronized PEA.(14) There is not one such study published for micronized or ultramicronized PEA.
Based on the abundant preclinical literature and the available clinical literature one can only draw one conclusion: only non-micronized PEA formulations are sufficiently documented to be effective and safe for the treatment of chronic pains and inflammation in humans.
References
(1) Kriek R. Marketing messages in pharmacological papers and scientific chapters: the case of palmitoylethanolamide and its formulations. Pharmacol Res. 2014 Jul;85:1-3. doi: 10.1016/j.phrs.2014.04.007. Epub 2014 Apr 24.
(3) Mazzari S1, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol. 1996 Apr 11;300(3):227-36.
(4) Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PT, Currie MG: Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 1996, 118:829–838.
(5) Costa B, Conti S, Giagnoni G, Colleoni M. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems. Br J Pharmacol. 2002 Oct;137(4):413-20.
(6) Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G. Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol. 2002 Jan;135(1):181-7.
(7) Yu HL, Deng XQ, Li YJ, Li YC, Quan ZS, Sun XY. N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice. Pharmacol Rep. 2011;63(3):834-9.
(8) Tikal K, Benesová O, Franková S. The effects of centrophenoxine and palmitoylethanolamide on the social behavior of rats malnourished in early postnatal life. Act Nerv Super (Praha). 1973 May;15(2):150-1.
(9) Perlík F, Krejcí J, Elis J, Pekárek J, Svejcar J. The effect of N-(2-hydroxyethyl)-palmitamide on delayed hypersensitivity in guinea-pig. Experientia. 1973 May 1;29(1):67-8.
(10) Lackovic V, Borecký L, Kresáková J.Effect of impulsin treatment of interferon production and antiviral resistance of mice. Arch Immunol Ther Exp (Warsz). 1977;25(5):655-61.
(11) Svec P, Béderová E, Svec F. The effect of long-term administration of N-(2-hydroxyethyl)palmitamide on the chemotherapy of RBA rat leukemia. Neoplasma. 1975;22(6):625-30. (12) Emmanuel S Onaivi, Takayuki Sugiura,Vincenzo Di Marzo Endocannabinoids: The Brain and Body's Marijuana and Beyond: pp 432-433, CRC press, 2006
(13) Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ. The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem. 2002 Mar;9(6):663-74.
(14) Keppel Hesselink JM, de Boer T, Witkamp RF. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. Int J Inflam. 2013;2013:151028. doi: 10.1155/2013/151028. Epub 2013 Aug 27.
Competing interests
Rutger Kriek, director of JP Russell Science Ltd, writes on behalf of JP Russell Science Ltd, a company that introduced pure palmitoylethanolamide formulations (PeaPure, PeaVera).
Journal of Neuroinflammation
Comment on ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’
27 October 2014
R. Kriek, on behalf of JP Russell Science Ltd (30 Chytron Street/Office A32, 1075 Nicosia, Cyprus; E: rutger.kriek@equationcs.com T: +35722257129)
Sir,
The recently published paper ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’ by Impellizzeri D, Bruschetta G, Cordaro M, Crupi R, Siracusa R, Esposito E and Cuzzocrea S contains some strong statements in favor of patented micronized and ultramicronized palmitoylethanolamide (PEA) formulations, based on clear mistakes in assessments and in selective reporting of literature, without reporting a conflict of interest. We will bring forward a number of important flaws and shortcomings of this paper.
1. Conflict of interest
Professor Salvatore Cuzzocrea is inventor of patent WO 2013121449 A1:
Compositions and methods for the modulation of specific amidases for n-acylethanolamines for use in the therapy of inflammatory diseases, together with senior management of Epitech Group Srl, Dr. Francesco Della Valle, en Dr. Maria Federica Della Valle, the patent holders of a number of patents on micronized and ultramicronized PEA. In the aforementioned patent PEA defines a number of claims, such as: “A further object of the invention is a compound of formula (I) for the use defined above in combination with one or more different compounds of formula (I) or with palmitoylethanolamide, for a combined, separate or sequential administration.”
