- Email: [email protected]
Miscellaneous Hormones
C H A P T E R
41 Miscellaneous Hormones Renee McCafferty*, Sidhartha D. Ray†,1 *Department of Pharmacy Practice, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA † Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA 1 Corresponding author: [email protected]
CALCITONIN [SEDA-34, 703; SEDA-35, 789; SEDA-36, 659; SEDA-37, 539]
GONADOTROPHIN-RELEASING HORMONE ANTAGONISTS [SEDA-35, 790; SEDA-36, 661; SEDA-37, 542]
Osteoarthritis Two randomized, double-blind, multi-center, placebocontrolled trials evaluate efficacy and safety of oral salmon calcitonin in patients with painful osteoarthritis with structural damage. Adverse events were mainly gastrointestinal (diarrhea, nausea, vomiting) and resolved upon calcitonin discontinuation. FDA recently cautioned against using salmon calcitonin in osteoporosis due to inferior efficacy and possibly more adverse effects when compared to other bone treatments. Authors conclude that the present formulation of salmon calcitonin did not provide reproducible benefits in patients with symptomatic knee osteoarthritis [1C].
Anti-Inflammatory Effects Adverse event rates were similar between cetrorelix (GnRH antagonist) and placebo when used for their anti-inflammatory effect against RA [3C].
Advanced Prostate Cancer GnRH antagonists were compared to standard androgen suppression therapy for advanced prostate cancer in a systematic review. There were more injection-site events with GnRH antagonists but less cardiovascular events [4M].
GONADOTROPINS (GONADORELIN, GnRH AND ANALOGUES) [SEDA-35, 789; SEDA-36, 660; SEDA-37, 539]
SOMATROPIN (HUMAN GROWTH HORMONE, hGH) [SEDA-35, 791; SEDA-36, 661; SEDA-37, 542]
Idiopathic Central Precocious Puberty
Pediatric Clinical Studies
Effectiveness and safety of domestic leuprorelin (GnRH analog) and imported leuprorelin were compared in 236 Chinese girls with idiopathic central precocious puberty and found to be comparable [2C].
Side Effects of Drugs Annual, Volume 38 ISSN: 0378-6080 http://dx.doi.org/10.1016/bs.seda.2016.09.007
A pilot study was done involving 15 boys with predicted adult short stature who were all given recombinant human growth hormone (rhGH). Authors concluded that rhGH is very likely to be beneficial in late
463
© 2016 Elsevier B.V. All rights reserved.
464
41. MISCELLANEOUS HORMONES
puberty as long as the knee epiphyses are still open. No secondary effects, such as headaches or hyperglycemia, were detected [5c]. A two-phase trial looked at bone mineral density in children with Prader–Willi syndrome treated with growth hormone. No adverse effects were reported. Bone mineral density remained stable during the first phase of the study, 4 years of treatment with GH during prepubertal years. During the second study phase, GH continued to be given for a total of 9 years. During longer-term administration (after 4 years), bone mineral density tended to decrease but stayed within the normal range. The authors included recommendations for GH-treated children with Prader–Willi syndrome to increase bone mineral density monitoring, especially during puberty, and stimulate physical activity to increase lean body mass. While stating the need for further study of complex hormonal treatments in this population, recommendations are included regarding optimal timing of concomitant sex hormone replacement [6C].
MELATONIN AND ANALOGUES [SED-15, 224; SEDA-35, 792; SEDA-36, 664; SEDA-37, 545] Migraine Prophylaxis In a study of 60 children suffering from migraine headaches, melatonin 0.3 mg/kg daily for 3 months was given for migraine prophylaxis. Adverse events were reported in a total of 14 children (23.3%) consisting of sleepiness, vomiting, mild hypotension and constipation. Frequency, severity and duration of migraines were all reduced significantly which led the authors to conclude that melatonin may be effective migraine prophylaxis in children without causing life-threatening side effects [7c].
