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Mortality from heart failure remains high. Many subjects who have been hospitalized with acute decompensated heart failure leave hospital with residual congestion, despite treatment with loop diuretics. In an attempt to improve this, the Acetazolamide in Decompensated heart failure with Volume OveRload (ADVOR) trial was undertaken, where acetazolamide was added to the loop diuretic bumetanide.This article discusses ADVOR. The primary endpoint of ADVOR was the reversal of congestion, which was increased by adding acetazolamide to bumetanide. However, acetazolamide did not shorten hospital stay or the composite of rehospitalisation and death after three months.The limitations of ADVOR include that acetazolamide did not improve quality of life and that the testing was in white subjects only. During the hospital stay for decompensation, medicines that inhibit the angiotensin and mineralocorticoid systems were increased, which suggests that the treatment for heart failure was not ideal on hospitalization. As the death rates in ADVOR were lower than in previous studies, this suggests that the overall treatment of decompensated/heart failure is improving. However, in the author's opinion, although the addition of acetazolamide is a small improvement in the treatment of acute decompensated heart failure with volume overload, more options need to be considered.

The involvement of B-cells in multiple sclerosis has only recently emerged. Ublituximab is a monoclonal antibody that binds to the B-cell antigen CD20 with enhanced B-cell targeting.This evaluation is of the identical ULTIMATE (UbLiTuximab In Multiple Sclerosis Treatment Effects) I and II trials comparing ublituximab (TG-1101) and teriflunomide in relapsing multiple sclerosis. The primary efficacy end point was the annualized relapse rate and was lower in the ublituximab than the teriflunomide group.The continuation rates to oral teriflunomide in ULTIMATE were higher than in other trials, possibly because of the supervised double-dummy protocol used with intravenous ublituximab. This may have contributed to the higher efficacy with teriflunomide in this trial than previously reported. Nevertheless, ublituximab was more effective than teriflunomide at reducing the annualized relapse rates and MRI endpoints, but not for no evidence of disease activity (NEDA). Subsequently, a meta-analysis of the ULTIMATE trials did show that ublituximab was superior to teriflunomide in NEDA. Long-term studies of the adverse effects of ublituximab are required. Despite the positive results from ULTIMATE for ublituximab, it is still under the scrutiny of the Food and Drug Administration (FDA), and conclusions should await their findings.

Obesity is a major risk factor for cardiovascular disease, diabetes, osteoarthritis, and some cancers. Weight loss is an obvious management for this, but a major problem is that after weight loss, many people regain weight.In the following evaluation of S-LITE (NCT04122716, Combined effects of GLP-1 analogue and exercise on maintenance of weight loss after very-low calorie diet), the author gives emphasis to the prevention of weight regain by liraglutide, not the effects of exercise. In S-LITE, liraglutide (with or without exercise) was effective in reducing weight regain in subjects with obesity.The subjects with obesity in S-LITE were limited by the enrollment criteria, and the findings of S-LITE cannot be generalized. The increased heart rate with liraglutide did not occur when liraglutide was combined with exercise, and this suggests that liraglutide should probably not be used alone, but only with exercise to maintain weight loss. As the only presently available medicine to have been shown to be effective against weight regain, liraglutide should probably be preferred to other weight-loss medicines in this circumstance. However, without clear evidence that liraglutide treatment for obesity prevents diabetes and/or reduces cardiovascular risk, it is difficult to justify using it.

Introduction: Homozygous Familial Hypercholesterolemia (HoFH) is a very severe genetic form of hypercholesterolemia. Lacking LDL receptors in the liver, subjects with HoFH have raised plasma levels...

Introduction: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in treating Alzheimer's disease. Aβ is formed by the cleavage of amyloid precursor protein by β-site amyloid precure protein cleaving enzyme (BACE1) and the BACE1 inhibitor verubecestat was developed to lower the brain levels of Aβ. However, in the EPOCH trial of verubecestat in mild-to-moderate Alzheimer's disease, it was not beneficial and increased adverse effects.Areas covered: Prior to completing EPOCH, APECS, which trialled verubecestat in prodromal Alzheimer's disease, was commenced. Like EPOCH, APECS was terminated early. In APECS, verubecestat 40 mg worsened cognition and increased adverse effects.Expert opinion: In recruiting subjects to clinical trials in Alzheimer's disease, a clinical diagnosis involving the measurement of Aβ should be undertaken for all subjects, as this may help to clarify the findings. In my opinion, the failure of verubecestat in EPOCH and APECS probably could have been avoided if a safety and potential efficacy trial (phase 2) had been completed prior to starting phase 3. It seems to me that, as we have a poor understanding of the underlying mechanisms/cause of Alzheimer's disease, this is where the research emphasis should be, not phase 3 clinical trials.

