Hydrazone-Tethered 5-(Pyridin-4-yl)-4H-1,2,4-triazole-3-thiol Hybrids: Synthesis, Characterisation, in silico ADME Studies, and in†vitro Antimycobacterial Evaluation and Cytotoxicity.

Compounds containing arylpyrrole-, 1,2,4-triazole- and hydrazone structural frameworks have been widely studied and demonstrated to exhibit a wide range of pharmacological properties. Herein, an exploratory series of new 1,2,4-triazole derivatives designed by amalgamation of arylpyrrole and 1,2,4-triazole structural units via a hydrazone linkage is reported. The synthesised compounds were tested in vitro for their potential activity against Mycobacterium tuberculosis (MTB) H37 Rv strain. The most promising compound 13 - the derivative without the benzene ring appended to the pyrrole unit displayed acceptable activity (MIC90 =3.99 µM) against MTB H37 Rv, while other compounds from the series exhibited modest to weak antimycobacterial activity with MIC90 values in the range between 7.0 and >125 µM. Furthermore, in silico results, predicated using the SwissADME web tool, show that the prepared compounds display desirable ADME profile with parameters within acceptable range.

Synthesis, Structure and In Vitro Anti-Trypanosomal Activity of Non-Toxic Arylpyrrole-Based Chalcone Derivatives.

With an intention of identifying chalcone derivatives exhibiting anti-protozoal activity, a cohort of relatively unexplored arylpyrrole-based chalcone derivatives were synthesized in moderate to good yields. The resultant compounds were evaluated in vitro for their potential activity against a cultured Trypanosoma brucei brucei 427 strain. Several compounds displayed mostly modest in vitro anti-trypanosomal activity with compounds 10e and 10h emerging as active candidates with IC50 values of 4.09 and 5.11 µM, respectively. More importantly, a concomitant assessment of their activity against a human cervix adenocarcinoma (HeLa) cell line revealed that these compounds are non-toxic.

Toward a representation format for sharable clinical guidelines.

Clinical guidelines are being developed for the purpose of reducing medical errors and unjustified variations in medical practice, and for basing medical practice on evidence. Encoding guidelines in a computer-interpretable format and integrating them with the electronic medical record can enable delivery of patient-specific recommendations when and where needed. Since great effort must be expended in developing high-quality guidelines, and in making them computer-interpretable, it is highly desirable to be able to share computer-interpretable guidelines (CIGs) among institutions. Adoption of a common format for representing CIGs is one approach to sharing. Factors that need to be considered in creating a format for sharable CIGs include (i) the scope of guidelines and their intended applications, (ii) the method of delivery of the recommendations, and (iii) the environment, consisting of the practice setting and the information system in which the guidelines will be applied. Several investigators have proposed solutions that improve the sharability of CIGs and, more generally, of medical knowledge. These approaches can be useful in the development of a format for sharable CIGs. Challenges in sharing CIGs also include the need to extend the traditional framework for disseminating guidelines to enable them to be integrated into practice. These extensions include processes for (i) local adaptation of recommendations encoded in shared generic guidelines and (ii) integration of guidelines into the institutional information systems.

Finding appropriate clinical trials: evaluating encoded eligibility criteria with incomplete data.

We describe our work on creating a system that selects appropriate clinical trials by automating the evaluation of eligibility criteria. We developed a data model of eligibility for breast cancer clinical trials, upon which the criteria were encoded. Standard vocabularies are utilized to represent concepts used in the system, and retrieve their hierarchical relationships. The system incorporates Bayesian networks to handle missing patient information. Protocols are ranked by the belief that the patient is eligible for each of them. In a preliminary evaluation, we found good agreement (kappa 0.86) between the system and an independent physician in selection of protocols, but poor agreement (kappa 0.24) in protocol ranking. We conclude that our approach is feasible, and potentially useful in assisting both physicians and patients in the task of selecting appropriate trials.

Using features of Arden Syntax with object-oriented medical data models for guideline modeling.

Computer-interpretable guidelines (CIGs) can deliver patient-specific decision support at the point of care. CIGs base their recommendations on eligibility and decision criteria that relate medical concepts to patient data. CIG models use expression languages for specifying these criteria, and define models for medical data to which the expressions can refer. In developing version 3 of the GuideLine Interchange Format (GLIF3), we used existing standards as the medical data model and expression language. We investigated the object-oriented HL7 Reference Information Model (RIM) as a default data model. We developed an expression language, called GEL, based on Arden Syntax's logic grammar. Together with other GLIF constructs, GEL reconciles incompatibilities between the data models of Arden Syntax and the HL7 RIM. These incompatibilities include Arden's lack of support for complex data types and time intervals, and the mismatch between Arden's single primary time and multiple time attributes of the HL7 RIM.

TraumaSCAN: assessing penetrating trauma with geometric and probabilistic reasoning.

This paper presents TraumaSCAN, a prototype computer system for assessing the effects of penetrating trauma to the chest and abdomen. TraumaSCAN combines geometric reasoning about potentially injured anatomic structures with (probabilistic) diagnostic reasoning about the consequences of these injuries. We also present results obtained from testing TraumaSCAN retrospectively on 26 actual gunshot wound cases.

GLIF3: the evolution of a guideline representation format.

