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Suberythemal ultraviolet exposure and reduction in blood pressure
UV Light and Blood Pressure
José Luis Hernández, MD, PhD Marcos Pajarón, MD Oscar García-Regata, MD, Virginia Jiménez, MD, Jesús González-Macías, MD, PhD Hospital Marqués de Valdecilla University of Cantabria Santander, Spain Ciro Ramos-Estébanez Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts 1. Pollack MJ. Intractable hiccups: a serious sign of underlying systemic disease. J Clin Gastroenterol. 2003;37:272–273. 2. Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, crossover study. Am J Gastroenterol. 1992;87:1789– 1791. 3. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57:451– 462. 4. Porzio G, Aielli F, Narducci F, et al. Hiccup in patients with advanced cancer successfully treated with gabapentin: report of three cases. N Z Med J 2003;116:605– 607. 5. Petroianu G, Hein G, Stegmeier-Petroianu A, et al. Gabapentin “add-on therapy” for idiopathic chronic hiccup (ICH). J Clin Gastroenterol. 2000;30:321–324. 6. van Hooft JA, Dougherty JJ, Endeman D, et al. Gabapentin inhibits presynaptic Ca(2⫹) influx and synaptic transmission in rat hippocampus and neocortex. Eur J Pharmacol. 2002;449:221–228.
SUBERYTHEMAL ULTRAVIOLET EXPOSURE AND REDUCTION IN BLOOD PRESSURE To the Editor: Increased levels of blood pressure vary with latitude; toward the equator there is less hypertension (1). Krause et al attributed this effect to higher vitamin D levels found in sunnier climates (2). This report examines potential alternative roles of ultraviolet (UV) exposure and whether a single exposure can achieve a reduction in blood pressure. Nineteen white and black nor-
Figure. Statistically significant but modest decreases in systolic blood pressure were observed following exposure to infrared lamps at 3 and 5 minutes after exposure (*P ⬍0.01). Following ultraviolet exposure, all volunteers showed a highly significant decrease in systolic blood pressure (†P ⬍0.003). Bars indicate mean, error bars indicate SEM.
motensive and hypertensive (treated and untreated) volunteers were selected. The U.S. Food and Drug Administration has adopted categorizing different races and complexions into six skin types based upon ease of sunburn and propensity to develop pigmentation. Skin types I and II are the fairest and are at the greatest risk for sunlight-induced injury, whereas skin types V and VI are the darkest and have little risk for sunlight-induced injury. Selected volunteers ranged over the entire set of skin types based upon their inherent propensity to sunburn and tan. Two sources of exposure were used: two 250-watt infrared, reflectorized incandescenttype lamps; and a UV-A/UV-B phototherapy cabinet. The protocol required a baseline blood pressure measurement followed by an infrared exposure of 8 minutes and 20 seconds that was immediately followed by blood pressure measurements at 0, 3, and 5 minutes. Following this, volunteers reentered the UV-A/UV-B cabinet to receive an exposure of a mixture of UV-B and UV-A radiation. Fair-skinned, white Month 2004
volunteers of skin types I and II received a 7.8 J/cm2 exposure involving only the UV-A lamps, or 1.5 standard erythema doses, an erythemic effective exposure of 10 mJ/cm2. It is approximately 1/2 of a minimal erythemal dose of a fair-skinned person. Skin types III and IV received the same 7.8 J/cm2 dose from the UV-A lamps plus an additional 0.02 J/cm2 dose from the UV-B lamps, or 2.25 standard erythema doses. For volunteers with skin types V and VI, the same 7.8 J/cm2 dose was administered from the UV-A lamps, and a 0.04 J/cm2 dose of UV-B radiation was administered, for a total of three standard erythema doses. Thus, the UV dose maintained constant UV-A dosage and varied the amount of erythemic UV-B dosage with the UV-B lamps. The UV doses administered were approximately equivalent to a 12- to 24-minute exposure of sunlight. The protocol was approved and monitored by our institutional review board. The Figure summarizes the study results. We did not observe any differences based on the sex, race, or
THE AMERICAN JOURNAL OF MEDICINE威
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Letters to the Editor
blood pressure status of individual volunteers. We did observe a moderate drop in blood pressure following exposure to the infrared lamps at 3 and 5 minutes. Because blood pressure measurements were made only for a 5-minute period following infrared exposure, we cannot state how long that reduction would have lasted. The reduction following UV exposure was significantly greater (P ⬍0.003) and appeared to last considerably longer. One hour after exposure, systolic blood pressure was increasing, but it was still lower than the initial recording. At this time, we cannot state how long this reduction in systolic blood pressure would last. A statistically significant reduction (P ⬍0.05) in diastolic blood pressure was seen only at 15 and 30 minutes following UV exposure. Krause et al reported substantial reductions in both systolic and diastolic blood pressures following a series of UV-B exposures using a lamp that may have been spectrally similar to our UV-A source (2). A light-induced nitric oxide–mediated phenomenon termed photorelaxation occurs in vascular and other smooth muscle (3,4). A comparable mechanism seems likely to account for the reduction in blood pressure in newborns under phototherapy (5) and in this preliminary study. Photorelaxation is a response primarily to UV-A radiation and raises the possibility of achieving therapeutic effects from currently available phototherapy devices and even from indoor tanning units. Karl T. Weber, MD E. William Rosenberg, MD University of Tennessee Health Sciences Center Memphis, Tennessee Robert M. Sayre, PhD University of Tennessee Health Sciences Center Memphis, Tennessee Rapid Precision Testing Laboratories Cordova, Tennessee 282
