Shalini Sri Ranganathan

The status of paediatric medicines initiatives around the world—what has happened and what has not?

PurposeThis review was conducted to examine the current status of paediatric medicines initiatives across the globe.MethodsThe authors made a non-systematic descriptive review of current world situation.ResultsTwo regions, the United States (US) and the European Union (EU), and the World Health Organization (WHO) have introduced strong paediatric initiatives to improve children’s health through improving access to better paediatric medicines. The experience from the US initiative indicates that it is possible to stimulate development and study of paediatric medicines and provide important new information for improvement of paediatric therapy. The early results from the EU initiative are similarly encouraging. In Canada, Japan, Australia and other developed countries, specific paediatric medicines initiatives have been less extensive and weaker, with modest results. Disappointingly, current evidence suggests that results from clinical trials outside the US often do not benefit children in the country in which the trials were largely conducted. Pharmaceutical companies that have derived a financial benefit commensurate with the cost of doing the paediatric trials in one country do not seem to be making the results of these trials available to all countries if there is no financial incentive to the company. The WHO campaign ‘make medicines child size’ has produced substantive accomplishments in building improved foundations to improve mechanisms that will enhance children’s access to critical medicines in resource-limited settings. However, practically all of this work has been performed using an amalgamation of short-term funding from a variety of sources as opposed to a sustained, programmatic commitment.ConclusionsAlthough much still needs to be done, it’s clear that with concerted efforts and appropriate resources, change is possible but slow. Retaining and fostering public and political interest in paediatric medicines is challenging, but pivotal for success.

Fulminant hepatic failure and paracetamol overuse with therapeutic intent in febrile children.

ObjectiveTo evaluate the risk of fulminant hepatic failure in relation to paracetamol overuse with therapeutic intent in febrile children.MethodsIt was a case control study. Paracetamol ingestion for the current febrile illness was compared between 25 cases of fulminant hepatic failure and 33 hospital age matched controls.ResultsSupra-therapeutic doses of paracetamol (mean 145 mg/kg/day) were consumed by all 25 cases compared to none in the control group. Mean paracetamol level in the cases and controls were, respectively, 26.84 μg/dl and 0.051 μg/dl (p<0.001). The mean duration of paracetamol intake prior to admission in cases was 3.45 days compared to 1.85 days in the control group. Nineteen, 5 and 3 were, respectively, graded as hepatic encephalopathy grade 1,2 and 3. All six patients in grade 2 and 3 had hepatomegaly compared to 78% in the grade 1. Four had jaundice and all were in grade 2 or 3. Mean alanine aminotransferase was 2781 U/L None of the randomly selected cases (6) had serological evidence of Hepatitis A, Hepatitis B or Dengue. Three cases died.ConclusionExposure to multiple supratherapeutic doses of paracetamol is a risk factor to develop fulminant hepatic failure in children with an acute viral like febrile illness.

The efficacy of moderate-to-high dose oral prednisolone versus low-to-moderate dose intramuscular corticotropin for improvement of hypsarrhythmia in West syndrome: a randomized, single-blind, parallel clinical trial.

BACKGROUND The role of therapy on improvement of hypsarrhythmia has not been systematically assessed. This study was performed to assess the efficacy of oral prednisolone and intramuscular adrenocorticotrophin hormone in improving hypsarrhythmia in West syndrome. METHOD Children (2 months-2 years), with previously untreated West syndrome, were randomized to receive 40-60 IU every other day of intramuscular adrenocorticotrophin hormone or 40-60 mg/day of oral prednisolone for 14 days. Children with tuberous sclerosis were excluded. Improvement of hypsarrhythmia was assessed blindly using a hypsarrhythmia severity scale before and after completion of therapy. Adverse effects were assessed on day 14 using symptom diary. (Clinical trial registry identifier: SLCTR/2010/010.) RESULTS From 92 newly diagnosed West syndrome infants, 48 were randomized to receive prednisolone and 44 to receive adrenocorticotrophin hormone. Eighty infants completed the posttreatment evaluation according to specifications. The hypsarrhythmia severity score, significantly improved with hormonal therapy for 2 weeks (10.45 ± 2.65 vs 3.45 ± 2.67); P < 0.01. When individual treatment arms were compared using mean differences in the improvement of scores, improvement in prednisolone arm (7.95 ± 2.76) was significantly greater than that in the adrenocorticotrophin hormone arm (6.00 ± 2.61); P < 0.01. Both forms of therapy were tolerated well. Frequent crying, irritability, weight gain, increased appetite, and abdominal distension were more common (but not statistically significant) with prednisolone. CONCLUSIONS Hypsarrhythmia severity score improved significantly with both hormonal therapies, but this improvement was significantly better with oral prednisolone than intramuscular adrenocorticotrophin hormone. This is the first ever documentation of a superior therapeutic role of oral steroids in West syndrome.