Insomnia Reviews A review of melatonin used in chronopharmacology of insomnia remarked on its remarkable tolerability and stated that it has been given at very large doses over long periods of time without signs of abuse potential. The authors compare the safety of melatonin to that of other hypnotics and recommend that it be first-line therapy for insomnia in patients 55 years and over. The analog, tasimelteon has emerged for sleep resynchronization in blind patients without light perception. Agomelatine is another new melatonin analog marketed in Europe as an antidepressant [8R]. This review of melatonin’s effectiveness to promote healthy sleep reports that most common side effects of melatonin include headache, somnolence, palpitations and abdominal pain. The following adverse events
are reported infrequently: nasopharyngitis, arthralgia, tachycardia, dizziness, nausea, vomiting, nightmares, difficulty swallowing and breathing, hypnotic activity, heavy head, heartburn, flatulence, swelling of arms/legs, sweating/hot flash, exanthema, sleeping difficulties, depression, problems with the rectal probe, and sleep walking. Melatonin has been reported to reduce body temperature which could keep the drug from being useful during cold stress. Central nervous system effects (somnolence, headaches, increased frequency of seizures, nightmares) may be caused by melatonin supplementation. In healthy subjects, daytime dosing of melatonin (0.1–1.0 mg) caused drowsiness, fatigue, and performance decrements, peaking at around 3–4 hours. If melatonin is used to promote daytime sleep, circadian phase shifts may occur. If used to promote circadian phase shifts, sleepiness at undesired times may occur. The authors suggest that promotion of daytime sleep may not be appropriate in some military situations. Blood pressure effects (up or down) and dermatologic effects may occur. While this review notes no serious adverse events or health risks with melatonin use, it recommends addressing potential health effects of the drug [9R]. This review focuses more on the pharmacology of melatonin. The point is made melatonin has an immunostimulant effect which may make it problematic, even contraindicated as therapy in patients with autoimmune disorders. Agomelatine is touted as improving sleep as it is used for its antidepressant effects in comparison to some other antidepressants which are known to trigger sleep disorders. Ramelteon has been shown to be highly variable for maintaining sleep in elderly patients. Tasimelteon was approved by the FDA in 2014 for treatment of non-24-hour sleep–wake rhythm disorder in blind adults. Melatonin-controlled release tablets are approved for use in Europe in patients >55 years of age at 2 mg/day. Doses, as high as 300 mg/day for up to 2 years, have been found to be safe in amyotrophic lateral sclerosis patients. One source reported that adverse effects of melatonin include nausea, headache, rebound insomnia and a risk for hepatotoxicity. Withdrawal symptoms may occur if used for 6–12 months [10R]. Melatonin inhibits proliferation of most tumor cells through intracellular signaling. Its potent antioxidant effects are known, but it is hypothesized to have prooxidant effects on some tumor cells, especially Ewing sarcoma cells. The type of tumor cell metabolism seems to determine whether melatonin will cause cell death (Warburg effect) or inhibit cell proliferation. The authors suggest that melatonin could be used as a personalized antitumoral agent if the metabolic profile of a patient’s tumor could be characterized [11E]. Agomelatine, a melatonin analogue, has been marketed since 2009 in some countries for its antidepressant effects. It has known potential to cause liver injury
OXYTOCIN AND ANALOGUES [SEDA-35, 793; SEDA-36, 665; SEDA-37, 546]
associated with elevations in serum transaminase levels >3 upper limit of normal. Serious hepatic reactions such as cytolytic hepatitis, jaundice and liver enzyme levels > 10 upper limit of normal are reported to occur at a rate of one in every 1000–10 000 persons. Six patients with hepatic risk factors have been reported worldwide to have developed hepatic failure resulting in death or liver transplant. In response, the manufacturer of agomelatine has issued liver monitoring guidance. Authors of this review state that liver injury associated with agomelatine is idiopathic and usually reversible. They suggest warning against factors that may increase risk for liver injury (concomitant alcohol consumption). Patients should be counseled that fatigue, nausea, vomiting and dark urine may indicate liver injury and should be reported immediately [12R]. Case Reports A 19-year-old experienced severe sedation when melatonin was added to his regimen of citalopram, nortriptyline and oxycodone. His sedation improved upon melatonin discontinuation and worsened when melatonin was reintroduced. Although other meds in his regimen may cause sedation, a melatonin interaction was determined to be “possible” to “likely.” A combined additive pharmacodynamics interaction may have occurred. Melatonin is known to inhibit multiple cytochrome p450 isoenzymes and can inhibit the effects of concomitant medications that depend on these isoenzymes for metabolism and clearance. Professionals prescribing, dispensing or recommending melatonin should advise caution in consideration of potentially interacting drugs and if the patient is to be driving or operating heavy machinery [13A]. Ramelteon, a melatonin-receptor agonist, is suspected to have caused nightmares in a 30-year-old male patient with history of attention-deficit hyperactive disorder. He had been treated with dextroamphetamine/amphetamine and zolpidem for years. He had tried over-thecounter melatonin in the past without much relief for his insomnia and was interested in taking an agent for sleep that was not a controlled substance. Zolpidem was tapered from 10 to 5 mg daily at bedtime for a week, and then stopped. The patient reports beginning ramelteon 2–3 days after stopping zolpidem. A few days after starting nightly ramelteon, he developed vivid nightmares which stopped after he discontinued ramelteon. Nightmares have been reported to occur with melatonin therapy. Non-benzodiazepine hypnotics such as zolpidem can decrease REM sleep on EEG. Ramelteon effects on REM sleep are not well characterized. Animal studies have shown that sleep induced by ramelteon and melatonin was indistinguishable from control animals. The authors state that zolpidem discontinuation does not
465
cause withdrawal nightmares as benzodiazepines can. Nightmares have been reported with zolpidem discontinuation so further study could be beneficial [14A].
OXYTOCIN AND ANALOGUES [SEDA-35, 793; SEDA-36, 665; SEDA-37, 546] Cardiovascular Effects Oxytocin is known to cause hypotension and tachycardia. It may also cause nausea and vomiting, myocardial ischaemia and arrhythmias, especially when given in boluses >5 units. Chest pain and pulmonary edema may also occur. It would be highly desirable to prevent these side effects. Phenylephrine 80 mcg co-administered with the oxytocin dose has helped prevent these cardiovascular effects from oxytocin but was found to be excessive. This study co-administered 50 mcg of phenylephrine with oxytocin and found that dose do not reliably prevent hemodynamic effects of the oxytocin bolus [15C].
