{"id":49724,"date":"2023-06-30T11:36:02","date_gmt":"2023-06-30T11:36:02","guid":{"rendered":"https:\/\/biomedpharmajournal.org\/?p=49724"},"modified":"2023-07-11T05:50:51","modified_gmt":"2023-07-11T05:50:51","slug":"history-as-a-source-of-innovation-in-antimicrobial-drug-discovery","status":"publish","type":"post","link":"https:\/\/biomedpharmajournal.org\/staging\/vol16no2\/history-as-a-source-of-innovation-in-antimicrobial-drug-discovery\/","title":{"rendered":"History as a Source of Innovation in Antimicrobial Drug Discovery"},"content":{"rendered":"\n

Introduction<\/strong><\/p>\n\n\n\n

Pharmacy emerged from\nhuman efforts to relieve their physical suffering through remedies prepared with\nnatural ingredients. Ancient and medieval pharmacopeias contain information on\nthe use of medical material, that may be from plant, mineral, or animal origin.\nIt is thus still possible that these thousand-year-old pharmacopeias hold\nsecrets that could contribute to nowadays medicines. Many leading drugs\n(anticancer, antimalarial, painkillers, etc.) are indeed derived from these ancestral\ntraditional pharmacopeias [1]. However, of the >\n30,000 plants described in traditional pharmacopeias, less than 5,000 have been\nstudied [2]. The question is\nwhether and how to exploit this vast pool of potential therapeutics [3,4]. <\/p>\n\n\n\n

In the last decade, medicinal\nplant research has turned to old medicinal-botanical texts, to study the history\nand evolution of pharmacopeias, and to identify lead compounds for new drug discovery\n[5\u20138]. Despite this pivot\nin research focus, experiments that test the activities of entire historical\nremedies are rare, difficult to conduct, and the subject of much\nmisunderstanding. This is due to several factors including:<\/p>\n\n\n\n

The folkloric image associated with ancient medicines. It is difficult to evaluate remedies objectively due to the frequent intrusion of magical and sacred although their development remained rationally designed at its base. It may therefore be difficult to evaluate the biological effect of each ingredient. However, very often this interference is not constitutive, but superadded: the rational\/irrational association can usually be clearly separated. Further, the diagnosis of a malady can also be complex, often involving supernatural aetiologies alongside natural causes. In contrast to modern medicine, which seeks a direct cause for a pathology, ancient systems often seek to flush out deep-seated causes. This disorganizes and devalues the care provided, which is nevertheless often rational.<\/p>\n\n\n\n

The difficulty of transposing ancient practices into our present culture. This requires a huge interdisciplinary research effort alongside, a dialogue between disciplines, very well explained by Harrisson and Connelly [9]. Furthermore, on the opposite to current medicines containing a single active ingredient, medieval remedies are usually preparations made from several ingredients, acting synergistically [10\u201312]. It is thus possible that each ingredient taken individually does not carry a strong activity, but that the combination can bring a certain, desired effectiveness. Nonetheless, the effectiveness of a remedy, which is the sum of its multiple actions, will be more difficult to evaluate and to determine, and is not necessarily favored by current research.<\/p>\n\n\n\n

The juxtaposition of two medicines, traditional and modern. While modern medicine gained power and prestige, traditional medicine felled victim to trivialization and\/or the increasingly untrained bodies of people practicing it over the course of many years. This resulted in the degradation of ancient knowledge, and a more superficial scientific approach. It is thus necessary to restore confidence and rationality in the study of traditional medicines, and to find room for dialogue between both approaches, that are ultimately rather complementary than opposed, i.e. <\/em>[13\u201317]. <\/p>\n\n\n\n

Although discredited\nin recent years, traditional medicines have nevertheless been marked throughout\ntheir history by a rationality, and a scientific approach that enabled the\nemergence of remedies that we could quite rightly consider as innovative by\nmodern standards despite being designed millennia ago. It is important to\nremember that traditional practices were characterized by the seal of research,\ncarried out by prominent scientists who led to major discoveries and developments.\nAncient pharmacopoeias could again be considered as a relevant starting point\nfor the search for new remedies. This will be illustrated through a few\nexamples from the scientific literature. This review will focus on the medieval\nArab period perceived as the golden age of ancient medicine, and through the lens\nof the fight against microbial infections, one of the major medical concerns of\nthe medieval era.<\/p>\n\n\n\n