Introduction Lopinavir in combination with ritonavir is approved for the treatment of HIV and has recently been subject to a clinical trial in severe COVID-19. Areas covered This evaluation is of LOTUS China (the Lopinavir Trial for Suppression of SARS-Cov-2 in China), which was a randomized trial in hospitalized subjects with COVID-9 in a respiratory sample and pneumonia. As, in severe COVID-19, lopinavir/ritonavir had no beneficial effects but increased gastrointestinal adverse effects, this combination should not be used at this stage of COVID-19. Expert opinion In my opinion, the rationale for undertaking a trial of lopinavir/ritonavir in COVID-19 was poor. The analysis of a modified intention to treat group analysis in LOTUS China may have introduced bias. After LOTUS China, there is probably no future for lopinavir in the treatment of severe COVID-19, but some clinical trials for prevention or in various stages of COVID-19 have recently started or are ongoing. The major limitation of these trials is that as lopinavir does not inhibit COVID-19, it is unlikely to prevent infection, reduce viral load, or reduce the severity. However, these trials may be worthwhile in finally determining whether lopinavir has any role in preventing or treating COVID-19.

Introduction: The amyloid-beta (Aβ) cascade hypothesis is that reducing Aβ levels in the brain will be beneficial in the treatment of Alzheimer’s disease. Solanezumab is a humanized analog of a mur...

Glucagon-like peptide-1 (GLP-1) is produced by the gut, and in a glucose-dependent manner stimulates insulin secretion while inhibiting glucagon secretion, reduces appetite and energy intake, and delays gastric emptying. The GLP-1R agonist semaglutide has recently been registered to treat type 2 diabetes. Area covered: This review is of semaglutide in type 2 diabetes, and considers which properties of this GLP-1R agonist, may be responsible for its clinical outcome benefits . Expert opinion: The pharmacokinetics of semaglutide make it ideal for once-weekly dosing. SUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) showed that semaglutide 0.5 or 1 mg subcutaneously once-weekly reduced cardiovascular outcomes in subjects with type 2 diabetes and cardiovascular disease or risk, mean age 65 years, baseline HbA1c 8.7% and mean body weight of 92 kg. Although, semaglutide may be a useful drug in this population, it increased retinopathy to a small extent and this needs further investigation. Also, it is not known whether semaglutide will improve cardiovascular outcomes in other populations including those with lower ages, HbA1c values, and body weights similar to those included in the unsuccessful clinical outcome trials with the GLP-1R agonists, lixisenatide and exenatide.

Evaluation of: Ahrén B, Johnson SL, Stewart M et al. HARMONY 3: 104-Week randomized, double-blind, placebo- and active-controlled trial assessing the efficacy and safety of albiglutide compared with placebo, sitagliptin, and glimepiride in patients with type 3 diabetes taking metformin. Diabetes Care 2014;37:2141-8 and Rosenstock J, Fonseca VA, Grass JL et al. Advancing basal insulin replacement in type 2 diabetes inadequately controlled with insulin glargine plus oral agents: a comparison of adding albiglutide, a weekly GLP-1 receptor agonist, versus thrice-daily prandial insulin lispro. Diabetes Care 2014;37:2317-25. Agonists of glucagon-like peptide-1 (GLP-1) receptors are used in the treatment of Type 2 diabetes. Albiglutide is a new long-acting GLP-1 receptor agonist being developed for once weekly use. This is an evaluation of two clinical trials in the HARMONY clinical trials series. HARMONY 3 compares albiglutide with sitagliptin and glimepiride in subjects with Type 2 diabetes poorly controlled with metformin, and HARMONY 6 compares albiglutide with insulin lispro in subjects poorly controlled with slow/medium release preparations of insulin. Both studies showed that albiglutide lowered HbA1c and had advantages over its comparator drugs. However, questions remain about the safety of albiglutide. Albiglutide is not being used in subjects with a history of thyroid cancer because it is not known whether this is a rare adverse effect with albiglutide. Also, the safety of albiglutide in subjects with Type 2 diabetes and high cardiovascular risk is unknown.

