Bioactive phytocompound mulberroside C and endophytes of Morus alba as potential inhibitors of HIV-1 replication: a mechanistic evaluation.

OBJECTIVES: Despite considerable advancement in antiretroviral therapy, development of safe, effective, and multi-targeted drugs for HIV still remains a big challenge. Endophytes are untouched and, hence, an important and novel sources in drug discovery endeavours. The present study was conducted to identify the anti-HIV compounds from Morus alba and endophytes isolated from it. METHODS: The extracts of isolated endophytes were screened using high-performance liquid chromatography (HPLC). Further, all samples were analysed for their cytotoxicity using a thiazolyl blue tetrazolium bromide assay. Subsequently, anti-HIV activity was performed using cell-based and cell-free assay. At the end, potential endophytes were identified using gene sequencing. RESULTS: A total of 27 endophytes were isolated from the eight stem bark samples of M. alba. Of the 27 endophytes, extracts of total of four endophytes showed a profile similar to the M. alba plant when analysed by HPLC. Further experimentation with extracts of these four endophytes, along with an extract of M. alba stem bark and its bioactive molecule, mulberroside C, revealed that all these six samples have good inhibitory potential for HIV. Among them, mulberroside C and two endophytic fungal extracts showed very potent anti-HIV activity. Subsequently, mechanistic studies at the molecular level showed that out of six test samples, three acted as protease inhibitors. Further, all four potential endophytes were identified using gene sequencing. CONCLUSIONS: The overall findings of these studies can help in the development of a novel anti-HIV candidate from mulberroside C, an extract of stem bark of M. alba and extracts of these endophytes. However, further validation and clinical studies are required to develop an anti-HIV drug.

Use of glucagon-like peptide-1 receptor agonists among individuals on basal insulin requiring treatment intensification.

As Type 2 diabetes progresses, treatment is intensified with additional therapies in an effort to manage hyperglycaemia effectively and therefore avoid complications. When greater efficacy is required, options for injectable treatments include glucagon-like peptide-1 receptor agonists and insulin, which may be added on to oral glucose-lowering treatments. Among individuals receiving long-acting basal insulin as their first injectable treatment, ~40-60% are unable to achieve or maintain their target HbA1c goals. For these people, treatment intensification options are relatively limited and include the addition of short-acting prandial insulin or a glucagon-like peptide-1 receptor agonist. Glucagon-like peptide-1 receptor agonists vary in their effects, with short- and long-acting agents having a greater impact on postprandial and fasting hyperglycaemia, respectively. Studies comparing treatment intensification options have found both glucagon-like peptide-1 receptor agonists and prandial insulin to be effective in reducing HbA1c concentrations; however, recipients of glucagon-like peptide-1 receptor agonists lost weight and had a greater frequency of gastrointestinal adverse events, whereas those receiving prandial insulin gained weight and had a greater incidence of hypoglycaemia. In addition to the separate administration of a glucagon-like peptide-1 receptor agonist and basal insulin, fixed-ratio combinations of a glucagon-like peptide-1 receptor agonist and basal insulin offer a single administration for both treatments but have less flexibility in dose titration than treatment with their individual components. For individuals who require treatment intensification beyond basal insulin, use of these various options allows physicians to target the individual needs of their patients for the achievement of optimal long-term glycaemic control.

Adult Traumatic Inferior Hip Dislocation: Rare Case Ended with Open Reduction.

INTRODUCTION: An inferior hip dislocation also called luxatio erecta femoris is a rare type of hip dislocation that is not widely reported in literature. Only 12 cases are reported in British literature. CASE REPORT: This article reports a 17-year-old male involved in a road traffic accident, sustaining inferior hip dislocation. Following resuscitation, computed tomography confirmed the clinical diagnoses. Several attempts to perform a closed reduction of the hip under sedation and general anesthesia failed to reduce the dislocation. The patient underwent open reduction of his hip and capsule repair. Postoperatively no traction was applied, and the patient advised non-weight bearing on that side for 3 months. CONCLUSION: To our knowledge, this is the first reported case of an adult with an inferior hip dislocation not associated with a trochanteric fracture and required open reduction.

