Global Barriers to Accessing Off-Patent Endocrine Therapies: A Renaissance of the Orphan Disease?

CONTEXT: Clinical endocrinology encompasses many diseases requiring long-term drug therapy. Prohibitive pricing of some endocrine drugs classified as essential by the World Health Organization has created suboptimal care of patients with endocrine disorders. EVIDENCE ACQUISITION: This review is based on evidence obtained from several databases and search engines including PubMed, Google, and Google Scholar; reference searches; manual searching for web pages of international regulatory bodies; and the authors' experience from different healthcare settings. EVIDENCE SYNTHESIS: After the expiry of a patent, generic versions with the opportunity for increased availability and a price reduction are expected. There are access barriers worldwide for many off-patent endocrine drugs. The high price is the main issue for several medicines including insulin, hydrocortisone, testosterone, and gonadotropins. This is caused by several factors including the market monopoly due to the lack of registered generics or suppliers limiting the benefit of competition and a complex supply chain. Additionally, the lack of some medicines has been concerning due to market factors such as the relatively small number of patients, making it less attractive for the manufacturers. Commissioning of nonprofit manufacturers and state manufacturing as well as strict price control measures could alleviate this situation. CONCLUSION: Lack of availability and disproportionate price inflation affecting essential off-patent endocrine therapies is common due to several interrelated factors. Global collaboration among healthcare organizations with the support of policymaking bodies might be needed to mitigate this.

Monitoring Endocrine Nursing in South Asia (MENSA).

Background: South Asian countries face the colossal challenge of tackling the massive burden of diabetes and other endocrine disorders. These patients grossly outnumber the specialists trained to deal with these conditions. A trained cadre of diabetes specialist nurses (DSN) and endocrine specialist nurses (ESN) might help bridge this gap. Exploring the perception of DSN/ESN among South Asian doctors will help to understand their role, responsibilities and future prospects. Methods: One hundred and seventy-four endocrinologists from South Asia participated in an online survey on their perception of DSNs and ESNs. Results: Out of the 174 respondents, 61 (35%) were currently working with DSN/ESN, 79 (45.4%) had worked in the past and 131 (75.2%) were willing to start recruiting or employ additional DSN/ESN in the future. The majority considered that the primary function of DSN and ESN is to educate on diabetes (n = 86, 96.6%) and endocrine disorders (n = 34, 57.6%), respectively, followed by anthropometry and initial work-up. Only a small minority felt they could write independent follow-up prescriptions (nurse-led clinics) [DSN - 16 (18%) and ESN - 3 (5.1%)]. Graduation with a certificate course in diabetes and basic endocrinology was considered a sufficient qualification by 68 (39.1%) respondents. Endocrinologists from countries other than India were more willing to recruit ESN/DSN in the future (89.7% vs 72.4%; P < 0.03) and approve a nurse-led clinic (62.1% vs 29.7%; P < 0.03). Upon multiple logistic regression, working in countries other than India was an independent predictor of future willingness to work with DSN/ESN (odds ratio (OR): 4.48, 95% confidence interval (CI) 1.09-18.43, P = 0.03). Conclusion: DSN and ESN could facilitate the management of healthcare-seekers with diabetes and endocrine disorders. A certification course to train nurses on diabetes and basic endocrine disorders following graduation could be helpful. Major hindrances in creating a regular cadre of DSN/ESN were limited opportunities for career progression and lack of additional remuneration for services.

A challenging case of Cushing's disease complicated with multiple thrombotic phenomena following trans-sphenoidal surgery; a case report.

