- Email: [email protected]
Potential therapeutic advantages of guanosine over inosine in multiple sclerosis
Correspondence / Medical Hypotheses 73 (2009) 623–631
ished at the first time of kidney transplant, although some Chinese surgeons have tried to use pedicled greater omentum graft repairing the complicated and intractable urinary fistulas after kidney transplantation and profited from it [9]. Since urinary fistula after kidney transplantation is an iatrogenic injury, so why do not we use pedicled greater omentum covering the anastomotic stoma directly at the first transplant operation before the occurrence of urinary fistula? Therefore, we suppose it may be a feasible approach to reduce the incidence of urinary fistula by using pedicled greater omentum routinely at the kidney transplant operation. The placed omentum graft may play a role in improving the blood supply of ureter, removing toxic substances, fighting infection and promoting repairing. Further more, it may simultaneously have a potential ability of preventing lymphocysts or lymphatic fistula after kidney transplantation.
References [1] Siamak Saifzadeh, Behzad Pourreza, Rahim Hobbenaghi, Bahram Dalir Naghadeh, Siamak Kazemi. Autogenous greater omentum, as a free nonvascularized graft, enhances bone healing: an experimental nonunion model. J Invest Surg 2009;2:129–37. [2] Singh Ashok K, Pancholi Nishit, Patel Jilpa, Litbarg Natalia O, Gudehithlu Krishnamurthy P, Sethupathi Perianna, Kraus Mark, Dunea George, Arruda Jose AL. Omentum facilitates liver regeneration. World J Gastroenterol 2009;15(9):1057–64. [3] Duffill J, Buckley J, Lang D, Neil-Dwyer G, McGinn F, Wade D. Prospective study of omental transposition in patients with chronic spinal injury. J Neurol Neurosurg Psychiatr 2001;71:73–80. [4] Battaglia M, Ditonno P, Selvaggio O, et al. Double J stent with antireflux device in the prevention of short-term urological complications after cadaveric kidney transplantation: single-center prospective randomized study. Transplant Proc. 2005;37(6):2525–6. [5] Kim Jang Yong, Kim Young-Wook, Kim Chel Joong, Lim Hye In, Kim Dong Ik, Huh Seung. Successful surgical treatment of aortoenteric fistula. J Kor Med Sci 2007;22:846–50. [6] Parnitvitidkun Shusit. Urological complications in gynecologic and obstetric operations at Surin Hospital. THAI J Surg 2006;27:149–52. [7] Gogus C, Yaman O, Soygur T, et al. Urological complications in renal transplantation. Long-term follow-up of the Woodruff ureteroneocystostomy procedure in 433 patients. Urol Int 2002;69:99. [8] Li Marzi V, Filocamo MT, Dattolo E, et al. The treatment of fistula and ureteral stenosis after kidney transplantation. Transplant Proc. 2005;37:2516–7. [9] Li Qiansheng, Jin Fengshuo, Zhu Fangqiang, et al. Pedicaled omentum grafts for the repair of complex urinary fistula after renal transplantation. Chin J Upol. 2007;28(9):632–4.