Realities of paediatric pharmacotherapy in the developing world

Diseases causing high mortality in children under 5 years of age in resource limited settings (RLS) could be treated if children in these countries had access to existing medicines. It took 30 years before the WHO Essential Medicines List (EML) considered the issue of medicines for children, with the first EML for children being published in 2007. Recent data indicate that less than half of the key paediatric essential medicines are available in countries of sub-Saharan Africa. Problems include substandard medicines, irrational use of medicines, inefficiency and even possible corruption in pharmaceutical management systems. These are global issues which affect RLS most. Clinical trials in developing countries for the benefit of children are needed but challenging in several ways. In this review, the authors will consider the following areas where progress could improve paediatric pharmacotherapy in RLS: registration and regulation of medicines, rational use of medicines, clinical trials in children and restriction of corruption in pharmaceutical management systems.

Randomized, Single-Blind, Parallel Clinical Trial on Efficacy of Oral Prednisolone Versus Intramuscular Corticotropin on Immediate and Continued Spasm Control in West Syndrome

OBJECTIVE A single-center, single-blind, parallel-group, randomized clinical trial was performed to test the null hypothesis that adrenocorticotropic hormone is not superior to high-dose prednisolone for treatment of newly diagnosed West syndrome. METHODS Newly diagnosed infants with West syndrome were randomized to receive 14 days of oral prednisolone (40-60 mg/day) or a synthetically prepared intramuscular long-acting adrenocorticotropic hormone (40-60 IU/every other day [0.5-0.75 mg]) according to the United Kingdom Infantile Spasm Study protocol. They were blindly evaluated for infantile spasm remission by day 14, electroclinical remission (spasm cessation + resolution of hypsarrhythmia on a 30-minute electroencephalograph) by day 14 and continued spasm freedom for 28 days. RESULTS Ninety-seven patients were enrolled in the study, with 48 of them receiving prednisolone and 49 receiving ACTH. There was no significant difference in the baseline characteristics or risk factors for the two treatment groups. By day 14, cessation of infantile spasms occurred in 28/48 (58.3%) infants on prednisolone compared with only 18/49 (36.7%) infants given adrenocorticotropic hormone (P = 0.03) and electroclinical remission in 21 on prednisolone compared with nine on adrenocorticotropic hormone (P = 0.007). Sustained spasm control for 28 consecutive days following electroclinical remission occurred in 15 children on prednisolone compared with six on adrenocorticotropic hormone (P = 0.008). The total number of days required for spasm cessation was significantly less in those treated with prednisolone (3.85 days ± 2.4) compared with adrenocorticotropic hormone (8.65 days ± 3.7) (P = 0.001). Among patients who did not achieve remission, there was a non-significant trend toward greater quantitative reduction of spasms with prednisolone than with adrenocorticotropic hormone (P = 0.079). CONCLUSION Synthetic adrenocorticotropic hormone of 40-60 IU/every other day did not yield superior rates of electroencephalographic or clinical remission when compared with prednisolone of 40-60 mg/day. Significantly, more patients achieved electroclinical remission when treated with prednisolone than with adrenocorticotropic hormone.