BACKGROUND: Cushing's syndrome occurs due to overproduction of cortisol from adrenal glands. Endogenous hypercortisolemia can occur secondary to adrenocorticotropic hormone (ACTH) dependent as well as independent causes. The presence of non-specific symptoms and signs contributes to a delay in diagnosis. Early identification and prompt definitive management is crucial. It is important to be alert about the post-operative complications including multiple thrombotic phenomena, which can add to the mortality. We report a case of Cushing's disease in a young female managed with trans-sphenoidal surgery, followed by a challenging post-operative period complicated with multiple thrombotic phenomena, ultimately succumbed. CASE PRESENTATION: A 32-year-old Sri Lankan female presented with overt features of Cushing's syndrome and diagnosed to have ACTH dependent Cushing's disease with pituitary microadenoma. She underwent trans-sphenoidal surgery, following which she developed fatal multiple complications including diverticular rupture and ischemic colitis, needing hemicolectomy, followed by a parieto-occipital infarction. CONCLUSION: This case highlights important and aggressive complications associated with Cushing's syndrome giving rise to a challenging post-operative course. Diverticular rupture had been described in association with hypercortisolemia and this case adds to the existing literature. Post-operative ischemic colitis and stroke which contributed to the death of this patient could have been due to the procoagulant state associated with Cushing's syndrome, with a high risk during the immediate post-operative period. This emphasizes the need to consider post-operative thromboprophylaxis in patients undergoing surgery for Cushing's syndrome.

Prevention and management of COVID-19 among patients with diabetes: an appraisal of the literature.

The coronavirus disease 2019 (COVID-19) pandemic has emerged as one of the greatest challenges faced by humankind in the recent past. People with diabetes and related comorbidities are at increased risk of its complications and of COVID-19-related death. Older age, multi-morbidity, hyperglycaemia, cardiac injury and severe inflammatory response are predictors of poor outcome. The complex interplay between COVID-19, diabetes and the effects of related therapies is being explored. Most patients experience a mild illness with COVID-19, while people with diabetes are at increased risk of severe disease. Optimising glycaemic control and adopting measures to prevent disease spread are critical aspects. The management of mild disease is supportive, while very many immunomodulatory and antiviral therapies are being investigated for the treatment of severe disease. Several of these agents have specific considerations for use in people with diabetes. Since mass population lockdowns are considered a key step in controlling disease spread, it follows that, in addition to the direct vulnerability to severe COVID-19, people with diabetes can be affected by limited access to healthcare, insulin, other medications and blood glucose monitoring equipment. Measures to prevent disease spread at the individual and community level are the key to mitigating the rapidly escalating pandemic, while agents for chemoprophylaxis and vaccines are being explored. People with diabetes should be recognised as a vulnerable group for complicated disease and are at risk during times of disturbed social systems. Strategies are needed to safeguard the health of patients with diabetes during the pandemic. This review summarises the current knowledge and perceived challenges for prevention and management of COVID-19 in people with diabetes.

Seeking the unseen: Localization and surgery for an occult sporadic insulinoma.

Insulinomas are rare pancreatic neuroendocrine tumours and the commonest cause for endogenous hyperinsulinaemic hypoglycemia. Small tumours are not easily detected by conventional cross-sectional imaging making localization prior to surgical removal a challenge. Selective arterial calcium stimulation is an invaluable adjunct to localization in such circumstances. This is further supplemented by intraoperative ultrasonography. A 39-year-old male was referred with features of Whipple's triad of 10 months duration. Clinical and biochemical evaluation including C-peptide and serum insulin levels during supervised hypoglycemia concluded endogenous hyperinsulinaemia as the underlying aetiology. Contrast CT and MRI of the abdomen failed to localize the tumour. Selective arterial calcium stimulation localized the lesion in distal pancreas. During the surgery, tumour was further localized to the tail of the pancreas using intraoperative ultrasonography and enucleated. Histology confirmed an insulinoma and patient made an unremarkable recovery and was well more than a year after the surgery.

Hyperparathyroidism Jaw Tumor Syndrome Presenting as Recurrent Femur Fractures in a Young Woman; a Rare Presentation of a Rare Disease.