Wenqian Huo Qiansheng Li Zhilin Nie Keqin Zhang Fengshuo Jin Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China Tel.: +86 023 68757940 E-mail address: [email protected] doi:10.1016/j.mehy.2009.06.042
Potential therapeutic advantages of guanosine over inosine in multiple sclerosis In the recent and excellent article by McCarty et al. (2009) [9], the authors discussed research on the use of supplemental inosine
627
(INO) to elevate serum uric acid (UA) and thereby serve as an adjunctive treatment for multiple sclerosis (MS) or Parkinson’s disease [9,14]. The authors also discussed research pointing to therapeutic effects of INO that could occur independently of elevations in serum UA [9], and there is a reason to think that INO could produce some UA-independent effects in MS. Researchers have suggested that guanosine (GUO) may be useful for promoting remyelination in MS [4], however, and oral or parenteral GUO could produce stronger, UA-independent effects than INO and still confer the benefits associated with elevations in serum and cerebrospinal fluid (CSF) UA [9,14]. Oral inosine, given to humans as a single dose of 20 mg/kg (1400 mg), elevated the plasma and urinary hypoxanthine (HPX) and xanthine concentrations slightly but significantly and produced nonsignificant elevations in plasma INO [19], and the entry of HPX and INO into the brain could produce therapeutic effects in MS. The dosage used in MS (2–3 g/day, or 29–43 mg/kg) is roughly twice that dose [14] and could produce larger elevations of plasma HPX and INO. This is significant because intravenous HPX, given at a total dosage of 104 mg/kg (600 lmol/kg/h for 76 min), reduced markers of brain damage in response to ischemia and hypoxia in rabbits [11]. The mean, postischemic HPX concentration in the cerebral cortex was actually lower in rabbits that had been given HPX, and the authors suggested that the salvage of HPX into INO and adenosine, in the brain, could account for that apparent paradox [11]. The intraperitoneal (i.p.) administration of GUO, at remarkably low dosages, can reduce extracellular glutamate concentrations in the brain [12,18] and improve the outcomes or recoveries of rats given experimental spinal cord injuries (SCIs) or brain injuries [1,4–6,16]. Even 5 weeks after a SCI, GUO induced remyelination and increased the numbers of mature oligodendrocytes and oligodendrocyte progenitor cells around the sites of SCIs in rats [4]. Either oral or i.p. GUO can also exert anticonvulsant effects in rats, largely by stimulating the astrocytic uptake of extracellular glutamate [12,13,18], and an increase in glutamate uptake by oligodendrocytes might reduce disease activity in MS [15]. Doses of 8 mg/ kg i.p. GUO have been therapeutic in rats given SCIs or brain injuries [1,4,5,16], but researchers have generally used i.p. INO at much higher dosages, such as 100–400 [3] or 225 mg/kg [8], to protect against acute ischemic brain injuries or SCIs [3,8]. The therapeutic effects of low doses of GUO would be advantageous in humans, given that oral purines could produce hyperuricemia, in humans, at doses higher than 2–3 g/day [14]. Oral GUO is viewed as being more absorbable than other purines, in humans [2], and appears to be reasonably bioavailable in rats [18]. Either oral or i.p. GUO has produced elevations in the concentrations of GUO in the CSF [13,18] or spinal tissue [4] of rats. The high solubility of GUO 50 -monophosphate (GMP) disodium in water [10], in comparison to that of free GUO [10,18], would help to maximize its oral bioavailability. The maximal bioavailability of jejunally-administered ATP in rats, as implied by the peak concentration of adenosine in the hepatic portal blood, emerges only after chronic dosing [7], and the bioavailability of GUO may also only become maximal after multiple dosages. The feedback inhibition of xanthine oxidoreductase activity by UA should also become more pronounced as serum UA concentrations increase [17], and this effect could, by reducing the presystemic metabolism of GUO to UA, gradually increase the bioavailability of GUO. Researchers could compare, in relation to controls, the effects of oral or parenteral GMP disodium, a highly-soluble salt of GMP, with the effects of an equimolar dose of oral or parenteral INO 50 -monophosphate disodium on the progression of MS and see if the expected therapeutic effects correlate with serum or CSF UA levels.
628
Correspondence / Medical Hypotheses 73 (2009) 623–631