Antibiotic resistance<\/strong><\/p>\n\n\n\n

Infections have\nmarked human history. Today, aside from the COVID-19 pandemic, infections are considered\nless anxiety-provoking compared to other pathologies like cancer, but this was not\nalways the case: at medieval times, drinking water, cutting, or injuring\noneself could lead to dangerous or even fatal infections. As these infections\nwere a daily preoccupation, physicians also developed many leading remedies to\ncounter them [4].<\/p>\n\n\n\n

The advent of\nantibiotics, with Fleming\u2019s discovery of penicillin in 1928, a compound\nproduced by the fungus Penicillium notatum<\/em>, revolutionized the treatment\nof infections [18,19], leading to the\nbelief that microbial infections were \u2018over\u2019. The use of traditional medicines\nwas thus no longer relevant and lost much of its prestige. This was nevertheless\nregardless of the ability of bacteria to resist antibiotics. If microbes can produce\nantibiotics (most of the antibiotics used are of microbial origin), it is\nindeed logical that other microbes have found ways to resist these same\nantibiotics. The resistances have then spread widely with the unreasonable use\nof antibiotics, i.e.<\/em> [20\u201322].<\/p>\n\n\n\n

Bacteria strains\nresistant to antibiotics were detected quite quickly after their introduction to\nthe market. This was the case for penicillin, with resistant Staphylococcus aureus<\/em> found in the 1940s [23,24].  Streptococcus pyogenes<\/em> resistant to sulfonamide was also readily detected in\nmilitary hospitals during the second World War [25\u201327]. Mycobacterium\ntuberculosis<\/em> with streptomycin\nresistance was revealed as well in 1948 [28]. Resistance to multiple drugs was first observed in\nthe late 1950s to 1960s among enteric bacteria, like Escherichia coli<\/em>, or other from the Shigella <\/em>and Salmonella <\/em>genus <\/em>[29]. These resistances caused also a gradual re-emergence\nof pathologies like tuberculosis, since the 1980s, mainly due to multi-drug\nresistant strains, and was aggravated by the emergence of the human\nimmunodeficiency virus [30].<\/p>\n\n\n\n

As a consequence of\nthe pervasiveness of the above bacterial strains, the emergence of antibiotic\nresistance has been rising rapidly all over the world. Ultimately, a new\nresistance appeared with every new antibiotic synthesized (Figure 1). We are therefore faced with a growing global health\nthreat. In 2019, a study showed the involvement of antibiotic-resistant\nbacteria in the deaths of more than 1.2 million people [31]. This may be attributed to different factors, such as\nthe abusive use of antibiotics, as well as a shortage of new drug development\nby the pharmaceutical industry, etc… [32].<\/p>\n\n\n\n

In the fear that\nantibiotics that are effective today might no longer be functional tomorrow,\nand with the rapid spread of antibiotic resistance, there is an important need\nto develop new strategies to limit the use antibiotics and to find new\ntherapeutic solutions. Ancient societies have used and\/or combined countless\nnatural substances to treat diseases, trying, testing, and improving these\nstrategies over the course of many centuries. Thus, ancient methodologies could\nserve as basis for the discovery of novel therapeutic strategies. However, the\nestablishment of interdisciplinary consortia dedicated to the study of these\nremedies must be implemented,\nas well as the demonstration of the interest, feasibility, and future prospects\nof such approaches.<\/p>\n\n\n\n

Rationality in the design of remedies<\/strong><\/p>\n\n\n\n

If different studies\nalready highlighted some interest in studying past remedies or highlighted antibiotic\nuse from past records, i.e.<\/em> [33\u201340], the consideration of these past remedies as a\nreservoir of pertinent strategies to combat infection would require more\ncomplex and coordinated strategies, involving intense collaboration between art,\nsocial and experimental sciences.<\/p>\n\n\n\n