Autism Risk Maternal exposure to oxytocin during birth, induction and/or augmentation of labor, has been suspected to increase the rate of autism as the infant develops. A cohort of 557, 040 live births was identified according to Denmark’s birth registry between January 1, 2000 and December 31, 2009. Of this group, each child living on his first birthday was followed until December 31, 2012. An epidemiological analysis was performed to explore possible association between oxytocin exposures at birth with subsequent development of autism. A modest association between oxytocin-augmented labor and risk for autism was found in males but the therapeutic benefit of oxytocin administration during labor warrants caution in interpretation of these results [16c].
Caloric Intake A randomized, placebo-controlled crossover study of 25 healthy, fasting men gave a single-dose of intranasal oxytocin (24 IU) or placebo then double portions of a breakfast meal each subject selected from a menu. Content of food consumed was measured along with relevant parameters in the study subjects. Men receiving oxytocin prior to meals consumed less fat and less overall calories while not affecting the caloric content of food ordered from the menu. Increased levels of cholecystokinin were found after oxytocin, unrelated to caloric intake. Indirect calorimetry showed an increased fat utilization and decreased carbohydrate utilization as well as a trend toward a reduction in triglyceride levels following
466
41. MISCELLANEOUS HORMONES
oxytocin administration. Oxytocin also reduced insulin levels without changing glucose levels which implies increased insulin sensitivity. There was a slight decrease in body temperature (0.3 °F, p ¼ 0.006) after oxytocin. A few mild adverse effects were reported with no rate difference between oxytocin and placebo [17C].
SOMATOSTATIN (GROWTH HORMONE RELEASE-INHIBITING HORMONE) AND ANALOGUES [SED-15, 3160; SEDA-35, 794; SEDA-36, 666; SEDA-37, 549]
tolvaptan were compared with placebo, they were found to have good effects at elevating serum sodium levels and improvement of ascites. Monitoring was recommended to avoid treatment-related adverse events such as overcorrection of hyponatremia. Authors acknowledge the lack of evidence that vasopressin antagonists extend life in cirrhosis and call for future randomized controlled trials to study survival with each agent [20R].
Tolvaptan
Long-acting release pasireotide, a somatostatin analog, was compared with octreotide long-acting repeatable for managing carcinoid symptoms refractory to firstgeneration somatostatin analogues. Efficacy was similar but pasireotide was associated with more hyperglycemia, fatigue and nausea. Two patients stopped pasireotide due to grade 4 hyperglycemia [18C]. An open-label extension trial was conducted in 58 patients with Cushing’s disease who had been taking pasireotide for 12 months. The initial 12 months of the trial began with 162 Cushing’s patients treated with either 600 or 900 mcg pasireotide twice daily. A total of 24 months of pasireotide was completed by 40 patients so its efficacy and safety could be further assessed. Throughout the study period, reductions in urinary free cortisol, serum cortisol and plasma ACTH were maintained. Clinical signs were also consistently improved such as blood pressure, weight and total cholesterol levels. Adverse events were reported by 98.1% of studied patients within the 24-month period. Gastrointestinal disorders were most common at 81.5% of patients (55.6% reported diarrhea, 48.1% nausea). Hyperglycemia was observed in 38.9% of which 11.7% were grade 3 and 8.6% were grade 4. Cholelithiasis occurred in 31.5% and was suspected to be drug related. Over the 24-month period, 42 patients (25.9%) had adverse events that were rated as serious. No patient deaths occurred. Authors conclude that the safety profile of pasireotide was typical for a somatostatin analogue except glucose level changes which they recommended monitoring closely [19C].
A retrospective study of patients who had received tolvaptan was performed to provide insight into risk factors associated with development of hyponatremia. Keeping the daily dose of tolvaptan <7.5 mg was recommended in short- and long-term treatments. Age >75 years was also found to be predictive of late onset hyponatremia so caution is justified in this age group [21c]. A blinded re-examination of data from multiple tolvaptan trials for autosomal dominant polycystic kidney disease (ADPKD) was performed to better define the clinical pattern of potentially associated liver injury. The risk of liver failure in ADPKD after long-term tolvaptan therapy was estimated at 1:4000 with onset occurring within 3–18 months of receiving tolvaptan. All subjects experiencing hepatic injury recovered with no reports of liver failure. Frequent monitoring of liver function tests is recommended to reduce risk of liver injury during long-term tolvaptan use [22c]. In a meta-analysis of randomized controlled trials using tolvaptan in heart failure was performed to better describe the short- and long-term effects and allow evaluation as to its place in therapy. It was found that while tolvaptan may not bring long-term benefits in heart failure patients, it improves volume overload and hyponatremia without obvious increases in potassium and creatinine [23R]. Interim results of an ongoing study comparing tolvaptan use in heart failure patients >80 years of age with those <80 years. Tolvaptan was found to have similar safety and effectiveness profiles, but higher starting doses were found to be associated with more hypernatremia in those >80. Starting tolvaptan at no more than a 7.5 mg dose contributes to prevention of hypernatremia in heart failure patients >80 years of age [24C].