References [1] Chang R, Algird A, Bau C, Rathbone MP, Jiang S. Neuroprotective effects of guanosine on stroke models in vitro and in vivo. Neurosci Lett 2008;431(2):101–5. [2] Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363(9417):1277–81. [3] Hsiao G, Lin KH, Chang Y, et al. Protective mechanisms of inosine in platelet activation and cerebral ischemic damage. Arterioscler Thromb Vasc Biol 2005;25(9):1998–2004. [4] Jiang S, Ballerini P, Buccella S, et al. Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine. Purinergic Signal 2008;4(1):61–71. [5] Jiang S, Bendjelloul F, Ballerini P, et al. Guanosine reduces apoptosis and inflammation associated with restoration of function in rats with acute spinal cord injury. Purinergic Signal 2007;3(4):411–21. [6] Jiang S, Khan MI, Lu Y, et al. Guanosine promotes myelination and functional recovery in chronic spinal injury. Neuroreport 2003;14(18):2463–7. [7] Kichenin K, Seman M. Chronic oral administration of ATP modulates nucleoside transport and purine metabolism in rats. J Pharmacol Exp Ther 2000;294(1):126–33. [8] Liu F, You SW, Yao LP, et al. Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 2006;44(7):421–6. [9] McCarty MF et al. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals – clinical potential in inflammatory disorders. Med Hypotheses 2009. doi:10.1016/j.mehy.2008.09.058. [10] The Merck Index. 12th ed. Whitehouse Station, NJ: Merck & Co., Inc.; 1997. [11] Mink R, Johnston J. The effect of infusing hypoxanthine or xanthine on hypoxic-ischemic brain injury in rabbits. Brain Res 2007;1147:256–64. [12] Schmidt AP, Lara DR, Souza DO. Proposal of a guanine-based purinergic system in the mammalian central nervous system. Pharmacol Ther 2007;116(3): 401–16. [13] Soares FA, Schmidt AP, Farina M, et al. Anticonvulsant effect of GMP depends on its conversion to guanosine. Brain Res 2004;1005(1–2):182–6. [14] Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 2001;7(5):313–9. [15] Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 2005;128(Pt 5):1016–25. [16] Su C, Elfeki N, Ballerini P, et al. Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. J Neurosci Res 2009;87(3):617–25. [17] Tan S, Radi R, Gaudier F, et al. Physiologic levels of uric acid inhibit xanthine oxidase in human plasma. Pediatr Res 1993;34(3):303–7. [18] Vinadé ER, Schmidt AP, Frizzo MES, et al. Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats. J Neurosci Res 2005;79(1–2):248–53. [19] Yamamoto T, Moriwaki Y, Cheng J, et al. Effect of inosine on the plasma concentration of uridine and purine bases. Metabolism 2002;51(4):438–42.
Erik A. Hanson The University of Minnesota, 20 Classroom Office Building, 1994 Buford Ave., St. Paul, MN 55108, United States Tel.: +1 952 922 6661 E-mail address: [email protected] doi:10.1016/j.mehy.2009.06.005
Angiotensin-converting enzyme inhibitors: Do they contribute to delayed chemotherapy induced nausea and vomiting? It is not known whether there is a relationship between angiotensin-converting enzyme inhibitors (ACE-Is) and chemotherapy induced nausea and vomiting (CINV) since it has not been reported until now. Cancer patients may have other diseases in which ACEIs have to be used, such as hypertension or others. These patients may suffer from more CINV, when they are given chemotherapy.
But, we do not know the rate of CINV, especially delayed CINV, in this group. It may be easily missed out in daily practice since we are usually focused on cancer related major problems. ACE-Is inhibit angiotensin-converting enzyme (ACE). It is a well-known process that ACE is a zinc-metalloprotease which has a role in convertion of angiotensin I to angiotensin II and degradation of some neuropeptides, such as substance P, dynorphin and neurotensin [1,2]. ACE-Is are widely used in hypertension, atherosclerotic coronary diseases, congestive hearth diseases and diabetic nephropathy. They reduce cardiac mortality and morbidity in coronary diseases. They are also antiproteinuric agents. ACE plasma concentration is affected by ACE insertion/deletion (I/D) polymorphism [3]. The activity of D allele of ACE seems to be higher than I allele [4]. There may be an association between ACE I/ D polymorphism and risk of cardiovascular diseases [5]. It was also reported that ACE (I/D) polymorphism might have affected substance P levels [6]. Substance P is a vasoactive neurotransmitter which binds to neurokinin receptors [6,7]. Substance P related genes are NKNA (7q21–q22), NK1R (2pter–2qter), peptidylglycine alpha-amidating monooxygenase (PAM) (5q14–5q21) and ACE (17q23). Substance P is activated by PAM, and active form binds to neurokinin-1 receptor (NK1R) [8]. Substance P has a role in pain onset. Fusayasu et al. have presented a relation between substance P level and ACE activity in patients who have migraine (p < 0.01) [9]. Substance P may also be associated with affect disorders [2,6]. It has been reported that ACE-Is might have contributed to complex regional pain syndrome by inhibiting degradation of some mediators which have role in pain onset, like bradykinin and substance P [10]. We consider that ACE-Is may also contribute to cancer pain by