Accelerated Development of Pharmaceuticals Past, Present, and Future.

This paper reviews the accelerated development of pharmaceuticals, exploring past, present, and future perspectives. It provides a historical overview of early strategies used to expedite development, beginning with initiatives from the 1990s. The work of Gardner and Byrn in accelerated development analysis during this era is highlighted. The narrative progresses to the 2000s, discussing the emergence of PK/PD in accelerating pharmaceutical development. The paper further examines case studies in the accelerated development field, including the INDIGO and Chorus programs. It concludes with an analysis of the current state of the field, referencing the NIPTE conference, which focused on the industrial perspective of accelerated development. Additionally, the paper outlines strategies for the rapid development of Solid Lipid Nanoparticle manufacturing and vaccine production.

[The metamorphoses of denationalization of 1993. Report-I. The market fight for medications import].

In the history of the Russian pharmaceutical market the year of 1993 became the year of formation of rules of market relations and changing under them of market landscape. The significant segment of state-centralized purchases moved under responsibility of regional authorities and their health care authorities. At that, powers of three former state organizations being occupied with purchases of imported medications were distributed between new state companies of Ministry of Health and commercial organizations and firms that entered pharmaceutical market. This diversity rather soon gave rise to competitive fight for budget funds and experiments of Government with market regulation. The traces of these clashes and attempts to make market regulated can be found in Ministry of Health archives and journal publications. The Report I reveals circumstances of entrance of Ministry of Health into market relationships and its acquisition of market player identity.

Are Ancestral Medical Practices the Future Solution to Today's Medical Problems?

Our cells and organs are threatened and, in most cases, constantly subjected to the aggression of numerous situations, both endogenous, characterized by unfavorable genetics, and exogenous, by deficient or inadequate nutrition, and even by a hostile environment; in most cases, they ultimately cause a cascade of degenerative and cardiovascular diseases, cancer, and infections, as well as those related to the metabolic syndrome, all of which eventually generate irreversible damage to the organism and, consequently, a significant deterioration in its survival [...].

Adolf Thierry and the first pharmaceutical factory in Southeast Europe.

The paper explores the beginnings of pharmaceutical industry development in Croatia and the establishment of the first pharmaceutical factory in Southeast Europe. Adolf Thierry de Chateauvieux (St. Pölten, 1854 - Pregrada, 1920), a nobleman hailing from France, immigrated to Croatia at the end of the 19 th century. He bought the Angjelu cuvaru ( Guardian Angel ) pharmacy (1892) in the small town of Pregrada and established the first pharmaceutical factory (1894) in this part of Europe. The factory had an equipped laboratory, a production facility, a storage room for raw materials and balsams, a room for packaging and shipping finished products and a commercial office. Production was mainly based on herbal remedies. The most famous were Thierry's Balsam and Thierry's Centifolia Ointment, both registered and patented in London (1900). By virtue of Adolf Thierry's entrepreneurial spirit and skilful product advertisement, his medicinal preparations were distributed across Europe, America, India and Africa, a testament to which is the well-preserved and researched documentation.

Disclosing the composition of unknown historical drug formulations: an emblematic case from the Spezieria of St. Maria della Scala in Rome.

This paper reports a pioneering study of an unknown historical drug formulation preserved in the Spezieria of Santa Maria della Scala in Rome, founded at the end of the seventeenth century by the Discalced Carmelites. Due to limited literature related to pharmaceutical remedies and drugs of the Early Modern Era (between the XV and XVIII centuries) and the complexity in their formulations, the study of these drugs represents a great challenge. The untargeted nature of the selected drug required a multi-analytical approach with complementary techniques to formulate a compositional hypothesis: FT-IR spectroscopy, gas chromatography-associated/mass spectrometry (GC-MS) and nuclear magnetic resonance (NMR) were successfully employed to identify different organic compounds. Systematic archaeobotanical research was performed as well, allowing us to acquire data related to the possible genus of plants from which these natural compounds derive and their geographical origin. The unknown drug formulation turned out to be a complex mixture used as an ointment with an anti-inflammatory purpose. It mainly contains a mixture of Venetian turpentine; a Pine resin (colophony) from the Pinaceae family; an exudate of a plant from South America, whose identified components are triterpenic compounds such as alpha- and beta-amyrins, betulin and lupeol; and saturated fatty acids which act as carriers and/or to reduce the viscosity of abovementioned exudates and resins. The study of historical drugs is important not only in order to know the practices handed down by the speziali in the past but also to reconstruct historical recipes, which can inspire new dermatological, cosmetic, hygienic and current healing products.Graphical abstract.

