Clinical challenges with excipients in insulin formulations and role of concentrated insulin

Most of the insulin formulations in clinical use contain phenol, meta-cresol or both as excipients. These excipients in insulin preparations provide stability and have antimicrobial properties. However, they are reported to be associated with undesirable side-effects especially localised allergic reactions. Amount of excipients injected per unit dose of insulin is a major determining factor in causation of these reactions. This review discusses the excipients in different insulin formulations available in India with potential of precipitating undesirable effects and the use of concentrated insulins to reduce these complications. To avoid the detrimental effects associated with excipients, removal of preservatives or use of insulin preparations devoid of excipients can be an option. Besides these approaches, one approach that can be considered is the use of concentrated insulin to reduce the volume of insulin dose and thereby the excipients. Concentrated insulins address the high insulin requirements of the growing population of patients with type 2 diabetes who require higher insulin doses. Concentrated insulins help in reduction of dose volume as well as amount of excipients injected per unit dose of insulin. U200 (concentrated r-DNA Human Insulin Premix 30/70-200 IU/ml) can be advantageous with better absorption from smaller quantity injected, lesser variability in absorption, lesser pain and discomfort due to smaller quantity, lesser chances of hypoglycaemia all of which can lead to better patient compliance. Thus, concentrated insulin U200 can be one of the alternatives to prevent/reduce clinical complications with excipients in insulins.

Utility of Biomarkers in Sepsis: Mirror Reflection of Inner Truculent Devil.

There is a plethora of biomarkers proposed and being researched in the field of sepsis. The complex pathophysiology of sepsis involves many mediators of inflammation pertaining to coagulation, complement, contact system activation, inflammation, apoptosis, etc. Markers related to those processes can gauge the degree of sepsis. Compared with localized pathology, the systemic nature and involvement of multiple organs in sepsis gives scope for numerous potential biomarkers. There is no 'gold standard' for the diagnosis of sepsis. Currently available/in-research biomarkers are compared for their efficacy with methods used to diagnose and monitor sepsis such as combination of clinical signs and available laboratory variables. An arbitrary classification of these biomarkers is made and the literature surrounding these markers and their efficacy in diagnosis of sepsis is reviewed.

IGF-1 and IGFBP 3 in Growth Hormone Deficiency Role of Insulin Like Growth Factor-1 (IGF-1) and IGF Binding Protein 3 in the Diagnosis of Growth Hormone Deficiency: Changing Paradigm.

GH stimulation tests are widely used in the diagnosis of GH deficiency (GHD), although they are associated with a high false positive rate. Serum IGF-I levels are monitored during GH replacement treatment in subjects with GH deficiency (GHD) to guide GH dose adjustment and to minimize occurrence of GHrelated side-effects. The need for reliance on provocative testing is based on evidence that the evaluation of spontaneous growth hormone (GH) secretion over 24 hours and the measurement of IGF-I and IGFBP-3 levels do not distinguish between normal and GHD subjects. Regarding IGF-I, it has been demonstrated that very low levels in patients highly suspected for GHD (i.e., patients with childhood-onset, severe GHD, or with multiple hypopituitarism acquired in adulthood) may be considered definitive evidence for severe GHD obviating the need for provocative tests. However, normal IGF-I levels do not rule out severe GHD and therefore adults suspected for GHD and with normal IGF-I levels must undergo a provocative test of GH secretion. We hereby review the various literatures at disposal justifying the use of IGF-1 and IGBP3 for diagnosis of growth hormone deficiency. Data Source: We searched PUBMED and MEDLINE database for relevant articles including key words. References of each article were further reviewed for final synthesis of the manuscript.

Hirschsprung’s Disease with Congenital Hypothyroidism.

We report a female newborn baby who presented with vomiting and abdominal distension on day 21 of life. Examination revealed facial puffiness, open posterior fontanelles, dry skin, cold peripheries and prominent abdominal veins with visible peristalsis. Barium enema revealed dilated proximal colon, empty rectum, funnel like transition zone between proximal dilated and distal constricted bowel. Serum TSH level was >150 μIU/mL. Biopsy revealed aganglionic segment suggesting Hirschsprung’s disease, an unusual association with congenital hypothyroidism.