VASOPRESSIN RECEPTOR ANTAGONISTS [SEDA-34, 713; SEDA-35, 797; SEDA-36, 668; SEDA-37, 552]
VASOPRESSIN AND ANALOGUES [SEDA-33, 915; SEDA-34, 714; SEDA-35, 798; SEDA-36, 669; SEDA-37, 552]
Cirrhosis with Ascites
Hemodynamic Support
Three vasopressin receptor antagonists were considered as a group for their use limitations in the treatment of cirrhosis with ascites. When lixivaptan, satavaptan or
In a retrospective, propensity-matched cohort of septic shock patients, vasopressin was favorably compared to hydrocortisone for hemodynamic support secondary to
Pasireotide Clinical Studies
REFERENCES
norepinephrine. Vasopressin was associated with quicker hemodynamic stability and discontinuation of hemodynamic support. Arrhythmias were more frequent with vasopressin, but incidence of superinfection, hyperglycemia and hyponatremia was less frequent when compared to patients receiving hydrocortisone. Authors concluded that vasopressin was a more advantageous endocrine agent for hemodynamic support in septic shock than hydrocortisone [25c].
DESMOPRESSIN (N-DEAMINO-8-DARGININE VASOPRESSIN, DDAVP) [SEDA-34, 714; SEDA-35, 798; SEDA-36, 669; SEDA-37, 552] Dermatologic Reaction Interstitial Granulomatous Drug Reaction (IGDR) has been reported in a 56-year-old man after he had taken intranasal desmopressin for diabetes insipidus developed after prolactinoma excision. Rechallenge was associated with a recurrence of the IGDR truncal lesions. Both the initial and rechallenge eruptions resolved within 2–3 weeks of desmopressin discontinuation [26A].
References [1] Karsdal MA, Byrjalsen I, Alexanderson P, et al. Treatment of symptomatic knee osteoarthritis with oral salmon calcitonin: results from two phase 3 trials. Osteoarthr Cartil. 2015;23:532–43 [C]. [2] Li WJ, Gong CX, Guo MJ, et al. Efficacy and safety of domestic leuprorelin in girls with idiopathic central precocious puberty: a multicenter, randomized, parallel, controlled trial. Chin Med J. 2015;128(10):1314–20 [C]. [3] Kass A, Hollan I, Fagerland MW, et al. Rapid anti-inflammatory effects of gonadotropin-releasing hormone antagonism in rheumatoid arthritis patients with high gonadotropin levels in the AGRA trial. PLoS One. 2015;10(10):e0139439 [C]. [4] Kunath F, Borgmann H, Bl€ umle A, et al. Gonadotropin-releasing hormone antagonists versus standard androgen suppression therapy for advanced prostate cancer: a systematic review with meta-analysis. BMJ Open. 2015;5:e008217 [M]. [5] Rothenbuhler A, Ormieres B, Kalifa G, et al. A pilot study of growth hormone administration in boys with predicted adult short stature and near-ending growth. Growth Horm IGF Res. 2015;25:96–102 [c]. [6] Bakker NE, Kuppens RJ, Siemensma EPC, et al. Bone mineral density in children and adolescents with Prader-Willi syndrome: a longitudinal study during puberty and 9 years of growth hormone treatment. J Clin Endocrinol Metab. 2015;100(4):1609–18 [C]. [7] Fallah R, Shoroki FF, Ferdosian F. Safety and efficacy of melatonin in pediatric migraine prophylaxis. Curr Drug Saf. 2015;10(2):132–5 [c].
