TECHNOLOGY OF MEDICINES AND GALENICAL PREPARATIONS: THE CASE OF PRESCRIPTION FORMULASFROM “ANTIDOTARIUM” NICOLAI BY NICHOLAS OF SALERNO

Introduction. This study deals with the problem of similarity of the principles and approaches of drug technologies in the medieval manuscript “Antidotarium Nicolai” by Nicholas of Salerno with modern pharmaceutical technologies.The aim of study is a textual investigation of “Antidotarium Nicolai”, a detailed research of the content of the manuscript, recipes and technologies for making medicines.Materials and methods. In order to achieve this goal, eighty-five recipes of “Antidotarium Nicolai” have been identified, systematized and analyzed in a documentary translation from medieval French. An interdisciplinary study of the content of the manuscript was carried out with the help of factor analysis of the historical source and modern scientific literature.Results and discussion. Having described the content and aspects of the prescriptions of “Antidotarium Nicolai”, the authors note the similarity of the technologies of drugs and galenical preparations with modern pharmaceutical technology, in particular, with the technology of pharmacy production. In “Antidotarium Nicolai” it is stated that preparations based on herbal medicinal raw materials may be second-line therapy agents for completing treatment after the application of basic pharmacological preparations.Conclusion. The results of this work reveal the potential for the use of herbal medicines in the conditions of modern evidence-based medicine, in particular, in the organization of long-term treatment and secondary prevention of chronic diseases in patients who need to maintain their ability to work, and provide them with a sufficiently high level of quality of life. A detailed translation of the full text of the manuscript, the analysis of its content in accordance with the requirements of rational pharmacotherapy and phytotherapy, further favors to identify the prospects for the development of new drugs, multi-component in their chemical composition with a wide range of therapeutic effects.

Несмотря на большое количество переизданий, наиболее важными являются переводы «Антидотария» на средневековый английский, средневековый французский и голландский языки.На сегодняшний день основной интерес представляет перевод манускрипта на средневековый французский язык.В научном сообществе принято считать, что французский язык наиболее близок к латыни, но не к «классической», а скорее «деревенской» -lingua romana rustica, обозначающий романский (французский) язык [4,5].Ввиду того, что оригинал был написан на средневековой латыни, данная лингвистическая форма ближе к первоначальному языку рукописи.Таким образом, за основу была взята работа Paul Dorveaux (1851-1938 гг.).Издание, вышедшее в 1896 г., называлось «L'antidotaire Nicolas.Deux traductions françaises de l'Antidotarium Nicolai.L'une du XIVè siècle suivie de quelques recettes de la même époque et d'un glossaire.L'autre du XVè siècle incomplète.Publiées d'après les manuscrits français 25327 et 14827 de la Bibliothèque nationale».Автор, являясь французским историком и врачом, восстановил 85 прописей на средневековом французском языке.Для сравнения, в наиболее ран-achieve this goal, eighty-five recipes of "Antidotarium Nicolai" have been identified, systematized and analyzed in a documentary translation from medieval French.An interdisciplinary study of the content of the manuscript was carried out with the help of factor analysis of the historical source and modern scientific literature.Results and discussion.Having described the content and aspects of the prescriptions of "Antidotarium Nicolai", the authors note the similarity of the technologies of drugs and galenical preparations with modern pharmaceutical technology, in particular, with the technology of pharmacy production.In "Antidotarium Nicolai" it is stated that preparations based on herbal medicinal raw materials may be second-line therapy agents for completing treatment after the application of basic pharmacological preparations.Conclusion.The results of this work reveal the potential for the use of herbal medicines in the conditions of modern evidence-based medicine, in particular, in the organization of long-term treatment and secondary prevention of chronic diseases in patients who need to maintain their ability to work, and provide them with a sufficiently high level of quality of life.A detailed translation of the full text of the manuscript, the analysis of its content in accordance with the requirements of rational pharmacotherapy and phytotherapy, further favors to identify the prospects for the development of new drugs, multi-component in their chemical composition with a wide range of therapeutic effects.

INTRODUCTION.
