Drug Discovery Today Volume 20, Number 1 January 2015
PERSPECTIVE
feature An analysis of FDA-approved drugs for pain and anesthesia The need to alleviate pain is among the first recorded uses for medicines, dating back to the onset of the Neolithic period. The need persists and many of today’s best-known drugs (e.g. aspirin, acetaminophen, morphine) are included within this category. An analysis of FDA-approved new molecular entities (NMEs) for pain and anesthesia reveals a fluctuating rate of new introductions, which has plummeted in recent years. The largest emphasis has been placed on acute pain, largely targeting G-protein-coupled receptors and a relatively narrow subset of molecular pathways. NMEs targeting anesthesia tend to focus on channels and four molecular pathways capture a large majority of NMEs for this indication.
Introduction Opium is arguably the world’s oldest drug [1]. In texts dating back to the ancient Sumerians of Lower Mesopotamia, the opium poppy is referred to as the Hul Gil or ‘joy plant’ based on its ability to induce a state of euphoria. Through time, opium has been valued and abused by many ancient and modern cultures for its anesthetic and pain-killing properties. In 1803, Friedrich Sertuerner dissolved opium in acid and identified the alkaloid compound, which constitutes the active ingredient of opium [2]. The resulting drug was named morphine, in honor of Morpheus, the Greek god of dreams. Commercial production of morphine commenced in 1827 as the flagship product for a small company that would ultimately become the organizations now known as Merck KGaA and Merck & Co. [3]. Shortly thereafter, morphine was introduced into the USA as a means to ameliorate pain and promote anesthesia, and was widely used by the time of the American Civil War [4].
Since the early introduction of morphine (which preceded the formation of the FDA by more than a century), 110 new molecular entities (NMEs) have been approved by the FDA (Fig. 1a). Indeed, four of the first five NMEs identified in our analyses of all FDA-approved drugs (morphine, aspirin, gallamine triethiodide and pentobarbital) targeted analgesia or anesthesia. The accumulation of pain and anesthesia NMEs has grown consistently over time, with an annual average of 1.3 new approvals since the beginning of the 1930s. This growth was characterized by two periods of relatively high rates of approvals in the 1950s and 1990s. The NMEs evaluated in this category reveal trends that are rather unique to pain and anesthesia. First, no biologic-based medicine has ever been approved for analgesia or anesthesia as the first indication. This contrasts with the fact that 14% of all NMEs approved since the 1990s are biologics [5]. Note: whereas botulinum toxin is now used for migraine headaches, the initial approval for this NME was for blepharospasm.
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.09.002
Likewise, no NMEs in this category have received an orphan approval for the first indication, whereas roughly one-third of all approvals over the past few decades address this subset of indications [6]. Finally, the participation of biotechnology companies in pain and anesthesia medicines has been relatively modest. Only three NME approvals (2.7%) were granted to organizations within this sector, whereas 40% of all NMEs, regardless of indication, have been awarded to biotechnology organizations over the past two decades [5]. Because the amelioration of pain and anesthesia represent different uses, we evaluated them together and separately (Fig. 1b). When viewed on a decade-by-decade basis, anesthesia and analgesia medicines show comparable trends in terms of annual approval rates. Approvals for pain steadily increased, peaking in the 1990s and diminishing rapidly thereafter. A similar trend was observed with anesthesia drugs, with two peaks, first in the 1950s and then in the 1990s, before declining rapidly. Indeed, www.drugdiscoverytoday.com
3
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected]
PERSPECTIVE
Drug Discovery Today Volume 20, Number 1 January 2015
(a) Cumulative NMEs
120 100 80 60 40 20 0 1930
1940
1950
1960
1970
1980
1990
2000
2010
Whereas pain medications disproportionately focus on GPCRs, ion channels seem to be the preferred targets for anesthesia NMEs. Of the 50 NMEs targeting anesthesia, 28 (56%) regulate ion channels, followed by those targeting GPCRs (28%) and gap junctions (10%). From the standpoint of molecular pathways, four (gap junction, nicotinic acetylcholine receptor, sodium channel and GABA pathways) capture 88% of all anesthesia NMEs (Fig. 3).
