JBRF has launched a study which will explore the safety and efficacy of ketamine to treat pediatric bipolar disorder in children ages 6-12. One third of the children in the study will be characterized by the Fear of Harm (FOH) phenotype; a subtype of bipolar disorder recently defined from research supported by the Juvenile Bipolar Research Foundation (JBRF).

The following provides:

  • a brief description the FOH phenotype and the pilot study that preceded this current study.
  • information about the use, efficacy and safety of ketamine in general.
  • information specific to the safety measurements incorporated into the current study protocol.

________________________________________

JBRF SUPPORTED RESEARCH 

The FOH phenotype describes a population of children who are severely impaired, often refractory to treatment, and currently fall under a bipolar classification. Symptoms experienced by these children include not only those typical of bipolar disorder, but also a broad range of symptoms currently included in classifications considered co-morbid to bipolar disorder as well as some symptoms never previously associated with any psychiatric classification[1]. This new constellation of symptoms allowed investigators to trace the condition to a particular neuropathway that is the most ancient sensory pathway in the brain and is intimately involved in homeostasis. Further exploration of this pathway has led to a neuroanatomical model of the condition as well as a hypothesis of its pathophysiology. From this framework, ketamine was selected as an appropriate agent to target the dysregulation[2].

A pilot study was conducted within a private practice setting. Intranasal ketamine was administered to 12 subjects, aged 6-30, all of whom screened positive for pediatric-onset bipolar disorder with FOH phenotype. Treatment resulted in a rapid and enduring resolution of a large majority of their most severe behavioral and physiological symptoms. As of January, 2011, continuous treatment of these subjects ranged from 3 months to almost two and a half years. By this writing, another 25 children have enrolled in this naturalistic pilot treatment study and experienced similar positive responses. All subjects continue to receive regular administrations of ketamine.

This current study has been initiated to document these observations through a double-blind placebo-controlled study.

The study has received both Internal Review Board (BioMed IRB) and Food and Drug Administration (FDA) approval. Registration of the study can be found at:

http://www.clinicaltrials.gov/ct2/show/NCT01504659?term=ketamine+bipolar+disorder&rank=1

USE, EFFICACY AND SAFETY INFORMATION OF KETAMINE

CHARACTERISTICS and HISTORICAL USE:

Since its creation in 1961 and introduction to clinical practice in 1970, ketamine has garnered a long record of efficacy and safety as a sedation and analgesic agent. It has been used both in combination with other sedation agents and by itself in both clinical and veterinary arenas. Ketamine is a core medicine in the World Health Organization’s “Essential Drugs List” and its ability to provide sedation without the need for intubation has made it a standard technique for the American Red Cross.[i]

When ketamine is administered in doses between 1-3mg/kg IV or 3-4mg/kg IM, it induces a unique dissociative state which disconnects the central nervous system (CNS) from external stimuli (i.e. pain, sight, sound) and accomplishes potent analgesia, amnesia and sedation.[ii] However, this state is pharmacologically and clinically distinct from general anesthetics in three important ways: 1) it does not impair respiration, airway reflexes or cardiovascular stability, 2) it does not exert its effect along a dose-response continuum; that is, once a dissociative state is reached, that state does not deepen nor will it deepen with additional drug administration, and 3) it does not exert its effects through global CNS depression, instead it dissociates the CNS through its effects on the thalamoneocortical and limbic systems.[iii] Due to the first two points, unlike anesthetic agents, once a dissociative-sedation state is produced by ketamine, increased administration is not accompanied by an increased probability of ventilatory depression[iv] and therefore intubation is rarely needed. Within the range of standard, clinically administered dissociative sedation doses and using standard administration methods, there are neither clinically important changes in airway integrity and respiration[v] nor clinically important incidence or severity of adverse events.[vi] Only high and/or rapid IV administration predicted an increased risk of agitation.[vii],[vii].

Ketamine use in the United States far less frequent than elsewhere. This is likely due, in large part, to wariness over emergence reactions that sometimes follow the use of this phencyclidine derivative.[ix],[x] The experience has limited use of the drug despite the fact that in all but a few cases[xi],[xii],[xiii] out of the many hundreds of thousands[xiv],[xv] in which use has been reported, the effects have been transient and typically resolve within 30-120 minutes.[xvi],[xvii] Ketamine is the number one agent used to sedate children in the emergency room and is frequently used in dental offices.

