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PubMed1977

[The danger of developing drug dependence in adolescents].

The authors, by reference to a number of patients taking higher-than-prescribed doses of tranquilizers, sedatives, and hypnotics, thus becoming addicted to using them as drugs, describe some of the motivations of juveniles to take drugs. Problems associated with habituation to the use of drugs are discussed from sociological, medical, and psychological points of view. Also, attention is drawn to the fact that disturbed secondary structures in both family and personal life as well as certain primary premorbid psychopathological structures may, in principle, lead to drug addiction. The need for early recognition and prophylaxis is pointed out.

Adolescent↗
PubMed1978

The rate of development of new drugs in the United States, 1963 through 1975.

Information was obtained on 1,103 new chemical entities (NCEs) first tested in man from 1963 through mid-1975 by 36 U. S.-owned and 10 foreign-owned pharmaceutical companies operating in the U. S. Of these NCEs 1,029 reached the stage of IND filing. The portion of the U. S. industry responsible for the NCEs was relatively concentrated; 7 of the 36 companies accounted for half of the NCEs and 4 of these accounted for one-third. Although the annual worldwide rate of testing of NCEs by U. S. companies appeared to rise and then fall from 1963 through 1966, since 1966 the rate has been fairly constant. With time, however, a higher proportion of U. S.-owned NCEs is being first studied in man abroad. The annual rate of IND filings for U. S.-owned NCEs generally declined from 1965 to 1972, whereas the rate was fairly constant for foreign-owned NCEs over the entire period. The overall success rate in drug development has been low; nearly 90% of the NCEs studied in man are dropped prior to NDA submission, but about 88% of the NDAs submitted are approved for market. The 1974-1975 data indicate that the mean durations of the IND and NDA phase were then 4 and 2 years, respectively. However, there were variations in the time required for DNA approval between different pharmacologic areas. The data described in this paper represent the first baselines against which future trends in the processes of drug development and approval can be measured.

Chemistry, Pharmaceutical↗
PubMed1975

Systems approach to vaginal delivery of drugs I: development of in situ vaginal drug absorption procedure.

In the framework of the development of drug delivery systems for locally administered contraceptive drugs, a reliable method that can afford quantitative evaluation of drug absorption behavior was explored using the rabit doe. A system was constructed based upon perfusing the drug solution in the vaginal tract. For this purpose, a "rib-cage" type cell was constructed and surgically implanted in the rabbit prior to an experiment. The primary purpose of the present paper is to evaluate the method, including the surgical operation and the perfusion system. The absorption experiments were carried out using n-butanol-1minus 14C as the model solute to survey the reproducibility of the absorption behavior. Experiments were conducted with a number of rabbits on several successive days to determine the day-to-day and animal-to-animal variations. The drug disappearance in the reservoir followed first-order kinetics from which the apparent permeability coefficient was calculated. The results indicated that a set of experiments may be carried out on a single animal and that the method generally affords rather high precision.

Absorption↗
PubMed1978

Drug research, development and expenditure - what about the future?

Drug research and development today is an undertaking requiring special skills and understanding, formidable financial resources and the closely co-ordinated co-operation of everyone concerned with the drug programme in all its aspects. Incorrect results, wrong deductions or decisions and unrealistic delays due to bureaucratic obstructions, all have an adverse effect in the final analysis. The price (financially and otherwise) we have to pay for the end-product is invariably intimately related to what happened during the entire development process. Everyone connected with drug development, in whatever capacity, has a moral obligation to ensure that the development programme follows a path which is as smooth as possible.

Forecasting↗
PubMed2024

Drug repurposing in status epilepticus.

The treatment of status epilepticus (SE) has changed little in the last 20 years, largely because of the high risks and costs of new drug development for SE. Moreover, SE poses specific challenges to drug development, such as patient diversity, logistical hurdles, and the need for acute treatment strategies that differ from chronic seizure prevention. This has reduced the appetite of industry to develop new drugs in this area. Drug repurposing is an attractive approach to address this unmet need. It offers significant advantages, including reduced development time, lower costs, and higher success rates, compared to novel drug development. Here I demonstrate how novel methods integrating biological knowledge and computational methods can be applied to drug repurposing in status epilepticus. Biological approaches focus on addressing mechanisms underlying drug resistance in SE (using for example ketamine, tacrolimus and safinamide) and longer-term consequences (using for example omaveloxolone, celecoxib and losartan). Additionally, artificial intelligence platforms, such as ChatGPT, can rapidly generate promising drug lists, while in silico methods can analyze gene expression changes to predict molecular targets. Combining AI and in silico approaches has identified several candidate drugs, including metformin, sirolimus and riluzole, for SE treatment. Despite the promise of repurposing, challenges remain, such as intellectual property issues and regulatory barriers. Nonetheless, drug repurposing presents a viable solution to the high costs and slow progress of traditional drug development for SE. This paper is based on a presentation made at the 9th London-Innsbruck Colloquium on Status Epilepticus and Acute Seizures, in April 2024.