Year
Average annual NME
(b)
Concluding remarks: outcomes and implications
1.4 1.2 1 0.8 0.6 0.4 0.2 0 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s
Decade Drug Discovery Today
FIGURE 1
Features PERSPECTIVE
Accumulation of new molecular entities (NMEs) targeting pain and anesthesia. (a) The number of NMEs targeting pain and anesthesia is shown on an annual basis. Please note that three NMEs (morphine, aspirin and gallamine triethiodide) had been approved before 1930. (b) The approval rates of NMEs for pain (red) and anesthesia (blue) are indicated on a decade-by-decade basis.
there has been a drop in new approvals for both indications and there have been no NMEs approved with pain or medication as its first indication in the present decade.
Pain NMEs An assessment of each indication separately reveals further detail about changes over time (Fig. 2a). For example, most NMEs approved from the 1940s through the 1960s targeted acute pain, with a subset focused upon ameliorating pain from migraine headaches. The year 1980 witnessed the approval of phenyl butazone, the first analgesic that gained an approval specifically for arthritis. Approvals for arthritis NMEs grew over the next two decades but abruptly stopped with the most recent approval in the year 2000. Other specialty subsets of pain have also been the focus of new drug development, albeit transiently. For example, the first NME focused on surgical analgesia was approved in 1981 and these drugs remained at a steady level through the first decade of the new millennium. However, no NME for this indication has received approval since 2008. The smallest subset of 4
www.drugdiscoverytoday.com
analgesics, those targeting chronic pain, consists of four NMEs approved between 2004 and 2009. From a mechanistic standpoint, NMEs targeting G-protein-coupled receptors (GPCRs) account for almost half (49%) of all pain medications, followed by synthases (23%) and ion channels (11%) (Fig. 2b). Diving deeper, four different pathways [serotonin, cyclooxygenase (COX), mu opioid receptor and calcium channel] account for more than 80% of all analgesics approved to date (Fig. 2c).
Anesthesia NMEs Anesthesia NMEs can be broadly categorized into three categories: local anesthesia, general anesthesia and muscle relaxants. General anesthesia NMEs represent 43% of all NMEs in this category, with the remaining NMEs almost equally divided between local anesthesia and muscle relaxants. Local anesthesia predominated in the early stages of the drug development enterprise (from the 1930s through the 1950s), whereas the approval of muscle relaxants has been more recent (peaking in the 1990s and abruptly stopping thereafter).
The major finding of our present study is that, although drug targeting of analgesia and anesthesia characterized many of the early successes of the pharmaceutical industry, approval activity for these indications has declined dramatically in the past two decades. Other notable findings include the relative paucity of biologics, orphan indications and biotechnology company participation in NME development for pain and anesthesia. Mechanistically, analgesics tend to target GPCRs (e.g. mu opioid channels), whereas anesthesia medicines disproportionately entail regulators of ion channels. The trends in approvals could indicate that research and development efforts to develop new medicines for pain and anesthesia are declining, with no approvals in the past halfdecade. It is too early to determine if this represents a temporary decline or a more permanent focus away from these indications. The market need persists, particularly in light of an aging population in much of the developed world [7]. Furthermore, many current standards of care are poorly tolerated [8]. Another potential reason for the apparent decline in industry interest might be that the market for analgesia is viewed by some as fragmented and competitive [9]. Furthermore, the highprofile withdrawal of rofecoxib (Vioxx1) by Merck in 2004 highlighted reputational and regulatory risks associated with pain medications [10]. Compounding this, a potential for unlawful abuse is often associated with pain and anesthesia medications and could render these fields less attractive for large, established companies. In this context, it could be notable that many of the most recent approvals were awarded to smaller (e.g. Deproco, Anaquest), international (e.g. Organon, Astra, Eisai) or private (e.g. Purdue Pharma) companies. It is also tempting to speculate that a seeming lack of interest by biotechnology companies in these indications (based on the relatively small number of NMEs granted to biotechnology companies) relates to this decline. Our prior work
Drug Discovery Today Volume 20, Number 1 January 2015
PERSPECTIVE
100% Fraction of approved NMEs
(a)
80% Arthritis
60%
Migraine 40%
Chronic pain Surgical
20% Acute pain 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade (c)
(b) Other, 2 Transporter, 2
Unclear, 6
Other, 2
Unclear, 8 Serotonin, 11
GPCR, 28 Synthase, 13
Opioid, 17
Channel, 6
COX, 15
Calcium Channel, 5 Drug Discovery Today
has shown that biotechnology companies now contribute to approximately two-thirds of all NMEs (when evaluating sources of patents, IND submissions or clinical trials) [5]. In evaluating pain and anesthesia NMEs, contributions from biotechnology companies were notably low, even in these earlier-stage activities. Importantly, the work herein was based on NMEs already approved by the FDA and does not consider ongoing or future investigation that might currently be in development by biotechnology companies.
