Pediatr Cardiol DOI 10.1007/s00246-015-1113-9
ORIGINAL ARTICLE
Treatment of Pulmonary Arterial Hypertension Using Extemporaneous Formulation of Sildenafil in Mexican Children Hugo Jua´rez Olguı´n • Laura Camacho Reyes • Arturo Roldan Arce • David Caldero´n Guzma´n
Received: 20 November 2014 / Accepted: 13 January 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary arterial hypertension (PAH) is a sickness with high rate of mortality that consists of elevation in pressure of the vessels through which blood flows to the lung. Sildenafil is a therapeutic option for the treatment of PAH in children for the fact that it relaxes the blood vessels and thereby improves pulmonary blood flow. The aim was to analyze the clinical behavior of an extemporaneous formulation of sildenafil as a therapeutic option in children with PAH, twelve children with PAH were studied. The ages and weights of the children ranged from 5 to 15 years and from 13 to 27 kg. All patients received a capsule of 1 mg/kg of sildenafil prepared as extemporaneous formulation in the pharmacology laboratory. Blood levels of sildenafil were analyzed in order to evaluate its availability of developed formulation. Management has derived from physiopathological knowledge and clinical presentations of patients. The mean maximum concentration was 550 ng/ml which is greater than levels reported in adults. Moreover, a therapeutic monitoring of H. J. Olguı´n (&) Laboratorio de Farmacologı´a, Instituto Nacional de Pediatrı´a (INP), Av Ima´n # 1, 3er piso, Col Cuicuilco, CP 04530 Mexico City, Mexico e-mail: [email protected]; [email protected] H. J. Olguı´n Departamento de Farmacologı´a, Facultad de Medicina, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico L. C. Reyes A. R. Arce Servicio de Cardiologı´a, Instituto Nacional de Pediatrı´a (INP), Mexico City, Mexico D. C. Guzma´n Laboratorio de Neuroquı´mica, Instituto Nacional de Pediatrı´a (INP), Mexico City, Mexico
sildenafil was carried out in order to establish an adequate therapeutic range for children and to show that dosages prepared extemporaneously meet the therapeutic needs for the management of PAH. With an average follow-up of once every 2 months, it was found that the evolution of the patients was favorable and without adverse effects that could put their life at risk. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option. Keywords Children Pulmonary arterial hypertension Sildenafil Unitary doses
Introduction Pulmonary arterial hypertension (PAH) is a sickness that consists of elevation in the pressure of blood vessels responsible for irrigating the lung. It is defined as the presence of median pulmonary arterial pressure (PAP) higher than 25 mmHg in resting state or higher than 30 mmHg during exercise [18]. Until now, the exact etiologies of the elevation of arterial pressure and hypertension development are unknown; nevertheless, it is well known that narrowing of the vessel lumen that irrigates the lung is the principal origin [3, 17]. In general, the higher the volume of blood pumped by the heart and the lesser lumen diameter of the arteries, the higher is the arterial pressure. This means that the miocardic muscles have to exert more effort to pump the same amount of blood [11]. In particular, infants and children with congenital cardiopathy in need of surgical repair could potentially present deadly postoperatory pulmonary hypertensive crisis [2]. For the fact that the incidence of this pathology is relatively low, there is an under-diagnosis or lack of knowledge of
123
Pediatr Cardiol
the same and even among medical doctors, it is highly easy to confuse with other differential pathologies such as asthma, chronic obstructive lung disease, or other kind of disorders that could cause respiratory distress [4]. Even when there is lack of registrar on the incidence of this pathology in our country, reports in the literature put the occurrence from 0.5 to 1.5 cases for every 1,000 living newborns in USA and England. The mortality rate oscillates from 10 to 50 % depending on the triggering factor PAH. Majority of the times, it jointly appears with congenital cardiopathy [5], and half of the patients do not survive for more than 2 or 3 years after the diagnosis if they do not receive timely treatment [10]. One of the principal difficulties in opportune diagnosis of the pathology is the gradual development of the symptoms. Majority of the times, the lapse between the development of the disease and the appearance of its symptoms may be 2 to 5 years. Almost all the patients with symptoms of PAH, without minding the cause, have dyspnea, and little tolerance to physical exercise which often times is interpreted by the patient as sensation of fatigue. The clinical suspicion of PAH could arise from symptoms such as dyspnea, chest pain, and effort syncope or clinical findings like systemic venous congestion. Radiological, electrocardiographical, or echocardiographical (ECG) findings may also depict the onset of the disease. ECG permits the establishment if the cause of PAH is due to cardiac (valve or myocardia) affection [13]. Moreover, the same study would give insight to the existence of congenital septal defect or its absence. The respiratory function test (RPT) together with chest X-ray allows us to know if there is obstructive or restrictive pneumonia as a secondary cause of PAH. Nevertheless, the definitive diagnostic process lays on realization