A pioneering interdisciplinary\nconsortium (Ancientbiotic, https:\/\/ancientbiotics.co.uk\/) has been set up to\nstudy a 10th Century medical text known as \u2018Bald\u2019s Leechbook\u2019 containing a\nplentitude of remedies. From this book, a collyrae (Table 1) has been chosen to\nhighlight the potential of these medicines to combat infections. The goal was\nto study the medical approaches of past physicians and to demonstrate the\nefficacy of an ancient remedy. By faithfully reproducing this remedy, the\nauthors demonstrated that it drastically limited the growth of bacterial\npathogens like Staphylococcus aureus, Pseudomonas aeruginosa or Neisseria <\/em>gonorrhoeae<\/em> <\/em>in vitro<\/em>, and\/or on a mouse model of eye infection, with a\nreasonable safety profile [41\u201344]. <\/p>\n\n\n\n

The same study also\nshowed that the mixture of ingredients in Bald’s eye drops is more effective\nthan the addition of each individual components. This imply that the\ncombination of specific ingredients, none of which may have significant\nantibacterial activity, may enhance their bioactivity. It seems thus possible\nthat some of the combinations developed by these physicians were designed\nthrough rational methods. It could therefore be possible to construct remedies of\nsignificant therapeutic potential from a combination of ingredients that\nexhibit no significant bioactivity as isolated components. The idea would be to\nconsider these ingredients in the context of all or part of the remedies,\nrather than investigating each ingredient individually. <\/p>\n\n\n\n

As a follow-up of\nthis study, the consortium also developed a software to analyze the entire\nmanuscript in order to highlight the most promising remedies. Groups of\ningredients were revealed, some of them often used together, such as aloe vera\nand sarcocolla [45]. Another recent\ncomputer analysis equally highlighted the recurring appearance of combinations\nof ingredients, like saffron and opium or fennel and celery seeds, when\nanalyzing remedies for urinary tract diseases identified in different Arabic\npharmacopeias spanning over the course of more than 3 centuries [46]. These re-occuring\ncombinations point to a rational approach in the development of treatment\nremedies, where a base of certain ingredients would have been maintained and\nused as a framework for the design of new candidates. The same ingredients could\nproduce synergistic activity if combined, and should deserve special attention.\nThanks to these studies, it becomes more and more evident that the science of\nmedicine in medieval times was the result of a very rational and scientific\napproach, far from the folkloric image it usually has. Further studies of\nremedies from other manuscripts and ancient practices will be required to\nconfirm these initial hypotheses and\/or to possibly allow the identification of\ninnovative active principles from complex combinations or even unexpected\nmaterials [35,47].<\/p>\n\n\n\n

While traditional remedies\nwere developed from common ingredients, many remedies also contain toxic molecules,\namong which the most emblematic being heavy metals, such as lead, mercury, and\narsenic. Reconsidering these remedies for future development requires to prove that\nancient physicians perfectly mastered the use of these ingredients, took into\naccount their toxicities, and did not take ill-considered risks concerning the\nhealth of their patients. For example, lead was widely used since antiquity to prepare\nmake-up products (including kohl) or remedies. Two recent studies have analyzed\nthese uses, based on makeup found in Egyptian tombs [48], and the reconstitution\nof a cutaneous remedy reported by Al Kindi (Table 1), from the medieval Arab\nperiod [49]. These two studies demonstrated\nthat ancient alchemists mastered the transformation of metals and were able to\nconfer them different therapeutic potentials, depending on the transformation\nprocesses used. In the \u201ckhols\u201d used for make-up, litharge was transformed into\nlaurionite and phosgenite, with pro-inflammatory properties, which prevented\ninfections [48]. Reconstruction and\nanalysis of the ancient remedy showed that alchemists produced soluble lead with\nanti-inflammatory properties, to promote healing [49]. Moreover, the\ntoxicity of lead was reported as early as antiquity [50]. As an\nanti-infective, it was mostly used cutaenously. This limited the diffusion of the\nmetal in the body, restricting its action on the local site of infection. These\nprecautions may therefore have changed the benefit-risk balance of lead.\nOverall, the evidence suggests that ancient physicians knew about the inherent toxicity\nof toxic ingredients like metals, and handled carefully their use. <\/p>\n\n\n\n