Another finding is a seemingly narrow range of targets for pain and anesthesia NMEs. The majority of analgesics target GPCRs, whereas anesthesia drugs tend to focus on ion channels. We observed emphasis on these two target classes with other indications (e.g. psychiatric and neurological drugs). In this context, it is also interesting that these indications also tend to be disproportionately over-represented by conventional pharmaceutical companies. Such a finding might be coincidental or relate to fundamental biology of the key mechanisms
governing the nervous system and thus favor GPCRs and ion channels. Another possibility is that the chemical libraries used for screening or the approaches utilized for target discovery and validation tend to favor targeting of these pathways. Altogether, in the context of an aging population, these findings suggest that unmet needs in the fields of pain and anesthesia could provide attractive market opportunities for those organizations with unique approaches, capabilities and sufficient risk:tolerance to enter the field.
www.drugdiscoverytoday.com
5
Features PERSPECTIVE
FIGURE 2
Overview of analgesia new molecular entities (NMEs). (a) The relative distribution of specific indications targeted by analgesia NME approvals is indicated on a decade-by-decade basis. The target types (b) and individual pathways (c) impacted by NMEs focused on pain are indicated. Abbreviations: COX, cyclooxygenase; GPCR, G-protein-coupled receptor.
PERSPECTIVE
Drug Discovery Today Volume 20, Number 1 January 2015
(a) Fraction of approved NMEs
100% 80% 60% Local anaesthesia 40%
General anaesthesia Muscle relaxant
20% 0% 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
(b)
(c)
Unclear, 3
Unclear, 3 Other, 3
Gap junction, 5
GABA, 9 GPCR, 14
Gap Junction, 5 Sodium channel, 11 Nicotinic acetylcholine 15
Channel, 28
Drug Discovery Today
FIGURE 3
Features PERSPECTIVE
Overview of anesthesia new molecular entities (NMEs). (a) The relative distributions of different types of anesthesia medicines are indicated on a decade-bydecade basis. The target types (b) and individual pathways (c) impacted by NMEs focused on anesthesia are indicated. Abbreviation: GPCR, G-protein-coupled receptor.
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery (http:// ycmd.yale.edu/) to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project.
3 4 5
6
References 1 Booth, M., ed. (1999) Opium: A History, Macmillan 2 Sertu¨rner, F.W. (1806) Darstellung der reinen Mohnsa¨ure (Opiumsa¨ure) nebst einer chemischen
6
www.drugdiscoverytoday.com
7
Untersuchung des Opiums mit vorzu¨glicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin geho¨rigen Bemerkungen. J. Pharm. Aerzte Apoth. 14, 47–93 (in German) Vagelos, P.R. and Galambos, L., eds) (2004) Medicine, Science and Merck, Cambridge University Press Bollet, A.J., ed. (2001) Civil War Medicine: Challenges and Triumphs, Galen Pr Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today http://dx.doi.org/ 10.1016/j.drudis.2014.04.006 Kinch, M.S. et al. (2014) Trends in pharmaceutical targeting of clinical indications: 1930–2013. Drug Discov. Todayhttp://dx.doi.org/10.1016/j.drudis.2014.05.021 Melnikova, I. (2010) Pain market. Nat. Rev. Drug Discov. 9, 589–590
8 Woodcock, J. (2009) A difficult balance – pain management, drug safety, and the FDA. N. Engl. J. Med. 361, 2105–2107 9 Dutton, G. (2012) Pain management market ripe with immediate opportunities. Genet. Eng. Biotechnol. News 32, 11 10 Couzin, J. (2004) Drug safety. Withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science 306, 384
Michael S. Kinch Yale Center for Molecular Discovery, West Haven, CT 06516, USA
PERSPECTIVE
feature An analysis of FDA-approved drugs for pain and anesthesia The need to alleviate pain is among the first recorded uses for medicines, dating back to the onset of the Neolithic period. The need persists and many of today’s best-known drugs (e.g. aspirin, acetaminophen, morphine) are included within this category. An analysis of FDA-approved new molecular entities (NMEs) for pain and anesthesia reveals a fluctuating rate of new introductions, which has plummeted in recent years. The largest emphasis has been placed on acute pain, largely targeting G-protein-coupled receptors and a relatively narrow subset of molecular pathways. NMEs targeting anesthesia tend to focus on channels and four molecular pathways capture a large majority of NMEs for this indication.