BACKGROUND: Primary hyperparathyroidism usually occurs secondary to parathyroid adenoma, multiglandular hyperplasia, or parathyroid carcinoma. The patients usually present with incidentally discovered high calcium level and systemic or skeletal manifestations. In young patients with primary hyperparathyroidism, familial syndromes including multiple endocrine neoplasia types 1, 2, and 4 and hyperparathyroidism jaw tumor syndrome should be considered. Case Description. We present a case of a 22-year-old Sri Lankan woman who presented with femur fractures in a background of childhood nephroblastoma and maxillary fibro-osseous tumor. The patient had biochemical parameters suggestive of primary hyperparathyroidism with a parathyroid mass. The histology following excision of the mass revealed a parathyroid adenoma. Based on the associated clinical manifestations, hyperparathyroidism jaw tumor syndrome was suspected, and genetic studies reported a positive CDC73 mutation with a whole-gene deletion of exon 1-17. CONCLUSION: Hyperparathyroidism jaw tumor syndrome is an important diagnosis to consider in a young patient presenting with classic clinical features due to the risk of malignancy, familial involvement, and need to monitor for progressive systemic manifestations. As this is a rare disease, it can often be missed due to low degree of suspicion and the ability of the jaw tumor to mimic a metastatic deposit.

Prevalence of Depression and Associated Factors among Patients with Type 2 Diabetes Attending the Diabetic Clinic at a Tertiary Care Hospital in Sri Lanka: A Descriptive Study.

BACKGROUND: Research focusing on the psychological aspect of diabetes is limited in Sri Lanka. AIM: Determine the prevalence of depression among patients with type 2 diabetes mellitus (T2DM) attending an out-patient clinic at a tertiary care hospital in Colombo, the capital of Sri Lanka. METHODS: A descriptive cross-sectional study carried out among patients diagnosed with T2DM. Pregnant and patients with a prior psychiatric history were excluded. Depression assessed using validated Sinhala and Tamil version of the Beck's Depression Index. Sociodemographic data and health related data were obtained from interviewer-based questionnaires and health records. RESULTS: Of the 3000 patients, 72.7% were female. Mean age was 58.3 ±10.3 years and mean duration of diabetes 10.8 ± 7.3 years. Percentage of depression was 5.9% in the entire patient population with mild, moderate, and severe depression in 4.0%, 1.6%, and 0.3%, respectively. In multiple logistic regression, depression was significantly associated with female gender (OR 2.63, 95% CI 1.26-5.46; P=0.009), living without a spouse (single/divorced/widowed) (OR 1.83, 95% CI 1.12-2.98; P=0.01), lower education level (OR 1.92, 95% CI 1.14-3.22; P=0.01), and peripheral neuropathy (OR 1.79, 95% CI 1.00-3.18; P=0.04). Only 13.3% of the respondents said that doctors have ever inquired to their mental well-being. CONCLUSION: Depression was low in prevalence comparative to neighboring countries in the region. Patients were much more affected by the social factors than disease related factors. An individualized holistic approach taking psychosocial issues to consideration should be focused in the comprehensive plan of management.

Prevalence of Chronic Complications, Their Risk Factors, and the Cardiovascular Risk Factors among Patients with Type 2 Diabetes Attending the Diabetic Clinic at a Tertiary Care Hospital in Sri Lanka.

Diabetes incurs heavy burden to patients and the healthcare system. Assessment of disease burden is important in taking necessary precautions and management decisions. We aimed to determine the prevalence of macro- and microvascular complications, their risk factors, and coronary artery disease (CAD) risk factors among patients with type 2 diabetes mellitus (T2DM). A descriptive cross-sectional single-centre study was carried out among 3000 patients with T2DM attending the diabetic clinic at the National Hospital of Sri Lanka from January to July 2016. The study population had 72.7% females and 27.3% males. Mean age and disease duration were 58.3 ± 10.3 and 10.8 ± 7 years, respectively. Prevalence of CAD, stroke, and peripheral vascular disease were 10.6%, 1.1%, and 4.7% while diabetic retinopathy, neuropathy, nephropathy, diabetic foot, and lower extremity amputation (LEA) were 26.1%, 62.6%, 50.8%, 2.6%, and 1.3%, respectively. Prevalence of overweight/obesity, hypertension, dyslipidemia, and smoking were 80%, 77.6%, 76.7%, and 11%, respectively. Increased age, disease duration, and HBA1c were risk factors for microvascular disease and diabetic foot while age was the only risk factor for macrovascular complications. Occurrence of CAD, peripheral neuropathy, diabetic foot, and LEA was significantly higher among males than when compared to females. This study highlights the major burden of chronic complications and high prevalence of CAD risk factors in this population.