These few exemples demonstrate that the study\nof the history of medicine combined with modern investigation could prove the\nrationality of the approaches followed by these physicians. One of the periods\nwhere this scientific approach was at its peak, both in terms of the variety of\nactors and of the scientific approach, was the medieval Arab period (Table 1).\nThe methodology applied by these scientists could still be relevant today and\nwill be explained in the following section.<\/p>\n\n\n\n

The Arab medieval Golden age of medicine<\/strong><\/p>\n\n\n\n

Medicine\nwas certainly the most studied and the most developed science studied in the\nmedieval Arab world. This was the Golden Age of Arab medicine with considerable\nscientific contributions between the 9th<\/sup> and 13th<\/sup>\ncenturies, i.e.<\/em> [51\u201355]. Many of\nthe achievements of Arab-Muslim physicians were based on the legacy of Greek\nand Roman physicians [51,56]. This\neffervescence of knowledge and intelligence then spread throughout the world\nand significantly influenced medical theory, surgical practice and other\ndisciplines. <\/p>\n\n\n\n

Origin of the Golden Age<\/strong><\/p>\n\n\n\n

Several factors led to this Golden Age, including religious\nsupport. Religion could indeed easily favor, delay, or condemn medical\nprogresses. In this context, the guidelines of the Prophet clearly encouraged\nsuch studies. The extension of the Muslim Empire during this time also brought\nout an exchange of ideas from India to Iran, or Spain (Figure 2). Communication\nroutes became safer, facilitating travel and trade. Alongside these\ndevelopments, Arabic language was identified as an international one, which\nfacilitated the exchange of scholarly ideas [54]. The ancient manuscripts of greek, latin or\neven sansktit [57] were\ntranslated in Arabic by the most competent scholars. Another significantly contribution\nto the Golden Age was the establishment of a paper mills in Baghdad (for a long\ntime the nerve center of the Arab-Muslim world [58]) to replace parchment (skin\nof animals) or papyrus (plant origin) by paper using linen. This enabled many\npeople to gain access to books and develop their education [54]. The most precious texts were stored in the House of\nWisdom, founded in Baghdad in 1005 by the Caliph Al Mamun [56].<\/p>\n\n\n\n

There were also significant advances in chemistry,\nwhere Arab alchemists became familiarized with plants and developed different\ntechniques such as distillation, crystallization, calcination, etc\u2026<\/em> [54]. An entire outgrowth\nof alchemy consisted in isolating and studying a broad spectrum of natural\nsources, minerals, and compounds, to discover a \u2018magic elixir\u2019 or a medical\npotion that would preserve people from all fatal diseases. <\/p>\n\n\n\n

Likewise, in microbiology, plague and leprosy were\nconsidered as infective and contagious diseases. For example, Islamic practitioners\nintroduced the concept of quarantining (XIth<\/sup> century) as a form of disease\ncontrol. Hygienic methods were also implemented at the same time, in the form\nof proper sterilization, putting in place practices such as the use of alcohol\nprior to surgery and skin wounds treatment [54].<\/p>\n\n\n\n

Developments also\noccurred in pharmacology. Practitioners became acquainted with herbs, introduced\nnew drugs such as camphor, musk, sandalwood, developed excipients, created\nflavoring extracts, and experimented with poisons and antidote [59,60]. The first pharmacy was\nestablished in Baghdad in 754. Four centuries later, the pharmacology science was\nseparated from both medicine and alchemy, these disciplines becoming\nindependent (illustrated Figure 3).<\/p>\n\n\n\n

Medical education and institution<\/strong><\/p>\n\n\n\n

Physicians during\nthis era followed long training courses, often being six to\nseven years. This education comprised an initial theoretical training in sciences,\nfollowed by clinical training in hospitals. The medical practice was even governed\nby a code of ethics towards patients, colleagues, and the community [61,62]. <\/p>\n\n\n\n

Secular hospitals were\nestablished throughout the Arab world, starting in Damascus in 706. These\nhospitals were well equipped. Patient monitoring, drug development and clinical\ntrials were reported and provided key records for the development of the\nscientific method [63]. <\/p>\n\n\n\n