Portable medicine chests and supply of medicines in Serbia from the 1830s to the mid-20th century: analysis of medicines list.

The first portable medicine chests appeared in Serbia immediately after liberation from Ottoman rule around 1830. The network of portable medicine chests grew very quickly and became the first effective public health method of supplying medicines and medical items to people living in cities without community pharmacies and to the rural population in villages. According to their purposes, three categories of portable medicine chests could be identified: Portable medicine chests owned by physicians or veterinarians in the cities, portable medicine chests established by the Department of Workers Health Insurance, and portable medicine chests of the Health Cooperatives that operated in the villages This paper analyzes all three types of portable medicine chests. We specifically examine the regulations concerning the management of portable medicine chests, their content, and supply chains of medicines from the third decade of the 19 th century through the first half of the 20th century. We conclude that portable medicine chests represent a specific type of pharmacy in the territory of Serbia that provided very effective medical service. The medicines in these pharmacies were handled and dispensed to patients by physicians not by pharmacists. Patent medicines, compounded medicines, sanitary items and bandage materials were dispensed as well. Future research is needed to ascertain if physicians who owned or worked with the portable medicine chests actually prepared and compounded simple preparations as they were specified in the laws.

[Pooled Human Immunoglobulin Preparations as Immunomodulating Drugs].

It is time to celebrate the 125th anniversary of the first successful attempt to develop and use a specific high-titer antitoxic serum for treating diphtheria, a deadly infectious disease. This was followed by major advances in passive immunotherapy 75 years ago (production of pooled human IgG for subcutaneous injection) and 50 years ago (widespread technology for producing immunoglobulin preparations for intravenous administration). More than 200 tons of pooled human IgG are produced per year worldwide. The preparation is used primarily for IgG substitution in patients with primary and secondary immunodeficiencies, as well as for an immunomodulating treatment of a growing number of autoimmune and inflammatory diseases. These preparations contain the pooled IgG antibody repertoire of a large population of healthy plasma donors. This repertoire includes antibodies that neutralize pathogens and their factors of virulence, anti-idiotypic antibodies, and antibodies to other foreign and own proteins, as well as to carbohydrate antigens. Naturally polyspecific antibodies that are present in all healthy individuals play an important role as a first-line defense against bacteria and viruses. After exposure to protein-modifying agents, some IgG molecules can acquire the ability to bind novel structurally unrelated antigens. This phenomenon is referred to as induced polyspecificity. The list of these protein-modifying molecules was shown to include low-pH buffers, free heme, pro-oxidative ferrous ions, reactive oxygen species, etc. Such modified antibody preparations may have a therapeutic potential, since their administration to animals with experimental sepsis or aseptic systemic response syndromes significantly improved survival rates, while the same dose of the native preparation had no effect. We also hypothesize that the aggressive protein-modifying molecules released in sites of inflammation and tissue damage could also modify the antigen-binding behavior of surface immunoglobulin B cell receptors and the structurally related T cell receptors. This "specificity editing" of both types of receptors may play a major role in the body's defense mechanisms.

Pharmaceuticals and modern statecraft in South Africa: the cases of opium, thalidomide and contraception.

This article provides a history of three pharmaceuticals in the making of modern South Africa. Borrowing and adapting Arthur Daemmrich's term 'pharmacopolitics', we examine how forms of pharmaceutical governance became integral to the creation and institutional practices of this state. Through case studies of three medicaments: opium (late 19th to early 20th century), thalidomide (late 1950s to early 1960s) and contraception (1970s to 2010s), we explore the intertwining of pharmaceutical regulation, provision and consumption. Our focus is on the modernist imperative towards the rationalisation of pharmaceutical oversight, as an extension of the state's bureaucratic and ideological objectives, and, importantly, as its obligation. We also explore adaptive and illicit uses of medicines, both by purveyors of pharmaceuticals, and among consumers. The historical sweep of our study allows for an analysis of continuities and changes in pharmaceutical governance. The focus on South Africa highlights how the concept of pharmacopolitics can usefully be extended to transnational-as well as local-medical histories. Through the diversity of our sources, and the breadth of their chronology, we aim to historicise modern pharmaceutical practices in South Africa, from the late colonial era to the Post-Apartheid present.

Determining a Drug's Properties: Medieval Experimental Protocols.