467
[8] Golombek DA, Seithikurippu RP, Brown GM, et al. Some implications of melatonin use in chronopharmacology of insomnia. Eur J Pharmacol. 2015;762:42–8 [R]. [9] Costello RB, Lentino CV, Boyd CC, et al. The effectiveness of melatonin for promoting healthy sleep: a rapid evidence assessment of the literature. Nutr J. 2014;13:106 [R]. [10] Emet M, Ozcan H, Ozel L, et al. A review of melatonin, its receptors and drugs. Eurasian J Med. 2016;48:135–41 [R]. [11] Sanchez-Sanchez AM, Antolin I, Puente-Moncada N, et al. Melatonin cytotoxicity is associated to Warburg effect inhibition in Ewing sarcoma cells. PLoS One. 2015;10(8):e0135420. http://dx.doi. org/10.1371/journal.pone.0135420. eCollection 2015. [E]. [12] Freiesleben SD, Furczyk K. A systematic review of agomelatineinduced liver injury. J Mol Psychiatry. 2015;3:4 [R]. [13] Foster BC, Cvijovic K, Boon HS, et al. Melatonin interaction resulting in severe sedation. J Pharm Pharm Sci. 2015;18(2):124–31 [A]. [14] Shah C, Kablinger A. Ramelteon-induced nightmares: a case report. Asian J Psychiatr. 2015;18:111–2 [A]. [15] Rumboll CK, Dyer RA, Lombard CJ. The use of phenylephrine to obtund oxytocin-induced hypotension and tachycardia during caesarean section. Int J Obstet Anesth. 2015;24(4):297–302 [C]. [16] Weisman O, Agerbo E, Carter CS, et al. Oxytocin-augmented labor and risk for autism in males. Behav Brain Res. 2015;284: 207–12 [c]. [17] Lawson EA, Marengi DA, DeSanti RL, et al. Oxytocin reduces caloric intake in men. Obesity (Silver Spring). 2015;23(5): 950–6 [C]. [18] Wolin EM, Jarzab B, Eriksson B, et al. Phase III study of pasireotide long-acting release in patients with metastatic neuroendocrine tumors and carcinoid symptoms refractory to available somatostatin analogues. Drug Des Devel Ther. 2015;9:5075–86 [C]. [19] Schopohl J, Gu F, Rubens R, et al. Pasireotide can induce sustained decreases in urinary cortisol and provide clinical benefit in patients with Cushing’s disease: results from an open-ended, open-label extension trial. Pituitary. 2015;18:604 [C]. [20] Yan L, Xie F, Lu J, et al. The treatment of vasopressin V2-receptor antagonists in cirrhosis patients with ascites: a meta-analysis of randomized controlled trials. BMC Gastroenterol. 2015;15:65 [R]. [21] Hirai K, Shimomura T, Moriwaki H, et al. Risk factors for hypernatremia in patients with short- and long-term tolvaptan treatment. Eur J Clin Pharmacol. 2016;72(10):1177–83. http://dx. doi.org/10.1007/s00228-016-2091-4. [c]. [22] Watkins PB, Lewis JH, Kaplowitz N, et al. Clinical pattern of tolvaptan-associated liver injury in subjects with autosomal dominant polycystic kidney disease: analysis of clinical trials database. Drug Saf. 2015;38(11):1103–13 [c]. [23] Xiong B, Huang Y, Tan J, et al. The short-term and log-term effects of tolvaptan in patients with heart failure: a meta-analysis of randomized controlled trials. Heart Fail Rev. 2015;20(6):633–42. http://dx.doi.org/10.1007/s10741-015-9503-x. [R]. [24] Kinugawa K, Inomata T, Sato N, et al. Effectiveness and adverse events of tolvaptan in octogenarians with heart failure. Int Heart J. 2015;56:137–43 [C]. [25] Bissell BD, Erdman MJ, Smotherman C, et al. The impact of endocrine supplementation on adverse events in septic shock. J Crit Care. 2015;30(6):1169–73 [c]. [26] Vincenzo M, Guiseppe S, Maria O, et al. Interstitial granulomatous drug reaction after intranasal desmopressin administration. Indian J Dermatol. 2016;61(1):125 [A].
41 Miscellaneous Hormones Renee McCafferty*, Sidhartha D. Ray†,1 *Department of Pharmacy Practice, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA † Department of Pharmaceutical Sciences, Manchester University College of Pharmacy, Natural and Health Sciences, Fort Wayne, IN, USA 1 Corresponding author: [email protected]
CALCITONIN [SEDA-34, 703; SEDA-35, 789; SEDA-36, 659; SEDA-37, 539]
GONADOTROPHIN-RELEASING HORMONE ANTAGONISTS [SEDA-35, 790; SEDA-36, 661; SEDA-37, 542]
Osteoarthritis Two randomized, double-blind, multi-center, placebocontrolled trials evaluate efficacy and safety of oral salmon calcitonin in patients with painful osteoarthritis with structural damage. Adverse events were mainly gastrointestinal (diarrhea, nausea, vomiting) and resolved upon calcitonin discontinuation. FDA recently cautioned against using salmon calcitonin in osteoporosis due to inferior efficacy and possibly more adverse effects when compared to other bone treatments. Authors conclude that the present formulation of salmon calcitonin did not provide reproducible benefits in patients with symptomatic knee osteoarthritis [1C].
Anti-Inflammatory Effects Adverse event rates were similar between cetrorelix (GnRH antagonist) and placebo when used for their anti-inflammatory effect against RA [3C].
Advanced Prostate Cancer GnRH antagonists were compared to standard androgen suppression therapy for advanced prostate cancer in a systematic review. There were more injection-site events with GnRH antagonists but less cardiovascular events [4M].
GONADOTROPINS (GONADORELIN, GnRH AND ANALOGUES) [SEDA-35, 789; SEDA-36, 660; SEDA-37, 539]
SOMATROPIN (HUMAN GROWTH HORMONE, hGH) [SEDA-35, 791; SEDA-36, 661; SEDA-37, 542]
Idiopathic Central Precocious Puberty
Pediatric Clinical Studies
Effectiveness and safety of domestic leuprorelin (GnRH analog) and imported leuprorelin were compared in 236 Chinese girls with idiopathic central precocious puberty and found to be comparable [2C].