of right cardiac catheter (RCC) that confirms the diagnosis, establishes its severity, and the possibility of potential reversibility through acute pharmacological challenge. Vasodilators have proved to be efficacious in the management of PAH. It has been shown that 20 % of the patients treated with this group of drugs witnessed a significant reduction in their pulmonary pressure [1]. Presently, the most evaluated drug in this group is intravenous prostacyclin, although the side effects and the application of pump for its infusion which constitute uncomfortable disadvantages and a fact that have led to researches on new formulas could improve the former [19]. Recently, the introduction of sildenafil in the treatment of PAH in children has come into vogue since it was found to be effective in the relaxation of the blood vessels of the lung, thus, permitting easy blood flow to this zone [21, 22]. The pharmacological action of sildenafil rests on increasing the effect of nitric oxide by inhibiting type 5 phosphodiesterase
123
(FDE5) enzyme, responsible for the degradation of cGMP for its similarity with sildenafil [14], an effect which leads to high concentrations of cGMP, and this way gives rise to the relaxation of smooth muscles of the lung which favors blood flow [6]. Reports of studies carried out in adults indicate that sildenafil undergoes rapid absorption after its oral administration with approximately 40 % of absolute bioavailability. The maximum plasma concentration is reached from 30 to 120 min with an average of 60 min after its oral administration in fasting condition [7]. Sildenafil is metabolized to an active metabolite. In children or patients with hepatic failure, it has been observed decrease in its elimination. Recently, an extemporaneous formulation of sildenafil was developed in our laboratory because in Mexico a pediatric formulation containing sildenafil does not exist [15]. The objective of this work is to analyze the clinical behavior of children with PAH using an extemporaneous formulation of sildenafil as therapeutic option.
Patients A prospective, descriptive, transversal, and longitudinal study involving the participation and follow-up of patients diagnosed of PAH at Cardiology Service of National Institute of Pediatrics (INP), Mexico City. The patients were referred to cardiology service for presenting symptoms compatible with restrictive or mixed obstructive pulmonary disease, collagen and parasitic diseases with pulmonary involvement, and chronic hemolytic anemia among others. A detailed clinical history and point by point physical exploration for the diagnosis of PAH were carried out. ECG and chest X-ray to reinforce the clinical impression of pulmonary hypertension were also performed. Once this impression was confirmed, the patients were made to receive sildenafil (1 mg/kg) twice per day of an extemporal formula prepared from sildenafil (Viagra) in our laboratory [15]. Moreover, the treatment was complemented with spironolactone and/or furosemide. A followup of the patients to determine treatment response was realized in the external consult of cardiology service every 2 months where their clinical condition and general status were evaluated. Moreover, a 6-min walk test to establish their functional state and prognosis and also to measure therapeutic response was carried out. The research protocol was approved by the Research Ethics Committee of the INP, Me´xico, and informed consent was obtained from the parent or guardian of each patient, according to principles of Helsinki Declaration. Acceptance into the study did not involve greater risks than those related to sampling to measure levels of sildenafil. The volume was minimal and did not put at risk the balance or imbalance of fluids.
Pediatr Cardiol
Results
Discussion
Until date, 12 patients with age and weight range of 5–15 years and 13–27 kg have been included in the study. Majority of the children that accepted to participate in the study, prior to the consent of their parents or guardians, were of early ages. The demographic characteristics of the patients as well as their physiological state (associated to the sickness) are shown in Tables 1 and 2. The gestational records revealed that majority of the patients were preterms (Fig. 1). Moreover, it was found that within the perinatal records, apnea secondary to prematurity predominated in the patients included in the study (Fig. 2). In some patients, ECG complemented with RCC was sufficient since these studies are fundamental in diagnosis and clinical follow-up of patients with PAH (Fig. 3), and to whom in addition to the above, a complete pulmonary hemodynamic study is carried out. Some of our patients crossed with data of under-development especially in their weight and size. Nevertheless, their participation in the study was authorized by their parents or guardians as well as their cardiology doctors who accompanied the patients during the study as a part of inclusion criteria. The patients were monitored with ECG during their study; however, no important alterations in their echocardiographical parameters were found. All patients are still receiving 1 mg/kg of sildenafil in an individualized presentation exclusively prepared and adequated by our laboratory. In general for older children, we asked them if they can swallow the capsule, but if not, the content of the powder is dispensed in suspension administrated.