Famous figures of the Arab medicine age<\/strong><\/p>\n\n\n\n

Among the era\u2019s many prominent figures was Zakarya Al-Razi, known in Latin as Rhazes <\/strong>(Figure 2, Table 1), a pharmacologist and physician of Persian origin who\nheaded the hospital founded in Baghdad [64]. Zakarya Al-Razi devoted his life to\nmedical research and became the founder of chemotherapy by using mineral drugs\nfor external and internal use in cancers [64]. Since his youth, he was interested in alchemy, and\nlater he became the first to develop metal-chemical preparations such as\narsenic, copper sulfate, iron sulfate, and different forms of mercury to\ndevelop novel drugs [65]. He went on to write his famous book Al-Hawi<\/em>, a 30 volumes encyclopedia\nthat provides a general description of disorders, fevers, plagues, and skin\ndiseases, accompanied with a complete pharmacopeia, tables of terminology,\nweights, and measures [65]. He was the first to administer opium as an\nanesthetic after testing it on animals [64]. <\/p>\n\n\n\n

One of the\nmost famous Muslim scientists is Abdu Ali Ibn Husayn\nibn Abdullah Ibn Sina, also known as Avicenna (Figure 2, Table 1). Of Persian origin, from Rayy, he was known\nas the Prince of medicine and developed a methodological approach that would be\ntaught in European universities until the 19th century [64]. His book Al-Qanun fi al-Tibb -Canon\nof Medicine<\/em>– represented the\nfirst pharmacopeia, including medicinal, chemical, and physical properties of more\nthan 600 herbal drugs [66].  In addition to these accomplishments, Avicenna  was the first to\ndescribe many different microbiological diseases such as anthrax and\ntuberculosis, and emphasized the crucial role of hygiene and dietetics [54]. He stressed the need\nto study new drugs before releasing them to the patients by setting rules to\ntest their effectiveness [64].<\/p>\n\n\n\n

Another interesting figure in the history of medieval\nscience is Abu Yusuf Yaaqub Ibn Ishaq Al Kindi (Figure 2, Table 1), considered as the\nFather of Arab philosophy. He was interested in a many fields including\nmetaphysics, philosophy and logic to optics and pharmacology [67].  Among his many medical\nwritings, the most reputable and well-known might well be the medical formulary\n\u201cAqrabadhin<\/em>\u201d. This term is derived from the Greek word for ‘list’.\nThe book details the pharmaceutical preparations derived from botanical,\nanimals, and minerals sources, in the form of lists of medications [67,68]. He also wrote a treatise Risala fi ma’ rifat quwwat al-adwiya al-murakkaba<\/em>, translated as De gradibus<\/em>, and exploited mathematical rules to quantify the\nstrength of drugs [69].<\/p>\n\n\n\n

Diya al-Din Abu Muhammad\nAbdallah Ibn Ahmad Ibn al Baytar (Figure 2, Table 1) is another famous Arab scientist, a Muslim botanist\nand pharmacologist of the Medieval era. His knowledge and passion for natural\nsciences was inspired by his father Ahmad Ibn Abd-al Malik [70]. He studied the Galenic pharmacopeia, based on the\nidentification of the active principles of medicinal plant extracts.  His most accomplished work, entitled, Kitab al-Gami\u2019 li-mufradat al-adwiya wa-l-agdiya<\/em> translated as \u2018Collection of simple remedies and food\u2019 <\/sup>[69] is considered as his seminal work. It was based on Dioscorides, Galien, Al-Razi and Ibn Sina, on which he applied\nhis own observations and corrections and mentioned simple nutrients and about\n1400 drugs based on plants, animals, and mineral [70]. <\/p>\n\n\n\n

Drug development during the Arab Medieval ages<\/strong><\/p>\n\n\n\n

During the Medieval ages, Arabs significantly contributed to health and medicine. During this time, the use of drugs still relied upon scientific hypotheses introduced by the Greeks, related to \u2018the theory of bodily humors\u2019. Essentially, this theory states that humans fall sick due to imbalances of bodily humors [71].  Hippocrates (Figure 2, Table 1) stated that the human body is made up of four substances: yellow bile, black bile, water, and blood. Arab physicians agreed with this theory [72] and affirmed that physical and spiritual wellbeing was essential, and that a disease should be viewed as an opportunity to purify and balance emotional and physical feelings through rest, healthy food, breathing fresh air, and practicing proper hygiene [73]. Even if this theory was proven incorrect, the development of drugs still adhered to scientific standards, and was further framed by ethical rules [74].<\/p>\n\n\n\n