Side Effects of Drugs Annual, Volume 38 ISSN: 0378-6080 http://dx.doi.org/10.1016/bs.seda.2016.09.007
A pilot study was done involving 15 boys with predicted adult short stature who were all given recombinant human growth hormone (rhGH). Authors concluded that rhGH is very likely to be beneficial in late
463
© 2016 Elsevier B.V. All rights reserved.
464
41. MISCELLANEOUS HORMONES
puberty as long as the knee epiphyses are still open. No secondary effects, such as headaches or hyperglycemia, were detected [5c]. A two-phase trial looked at bone mineral density in children with Prader–Willi syndrome treated with growth hormone. No adverse effects were reported. Bone mineral density remained stable during the first phase of the study, 4 years of treatment with GH during prepubertal years. During the second study phase, GH continued to be given for a total of 9 years. During longer-term administration (after 4 years), bone mineral density tended to decrease but stayed within the normal range. The authors included recommendations for GH-treated children with Prader–Willi syndrome to increase bone mineral density monitoring, especially during puberty, and stimulate physical activity to increase lean body mass. While stating the need for further study of complex hormonal treatments in this population, recommendations are included regarding optimal timing of concomitant sex hormone replacement [6C].
MELATONIN AND ANALOGUES [SED-15, 224; SEDA-35, 792; SEDA-36, 664; SEDA-37, 545] Migraine Prophylaxis In a study of 60 children suffering from migraine headaches, melatonin 0.3 mg/kg daily for 3 months was given for migraine prophylaxis. Adverse events were reported in a total of 14 children (23.3%) consisting of sleepiness, vomiting, mild hypotension and constipation. Frequency, severity and duration of migraines were all reduced significantly which led the authors to conclude that melatonin may be effective migraine prophylaxis in children without causing life-threatening side effects [7c].
Insomnia Reviews A review of melatonin used in chronopharmacology of insomnia remarked on its remarkable tolerability and stated that it has been given at very large doses over long periods of time without signs of abuse potential. The authors compare the safety of melatonin to that of other hypnotics and recommend that it be first-line therapy for insomnia in patients 55 years and over. The analog, tasimelteon has emerged for sleep resynchronization in blind patients without light perception. Agomelatine is another new melatonin analog marketed in Europe as an antidepressant [8R]. This review of melatonin’s effectiveness to promote healthy sleep reports that most common side effects of melatonin include headache, somnolence, palpitations and abdominal pain. The following adverse events
are reported infrequently: nasopharyngitis, arthralgia, tachycardia, dizziness, nausea, vomiting, nightmares, difficulty swallowing and breathing, hypnotic activity, heavy head, heartburn, flatulence, swelling of arms/legs, sweating/hot flash, exanthema, sleeping difficulties, depression, problems with the rectal probe, and sleep walking. Melatonin has been reported to reduce body temperature which could keep the drug from being useful during cold stress. Central nervous system effects (somnolence, headaches, increased frequency of seizures, nightmares) may be caused by melatonin supplementation. In healthy subjects, daytime dosing of melatonin (0.1–1.0 mg) caused drowsiness, fatigue, and performance decrements, peaking at around 3–4 hours. If melatonin is used to promote daytime sleep, circadian phase shifts may occur. If used to promote circadian phase shifts, sleepiness at undesired times may occur. The authors suggest that promotion of daytime sleep may not be appropriate in some military situations. Blood pressure effects (up or down) and dermatologic effects may occur. While this review notes no serious adverse events or health risks with melatonin use, it recommends addressing potential health effects of the drug [9R]. This review focuses more on the pharmacology of melatonin. The point is made melatonin has an immunostimulant effect which may make it problematic, even contraindicated as therapy in patients with autoimmune disorders. Agomelatine is touted as improving sleep as it is used for its antidepressant effects in comparison to some other antidepressants which are known to trigger sleep disorders. Ramelteon has been shown to be highly variable for maintaining sleep in elderly patients. Tasimelteon was approved by the FDA in 2014 for treatment of non-24-hour sleep–wake rhythm disorder in blind adults. Melatonin-controlled release tablets are approved for use in Europe in patients >55 years of age at 2 mg/day. Doses, as high as 300 mg/day for up to 2 years, have been found to be safe in amyotrophic lateral sclerosis patients. One source reported that adverse effects of melatonin include nausea, headache, rebound insomnia and a risk for hepatotoxicity. Withdrawal symptoms may occur if used for 6–12 months [10R]. Melatonin inhibits proliferation of most tumor cells through intracellular signaling. Its potent antioxidant effects are known, but it is hypothesized to have prooxidant effects on some tumor cells, especially Ewing sarcoma cells. The type of tumor cell metabolism seems to determine whether melatonin will cause cell death (Warburg effect) or inhibit cell proliferation. The authors suggest that melatonin could be used as a personalized antitumoral agent if the metabolic profile of a patient’s tumor could be characterized [11E]. Agomelatine, a melatonin analogue, has been marketed since 2009 in some countries for its antidepressant effects. It has known potential to cause liver injury