Animals↗
PubMed1979

Constraints of drug regulation on the development of new drugs.

A review is given of the various regulations for the preclinical and clinical evaluation of new drugs, their effects on the clearance of new medicines for general use by practising physicians, and their repercussion on industrial drug research. Undoubtedly, extensive and continuously increasing regulatory procedures, which in addition have to be satisfied repeatedly in individual countries, claim an unproportionally high percentage of the industrial capacity for research and development of new drugs, leaving too little for basic research, which is a prerequisite for the discovery of new medicines that are more than just "me too" products. Despite the fact that regulatory language differs from scientific attitude and arguments, the wall of regulations should be neither too thick nor too high to impede research and to hinder the prompt application of important new drugs. Even the most sophisticated and extensive drug regulations cannot prevent the use of drugs which is not indicated, because it is impossible to regulate ignorance. To regulate drugs is necessary, but the governments and their drug agencies should also encourage drug research and should support industry in the development of new drugs. On the other hand, the drug companies must adhere to the accepted standards and create an atmosphere of confidence by presenting reliable and complete data.

Drug Industry↗
PubMed1979

Developing drug-use profiles from drug-charge records.

The potential for developing a drug-use profile from drug-charge records was studied at an 830-bed community hospital. Patient drug charges were reviewed retrospectively for one year (1975) to identify: (1) which key drugs accounted for a high percentage of cost and usage; (2) where key drugs were used within the hospital; (3) how they were used; and (4) who were the chief prescribers. Of the drugs used, 8% accounted for 80% of total drug product costs. Seven drug groups (10% of the total drug groups) appeared in the top 10 of both drug cost and quantity categories. Six individual drugs also appeared in the top 10 of both categories. According to cost, cephalosporin antibiotics were ranked first among drug groups but were sixth according to quantity. Analgesics-antipyretics were ranked first among drug groups by quantity and second by cost. Cephalothin was ranked first among individual drugs by cost and was not in the top 10 in quantity. Diazepam was ranked first among individual drugs by quantity and third by cost. Patients' drug-charge records can be used effectively to generate drug-use profiles for ongoing drug use review, quality assurance and cost containment programs.

California↗
PubMed2026

Dual plasmepsin IX and X inhibitors are refractory to development of resistance.

Artemisinin-based combination therapies (ACTs) remain the cornerstone of malaria treatment, but emerging resistance threatens their efficacy. The potential for the development of drug resistance against plasmepsin X (PMX)-selective inhibitors and dual plasmepsin IX/X (PMIX/X) inhibitors was investigated in Plasmodium falciparum. A series of PMX-selective (WM4, WM76, WM92) and PMIX/X dual inhibitors (WM382, WM09, WM42) were characterised for potency against parasite growth and enzyme inhibition. In vitro selection experiments showed that all compounds had a high barrier to resistance, although parasites with reduced sensitivity to PMX‑selective inhibitors could still be selected. Resistance mechanisms involved pmx gene amplification and point mutations (D245N, S315P, S359P, I363L) that alter inhibitor binding. Recombinant expression and Michaelis-Menten kinetics demonstrated that these mutations impair drug binding whilst preserving PMX catalytic function. Reverse genetics confirmed that introducing these mutations into the pmx gene resulted in decreased potency of the inhibitors. In this study, resistance to the PMIX/X dual inhibitors evaluated here could not be selected, despite prolonged selection pressure. Antimalarial Resistome Barcoding (AReBar) assays confirmed the absence of pre-existing resistance to either inhibitor class. Critically, PMIX/X dual inhibitors maintained efficacy against parasites with decreased sensitivity to PMX-selective compounds. These findings demonstrate that dual PMIX/X inhibitors present a substantially higher barrier to resistance than PMX-selective inhibitors, informing antimalarial drug development strategies and highlighting dual-target inhibition as a promising approach to mitigate resistance risks.

Aspartic Acid Endopeptidases↗