The Guideline Interchange Format (GLIF) is a language for structured representation of guidelines. It was developed to facilitate sharing clinical guidelines. GLIF version 2 enabled modeling a guideline as a flowchart of structured steps, representing clinical actions and decisions. However, the attributes of structured constructs were defined as text strings that could not be parsed, and such guidelines could not be used for computer-based execution that requires automatic inference. GLIF3 is a new version of GLIF designed to support computer-based execution. GLIF3 builds upon the framework set by GLIF2 but augments it by introducing several new constructs and extending GLIF2 constructs to allow a more formal definition of decision criteria, action specifications and patient data. GLIF3 enables guideline encoding at three levels: a conceptual flowchart, a computable specification that can be verified for logical consistency and completeness, and an implementable specification that can be incorporated into particular institutional information systems.

Probabilistic predictions of penetrating injury to anatomic structures.

This paper presents an interactive 3D graphical system which allows the user to visualize different bullet path hypotheses and stab wound paths and computes the probability that an anatomical structure associated with a given penetration path is injured. Probabilities can help to identify those anatomical structures which have potentially critical damage from penetrating trauma and differentiate these from structures that are not seriously injured.

Simulated casualties and medics for emergency training.

The MediSim system extends virtual environment technology to allow medical personnel to interact with and train on simulated casualties. The casualty model employs a three-dimensional animated human body that displays appropriate physical and behavioral responses to injury and/or treatment. Medical corpsmen behaviors were developed to allow the actions of simulated medical personnel to conform to both military practice and medical protocols during patient assessment and stabilization. A trainee may initiate medic actions through a mouse and menu interface; a VR interface has also been created by Stansfield's research group at Sandia National Labs.

Generating penetration path hypotheses for decision support in multiple trauma.

We present a 3D graphical system that allows users to visualize different penetration path hypotheses for (multiple) gunshot or stab wounds, using a 3D graphical model of a human body with appropriate anatomical structures. The system also identifies the anatomical structures associated with each hypothesis. The various penetration path hypotheses follow from a combinatorial analysis of the set of surface wounds. The affected structures are determined by performing a detailed interpenetration analysis between 3D models of a penetration path and each anatomical structure within the body.

Factors influencing the duration of isometamidium chloride (Samorin) prophylaxis against experimental challenge with metacyclic forms of Trypanosoma congolense.

The duration of a single isometamidium chloride (Samorin) prophylactic treatment against Trypanosoma congolense ILNat. 3.1 and T. congolense IL 285 was examined in 24 Boran steers with regard to (1) the dose of drug, (2) the level of metacyclic challenge and (3) the influence of infection with an unrelated serodeme at the time of treatment. The cattle were repeatedly challenged at monthly intervals between 2 and 7 months following treatment, either by five infected Glossina morsitans centralis or by intradermal inoculation of 5 X 10(3) or 5 X 10(5) in vitro-derived metacyclic trypanosomes. A dose of 1 mg kg-1 afforded complete protection for 4 months and 0.5 mg kg-1 for 3 months against the two T. congolense serodemes examined, irrespective of the method or weight of challenge. In another group of cattle, which had an established infection at the time of treatment, the duration of chemoprophylaxis against an unrelated serodeme was the same as the other groups which had no previous experience of trypanosome infection. Antibodies to metacyclics did not appear in any of the cattle as long as the chemoprophylaxis was effective. An exception to this was the group challenged with 5 X 10(5) in vitro-derived metacyclic parasites, in which low antibody titres were detected. In all cases these proved to be non-protective. It was concluded that, under the experimental conditions employed, (1) there was a direct relationship between drug dosage and the duration of chemoprophylaxis, (2) the weight of metacyclic challenge did not affect the duration of chemoprophylaxis and (3) when used to treat an existing infection, isometamidium chloride exerted the same degree of chemoprophylactic activity.

Reasons for failure of antihypertensive treatment.

One hundred patients whose hypertension was originally well controlled were carefully screened when a routine clinic visit showed that their blood pressure was above 170/100 mm Hg. Simple misconceptions accounted for 75 failures: 38 did not know they had to continue their drugs, 14 thought they should not take antihypertensive drugs if they had not had a meal, 13 did not know which drugs controlled their blood pressure, and 10 believed it was better not to take their drugs on clinic days. Eleven patients were using racemic alpha-methyldopa, which was ineffective; 11 others said they could not afford the drugs; only three intentionally stopped their drugs because of unpleasant side effects. Patients need to be thoroughly informed about their treatment and the number of drugs kept to a minimum.

Clinical trial of bacampicillin in acute bacterial infections.

A clinical trial of bacampicillin was carried out in 20 patients. The antibiotic was found to be effective in acute lobar pneumonia, pyogenic meningitis, acute and chronic bronchitis, acute pharyngitis, acute tonsillitis, cellulitis, furunculosis, and pyomyositis caused by such ampicillin-sensitive organisms as Neisseria meningitidis, Diplococcus pneumoniae, Staphylococcus aureus, Haemophilus influenzae, Streptococcus pyogenes, Klebsiella pneumoniae, and Escherichia coli. Rash in three patients was the only side effect encountered. It is concluded that while bacampicillin may have overcome some of the disadvantages of ampicillin, it retains its main attributes and some shortcomings.

"Timolol in essential hypertension" a preliminary report.

A study of a new beta-adrenergic blocking drug TIMOLOL (Blocadren) in the treatment of essential hypertension has been undertaken. Twelve hypertensive patients previously undiagnosed and untreated were studied. Results with a twice a day dose of the drug showed a satisfactory fall in systolic and diastolic pressures in all but one patient, who was withdrawn from the trial because of excessive bradycardia. Apart from bradycardia, no serious side effects were observed in the patients. Observation over longer period is advocated to determine the place of Timolol in our antihypertensive armamentorium.