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  IN THIS Article
 ::  Abstract
 :: Introduction
 ::  Sildenafil: Phar...
 ::  Sildenafil: Clin...
 :: Conclusion
 :: Acknowledgment
 ::  Recent Controver...
 ::  References
 ::  Article Tables

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  Table of Contents     
Year : 2015  |  Volume : 61  |  Issue : 3  |  Page : 181-192

Sildenafil in pediatric pulmonary arterial hypertension

Department of Pediatrics, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra, India

Date of Submission23-Dec-2014
Date of Decision09-Feb-2015
Date of Acceptance07-Apr-2015
Date of Web Publication26-Jun-2015

Correspondence Address:
A K Dhariwal
Department of Pediatrics, Topiwala National Medical College and BYL Nair Charitable Hospital, Mumbai, Maharashtra
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Source of Support: No funds or grants were received from any funding agency in the public, commercial, or not-for-profit sectors,, Conflict of Interest: None

DOI: 10.4103/0022-3859.159421

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 :: Abstract 

Pulmonary arterial hypertension (PAH) is a life-threatening disease of varied etiologies. Although PAH has no curative treatment, a greater understanding of pathophysiology, technological advances resulting in early diagnosis, and the availability of several newer drugs have improved the outlook for patients with PAH. Sildenafil is one of the therapeutic agents used extensively in the treatment of PAH in children, as an off-label drug. In 2012, the United States Food and Drug Administration (USFDA) issued a warning regarding the of use high-dose sildenafil in children with PAH. This has led to a peculiar situation where there is a paucity of approved therapies for the management of PAH in children and the use of the most extensively used drug being discouraged by the regulator. This article provides a review of the use of sildenafil in the treatment of PAH in children.

Keywords: Child, phosphodiesterase (PDE)-5 inhibitor, Pulmonary hypertension therapy

How to cite this article:
Dhariwal A K, Bavdekar S B. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med 2015;61:181-92

How to cite this URL:
Dhariwal A K, Bavdekar S B. Sildenafil in pediatric pulmonary arterial hypertension. J Postgrad Med [serial online] 2015 [cited 2023 Sep 27];61:181-92. Available from:

 :: Introduction Top

Pulmonary arterial hypertension (PAH), characterized by the progressive obliteration of the pulmonary vasculature, is associated with high mortality and great morbidity, especially in children. [1] Better understanding of the pathophysiology of PAH, advances in technology allowing for early diagnosis, and the availability of several newer therapeutic agents have improved the outlook for patients with PAH. Inhaled nitric oxide (iNO), iloprost, bosentan, and sildenafil are used in the treatment of children with PAH. Among these, sildenafil is the most widely used and has, in great part, contributed to improved survival in this group, from a historical less-than-1-year survival in untreated children in the 1980s to a 97% 5-year survival rate in children with severe PAH. [1] However, it must be conceded that most of the agents mentioned are used off-label in children and the use is based mainly on experience in adults with PAH. The recently issued U.S. Food and Drug Administration (USFDA) warning has created fresh doubts in the minds of treating pediatricians regarding the use of sildenafil in children with PAH. [2] This communication attempts to review the place of sildenafil in the treatment of childhood PAH.

PAH in children: Pathophysiology and classification

PAH is defined as a mean pulmonary artery pressure (PAP) of 25 mmHg or higher at rest, with a normal pulmonary capillary wedge pressure (<15 mmHg) and increased pulmonary vascular resistance (PVR) index (PVRI>3 Woods units × m²). [3] This definition applies to all but the youngest patients. According to the latest classification provided by the World Congress on Pulmonary Hypertension [Table 1], [4] PAH forms a segment of the wider pulmonary hypertension (PH) spectrum. Additionally, PAH is subcategorized into the idiopathic (IPAH) and associated (APAH) forms secondary to other pathologies. Recent genetic evidence identifying PAH-associated alleles has further divided IPAH into hereditary (HPAH) forms as well.
Table 1: Classification of PAH*[4]

Click here to view

The etiology of PH in children is more diverse. In children, the predominant diagnoses are PAH associated with congenital heart disease (CHD) and IPAH. [1] Persistent PH of the newborn (PPHN) is the most common cause of PH in the neonatal period. PH associated with neonatal and chronic lung disease [e.g., bronchopulmonary dysplasia (BPD)] is another less common and probably underreported cause encountered in the pediatric population. [1] There are other differences as well. Children with PAH seem to have a greater inability to increase cardiac output in response to exercise, hence, these children commonly present with exercise-associated syncopal attacks. In addition, while adults typically present with a diminished cardiac index, children usually have a normal cardiac index at the time of presentation.

