The year's new drugs and biologics 2020.

2020 will go down in history as a year marked in every respect by the emergence and astonishingly rapid spread of the first major global viral pandemic in a century. It seems like nearly every event or story of the year was influenced in some way by COVID-19, and in that respect, the year ended on a high note with the authorization for emergency use of the first vaccines to prevent SARS-CoV-2 infection and drugs to treat COVID-19. Despite the pandemic's dominance of the 2020 headlines, productivity was at a record high level across all therapeutic areas, as seen by the number of products in this year's review: approximately 50% more than the previous year. Notable achievements include the launch of the first treatment for hepatitis D; regulatory decisions on a suite of biologics for the prevention and treatment of Ebola virus disease, fruit of the 2016-2018 outbreak in the Democratic Republic of Congo; the approval of the first-ever drug to treat Hutchinson-Gilford progeria syndrome, a rare genetic disorder that leads to premature aging; the first treatment developed specifically for thyroid eye disease, also known as Graves' ophthalmopathy; the first nonhormonal, on-demand, vaginal pH-regulating contraceptive; and the first oral allergen immunotherapy for peanut allergy.

The year's new drugs and biologics--2007.

This annual article presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2007, 30 new medicines--this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents--reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for 45% of the new medicines launched in 2007. Several new features were introduced last year, and have been maintained due to a high level of interest from readers: a deeper insight into the three first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life span of medicines; and an analysis of the market for these new medicines. We also provide a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.

The year's new drugs and biologics--2006.

This annual series presents new drugs and biologics that were launched or approved for the first time during the previous year. In 2006, 41 new medicines--this figure includes both drugs and biologics for therapeutic use as well as new diagnostic agents and, for the first time this year, an important new herbal medicine--reached their first markets. Drug repositioning continues to have a significant impact, with line extensions (new indications, new formulations and new combinations of previously marketed products) accounting for more than 20 of the new medicines launched in 2006. This year's edition of the article also includes several new features: a deeper insight into the five first-in-class drugs launched for the first time last year, providing a better understanding of their novel mechanisms of action; an analysis of the discovery and development periods for the year's new products; a comprehensive overview of drug repositioning as a strategy for extending the life spans of medicines; and an analysis of the market for these new medicines. New generic drug approvals are also reviewed, as well as a brief glimpse at selected drugs and biologics which could reach their first markets in the foreseeable future.

Effects of polyunsaturated fatty acids and prostaglandins on oocyte maturation in a marine teleost, the European sea bass (Dicentrarchus labrax).

The effects of the polyunsaturated fatty acids (PUFAs), arachidonic acid (AA), eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and prostaglandins (PGs) on oocyte maturation were investigated in a marine teleost, the sea bass (Dicentrarchus labrax). Follicle-enclosed postvitellogenic, preovulatory oocytes were cultured in vitro and maturation was verified by assessing volume increase, lipid droplet coalescence, yolk clarification, and germinal vesicle migration and breakdown. Human chorionic gonadotropin was administered as the maturation-inducing gonadotropin (GTH) and was capable of inducing maturation in a time- and dose-dependent manner. Free AA induced maturation in a dose- and time-dependent manner and enhanced GTH-induced maturation, while EPA, DHA, and oleic acid were ineffective. Maturation induced by GTH was significantly suppressed by a phospholipase A(2) blocker, suggesting that mobilization of AA was involved in GTH-induced maturation. Moreover, EPA and DHA exhibited a significant, dose-dependent attenuation of GTH-induced maturation. Maturation induced by GTH was inhibited in the presence of a cyclooxygenase inhibitor, indomethacin, and this inhibition was reversed by addition of AA, PGE(2), or PGF(2alpha). PGE(2) and PGF(2alpha) alone were both effective stimulators of maturation, while PGE(1) and PGE(3) were ineffective. The effect of PUFAs on oocyte maturation in vitro were corroborated with studies in vivo. Oocytes were obtained from females fed a commercial, PUFA-enriched diet (RD) and maturational behavior was compared with oocytes from females fed a natural diet (ND) with a higher EPA content and n-3:n-6 ratio. Although no significant difference was observed in the rate of spontaneous oocyte maturation, a higher percentage of GTH-induced maturation and lower percentage of atresia were observed in RD oocytes. Moreover, while basal PGE production from oocytes from both groups was the same, RD oocytes produced significantly higher levels of PGE in the presence of hCG. The results from this study provide evidence for the participation of AA metabolism in GTH-induced oocyte maturation, and suggest that other PUFAs and PGs may play important roles in the induction of maturation in a marine teleost.

Pituitary levels of three forms of GnRH in the male European sea bass (Dicentrarchus labrax, L.) during sex differentiation and first spawning season.