Insulin degludec does not increase antibody formation versus insulin glargine: an evaluation of phase IIIa trials.

We examined insulin antibody formation in patients with type 1 (T1D) or type 2 diabetes (T2D) treated with once-daily insulin degludec (IDeg) or insulin glargine (IGlar) to evaluate the impact of antibody formation on efficacy and safety. Insulin antibodies were measured using subtraction radioimmunoassays in six phase IIIa clinical trials using IDeg (n = 2250) and IGlar (n = 1184). Spearman's correlation coefficient was used to evaluate associations between cross-reacting antibodies and change from baseline glycated haemoglobin (HbA1c) and insulin dose. IDeg- and IGlar-specific antibodies remained low [<1% bound/total radioactivity (B/T)] and with low levels of antibodies cross-reacting with human insulin in patients with T1D (<20% B/T) and T2D (<6% B/T). Spearman's correlation coefficients between insulin antibody levels and change in HbA1c or insulin dose were low in both treatment groups. No clinically meaningful differences in adverse event (AE) rates were observed in patients with >10% B/T or without an absolute increase in antibodies cross-reacting with human insulin. IDeg treatment resulted in few immunogenic responses in patients with T1D and T2D; antibody formation was not associated with change in HbA1c, insulin dose or rates of AEs.

Intensifying insulin regimen after basal insulin optimization in adults with type 2 diabetes: a 24-week, randomized, open-label trial comparing insulin glargine plus insulin glulisine with biphasic insulin aspart (LanScape).

AIM: To test the hypothesis that a 'basal plus' regimen--adding once-daily main-meal fast-acting insulin to basal insulin once daily--would be non-inferior to biphasic insulin twice daily as assessed by glycated haemoglobin (HbA1c) concentration (predefined as ≤0.4%), but would provide superior treatment satisfaction. METHODS: This open-label trial enrolled adults to an 8- or 12-week run-in period, during which oral therapies except metformin were stopped and insulin glargine dose was titrated. Those with fasting glucose <7 mmol/l but HbA1c >7% (53 mmol/mol) were randomized to insulin glargine/glulisine once daily (n = 170) or insulin aspart/aspart protamine 30/70 twice daily (n = 165) for 24 weeks, with dose titration to glucose targets using standardized algorithms. RESULTS: For HbA1c, the basal plus regimen was non-inferior to biphasic insulin (least squares mean difference, 0.21%, upper 97.5% confidence limit 0.38%) meeting the predefined non-inferiority margin of 0.4%. Treatment satisfaction (Diabetes Treatment Satisfaction Questionnaire change version and Insulin Treatment Satisfaction Questionnaire total scores) significantly favoured basal plus. No difference was observed between the basal plus and the biphasic insulin groups in responders (HbA1c <7%, 20.6 vs 27.9%; p = 0.12), weight gain (2.06 vs 2.50 kg; p = 0.2), diabetes-specific quality of life (Audit of Diabetes-Dependent Quality of Life average weighted impact (AWI) score) and generic health status (five-dimension European Quality of Life questionnaire). Overall hypoglycaemia rates were similar between groups (15.3 vs 18.2 events/patient-year; p = 0.22); nocturnal hypoglycaemia was higher with the basal plus regimen (5.7 vs 3.6 events/patient-year; p = 0.02). CONCLUSION: In long-standing type 2 diabetes with suboptimal glycaemia despite oral therapies and basal insulin, the basal plus regimen was non-inferior to biphasic insulin for biomedical outcomes, with a similar overall hypoglycaemia rate but more nocturnal events.

Liraglutide pharmacokinetics and dose-exposure response in Asian subjects with Type 2 diabetes from China, India and South Korea.