Pulmonary arterial hypertension is a progressive and fatal disease that lacks a definitive curative treatment. In recent years, knowledge in the mechanisms of vascular damage characteristics of the disease has witnessed a very great advance [9]. Presently, it continues to be a rare sickness. Majority of the time, it is under-diagnosed, even when counting with a greater knowledge on its physiopathology [20]. Sildenafil citrate is a powerful vasodilator famous in the treatment of erectile dysfunction. Nevertheless, the use has been extended to the treatment of pulmonary hypertension not only in adults but also in children. The drug is being used in at INP on dose–response basis. Therefore, it is of paramount interest to have a more exact estimation of its behavior [8]. In children, the dose is 1 mg/kg with maximum total dose of 25 mg. The elimination of sildenafil is principally by hepatic metabolism with the involvement of P-450 3A4 cytochrome. It is converted to an active metabolite by the action of this cytochrome. The characteristics of this active metabolite are similar to the original compound, sildenafil. In adults, the maximum concentration (Cmax) is approximately 200 ng/ml [7]. Cmax observed obtained during the therapeutic monitoring among the patients studied was from 330 to 550 ng/ml, as resulting of the therapeutic monitoring, using a newly developed formulation in our laboratory [16], which depicts a considerable elevation in the concentration even when we use doses similar to that administered in adults whose maximum total dose is 100 mg. Although it is difficult to establish correlation between Cmax and efficacy for the low number of patients
Table 1 Demographic characteristics of patients with pulmonary arterial hypertension included in the study Patients
Age
Gender
Weight (kg)
Size (cm)
Diagnosis
Other sickness
1
5 years
M
13
90
PAH
Derivation of pulmonary vein
2
6 years 9 months
M
6.5
115
PAH
Psychomotor retardation
3
6 years 2 months
M
15
100
PAH
Gastroesophageal reflux (GER)
4
10 years 5 months
M
18
113
ICV, PAH
CIA with triatum
5
2 years 8 days
M
7.9
90
PAH
Epilepsy, Down Sx
6
6 years 3 months
M
11.8
98
PAH, ICV
Thrombosis of vena porta, porto pulmonary syndrome
7
1 years 5 months
M
8.9
74
PAH
GER, Pulmonary dysplasia, hypothyroidism
8
15 years
F
26
148
PAH
Psychomotor retardation
9
12 years 4 months
F
18
112
PAH
GER, CIA, Psychomotor retardation
10
3 years 6 months
M
12
102
PAH
Down Sx
11 12
6 years 5 months 4 years 8 months
M M
16 14
105 119
PAH PAH
Gastroesophageal reflux (GER) GER
123
Pediatr Cardiol Table 2 Dosage and vital signs of the patients with pulmonary arterial hypertension during therapeutic monitoring of sildenafil
CF cardiac frequency, AT arterial tension, RF respiratory frequency a
Total dose of sildenafil, given twice/day, Cmax: Concentration maximum observed 2-h postdose
Cmax (ng/ml)
43.1
36.7
13
402
22
36.7
1
144.6
83.8
58.8
2
99.9
88.7
59.3
3
122.4
91.2
57.5
23.4
36.1
15
376
4
108.7
90
68.8
19.7
36
18
470
5
131.2
88.7
58.7
43
36.5
7.9
424
RF
98.7
545
6.5
343
80.7
52.1
20.3
36.5
11.8
7
128
85
50
56.8
36.1
8.9
8
99
101.4
60
21.7
35.9
9
101
87.5
53.7
17.9
34.5
18
550
10
100
70
60
22
36.5
12
452
11
112.4
12
95
26
377 442
93.2
67.5
28.4
36.2
16
396
70
55
19
36.3
14
330
Fig. 1 Gestational clinical records at birth of the patients with pulmonary arterial hypertension
Fig. 2 Perinatal clinical records and maneuvers at birth of the patients with pulmonary arterial hypertension A apnea after premature, B advanced maneuvers to reanimation, C intubation and ingress to therapy service, D required incubation, E onfalorrexis at born
analyzed until now, however, those values were maintained as efficacy and non-toxic after clinic evaluation of patients. The study was realized under multiple dose modality in order to reach the steady state of sildenafil (at least in 2 days of treatment) where therapeutic monitoring is
123
Diastolic AT
Total dose (mg)a
CF
6
Systolic AT
Temp
Patients
Fig. 3 Diagnosis for the evaluation of the presence of the disease basically consists of echocardiogram (ECG) confirmed with right cardiac catheter (RCC)