Table 1: Glossary of terms and names used in the review<\/strong><\/p>\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n
\n

Family term<\/strong><\/p>\n<\/td>\n

\n

Name<\/strong><\/p>\n<\/td>\n

\n

Description<\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

Infection<\/strong><\/p>\n<\/td>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

 <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Present definition<\/p>\n<\/td>\n

\n

Development in a living being of micro-organisms that can cause injury by multiplying and possibly secreting toxins or spreading through the bloodstream<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Past definition <\/p>\n<\/td>\n

\n

Infections are described by the symptoms they cause. Their description should inform us on the nature of the infection with today standards. This usually demands a broad-ranging, interdisciplinary approach, to study the manuscript, understand the description of the disease, symptoms, the curative ingredients and infer from these descriptions a plausible causing agent, that is not without difficulties [84\u201386].   <\/p>\n<\/td>\n<\/tr>\n

\n

Professionnals<\/strong><\/p>\n<\/td>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

 <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Physician<\/p>\n<\/td>\n

\n

A person able to practise medicine, from diagnosis to treatment (except surgery)<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Alchemist<\/p>\n<\/td>\n

\n

A person who practises alchemy, the medieval forerunner of chemistry, concerned with the transformation or transmutation of matter, through distillation, crystallization\u2026<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Pharmacian<\/p>\n<\/td>\n

\n

A person who can prepare and sell certain drugs by prescription only. They were aware of the importance of raw materials, botanic and the importance of the preparation protocol precision<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

scholar<\/p>\n<\/td>\n

\n

A person who is highly educated or has an aptitude for studying.<\/p>\n<\/td>\n<\/tr>\n

\n

Time period<\/strong><\/p>\n<\/td>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n<\/td>\n<\/tr>\n
\n

 <\/strong><\/p>\n<\/td>\n

\n

Antiquity<\/p>\n<\/td>\n

\n

30th<\/sup> century BC -5th<\/sup> century<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Medieval time<\/p>\n<\/td>\n

\n

5-15th<\/sup> century<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Arab medical golden age<\/p>\n<\/td>\n

\n

9-13th<\/sup> century<\/p>\n<\/td>\n<\/tr>\n

\n

Famous figures<\/strong><\/p>\n<\/td>\n

\n<\/td>\n\n

 <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Hyppocrate<\/p>\n

\n<\/p><\/td>\n

\n

Born around 460 BC in Cos and died in 377 BC in Larissa, was a Greek physician of the Periclean century, but also a philosopher, traditionally considered as the father of medicine<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Dioscorides<\/p>\n<\/td>\n

\n

Born between 20-40 in Anazarbe and died around 90. He was a Greek physician, pharmacologist and botanist whose work was a major source of knowledge about plant, animal or mineral based remedies during the 1500s. He is the author of the treatise ‘De materia medica’<\/em>.<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Zakarya Al-Razi<\/p>\n

\n<\/p><\/td>\n

\n

Born in 865 in the town of Clay, died around 925 in Tehran was a Persian multidisciplinary scholar who made important contributions to medicine, alchemy and philosophy<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Abu Yusuf Yaaqub Ibn Ishaq Al Kindi<\/p>\n

\n<\/p><\/td>\n

\n

Born in 801 in the town of Koufan, died in 873 in Bagdad. As an encyclopedic mind, he sought to synthesize, organize and evaluate all the knowledge of his time (philosophy, mathematics, astronomy, physics, chemistry, technology\u2026)<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Abdu Ali Ibn Husayn Ibn Abdullah Ibn Sina<\/p>\n<\/td>\n

\n

born in 980 in Ravi, died in 1037 in Hamadan, philosopher and physician, author of reference works in medicine and philosophy<\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Diya al-Din Abu Muhammad Abdallah Ibn Ahmad Ibn al Baytar<\/p>\n<\/td>\n

\n

born around 1197 in the province of Malaga and died in 1248 in Damascus, an Arab-Andalusian physician, who published several works in which he brought together the pharmaceutical knowledge of his time<\/p>\n<\/td>\n<\/tr>\n