August 15, 2004
1. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30:150–156. 2. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352:709 –710. 3. Flitney FW, Megson IL. Nitric oxide and the mechanism of rat vascular smooth muscle photorelaxation. J Physiol. 2003;550:819–828. 4. Buyukafsar K, Levent A, Un I, Ark M, Arikan O, Ozveren E. Mediation of nitric oxide from photosensitive stores in the photorelaxation of the rabbit corpus cavernosum. Eur J Pharmacol. 2003;459:263–267. 5. Ergenekon E, Gücüyener K, Dursun H, et al. Nitric oxide production in newborns under phototherapy. Nitric Oxide. 2002;6:69 –72.
TENOFOVIR-ASSOCIATED NEPHROTOXICITY: FANCONI SYNDROME AND RENAL FAILURE To the Editor: Therapy for human immunodeficiency virus (HIV)– and acquired immunodeficiency syndrome (AIDS)–related illnesses has been revolutionized by newer generations of antiretroviral medications. The potential side effects of these medications are usually not fully recognized until widespread clinical use is initiated. Tenofovir was approved for use by the Food and Drug Administration in 2001 for the treatment of HIV. Despite the absence of renal toxicity observed in the major clinical trials of tenofovir, several case reports suggest that nephrotoxicity, although uncommon and reversible, is present. In December 2002, Coca and Perazella (1) described acute renal failure in a patient with baseline chronic kidney disease treated with tenofovir disoproxil fumarate. We now describe a case series of our ongoing experience with tenofovir-related renal disease (Table 1). Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir inhibits the activity of HIV reverse transcriptase by competing
THE AMERICAN JOURNAL OF MEDICINE威
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with deoxyadenosine 5=-triple phosphate and terminating DNA chain formation. Tenofovir belongs to the family of nucleotide reverse transcriptase inhibitors that includes cidofovir and adefovir. Both cidofovir and adefovir have well documented renal toxicities, including proximal renal dysfunction and acute renal failure (2,3). Similar effects were not expected with tenofovir due to decreased interaction with human organic transporter 1 and minimal mitochondrial DNA toxicity in vitro (3,4). However, as clinical experience with tenofovir has grown, so has the appearance of case reports documenting nephrotoxicity. Tenofovir is primarily excreted by the kidneys. Elimination is accomplished by glomerular filtration as well as by active tubular secretion. There are several medications that compete for renal tubular secretion, including acyclovir, cidofovir, ganciclovir, valcyclovir, and valganciclovir. Coadministration may lead to increased serum levels of tenofovir. Nephrotoxicity in animal models was related to dose as well as to duration of therapy. Additionally, tenofovir inhibits CYP1A2, and drug levels may be increased when given with other antiretroviral medication. Most notably lopinavir/ritonavir (as seen in patient 5), didanosine (as seen in patient 4), and indinavir may increase serum concentrations of tenofovir from 3% to 53% (5). A number of different manifestations of kidney disease have been described with tenofovir, including Fanconi syndrome, diabetes insipidus, and acute renal failure (6). In all five cases reported there was evidence of tubulopathy. Proximal tubular damage manifested as glucosuria, acidosis (proximal tubular bicarbonate wasting), low-grade proteinuria, hypokalemia, and hypophosphatemia. Additionally, renal tubular epithelial cells and casts were observed in all 5 patients’ urinary sediments. Finally, similar to Karras et al (6), our series of patients had normal renal function, without ev-
José Luis Hernández, MD, PhD Marcos Pajarón, MD Oscar García-Regata, MD, Virginia Jiménez, MD, Jesús González-Macías, MD, PhD Hospital Marqués de Valdecilla University of Cantabria Santander, Spain Ciro Ramos-Estébanez Department of Neurology Beth Israel Deaconess Medical Center Boston, Massachusetts 1. Pollack MJ. Intractable hiccups: a serious sign of underlying systemic disease. J Clin Gastroenterol. 2003;37:272–273. 2. Ramirez FC, Graham DY. Treatment of intractable hiccup with baclofen: results of a double-blind randomized, controlled, crossover study. Am J Gastroenterol. 1992;87:1789– 1791. 3. Rose MA, Kam PC. Gabapentin: pharmacology and its use in pain management. Anaesthesia. 2002;57:451– 462. 4. Porzio G, Aielli F, Narducci F, et al. Hiccup in patients with advanced cancer successfully treated with gabapentin: report of three cases. N Z Med J 2003;116:605– 607. 5. Petroianu G, Hein G, Stegmeier-Petroianu A, et al. Gabapentin “add-on therapy” for idiopathic chronic hiccup (ICH). J Clin Gastroenterol. 2000;30:321–324. 6. van Hooft JA, Dougherty JJ, Endeman D, et al. Gabapentin inhibits presynaptic Ca(2⫹) influx and synaptic transmission in rat hippocampus and neocortex. Eur J Pharmacol. 2002;449:221–228.