recommended. Bioavailability and pharmacokinetics are related; however, the aim for the actual study was different, where only concentration of an extemporaneous formulation of sildenafil was studied trying to stablish its applicability, and it would be premature to conclude whether any therapeutic failure (non-effective) or toxic effect would present. Based on the above, the treatment scheme ought to be adjusted taking into consideration the parameters of every population. This would, as far as possible, contribute in reducing events of intoxication due to elevated levels. In adults, incidences of headache, sleeplessness, and dizziness have been reported [12]. Although, in clinical studies, it has been demonstrated that sildenafil has systemic vasodilator properties that give rise to transitory reduction in arterial pressure. The adverse events found in our patients were headache in two cases, abdominal pain in one case, and hypotension also in one case. However, these adverse events with mild to moderate intensity were transitory, and therefore, sildenafil could be said to show a good level of security.
Pediatr Cardiol
The preparation of extemporaneous sildenafil with individualized doses is a good alternative to dosify sildenafil that our laboratory offered as a support for the clinicians who have the mission to treat and control PAH in ambulatory patients. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option. Nevertheless, it should be reiterated that it is untimely to take this as definitive conclusion that would ensure its efficacy and safety. We believe that further research is necessary in this respect. Acknowledgments We thank Dr Cyril Ndidi Nwoye, a native English speaker and a renowned, professional translator, for working in the translation and correction of the manuscript. No funding was received from none of the institutions. Conflict of interest interest.
The authors declare that there is no conflict of
References 1. Adatia I, Shekerdemian L (2010) The role of calcium channel blockers, steroids, anticoagulation, antiplatelet drugs, and endothelin receptor antagonists. Pediatr Crit Care Med 11(S2):46–52 2. Banjar H (2010) Review of management guidelines of pulmonary arterial hypertension in the pediatric population. Pulm Vasc Res Inst 2:100–113 3. Banjar HH (2013) Causes of pulmonary hypertension among children. Curr Pediatr Res 17:31–36 4. Barst RJ, McGoon M, Torbicki A (2004) Diagnosis and differential assessment of pulmonary arterial hypertension. J Am Coll Cardiol 43:40S–47S 5. Beghetti M (2004) Congenital heart disease and pulmonary hypertension. Rev Port Cardiol 23:273–281 6. Cannon BC, Feltes TF, Kennard FJ, Grifka RG (2005) Nitric oxide in the evaluation of congenital heart disease with pulmonary hypertension: factors related to nitric oxide response. Pediatr Cardiol 26:565–569 7. Chaumais MC, Perrin S, Sitbon O, Simonneau G, Humbert M, Montani D (2013) Pharmacokinetic evaluation of sildenafil as a pulmonary hypertension treatment. Expert Opin Drug Metab Toxicol 9:1193–1205
8. Chockalingam A, Gnanavelu G, Venkatesan S (2005) Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol 99:91–95 9. European Society of Cardiology (ESC) (2009) Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 30:2493–2537 10. Farber HW, Loscalzo J (2004) Pulmonary arterial hypertension, mechanisms of disease. N Engl J Med 351:1655–1665 11. Kulik TJ (2010) Pathophysiology of acute pulmonary vasoconstriction. Pediatr Crit Care Med 11:10–14 12. Mikhail GW, Prasad SK, Li W (2004) Clinical and haemodynamic effects of sildenafil in pulmonary hypertension: acute and midterm effects. Eur Heart J 25:431–436 13. Mullen MP (2010) Diagnostic strategies for acute presentation of pulmonary hypertension in children: particular focus on use of echocardiography, cardiac catheterization, magnetic resonance imaging, chest computed tomography, and lung biopsy. Pediatr Crit Care Med 11(S2):23–26 14. Namachivayam P, Theilen U, Warwick WB, Cooper SM (2006) Sildenafil prevents rebound pulmonary hypertension after withdrawal of nitric. Am J Resp Crit Care Med 174:1042–1047 15. Ramirez Mendiola B, Rivera Espinosa L, Chavez Pacheco JL, Juarez Olguin H, Alemon Medina R, Flores Perez C (2012) Stability, uniform content and therapeutic efficacy of sildenafil extemporaneous capsules. Afr J Pharm Pharmacol 6:162–168 ´ lvarez R, Jua´rez16. Ramı´rez-Mendiola B, Flores-Pe´rez C, Garcı´a-A ´ ´ Olguın H, Flores-Perez J, Pacheco JLC (2013) A reliable method to quantify sildenafil and its metabolite N-demethylsildenafil by HPLC in plasma of children. Drug Res 63:473–476 17. Rich S (2004) Classification and clinical features of pulmonary hypertension. In: Peacock A, Rubin LJ (eds) Pulmonary circulation, 2nd edn. Arnold, London, pp 147–153 18. Sandoval ZJ (2006) Hipertensio´n arterial pulmonar. Arch Cardiol Mex 76(Supl2):69–75 19. Simonneau G, Barst RJ, Galie´ N (2002) Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 165:800–804 20. Uranga I, Barrueta OI, Oribe IM, Lertxundi AE (2004) Tratamiento de la hipertensio´n pulmonar. Farm Hosp 28:275–285 21. Wang RC, Jiang FM, Zheng QL, Li CT, Peng XY, He CY et al (2014) Efficacy and safety of sildenafil treatment in pulmonary arterial hypertension: a systematic review. Respir Med 108:531–537 22. Yanagisawa R, Kataoka M, Taguchi H, Kawakami T, Tamura Y, Fukuda K et al (2012) Impact of first-line sildenafil monotreatment for pulmonary arterial hypertension. Circ J 76:1245–1252
123
ORIGINAL ARTICLE
Treatment of Pulmonary Arterial Hypertension Using Extemporaneous Formulation of Sildenafil in Mexican Children Hugo Jua´rez Olguı´n • Laura Camacho Reyes • Arturo Roldan Arce • David Caldero´n Guzma´n
Received: 20 November 2014 / Accepted: 13 January 2015 Ó Springer Science+Business Media New York 2015
Abstract Pulmonary arterial hypertension (PAH) is a sickness with high rate of mortality that consists of elevation in pressure of the vessels through which blood flows to the lung. Sildenafil is a therapeutic option for the treatment of PAH in children for the fact that it relaxes the blood vessels and thereby improves pulmonary blood flow. The aim was to analyze the clinical behavior of an extemporaneous formulation of sildenafil as a therapeutic option in children with PAH, twelve children with PAH were studied. The ages and weights of the children ranged from 5 to 15 years and from 13 to 27 kg. All patients received a capsule of 1 mg/kg of sildenafil prepared as extemporaneous formulation in the pharmacology laboratory. Blood levels of sildenafil were analyzed in order to evaluate its availability of developed formulation. Management has derived from physiopathological knowledge and clinical presentations of patients. The mean maximum concentration was 550 ng/ml which is greater than levels reported in adults. Moreover, a therapeutic monitoring of H. J. Olguı´n (&) Laboratorio de Farmacologı´a, Instituto Nacional de Pediatrı´a (INP), Av Ima´n # 1, 3er piso, Col Cuicuilco, CP 04530 Mexico City, Mexico e-mail: [email protected]; [email protected] H. J. Olguı´n Departamento de Farmacologı´a, Facultad de Medicina, Universidad Nacional Auto´noma de Me´xico, Mexico City, Mexico L. C. Reyes A. R. Arce Servicio de Cardiologı´a, Instituto Nacional de Pediatrı´a (INP), Mexico City, Mexico D. C. Guzma´n Laboratorio de Neuroquı´mica, Instituto Nacional de Pediatrı´a (INP), Mexico City, Mexico
sildenafil was carried out in order to establish an adequate therapeutic range for children and to show that dosages prepared extemporaneously meet the therapeutic needs for the management of PAH. With an average follow-up of once every 2 months, it was found that the evolution of the patients was favorable and without adverse effects that could put their life at risk. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option. Keywords Children Pulmonary arterial hypertension Sildenafil Unitary doses
Introduction Pulmonary arterial hypertension (PAH) is a sickness that consists of elevation in the pressure of blood vessels responsible for irrigating the lung. It is defined as the presence of median pulmonary arterial pressure (PAP) higher than 25 mmHg in resting state or higher than 30 mmHg during exercise [18]. Until now, the exact etiologies of the elevation of arterial pressure and hypertension development are unknown; nevertheless, it is well known that narrowing of the vessel lumen that irrigates the lung is the principal origin [3, 17]. In general, the higher the volume of blood pumped by the heart and the lesser lumen diameter of the arteries, the higher is the arterial pressure. This means that the miocardic muscles have to exert more effort to pump the same amount of blood [11]. In particular, infants and children with congenital cardiopathy in need of surgical repair could potentially present deadly postoperatory pulmonary hypertensive crisis [2]. For the fact that the incidence of this pathology is relatively low, there is an under-diagnosis or lack of knowledge of