It is interesting to note that since the submission date of the patent in 2012 the group of Dr Cuzzocrea suddenly started publishing a sprawl of papers on ultramicronized PEA formulations patented by Epitech Group Srl. In some of these publications data gathered with non-micronized PEA have been misrepresented as if the data were based on ultramicronized PEA. (Kriek 2014). (1) Surprisingly, in all these papers, and in the recent papers published in the Journal of Neuroinflammation, however ‘no conflict of interest’ was reported by professor Cuzzocrea. (2)
2. Selective reporting of literature (selection bias): ignoring of efficacy data with nonmicronized oral PEA
In the paper ‘Micronized/ultramicronized palmitoylethanolamide displays superior oral efficacy compared to nonmicronized palmitoylethanolamide in a rat model of inflammatory pain’ the authors do not discuss a number of important and relevant articles supporting the oral efficacy of unmicronized PEA in various paradigms and its dose-dependency. It was a research group under the guidance of the Nobel laureate professor Rita Levi-Montalcini who already in 1996 used the same paradigm of inflammatory pain in the rat as used in the article by Cuzzocrea et al. for the analysis of PEA’s mechanism of action. They described a clear and significant oral dose-response curve for PEA (at that time explored under the code name of the company LifeGroup Spa LG 2110/1 and under its chemical name: N-(2-Hydroxyethyl) hexadecanamide). (3) The conclusion of the experiments from the group of Levi-Montalcini was clear: These results indicate that orally administered N-(2-hydroxy- ethyl)hexadecanamide is effective in: (a) directly down-modulating mast cell activation in vivo; (b) suppressing pathological consequences initiated by mast cell activation independently of the activating stimuli; (c) exerting an anti-inflammatory action distinguishable from that of classical steroidal and non-steroidal anti-inflammatory agents. Furthermore, the authors demonstrated that 10 mg PEA/kg taken orally could also reduce mechanical hyperalgesia comparable to indomethacine.
Instead of referring to this article while discussing the carrageenan-induced paw edema model, the group of Cuzzocrea at al refers to a different paper, also published in 1996, where PEA was not mentioned.(4)
In the same model professor Barbara Costa’s group in 2002 also documented efficacy of oral, unmicronized PEA.(5) PEA (1, 3, 5, 10 mg kg−1) was compared to indomethacin (5 mg kg−1). PEA (10 mg kg−1), like indomethacin, reduced COX activity down to the same value as in non-inflamed tissues. Furthermore PEA had a curative effect on inflammation, inhibiting the carrageenan-induced edema in a dose- and time-dependent manner over days. These findings were replicated in other experiments.(6)
In a different rat model used by a different research group, the rat forced swimming test for analyzing antidepressant activity, nonmicronized PEA in a dose of 10 mg/kg was far superior to the golden standard fluoxetine in a dose of 20 mg/kg.(7)
The biological effects of oral nonmicronized PEA are already known since 1973 and shown in a number of studies.(8-10) In some studies PEA was given orally during a prolonged period of time, with clear therapeutic efficacy in the models used. Never did anyone question the validity of these data or suggested that oral nonmicronized PEA has no biological effect. A discussion of the results from these papers is missing in the paper of Impellizzeri et al. and this clearly demonstrates selective literature reporting.
The results of a number of these publications centering around the oral bioactivity of nonmicronized PEA even found its way into authorative textbooks, as well milestone review articles. (12-13)
In the light of the remarkably deviant results of Impellizzeri et al., it is remarkable that there is no discussion whatsoever of those positive results. Selective use of literature and data is a technique that is frequently used by companies to give an unrealistically positive picture of products. In this framework, one also wonders why there is so much emphasis in the article on the commercial sources of the different products tested, and why the conflict of interest of professor Cuzzocrea is not reported.
3. Unlikely results for purity
In the paper the authors claim to have assessed the purity of various PEA formulations, including PeaPure and PeaVera. JP Russell Science only accepts PEA for its PeaPure and PeaVera after two different, independent laboratories, using state of the art HPLC methods, have provided results for purity of any batch. In the batches used by the authors purity has been documented by these laboratories as 99,8% and 100,1% . It is therefore highly improbable to find purity of 87-88% for PeaPure and PeaVera.