Among Galenic texts attracting attention circa 1300 was De complexionibus, which described a crude protocol for determining the qualitative character and intensity of any given medicine. This caught the attention of physicians at Montpellier, where three generations of writers made it into a carefully structured test procedure for identifying by a via experimenti the nature of a drug's effect on healthful function: they introduced a null point as the referent for their measurements, identified a range of contingent factors that had to be controlled for, and devised ways to standardize the sample being tested. Their protocol was certainly designed to be used, but in practice they seemed to have preferred an alternative via rationis that inferred the effect of a medicine from sensory attributes like taste and color, acknowledging that taste tests were coarser and less certain than a structured experimental procedure, but were easier and quicker to perform than the elaborate alternative.

Testing Drugs and Trying Cures: Experiment and Medicine in Medieval and Early Modern Europe.

This article examines traditions of testing drugs (as substances) and trying cures (on patients) in medieval and early modern Europe. It argues that the history of drug testing needs to be a more central story to overall histories of scientific experiment. The practice of conducting thoughtful-and sometimes contrived-tests on drugs has a rich and varied tradition dating back to antiquity, which expanded in the Middle Ages and early modern period. Learned physicians paired text-based knowledge (reason) with hands-on testing (experience or experiment) in order to make claims about drugs' properties or effects on humans. Lay practitioners similarly used hands-on testing to gain knowledge of pharmaceutical effects. Although drug testing practices expanded in scale, actors, and sites, therpublished a work extolling the virtues of drugs froe was significant continuity from the Middle Ages to the eighteenth century.

Testing Drugs and Attesting Cures: Pharmaceutical Monopolies and Military Contracts in Eighteenth-Century France.

This article explores the role of testing in the allocation of royal monopoly privileges for drugs in eighteenth-century France by following the multi-generational fortunes of a single "secret remedy" from 1713 to 1776: the poudre fébrifuge of the Chevalier de Guiller. On at least five occasions, this drug was tested on patients in order to decide whether it should be protected by a privilege and whether or not its vendors should be awarded lucrative contracts to supply it in bulk to the French military. Although efforts were made early in the century to test the drug through large-scale hospital trials and to relegate privilege granting to a bureaucratic commission, the case of the poudre fébrifuge instead suggests that military expediency and relatively small-scale trials administered personally by royal practitioners remained decisive in determining whether or not a drug received a monopoly privilege or a military contract.

[Mysteries of a medicine chest ].

This article retraces the history of an old medicine chest, used at the beginning of the 19th century, but probably designed earlier. Possibly made in A ustria, with a two-headed eagle lining the bottom of the lid, this first-aid kit belongs to a small group of related chests. It should be noted that these chests were used for a wide variety of different purposes over time. Also named a «droguier¼ in French, this light chest, made of walnut, and, according to family lore, found in Normandy, would have belonged to a doctor, as confirmed by a short invoice found among numerous documents. The identity of the supplier of numerous old medicines is shown on the labels on the flasks (many of which are intact) and other boxes (containing, in particular, herbal drugs) : «Clément, Apothicaire. Rue St Onge N°. 42. près le Bd. du Temple A Paris¼, whose history is recounted here step by step.

[The Journal de chimie médicale (Journal of Medical Chemistry) : a major innovation on French public health during the 19th century ].

JBA Chevallier is first known for his publication in 1850 of his book on falsifications. But he had also a major role for the opening of the pharmacy world to toxicological and Public Health issues, through the founding in 1825, and the management for more than 50 years, of the Journal de chimie médicale, de pharmacie et de toxicologie (Journal of Medical Chemistry, of Pharmacy and of Toxicology). The purpose of the present study has been to look at the evolution of that publication over the years and to compare its content with the reference pharmaceutical journal at that time : the Journal de pharmacie et de chimie (Journal of Pharmacy and Chemistry). One can observe that the editorial lines of both journals will progressively diverge from each other, but Chevallier remained strongly connected with pharmacy, his journal merging finally in 1876 with the Répertoire de pharmacie (Index of Pharmacy).

Identifying and assessing highly hazardous drugs within quality risk management programs.

Historically, pharmaceutical industry regulatory guidelines have assigned certain active pharmaceutical ingredients (APIs) to various categories of concern, such as "cytotoxic", "hormones", and "steroids". These categories have been used to identify APIs requiring segregation or dedication in order to prevent cross-contamination and protect the quality and safety of drug products. Since these terms were never defined by regulatory authorities, and many novel pharmacological mechanisms challenge these categories, there is a recognized need to modify the historical use of these terms. The application of a risk-based approach using a health-based limit, such as an acceptable daily exposure (ADE), is more appropriate for the development of a Quality Risk Management Program (QRMP) than the use of categories of concern. The toxicological and pharmacological characteristics of these categories are discussed to help identify and prioritize compounds requiring special attention. Controlling airborne concentrations and the contamination of product contact surfaces in accordance with values derived from quantitative risk assessments can prevent adverse effects in workers and patients, regardless of specific categorical designations to which these APIs have been assigned. The authors acknowledge the movement away from placing compounds into categories and, while not yet universal, the importance of basing QRMPs on compound-specific ADEs and risk assessments. Based on the results of a risk assessment, segregation and dedication may also be required for some compounds to prevent cross contamination during manufacture of APIs.

