The first biosimilar approved for the treatment of osteoporosis

To demonstrate the clinical comparability between RGB-10 (a biosimilar teriparatide) and the originator, a comparative pharmacokinetic trial was conducted. The study was successful in establishing bioequivalence. Marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency in 2017.Teriparatide, the first bone anabolic agent, is the biologically active fragment of human parathyroid hormone. The imminent patent expiry of the originator will open the door for biosimilars to enter the osteology market, thereby improving access to a highly effective, yet prohibitively expensive therapy.Subsequent to establishing comparability on the quality and non-clinical levels between RGB-10, a biosimilar teriparatide, and its reference product (Forsteo®), a randomised, double-blind, 2-way cross-over comparative study (duration: four days) was conducted in 54 healthy women (ages: 18 to 55 years) to demonstrate the pharmacokinetic/pharmacodynamic (PK/PD) equivalence and comparable safety of these products. Extents of exposure (AUC0-tlast) and peak exposure (Cmax), as measured by means of ELISA, were evaluated as co-primary PK endpoints, and serum calcium levels, as measured using standard automated techniques, were assessed for PD effects. Safety was monitored throughout the study.The 94.12% CIs for the ratio of the test to the reference treatments, used due to the two-stage design (85.20-98.60% and 85.51-99.52% for AUC0-tlast and Cmax, respectively), fell within the 80.00-125.00% acceptance range. The calcium PD parameters were essentially identical with geometric mean ratios (GMRs) of 99.93% and 99.87% for AUC and Cmax, respectively. Analysis of the safety data did not reveal any differences between RGB-10 and its reference.Based on the high level of similarity in the preclinical data and the results of this clinical study, marketing authorisation for RGB-10 (Terrosa®) was granted by the European Medicines Agency (EMA) in 2017

Functional study on the effects of nifedipine, cromakalim, and the absence of extracellular Ca2+on α1-adrenoceptor-mediated excitation-contraction coupling in isolated rat portal vein: Comparison with depolarization-mediated excitation-contraction coupling

The effects of Ca2+-entry blockade by nifedipine, K+channel opening by cromakalim, and of omitting extracellular Ca2+on the contractile response elicited by a supramaximum concentration of the 'full' and selective α1- adrenoceptor agonist phenylephrine (10-4M) were compared with those elicited by a supramaximal concentration of KCl (50 mM) in isolated rat portal vein. The contractile response to phenylephrine appeared to be biphasically composed of an early 'transient' phase and a slowly developing 'sustained' phase that reached maximum values after 30 s and 5 min after initiation of contraction, respectively. The contractile response to KCl (50 mM) exhibited a triphasic pattern consisting of 'spike,' 'transient', and 'sustained' components that peaked after 8 s, 25 s, and 10 min, respectively. Nifedipine was able to eliminate all components of the contractions in response to both phenylephrine and KCl almost completely. Nifedipine was ~10 times more potent at suppressing the slowly developing sustained components of the contractions in response to both stimuli than the early transient components. The spontaneous myogenic contractions were inhibited by nifedipine with intermediate potency. Cromakalim, in contrast to nifedipine, selectively eliminated the early transient components of the contractions in response to both phenylephrine and KCl. The sustained components of the contractions in response to both stimuli were relatively resistant to K+channel opening, although higher concentrations (>1 μM) of cromakalim were capable of antagonizing the sustained response to phenylephrine accompanied by oscillations in tone. Cromakalim was most potent in counteracting spontaneous myogenic contractions. When phenylephrine and KCl were added with or without external Ca2+after different periods of equilibration in nominally Ca2+-free medium, different washout kinetics for the different components of the contractions in response to both stimuli were observed. The early transient phases of tension development in response to both stimuli were completely lost after ~6 min of equilibration in nominally Ca2+-free medium, whereas the slowly developing sustained components of the contractions were immediately lost after the change to nominally Ca2+-free medium. Externally added Ca2+, when administered together with phenylephrine or KCl after the preparations had been exposed for different times to nominally Ca2+-free medium, could not restore the early transient components. In isolated rat portal vein, apart from absolute differences in height and time course of tension development which are probably caused by a difference in release of intracellular second messengers during the two responses, the contraction mediated by strong α1-adrenoceptor stimulation could, as tested, hardly be distinguished from the one produced by a maximum effective concentration of KCl. As for KCl stimulation, the Ca2+influx essential for contraction during the entire response to supramaximal α1- adrenoceptor stimulation can be almost completely, though differentially, inhibited by nifedipine or short periods of absence of extracellular Ca2+. For nifedipine, this differential inhibition probably reflects the voltage and time dependency of the interaction of this 1,4-dihydropyridine with the L-type Ca2+channel. As reflected by its slower washout kinetics, the transient component of the contraction in response to phenylephrine is, apart from Ca2+influx, also caused by release of intracellularly stored Ca2+. This concept is strengthened first because the transient component was selectively inhibited by cromakalim, a compound which was recently shown to deplete intracellular Ca2+stores by an unknown mechanism and second because this response cannot be immediately restored by readdition of extracellular Ca2+after depletion

The effect of some α-adrenoceptor antagonists on spontaneous myogenic activity in the rat portal vein and the putative involvement of ATP-sensitive K+channels

