- Email: [email protected]
Prostaglandin F2α in the treatment of vinca alkaloid-induced hens
BRIEF CLINICAL
sisted and he began to report symptoms associated with anxiety, including increased irritability, impaired concentration, tremors, flushes, and shortness of breath. He described himself as “irrational at times,” and noted “rushed” speech and feeling as though his “mind was skipping.” He perceived that the situation was “similar to a nervous breakdown.” He denied significant events or changes in his life that might account for this change in emotional status. Pravastatin 40 mg was substituted for lovastatin, and within 48 hours, he experienced resolution in all symptoms. He remains free of sleep disturbance and anxiety 13 months after starting pravastatin treatment.
COMMENTS Sleep disturbances are associated with the lipophilic HMG-CoA reductase inhibitor agents simvastatin and lovastatin [l-4]. Sleep disturbance may be related to differential penetration of these agents across the blood-brain barrier, a property related to lipophilicity [7]. Self-reported sleep difficulties with lovastatin include frequent awakenings, shorter sleep durations, and early-morning awakenings [1,3]. To our knowledge, other instances of HMG-CoA reductase-induced sleep disturbance have not been correlated with behavioral changes. In these cases, the association between sleep disturbance, anxiety, irritability, and difficulty coping with stress is temporally linked. Neither patient had preexistent insomnia, a leading risk factor for current sleep disturbances [B]. In Patient 1, the sleep disturbance developed immediately; however, this complaint was alleviated initially by altering the dosing schedule to the morning. Almost 3 months later, insomnia became manifest again. In Patient 2, the sleep disturbance occurred only after the daily dose of lovastatin was increased from 40 mg to 60 mg daily. Manifestations of sleep
Prostaglandin Fza in the Treatment of Vinca AlkaloidInduced Ileus HIROSHISAITO, M.D., The Johns Hopkins University School Maryland, TOMOKOYAMAMOTO, M.D., MASAYUKIKIMURA, M.D., Chubu National Hospital, Aichi, Japan, KAORUSHIMOKATA,M.D., Nagoya University of Medicine, Baltimore,
School of Medicine, Nagoya, Japan
The vinca alkaloids (vincristine, vinblastine, and vindesine) have broad-spectrum antitumor activity November
OBSERVATIONS
disturbance and associated symptoms have not recurred with pravastatin by an 15 and 13-month treatment period for each case respectively. The sleep maintenance disturbances reported with lovastatin and simvastatin are consistent with complaints described in these case reports. Whether the anxious mood reported in these two patients was secondary to sleep disturbance or an independent drug effect cannot be determined by this anecdotal report. These cases raise concerns regarding CNS-related changes with lipid-altering therapy, in particular the lipophilic HMG-CoA reductase inhibitors. The association between lipidlowering therapy and CNS-related events should be monitored by physicians using these agents. Attention to sleep disturbance and changes in emotional status is an important and unappreciated aspect in the management of dyslipidemic patients.
REFERENCES 1. Schaefer EJ. HMG-CoA reductase
inhibitors for hypercholesterolemia.
J Med 1988; 319: 1222. 2. Barth KD, Kruisbrink OAE. Van Dijk AL. Inhibitors
N Engl
of hydroxymethyglutaryl
coenzyme A reductase for treating hypercholesterolemia. BMJ 1990; 301: 669. 3. Vgontzas AN, Kales A, Bixler EO, Manfreidi RL, Tyson KL. Effects of pravastatin and lovastatin
on sleep efficiency
and sleep stages.