AIMS: To investigate the population pharmacokinetics and exposure-response relationship of liraglutide, a human glucagon-like peptide-1 (GLP-1) analogue, in Asian subjects with Type 2 diabetes mellitus. METHODS: Data were derived from a published 16-week, randomized, double-blind, double-dummy, active-controlled, parallel-group trial of liraglutide in China, India and South Korea. The analysis utilized 2061 pharmacokinetic (PK) samples from 605 subjects exposed to liraglutide 0.6, 1.2 or 1.8 mg once daily. Demographic factors (body weight, age, gender, country) of importance for liraglutide clearance were evaluated. An exploratory exposure-response analysis was conducted to investigate effects on glycated haemoglobin (HbA1c) and body weight. RESULTS: Estimated liraglutide exposure (area under the curve; AUC) appeared to increase proportionally with increasing liraglutide dose (0.6-1.8 mg). The covariate analysis confirmed previous findings in a global clinical trial. Body weight was a predictor of liraglutide exposure; compared to a reference subject of 67 kg, exposure was 32% lower for maximum (115 kg) and 54% higher for minimum (37 kg) observed body weights. Gender, age and country had no relevant effect on exposure. Exposure-response analysis supported the use of 1.2mg as maintenance dose with the option of individual dose escalation to 1.8 mg to optimize treatment outcomes. CONCLUSIONS: Exposure appeared to increase proportionally with increasing liraglutide dose in Asian subjects with Type 2 diabetes mellitus. The only PK relevant predictor of exposure was body weight. The exposure-response relationships for HbA1c and body weight in Asian subjects were similar to observations in global populations.

Serial surveillance of carcinoid heart disease: factors associated with echocardiographic progression and mortality.

BACKGROUND: Carcinoid heart disease is a complication of metastatic neuroendocrine tumours (NETs). We sought to identify factors associated with echocardiographic progression of carcinoid heart disease and death in patients with metastatic NETs. METHODS: Patients with advanced non-pancreatic NETs and documented liver metastases and/or carcinoid syndrome underwent prospective serial clinical, biochemical, echocardiographic and radiological assessment. Patients were categorised as carcinoid heart disease progressors, non-progressors or deceased. Multinomial regression was used to assess the univariate association between variables and carcinoid heart disease progression. RESULTS: One hundred and thirty-seven patients were included. Thirteen patients (9%) were progressors, 95 (69%) non-progressors and 29 (21%) patients deceased. Baseline median levels of serum N-terminal pro-brain natriuretic peptide (NT-proBNP) and plasma 5-hydroxyindoleacetic acid (5-HIAA) were significantly higher in the progressors. Every 100 nmol l(-1) increase in 5-HIAA yielded a 5% greater odds of disease progression (OR 1.05, 95% CI: 1.01, 1.09; P=0.012) and a 7% greater odds of death (OR 1.07, 95% CI: 1.03, 1.10; P=0.001). A 100 ng l(-1) increase in NT-proBNP did not increase the risk of progression, but did increase the risk of death by 11%. CONCLUSIONS: The biochemical burden of disease, in particular baseline plasma 5-HIAA concentration, is independently associated with carcinoid heart disease progression and death. Clinical and radiological factors are less useful prognostic indicators of carcinoid heart disease progression and/or death.

Effect of once-daily insulin detemir on oral antidiabetic drug (OAD) use in patients with type 2 diabetes.