In the present study, levels of three GnRH forms [seabream GnRH (sbGnRH), chicken GnRH-II (cGnRH-II), and salmon GnRH (sGnRH)] were analyzed in the pituitary of male sea bass during sex differentiation and the first spawning season. Plasma levels of gonadotropin (GTH-2), testosterone (T), and 11-ketotestosterone (11-KT) were determined during the same periods. All GnRH forms were present in the pituitary. sbGnRH levels were 9-fold higher than cGnRH-II and 17-fold higher than sGnRH levels. The highest GnRHs levels were detected in November 1995, when fish were 9 months old and when the gonads started to differentiate. Levels of the three forms decreased and remained low during the first spawning season, with the exception of sbGnRH, which showed a significant increase in November 1996. Plasma GTH-2 levels were lowest in November 1995, later increasing 2.5 times during the next months. During the first spawning season, plasma GTH-2 levels peaked in December 1996, 1 month after the peak of sbGnRH. During sex differentiation, plasma T levels were high in November 1995 but decreased over the next months, while levels of 11-KT remained low and unchanged. During the first spawning season, both steroids peaked in January 1997. These results suggest a possible role for all three GnRH forms in achieving gonadal differentiation, while sbGnRH may be the most relevant form in the regulation of the first spawning season in male sea bass. Moreover, GTH-2 and 11-KT may play important roles in gonadal maturation, since plasma GTH-2 and 11-KT levels were high throughout the period of spermiation.

Energetic dependence of NPY-induced LH secretion in a teleost fish (Dicentrarchus labrax).

The purpose of this work was to examine the role of energetic status in neuropeptide Y (NPY)-induced luteinizing hormone (LH) secretion and glucose metabolism in fish. Fasted juvenile sea bass (Dicentrarchus labrax) were injected intraperitoneally with pig (p) NPY or pNPY + glucose, whereas fed animals were injected with pNPY alone and plasma glucose, insulin, and LH levels were examined. pNPY alone or in combination with glucose was found to induce a dose-dependent increase in LH secretion in fasted animals. Similar LH responses to pNPY were observed in vitro in dispersed pituitary cells isolated from fed and fasted animals incubated in L-15 and restricted media. Injection of pNPY + glucose in fasted animals resulted in depletion of glucose. Insulin plasma levels decreased in fasted animals coinjected with pNPY + glucose but remained stable when NPY was administrated alone to fed and fasted animals. Results suggest that 1) NPY-induced LH secretion in fish is dependent on energetic status and 2) NPY is capable of modifying glucose metabolism.

Myometrium of the spiny dogfish Squalus acanthias: peptide and steroid regulation.

The phylogenetic age of endocrine control of viviparous reproduction in vertebrates may be estimated by examination of elasmobranch models. We have shown in pregnant Squalus acanthias that Squalus relaxin (sRLX) significantly decreased the frequency of myometrial contractions in a dose-dependent reversible manner in vitro and in vivo, without altering the intensity or duration of contractions. In contrast, neurointermediate lobe extract provoked a marked and reversible enhancement of the duration and intensity of contractions but was ineffective in altering the frequency of contractions. In steroid-primed animals, untreated and estradiol-17 beta (E2)-treated animals exhibited a decrease in the frequency of activity after injection of sRLX in vivo while pretreatment with progesterone (P4) alone or in combination with E2 fully suppressed the effects of sRLX. These results suggest that homologous sRLX slows the frequency of spontaneous uterine contractions in third-trimester sharks (stage C) in which endogenous P4 is reduced and E2 levels are rising. These data demonstrate the physiological importance of these hormones and the antiquity of reproductive tract control mechanisms.

Modulation of cardiac sodium channels by cAMP receptors on the myocyte surface.

The phosphorylation of the cardiac sodium channel by adenosine 3',5'-monophosphate (cAMP)-dependent protein kinase A leads to its inactivation. It was shown that extracellular cAMP can also modulate the sodium channel of rat, guinea pig, and frog ventricular myocytes in a rapid (less than 50 milliseconds), reversible, and dose-dependent manner. The decrease in the sodium current was accompanied by a 10- to 15-millivolt shift in the steady-state availability of the sodium channel toward more negative potentials and was inhibited by guanosine-5'-O-(2-thiodiphosphate) or pertussis toxin, suggesting that the extracellular modulation of the sodium channel by cAMP is mediated by a membrane-delimited mechanism that includes a pertussis toxin-sensitive G protein.

Atrionatriuretic peptide transforms cardiac sodium channels into calcium-conducting channels.

The atrionatriuretic peptide (ANP) is released from atrial cells in response to increased extracellular fluid volume and reduces sodium absorption by the kidney, thus reducing the blood volume. In this report, ANP suppressed the calcium and sodium currents in rat and guinea pig ventricular myocytes. The suppression of sodium current was caused by enhanced permeability of the sodium channel to calcium without significant changes in the kinetics or the tetrodotoxin sensitivity of the channel. Thus, ANP may regulate the sodium channel by altering its cationic selectivity site to calcium, thereby repressing the sodium current. The suppression of sodium and calcium channels and the resultant depressed excitability of the atrial cells may help to regulate ANP secretion.