Clin Pharmacol
Ther
1991; 50: 730-7. 4. Simvastatin. Lancet 1992; 339: 547. 5. Lubin A, Moses JM, Johnson LC, et al. The recuperative effects of REM sleep and stage 4 sleep on human performance after complete sleep loss: experiment
1. Psychophysiology 1974; 11: 133-46. 6. Roth T. Richardson GR. Sullivan JP, Lee RM, Merlotti L, Roehrs T. Comparative effects of pravastatin and lovastatin mance. Clin Cardiol 1992; 15: 426-32.
on nighttime
sleep and daytime perfor-
7. Botti RE, Triscari J, Pan HY, Zayat J. Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacoi 1991;
14: 256-61. 8. Klink ME, Quan SF, Kaltenborn
WT, Lebowitz MD. Risk factors associated
with
complaints of insomnia in a general adult population: influence of previous complaints of insomnia. Arch Intern Med 1992; 152: 1634-7. Submitted
January
4, 1993, and accepted
in revised form April 15. 1993
and have been widely used against a variety of malignancies. Although a dose-related, peripheral, sensory-motor neuropathy is the most common manifestation of neurotoxicity due to the vinca alkaloids, autonomic neuropathy manifested as constipation and paralytic ileus has been also reported as a result of reduction of the motility of the gastrointestinal tract. Several agents including metoclopramide, sincalide, and lactulose have been reported to be effective in the treatment of vincristine-induced ileus and constipation with limited experience [l-3]. We report three cases in which paralytic ileus due to vindesine or vinblastine 1993
The American
Journal
of Medicine
Volume
95
549
BRIEF CLINICAL OBSERVATIONS
was successfully treated with intravenous of prostaglandin Fzol.
infusion
CASE REPORTS Patient 1 A M-year-old woman with adenocarcinoma of the lung was treated with cisplatin and vindesine after drainage of a malignant pericardial effusion. Nausea and vomiting were well controlled with highdose metoclopramide and dexamethasone. She began to have nausea and vomiting 2 days after the chemotherapy and had no bowel movement despite multiple uses of laxatives and enemas for 5 days after the chemotherapy. Examination of the abdomen showed distention and absence of bowel sounds. An abdominal radiograph obtained 4 days after the chemotherapy revealed dilated loops of large and small intestines and a fecal mass in the cecum and ascending colon consistent with paralytic ileus (Figuye 1, top). Prostaglandin Fz~ infusion (0.3 pg/kg/min for 120 minutes, twice daily) was begun. An abdominal radiograph taken 2 days later showed improvement of the ileus (Figure 1, bottom). She complained of sweating, pain at the intravenous site, and abdominal cramping during the infusion, but all of which were tolerated well. Patient 2 A 7%year-old man with large cell carcinoma of the lung was treated with vinblastine combined with cisplatin and ifosfamide. High-dose metoclopramide was given with dexamethasone as antiemetics. The next day, he complained of colicky pain in the right lower quadrant of the abdomen. Examination of the abdomen revealed distention and absent bowel sounds. An abdominal radiograph demonstrated dilated loops of large and small intestines consistent with paralytic ileus. Administration of metoclopramide (10 mg intravenous bolus every 6 hours) was started. An abdominal radiograph taken on the next day revealed partial resolution of the ileus. Although intravenous metoclopramide was continued, an abdominal radiograph obtained 2 days later showed recurrence of paralytic ileus. Prostaglandin Fgar infusion (0.5 pg/kg/min for 120 minutes, twice daily) was begun. He had a bowel movement on the next day. An abdominal radiograph taken 3 days after the infusion showed improvement of the ileus. He complained of abdominal cramping during the infusion but it was self-limited. Figure 1. Top. Abdominal radiograph before prostaglandin Fsa infusion showing dilated loops of the intestine and fecal mass in the cecum and ascending colon in Patient 1. Note that a silicon drain was inserted through the xiphisternal route. Bottom. Abdominal radiograph 2 days after prostaglandin Faa infusion showing improvement of ileus.