Introduction Opium is arguably the world’s oldest drug [1]. In texts dating back to the ancient Sumerians of Lower Mesopotamia, the opium poppy is referred to as the Hul Gil or ‘joy plant’ based on its ability to induce a state of euphoria. Through time, opium has been valued and abused by many ancient and modern cultures for its anesthetic and pain-killing properties. In 1803, Friedrich Sertuerner dissolved opium in acid and identified the alkaloid compound, which constitutes the active ingredient of opium [2]. The resulting drug was named morphine, in honor of Morpheus, the Greek god of dreams. Commercial production of morphine commenced in 1827 as the flagship product for a small company that would ultimately become the organizations now known as Merck KGaA and Merck & Co. [3]. Shortly thereafter, morphine was introduced into the USA as a means to ameliorate pain and promote anesthesia, and was widely used by the time of the American Civil War [4].
Since the early introduction of morphine (which preceded the formation of the FDA by more than a century), 110 new molecular entities (NMEs) have been approved by the FDA (Fig. 1a). Indeed, four of the first five NMEs identified in our analyses of all FDA-approved drugs (morphine, aspirin, gallamine triethiodide and pentobarbital) targeted analgesia or anesthesia. The accumulation of pain and anesthesia NMEs has grown consistently over time, with an annual average of 1.3 new approvals since the beginning of the 1930s. This growth was characterized by two periods of relatively high rates of approvals in the 1950s and 1990s. The NMEs evaluated in this category reveal trends that are rather unique to pain and anesthesia. First, no biologic-based medicine has ever been approved for analgesia or anesthesia as the first indication. This contrasts with the fact that 14% of all NMEs approved since the 1990s are biologics [5]. Note: whereas botulinum toxin is now used for migraine headaches, the initial approval for this NME was for blepharospasm.
1359-6446/06/$ - see front matter ß 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.drudis.2014.09.002
Likewise, no NMEs in this category have received an orphan approval for the first indication, whereas roughly one-third of all approvals over the past few decades address this subset of indications [6]. Finally, the participation of biotechnology companies in pain and anesthesia medicines has been relatively modest. Only three NME approvals (2.7%) were granted to organizations within this sector, whereas 40% of all NMEs, regardless of indication, have been awarded to biotechnology organizations over the past two decades [5]. Because the amelioration of pain and anesthesia represent different uses, we evaluated them together and separately (Fig. 1b). When viewed on a decade-by-decade basis, anesthesia and analgesia medicines show comparable trends in terms of annual approval rates. Approvals for pain steadily increased, peaking in the 1990s and diminishing rapidly thereafter. A similar trend was observed with anesthesia drugs, with two peaks, first in the 1950s and then in the 1990s, before declining rapidly. Indeed, www.drugdiscoverytoday.com
3
Features PERSPECTIVE
Michael S. Kinch, [email protected], [email protected]
PERSPECTIVE
Drug Discovery Today Volume 20, Number 1 January 2015
(a) Cumulative NMEs
120 100 80 60 40 20 0 1930
1940
1950
1960
1970
1980
1990
2000
2010
Whereas pain medications disproportionately focus on GPCRs, ion channels seem to be the preferred targets for anesthesia NMEs. Of the 50 NMEs targeting anesthesia, 28 (56%) regulate ion channels, followed by those targeting GPCRs (28%) and gap junctions (10%). From the standpoint of molecular pathways, four (gap junction, nicotinic acetylcholine receptor, sodium channel and GABA pathways) capture 88% of all anesthesia NMEs (Fig. 3).
Year
Average annual NME
(b)
Concluding remarks: outcomes and implications
1.4 1.2 1 0.8 0.6 0.4 0.2 0 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s
Decade Drug Discovery Today
FIGURE 1
Features PERSPECTIVE
Accumulation of new molecular entities (NMEs) targeting pain and anesthesia. (a) The number of NMEs targeting pain and anesthesia is shown on an annual basis. Please note that three NMEs (morphine, aspirin and gallamine triethiodide) had been approved before 1930. (b) The approval rates of NMEs for pain (red) and anesthesia (blue) are indicated on a decade-by-decade basis.
there has been a drop in new approvals for both indications and there have been no NMEs approved with pain or medication as its first indication in the present decade.