In addition to its widespread dissociative use, ketamine has a long clinical history of off-label use as an analgesic. It has been used as a treatment for a wide spectrum of pain syndromes, including neuropathic pain, phantom limb pain, postoperative pain, acute traumatic pain, complex regional pain syndrome and breakthrough and regional chronic pain.[xviii],[xix],[xx],[xxi] In some neurological ICUs, ketamine has been used in cases of prolonged status epilepticus in order to protect neurons from glutamatergic damage.[xxii]  Finally, ketamine has been known to have bronchodilatory effects and to be used in the treatment of bronchospasm.[xxiii]

OVERDOSE INFORMATION:

The several documented cases of unintentional ketamine overdose, up to 100 times that required, have been followed by prolonged, but complete, recovery.[xxiv] Median lethal dose of intraperitoneal ketamine hydrochloride is 224 mg/kg in rats and 229 mg/kg in mice.[xxv] In guinea pigs, the LD50 of ketamine hydrochloride ranges from 351 to 373 mg/kg when given by intramuscular injection with 10 mg/kg of xylazine (a short-acting sedative).[xxvi]

ADVERSE EVENTS and SIDE EFFECTS ASSOCIATED WITH THE MEDICAL USE OF KETAMINE:

Emergence from ketamine sedation causes the well known psychotomimetic effects associated with the drug. The percentage of children who experience emergence phenomena or recovery agitation is much smaller than that of adults and almost no children express or exhibit distress from them when emerging from ketamine sedation.[xxvii],[xxviii] While reports of recovery agitation are not infrequent (app. 20%), the event was only judged moderate to severe in 1.6% of the cases.[xxix] In one trial in which the reaction was quantified, the investigators found that the median agitation score was 5 out of 100.[xxx] It is worth noting here that these observations pertain to the use of ketamine to achieve complete, rather than partial dissociation as the case will be for our study.

Since ketamine does not depress the respiratory system it does not require respiratory support. While some adverse respiratory events have been documented, the incidence and nature of these events are not of clinical importance. A 2009 meta-analysis of 8,282 pediatric ketamine sedation cases found  incidence of airway malalignment and respiratory depression together was 2.8% (234 cases), apnea was 0.8% (63 cases) and laryngospasm was 0.3% (22 cases).[xxxi] The commensurate corrective action required for these kinds of advents was recorded in an earlier study of 1,022 cases. In that study, for the 7 cases of airway complications, repositioning of the head alleviated partial obstruction and no assisted ventilation was performed. In the seven cases of transient laryngospasm, apnea or respiratory depression, none of the cases required endotracheal intubation and all cases were completed with uneventful recovery.[xxxii]  We are not aware of any instances of adverse respiratory events in children in which an intranasal administration of ketamine is used.[xxxiii],[xxxiv],[xxxv]

The presence of lower urinary tract symptoms (LUTS) associated with ketamine use has garnered recent attention and concern in the urological community. Our review of the literature indicates that LUTS follows extremely high doses of ketamine (between hundreds and thousands of times higher than the doses in the study), typically over a long period of time and during which medical attention is not sought despite the presence of symptoms.

Other side effects of ketamine include nausea, vomiting, fatigue and headache.

Despite the phencyclidine characteristic of ketamine, ketamine does not create a physical addiction.[xxxvi]

KETAMINE AND NEUROTOXICITY:

Studies have documented that ketamine has a neurotoxic impact on the fetal or neonatal rat brain. However, Scallet et al. (2004) extended the findings of these toxicological studies by comparing the ketamine serum levels associated with neurotoxicity in the rats to the ketamine serum levels typical of ketamine use in humans. Their study determined that ketamine serum levels at which neurodegeneration occurs in the neonatal rat is 7-fold greater than the mean ketamine serum level resultant from dissociation in humans. When ketamine was administered to PND 7 rats, at a dose which generated a similar ketamine serum levels to human dissociation, no neurodegeneration occurred.[xxxvii]  Since the ketamine dose used in our study is commensurate with an analgesic, rather than dissociative use, it is safe to say that there is a wide margin of safety to the risk of neurodegeneration.