OXYTOCIN AND ANALOGUES [SEDA-35, 793; SEDA-36, 665; SEDA-37, 546]
associated with elevations in serum transaminase levels >3 upper limit of normal. Serious hepatic reactions such as cytolytic hepatitis, jaundice and liver enzyme levels > 10 upper limit of normal are reported to occur at a rate of one in every 1000–10 000 persons. Six patients with hepatic risk factors have been reported worldwide to have developed hepatic failure resulting in death or liver transplant. In response, the manufacturer of agomelatine has issued liver monitoring guidance. Authors of this review state that liver injury associated with agomelatine is idiopathic and usually reversible. They suggest warning against factors that may increase risk for liver injury (concomitant alcohol consumption). Patients should be counseled that fatigue, nausea, vomiting and dark urine may indicate liver injury and should be reported immediately [12R]. Case Reports A 19-year-old experienced severe sedation when melatonin was added to his regimen of citalopram, nortriptyline and oxycodone. His sedation improved upon melatonin discontinuation and worsened when melatonin was reintroduced. Although other meds in his regimen may cause sedation, a melatonin interaction was determined to be “possible” to “likely.” A combined additive pharmacodynamics interaction may have occurred. Melatonin is known to inhibit multiple cytochrome p450 isoenzymes and can inhibit the effects of concomitant medications that depend on these isoenzymes for metabolism and clearance. Professionals prescribing, dispensing or recommending melatonin should advise caution in consideration of potentially interacting drugs and if the patient is to be driving or operating heavy machinery [13A]. Ramelteon, a melatonin-receptor agonist, is suspected to have caused nightmares in a 30-year-old male patient with history of attention-deficit hyperactive disorder. He had been treated with dextroamphetamine/amphetamine and zolpidem for years. He had tried over-thecounter melatonin in the past without much relief for his insomnia and was interested in taking an agent for sleep that was not a controlled substance. Zolpidem was tapered from 10 to 5 mg daily at bedtime for a week, and then stopped. The patient reports beginning ramelteon 2–3 days after stopping zolpidem. A few days after starting nightly ramelteon, he developed vivid nightmares which stopped after he discontinued ramelteon. Nightmares have been reported to occur with melatonin therapy. Non-benzodiazepine hypnotics such as zolpidem can decrease REM sleep on EEG. Ramelteon effects on REM sleep are not well characterized. Animal studies have shown that sleep induced by ramelteon and melatonin was indistinguishable from control animals. The authors state that zolpidem discontinuation does not
465
cause withdrawal nightmares as benzodiazepines can. Nightmares have been reported with zolpidem discontinuation so further study could be beneficial [14A].
OXYTOCIN AND ANALOGUES [SEDA-35, 793; SEDA-36, 665; SEDA-37, 546] Cardiovascular Effects Oxytocin is known to cause hypotension and tachycardia. It may also cause nausea and vomiting, myocardial ischaemia and arrhythmias, especially when given in boluses >5 units. Chest pain and pulmonary edema may also occur. It would be highly desirable to prevent these side effects. Phenylephrine 80 mcg co-administered with the oxytocin dose has helped prevent these cardiovascular effects from oxytocin but was found to be excessive. This study co-administered 50 mcg of phenylephrine with oxytocin and found that dose do not reliably prevent hemodynamic effects of the oxytocin bolus [15C].
Autism Risk Maternal exposure to oxytocin during birth, induction and/or augmentation of labor, has been suspected to increase the rate of autism as the infant develops. A cohort of 557, 040 live births was identified according to Denmark’s birth registry between January 1, 2000 and December 31, 2009. Of this group, each child living on his first birthday was followed until December 31, 2012. An epidemiological analysis was performed to explore possible association between oxytocin exposures at birth with subsequent development of autism. A modest association between oxytocin-augmented labor and risk for autism was found in males but the therapeutic benefit of oxytocin administration during labor warrants caution in interpretation of these results [16c].
Caloric Intake A randomized, placebo-controlled crossover study of 25 healthy, fasting men gave a single-dose of intranasal oxytocin (24 IU) or placebo then double portions of a breakfast meal each subject selected from a menu. Content of food consumed was measured along with relevant parameters in the study subjects. Men receiving oxytocin prior to meals consumed less fat and less overall calories while not affecting the caloric content of food ordered from the menu. Increased levels of cholecystokinin were found after oxytocin, unrelated to caloric intake. Indirect calorimetry showed an increased fat utilization and decreased carbohydrate utilization as well as a trend toward a reduction in triglyceride levels following
466
41. MISCELLANEOUS HORMONES
oxytocin administration. Oxytocin also reduced insulin levels without changing glucose levels which implies increased insulin sensitivity. There was a slight decrease in body temperature (0.3 °F, p ¼ 0.006) after oxytocin. A few mild adverse effects were reported with no rate difference between oxytocin and placebo [17C].