A cost effectiveness analysis of the preferred antidotes for acute paracetamol poisoning patients in Sri Lanka

BackgroundAcute paracetamol poisoning is a rapidly increasing problem in Sri Lanka. The antidotes are expensive and yet no health economic evaluation has been done on the therapy for acute paracetamol poisoning in the developing world. The aim of this study is to determine the cost effectiveness of using N-acetylcysteine over methionine in the management of acute paracetamol poisoning in Sri Lanka.MethodsEconomic analysis was applied using public healthcare system payer perspective.Costs were obtained from a series of patients admitted to the National Hospital of Sri Lanka with a history of acute paracetamol overdose. Evidence on effectiveness was obtained from a systematic review of the literature. Death due to hepatotoxicity was used as the primary outcome of interest. Analysis and development of decision tree models was done using Tree Age Pro 2008.ResultsAn affordable treatment threshold of Sri Lankan rupees 1,537,120/death prevented was set from the expected years of productive life gained and the average contribution to GDP. A cost-minimisation analysis was appropriate for patients presenting within 10 hours and methionine was the least costly antidote. For patients presenting 10-24 hours after poisoning, n-acetylcysteine was more effective and the incremental cost effectiveness ratio of Sri Lankan rupees 316,182/life saved was well under the threshold. One-way and multi-way sensitivity analysis also supported methionine for patients treated within 10 hours and n-acetylcysteine for patients treated within 10-24 hours as preferred antidotes.ConclusionsPost ingestion time is an important determinant of preferred antidotal therapy for acute paracetamol poisoning patients in Sri Lanka. Using n-acetylcysteine in all patients is not cost effective. On economic grounds, methionine should become the preferred antidote for Sri Lankan patients treated within 10 hours of the acute ingestion and n-acetylcysteine should continue to be given to patients treated within 10-24 hours.

Essential medicines for children

Millions of children die every year before they reach the age of 5 years, of conditions largely treatable with existing medicines. The WHO Model List of Essential Medicines was launched in 1977 to make the most necessary drugs available to populations whose basic health needs could not be met by the existing supply system. During the first 30 years of the Model List of Essential Medicines, childrens needs were not systematically considered. After adoption of the ‘Better medicines for children’ resolution by the World Health Assembly, things changed. The first WHO Model List of Essential Medicines for Children was drawn up by a Paediatric Expert Subcommittee and adopted in October 2007. The most recent, 4th Model List of Essential Medicines for Children was adopted in 2013. Data from country surveys show that access to essential medicines for children is still generally poor; much more work is needed.

Pharmacovigilance through consumer feedback (reporting) in the mass treatment of lymphatic filariasis using diethylcarbamazine and albendazole in two districts of Sri Lanka

Objective  To document the types and severity of adverse drug reactions to diethylcarbamazine and albendazole in randomly selected urban populations from Colombo and rural populations from Gampaha, Sri Lanka.

A quick inexpensive laboratory method in acute paracetamol poisoning could improve risk assessment, management and resource utilization

Objectives: Acute paracetamol poisoning is an emerging problem in Sri Lanka. Management guidelines recommend ingested dose and serum paracetamol concentrations to assess the risk. Our aim was to determine the usefulness of the patients history of an ingested dose of >150 mg/kg and paracetamol concentration obtained by a simple colorimetric method to assess risk in patients with acute paracetamol poisoning. Materials and Methods: Serum paracetamol concentrations were determined in 100 patients with a history of paracetamol overdose using High Performance Liquid Chromatography (HPLC); (reference method). The results were compared to those obtained with a colorimetric method. The utility of risk assessment by reported dose ingested and colorimetric analysis were compared. Results: The area under the receiver operating characteristic curve for the history of ingested dose was 0.578 and there was no dose cut-off providing useful risk categorization. Both analytical methods had less than 5% intra- and inter-batch variation and were accurate on spiked samples. The time from blood collection to result was six times faster and ten times cheaper for colorimetry (30 minutes, US

Rational Use of Medicines (RUM) for Children in the Developing World: Current Status, Key Challenges and Potential Solutions

2) than for HPLC (180 minutes, US