123
Pediatr Cardiol
the same and even among medical doctors, it is highly easy to confuse with other differential pathologies such as asthma, chronic obstructive lung disease, or other kind of disorders that could cause respiratory distress [4]. Even when there is lack of registrar on the incidence of this pathology in our country, reports in the literature put the occurrence from 0.5 to 1.5 cases for every 1,000 living newborns in USA and England. The mortality rate oscillates from 10 to 50 % depending on the triggering factor PAH. Majority of the times, it jointly appears with congenital cardiopathy [5], and half of the patients do not survive for more than 2 or 3 years after the diagnosis if they do not receive timely treatment [10]. One of the principal difficulties in opportune diagnosis of the pathology is the gradual development of the symptoms. Majority of the times, the lapse between the development of the disease and the appearance of its symptoms may be 2 to 5 years. Almost all the patients with symptoms of PAH, without minding the cause, have dyspnea, and little tolerance to physical exercise which often times is interpreted by the patient as sensation of fatigue. The clinical suspicion of PAH could arise from symptoms such as dyspnea, chest pain, and effort syncope or clinical findings like systemic venous congestion. Radiological, electrocardiographical, or echocardiographical (ECG) findings may also depict the onset of the disease. ECG permits the establishment if the cause of PAH is due to cardiac (valve or myocardia) affection [13]. Moreover, the same study would give insight to the existence of congenital septal defect or its absence. The respiratory function test (RPT) together with chest X-ray allows us to know if there is obstructive or restrictive pneumonia as a secondary cause of PAH. Nevertheless, the definitive diagnostic process lays on realization of right cardiac catheter (RCC) that confirms the diagnosis, establishes its severity, and the possibility of potential reversibility through acute pharmacological challenge. Vasodilators have proved to be efficacious in the management of PAH. It has been shown that 20 % of the patients treated with this group of drugs witnessed a significant reduction in their pulmonary pressure [1]. Presently, the most evaluated drug in this group is intravenous prostacyclin, although the side effects and the application of pump for its infusion which constitute uncomfortable disadvantages and a fact that have led to researches on new formulas could improve the former [19]. Recently, the introduction of sildenafil in the treatment of PAH in children has come into vogue since it was found to be effective in the relaxation of the blood vessels of the lung, thus, permitting easy blood flow to this zone [21, 22]. The pharmacological action of sildenafil rests on increasing the effect of nitric oxide by inhibiting type 5 phosphodiesterase
123
(FDE5) enzyme, responsible for the degradation of cGMP for its similarity with sildenafil [14], an effect which leads to high concentrations of cGMP, and this way gives rise to the relaxation of smooth muscles of the lung which favors blood flow [6]. Reports of studies carried out in adults indicate that sildenafil undergoes rapid absorption after its oral administration with approximately 40 % of absolute bioavailability. The maximum plasma concentration is reached from 30 to 120 min with an average of 60 min after its oral administration in fasting condition [7]. Sildenafil is metabolized to an active metabolite. In children or patients with hepatic failure, it has been observed decrease in its elimination. Recently, an extemporaneous formulation of sildenafil was developed in our laboratory because in Mexico a pediatric formulation containing sildenafil does not exist [15]. The objective of this work is to analyze the clinical behavior of children with PAH using an extemporaneous formulation of sildenafil as therapeutic option.