Further, a neurotoxicity study conducted by Wang et al. in 2005 demonstrated that, while widespread and dose dependent apoptotic neurodegeneration occurred in in vivo PND 1 rat forebrains when treated with increasing amount of N-methyl-d-aspartate (NMDA) antagonists such as ketamine (up to 20µM),  that this effect is restricted to the period of synaptogenesis.[xxxviii]

THE USE OF KETAMINE FOR MOOD DISORDER:

Concurrent to the pilot study described above, several small, controlled studies have illustrated the considerable potential of ketamine to provide fast-acting and sustained relief in refractory depression, refractory bipolar disorder and in patients with severe suicidal ideation. Due to their impressive findings, these studies have recently come into the popular media. The landmark clinical study, by Berman et al. (2000) found that in a randomized, double-blind study, 7 subjects with major depressive disorder experienced significant improvement in depressive symptoms within 72 hrs. post-treatment with  0.5 mg/kg IV ketamine.[xxxix]  In 2 randomized, placebo-controlled, double-blind crossover studies by Zarate el al., one in 2006 in which 18 patients with refractory major depressive disorder were studied and the other in 2010, in which 18 patients with refractory bipolar depression were studied, investigators found that 71% of the patients in each study achieved significant, rapid and enduring clinical improvement after intravenous infusion of 0.5 mg/kg ketamine.[xl],[xli] Similar findings have now been replicated by several groups.[xlii],[xliii],[xliv],[xlv]

There are many characteristics that associate children with the FOH phenotype to the treatment refractory adults of the above studies –but they will not be addressed here. What is relevant is that, like the adults in the above studies, children with the FOH phenotype have responded to ketamine in an equally positive manner. Administration of the intranasal formulation is easy to manage and its effects typically endure for 3-5 days.

INFORMATION RELEVANT TO THE IMPLEMENTATION AND SAFETY OF THIS STUDY

EXCLUSION CRITERIA:

Except for contraindications directly related to surgical considerations, exclusion criteria for our study follows the Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update[xlvi] by Green et al. While these contraindications are advised for the dissociative use of drug, rather than the sub-dissociative use called for in our study, adoption of them will ensure an extra margin of safety. Screening prior to enrollment will disqualify children with exclusionary criteria.

 DATA COLLECTION:

Ketamine will be administered to the child in his/her home by a PA, NP or APRN specifically trained for this study. He or she will arrive an hour before the administration to confirm that the child is healthy enough to receive the dose and to irrigate the child’s nasal passages. The latter is to maximize an accurate delivery of drug/placebo. After administration, the PA, NP or APRN will remain in the child’s home for another 2 hours to monitor for adverse events. Two hours is the well established window in which all the side effects of ketamine resolve.

 DOSING PROTOCOL:

For this study, children have been divided into two groups depending upon weight. Group A, with minimum-maximum weight of 20 kg-40 kg will receive a fixed initial dose of 10 mg (0.25-0.5mg/kg). Group B with minimum – maximum weight of 40.01kg-100kg will get a fixed initial dose of 20 mg (0.20-0.5mg/kg). Over the following 3 administrations, the dose will increase by 10mg unless a therapeutic response has been achieved in which case the dose level will hold.  This means that the maximum dose for the smaller children will be 2mg/kg. The maximum dose for the larger children will be 1.25mg/kg. These doses are significantly lower than a dissociative dose and are more similar to an analgesic dose. While psychotomimetic effects may occur at these lower doses, there is a wide berth to dissociative sedation levels.

SAFETY MEASURES:

During the two hours post-dose that the PA/NP/APRN remains with the child, she/he will use the Clinician-Administered Dissociative States Scale (CADSS) to measure the psychotomimetic emergence reactions which can follow the use of ketamine. Additionally, she/he will administer the Systematic Assessment for Treatment Emergent Effects (SAFTEE) and the Brief Psychiatric Rating Scale (BPRS). Finally, vital signs will be measured prior to, and at increasing intervals for the 60 minutes after the dose.

As for the rare respiratory distress caused by ketamine, our review of the literature finds that the overwhelming recommendation is for the presence of a person dedicated to the observation of the patient who is skilled in advanced airway management and has access to appropriate equipment such as a bag valve mask. The current study wholly adopts this recommendation.