Case report: rare skeletal manifestations in a child with primary hyperparathyroidism.

BACKGROUND: Primary hyperparathyroidism (PHPT) is uncommon among children with an incidence of 1:300,000. This diagnosis is often missed in children in contrast to adults where it is detected at a pre symptomatic stage due to routine blood investigations. Etiology of PHPT can be due to adenoma, hyperplasia or rarely carcinoma. CASE PRESENTATION: A 12 year old Sri Lankan girl presented with progressive difficulty in walking since 1 year. On examination she had bilateral genu valgum. Skeletal survey revealed valgus deformity of knee joints, bilateral subluxation of upper femoral epiphysis(SUFE), epiphyseal displacement of bilateral humeri, rugger jersey spine and subperiosteal bone resorptions in lateral aspects of 2nd and 3rd middle phalanges. There were no radiological manifestations of rickets. Metabolic profile revealed hypercalcemia with hypophosphatemia. Intact parathyroid hormone levels were elevated at 790 pg/ml. Vitamin D levels were deficient. She had low bone mineral density with Z score of -3.4. Vitamin D supplementation resulted in worsening of hypercalcemia without reduction in PTH levels. Tc 99 Sestamibi uptake scan showed abnormal tracer retention in left inferior pole of thyroid. A large parathyroid gland was removed with histology favoring parathyroid adenoma. Post operatively she developed hypocalcemia. Bilateral osteotomy was done for SUFE and further surgeries for correction of limb deformities planned. CONCLUSION: PHPT in children is usually diagnosed late when irreversible organ damage has occurred. Children can present with non specific symptoms involving gastrointestinal, musculoskeletal, renal and neurological systems. PHPT can cause disarray in bone and epiphysis in children during pubertal growth spurt. Genu valgum and SUFE are rare skeletal manifestations in PHPT and only 10 cases of genu valgum and 9 cases of SUFE have been reported up to now. So far no cases have been reported on epiphyseal displacement of humeri. Awareness regarding the occurrence of these rare skeletal manifestations especially during puberty is important for early diagnosis to prevent irreversible outcomes.

Extreme hypernatremia as a probable cause of fatal arrhythmia: a case report.

BACKGROUND: Hypernatremia is a frequent occurrence among hospitalized patients. Severe hypernatremia is associated with mortality rates of over 60 %. Extreme hypernatremia, defined as sodium levels >190 mmol/l, is a rare occurrence. The literature on electrocardiographic changes occurring with this degree of hypernatremia is extremely scarce. We report the case of an 11-year-old Sri Lankan girl who presented with sodium levels of 226 mmol/l following infusion with 3 % hypertonic saline who developed diffuse QT prolongation leading to fatal ventricular tachycardia. CASE PRESENTATION: An 11-year-old Sri Lankan girl presented with fever, headache, vomiting, and altered level of consciousness. Following admission she developed generalized tonic-clonic seizures and was intubated and ventilated. She had a recent history of polyuria and polydipsia. Magnetic resonance imaging of her brain revealed hydrocephalus due to possible craniopharyngioma. A ventriculoperitoneal shunt was inserted and she was infused with 3 % hypertonic saline in an attempt to reduce intracranial pressure. The following day she became polyuric and dehydrated with tachycardia and low blood pressure. Biochemistry revealed serum sodium of 226 mmol/l, measured serum osmolality of 470 mOsm/kg, urine osmolality of 280 mOsm/kg, urine spot sodium of 116 mmol/l, blood urea of 8.1 mmol/l, and blood glucose of 8.5 mmol/l. Her serum potassium, calcium, and magnesium levels were normal. Extreme hypernatremia due to infusion of 3 % hypertonic saline in the background of cranial diabetes insipidus was considered. She was managed aggressively with 5 % dextrose infusion and clear water via nasogastric feeding to correct the fluid deficit of 7 liters over 36 hours. Her sodium levels dropped to 160 mmol/l the following day. However, she developed electrocardiographic changes with widespread gross QT prolongation with ST segment deviations followed by fatal ventricular tachycardia. CONCLUSIONS: Extreme hypernatremia is rare, and the literature on electrocardiographic changes occurring at such high levels of sodium is scarce. At present there are no established guidelines on rate and mode of correction of such high sodium levels. This case highlights the electrocardiographic changes observed during extreme hypernatremia, controversies in managing increased intracranial pressure with hypertonic saline, and dilemmas encountered in managing extreme hypernatremia.