WHAT IS KNOWN AND OBJECTIVE: There are acknowledged benefits to continuing metformin when initiating insulin, but there appears to be growing concern over the role of sulphonylureas and thiazolidinediones when used in combination with insulin. This analysis investigates the effects of continuing or discontinuing oral antidiabetic drugs (OADs) following the initiation of once-daily insulin detemir. METHODS: SOLVE is a 24-week, multinational observational study of insulin detemir initiation in patients with type 2 diabetes mellitus treated with one or more OADs. RESULTS: In the total cohort (n = 17 374), there were significant improvements in HbA1c (-1·3%, 95% CI -1·34; -1·27%) and weight (-0·6 kg, 95% CI -0·65; -0·47 kg), with an increase in the incidence rate of minor hypoglycaemia (+0·256 events ppy, P < 0·001), but not severe hypoglycaemia (-0·038 events ppy, P < 0·001). Study participants had information on OAD use either prior to (n = 17 086) or during insulin initiation (n = 16 346). HbA1c reductions were significantly greater in patients continuing treatment with metformin (-1·3% vs. -1·1%, P < 0·01), thiazolidinediones (-1·3% vs. -1·0%, P < 0·01) and DPP-IV inhibitors (-1·3% vs. -0·9%, P < 0·001). Final insulin doses were significantly greater in patients discontinuing treatment with sulphonylureas (0·29 vs. 0·26 IU/kg, P < 0·001), glinides (0·28 vs. 0·26 IU/kg, P < 0·01), thiazolidinediones (0·31 vs. 0·26 IU/kg, P < 0·001) and DPP-IV inhibitors (0·35 vs. 0·29 IU/kg, P < 0·001) compared with patients continuing these respective agents. All patient subgroups had a mean weight loss irrespective of OAD continuation, apart from those continuing thiazolidinediones (+0·2 kg). The largest improvements in weight were seen following the withdrawal of sulphonylureas and thiazolidinediones (-1·1 and -1·1 kg, respectively). WHAT IS NEW AND CONCLUSION: Discontinuation (or switching) of OADs at the time of insulin initiation appears to be governed principally by concerns about hypoglycaemia and weight. HbA1c improvements were smaller in patients discontinuing OADs at the time of insulin initiation and may be associated with insufficient insulin titration.

Resource utilisation and quality of life following initiation of insulin detemir in patients with type 2 diabetes mellitus.

OBJECTIVE: Barriers to insulin initiation in type 2 diabetes mellitus (T2DM) include fear of treatment complexity and perceived lack of time and resources by primary care physicians. The SOLVE study investigated the effect of insulin initiation on resource utilisation and patient quality of life. METHODS: SOLVE was a 24-week cohort study in 10 countries evaluating the safety and effectiveness of initiating once-daily insulin detemir in patients with T2DM. Patient quality of life was assessed using the Insulin Treatment Appraisal Scale (ITAS). RESULTS: A total of 14,611 (84%) patients completed the 24-week study. During the study, HbA1c improved by 1.3 ± 1.5%. The corresponding insulin dose increased from 13 ± 6 IU (0.16 ± 0.09 IU/kg) at baseline, to 22 ± 16 IU (0.27 ± 0.17 IU/kg) at final visit. FlexPen was the preferred device (63%) for insulin administration. The time taken to teach patients to self-inject and perform dose self-adjustment was 15 ± 13 min and 11 ± 11 min, respectively. The quality of life analysis included 6875 patients. The addition of insulin was associated with an improvement in mean ITAS score [-3.5 (95% CI -3.8, -3.3), p < 0.001]. Physicians reported the use or self-adjustment of insulin detemir as easy or very easy in 79% of participants; and satisfaction with the level of glycaemic control was reported for 74% of patients. CONCLUSIONS: Initiating basal insulin therapy resulted in a substantial decrease in HbA1c and improved patients' perceptions of insulin treatment.

Variability of glucose-lowering effect as a limiting factor in optimizing basal insulin therapy: a review.

Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding factor in disease management but it is possibly also of direct prognostic consequence and is increasingly recognized as an informative measurement in diabetes management. The scope for insulin-induced glucose variability is particularly great with basal insulins because of their prolonged absorption from high-dose depots. Pharmacodynamic (PD) variability manifests as both fluctuations in the level of glucose-lowering effect over time, and as inconsistencies in the response from one injection to another. Well-controlled pharmacokinetic (PK)/PD studies using repeated isoglycaemic clamp methodology clearly how that many injected basal insulin products have high variable absorption with correspondingly variable action. Incomplete resuspension and precipitation appear to be important issues with regard to unpredictability in this action, while an inadequate duration of action relative to the dosing interval results in a fluctuating action profile. There are some ultra-long-acting basal insulins with novel protraction mechanisms currently in clinical development for which clamp studies show markedly improved PK/PD profiles.

Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity.

BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

Incretin-based therapy in combination with basal insulin: a promising tactic for the treatment of type 2 diabetes.

Incretin therapies such as dipeptidyl peptidase-4 inhibitors (DPP-4Is) and GLP-1 receptor agonists (GLP-1RAs) have become well-established treatments for type 2 diabetes. Both drug classes reduce blood glucose through physiological pathways mediated by the GLP-1 receptor, resulting in glucose-dependent enhancement of residual insulin secretion and inhibition of glucagon secretion. In addition, the GLP-1RAs reduce gastrointestinal motility and appear to have appetite-suppressing actions and, so, are often able to produce clinically useful weight loss. The glucose-dependency of their glucagon-inhibiting and insulin-enhancing effects, together with their weight-sparing properties, make the incretin therapies a logical proposition for use in combination with exogenous basal insulin therapy. This combination offers the prospect of an additive or synergistic glucose-lowering effect without a greatly elevated risk of hypoglycaemia compared with insulin monotherapy, and any insulin-associated weight gain might also be mitigated. Furthermore, the incretin therapies can be combined with metformin, which is usually continued when basal insulin is introduced in type 2 diabetes. Although the combination of incretin and insulin therapy is currently not addressed in internationally recognized treatment guidelines, several clinical studies have assessed its use. The data, summarized in this review, are encouraging and show that glycaemic control is improved and weight gain is limited or reversed (especially with the combined use of GLP-1RAs and basal insulin), and that the use of an incretin therapy can also greatly reduce insulin dose requirements. The addition of basal insulin to established incretin therapy is straightforward, but insulin dose adjustment (though not discontinuation) is usually necessary if the sequence is reversed.

The safety and efficacy of adding once-daily insulin detemir to oral hypoglycaemic agents in patients with type 2 diabetes in a clinical practice setting in 10 countries.

AIMS: Evaluate the safety and efficacy of once-daily insulin detemir initiated in routine clinical practice in patients with type 2 diabetes mellitus inadequately controlled with oral hypoglycaemic agents (OHAs). METHODS: This large observational study was conducted in 10 countries. Adverse event data (including hypoglycaemia) and glycaemic control were recorded before and 24 weeks following insulin initiation while patients continued routine clinical management. RESULTS: In this study, 17 374 patients (53% male) were included. Mean pre-insulin values (±s.d.) were: age 62 ± 12 years; body mass index (BMI) 29.3 ± 5.4 kg/m(2); diabetes duration 10 ± 7 years; haemoglobin A1c (HbA1c) 8.9 ± 1.6%. During the study, 27 patients experienced serious adverse drug reaction, severe hypoglycaemic events or both; and there were 31 episodes of severe hypoglycaemia in 21 patients. After 24 weeks, HbA1c was 7.5 ± 1.2% (change of -1.3%; p < 0.001) and mean weight change was -0.6 kg (confidence interval -0.7, -0.5 kg, p < 0.001). Daily insulin dose increased from 13 ± 6 U (0.16 ± 0.09 U/kg) to 22 ± 16 U (0.27 ± 0.17U/kg) by 24 weeks. Multivariate regression analysis identified several independent demographic and treatment predictors of end of study HbA1c. CONCLUSIONS: Addition of once-daily insulin detemir to patients with type 2 diabetes mellitus on OHA therapy resulted in few adverse events, significant improvements in glycaemic control, small reductions in weight and low rates of hypoglycaemia. On the basis of this study, concerns about hypoglycaemia or weight gain should not preclude initiation of basal insulin analogues in patients with poor glycaemic control on OHAs.

Commissioning specialist diabetes services for adults with diabetes: summary of a Diabetes UK Task and Finish group report.