As for reports of LUTS associated with ketamine use, the medical screening and urinalysis prior to participation (as indicated in the Medical Clearance) will insure that the child has no preexisting bladder condition. Further, we will inquire about changes in urination pattern during the study, at three month follow up, and advise parents to seek treatment at any time that they notice such a change. No child who is currently treated with ketamine has experienced any LUTS.

Other less serious adverse effects such as nausea or vomiting, while unpleasant, are not of clinical concern. Side effects specific to the intranasal administration also include a bitter taste (which is mitigated by sucking on hard candy during drug administration), and a sensation of burning in the pharynx.75 In the pilot study, we have also reported on a chilling sensation prior to therapeutic response.


[1] Our research indicates that two thirds of the children who currently have a community diagnosis of bipolar disorder fall within an FOH spectrum: 1/3 high and 1/3 low. We are very concerned with the looming re-allocation of some of these children to the proposed Temper Dysregulation Disorder (TDD) classification pursuant to its codification.


[i] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

[ii] Green SM, Krauss B. The semantics of ketamine. Ann Emerg Med. Nov 2000;36(5):480-482.

[iii] Green SM, Krauss B. The semantics of ketamine. Ann Emerg Med. Nov 2000;36(5):480-482.

[iv] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

[v] Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. Aug 2009;54(2):158-168 e151-154.

[vi] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[vii] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[viii] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

[ix] Schmid RL, Sandler AN, Katz J. Use and efficacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes. Pain. 1999;82(2):111-125.

[x] Pittenger C, Sanacora G, Krystal JH. The NMDA Receptor as a Therapeutic Target in Major Depressive Disorder. CNS and Neurological Disorders – Drug Targets. 2007;6:101-115.

[xi] Fine J, Finestone SC. Sensory disturbances following ketamine anesthesia: recurrent hallucinations. Anesth Analg. May-Jun 1973;52(3):428-430.

[xii] Meyers EF, Charles P. Prolonged adverse reactions to ketamine in children. Anesthesiology. Jul 1978;49(1):39-40.

[xiii] Perel A, Davidson JT. Recurrent hallucinations following ketamine. Anaesthesia. Oct 1976;31(8):1081-1083.

[xiv] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xv] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xvi] Green SM, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xvii] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xviii] Carr DB, Goudas LC, Denman WT, et al. Safety and efficacy of intranasal ketamine for the treatment of breakthrough pain in patients with chronic pain: a randomized, double-blind, placebo-controlled, crossover study. Pain. Mar 2004;108(1-2):17-27.

[xix] Innovative Drug Delivery Systems I. Investigator’s Brochure, v7, PMI-100/150 (intranasal ketamine 100 – 150 mg/mL)1995.

[xx] Huge V, Lauchart M, Magerl W, et al. Effects of low-dose intranasal (S)-ketamine in patients with neuropathic pain. Eur J Pain. Apr 2010;14(4):387-394.

[xxi] Goldberg ME, Domsky R, Scaringe D, et al. Multi-day low dose ketamine infusion for the treatment of complex regional pain syndrome. Pain Physician. Apr 2005;8(2):175-179.

[xxii] Borris DJ, Bertram EH, Kapur J. Ketamine controls prolonged status epilepticus. Epilepsy research. 2000;42(2):117-122.

[xxiii] White PF, Way WL, Trevor AJ. Ketamine–its pharmacology and therapeutic uses. Anesthesiology. Feb 1982;56(2):119-136.

[xxiv] Green SM, Clark R, Hostetler MA, Cohen M, Carlson D, Rothrock SG. Inadvertent ketamine overdose in children: Clinical manifestations and outcome. Annals of Emergency Medicine. 1999;34(4, Part 1):492-497.

[xxv] Goldenthal EI. A compilation of LD50 values in newborn and adult animals. Toxicol Appl Pharmacol. 1971;18:185-207.

[xxvi] D’Alleinne CP, Mann DD. Evaluation of ketamine/xylazine anesthesia in the guineapig: toxicological parameters. Veterinary and Human Toxicology. 1981; 24, 4.10-2

[xxvii] SM Green, Johnson NE. Ketamine sedation for pediatric procedures: Part 2, Review and implications. Ann Emerg Med. Sep 1990;19(9):1033-1046.