SOMATOSTATIN (GROWTH HORMONE RELEASE-INHIBITING HORMONE) AND ANALOGUES [SED-15, 3160; SEDA-35, 794; SEDA-36, 666; SEDA-37, 549]
tolvaptan were compared with placebo, they were found to have good effects at elevating serum sodium levels and improvement of ascites. Monitoring was recommended to avoid treatment-related adverse events such as overcorrection of hyponatremia. Authors acknowledge the lack of evidence that vasopressin antagonists extend life in cirrhosis and call for future randomized controlled trials to study survival with each agent [20R].
Tolvaptan
Long-acting release pasireotide, a somatostatin analog, was compared with octreotide long-acting repeatable for managing carcinoid symptoms refractory to firstgeneration somatostatin analogues. Efficacy was similar but pasireotide was associated with more hyperglycemia, fatigue and nausea. Two patients stopped pasireotide due to grade 4 hyperglycemia [18C]. An open-label extension trial was conducted in 58 patients with Cushing’s disease who had been taking pasireotide for 12 months. The initial 12 months of the trial began with 162 Cushing’s patients treated with either 600 or 900 mcg pasireotide twice daily. A total of 24 months of pasireotide was completed by 40 patients so its efficacy and safety could be further assessed. Throughout the study period, reductions in urinary free cortisol, serum cortisol and plasma ACTH were maintained. Clinical signs were also consistently improved such as blood pressure, weight and total cholesterol levels. Adverse events were reported by 98.1% of studied patients within the 24-month period. Gastrointestinal disorders were most common at 81.5% of patients (55.6% reported diarrhea, 48.1% nausea). Hyperglycemia was observed in 38.9% of which 11.7% were grade 3 and 8.6% were grade 4. Cholelithiasis occurred in 31.5% and was suspected to be drug related. Over the 24-month period, 42 patients (25.9%) had adverse events that were rated as serious. No patient deaths occurred. Authors conclude that the safety profile of pasireotide was typical for a somatostatin analogue except glucose level changes which they recommended monitoring closely [19C].
A retrospective study of patients who had received tolvaptan was performed to provide insight into risk factors associated with development of hyponatremia. Keeping the daily dose of tolvaptan <7.5 mg was recommended in short- and long-term treatments. Age >75 years was also found to be predictive of late onset hyponatremia so caution is justified in this age group [21c]. A blinded re-examination of data from multiple tolvaptan trials for autosomal dominant polycystic kidney disease (ADPKD) was performed to better define the clinical pattern of potentially associated liver injury. The risk of liver failure in ADPKD after long-term tolvaptan therapy was estimated at 1:4000 with onset occurring within 3–18 months of receiving tolvaptan. All subjects experiencing hepatic injury recovered with no reports of liver failure. Frequent monitoring of liver function tests is recommended to reduce risk of liver injury during long-term tolvaptan use [22c]. In a meta-analysis of randomized controlled trials using tolvaptan in heart failure was performed to better describe the short- and long-term effects and allow evaluation as to its place in therapy. It was found that while tolvaptan may not bring long-term benefits in heart failure patients, it improves volume overload and hyponatremia without obvious increases in potassium and creatinine [23R]. Interim results of an ongoing study comparing tolvaptan use in heart failure patients >80 years of age with those <80 years. Tolvaptan was found to have similar safety and effectiveness profiles, but higher starting doses were found to be associated with more hypernatremia in those >80. Starting tolvaptan at no more than a 7.5 mg dose contributes to prevention of hypernatremia in heart failure patients >80 years of age [24C].
VASOPRESSIN RECEPTOR ANTAGONISTS [SEDA-34, 713; SEDA-35, 797; SEDA-36, 668; SEDA-37, 552]
VASOPRESSIN AND ANALOGUES [SEDA-33, 915; SEDA-34, 714; SEDA-35, 798; SEDA-36, 669; SEDA-37, 552]
Cirrhosis with Ascites
Hemodynamic Support
Three vasopressin receptor antagonists were considered as a group for their use limitations in the treatment of cirrhosis with ascites. When lixivaptan, satavaptan or
In a retrospective, propensity-matched cohort of septic shock patients, vasopressin was favorably compared to hydrocortisone for hemodynamic support secondary to
Pasireotide Clinical Studies
REFERENCES
norepinephrine. Vasopressin was associated with quicker hemodynamic stability and discontinuation of hemodynamic support. Arrhythmias were more frequent with vasopressin, but incidence of superinfection, hyperglycemia and hyponatremia was less frequent when compared to patients receiving hydrocortisone. Authors concluded that vasopressin was a more advantageous endocrine agent for hemodynamic support in septic shock than hydrocortisone [25c].
DESMOPRESSIN (N-DEAMINO-8-DARGININE VASOPRESSIN, DDAVP) [SEDA-34, 714; SEDA-35, 798; SEDA-36, 669; SEDA-37, 552] Dermatologic Reaction Interstitial Granulomatous Drug Reaction (IGDR) has been reported in a 56-year-old man after he had taken intranasal desmopressin for diabetes insipidus developed after prolactinoma excision. Rechallenge was associated with a recurrence of the IGDR truncal lesions. Both the initial and rechallenge eruptions resolved within 2–3 weeks of desmopressin discontinuation [26A].
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