In the present study we showed that the α-adrenoceptor antagonists phentolamine, yohimbine, prazosin, corynanthine and idazoxan, when cumulatively applied in high concentrations (1-100 μmol/l), can increase spontaneous myogenic activity in the rat portal vein. 5-Methyl-urapidil and rauwolscine were ineffective in this respect. Pretreatment with phenoxybenzamine in a concentration of 1 μmol/l (20 min), which results in alkylation of all functional α-adrenoceptors in the rat portal vein, was unable to antagonize the increase in spontaneous myogenic activity elicited by phentolamine. Antazoline (1-100 μmol/l), a H1antagonist and 2-substituted imidazoline which is devoid of α-adrenoceptor blocking properties, exhibited similar effects on spontaneous myogenic activity as its structurally closely related analogue phentolamine. Since phentolamine is reported to interact with ATP-sensitive K+channels we investigated the role of K+channels in more detail. The K+channel openers cromakalim and diazoxide elicited a decrease in spontaneous myogenic activity. Glibenclamide (0.3-3 μmol/l), a selective blocker of ATP-sensitive K+channels in cardiac and pancreatic tissues, and phentolamine (1-10 μmol/l) shifted the concentration-response curves of cromakalim and diazoxide concentration dependently to the right. Yohimbine showed only a modest effect in the highest concentration (100 μmol/l) applied. E-4031 (0.01-0.3 μmol/l), a sotalol derivative and one of the most selective blockers of the delayed rectifier current (I(k)) in cardiac tissue, was a potent contractile agent when added to the rat portal vein in the same way as the α-adrenoceptor antagonists. All other α-adrenoceptor antagonists as well as E-4031, when tested in concentrations which maximally stimulated spontaneous myogenic activity, failed to influence the relaxations induced by cromakalim and diazoxide. The results of the present study cannot be explained on the basis of α-adrenoceptor blockade. Phentolamine, in contrast to the other α-adrenoceptor antagonists, can block glibenclamide-sensitive K+channels in the rat portal vein. However, it seems unlikely that this property can explain its potent effects on spontaneous myogenic activity, since glibenclamide itself was inactive

FUNCTIONAL-STUDY ON THE EFFECTS OF NIFEDIPINE, CROMAKALIM, AND THE ABSENCE OF EXTRACELLULAR CA2+ ON ALPHA-1-ADRENOCEPTOR MEDIATED EXCITATION-CONTRACTION COUPLING IN ISOLATED RAT PORTAL-VEIN - COMPARISON WITH DEPOLARIZATION-MEDIATED EXCITATION-CONTRACTION COUPLING

The effects of Ca2+-entry blockade by nifedipine, K+ channel opening by cromakalim, and of omitting extracellular Ca2+ on the contractile response elicited by a supramaximum concentration of the ''full'' and selective alpha1-adrenoceptor agonist phenylephrine (10(-4) M) were compared with those elicited by a supramaximal concentration of KCl (50 mM) in isolated rat portal vein. The contractile response to phenylephrine appeared to be biphasically composed of an early ''transient'' phase and a slowly developing ''sustained'' phase that reached maximum values after 30 s and 5 min after initiation of contraction, respectively. The contractile response to KCl (50 mM) exhibited a triphasic pattern consisting of ''spike,'' ''transient'', and ''sustained'' components that peaked after 8 s, 25 s, and 10 min, respectively. Nifedipine was able to eliminate all components of the contractions in response to both phenylephrine and KCl almost completely. Nifedipine was approximately 10 times more potent at suppressing the slowly developing sustained components of the contractions in response to both stimuli than the early transient components. The spontaneous myogenic contractions were inhibited by nifedipine with intermediate potency. Cromakalim, in contrast to nifedipine, selectively eliminated the early transient components of the contractions in response to both phenylephrine and KCl. The sustained components of the contractions in response to both stimuli were relatively resistant to K+ channel opening, although higher concentrations (>1 muM) of cromakalim were capable of antagonizing the sustained response to phenylephrine accompanied by oscillations in tone. Cromakalim was most potent in counteracting spontaneous myogenic contractions. When phenylephrine and KCl were added with or without external Ca2+ after different periods of equilibration in nominally Ca2+-free medium, different washout kinetics for the different components of the contractions in response to both stimuli were observed. The early transient phases of tension development in response to both stimuli were completely lost after -6 min of equilibration in nominally Ca2+-free medium, whereas the slowly developing sustained components of the contractions were immediately lost after the change to nominally Ca2+-free medium. Externally added Ca2+, when administered together with phenylephrine or KCl after the preparations had been exposed for different times to nominally Ca2+-free medium, could not restore the early transient components. In isolated rat portal vein, apart from absolute differences in height and time course of tension development which are probably caused by a difference in release of intracellular second messengers during the two responses, the contraction mediated by strong alpha1-adrenoceptor stimulation could, as tested, hardly be distinguished from the one produced by a maximum effective concentration of KCl. As for KCl stimulation, the Ca2+ influx essential for contraction during the entire response to supramaximal alpha1-adrenoceptor stimulation can be almost completely, though differentially, inhibited by nifedipine or short periods of absence of extracellular Ca2+. For nifedipine, this differential inhibition probably reflects the voltage and time dependency of the interaction of this 1,4-dihydropyridine with the L-type Ca2+ channel. As reflected by its slower washout kinetics, the transient component of the contraction in response to phenylephrine is, apart from Ca2+ influx, also caused by release of intracellularly stored Ca2+. This concept is strengthened first because the transient component was selectively inhibited by cromakalim, a compound which was recently shown to deplete intracellular Ca2+ stores by an unknown mechanism and second because this response cannot be immediately restored by readdition of extracellular Ca2+ after depletion