SUBERYTHEMAL ULTRAVIOLET EXPOSURE AND REDUCTION IN BLOOD PRESSURE To the Editor: Increased levels of blood pressure vary with latitude; toward the equator there is less hypertension (1). Krause et al attributed this effect to higher vitamin D levels found in sunnier climates (2). This report examines potential alternative roles of ultraviolet (UV) exposure and whether a single exposure can achieve a reduction in blood pressure. Nineteen white and black nor-
Figure. Statistically significant but modest decreases in systolic blood pressure were observed following exposure to infrared lamps at 3 and 5 minutes after exposure (*P ⬍0.01). Following ultraviolet exposure, all volunteers showed a highly significant decrease in systolic blood pressure (†P ⬍0.003). Bars indicate mean, error bars indicate SEM.
motensive and hypertensive (treated and untreated) volunteers were selected. The U.S. Food and Drug Administration has adopted categorizing different races and complexions into six skin types based upon ease of sunburn and propensity to develop pigmentation. Skin types I and II are the fairest and are at the greatest risk for sunlight-induced injury, whereas skin types V and VI are the darkest and have little risk for sunlight-induced injury. Selected volunteers ranged over the entire set of skin types based upon their inherent propensity to sunburn and tan. Two sources of exposure were used: two 250-watt infrared, reflectorized incandescenttype lamps; and a UV-A/UV-B phototherapy cabinet. The protocol required a baseline blood pressure measurement followed by an infrared exposure of 8 minutes and 20 seconds that was immediately followed by blood pressure measurements at 0, 3, and 5 minutes. Following this, volunteers reentered the UV-A/UV-B cabinet to receive an exposure of a mixture of UV-B and UV-A radiation. Fair-skinned, white Month 2004
volunteers of skin types I and II received a 7.8 J/cm2 exposure involving only the UV-A lamps, or 1.5 standard erythema doses, an erythemic effective exposure of 10 mJ/cm2. It is approximately 1/2 of a minimal erythemal dose of a fair-skinned person. Skin types III and IV received the same 7.8 J/cm2 dose from the UV-A lamps plus an additional 0.02 J/cm2 dose from the UV-B lamps, or 2.25 standard erythema doses. For volunteers with skin types V and VI, the same 7.8 J/cm2 dose was administered from the UV-A lamps, and a 0.04 J/cm2 dose of UV-B radiation was administered, for a total of three standard erythema doses. Thus, the UV dose maintained constant UV-A dosage and varied the amount of erythemic UV-B dosage with the UV-B lamps. The UV doses administered were approximately equivalent to a 12- to 24-minute exposure of sunlight. The protocol was approved and monitored by our institutional review board. The Figure summarizes the study results. We did not observe any differences based on the sex, race, or
THE AMERICAN JOURNAL OF MEDICINE威
Volume 117 281
Letters to the Editor
blood pressure status of individual volunteers. We did observe a moderate drop in blood pressure following exposure to the infrared lamps at 3 and 5 minutes. Because blood pressure measurements were made only for a 5-minute period following infrared exposure, we cannot state how long that reduction would have lasted. The reduction following UV exposure was significantly greater (P ⬍0.003) and appeared to last considerably longer. One hour after exposure, systolic blood pressure was increasing, but it was still lower than the initial recording. At this time, we cannot state how long this reduction in systolic blood pressure would last. A statistically significant reduction (P ⬍0.05) in diastolic blood pressure was seen only at 15 and 30 minutes following UV exposure. Krause et al reported substantial reductions in both systolic and diastolic blood pressures following a series of UV-B exposures using a lamp that may have been spectrally similar to our UV-A source (2). A light-induced nitric oxide–mediated phenomenon termed photorelaxation occurs in vascular and other smooth muscle (3,4). A comparable mechanism seems likely to account for the reduction in blood pressure in newborns under phototherapy (5) and in this preliminary study. Photorelaxation is a response primarily to UV-A radiation and raises the possibility of achieving therapeutic effects from currently available phototherapy devices and even from indoor tanning units. Karl T. Weber, MD E. William Rosenberg, MD University of Tennessee Health Sciences Center Memphis, Tennessee Robert M. Sayre, PhD University of Tennessee Health Sciences Center Memphis, Tennessee Rapid Precision Testing Laboratories Cordova, Tennessee 282