Due to the difficulties in applying the Dana Point classification to children, a working group of the Pulmonary Vascular Research Institute developed a unique pediatric classification [Table 2]. In this classification, PH in children is defined as in adults for a biventricular circulation, but PH in the setting of single-ventricle physiology is defined as PVRI >3.0 Wood units × m 2 or a transpulmonary gradient >6 mm Hg. [5]
Table 2: Pulmonary vascular research institute classification of pediatric PH vascular disease (Panama 2011)[5]

Click here to view

An imbalance between the vasoconstrictor substances (thromboxane and endothelins) and vasodilatory substances [nitric oxide (NO) and prostacyclin] with increased concentrations of the former and reduced ones of the latter seem to be the predominant basis for the occurrence of PAH. This leads to vasoconstriction, smooth muscle proliferation, intra-arterial thrombosis, reduction in pulmonary arterial lumen size, and plexogenic arteriopathy. [6] Thus, medical therapies that interfere with these pathogenic processes are likely to yield beneficial results. The therapeutic options, therefore, consist of the following: [6]

  • Vasodilators of varying mechanisms:
    Prostacyclin analogs that increase intracellular cyclic adenosine monophosphate (cyclic AMP or cAMP).
    Calcium channel antagonists.
    Endothelin antagonists (ambrisentan, bosentan, sitaxentan).
    Phosphodiesterase (PDE)-5 inhibitors (e.g., sildenafil).
  • Oral anticoagulants that prevent thrombosis.
  • Antifibrinolytic agents (e.g., prostacyclin).

Despite the differences in etiologies, compensatory mechanisms, and presentation, the basic pathophysiology of PAH appears to be similar in children and adults, and thus most therapies used for treatment in adults seem to be also efficacious in children.

To date, sildenafil has been the most widely used treatment option for pediatric patients with PAH. [6] As recent developments have cast a shadow of doubt regarding the safety of sildenafil for use in infants and young children, it is most appropriate to review the available information and also the role of sildenafil to gain a proper perspective.

As shown in [Table 3], sildenafil was initially sought to be developed for the treatment of angina pectoris; the idea was given up due to its short half-life. Its "side effect" of male patients developing erections during the clinical trials was researched further and the molecule was licensed for the treatment of erectile dysfunction. However, even after the license was obtained for this indication, research continued regarding its use in treating PH. [2],[7],[8]
Table 3: Milestones in the development and role of sildenafil as a drug for the management of PAH in children[2],[7],[8]

Click here to view

 :: Sildenafil: Pharmacology Top

Sildenafil(1-[3-(6,7-dihydro-1-methyl-7-oxo-3-propyl-1H-pyrazolo [4,3-d]pyrimidin-5-yl)-4-ethoxyphenyl]sulphonyl]-4-methylpiperazine) is a water-soluble aromatic compound. [6],[7] Being an inhibitor of PDE-5, it increases the levels of cycline guanosine monophosphate (cGMP), thereby promoting vasodilatation in the pulmonary vascular bed. [6],[9]

The pharmacokinetic profile of oral sildenafil has not been extensively evaluated in children. In adults, it is rapidly absorbed after oral administration and the maximum serum concentrations are reached within 0.5-2 h of administration. [10] The drug undergoes extensive first-pass metabolism in the liver, and the oral bioavailability is 40%. Hepatic cytochrome P (CYP) 3A4 (major) and CYP-2C9 (minor) enzyme systems are responsible for the formation of active metabolites. The active metabolite N-desmethyl sildenafil makes up for 40% of its serum concentrations and is responsible for 20% of its pharmacological activity. [11] Sildenafil is eliminated as metabolites primarily in the feces (approximately 80% of the administered dose), with approximately 13% excreted in the urine. [11]