[xxviii] Howes MC. Ketamine for paediatric sedation/analgesia in the emergency department. Emerg Med J. May 2004;21(3):275-280.

[xxix] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety

[xxx] Sherwin TS, Green SM, Khan A, Chapman DS, Dannenberg B. Does adjunctive midazolam reduce recovery agitation after ketamine sedation for pediatric procedures? A randomized, double-blind, placebo-controlled trial. Annals of Emergency Medicine. 2000;35(3):229-238.

[xxxi] Green SM, Roback MG, Krauss B, et al. Predictors of airway and respiratory adverse events with ketamine sedation in the emergency department: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. Aug 2009;54(2):158-168 e151-154.

[xxxii] Green SM, Rothrock SG, Lynch EL, et al. Intramuscular Ketamine for Pediatric Sedation in the Emergency Department: Safety Profile in 1,022 Cases. Annals of Emergency Medicine. 1998;31(6):688-697.

[xxxiii] Abrams R, Morrison JE, Villasenor A, Hencmann D, Da Fonseca M, Mueller W. Safety and effectiveness of intranasal administration of sedative medications (ketamine, midazolam, or sufentanil) for urgent brief pediatric dental procedures. Ansethsia Progress. 1993;40(3):4.

[xxxiv] Diaz J. Intranasal ketamine preinduction of paediatric outpatients. Pediatric Anesthesia. 1997;7(4):273-278.

[xxxv] Weksler N, Ovadia L, Muati G, Stav A. Nasal ketamine for paediatric premedication. Can J Anaesth. Feb 1993;40(2):119-121.

[xxxvi] Dotson JW, Ackerman DL. Ketamine Abuse. Journal of Drug Issues. 1995;25(4):751-757.

[xxxvii] Scallet AC, Schmued LC, Slikker Jr W et al.. Developmental Neurotoxicity of Ketamine: Morphometric Confirmation, Exposure Parameters, and Multiple Flourescent Labeling of Apoptotic Neurons. Toxicol. Sci. (2004) 81 (2): 364-371.

[xxxviii] Wang C, Sadovova N, Fu X et al.. The role of the N-methl-D-Aspartate receptor in ketamine-induced apoptosis in rat forebrain culture. Neuroscience. (2005) 132 (4): 867-977.

[xxxix] Berman RM, Cappiello A, Anand A, et al. Antidepressant effects of ketamine in depressed patients. Biological Psychiatry. 2000;47(4):351-354.

[xl] Zarate CA, Jr., Singh JB, Carlson PJ, et al. A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression. Arch Gen Psychiatry. Aug 2006;63(8):856-864.

[xli] Diazgranados N, Ibrahim L, Brutsche NE, et al. A randomized add-on trial of an N-methyl-D-aspartate antagonist in treatment-resistant bipolar depression. Arch Gen Psychiatry. Aug 2010;67(8):793-802.

[xlii] Krystal JH. Ketamine and the potential role for rapid-acting antidepressant medications. Swiss Med Wkly. Apr 21 2007;137(15-16):215-216.

[xliii] Price RB, Nock MK, Charney DS, Mathew SJ. Effects of intravenous ketamine on explicit and implicit measures of suicidality in treatment-resistant depression. Biol Psychiatry. Sep 1 2009;66(5):522-526.

[xliv] Phelps LE, Brutsche N, Moral JR, Luckenbaugh DA, Manji HK, Zarate CA, Jr. Family history of alcohol dependence and initial antidepressant response to an N-methyl-D-aspartate antagonist. Biol Psychiatry. Jan 15 2009;65(2):181-184.

[xlv] Liebrenz M, Borgeat A, Leisinger R, Stohler R. Intravenous ketamine therapy in a patient with a treatment-resistant major depression. Swiss Med Wkly. Apr 21 2007;137(15-16):234-236.

[xlvi] Green SM, Roback MG, Kennedy RM, Krauss B. Clinical Practice Guideline for Emergency Department Ketamine Dissociative Sedation: 2011 Update. Ann Emerg Med. Jan 20 2011.