Pain NMEs An assessment of each indication separately reveals further detail about changes over time (Fig. 2a). For example, most NMEs approved from the 1940s through the 1960s targeted acute pain, with a subset focused upon ameliorating pain from migraine headaches. The year 1980 witnessed the approval of phenyl butazone, the first analgesic that gained an approval specifically for arthritis. Approvals for arthritis NMEs grew over the next two decades but abruptly stopped with the most recent approval in the year 2000. Other specialty subsets of pain have also been the focus of new drug development, albeit transiently. For example, the first NME focused on surgical analgesia was approved in 1981 and these drugs remained at a steady level through the first decade of the new millennium. However, no NME for this indication has received approval since 2008. The smallest subset of 4
www.drugdiscoverytoday.com
analgesics, those targeting chronic pain, consists of four NMEs approved between 2004 and 2009. From a mechanistic standpoint, NMEs targeting G-protein-coupled receptors (GPCRs) account for almost half (49%) of all pain medications, followed by synthases (23%) and ion channels (11%) (Fig. 2b). Diving deeper, four different pathways [serotonin, cyclooxygenase (COX), mu opioid receptor and calcium channel] account for more than 80% of all analgesics approved to date (Fig. 2c).
Anesthesia NMEs Anesthesia NMEs can be broadly categorized into three categories: local anesthesia, general anesthesia and muscle relaxants. General anesthesia NMEs represent 43% of all NMEs in this category, with the remaining NMEs almost equally divided between local anesthesia and muscle relaxants. Local anesthesia predominated in the early stages of the drug development enterprise (from the 1930s through the 1950s), whereas the approval of muscle relaxants has been more recent (peaking in the 1990s and abruptly stopping thereafter).
The major finding of our present study is that, although drug targeting of analgesia and anesthesia characterized many of the early successes of the pharmaceutical industry, approval activity for these indications has declined dramatically in the past two decades. Other notable findings include the relative paucity of biologics, orphan indications and biotechnology company participation in NME development for pain and anesthesia. Mechanistically, analgesics tend to target GPCRs (e.g. mu opioid channels), whereas anesthesia medicines disproportionately entail regulators of ion channels. The trends in approvals could indicate that research and development efforts to develop new medicines for pain and anesthesia are declining, with no approvals in the past halfdecade. It is too early to determine if this represents a temporary decline or a more permanent focus away from these indications. The market need persists, particularly in light of an aging population in much of the developed world [7]. Furthermore, many current standards of care are poorly tolerated [8]. Another potential reason for the apparent decline in industry interest might be that the market for analgesia is viewed by some as fragmented and competitive [9]. Furthermore, the highprofile withdrawal of rofecoxib (Vioxx1) by Merck in 2004 highlighted reputational and regulatory risks associated with pain medications [10]. Compounding this, a potential for unlawful abuse is often associated with pain and anesthesia medications and could render these fields less attractive for large, established companies. In this context, it could be notable that many of the most recent approvals were awarded to smaller (e.g. Deproco, Anaquest), international (e.g. Organon, Astra, Eisai) or private (e.g. Purdue Pharma) companies. It is also tempting to speculate that a seeming lack of interest by biotechnology companies in these indications (based on the relatively small number of NMEs granted to biotechnology companies) relates to this decline. Our prior work
Drug Discovery Today Volume 20, Number 1 January 2015
PERSPECTIVE
100% Fraction of approved NMEs
(a)
80% Arthritis
60%
Migraine 40%
Chronic pain Surgical
20% Acute pain 0% 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade (c)
(b) Other, 2 Transporter, 2
Unclear, 6
Other, 2
Unclear, 8 Serotonin, 11
GPCR, 28 Synthase, 13
Opioid, 17
Channel, 6
COX, 15
Calcium Channel, 5 Drug Discovery Today
has shown that biotechnology companies now contribute to approximately two-thirds of all NMEs (when evaluating sources of patents, IND submissions or clinical trials) [5]. In evaluating pain and anesthesia NMEs, contributions from biotechnology companies were notably low, even in these earlier-stage activities. Importantly, the work herein was based on NMEs already approved by the FDA and does not consider ongoing or future investigation that might currently be in development by biotechnology companies.