Patients A prospective, descriptive, transversal, and longitudinal study involving the participation and follow-up of patients diagnosed of PAH at Cardiology Service of National Institute of Pediatrics (INP), Mexico City. The patients were referred to cardiology service for presenting symptoms compatible with restrictive or mixed obstructive pulmonary disease, collagen and parasitic diseases with pulmonary involvement, and chronic hemolytic anemia among others. A detailed clinical history and point by point physical exploration for the diagnosis of PAH were carried out. ECG and chest X-ray to reinforce the clinical impression of pulmonary hypertension were also performed. Once this impression was confirmed, the patients were made to receive sildenafil (1 mg/kg) twice per day of an extemporal formula prepared from sildenafil (Viagra) in our laboratory [15]. Moreover, the treatment was complemented with spironolactone and/or furosemide. A followup of the patients to determine treatment response was realized in the external consult of cardiology service every 2 months where their clinical condition and general status were evaluated. Moreover, a 6-min walk test to establish their functional state and prognosis and also to measure therapeutic response was carried out. The research protocol was approved by the Research Ethics Committee of the INP, Me´xico, and informed consent was obtained from the parent or guardian of each patient, according to principles of Helsinki Declaration. Acceptance into the study did not involve greater risks than those related to sampling to measure levels of sildenafil. The volume was minimal and did not put at risk the balance or imbalance of fluids.
Pediatr Cardiol
Results
Discussion
Until date, 12 patients with age and weight range of 5–15 years and 13–27 kg have been included in the study. Majority of the children that accepted to participate in the study, prior to the consent of their parents or guardians, were of early ages. The demographic characteristics of the patients as well as their physiological state (associated to the sickness) are shown in Tables 1 and 2. The gestational records revealed that majority of the patients were preterms (Fig. 1). Moreover, it was found that within the perinatal records, apnea secondary to prematurity predominated in the patients included in the study (Fig. 2). In some patients, ECG complemented with RCC was sufficient since these studies are fundamental in diagnosis and clinical follow-up of patients with PAH (Fig. 3), and to whom in addition to the above, a complete pulmonary hemodynamic study is carried out. Some of our patients crossed with data of under-development especially in their weight and size. Nevertheless, their participation in the study was authorized by their parents or guardians as well as their cardiology doctors who accompanied the patients during the study as a part of inclusion criteria. The patients were monitored with ECG during their study; however, no important alterations in their echocardiographical parameters were found. All patients are still receiving 1 mg/kg of sildenafil in an individualized presentation exclusively prepared and adequated by our laboratory. In general for older children, we asked them if they can swallow the capsule, but if not, the content of the powder is dispensed in suspension administrated.
Pulmonary arterial hypertension is a progressive and fatal disease that lacks a definitive curative treatment. In recent years, knowledge in the mechanisms of vascular damage characteristics of the disease has witnessed a very great advance [9]. Presently, it continues to be a rare sickness. Majority of the time, it is under-diagnosed, even when counting with a greater knowledge on its physiopathology [20]. Sildenafil citrate is a powerful vasodilator famous in the treatment of erectile dysfunction. Nevertheless, the use has been extended to the treatment of pulmonary hypertension not only in adults but also in children. The drug is being used in at INP on dose–response basis. Therefore, it is of paramount interest to have a more exact estimation of its behavior [8]. In children, the dose is 1 mg/kg with maximum total dose of 25 mg. The elimination of sildenafil is principally by hepatic metabolism with the involvement of P-450 3A4 cytochrome. It is converted to an active metabolite by the action of this cytochrome. The characteristics of this active metabolite are similar to the original compound, sildenafil. In adults, the maximum concentration (Cmax) is approximately 200 ng/ml [7]. Cmax observed obtained during the therapeutic monitoring among the patients studied was from 330 to 550 ng/ml, as resulting of the therapeutic monitoring, using a newly developed formulation in our laboratory [16], which depicts a considerable elevation in the concentration even when we use doses similar to that administered in adults whose maximum total dose is 100 mg. Although it is difficult to establish correlation between Cmax and efficacy for the low number of patients