550
November
1993
The American
Journal
of Medicine
Volume
Patient 3 A 73-year-old woman with adenocarcinoma of the lung was treated with two courses of the combination chemotherapy of vindesine, cisplatin, and mi95
BRIEF CLINICAL
tomycin C, and achieved a partial response. She then underwent a left upper lobe lobectomy and postoperatively received the third course of the chemotherapy of the same regimen. High-dose metoclopramide and lorazepam were given as antiemetics. Four days after the chemotherapy, she became constipated while taking oral metoclopramide (0.5 mg/kg three times a day) and laxatives. Constipation persisted for 3 more days and she began to have nausea and abdominal pain. An abdominal radiograph obtained 7 days after the chemotherapy revealed dilated loops of bowel consistent with paralytic ileus. Metoclopramide (20 mg intravenously every 6 hours) was given over the next 2 days. Because of no improvement in the ileus, prostaglandin Fso, infusion (0.3 pg/kg/min for 120 minutes, twice daily) was started. Bowel sounds were audible after the first dose of prostaglandin infusion. An abdominal radiograph obtained 2 days later showed improvement of the ileus. She had abdominal cramping during the infusion but it was self-limited.
OBSERVATIONS
tine-induced ileus and constipation [l-3]. However, in our report, the ileus did not respond to metoclopramide in Patient 3 and responded only initially in Patient 2. Furthermore, all three patients received high-dose metoclopramide before development of ileus. Prostaglandin Fzorcontracts both the longitudinal and circular smooth muscles from the human colon [7]. Recently, intravenous prostaglandin Fz~ infusion has been successfully used in a patient who developed vincristine-induced ileus [8]. We gave prostaglandin Fsorto three patients who developed paralytic ileus due to either vindesine or vinblastine, and all of them responded. Therefore, prostaglandin FsCyshould be considered in the treatment of vinca alkaloid-induced ileus. Further studies to define its role are needed.
REFERENCES 1. Garewal HS, Dalton WS. Metoclopramide
in vincristine-induced
Treat Rep 1985; 69: 1309-11. 2. Jackson DV Jr, Wu WC, Spurr CL. Treatment sincalide,
a cholecystokinin
83-5. 3. Harris AC, Jackson Aust 1977; 2: 573-4.
COMMENTS Although vincristine is known to be the most neurotoxic among the vinca alkaloids, vinblastine and vindesine are also neurotoxic and paralytic ileus due to these agents has been reported [4,5]. In our patients, two received vindesine and one received vinblastine. In most cases due to vinca alkaloids, ileus eventually resolves with conservative management including nasogastric suctioning. Prompt resolution of ileus, however, should be attempted to reduce further morbidity and mortality [4,6]. Metoclopramide, sin&de, and lactulose have been reported to be effective in the treatment of vincris-
November
analog. Cancer
JM. Lactulose
ileus. Cancer
of vincristine-induced Chemother
in vincristine-induced
ileus with
Pharmacol constipation.
1982; 8: Med J
4. Kanoh T. Fatal paralytic ileus following vindesine chemotherapy in a patient with myeloma-associated amyloidosis. Eur J Haematol 1989; 42: 108. 5. Johnson DH, Presant C. Einhorn L, Bartolucci AA, Greco FA. Cisplatin, vinblastine, and bleomycin in the treatment of metastatic melanoma: a phase II study of the Southeastern Cancer Study Group. Cancer Treat Rep 1985; 69: 821-4. 6. Toghill PJ, Burke JD. Death from paralytic ileus following vincristine therapy. Postgrad Med J 1970; 46: 330-l. 7. Bruch HP, Schmidt E, Laven R, Kehrer G, Wasner KH. The role of prostaglandines in peristalsis of the human colon. Acta Hepato-Gastroenterol 1978; 25: 303-7. 8. lkehara 0. Vincristineinduced paralytic and prostaglandin Fh. Am J Gastroenterol Submitted
1993
September
ileus: role of fiberoptic 1992; 87: 207-9.