inhibiting degradation of substance P. Substance P is an emetogenic neurotransmitter [11]. The nuclei in the brainstem, such as area postrema and nucleus tractus solitarius, have role in nausea and vomiting. Enterochromaffin cells of the gastrointestinal tract release 5-hydroxy-typtamine-3 (5HT3) and substance P in response to emetogenic agents, such as highly or moderately emetogenic chemotherapeutics. These mediators are transmitted to NK-1, 5HT-3 and 5HT-4 receptors at the vomiting center including area postrema which lacks blood-brain barrier, nucleus tractus solitarius and dorsal motor nucleus of vagus nerve and, finally vomiting occurs [7]. Chemotherapy induced nausea and vomiting (CINV) is a toxicity that upsets quality of life. Delayed CINV occurs after the first 24 h of chemotherapy, especially with highly emetogenic chemotherapeutic agents, such as cisplatin, mechlorethamine, streptozotosin, cyclophosphamide (>1500 mg/m2), carmustine and dacarbazine [12,13]. It is known that delayed CINV peaks between 24 and 72 h after receiving chemotherapeutics like cisplatin, and decreases on the following days [13]. NK1R antagonists are effective in acute and delayed CINV, whereas 5HT-3 antagonists prevent generally acute emesis [7]. Dexamethasone potentiates antiemetic effect 5HT-3 receptor antagonists [14]. NK1R antagonists, such as aprepitant and cosapitant mesylate, in combination with dexamethasone and 5HT3 receptor antagonists seem to be more effective in controlling delayed CINV after highly emetogenic chemotherapy [15]. ACE substrates seem to have importance in modulation of dopaminergic mechanisms [2]. We know that dopaminergic activity also has role in emesis. Metoclopropamide is a dopamine antagonist which is effective in both acute and delayed CINV. In conclusion, many cancer patients who are using ACE-Is for comorbid diseases, such as hypertension or coronary hearth diseases other than cancer, may need highly or moderately chemotherapeutics for treatment of primary cancer. We believe that these patients might have higher risk of CINV, especially delayed CINV.
ished at the first time of kidney transplant, although some Chinese surgeons have tried to use pedicled greater omentum graft repairing the complicated and intractable urinary fistulas after kidney transplantation and profited from it [9]. Since urinary fistula after kidney transplantation is an iatrogenic injury, so why do not we use pedicled greater omentum covering the anastomotic stoma directly at the first transplant operation before the occurrence of urinary fistula? Therefore, we suppose it may be a feasible approach to reduce the incidence of urinary fistula by using pedicled greater omentum routinely at the kidney transplant operation. The placed omentum graft may play a role in improving the blood supply of ureter, removing toxic substances, fighting infection and promoting repairing. Further more, it may simultaneously have a potential ability of preventing lymphocysts or lymphatic fistula after kidney transplantation.
References [1] Siamak Saifzadeh, Behzad Pourreza, Rahim Hobbenaghi, Bahram Dalir Naghadeh, Siamak Kazemi. Autogenous greater omentum, as a free nonvascularized graft, enhances bone healing: an experimental nonunion model. J Invest Surg 2009;2:129–37. [2] Singh Ashok K, Pancholi Nishit, Patel Jilpa, Litbarg Natalia O, Gudehithlu Krishnamurthy P, Sethupathi Perianna, Kraus Mark, Dunea George, Arruda Jose AL. Omentum facilitates liver regeneration. World J Gastroenterol 2009;15(9):1057–64. [3] Duffill J, Buckley J, Lang D, Neil-Dwyer G, McGinn F, Wade D. Prospective study of omental transposition in patients with chronic spinal injury. J Neurol Neurosurg Psychiatr 2001;71:73–80. [4] Battaglia M, Ditonno P, Selvaggio O, et al. Double J stent with antireflux device in the prevention of short-term urological complications after cadaveric kidney transplantation: single-center prospective randomized study. Transplant Proc. 2005;37(6):2525–6. [5] Kim Jang Yong, Kim Young-Wook, Kim Chel Joong, Lim Hye In, Kim Dong Ik, Huh Seung. Successful surgical treatment of aortoenteric fistula. J Kor Med Sci 2007;22:846–50. [6] Parnitvitidkun Shusit. Urological complications in gynecologic and obstetric operations at Surin Hospital. THAI J Surg 2006;27:149–52. [7] Gogus C, Yaman O, Soygur T, et al. Urological complications in renal transplantation. Long-term follow-up of the Woodruff ureteroneocystostomy procedure in 433 patients. Urol Int 2002;69:99. [8] Li Marzi V, Filocamo MT, Dattolo E, et al. The treatment of fistula and ureteral stenosis after kidney transplantation. Transplant Proc. 2005;37:2516–7. [9] Li Qiansheng, Jin Fengshuo, Zhu Fangqiang, et al. Pedicaled omentum grafts for the repair of complex urinary fistula after renal transplantation. Chin J Upol. 2007;28(9):632–4.