The increasing prevalence of diabetes, the drive to develop community services for diabetes and the Quality and Outcomes Framework for diabetes have led to improvements in the management of diabetes in primary care settings, with services traditionally provided only in specialist care now provided for many patients with diabetes by non-specialists. Consequently, there is a need to redefine roles, responsibilities and components of a specialist diabetes service to provide for the needs of patients in the National Health Service (NHS) today. The delivery of diabetes care is complex and touches on almost every aspect of the health service. It is the responsibility of those working within commissioning and specialist provider roles to work together with people with diabetes to develop, organize and deliver a full range of integrated diabetes care services. The local delivery model agreed within the local diabetes network, comprising specialist teams, primary care teams, commissioners and people with diabetes, should determine how the diabetes specialist services are organizsed. It should identify the roles and responsibilities of provider organizations to ensure that the right person provides the right care, at the right time, and in the right place. We summarize a report entitled 'Commissioning Diabetes Specialist Services for Adults with Diabetes', which has been produced, as a 'Task and Finish' group activity within Diabetes UK, to assist managers, commissioners and healthcare professionals to provide advice on the structure, roles and components of specialist diabetes services for adults.

Long-term effects of insulin glargine on the risk of breast cancer.

AIMS/HYPOTHESIS: There have been growing concerns regarding the long-term effects of insulin glargine (A21Gly,B31Arg,B32Arg human insulin) on the risk of breast cancer. METHODS: We used the UK's General Practice Research Database (GPRD) to identify a cohort of women aged 40 years or over with type 2 diabetes, treated with insulin during 2002-2006 and followed until the first breast cancer diagnosis or 31 December 2009. After the users of insulin glargine had been matched with users of other insulins on age, calendar time and duration of prior insulin use, the HR of breast cancer associated with insulin glargine use was estimated using a Cox proportional hazards model, adjusted for known risk factors for breast cancer. RESULTS: The cohort comprised 15,227 women, including 4,579 glargine users and 10,648 users of other insulins, of which 246 developed breast cancer during up to 8 years follow-up (incidence rate 4.1 per 1,000 per year). Insulin glargine use was not associated with an increased risk of breast cancer during the first 5 years of use (HR 0.9; 95% CI 0.7-1.3). The risk tended to increase after 5 years (HR 1.8; 95% CI 0.8-4.0), and significantly so for the women who had been on insulin before starting glargine (HR 2.7; 95% CI 1.1-6.5). CONCLUSIONS/INTERPRETATION: The risk of breast cancer in women with type 2 diabetes is not increased during the first 5 years of insulin glargine use. However, longer-term use may increase this risk, particularly in women with longstanding use of insulin before starting insulin glargine.

A review of modern insulin analogue pharmacokinetic and pharmacodynamic profiles in type 2 diabetes: improvements and limitations.

Insulin analogues have been engineered to enhance desired molecular properties without altering immunogenicity. The majority of insulin pharmacology studies are conducted in healthy volunteers and patients with type 1 diabetes. At present, there are more patients with type 2 than type 1 diabetes receiving insulin treatment. As the responsibility for initiating insulin therapy in these patients continues to shift to primary care, it will be important for general practitioners to understand the different pharmacological properties of insulin preparations in patients with type 2 diabetes, so that treatment can be adapted to meet patients' physiological and lifestyle requirements. The purpose of this review is to summarize pharmacological studies of insulin analogues in patients with type 2 diabetes. Faster onset of action of rapid acting insulin analogues has improved postprandial glycaemic control. Biphasic insulin analogues are associated with a lower incidence of nocturnal hypoglycaemia compared with human biphasic preparations and allow for intensification from once to twice or thrice daily dosing. More predictable glycaemic-lowering profiles of the insulin analogues have also led to reductions in nocturnal hypoglycaemia, particularly comparing long-acting insulin analogues with protaminated human insulin. Enhancing insulin self-association and reversible binding with albumin has led to further reductions in variability. However, improvements can still be made. Effective once daily clinical dosing of long-acting insulin analogues is not possible in all patients. In addition, the protaminated component of biphasic insulin analogues do not provide the duration of action or profile for physiological basal insulin replacement and neither insulin glargine nor insulin detemir are suitable for mixing with other insulin analogues as this would substantially alter their pharmacokinetic properties. Enhancing the pharmacological predictability and extending the duration of action could simplify insulin titration and further reduce the incidence of hypoglycaemia.