August 15, 2004
1. Rostand SG. Ultraviolet light may contribute to geographic and racial blood pressure differences. Hypertension. 1997;30:150–156. 2. Krause R, Buhring M, Hopfenmuller W, Holick MF, Sharma AM. Ultraviolet B and blood pressure. Lancet. 1998;352:709 –710. 3. Flitney FW, Megson IL. Nitric oxide and the mechanism of rat vascular smooth muscle photorelaxation. J Physiol. 2003;550:819–828. 4. Buyukafsar K, Levent A, Un I, Ark M, Arikan O, Ozveren E. Mediation of nitric oxide from photosensitive stores in the photorelaxation of the rabbit corpus cavernosum. Eur J Pharmacol. 2003;459:263–267. 5. Ergenekon E, Gücüyener K, Dursun H, et al. Nitric oxide production in newborns under phototherapy. Nitric Oxide. 2002;6:69 –72.
TENOFOVIR-ASSOCIATED NEPHROTOXICITY: FANCONI SYNDROME AND RENAL FAILURE To the Editor: Therapy for human immunodeficiency virus (HIV)– and acquired immunodeficiency syndrome (AIDS)–related illnesses has been revolutionized by newer generations of antiretroviral medications. The potential side effects of these medications are usually not fully recognized until widespread clinical use is initiated. Tenofovir was approved for use by the Food and Drug Administration in 2001 for the treatment of HIV. Despite the absence of renal toxicity observed in the major clinical trials of tenofovir, several case reports suggest that nephrotoxicity, although uncommon and reversible, is present. In December 2002, Coca and Perazella (1) described acute renal failure in a patient with baseline chronic kidney disease treated with tenofovir disoproxil fumarate. We now describe a case series of our ongoing experience with tenofovir-related renal disease (Table 1). Tenofovir disoproxil fumarate is an acyclic nucleoside phosphonate diester analog of adenosine monophosphate. Tenofovir inhibits the activity of HIV reverse transcriptase by competing
THE AMERICAN JOURNAL OF MEDICINE威
Volume 117
with deoxyadenosine 5=-triple phosphate and terminating DNA chain formation. Tenofovir belongs to the family of nucleotide reverse transcriptase inhibitors that includes cidofovir and adefovir. Both cidofovir and adefovir have well documented renal toxicities, including proximal renal dysfunction and acute renal failure (2,3). Similar effects were not expected with tenofovir due to decreased interaction with human organic transporter 1 and minimal mitochondrial DNA toxicity in vitro (3,4). However, as clinical experience with tenofovir has grown, so has the appearance of case reports documenting nephrotoxicity. Tenofovir is primarily excreted by the kidneys. Elimination is accomplished by glomerular filtration as well as by active tubular secretion. There are several medications that compete for renal tubular secretion, including acyclovir, cidofovir, ganciclovir, valcyclovir, and valganciclovir. Coadministration may lead to increased serum levels of tenofovir. Nephrotoxicity in animal models was related to dose as well as to duration of therapy. Additionally, tenofovir inhibits CYP1A2, and drug levels may be increased when given with other antiretroviral medication. Most notably lopinavir/ritonavir (as seen in patient 5), didanosine (as seen in patient 4), and indinavir may increase serum concentrations of tenofovir from 3% to 53% (5). A number of different manifestations of kidney disease have been described with tenofovir, including Fanconi syndrome, diabetes insipidus, and acute renal failure (6). In all five cases reported there was evidence of tubulopathy. Proximal tubular damage manifested as glucosuria, acidosis (proximal tubular bicarbonate wasting), low-grade proteinuria, hypokalemia, and hypophosphatemia. Additionally, renal tubular epithelial cells and casts were observed in all 5 patients’ urinary sediments. Finally, similar to Karras et al (6), our series of patients had normal renal function, without ev-