Wenqian Huo Qiansheng Li Zhilin Nie Keqin Zhang Fengshuo Jin Department of Urology, Institute of Surgery Research, Daping Hospital, Third Military Medical University, Chongqing 400042, China Tel.: +86 023 68757940 E-mail address: [email protected] doi:10.1016/j.mehy.2009.06.042
Potential therapeutic advantages of guanosine over inosine in multiple sclerosis In the recent and excellent article by McCarty et al. (2009) [9], the authors discussed research on the use of supplemental inosine
627
(INO) to elevate serum uric acid (UA) and thereby serve as an adjunctive treatment for multiple sclerosis (MS) or Parkinson’s disease [9,14]. The authors also discussed research pointing to therapeutic effects of INO that could occur independently of elevations in serum UA [9], and there is a reason to think that INO could produce some UA-independent effects in MS. Researchers have suggested that guanosine (GUO) may be useful for promoting remyelination in MS [4], however, and oral or parenteral GUO could produce stronger, UA-independent effects than INO and still confer the benefits associated with elevations in serum and cerebrospinal fluid (CSF) UA [9,14]. Oral inosine, given to humans as a single dose of 20 mg/kg (1400 mg), elevated the plasma and urinary hypoxanthine (HPX) and xanthine concentrations slightly but significantly and produced nonsignificant elevations in plasma INO [19], and the entry of HPX and INO into the brain could produce therapeutic effects in MS. The dosage used in MS (2–3 g/day, or 29–43 mg/kg) is roughly twice that dose [14] and could produce larger elevations of plasma HPX and INO. This is significant because intravenous HPX, given at a total dosage of 104 mg/kg (600 lmol/kg/h for 76 min), reduced markers of brain damage in response to ischemia and hypoxia in rabbits [11]. The mean, postischemic HPX concentration in the cerebral cortex was actually lower in rabbits that had been given HPX, and the authors suggested that the salvage of HPX into INO and adenosine, in the brain, could account for that apparent paradox [11]. The intraperitoneal (i.p.) administration of GUO, at remarkably low dosages, can reduce extracellular glutamate concentrations in the brain [12,18] and improve the outcomes or recoveries of rats given experimental spinal cord injuries (SCIs) or brain injuries [1,4–6,16]. Even 5 weeks after a SCI, GUO induced remyelination and increased the numbers of mature oligodendrocytes and oligodendrocyte progenitor cells around the sites of SCIs in rats [4]. Either oral or i.p. GUO can also exert anticonvulsant effects in rats, largely by stimulating the astrocytic uptake of extracellular glutamate [12,13,18], and an increase in glutamate uptake by oligodendrocytes might reduce disease activity in MS [15]. Doses of 8 mg/ kg i.p. GUO have been therapeutic in rats given SCIs or brain injuries [1,4,5,16], but researchers have generally used i.p. INO at much higher dosages, such as 100–400 [3] or 225 mg/kg [8], to protect against acute ischemic brain injuries or SCIs [3,8]. The therapeutic effects of low doses of GUO would be advantageous in humans, given that oral purines could produce hyperuricemia, in humans, at doses higher than 2–3 g/day [14]. Oral GUO is viewed as being more absorbable than other purines, in humans [2], and appears to be reasonably bioavailable in rats [18]. Either oral or i.p. GUO has produced elevations in the concentrations of GUO in the CSF [13,18] or spinal tissue [4] of rats. The high solubility of GUO 50 -monophosphate (GMP) disodium in water [10], in comparison to that of free GUO [10,18], would help to maximize its oral bioavailability. The maximal bioavailability of jejunally-administered ATP in rats, as implied by the peak concentration of adenosine in the hepatic portal blood, emerges only after chronic dosing [7], and the bioavailability of GUO may also only become maximal after multiple dosages. The feedback inhibition of xanthine oxidoreductase activity by UA should also become more pronounced as serum UA concentrations increase [17], and this effect could, by reducing the presystemic metabolism of GUO to UA, gradually increase the bioavailability of GUO. Researchers could compare, in relation to controls, the effects of oral or parenteral GMP disodium, a highly-soluble salt of GMP, with the effects of an equimolar dose of oral or parenteral INO 50 -monophosphate disodium on the progression of MS and see if the expected therapeutic effects correlate with serum or CSF UA levels.