The technology of medicines, as a basic part of pharmaceutical science, has a fundamental impact on medicine and public health in general.Tracing its history from the ancient times, it has been modified under the influence of evolutionary factors and regional characteristics of medical schools.A vivid example of that was Medieval Europe, where a kind of fusion of medical knowledge, accumulated by the West and the East, occurred.The evidence of this interpenetration was the manuscript "Antidotarium Nicolai" by master Nicholas of Salerno, also known as Nicolaus Salernitanus.This manuscript was the main pharmacopeia of the entire medieval world [1].Nowadays, the relevance of this worklies in studying the technologies of manufacturing drugs according to "Antidotarium Nicolai" recipes, based on the prescriptions translated into Russian, as well as the study of their practical potential for modern health care.Thus, by means of studying the prescriptions Фармация и фармакология Т. 6 № 4, 2018 История фармации и фармакологии history of pharmacy and pharmacology of the manuscript, our AIM is to compare the medieval technology of manufacturing medicines and galenical preparations with modern principles of pharmaceutical technology.
MATERIALS AND METHODS.To achieve this goal, eighty-five recipes from "Antidotarium Nicolai" by Nicholas of Salerno were identified, systematized and analyzed in a documentary translation from medieval French.The comparison of the source corpus with the historiographical material on the technology of medicines, made it possible to create an inter disciplinary study of "Antidotarium Nicolai".It gave us the opportunity to highlight the dominant idea of the problem under study.The hypothesis of the study is the thesis of the similarity of the principles and approaches to the production of medicines according to the prescription formulas of "Antidotarium Nicolai", created by master Nicholas of Salerno, with modern pharmaceutical technologies.
RESULTS.To consider the medieval technology of making medicines and galenical preparations, a translation of "Antidotarium Nicolai", also known as "Small Antidotarium", was carried out.This manuscript was based on "Great Antidotarium" and was developed in Salerno Medical Schoolby Master Nicholas.According to long-term works of Professor Vladimir Fedorovich Semenchenko, Doctor of Pharmaceutical Sciences, "Antidotarium Nicolai" was compiled by Nicholas, the rector of Salerno Medical School, in 1140 [2].Karl Sudhoff, a German physician and scholar in the field of medicine history, brought the mention of the manuscript into correlation with 1100-thyearin his work [3].Thus, "Antidotarium Nicolai" refers to the Greek-Arabic period of the development of Salerno Medical School.
The manuscript is extremely large-scale: ancient Greek, Roman, Eastern knowledge is collected and systematized in it [3]."Antidotarium Nicolai" had such a great impact on the development of pharmacy and medicine in general, that it was used until the XVII century, when official regional pharmacopoeia began to appear everywhere.
Despite a large number of republications, the most important are translations into medieval English, medieval French and Dutch.Nowadays, the translation of the manuscript into medieval French is of primary concern.In the scientific community, the French language is considered closest to Latin, though not to the "classic", but rather "rural" -lingua romana rustica, denoting the Romance (French) language [4,5].In view of the fact that the original was written in Medieval Latin, this linguistic form is closer to the original language of the manuscript.Thus, the work published in 1896 by Paul Dorveaux (1851-1938), known as "L'antidotaire Nicolas.Deux traductions françaises de l'Antidotarium Nicolai.L'une du XIVè siècle suivie de quelques recettes de la même époque et d'un glossaire.L'autre du XVè siècle incomplète.Publiées d'après les manuscrits français 25327 et 14827 de la Bibliothèque nationale", was taken as a basis.
The author, being a French historician and physician, restored 85 prescriptions in medieval French.For comparison, the earliest copy of "Antidotarium Nicolai" describes 119 prescription formulas.That copy is dated to the second half of the XII-th century and nowadays it is stored in the National Library of Great Britain [6].This difference is due to the fact, that the translation by Paul Dorveaux was based on the different edition of "Antidotarium Nicolai", more likely published in the XIV-th century.All the prescription formulas presented in "Antidotarium Nicolai", have an identical structure.At the beginning, a definition ofamedicinal preparationis given, followed then by examples of its medical application, often accompanied by a universal phrase "It is suitable for... ".For example, the seventh prescription, "Antidotum Emagogum", determines that the medicine "cleanses the uterus, and is given against many problems in women after childbirth".Alternatively, the forty-third prescription is defined as "Metridatum -the mother of all antidotes, suitable for pain in the head, in the ears, in the teeth and in the palate, that gradually beginning and grow".Such definitions of the pharmacodynamics properties of medicines helped a "master" to select the necessary tool to treat each specific case.