Sildenafil is available as tablets (20 mg), oral suspension (20 mg/mL, after reconstitution with 90 mL of water) and injection for intravenous (IV) use (10 mg/12.5 mL). The oral preparation of sildenafil is widely used in the management of PAH. The USFDA and the European Medicines Agency (EMEA) have approved a dose of 20 mg three times daily for adults with PAH. Doses higher than 20 mg are not approved as there is a flat, nonsignificant relationship between higher doses (20-80 mg three times daily) and clinical benefit. [7] While licensing it for the management of PAH in adults in 2005, the USFDA label stated that when prescribing it to children with PAH, the risks and benefits need to be weighed. However, this statement was amended by the USFDA in 2012 to state that sildenafil is not recommended (especially for long-term use) for children aged 1-17 years. [2] The EMEA allows for pediatric dosing: For children weighing 8-20 kg, 10 mg three times daily; for those weighing over 20 kg, 20 mg three times daily. [12] The issue of administering sildenafil to children weighing less than 8 kg has not been addressed. The dose of 0.5-2 mg/kg three times daily is generally used. The British National Formulary for Children advises a starting dose of 0.5 mg/kg/dose up to a maximum of 2 mg/kg/dose/every 6 h. [13] Because of its relatively short half-life, sildenafil may have to be given every 4 h, although it is usually administered every 6 h. [14] In 2012, an IV 0.8 mg/mL formulation of sildenafil gained European approval for the management of PAH in adults. This IV bolus is given three times daily for the continuation of sildenafil therapy in patients unable to tolerate oral administration. It has twice the potency of oral sildenafil. [15] It is not licensed for use in children. There are only limited reports of patients with PAH being treated with IV [16] and/ or nebulized routes. [17]

Adverse effects

Adverse effects such as epistaxis, respiratory symptoms (cough and nasal congestion), diarrhea and vomiting, gastroesophageal reflux and abdominal pain, headaches, tremors, erections, facial flushing, dizziness, irritability and rarely psychiatric disorders, fever, skin disorders, pain in limbs, and edema have been reported in children on sildenafil. [18],[19] The Sildenafil in Treatment-Naïve Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension long-term extension (STARTS-2) trial [19] showed worse survival in children receiving high doses of sildenafil as monotherapy. A recent study conducted by Roldan and colleagues in children found that there was a statistically significant increase in adverse drug reaction (ADR) frequency in patients receiving higher-than-recommended doses. However, it was not associated with a lower survival rate. [18] Sildenafil has the potential to adversely affect vision. Photophobia is a known side effect. Sildenafil has been blamed for retinal dysfunction, but the link is as yet unproven. [20]

Drug interactions

Sildenafil augments the vasodilatory and antihypertensive effects of nitrates (e.g., glyceryl trinitrate) and can produce profound hypotension leading to decreased coronary perfusion and myocardial infarction, which is problematic, and thus it is contraindicated in patients taking nitrates. [21] Sildenafil is metabolized primarily by cytochrome P450 (CYP450) 3A4, which is vulnerable to inhibition and induction by various agents, as outlined in [Table 4]. [22],[23],[24],[25]
Table 4: Important drug-drug interactions[22],[23],[24],[25]

Click here to view


Coadministration with nitrates is contraindicated. [7] Other contraindications include the presence of severe hypotension including volume depletion, left ventricular outflow obstruction, pulmonary veno-occlusive disease, multiple system atrophy, sickle cell anaemia associated-PAH; and additional caution is necessary if patients are receiving alpha-blockers. [7],[25] The withdrawal of sildenafil is recommended in the context of sudden visual loss, and sildenafil is contraindicated in ischemic optic neuropathy and hereditary degenerative retinal disorders. [25]

 :: Sildenafil: Clinical uses Top

According to the guidelines of the European Society of Cardiology and within the National Pulmonary Hypertension Service framework, sildenafil is a first-line drug for the management of nonvasoreactive pediatric IPAH and PAH associated with CHD in patients over 1 year of age. [26] This is based on data showing increases in maximum oxygen consumption of 10.2% after 16 weeks of sildenafil monotherapy (vs 0.5% on placebo) and reinforced by the STARTS trial revealing associated 90% 3-year survivals. [19],[27]

Following its success in licensed applications, sildenafil has been subject to substantial off-license applications, some of which have been reported in the published literature.