365 Comments
  1. Pingback: pickleball paddles
  2. Pingback: interserver coupon
  3. Pingback: Read More
  4. Pingback: click here
  5. Pingback: read more
  6. Pingback: new website
  7. Pingback: useful reference
  8. Pingback: my company
  9. Pingback: original site
  10. Pingback: additional hints
  11. Pingback: More Bonuses
  12. Pingback: Continued
  13. Pingback: Discover More
  14. Pingback: click resources
  15. Pingback: content
  16. Pingback: look here
  17. Pingback: read more
  18. Pingback: best info
  19. Pingback: new website
  20. Pingback: news
  21. Pingback: how to
  22. Pingback: about
  23. Pingback: useful reference
  24. Pingback: imp source
  25. Pingback: a fantastic read
  26. Pingback: my response
  27. Pingback: their explanation
  28. Pingback: her latest blog
  29. Pingback: More Bonuses
  30. Pingback: check that
  31. Pingback: you could try here
  32. Pingback: Learn More
  33. Pingback: Get the facts
  34. Pingback: official statement
  35. Pingback: important source
  36. Pingback: click here
  37. Pingback: read more
  38. Pingback: click here
  39. Pingback: click here
  40. Pingback: click here
  41. Pingback: read more
  42. Pingback: read more
  43. Pingback: read more
  44. Pingback: read more
  45. Pingback: website
  46. Pingback: click here
  47. Pingback: read more
  48. Pingback: more news
  49. Pingback: official site
  50. Pingback: her latest blog
  51. Pingback: Clicking Here
  52. Pingback: best value
  53. Pingback: new source
  54. Pingback: best news
  55. Pingback: learn now
  56. Pingback: click here
  57. Pingback: read more
  58. Pingback: important
  59. Pingback: find
  60. Pingback: continue reading
  61. Pingback: what to do
  62. Pingback: where to look
  63. Pingback: insight
  64. Pingback: quality article
  65. Pingback: sperry shoes
  66. Pingback: useful reference
  67. Pingback: their explanation
  68. Pingback: Homepage
  69. Pingback: a fantastic read
  70. Pingback: find this
  71. Pingback: browse this site
  72. Pingback: my response
  73. Pingback: More hints
  74. Pingback: try this web-site
  75. Pingback: explanation
  76. Pingback: read more
  77. Pingback: check my blog
  78. Pingback: click site
  79. Pingback: my review here
  80. Pingback: useful reference
  81. Pingback: Get More Info
  82. Pingback: see here
  83. Pingback: this website
  84. Pingback: great post to read
  85. Pingback: my company
  86. Pingback: imp source
  87. Pingback: click to read more
  88. Pingback: find more info
  89. Pingback: see it here
  90. Pingback: Homepage
  91. Pingback: a fantastic read
  92. Pingback: find this
  93. Pingback: Bonuses
  94. Pingback: read this article
  95. Pingback: click here now
  96. Pingback: browse this site
  97. Pingback: check here
  98. Pingback: original site
  99. Pingback: this page
  100. Pingback: news
  101. Pingback: click here
  102. Pingback: click here
  103. Pingback: click here
  104. Pingback: click here
  105. Pingback: read more
  106. Pingback: read more
  107. Pingback: read more
  108. Pingback: what is new
  109. Pingback: what is new
  110. Pingback: acne skin
  111. Pingback: more info
  112. Pingback: click here
  113. Pingback: read article
  114. Pingback: website
  115. Pingback: important
  116. Pingback: news
  117. Pingback: url
  118. Pingback: niagen
  119. Pingback: read more
  120. Pingback: click here
  121. Pingback: find now
  122. Pingback: news
  123. Pingback: important
  124. Pingback: new article
  125. Pingback: best information
  126. Pingback: see this here
  127. Pingback: Visit Website
  128. Pingback: keep reading
  129. Pingback: home page
  130. Pingback: more about this
  131. Pingback: hosting24 coupon
  132. Pingback: check my site
  133. Pingback: More Bonuses
  134. Pingback: click resources
  135. Pingback: Get the facts
  136. Pingback: click reference
  137. Pingback: you can look here
  138. Pingback: her explanation
  139. Pingback: why not try here
  140. Pingback: informative post
  141. Pingback: read more
  142. Pingback: news
  143. Pingback: link
  144. Pingback: best source
  145. Pingback: ebook
  146. Pingback: next