Further, the recipes contain "Designatio materiarum" (also known as "Orginatio"), the enumeration of all the substances that are necessary to prepare a medicinal preparation.This part of the recipe is extremely important, since the composition of the drug depends on it, and, as a consequence, the effects of the drug.After the word "Pren.",which is a medieval French analogue of the modern "Recipe", all the ingredients that are included in the drug are listed.It should be noted, that this part of the recipe could have a very small number of components.For example, in the fifty-seventh recipe "Quadrumeron" that was used "for asthma, silence, with fever and weakness of the kidneys", only four ingredients were used: Inula helenium, Foeniculum officinale, Pepper, Cuminum cyminum.However, some of the prescriptions, like the twenty-ninth recipe for "Esdra", suitable "for melancholy, fear and poor appetite", contain ninety-one ingredients, necessary for the preparation of the medicine.Probably, this phenomenon was associated with special indications for the use of a drug, intended for the treatment of mental and behavioral disorders.
The fact that all the medicinal substances listed in the manuscript of "Antidotarium Nicolai" entries were indicated without abbreviations, but in the usual sequence, was of no less importance.In modern pharmaceutical technology, when listing ingredients, it is generally accepted to write each substance in a separate line with a capital letter.The capital letter in "Antidotarium Nicolai" marked only the beginning of a new recipe.This factor is interesting because usually substances are prescribed in order of their importance.First, the main substance is indicated, and then the auxiliary substances (known as adjuvans) are prescribed.It is quite difficult to distinguish the main active substance in the recipes of "Antidotarium Nicolai" for a number of reasons, such as, e.g., the variability of the substances used.Some of the substances acted as fillers that gave medicinal substances definite DOI: 10.19163/2307-9266-2018-6-4-389-397 forms (constituents), other substances corrected flavor and smell (corrigens).It is worth mentioning that in the manuscript, thirty-two recipes of medicinal preparations were completed with the addition of honey.Honey served as a preservative for the prepared medicines, saving them from the appearance of unpleasant taste, smell, mold and the formation of toxins of microbial origin.In the introduction of the manuscript, Nicholas of Salerno high tighted a special place for honey: "To save them is to keep them in the clean honey, and have enough of it for preservation of spices and drugs; the honey can be cooked together with spices, to purify it, and to remove the bitterness".
After the listed groups of medicinal substances, a precise indication in the weight units was given, or in other words, a dosage.It is necessary to notify, that it was in "Antidotarium Nicolai", that the pharmaceutical units of measurement were unified, and clear characteristics and definitions of the grain, drachma, ounces, and pound were given.Later on, these Salern pharmaceutical measures of weights spread worldwide and became known as Nuremberg weights [7].The basis of the system of measures in "Antidotarium Nicolai" is a "drachma" -the weight unit in alchemy and pharmacy, corresponding to approximately 3 grams and 82 centigrams.The second weight unit by frequency of use was "ounce".Its first mention was found in fifth recipe "Alcancalon", used "against acute fever".One "ounce" approximately corresponded to 30 grams.One "pound", mentioned in the manuscript, was equal to 12 "ounces".Later, in Paris, "pound" became equal to 14 "ounces".Taking into account the correspondence of "ounce" to 30 grams, it can be determined that one "pound" was equal to 360 grams (approximately 94 "drachmas").A "grain had the smallest weight", that was equal to 53 milligrams (1/72 "drachma").In "Antidotarium Nicolai" there are references to unusual measures of weights, such as "Solid" (from the Latin word "solidus" -solid, strong, massive)."Solid" is a Roman gold coin, issued in 309 AD by Emperor Constantine.One coin weighed 1/72 of the Roman "pound", or 4.55 grams, and was used to determine the amount of substances in the preparation of certain soft dosage forms.The presented system of units of measurement, unified by Nicholas of Salerno, allowed "Antidotarium Nicolai" to become a more precise and practical tool for the production of medicines.Defining specific doses of pharmaceutical substances, Nicholas sought to minimize negligence in the preparation of drugs and their admission.