628
Correspondence / Medical Hypotheses 73 (2009) 623–631
References [1] Chang R, Algird A, Bau C, Rathbone MP, Jiang S. Neuroprotective effects of guanosine on stroke models in vitro and in vivo. Neurosci Lett 2008;431(2):101–5. [2] Choi HK, Atkinson K, Karlson EW, Willett W, Curhan G. Alcohol intake and risk of incident gout in men: a prospective study. Lancet 2004;363(9417):1277–81. [3] Hsiao G, Lin KH, Chang Y, et al. Protective mechanisms of inosine in platelet activation and cerebral ischemic damage. Arterioscler Thromb Vasc Biol 2005;25(9):1998–2004. [4] Jiang S, Ballerini P, Buccella S, et al. Remyelination after chronic spinal cord injury is associated with proliferation of endogenous adult progenitor cells after systemic administration of guanosine. Purinergic Signal 2008;4(1):61–71. [5] Jiang S, Bendjelloul F, Ballerini P, et al. Guanosine reduces apoptosis and inflammation associated with restoration of function in rats with acute spinal cord injury. Purinergic Signal 2007;3(4):411–21. [6] Jiang S, Khan MI, Lu Y, et al. Guanosine promotes myelination and functional recovery in chronic spinal injury. Neuroreport 2003;14(18):2463–7. [7] Kichenin K, Seman M. Chronic oral administration of ATP modulates nucleoside transport and purine metabolism in rats. J Pharmacol Exp Ther 2000;294(1):126–33. [8] Liu F, You SW, Yao LP, et al. Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 2006;44(7):421–6. [9] McCarty MF et al. High-dose folate and dietary purines promote scavenging of peroxynitrite-derived radicals – clinical potential in inflammatory disorders. Med Hypotheses 2009. doi:10.1016/j.mehy.2008.09.058. [10] The Merck Index. 12th ed. Whitehouse Station, NJ: Merck & Co., Inc.; 1997. [11] Mink R, Johnston J. The effect of infusing hypoxanthine or xanthine on hypoxic-ischemic brain injury in rabbits. Brain Res 2007;1147:256–64. [12] Schmidt AP, Lara DR, Souza DO. Proposal of a guanine-based purinergic system in the mammalian central nervous system. Pharmacol Ther 2007;116(3): 401–16. [13] Soares FA, Schmidt AP, Farina M, et al. Anticonvulsant effect of GMP depends on its conversion to guanosine. Brain Res 2004;1005(1–2):182–6. [14] Spitsin S, Hooper DC, Leist T, Streletz LJ, Mikheeva T, Koprowskil H. Inactivation of peroxynitrite in multiple sclerosis patients after oral administration of inosine may suggest possible approaches to therapy of the disease. Mult Scler 2001;7(5):313–9. [15] Srinivasan R, Sailasuta N, Hurd R, Nelson S, Pelletier D. Evidence of elevated glutamate in multiple sclerosis using magnetic resonance spectroscopy at 3 T. Brain 2005;128(Pt 5):1016–25. [16] Su C, Elfeki N, Ballerini P, et al. Guanosine improves motor behavior, reduces apoptosis, and stimulates neurogenesis in rats with parkinsonism. J Neurosci Res 2009;87(3):617–25. [17] Tan S, Radi R, Gaudier F, et al. Physiologic levels of uric acid inhibit xanthine oxidase in human plasma. Pediatr Res 1993;34(3):303–7. [18] Vinadé ER, Schmidt AP, Frizzo MES, et al. Effects of chronic administered guanosine on behavioral parameters and brain glutamate uptake in rats. J Neurosci Res 2005;79(1–2):248–53. [19] Yamamoto T, Moriwaki Y, Cheng J, et al. Effect of inosine on the plasma concentration of uridine and purine bases. Metabolism 2002;51(4):438–42.