Precocious Puberty and Pineal Cyst – An Uncommon Association.

We present a five year old boy with central precocious puberty and pineal gland cyst on neuroimaging. This association is uncommon and highlights the role of pineal gland in puberty.

Obesity and thyrotropinemia.

Objective. To study the relation between body mass index (BMI) and TSH in euthyroid and subclinical hypothyroid obese children and compared serum TSH level among obese and overweight children. Methods. Fifty consecutive children (aged 2-18 yr) presenting for obesity were studied. All cases with TSH > 10, low T3/T4, organic and syndromic obesity were excluded. Patients were divided into Group 1: Overweight (n=20) (BMI between 85th to 95th centile) and Group 2: Obesity (n=30) (BMI > 95th centile). Fisher’s exact test, Mann-Whitney U test and Pearson’s correlation were used for statistical analysis. P value < 0.05 was considered significant. Results. Elevated TSH level (between 4.5 – 10 mIU/L) with normal T3, T4 was seen in 4/20 overweight and 9/30 of obese children (P=0.5219). The mean TSH was comparable in both the groups (3.22 ± 3.1 mIU/L vs. 3.63 ± 2.2 mIU/L, P=0.3491). Overall TSH showed no correlation with BMI (r= 0.0014, P=0.9924). Conclusion. The preliminary data did not show any relation between severity of obesity and TSH level. Further large scale data from population are required to confirm these findings.

Symptomatic primary hyperparathyroidism: a retrospective analysis of fifty one cases from a single centre.

OBJECTIVE: Widely prevalent vitamin D deficiency and delayed diagnosis contributes to severe symptomatic primary hyperparathyroidism in India. We analysed fifty one consecutive patients of primary hyperparathyroidism managed at our centre. All of them were symptomatic. DESIGN: Retrospective analysis. MATERIAL AND METHODS: Fifty one consecutive cases of symptomatic primary hyperparathyroidism, presenting to our centre from January 1994 to May 2007 were retrospectively analyzed. Clinical presentation, biochemical, radiological and details of underlying parathyroid lesion were noted. RESULTS: A total of 51 cases of primary hyperparathyroidism were studied. Mean age was 39.5 +/- 11.5 yrs (Range 13 to 70 years, Female: Male 2:1). Mean duration of symptoms was 35.8 + 29.1 months. Bone pains and painful proximal myopathy were the commonest presentation (24/51), followed by pathological fractures in 12 cases. Distal Renal tubular acidosis was diagnosed in 4 cases, 3 of whom normalized after surgery. At initial evaluation, twenty one patients had elevated alkaline phosphatase with normal calcium levels indirectly suggesting associated vitamin D deficiency. Low serum levels of 25-hydroxy vitamin D were documented in five of them. Parathyroid carcinoma was diagnosed in 3 patients. Ectopic parathyroid adenoma was seen in 7 cases (3 mediastinal, 3 intrathyroidal, 1 near left carotid sheath). All the cases responded well to surgical excision. CONCLUSION: Lack of universal screening for hypercalcemia, normocalcemia contributed by associated vitamin D deficiency and lack of awareness about unusual presentations of primary hyperparathyroidism led to delayed diagnosis in our patients. Delayed diagnosis and associated vitamin D deficiency in our patients contributed to greater severity of symptomatic primary hyperparathyroidism.

Efficacy of teriparatide in increasing bone mineral density in postmenopausal women with osteoporosis--an Indian experience.