Effect of oral phosphate and alendronate on bone mineral density when given as adjunctive therapy to growth hormone replacement in adult growth hormone deficiency.

BACKGROUND: Adult GH deficiency (AGHD) is associated with osteoporosis, which occurs as the result of reduced sensitivity of the bone and kidney to the effect of PTH. AIM: The aim of the study was to examine the effect of oral phosphate and alendronate therapy on PTH sensitivity, bone turnover, and bone mineral density (BMD) in AGHD patients. METHODS: Forty-four AGHD patients were hospitalized for 24 h, and half-hourly blood and 3-hourly urine samples were collected for PTH, nephrogenous cAMP (marker of renal PTH activity), procollagen type-I amino-terminal propeptide, and type-I collagen ß C-telopeptide. Patients were randomized to one of six groups: patients who were previously naive to GH were randomized to receive GH replacement (GHR) alone, GHR+alendronate, or GHR+phosphate-sandoz, whereas patients already receiving GHR were randomized to continue GHR alone, GHR+alendronate, or GHR+phosphate-sandoz. Study visits were repeated after 1, 3, 6, and 12 months in the previously GH-naive group and after 12 months in the previously GH-replaced group. BMD was measured at 0 and 12 months. RESULTS: Patients receiving GHR+phosphate had greater increases in nephrogenous cAMP and bone markers than patients receiving GHR alone (P < 0.01), and this was associated with greater increases in BMD (P < 0.01). In the GHR+alendronate groups, type-I collagen ß C-telopeptide decreased (P < 0.001), and BMD increases were greater than in those receiving GHR alone (P < 0.05). The greatest increases in BMD were seen in patients receiving GHR+phosphate. CONCLUSIONS: Phosphate and alendronate therapy given in combination with GHR confer advantage in terms of BMD increase. Phosphate appears to exert its effect by increasing PTH target-organ action, whereas alendronate acts primarily through reduction in bone resorption.

Correlation of serum-adjusted calcium with ionized calcium over a 24-h period in patients with adult growth hormone deficiency before and after growth hormone replacement.

BACKGROUND: Difficulties associated with measuring ionized calcium in clinical practice have led to the use of total calcium, with or without adjustment for albumin concentration, as an estimate of calcium metabolism. We examined the correlation between ionized and total/adjusted calcium over a 24-h period in patients with adult growth hormone deficiency (AGHD), a group of patients with previously reported alterations in calcium metabolism. METHODS: Four patients with AGHD were consented to the study. They were hospitalized for 24 h where half-hourly blood samples were collected for ionized calcium, total calcium, albumin and creatinine, before and one month after the commencement of growth hormone replacement. Total calcium concentration was adjusted for serum albumin. RESULTS: Strong correlations were found between ionized calcium and adjusted calcium (r(2) = 0.840 and 0.766 for visits 1 and 2, respectively, P < 0.001), and between ionized calcium and total calcium (r(2) = 0.828 and 0.731 for visits 1 and 2, respectively, P < 0.001). Correlations remained significant during the day (ionized versus adjusted calcium: r(2) = 0.847 and 0.780 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.860 and 0.792 for visits 1 and 2, respectively, all P < 0.001) and at night (ionized versus adjusted calcium: r(2) = 0.831 and 0.802 for visits 1 and 2, respectively; ionized versus total calcium: r(2) = 0.767 and 0.722 for visits 1 and 2, respectively, all P < 0.001). CONCLUSION: The results of our study suggest that total calcium and serum-adjusted calcium can be used in place of ionized calcium as a reliable indicator of calcium metabolism over a 24-h period in patients with AGHD.