Erik A. Hanson The University of Minnesota, 20 Classroom Office Building, 1994 Buford Ave., St. Paul, MN 55108, United States Tel.: +1 952 922 6661 E-mail address: [email protected] doi:10.1016/j.mehy.2009.06.005
Angiotensin-converting enzyme inhibitors: Do they contribute to delayed chemotherapy induced nausea and vomiting? It is not known whether there is a relationship between angiotensin-converting enzyme inhibitors (ACE-Is) and chemotherapy induced nausea and vomiting (CINV) since it has not been reported until now. Cancer patients may have other diseases in which ACEIs have to be used, such as hypertension or others. These patients may suffer from more CINV, when they are given chemotherapy.
But, we do not know the rate of CINV, especially delayed CINV, in this group. It may be easily missed out in daily practice since we are usually focused on cancer related major problems. ACE-Is inhibit angiotensin-converting enzyme (ACE). It is a well-known process that ACE is a zinc-metalloprotease which has a role in convertion of angiotensin I to angiotensin II and degradation of some neuropeptides, such as substance P, dynorphin and neurotensin [1,2]. ACE-Is are widely used in hypertension, atherosclerotic coronary diseases, congestive hearth diseases and diabetic nephropathy. They reduce cardiac mortality and morbidity in coronary diseases. They are also antiproteinuric agents. ACE plasma concentration is affected by ACE insertion/deletion (I/D) polymorphism [3]. The activity of D allele of ACE seems to be higher than I allele [4]. There may be an association between ACE I/ D polymorphism and risk of cardiovascular diseases [5]. It was also reported that ACE (I/D) polymorphism might have affected substance P levels [6]. Substance P is a vasoactive neurotransmitter which binds to neurokinin receptors [6,7]. Substance P related genes are NKNA (7q21–q22), NK1R (2pter–2qter), peptidylglycine alpha-amidating monooxygenase (PAM) (5q14–5q21) and ACE (17q23). Substance P is activated by PAM, and active form binds to neurokinin-1 receptor (NK1R) [8]. Substance P has a role in pain onset. Fusayasu et al. have presented a relation between substance P level and ACE activity in patients who have migraine (p < 0.01) [9]. Substance P may also be associated with affect disorders [2,6]. It has been reported that ACE-Is might have contributed to complex regional pain syndrome by inhibiting degradation of some mediators which have role in pain onset, like bradykinin and substance P [10]. We consider that ACE-Is may also contribute to cancer pain by inhibiting degradation of substance P. Substance P is an emetogenic neurotransmitter [11]. The nuclei in the brainstem, such as area postrema and nucleus tractus solitarius, have role in nausea and vomiting. Enterochromaffin cells of the gastrointestinal tract release 5-hydroxy-typtamine-3 (5HT3) and substance P in response to emetogenic agents, such as highly or moderately emetogenic chemotherapeutics. These mediators are transmitted to NK-1, 5HT-3 and 5HT-4 receptors at the vomiting center including area postrema which lacks blood-brain barrier, nucleus tractus solitarius and dorsal motor nucleus of vagus nerve and, finally vomiting occurs [7]. Chemotherapy induced nausea and vomiting (CINV) is a toxicity that upsets quality of life. Delayed CINV occurs after the first 24 h of chemotherapy, especially with highly emetogenic chemotherapeutic agents, such as cisplatin, mechlorethamine, streptozotosin, cyclophosphamide (>1500 mg/m2), carmustine and dacarbazine [12,13]. It is known that delayed CINV peaks between 24 and 72 h after receiving chemotherapeutics like cisplatin, and decreases on the following days [13]. NK1R antagonists are effective in acute and delayed CINV, whereas 5HT-3 antagonists prevent generally acute emesis [7]. Dexamethasone potentiates antiemetic effect 5HT-3 receptor antagonists [14]. NK1R antagonists, such as aprepitant and cosapitant mesylate, in combination with dexamethasone and 5HT3 receptor antagonists seem to be more effective in controlling delayed CINV after highly emetogenic chemotherapy [15]. ACE substrates seem to have importance in modulation of dopaminergic mechanisms [2]. We know that dopaminergic activity also has role in emesis. Metoclopropamide is a dopamine antagonist which is effective in both acute and delayed CINV. In conclusion, many cancer patients who are using ACE-Is for comorbid diseases, such as hypertension or coronary hearth diseases other than cancer, may need highly or moderately chemotherapeutics for treatment of primary cancer. We believe that these patients might have higher risk of CINV, especially delayed CINV.