An interesting feature of "Antidotarium Nicolai" is the section called "prescription", or "signature" ("Praescriptio", or "Subscriptio").In this part of the recipe it was indicated how to prepare the necessary dosage and what technological operations were necessary to be done in the process of creating a drug.In order to describe the entire complex of medicinal forms of "Antidotarium Nicolai", the authors suggested using of the classification by the aggregate state, proposed by Julius Karlovich Trapp (1814-1908), the Russian pharmacist and pharma-cologist, as the most convenient classification.According to this classification, all forms of drugs can be divided into four groups [8].The correlation of "Antidotarium Nicolai" with the proposed classification allows identifying the following groups of drug forms: • solid dosage forms (lozenges, granules); • liquid dosage forms (solutions, suspensions, infusions and decoctions, syrups, mixtures, medical oils, aromatic waters); • soft medicinal forms (electuaries, ointments, patches, pills).The descriptions of the technologies were not present in every prescription.They often began with the phrase "It is prepared as...".The technologies were accompanied by detailed instructions that indicated the stages of preparation.In particular, the following stages were clearly described: • preparation and grinding of raw materials; • the order of adding and mixing the ingredients; • infusion and boiling under certain conditions; • mixing, filtering through a sieve and pressing raw materials; • dissolution of medicinal substances; • determination of readiness, by placing a drop of solution on the marble, and further identifying the stickiness; • time and place to storage the prepared means.Thus, the indicated manufacturing technologies were extremely detailed and elaborated.In combination with the use of a clear system of units of measurement, the possibility of error or misinterpretation was eliminated in the preparation of even the most complex medicines.Nowadays, this technology of making medicines is considered relatively simple [8].
The final part of a prescription in "Antidotarium Nicolai" was a signature ("Signatura").As it is known, the content of this fragment was often intended for a patient himself, since it is had a scheme of drug administration.A signature was always as detailed as possible, and the dosage, frequency and time for taking the medicine were indicated.It is interesting that in the twenty-sixth prescription of "Antidotarium Nicolai" it was recommended to take medicines with wine: such as warm wine, white wine, sweet wine, or wine with sage.For example, in the twelfth prescription "Diamargariton", which was prescribed "for pain of the heart and stomach", the drug was supposed to be taken "in the summer with water, and in winter with wine".The fifty-first prescription, "Pigra Galieni", that "suitable for chills in the head, stomach pain and stomach upsets and vomiting", and was intended to be taken in the bathtubs, along with warm wine.Some of the medicines were recommended to be used only along with hot herbal teas, or with herbal decoctions, or with cold or warm water, or with syrups or candied ginger.According to "Antidotarium Nicolai", the transformation of the drug in the body (pharmacokinetics) and the mechanism of action of the drug on the body (pharmacodynamics) depended on the choice of fluid for admission.

История фармации и фармакологии history of pharmacy and pharmacology
The fact that one of the most often mentioned dosages of the drug is "in the amount or weight of a single fruit of Chestnut" is also note worthy.The weight of a fruit of chestnut can vary from 10 to 25 grams, depending on the variety, which is an extremely wide range in the dosage, especially with such a complex composition of the medicines.Never the less, such weight units were much more accurate, than simple dosing.In addition to the "fruits of chestnut", some of the drugs were dosed quite differently.Some medicines were given in a strict amount of "drachmas", some by a certain number of pills, others by the number of spoons at one time, or even subjected to inhalation.For soft dosage forms, such as ointments, even the necessity to apply in special conditions -in sunlight or in heat -was indicated.