A review published by Huddlestone and coauthors in 2009 suggested that sildenafil is useful for weaning children who have undergone cardiac surgery from iNO. It is well-tolerated by children with IPAH and PAH associated with CHD. [11] However, the review also recommended large-scale randomized controlled trials (RCTs) to be conducted to confirm the overall safety and efficacy of sildenafil in the pediatric population. [Table 5] gives a summary of the recent case series and studies on the use of sildenafil in the pediatric population in the last 5 years (2009-2013). [16],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43]
Table 5: Summary of the recent case series and studies on the use of sildenafil in the pediatric population (2009-13)[16],[28],[29],[30],[31],[32],[33],[34],[35],[36],[37],[38],[39],[40],[41],[42],[43]

Click here to view

Transient postoperative PAH

Sildenafil is useful in relieving transient postoperative PAH associated with CHD surgery. This is a frequently employed but contentious application. It is not yet clear whether sildenafil should be used routinely to assist weaning from iNO or as an adjunct to therapy. [44] Furthermore, its prophylactic use is also being explored. [45] Here, one-off doses of 0.4 mg/kg have led to reductions in intensive care duration and time on mechanical ventilation. In a case report, sildenafil has been associated with the resolution of protein-losing enteropathy after the Fontan procedure. [46] Sildenafil is often used in combination with extracorporeal membrane oxygenation (ECMO) to facilitate the process of getting a patient come off cardiopulmonary bypass. [47]

Acute management of PAH

NO remains the gold-standard acute agent for the management of acute PAH. However, it carries the risk of development of methemoglobinemia. This risk has been reduced by delivering NO via inhalation (or, iNO) or by administering sildenafil concomitantly. Newborns receiving the combination should, however, be closely watched for the development of systemic hypotension. [48] NO therapy withdrawal is also associated with the risk of rebound PAH. This risk is minimized when sildenafil is used in combination with NO. [45] In a recent case report, oral sildenafil led to dramatic improvement in ventilation and saturation within 45 min when used as a rescue therapy in a 26-week-old infant in presumed pulmonary hypertensive crisis. [49]

Persistent PH of the newborn (PPHN)

In patients with PPHN, the PVR fails to regress after birth. A growing body of evidence supporting the use of sildenafil is fast emerging. [50] The Cochrane review found that sildenafil use was associated with increased arterial oxygenation and reduction in mortality. [50] It is necessary to confirm the drug's utility for this indication, as evidence is available from only a limited number of clinical trials. [51] Although there is no official guidance, doses ranging 250-500 μg/kg/dose three times daily (maximum: 30 mg/D) are in use. Indicators of a successful response include improved oxygenation indices, a 3 kPa increase in arterial oxygen partial pressure (PaO 2) , ability to wean fractional inspired oxygen (FiO 2 ), an increase in the arterial/alveolar pO 2 ratio and a decrease in the oxygenation index (OI). The response time varies 20-180 min after oral administration. The duration of treatment is not yet well-defined. One approach is to stop the medication if a clear response is obtained or if there is no response even after the administration of six to eight doses. Reduction in dose or cessation of treatment would be necessary if hypotension developed despite inotropic support. [14]

BPD-associated PH

The treatment of PH secondary to BPD in infants has evolved in recent years, improving survival rate and quality of life. Sildenafil is one of the potential agents that can be used in management. A recent review summarizing the evidence base for sildenafil alone and in combination with other recognized therapeutic agents for ameliorating pediatric PH in the presence of BPD [52] concluded that sildenafil is both safe and effective, as it improves survival from 61% to 81% at 12 months. Furthermore, there is data suggesting that the addition of endothelin antagonists and prostacyclin analogs to sildenafil therapy could be useful in the management of treatment-refractory PH. In contrast, another study enrolled 21 preterm infants with BPD-associated PH and demonstrated that a majority of patients showed no improvement in gas exchange at 48 h of treatment with sildenafil, and that four infants died during treatment, despite showing a significant reduction in estimated right ventricular peak systolic pressure. [53] The generally scarce evidence underlines that sildenafil should be used cautiously in infants with BPD-associated PH as a rescue therapy, even though the possibility of long term benefits of sildenafil on lung growth exists. It is also advisable that its use be restricted to specialist units and physicians, ideally with experience in dealing with both BPD and PH.