Table 1 Demographic characteristics of patients with pulmonary arterial hypertension included in the study Patients
Age
Gender
Weight (kg)
Size (cm)
Diagnosis
Other sickness
1
5 years
M
13
90
PAH
Derivation of pulmonary vein
2
6 years 9 months
M
6.5
115
PAH
Psychomotor retardation
3
6 years 2 months
M
15
100
PAH
Gastroesophageal reflux (GER)
4
10 years 5 months
M
18
113
ICV, PAH
CIA with triatum
5
2 years 8 days
M
7.9
90
PAH
Epilepsy, Down Sx
6
6 years 3 months
M
11.8
98
PAH, ICV
Thrombosis of vena porta, porto pulmonary syndrome
7
1 years 5 months
M
8.9
74
PAH
GER, Pulmonary dysplasia, hypothyroidism
8
15 years
F
26
148
PAH
Psychomotor retardation
9
12 years 4 months
F
18
112
PAH
GER, CIA, Psychomotor retardation
10
3 years 6 months
M
12
102
PAH
Down Sx
11 12
6 years 5 months 4 years 8 months
M M
16 14
105 119
PAH PAH
Gastroesophageal reflux (GER) GER
123
Pediatr Cardiol Table 2 Dosage and vital signs of the patients with pulmonary arterial hypertension during therapeutic monitoring of sildenafil
CF cardiac frequency, AT arterial tension, RF respiratory frequency a
Total dose of sildenafil, given twice/day, Cmax: Concentration maximum observed 2-h postdose
Cmax (ng/ml)
43.1
36.7
13
402
22
36.7
1
144.6
83.8
58.8
2
99.9
88.7
59.3
3
122.4
91.2
57.5
23.4
36.1
15
376
4
108.7
90
68.8
19.7
36
18
470
5
131.2
88.7
58.7
43
36.5
7.9
424
RF
98.7
545
6.5
343
80.7
52.1
20.3
36.5
11.8
7
128
85
50
56.8
36.1
8.9
8
99
101.4
60
21.7
35.9
9
101
87.5
53.7
17.9
34.5
18
550
10
100
70
60
22
36.5
12
452
11
112.4
12
95
26
377 442
93.2
67.5
28.4
36.2
16
396
70
55
19
36.3
14
330
Fig. 1 Gestational clinical records at birth of the patients with pulmonary arterial hypertension
Fig. 2 Perinatal clinical records and maneuvers at birth of the patients with pulmonary arterial hypertension A apnea after premature, B advanced maneuvers to reanimation, C intubation and ingress to therapy service, D required incubation, E onfalorrexis at born
analyzed until now, however, those values were maintained as efficacy and non-toxic after clinic evaluation of patients. The study was realized under multiple dose modality in order to reach the steady state of sildenafil (at least in 2 days of treatment) where therapeutic monitoring is
123
Diastolic AT
Total dose (mg)a
CF
6
Systolic AT
Temp
Patients
Fig. 3 Diagnosis for the evaluation of the presence of the disease basically consists of echocardiogram (ECG) confirmed with right cardiac catheter (RCC)
recommended. Bioavailability and pharmacokinetics are related; however, the aim for the actual study was different, where only concentration of an extemporaneous formulation of sildenafil was studied trying to stablish its applicability, and it would be premature to conclude whether any therapeutic failure (non-effective) or toxic effect would present. Based on the above, the treatment scheme ought to be adjusted taking into consideration the parameters of every population. This would, as far as possible, contribute in reducing events of intoxication due to elevated levels. In adults, incidences of headache, sleeplessness, and dizziness have been reported [12]. Although, in clinical studies, it has been demonstrated that sildenafil has systemic vasodilator properties that give rise to transitory reduction in arterial pressure. The adverse events found in our patients were headache in two cases, abdominal pain in one case, and hypotension also in one case. However, these adverse events with mild to moderate intensity were transitory, and therefore, sildenafil could be said to show a good level of security.
Pediatr Cardiol
The preparation of extemporaneous sildenafil with individualized doses is a good alternative to dosify sildenafil that our laboratory offered as a support for the clinicians who have the mission to treat and control PAH in ambulatory patients. The management of PAH with sildenafil prepared as extemporaneous formulation might be considered as a good therapeutic option. Nevertheless, it should be reiterated that it is untimely to take this as definitive conclusion that would ensure its efficacy and safety. We believe that further research is necessary in this respect. Acknowledgments We thank Dr Cyril Ndidi Nwoye, a native English speaker and a renowned, professional translator, for working in the translation and correction of the manuscript. No funding was received from none of the institutions. Conflict of interest interest.
The authors declare that there is no conflict of
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