Using default methodologies to derive an acceptable daily exposure (ADE).

This manuscript discusses the different historical and more recent default approaches that have been used to derive an acceptable daily exposure (ADE). While it is preferable to derive a health-based ADE based on a complete nonclinical and clinical data package, this is not always possible. For instance, for drug candidates in early development there may be no or limited nonclinical or clinical trial data. Alternative approaches that can support decision making with less complete data packages represent a variety of methods that rely on default assumptions or data inputs where chemical-specific data on health effects are lacking. A variety of default approaches are used including those based on certain toxicity estimates, a fraction of the therapeutic dose, cleaning-based limits, the threshold of toxicological concern (TTC), and application of hazard banding tools such as occupational exposure banding (OEB). Each of these default approaches is discussed in this manuscript, including their derivation, application, strengths, and limitations. In order to ensure patient safety when faced with toxicological and clinical data-gaps, default ADE methods should be purposefully as or more protective than ADEs derived from full data packages. Reliance on the subset of default approaches (e.g., TTC or OEB) that are based on toxicological data is preferred over other methods for establishing ADEs in early development while toxicology and clinical data are still being collected.

Between the Bazaar and the Bench: Making of the Drugs Trade in Colonial India, ca. 1900-1930.

This article analyzes why adulteration became a key trope of the Indian drug market. Adulteration had a pervasive presence, being present in medical discourses, public opinion and debate, and the nationalist claim for government intervention. The article first situates the roots of adulteration in the composite nature of this market, which involved the availability of drugs of different potencies as well as the presence of multiple layers of manufacturers, agents, and distributors. It then shows that such a market witnessed the availability of drugs of diverse potency and strengths, which were understood as elements of adulteration in contemporary medical and official discourse. Although contemporary critics argued that the lack of government legislation and control allowed adulteration to sustain itself, this article establishes that the culture of the dispensation of drugs in India necessarily involved a multitude of manufacturer-retailers, bazaar traders, and medical professionals practicing a range of therapies.

Pharmaceutical patenting and the transformation of American medical ethics.

The attitudes of physicians and drug manufacturers in the US toward patenting pharmaceuticals changed dramatically from the mid-nineteenth century to the mid-twentieth. Formerly, physicians and reputable manufacturers argued that pharmaceutical patents prioritized profit over the advancement of medical science. Reputable manufactures refused to patent their goods and most physicians shunned patented products. However, moving into the early twentieth century, physicians and drug manufacturers grew increasingly comfortable with the idea of pharmaceutical patents. In 1912, for example, the American Medical Association dropped the prohibition on physicians holding medical patents. Shifts in wider patenting cultures therefore transformed the ethical sensibilities of physicians.

The evil of the unknown--risk-benefit evaluation of new synthetic drugs in the 19th century.

In the 19th century, synthetic chemistry discovered completely new chemical entities for medicinal use, which dramatically enriched the therapeutic armamentarium. However, no information was available regarding the safety of these new drugs, which were unrelated to most of the medicinal agents formerly known. Therefore, the question arises, if and how far, considerations regarding the relationship between benefit and risks were made. In this study, chloroform, phenazone (antipyrine) and sulfonal, were investigated as examples for drugs newly introduced in the 19th century. The results revealed that these drugs were provided by the manufacturer, tested by the physicians in a multicentre pattern and side effects were published in the medical literature soon after. Within a few years, several hundred cases were reported but the data were rarely summarized statistically. Therefore, physicians needed to stay updated with the medical literature because neither systematic industrial research nor regulatory authorities existed. The number of case reports within the first years were sufficient to detect common (> 1/100 to < 1/10) side effects but rare events were also reported. An extraordinary example is the drug-induced toxic epidermal necrolysis, which is commonly known as the Lyell syndrome or its less severe form, the Stevens-Johnson syndrome. This reaction has been clearly described by Baruch Spitz (1854-1932) as a side effect of antipyrine in 1887, several decades before Stevens, Johnson and particularly Lyell.