Diet and medical treatment are the standard treatment for type 2 diabetes. In obese subjects with type 2 diabetes, bariatric surgery is effective in resolving diabetes. Two clinical trials comparing bariatric surgery to medical treatment were evaluated. Both the Surgical Treatment And Medications Potentially Eradicate Diabetes Efficiently (STAMPEDE) trial (laparoscopic Roux-En Y gastric bypass and sleeve gastrectomy) and the DIet and medical therapy versus BAriatric SurgerY in type 2 diabetes (DIBASY) trial (laparoscopic gastric bypass and biliopancreatic-diversion) showed that surgery was more effective than medical care in resolving or managing type 2 diabetes. Larger studies, or a compilation of studies, are needed to determine whether one of these procedures is better, or if they are all similarly effective, and this should also be weighed against the risk of the operations.

Osteoporosis and Paget's bone disease are the most common diseases of the bone. In addition to glucocorticoid treatment, there are many other secondary causes of osteoporosis. Bisphosphonates are used to treat these bone conditions. Zoledronic acid is the most potent bisphosphonate at inhibiting bone resorption. In osteoporosis, zoledronic acid increases bone mineral density for at least 1 year following a single intravenous administration. The efficacy and safety of zoledronic acid in the treatment of osteoporosis and Paget's bone disease are reviewed. This article also covers the studies of the effects of zoledronic acid in the bone loss associated with the secondary osteoporosis.

The anti-estrogen treatment for hormone-sensitive breast cancer and the androgen deprivation therapy for prostate cancer can lead to the development of osteoporosis and bone fractures. Metastases associated with prostate and breast cancer can also occur in bone. Bisphosphonates are used in these types of bone dysfunction. Zoledronic acid is the most potent bisphosphonate. In osteoporosis, zoledronic acid inhibits bone reabsorption and increases bone mineral density for at least a year after intravenous administration. The efficacy and safety of zoledronic acid in osteoporosis secondary to hormone-sensitive cancers (prostate and breast), and in the bone metastases associated with these cancers are reviewed.

Preterm delivery (before 37 completed weeks of gestation) is the major determinant of infant mortality. In women with a previous preterm birth associated with bacterial vaginosis, prophylactic antibiotics (e.g., metronidazole) reduce the risk of preterm birth and low birth weight. Trichomonas vaginalis increases the risk of preterm delivery, but metronidazole is not beneficial for this and may even be detrimental. Antibiotic use (e.g., erythromycin) prolongs pregnancy in late premature rupture and has health benefits for the neonate. However, antibiotics are probably not useful in preterm labour. Intramuscular 17alpha-progesterone and vaginal progesterone reduce the rate of preterm labour in high-risk pregnancies, including previous spontaneous preterm delivery. Magnesium sulfate, beta2-adrenoceptor agonists and the oxytocin-receptor antagonist, atosiban, are effective in reducing uterine contractions short-term, but there is little evidence that this leads to improved outcomes for the neonate. However, tocolysis with calcium-channel blockers does seem to lead to better outcomes for the neonate. Fetal side effects, such as ductus arteriosus constriction and impaired renal function, are associated with the inhibition of prostaglandin synthesis with indomethacin. New approaches and more effective drugs are required in the treatment of preterm delivery.

Restenosis rates are lower with stent implantation than with balloon angioplasty. Nevertheless, even with the use of stenting, restenosis still occurs in approximately a third of patients with diabetes, small coronary vessels and long lesions. Animal studies with paclitaxel (Taxol, Bristol-Myers Squibb)-eluting stents, mainly in endothelium-denuded normal vessels, have shown that although paclitaxel reduces restenosis in the short-term, this may only delay rather than prevent restenosis. In clinical trials, stents eluting the paclitaxel derivative, 7-hexanoyltaxol, or paclitaxel without a polymer, also delay rather than prevent restenosis. Slowing the release of paclitaxel with a polymer base in the TAXUS trade mark series of clinical trials reduced the revascularization rate at 12 months, indicating that polymer-based paclitaxel is effective for longer periods of time. Further follow-up is necessary to determine whether polymer-based release of paclitaxel represents a longer delay or prevention of restenosis. To date, paclitaxel is showing promise as an eluting agent to prevent restenosis associated with stenting.

The 44th Annual Scientific Meeting of the Australasian Society of Clinical and Experimental Pharmacologists and Toxicologists; ‘Found in translation: integrated approaches to drug development’, was held in Melbourne, Australia, from 28 November to 1 December 2010. This was a wide-ranging conference that included some discussion of new drugs and new targets for drug development. The new drugs included dynamin inhibitors, Xen2174, an oxytocin receptor agonist and annexin-A12–26. The new targets included B7-dependent costimulation, chemoattractant receptors, granulocyte–macrophage colony-stimulating factor and glutathione peroxidases.