BACKGROUND AND OBJECTIVE: Osteoporosis is emerging as a leading cause of substantial morbidity in India, particularly in postmenopausal women. Teriparatide (recombinant human parathyroid hormone [1-34]) increases bone formation and improves bone microarchitecture, thereby reducing the risk of fractures. This study was conducted to evaluate the efficacy of teriparatide in increasing bone mineral density (BMD) in postmenopausal women with osteoporosis. MATERIAL AND METHODS: A randomised, prospective, multicentre, open-label, controlled study was conducted on 82 postmenopausal women with established osteoporosis. Patients were randomly divided into control and teriparatide groups, each group consisting of 41 patients. All the patients were supplemented with 1000 mg of elemental calcium and 500 IU of vitamin D throughout the study period of 180 days. Besides, teriparatide group patients were administered teriparatide 20 microg daily subcutaneously. Lumbar spine, femoral neck and total hip BMD, bone mineral content (BMC) and bone area were measured by dual energy x-ray absorptiometry (DXA) at baseline and at the end of 6 months of treatment. Bone biomarkers, such as serum bone specific alkaline phosphatase (BSAP) and serum osteocalcin (OC), representing bone formation, and urinary deoxypyridinoline (DPD), representing bone resorption were assessed at baseline, and at 3 and 6 months of treatment. RESULTS: During the study period, 9 patients (11%) were lost to follow-up--6 in control group (7.3%) and 3 in teriparatide group (3.7%). There was an excellent compliance to both oral and injectable medication. The investigational product teriparatide was well tolerated and there were no serious adverse events. In addition, there were no significant differences between the groups in the incidence of adverse events. The percentage of increase in lumbar spine BMD, which is the primary endpoint, was significantly (P < 0.001) higher in teriparatide group compared to that in control group (6.58% vs. 1.06%). Further, teriparatide significantly increased percentage of change in lumbar spine T-score (P < 0.001), BMC (P < 0.001) and bone area (P < 0.028) compared to control group at 6 months. Administration of teriparatide resulted in a significant percentage of increase in all the bone biomarkers in teriparatide group compared to control group patients at 3 and 6 months over baseline, thereby showing that there was a significant increase in bone turnover in teriparatide group of patients. CONCLUSION: These results show that teriparatide is an effective and safe drug in increasing the BMD and therefore, teriparatide provides yet another new therapeutic option for reducing the risk management of osteoporosis in postmenopausal women (clinicaltrials.gov number, NCT00500409).

Ectopic parathyroid adenoma--the hidden culprit.

Primary Hyperparathyroidism is known to present with protean manifestations leading to misdiagnosis in the initial stages of the disease. Inability to locate the adenoma in an ectopic parathyroid gland may further delay the diagnosis of these cases. Aberrant migration during development may lead to intrathyroidal or other ectopic locations of parathyroid glands. This may lead to their misdiagnosis as a thyroid nodule or failure to locate parathyroids during surgery. Similarity in cytological picture between thyroids and parathyroids may further complicate diagnosis by fine needle aspiration cytology. Nuclear imaging scintigraphy accurately localizes the tumor in 90% of cases and simplifies the surgical management. We encountered three such cases with the parathyroid gland adenomas in ectopic locations in which pre-operative nuclear imaging played a major role.

Growth hormone-producing pituitary tumours: clinical profile and results of surgery.

BACKGROUND: Growth hormone-producing pituitary tumours present with a wide variety of manifestations. The optimum diagnostic work up, management and follow up of such patients is complex and involves a multidisciplinary approach. There is paucity of data from India with regard to the clinical presentation and results of surgery for growth hormone-producing tumours. METHODS: We studied the first 50 patients presenting during 1989-94 with growth hormone-producing pituitary tumours to our centre. The work up included detailed endocrine and radiological assessment. The surgical outcome was analysed for 35 patients who were operated (trans-sphenoidal 29, transcranial 6) at our centre. RESULTS: All the patients had macroadenomas [mean (SD) diameter 3.12 (0.87) cm]. Seventy-five per cent of the patients had supra- and/or parasellar extension and 57% had visual field defects. Tumour size correlated with the preoperative basal (r = 0.57) and glucose-suppressed (r = 0.54) growth hormone levels. Thirty-three of the 35 patients operated at our centre (trans-sphenoidal 28, transcranial 5) were available for follow up (median duration 34 months). After trans-sphenoidal surgery alone, 12 of the 28 (43%) patients had normalization of growth hormone levels (post-glucose growth hormone < 5 ng/ml), and 9 of 11 (82%) showed improvement in visual fields. CONCLUSION: In India, growth hormone-producing pituitary tumours are usually large in size. The growth hormone levels correlate with the size of the tumour. These tumours can be effectively treated by trans-sphenoidal or transcranial surgery.