Population-based dietary approaches for the prevention of noncommunicable diseases.

As the incidence of noncommunicable diseases such as diabetes continues to rise at an alarming rate in South-East Asia, it is imperative that urgent and population-wide strategies are adopted. The most important contributors to the rise in noncommunicable disease are a rise in mean caloric intake and a decrease in physical activity. The evidence for population-based dietary approaches to counter these factors is reviewed. Several structural and cohesive interdepartmental coordination efforts are required for effective implementation of prevention strategies. Since low- and middle-income countries may lack the frameworks for effective and integrated multi-stakeholder intervention, implementation of population-based dietary and physical-activity approaches may be delayed and may be too late for effective prevention in current at-risk cohorts. Evidence-based strategies to decrease energy intake and increase physical activity are now well established and their urgent adoption by Member States of the World Health Organization South-East Asia Region is essential. In the context of Sri Lanka, for example, it is recommended that the most effective and easy-to-implement interventions would be media campaigns, restrictions on advertisement of unhealthy foods, taxation of unhealthy foods, subsidies for production of healthy foods, and laws on nutrition labelling that introduce colour coding of packaged foods.

A Polypill for primary prevention of cardiovascular disease: a feasibility study of the World Health Organization.

BACKGROUND: The feasibility of conducting a large-scale Polypill clinical trial in developing countries remains unclear. More information is needed regarding the efficacy in reducing the risk factors of cardiovascular disease (CVD), side effects, improvement in adherence and physician/patient "acceptability" of the Polypill. METHODS: We conducted an open-label, parallel-group, randomized clinical trial involving three sites in Sri Lanka that enrolled a total of 216 patients without established CVD. The trial compared a Polypill (75 mg aspirin, 20 mg simvastatin, 10 mg lisinopril and 12.5 mg hydrochlorothiazide) to Standard Practice. After randomization, patients were followed monthly for three months. Pre-specified primary outcomes included reduction in systolic blood pressure, total cholesterol and estimated 10-year CVD risk. We also evaluated the recruitment process and acceptability of the Polypill by both physicians and patients. RESULTS: Patients were recruited in a six-month period as planned. Two hundred three patients (94.0%) completed the treatment program and returned for their three-month follow-up visits. No safety concerns were reported. These findings suggest a high rate of patient acceptability, a finding that is bolstered by the majority of patients completing the trial (90%) indicating that they would take the Polypill "for life" if proven to be effective in reducing CVD risk. Approximately 86% of the physicians surveyed agreed with and supported use of the Polypill for primary prevention and 93% for secondary prevention of CVD. Both the Polypill and Standard Practice resulted in marked reductions in systolic blood pressure, total cholesterol and 10-year risk of CVD. However, the differences between the treatment groups were not statistically significant. CONCLUSIONS: We successfully completed a Polypill feasibility trial in Sri Lanka. We were able to document high acceptability of the Polypill to patients and physicians. We were unable to estimate the risk factor reductions on the Polypill because the control group received similar treatment with individual drugs. The Polypill was however simpler and achieved comparable risk factor reductions, highlighting its potential usefulness in the prevention of CVD. TRIAL REGISTRATION NUMBER: NCT00567307.