  147. Pingback: click reference
  148. Pingback: look here
  149. Pingback: Going Here
  150. Pingback: a knockout post
  151. Pingback: important link
  152. Pingback: Extra resources
  153. Pingback: Niagen review
  154. Pingback: read more
  155. Pingback: click here
  156. Pingback: read more
  157. Pingback: webpage
  158. Pingback: visit them
  159. Pingback: new source
  160. Pingback: important
  161. Pingback: news
  162. Pingback: best info
  163. Pingback: information
  164. Pingback: read more
  165. Pingback: information
  166. Pingback: website
  167. Pingback: webpage
  168. Pingback: news
  169. Pingback: best source
  170. Pingback: best source
  171. Pingback: click here
  172. Pingback: Source
  173. Pingback: have a peek here
  174. Pingback: Check This Out
  175. Pingback: this contact form
  176. Pingback: navigate here
  177. Pingback: weblink
  178. Pingback: this content
  179. Pingback: click here
  180. Pingback: Source
  181. Pingback: have a peek here
  182. Pingback: Check This Out
  183. Pingback: this contact form
  184. Pingback: navigate here
  185. Pingback: check over here
  186. Pingback: check my blog
  187. Pingback: his explanation
  188. Pingback: more info here
  189. Pingback: official site
  190. Pingback: visit
  191. Pingback: check it out
  192. Pingback: directory
  193. Pingback: see this here
  194. Pingback: feres inşaat
  195. Pingback: feres gayrimenkul
  196. Pingback: feres
  197. Pingback: feres
  198. Pingback: additional hints
  199. Pingback: Bonuses
  200. Pingback: a fantastic read
  201. Pingback: find more info
  202. Pingback: find more info
  203. Pingback: great post to read
  204. Pingback: useful reference
  205. Pingback: my review here
  206. Pingback: click site
  207. Pingback: check my blog
  208. Pingback: this content
  209. Pingback: read more
  210. Pingback: midogen
  211. Pingback: midogen review
  212. Pingback: read more
  213. Pingback: click here
  214. Pingback: niagen
  215. Pingback: click here
  216. Pingback: More Bonuses
  217. Pingback: check my source
  218. Pingback: Check This Out
  219. Pingback: additional reading
  220. Pingback: great post to read
  221. Pingback: advice
  222. Pingback: go now
  223. Pingback: Related Site
  224. Pingback: useful link
  225. Pingback: pop over here
  226. Pingback: Full Article
  227. Pingback: read more
  228. Pingback: click here
  229. Pingback: pop over here
  230. Pingback: Full Article
  231. Pingback: read more
  232. Pingback: click here
  233. Pingback: click here
  234. Pingback: pop over here
  235. Pingback: Full Article
  236. Pingback: read more
  237. Pingback: click here
  238. Pingback: pop over here
  239. Pingback: Full Article
  240. Pingback: read more
  241. Pingback: click here
  242. Pingback: my review here
  243. Pingback: news
  244. Pingback: this content
  245. Pingback: click here
  246. Pingback: check over here
  247. Pingback: check my blog
  248. Pingback: my company
  249. Pingback: imp source
  250. Pingback: this page
  251. Pingback: Get More Info
  252. Pingback: great post to read
  253. Pingback: useful reference
  254. Pingback: my review here
  255. Pingback: a fantastic read
  256. Pingback: directory
  257. Pingback: his explanation
  258. Pingback: browse this site
  259. Pingback: dig this
  260. Pingback: read this article
  261. Pingback: Bonuses
  262. Pingback: look at this site
  263. Pingback: More hints
  264. Pingback: page
  265. Pingback: her latest blog
  266. Pingback: additional hints
  267. Pingback: More Bonuses
  268. Pingback: Continued
  269. Pingback: check over here
  270. Pingback: this content
  271. Pingback: weblink
  272. Pingback: navigate here
  273. Pingback: navigate here
  274. Pingback: this contact form
  275. Pingback: have a peek here
  276. Pingback: Source
  277. Pingback: check my blog
  278. Pingback: great post to read
  279. Pingback: see here
  280. Pingback: useful reference
  281. Pingback: see here
  282. Pingback: useful reference
  283. Pingback: Get More Info
  284. Pingback: click site
  285. Pingback: click site
  286. Pingback: my review here

Comments are closed.