18, 1992, and accepted
The American
Journal
colonoscopy
in revised form March 2, 1993
of Medicine
Volume
95
551
sisted and he began to report symptoms associated with anxiety, including increased irritability, impaired concentration, tremors, flushes, and shortness of breath. He described himself as “irrational at times,” and noted “rushed” speech and feeling as though his “mind was skipping.” He perceived that the situation was “similar to a nervous breakdown.” He denied significant events or changes in his life that might account for this change in emotional status. Pravastatin 40 mg was substituted for lovastatin, and within 48 hours, he experienced resolution in all symptoms. He remains free of sleep disturbance and anxiety 13 months after starting pravastatin treatment.
COMMENTS Sleep disturbances are associated with the lipophilic HMG-CoA reductase inhibitor agents simvastatin and lovastatin [l-4]. Sleep disturbance may be related to differential penetration of these agents across the blood-brain barrier, a property related to lipophilicity [7]. Self-reported sleep difficulties with lovastatin include frequent awakenings, shorter sleep durations, and early-morning awakenings [1,3]. To our knowledge, other instances of HMG-CoA reductase-induced sleep disturbance have not been correlated with behavioral changes. In these cases, the association between sleep disturbance, anxiety, irritability, and difficulty coping with stress is temporally linked. Neither patient had preexistent insomnia, a leading risk factor for current sleep disturbances [B]. In Patient 1, the sleep disturbance developed immediately; however, this complaint was alleviated initially by altering the dosing schedule to the morning. Almost 3 months later, insomnia became manifest again. In Patient 2, the sleep disturbance occurred only after the daily dose of lovastatin was increased from 40 mg to 60 mg daily. Manifestations of sleep
Prostaglandin Fza in the Treatment of Vinca AlkaloidInduced Ileus HIROSHISAITO, M.D., The Johns Hopkins University School Maryland, TOMOKOYAMAMOTO, M.D., MASAYUKIKIMURA, M.D., Chubu National Hospital, Aichi, Japan, KAORUSHIMOKATA,M.D., Nagoya University of Medicine, Baltimore,
School of Medicine, Nagoya, Japan
The vinca alkaloids (vincristine, vinblastine, and vindesine) have broad-spectrum antitumor activity November
OBSERVATIONS
disturbance and associated symptoms have not recurred with pravastatin by an 15 and 13-month treatment period for each case respectively. The sleep maintenance disturbances reported with lovastatin and simvastatin are consistent with complaints described in these case reports. Whether the anxious mood reported in these two patients was secondary to sleep disturbance or an independent drug effect cannot be determined by this anecdotal report. These cases raise concerns regarding CNS-related changes with lipid-altering therapy, in particular the lipophilic HMG-CoA reductase inhibitors. The association between lipidlowering therapy and CNS-related events should be monitored by physicians using these agents. Attention to sleep disturbance and changes in emotional status is an important and unappreciated aspect in the management of dyslipidemic patients.
REFERENCES 1. Schaefer EJ. HMG-CoA reductase
inhibitors for hypercholesterolemia.
J Med 1988; 319: 1222. 2. Barth KD, Kruisbrink OAE. Van Dijk AL. Inhibitors
N Engl
of hydroxymethyglutaryl
coenzyme A reductase for treating hypercholesterolemia. BMJ 1990; 301: 669. 3. Vgontzas AN, Kales A, Bixler EO, Manfreidi RL, Tyson KL. Effects of pravastatin and lovastatin
on sleep efficiency
and sleep stages.