4. Abundant clinical proof of efficacy for non-micronized PEA and absence of proof for (ultra-)micronized PEA formulations
Last but not least it is important to note that all double blind, placebo controlled clinical studies of sufficient power supporting PEA’s efficacy and safety in over 3000 patients have been conducted with low-tech non-micronized PEA.(14) There is not one such study published for micronized or ultramicronized PEA.
Based on the abundant preclinical literature and the available clinical literature one can only draw one conclusion: only non-micronized PEA formulations are sufficiently documented to be effective and safe for the treatment of chronic pains and inflammation in humans.
References
(1) Kriek R. Marketing messages in pharmacological papers and scientific chapters: the case of palmitoylethanolamide and its formulations. Pharmacol Res. 2014 Jul;85:1-3. doi: 10.1016/j.phrs.2014.04.007. Epub 2014 Apr 24.
(2) Keppel Hesselink JM. Marketing messages in pharmacological papers and conflict of interest? Comment J Neuroinflammation (2014-05-16 20:24) http://www.jneuroinflammation.com/content/10/1/91/comments#2095698
(3) Mazzari S1, Canella R, Petrelli L, Marcolongo G, Leon A. N-(2-hydroxyethyl)hexadecanamide is orally active in reducing edema formation and inflammatory hyperalgesia by down-modulating mast cell activation. Eur J Pharmacol. 1996 Apr 11;300(3):227-36.
(4) Salvemini D, Wang ZQ, Wyatt PS, Bourdon DM, Marino MH, Manning PT, Currie MG: Nitric oxide: a key mediator in the early and late phase of carrageenan-induced rat paw inflammation. Br J Pharmacol 1996, 118:829–838.
(5) Costa B, Conti S, Giagnoni G, Colleoni M. Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems. Br J Pharmacol. 2002 Oct;137(4):413-20.
(6) Conti S, Costa B, Colleoni M, Parolaro D, Giagnoni G. Antiinflammatory action of endocannabinoid palmitoylethanolamide and the synthetic cannabinoid nabilone in a model of acute inflammation in the rat. Br J Pharmacol. 2002 Jan;135(1):181-7.
(7) Yu HL, Deng XQ, Li YJ, Li YC, Quan ZS, Sun XY. N-palmitoylethanolamide, an endocannabinoid, exhibits antidepressant effects in the forced swim test and the tail suspension test in mice. Pharmacol Rep. 2011;63(3):834-9.
(8) Tikal K, Benesová O, Franková S. The effects of centrophenoxine and palmitoylethanolamide on the social behavior of rats malnourished in early postnatal life. Act Nerv Super (Praha). 1973 May;15(2):150-1.
(9) Perlík F, Krejcí J, Elis J, Pekárek J, Svejcar J. The effect of N-(2-hydroxyethyl)-palmitamide on delayed hypersensitivity in guinea-pig. Experientia. 1973 May 1;29(1):67-8.
(10) Lackovic V, Borecký L, Kresáková J.Effect of impulsin treatment of interferon production and antiviral resistance of mice. Arch Immunol Ther Exp (Warsz). 1977;25(5):655-61.
(11) Svec P, Béderová E, Svec F. The effect of long-term administration of N-(2-hydroxyethyl)palmitamide on the chemotherapy of RBA rat leukemia. Neoplasma. 1975;22(6):625-30.
(12) Emmanuel S Onaivi, Takayuki Sugiura,Vincenzo Di Marzo Endocannabinoids: The Brain and Body's Marijuana and Beyond: pp 432-433, CRC press, 2006
(13) Lambert DM, Vandevoorde S, Jonsson KO, Fowler CJ. The palmitoylethanolamide family: a new class of anti-inflammatory agents? Curr Med Chem. 2002 Mar;9(6):663-74.
(14) Keppel Hesselink JM, de Boer T, Witkamp RF. Palmitoylethanolamide: A Natural Body-Own Anti-Inflammatory Agent, Effective and Safe against Influenza and Common Cold. Int J Inflam. 2013;2013:151028. doi: 10.1155/2013/151028. Epub 2013 Aug 27.
Competing interests
Rutger Kriek, director of JP Russell Science Ltd, writes on behalf of JP Russell Science Ltd, a company that introduced pure palmitoylethanolamide formulations (PeaPure, PeaVera).