Congenital diaphragmatic hernia

Congenital diaphragmatic hernia is associated with PH directly and via links with BPD. Sildenafil has shown its efficacy in improving cardiac output via alleviation of PAPs. Its use in difficult cases has been established. [54] However, more evidence needs to be generated through appropriately powered RCTs before firm recommendations can be made.

Eisenmenger's syndrome

Limited evidence from case series and case reports suggests that sildenafil alone or in combination with L-arginine could be useful in patients with Eisenmenger's syndrome. [55],[56] However, in these patients, sildenafil has the potential to cause a reduction in pulmonary blood flow and an increase in cyanosis as a result of even mild systemic vasodilation and consequent increased right-to-left shunting. [22] Hence, larger trials are required to establish the safety of sildenafil in patients with Eisenmenger's syndrome.

Sildenafil combination therapy

Combination therapy can be used in patients who fail to respond to monotherapy. A randomized placebo-controlled trial showed that the addition of sildenafil to long-term IV epoprostenol therapy improved exercise capacity, hemodynamic measurements, time to clinical worsening, and quality of life. [57] A combination of bosentan, sildenafil, and inhaled iloprost has been shown to improve survival and reduce the need for lung transplantation in adult patients with severe PAH. [58] However, evidence in the case of children is still lacking, being limited to a few case series. [59],[60]

Intravenous sildenafil

Sildenafil is available as an IV injection in several countries including India (10 mg/12.5 mL). It reduces PAP, shortens time to extubation, and limits intensive care unit (ICU) stays in children with postoperative PH. [36] Its use in children who have undergone Fontan surgery has shown improvements in cardiopulmonary hemodynamics, cardiac index, and PVRI. [32],[28] Studies have shown that IV sildenafil infusion improves the OI in newborns with PPHN. [16] In an infant with respiratory failure, the substitution of oral sildenafil with IV infusion has resulted in clinical improvement where the former was ineffective. [61] However, some have raised certain concerns. Stocker and colleagues showed that when used in conjunction with iNO, sildenafil did produce reductions in the PVRI, [62] but that this was also associated with worsened arterial oxygenation and reduction in systemic blood pressure. Similarly, Schulze-Neick et al. showed that although IV sildenafil reduced PVR in children undergoing catheterization or cardiac surgery, it resulted in significant intrapulmonary shunting. [63]

The observed problems of systemic hypotension and impaired oxygenation experienced by patients receiving IV sildenafil raises concerns and could limit its use. Further studies are needed to determine the optimal dose needed to decrease PVR while still avoiding significant adverse events.

 :: Recent Controversies With the Use of Sildenafil in Pediatric Population Top

Other than iNO licensed for the treatment of newborns with PPHN and severe respiratory failure, there are no PAH therapies specifically approved for children. [66] Sildenafil (Revatio; Pfizer, New York, NY, USA), is approved by the USFDA for the treatment of PAH in adults. It has been used extensively in an off-label manner for the treatment of neonates, infants, and children with PAH associated with diverse heart and lung diseases. [16],[36],[55],[64],[65] Although the published literature has generally suggested favorable effects and outcomes in infants and young children with PAH, these reports constitute uncontrolled observations. [65]

In August 2012, the USFDA released a strong warning against the use of sildenafil for pediatric patients (ages 1-17 years) with PAH. [2] It stated that children taking a high dose of Revatio had a higher risk of death than children taking a low dose and that the low doses of Revatio are not effective in improving exercise ability. This was based on 3-year follow-up data in children showing dose-dependent increases in mortality (mortality ratio 3.5; P = 0.015) when using high doses (80 mg three times daily in children with body weight >45 kg) relative to low doses (10 mg three times daily in body weight >45 kg). [19] This warning, which is now part of the package insert, states that sildenafil is not to be used in children.

The studies leading to the USFDA rulings have been criticized. [12],[66],[67],[68] Abman and colleagues pointed out that there were substantial problems with the design of the study on the basis of whose data the recommendation was made. [66] In addition, there was no standardization of therapy after the initial 4-month trial period, there was substantial center-to-center variability in management, and information about the use of other therapies beyond sildenafil lacked clarity.