Another finding is a seemingly narrow range of targets for pain and anesthesia NMEs. The majority of analgesics target GPCRs, whereas anesthesia drugs tend to focus on ion channels. We observed emphasis on these two target classes with other indications (e.g. psychiatric and neurological drugs). In this context, it is also interesting that these indications also tend to be disproportionately over-represented by conventional pharmaceutical companies. Such a finding might be coincidental or relate to fundamental biology of the key mechanisms
governing the nervous system and thus favor GPCRs and ion channels. Another possibility is that the chemical libraries used for screening or the approaches utilized for target discovery and validation tend to favor targeting of these pathways. Altogether, in the context of an aging population, these findings suggest that unmet needs in the fields of pain and anesthesia could provide attractive market opportunities for those organizations with unique approaches, capabilities and sufficient risk:tolerance to enter the field.
www.drugdiscoverytoday.com
5
Features PERSPECTIVE
FIGURE 2
Overview of analgesia new molecular entities (NMEs). (a) The relative distribution of specific indications targeted by analgesia NME approvals is indicated on a decade-by-decade basis. The target types (b) and individual pathways (c) impacted by NMEs focused on pain are indicated. Abbreviations: COX, cyclooxygenase; GPCR, G-protein-coupled receptor.
PERSPECTIVE
Drug Discovery Today Volume 20, Number 1 January 2015
(a) Fraction of approved NMEs
100% 80% 60% Local anaesthesia 40%
General anaesthesia Muscle relaxant
20% 0% 1930s 1940s 1950s 1960s 1970s 1980s 1990s 2000s 2010s Decade
(b)
(c)
Unclear, 3
Unclear, 3 Other, 3
Gap junction, 5
GABA, 9 GPCR, 14
Gap Junction, 5 Sodium channel, 11 Nicotinic acetylcholine 15
Channel, 28
Drug Discovery Today
FIGURE 3
Features PERSPECTIVE
Overview of anesthesia new molecular entities (NMEs). (a) The relative distributions of different types of anesthesia medicines are indicated on a decade-bydecade basis. The target types (b) and individual pathways (c) impacted by NMEs focused on anesthesia are indicated. Abbreviation: GPCR, G-protein-coupled receptor.
Acknowledgments This work was conducted as part of a project at the Yale Center for Molecular Discovery (http:// ycmd.yale.edu/) to develop a collection of all FDA-approved small molecules as a resource for screening to emphasize drug repurposing. Please contact the authors if you or your organization would be interested in potential participation in this project.
3 4 5
6
References 1 Booth, M., ed. (1999) Opium: A History, Macmillan 2 Sertu¨rner, F.W. (1806) Darstellung der reinen Mohnsa¨ure (Opiumsa¨ure) nebst einer chemischen
6
www.drugdiscoverytoday.com
7
Untersuchung des Opiums mit vorzu¨glicher Hinsicht auf einen darin neu entdeckten Stoff und die dahin geho¨rigen Bemerkungen. J. Pharm. Aerzte Apoth. 14, 47–93 (in German) Vagelos, P.R. and Galambos, L., eds) (2004) Medicine, Science and Merck, Cambridge University Press Bollet, A.J., ed. (2001) Civil War Medicine: Challenges and Triumphs, Galen Pr Kinch, M.S. (2014) The rise (and decline?) of biotechnology. Drug Discov. Today http://dx.doi.org/ 10.1016/j.drudis.2014.04.006 Kinch, M.S. et al. (2014) Trends in pharmaceutical targeting of clinical indications: 1930–2013. Drug Discov. Todayhttp://dx.doi.org/10.1016/j.drudis.2014.05.021 Melnikova, I. (2010) Pain market. Nat. Rev. Drug Discov. 9, 589–590
8 Woodcock, J. (2009) A difficult balance – pain management, drug safety, and the FDA. N. Engl. J. Med. 361, 2105–2107 9 Dutton, G. (2012) Pain management market ripe with immediate opportunities. Genet. Eng. Biotechnol. News 32, 11 10 Couzin, J. (2004) Drug safety. Withdrawal of Vioxx casts a shadow over COX-2 inhibitors. Science 306, 384
Michael S. Kinch Yale Center for Molecular Discovery, West Haven, CT 06516, USA
