Discovery and Development of Calcimimetic and Calcilytic Compounds

Nemeth, Edward F.; Wagenen, Bradford C. Van; Balandrin, Manuel F.

doi:10.1016/bs.pmch.2017.12.001

Cited by 37 publications

(45 citation statements)

References 164 publications

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“…The study medication, cinacalcet (Amgen, Thousand Oaks, California, USA), is a calcimimetic agent which acts by modulating the calcium‐sensing receptors in the parathyroid glands and other tissues that participate in calcium homeostasis. By increasing sensitivity towards circulating calcium, secretion of PTH is decreased.…”

Section: Methodsmentioning

confidence: 99%

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy

Koman

Ohlsson

Bränström

et al. 2019

British Journal of Surgery

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Background Primary hyperparathyroidism is often associated with non‐disease‐specific symptoms. The aim of this study was to evaluate whether normalization of hypercalcaemia with short‐term medical treatment can be used to predict the effects of parathyroidectomy and guide in surgical decision‐making. Methods This observational study included patients who received calcimimetic treatment for 4 weeks before parathyroidectomy (30–60 mg daily). A panel of tests was used to assess various aspects of quality of life (European Organisation and Treatment of Cancer QLQ‐C30 core questionnaire, Hospital Anxiety and Depression Scale and Positive State of Mind questionnaire), cognitive function (Montreal Cognitive Assessment) and muscle strength (timed‐stands test). The tests were carried out at baseline, after 4 weeks of calcimimetic treatment, and at 6 weeks and 6 months after parathyroidectomy. The predictive values of changes during calcimimetic treatment were determined for each test. Results The study included 110 patients of median age 62 years (91 women). Calcimimetic treatment resulted in normalization of calcium levels and improvements in quality‐of‐life parameters. The time spent on the timed‐stands test was significantly shortened. Eleven of 38 participants with a baseline Montreal Cognitive Assessment score below 26, indicating mild cognitive impairment, reached scores of at least 26 during treatment with calcimimetic. Improvements during treatment with calcimimetic correlated well with postoperative outcomes (positive predictive values 74–96 per cent). Conclusion The method described in this study may be used to aid surgical decision‐making for patients with primary hyperparathyroidism and non‐disease‐specific symptoms by predicting the effects of normalization of hypercalcaemia.

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Section: Methodsmentioning

confidence: 99%

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy

Koman

Ohlsson

Bränström

et al. 2019

British Journal of Surgery

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“…Even considering the potential interference of the pharmaceutical industry in enhancing positive reports, the drug seems a major advance in the care of a challenging clinical problem [51][52][53][54][55][56][57][58][59][60][61][62][63][64]. Pharmacokinetic studies, animal data and expert opinions indicate that the new agent has obvious advantages over the oral drug in improving compliance (IV on dialysis instead of orally once or twice daily); it seems to have a better efficacy profile and appears to increase stability in the blood levels of calcium, phosphate and PTH, in keeping with a longer duration of action and lack of interference with food intake; its side effects are similar to those caused by earlier products, and can generally be avoided with a strict control policy [65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83][84].…”

Section: Discussionmentioning

confidence: 99%

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

Piccoli

Trabace

Chatrenet

et al. 2020

IJERPH

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Background. Dialysis treatment is improving, but several long-term problems remain unsolved, including metabolic bone disease linked to chronic kidney disease (CKD-MBD). The availability of new, efficacious but expensive drugs (intravenous calcimimetic agents) poses ethical problems, especially in the setting of budget limitations. Methods. Reasons of choice, side effects, biochemical trends were discussed in a cohort of 15 patients (13% of the dialysis population) who stared treatment with intravenous calcimimetics in a single center. All patients had previously been treated with oral calcimimetic agents; dialysis efficacy was at target in 14/15; hemodiafiltration was employed in 10/15. Median Charlson Comorbidity Index was 8. The indications were discussed according to the principlist ethics (beneficience, non maleficience, justice and autonomy). Biochemical results were analyzed to support the clinical-ethical choices. Results. In the context of a strict clinical and biochemical surveillance, the lack of side effects ensured “non-maleficence”; efficacy was at least similar to oral calcimimetic agents, but tolerance was better. Autonomy was respected through a shared decision-making model; all patients appreciated the reduction of the drug burden, and most acknowledged better control of their biochemical data. The ethical conflict resides in the balance between the clinical “beneficience, non-maleficience” advantage and “justice” (economic impact of treatment, potentially in attrition with other resources, since the drug is expensive and included in the dialysis bundle). The dilemma is more relevant when a patient’s life expectancy is short (economic impact without clear clinical advantages), or when non-compliance is an issue (unclear advantage if the whole treatment is not correctly taken). Conclusions. In a context of person-centered medicine, autonomy, beneficence and non-maleficence should weight more than economic justice. While ethical discussions are not aimed at finding “the right answer” but asking “the right questions”, this example can raise awareness of the importance of including an ethical analysis in the choice of “economically relevant” drugs.

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“…In addition, B2.1-E1 suppressed airway hyperresponsiveness and inflammation in mice. The challenges for the pharmaceutical industry are to design compounds that select conformations of the CaSR that preferentially target a particular signalling pathway, providing an approach for modulating CaSR function in a tissue-and disease-specific manner [77].…”

Section: Calcilyticsmentioning

confidence: 99%

The future of bronchodilation: looking for new classes of bronchodilators

2019

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@ERSpublicationsThere is a real interest among researchers and the pharmaceutical industry in developing novel bronchodilators. There are several new opportunities; however, they are mostly in a preclinical phase. They could better optimise bronchodilation. http://bit.ly/2lW1q39Cite this article as: Cazzola M, Rogliani P, Matera MG. The future of bronchodilation: looking for new classes of bronchodilators.ABSTRACT Available bronchodilators can satisfy many of the needs of patients suffering from airway disorders, but they often do not relieve symptoms and their long-term use raises safety concerns. Therefore, there is interest in developing new classes that could help to overcome the limits that characterise the existing classes. At least nine potential new classes of bronchodilators have been identified: 1) selective phosphodiesterase inhibitors; 2) bitter-taste receptor agonists; 3) E-prostanoid receptor 4 agonists; 4) Rho kinase inhibitors; 5) calcilytics; 6) agonists of peroxisome proliferator-activated receptor-γ; 7) agonists of relaxin receptor 1; 8) soluble guanylyl cyclase activators; and 9) pepducins. They are under consideration, but they are mostly in a preclinical phase and, consequently, we still do not know which classes will actually be developed for clinical use and whether it will be proven that a possible clinical benefit outweighs the impact of any adverse effect.It is likely that if developed, these new classes may be a useful addition to, rather than a substitution of, the bronchodilator therapy currently used, in order to achieve further optimisation of bronchodilation.

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Discovery and Development of Calcimimetic and Calcilytic Compounds

Cited by 37 publications

References 164 publications

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy

Short-term medical treatment of hypercalcaemia in primary hyperparathyroidism predicts symptomatic response after parathyroidectomy

New Intravenous Calcimimetic Agents: New Options, New Problems. An Example on How Clinical, Economical and Ethical Considerations Affect Choice of Treatment

The future of bronchodilation: looking for new classes of bronchodilators

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