\n

Remedies<\/strong><\/p>\n

 <\/strong><\/p>\n<\/td>\n

\n<\/td>\n\n

 <\/strong><\/p>\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

collyrae from the Bald\u2019s Leechbook<\/p>\n

<\/p>\n<\/td>\n

\n

Make an eye salve against a wen: take equal amounts of an Allium species and garlic, take equal amounts of wine and ox gall, mix with the alliums, put in a brass vessel, let stand for nine nights, clarify well, put in a horn and at night apply to the eye with a feather [44]\n<\/td>\n<\/tr>\n

\n

 <\/strong><\/p>\n<\/td>\n

\n

Lead-based cutaneous remedy from Al Kindi.<\/p>\n

\n<\/p><\/td>\n

\n

1 part of quicklime (CaO) and 1 part of litharge (PbO) are passed through a clay. They are covered with wine vinegar. Olive oil is added and also sheep fat. It is boiled together and stirred with a rod until it is mixed and almost black. The heating is renewed until the viscosity is like thick honey [49]\n<\/td>\n<\/tr>\n<\/tbody>\n<\/table>\n\n\n

The origin of drug\ndevelopment was founded on the accumulated knowledge from pre-Islamic periods,\nsuch as that of the Egyptian or Chinese medical systems, even if the Greek and\nRoman legacies still remained the basis of the developed knowledge throughout\nthe Arab Medieval ages. Arab physicians improved this knowledge, and enhanced the\nconcept of trials which is at the core of the scientific approach used today. Once\na remedy was identified, either based on plants, animals, metals and\/or\nminerals, its efficiency and toxicity was tested. Then, the administrated\nremedy could be either a simple diet, a simple drug based on plants, minerals\nand metals, or a mixture of one or more of the aforementioned (Figure 4) <\/em>[74,75].<\/p>\n\n\n\n

Ibn Sina extensively studied the nature and qualities of simple drugs in vol. 2 of the Canon<\/em>. He then set rules to respect in the drug development process. This  remained the basis of testing drugs <\/sup>[74]:<\/p>\n\n\n\n

The drug must be cleaned from any foreign substances\/impurities.<\/p>\n\n\n\n

Drugs must be tested on two different diseases to be sure of the effects. <\/p>\n\n\n\n

The mechanism of action must be evaluated.<\/p>\n\n\n\n

The drug must be tested on animals and then on human, to prove their efficacy.<\/p>\n\n\n\n

Altogether, the Arab physicians developed a scientific method based on experimentation, evidence-based knowledge, clinical trials, animal and\/or human trials, concepts that are also found in the contemporary scientific method.<\/p>\n\n\n\n\n\n
\"\"<\/td>\n\n

Figure <\/strong>1:<\/strong> A timeline of the evolution of antibiotic resistance.<\/strong><\/p>\n

<\/p>\n

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Figure 2: A map of the Arab Empire in Medieval times. The name of famous scientists cited in the text, the time and place of birth are provided.<\/strong><\/p>\n

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Figure 3: Illustration of the preparation of a remedy. Folio from a dispersed manuscript of an Arabic translation of the Materia Medica of Dioscorides [56,82].<\/strong><\/p>\n

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Figure 4: Drug development process during the Arab medieval age, adapted from [74,83].<\/strong><\/p>\n

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Conclusions – Perspectives<\/strong><\/p>\n\n\n\n

Health care systems\nhave always been deeply embedded in economic, religious, and societal beliefs,\nand are therefore the reflection of their perspective eras. When the era is\nreligious, an inter-relationship between medicine and belief is widely found, through\ndifferent forms, disturbing the perception and relevance of the medical and pharmacological\nadvances of these periods. Nonetheless, these inter-relations did not prevent\nthe rational development of medicine. All great civilizations developed a\nwisdom, an art of health and healing that is, empirically solid with proofs of\neffectiveness. It is this rationality that encourages to re-investigate ancient\npractices and pharmacopeias. Modern technological advances may enable to\nre-exploit these ancient remedies more easily [76\u201378]. <\/p>\n\n\n\n