Clin Pharmacol
Ther
1991; 50: 730-7. 4. Simvastatin. Lancet 1992; 339: 547. 5. Lubin A, Moses JM, Johnson LC, et al. The recuperative effects of REM sleep and stage 4 sleep on human performance after complete sleep loss: experiment
1. Psychophysiology 1974; 11: 133-46. 6. Roth T. Richardson GR. Sullivan JP, Lee RM, Merlotti L, Roehrs T. Comparative effects of pravastatin and lovastatin mance. Clin Cardiol 1992; 15: 426-32.
on nighttime
sleep and daytime perfor-
7. Botti RE, Triscari J, Pan HY, Zayat J. Concentrations of pravastatin and lovastatin in cerebrospinal fluid in healthy subjects. Clin Neuropharmacoi 1991;
14: 256-61. 8. Klink ME, Quan SF, Kaltenborn
WT, Lebowitz MD. Risk factors associated
with
complaints of insomnia in a general adult population: influence of previous complaints of insomnia. Arch Intern Med 1992; 152: 1634-7. Submitted
January
4, 1993, and accepted
in revised form April 15. 1993
and have been widely used against a variety of malignancies. Although a dose-related, peripheral, sensory-motor neuropathy is the most common manifestation of neurotoxicity due to the vinca alkaloids, autonomic neuropathy manifested as constipation and paralytic ileus has been also reported as a result of reduction of the motility of the gastrointestinal tract. Several agents including metoclopramide, sincalide, and lactulose have been reported to be effective in the treatment of vincristine-induced ileus and constipation with limited experience [l-3]. We report three cases in which paralytic ileus due to vindesine or vinblastine 1993
The American
Journal
of Medicine
Volume
95
549
BRIEF CLINICAL OBSERVATIONS
was successfully treated with intravenous of prostaglandin Fzol.
infusion
CASE REPORTS Patient 1 A M-year-old woman with adenocarcinoma of the lung was treated with cisplatin and vindesine after drainage of a malignant pericardial effusion. Nausea and vomiting were well controlled with highdose metoclopramide and dexamethasone. She began to have nausea and vomiting 2 days after the chemotherapy and had no bowel movement despite multiple uses of laxatives and enemas for 5 days after the chemotherapy. Examination of the abdomen showed distention and absence of bowel sounds. An abdominal radiograph obtained 4 days after the chemotherapy revealed dilated loops of large and small intestines and a fecal mass in the cecum and ascending colon consistent with paralytic ileus (Figuye 1, top). Prostaglandin Fz~ infusion (0.3 pg/kg/min for 120 minutes, twice daily) was begun. An abdominal radiograph taken 2 days later showed improvement of the ileus (Figure 1, bottom). She complained of sweating, pain at the intravenous site, and abdominal cramping during the infusion, but all of which were tolerated well. Patient 2 A 7%year-old man with large cell carcinoma of the lung was treated with vinblastine combined with cisplatin and ifosfamide. High-dose metoclopramide was given with dexamethasone as antiemetics. The next day, he complained of colicky pain in the right lower quadrant of the abdomen. Examination of the abdomen revealed distention and absent bowel sounds. An abdominal radiograph demonstrated dilated loops of large and small intestines consistent with paralytic ileus. Administration of metoclopramide (10 mg intravenous bolus every 6 hours) was started. An abdominal radiograph taken on the next day revealed partial resolution of the ileus. Although intravenous metoclopramide was continued, an abdominal radiograph obtained 2 days later showed recurrence of paralytic ileus. Prostaglandin Fgar infusion (0.5 pg/kg/min for 120 minutes, twice daily) was begun. He had a bowel movement on the next day. An abdominal radiograph taken 3 days after the infusion showed improvement of the ileus. He complained of abdominal cramping during the infusion but it was self-limited. Figure 1. Top. Abdominal radiograph before prostaglandin Fsa infusion showing dilated loops of the intestine and fecal mass in the cecum and ascending colon in Patient 1. Note that a silicon drain was inserted through the xiphisternal route. Bottom. Abdominal radiograph 2 days after prostaglandin Faa infusion showing improvement of ileus.