It is impossible not to mention another whole range of ways of using medicines in "Antidotarium Nicolai".Nicholas from Salerno specified that certain medications should be taken after meals, and some "on an empty stomach".The medication was administered at allotted time (in the morning and / or in the evening, and sometimes at night) and, as a rule, for the specified period.For example, the twenty-fourth prescription, "Diacastoreum","suitable for pain in the head and infirmities", was used only in the morning, and only for three days.Such clear instructions on taking medicines made "Antidotarium Nicolai" an extremely demanded book, both in medical practice and in the training of specialists of that time.It is no coincidence that "Antidotarium Nicolai" was widely in demand in many medieval universities, including Oxford and Cambridge, and was part of the compulsory reading for a degree in medicine [9].
In the signatures of some prescription formulas, a possibility of adding other substances to the recipe was taken into consideration.Some of them were necessary to expand the application of the final product, or possibly to eliminate or minimize side effects.Thus, the addition of two drachmas of Convolvulus scammonia to "Yerapigra" (that was used "from various sufferings of the head, ears, stomach and liver") added a strong laxative effect.However, in these additions to the signatures the clearness of the dosage of the components could be no longer observed.It can be assumed, that these remarks did not belong to Nicholas himself, but were added by the editors and commentators of the manuscript later [3].
DISCUSSION.Having described the content and technological aspects of the medicines in "Antidotarium Nicolai" it can be noted that the principles and approaches to the manufacture of drug sare similar to modern pharmaceutical technology, in particular the apothecary technology of drugs.This direction of pharmaceutical technology in England, France, and Holland is called "Galenic pharmacy" or "prescription art" [8].The core of this discipline, as in the Middle Ages, is based on working with "official" prescriptions, prepared according to standardized and approved recipes.The modern format of the recipes has been preserved practically unchanged, including sections similar to "Antidotarium Nicolai", such as those indicated in the Latin language: treatment, enumeration of medicinal substances, dosing and recommendation.Additionally introduced sections are devoted to the legal meaning of the prescription, in particular to the name of the treatment and prophylactic institution, the name of the attending physician assuming responsibility for the correctness of the appointment, and the patient's name.
However, the technology of drugs, in particular galenical preparations, has undergone certain changes, which formed a modern subgroup of neogalenical preparations.This subgroup represents similar extracts from the medicinal plant raw materials, but maximally released from "ballast" substances [8].Such substances are excessive for this type of drugs, negatively affecting the effectiveness and, as a consequence, the success of therapy.Such cleaning is carried out as carefully as possible, without the use of strong chemicals or high-heat processes, allowing the active substances to maintain their original natural state.Thus, nowadays,"galenical" preparations find their logical continuation in the form of neogalenical formulations.Similar in complexity, these groups of medicines have a certain advantages over synthetic chemical preparations [10].The use of drugs based on herbal medicines is often safer for treatment, than the use of synthetic drugs.Thus, in many countries, there is an increasing interest in medicines of natural origin, due to the peculiarities of the chemical composition of preparations of natural origin, the components of which are close in structure to the metabolites of the human body, and the relative safety of their use.This factor allows us to recommend these drugs much more often than synthetic drugs for symptomatic, preventive treatment or overthe-counter treatment.
CONCLUSION.Extemporaneous manufacturing since the Middle Ages to the present time remains a popular pharmaceutical service.Production pharmacies are a socially significant indicator of the quality of drug provision and care for a wide range of citizens.Nowadays most modern compounding pharmacies are producing dosage forms, widely represented in "Antidotarium Nicolai".Despite the multicomponent composition that affects the therapeutic effect and the cost of the manufactured product, some of the prescriptions have an available manufacturing technology that can be reproduced in the conditions of modern manufacturing pharmacies.With regard to the therapeutic aspect, it must be pointed out that galenical preparations can be second-line therapy to complete treatment after the use of essential medicines.This is especially important with long-term treatment and secondary prevention of chronic diseases.Thus, in "Antidotarium Nicolai" by Nicholas of Salerno, there is a certain potential that deserves a detailed translation and analysis in accordance with the realities of rational pharmacotherapy and herbal medicine.