The greatest benefit\nof history is its ability to integrate past and present knowledge to improve\nfuture understanding. Since ancient times, plants, insects, animals, minerals, turned\nout to be an exceptional source of bioactive molecules: they have already\nprovided humans with new first-class remedies [79]. In comparison to\nisolated ingredients, these pharmacopeias provide remedies with synergistic\ncombination of action. These remedies have enhanced therapeutic effects through\nthe combination of ingredients that would be of little medicinal interest if\nisolated. These studies are nevertheless complex and require the establishment\nof important interdisciplinary networks, including history, biology, chemistry and\npharmacology. Recognition of these networks and the valorization of their added\nvalue remain a challenge.<\/p>\n\n\n\n

The Arabic Golden Age\nwas an important period in the history of ancient medicines and paved the\nfoundations for a modern scientific approach. Their knowledge largely inspired\nWestern medicine from the Middle Ages to the Renaissance. The numerous\nmanuscripts found allowed to collect a large amount of information on medical\npractices and pharmacopeias, and to follow these practices in time and space.\nBy focusing mainly on remedies preserved over a wide geographical or temporal\nscale, ingredients of interest with the highest potential may be selected.<\/p>\n\n\n\n

This approach is well\nsuited for the search of antibacterial solutions, in the context of bacterial\nresistance to antibiotics. Infections were a daily concern in the Middle Ages,\nand the solutions proposed were numerous: we thus have access to a vast\nrepertoire of potential solutions. These ancient pharmacopeias contain a vast\narray of information on both innovative molecules and synergistic strategies\nmaking it more difficult for bacteria to develop resistance, while potentially\nreducing the impact on the surrounding microbiota (bactericidal molecules taken\nindividually being less deleterious). Thus, history holds a vast repertoire of\nremedies that might lead to medical innovation. In addition, some ancient\nremedies preserved throughout history, are still utilized today in the\ntraditional Arab pharmacopeia. If their efficacy could be validated\nhistorically and by using today’s scientific methodology, they could even be adopted\nin the context of integrated healthcare. \n<\/p>\n\n\n\n

Medical systems are constantly evolving. Novel medical systems are introduced when an old is challenged. This evolution often results in an interweaving of innovations and old practices, although the integration of ancient practices usually comes with parsimony or defiance [80]. This has always been the case, and is still true today, a time when we are witnessing a crisis in health care related to inadequate delivery and adaptation to changing patient expectations. This crisis amplifies the growing demand for complementary and alternative medicines, which have their origins in ancient and\/or traditional practices. This is reflected in the growing number of patients (over 70% according to the WHO) who are already turning to these practices. Despite the complementarity between modern and traditional medicines, it is their connection that seems to be problematic today. The differences in the way health and pathology are defined, studied and perceived, could also be at the source of the difficulties in uniting them. Therefore, it is imperative to study the cultures and societies that laid the foundations of ancient medicine [81]. Characterizing the scientific approach by which medicine and pharmacopeias were developed, and understanding how the different health systems have intertwined with each other over time could help to rationalize the debate, and ultimately, why not, lay the foundations for a modern conception of a common medicine ?<\/p>\n\n\n\n

Acknowledgments<\/strong><\/p>\n\n\n\n

We would like to thank Cody\nBowens for critical reading of the manuscript and Mutale Joan Chanda for her diligent\nproofreading of the manuscript<\/em>.<\/p>\n\n\n\n

Conflict of Interest<\/strong><\/p>\n\n\n\n

The authors declare no conflict of interest<\/p>\n\n\n\n

Funding Sources<\/strong><\/p>\n\n\n\n

This project was financially supported by the French Ministry of Europe and Foreign Affairs, Ministry of Higher Education, Research and Innovation and the French Institute of Rabat (PHC TOUBKAL 2019, Grant Number: 41520SE; PHC MAGHREB 2022 Grant No 47455NH; by the University of Strasbourg (projet Interdisciplinaire – Emergence) Grant Number CF\/PN\/CB\/N\u00b02017-974-3<\/em>, and by the program METALLO-MIX of CNRS – Grant Number 21887. B. Abdallah was financed by the Mascir Foundation (Rabat), and by the PHC TOUBKAL<\/em>. <\/p>\n\n\n\n

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