550
November
1993
The American
Journal
of Medicine
Volume
Patient 3 A 73-year-old woman with adenocarcinoma of the lung was treated with two courses of the combination chemotherapy of vindesine, cisplatin, and mi95
BRIEF CLINICAL
tomycin C, and achieved a partial response. She then underwent a left upper lobe lobectomy and postoperatively received the third course of the chemotherapy of the same regimen. High-dose metoclopramide and lorazepam were given as antiemetics. Four days after the chemotherapy, she became constipated while taking oral metoclopramide (0.5 mg/kg three times a day) and laxatives. Constipation persisted for 3 more days and she began to have nausea and abdominal pain. An abdominal radiograph obtained 7 days after the chemotherapy revealed dilated loops of bowel consistent with paralytic ileus. Metoclopramide (20 mg intravenously every 6 hours) was given over the next 2 days. Because of no improvement in the ileus, prostaglandin Fso, infusion (0.3 pg/kg/min for 120 minutes, twice daily) was started. Bowel sounds were audible after the first dose of prostaglandin infusion. An abdominal radiograph obtained 2 days later showed improvement of the ileus. She had abdominal cramping during the infusion but it was self-limited.
OBSERVATIONS
tine-induced ileus and constipation [l-3]. However, in our report, the ileus did not respond to metoclopramide in Patient 3 and responded only initially in Patient 2. Furthermore, all three patients received high-dose metoclopramide before development of ileus. Prostaglandin Fzorcontracts both the longitudinal and circular smooth muscles from the human colon [7]. Recently, intravenous prostaglandin Fz~ infusion has been successfully used in a patient who developed vincristine-induced ileus [8]. We gave prostaglandin Fsorto three patients who developed paralytic ileus due to either vindesine or vinblastine, and all of them responded. Therefore, prostaglandin FsCyshould be considered in the treatment of vinca alkaloid-induced ileus. Further studies to define its role are needed.
REFERENCES 1. Garewal HS, Dalton WS. Metoclopramide
in vincristine-induced
Treat Rep 1985; 69: 1309-11. 2. Jackson DV Jr, Wu WC, Spurr CL. Treatment sincalide,
a cholecystokinin
83-5. 3. Harris AC, Jackson Aust 1977; 2: 573-4.
COMMENTS Although vincristine is known to be the most neurotoxic among the vinca alkaloids, vinblastine and vindesine are also neurotoxic and paralytic ileus due to these agents has been reported [4,5]. In our patients, two received vindesine and one received vinblastine. In most cases due to vinca alkaloids, ileus eventually resolves with conservative management including nasogastric suctioning. Prompt resolution of ileus, however, should be attempted to reduce further morbidity and mortality [4,6]. Metoclopramide, sin&de, and lactulose have been reported to be effective in the treatment of vincris-
November
analog. Cancer
JM. Lactulose
ileus. Cancer
of vincristine-induced Chemother
in vincristine-induced
ileus with
Pharmacol constipation.
1982; 8: Med J
4. Kanoh T. Fatal paralytic ileus following vindesine chemotherapy in a patient with myeloma-associated amyloidosis. Eur J Haematol 1989; 42: 108. 5. Johnson DH, Presant C. Einhorn L, Bartolucci AA, Greco FA. Cisplatin, vinblastine, and bleomycin in the treatment of metastatic melanoma: a phase II study of the Southeastern Cancer Study Group. Cancer Treat Rep 1985; 69: 821-4. 6. Toghill PJ, Burke JD. Death from paralytic ileus following vincristine therapy. Postgrad Med J 1970; 46: 330-l. 7. Bruch HP, Schmidt E, Laven R, Kehrer G, Wasner KH. The role of prostaglandines in peristalsis of the human colon. Acta Hepato-Gastroenterol 1978; 25: 303-7. 8. lkehara 0. Vincristineinduced paralytic and prostaglandin Fh. Am J Gastroenterol Submitted
1993
September
ileus: role of fiberoptic 1992; 87: 207-9.
18, 1992, and accepted
The American
Journal
colonoscopy
in revised form March 2, 1993
of Medicine
Volume
95
551