Ironically, based on the same data, the EMEA recommended the use of sildenafil in children aged 1-17 years with a maximum daily dosage of 10 mg three times daily in children weighing less than 20 kg or 20 mg three times daily in those weighing over 20 kg. [12] They cautioned against using higher doses. The Pediatric Pulmonary Hypertension Network has recommended using sildenafil in accordance with the EMEA dosing recommendation. [66] Bhutta and colleagues [67] have pointed out that the interpretation of the study results by the USFDA has added to the confusion. The STARTS investigators [19] reported that in patients who received long-term sildenafil therapy, deaths were related to underlying etiology and baseline disease. They further pointed out that multivariate analysis of STARTS-2 results shows that factors associated with mortality were HPAH etiology, high PVRI, and high right atrial pressure and adjustment, for these three factors reduced the hazard ratios for mortality for the high versus the low dose. They conducted a review of the Pediatric Health Information System (PHIS) database to assess the landscape of sildenafil use among children and highlighted the impact of the USFDA warning on the pediatric population. [67] Their investigation showed that sildenafil use has increased over the study period (January 2004-December 2011) and that there was a temporally associated decrease in mortality. The reduction in mortality cannot be attributed to sildenafil alone. It may be due to a variety of reasons, such as use in lower-risk populations, different dosing regimens of sildenafil, and concomitant use of other therapeutic agents. More carefully designed studies that are adequately powered to detect differences in mortality are needed for better understanding of the role of sildenafil either as monotherapy or in conjunction with other therapies.

In view of the criticism and the recently published results of the STARTS-2 trial, the USFDA in a recent communication in 2014 clarified the warning issued in August 2012, stating that its warning was mainly against using high doses and chronic use of the drug, and that sildenafil may be considered in situations where the benefits of treatment with the drug are likely to outweigh its potential risks for each patient. [8],[68]

Novel PDE-5 inhibitors

To date, sildenafil is the most extensively studied PDE-5 inhibitor. Currently, two more PDE-5 inhibitors, tadalafil and vardenafil, are under evaluation. The newer compounds are considered to be better than sildenafil in terms of greater selectivity for PDE-5, absence of the effect of food on absorption, faster onset of action, and longer duration of action. [69] Tadalafil has the least effect on PDE-6 and is thus not associated with visual disturbances of blurring and blue-green color tinges that may occur with sildenafil. [69] Tadalafil has a greater effect on PDE-11; thus, backache and myalgia can occur frequently after its use. [69] Tadalafil is the most heavily researched alternative and has proven efficacy at 1 mg/kg doses in pediatric PAH. [25] In addition, its longer half-life enables once-daily dosing, improving outpatient compliance. Tadalafil has been found to improve functional capacity and oxygen saturation better than sildenafil. It also requires fewer daily doses than sildenafil. [70]

PDE-5 inhibitors are emerging as novel therapeutic tools with the potential to protect or enhance endothelial function in humans and to selectively improve regional blood flow. In addition to PH, these are being tried for conditions such as Raynaud's phenomenon, respiratory disorders with ventilation/perfusion mismatch, congestive cardiac failure, hypertension, and stroke. [69] It is hoped that this group of drugs will soon emerge as a novel weapon in the armamentarium against various cardiovascular and pulmonary diseases.

 :: Conclusion Top

The past decade has shown a major development in the management of PH by the introduction of sildenafil and other PDE-5 inhibitors. Sildenafil is USFDA-approved only in adults with PAH, not in children. Data from adults were extrapolated for its use in children. Various studies and case series have shown beneficial effects of sildenafil in pediatric PAH; however, caution has to be taken regarding its long-term use with higher doses, as recently highlighted by the USFDA. Sildenafil is a cost-effective option for the treatment of pediatric PAH, especially for developing countries. Health care professionals must consider whether the benefits of treatment with the drug are likely to outweigh its potential risks for each patient. Further research with appropriately chosen study groups is needed for USFDA approval of this drug.

 :: Acknowledgment Top

The authors thank Dr. Ramesh Bharmal, Dean of Topiwala National Medical College and BYL Nair Charitable Hospital for granting permission to publish this manuscript.

 :: References Top

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[PUBMED]  Medknow Journal  
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