How adverse drug reactions can play a role in innovative drug research

We describe how adverse drug reactions (ADRs) can play an important role in pharmaceutical research and drug development. Not only do ADRs represent the risks and drawbacks associated with drugs but they can also be related to other knowledge available in pharmaceutical and medical research. We offer a model that can be used to systematically map the pathways through which ADRs can lead to innovative research. These pathways include chemical, therapeutic or pathophysiological steps that can be taken to arrive at new knowledge based on ADRs. We used the development of angiotensin-converting enzyme inhibitors, especially captopril, as a case study. The similarity between the ADR profiles of captopril and penicillamine was a starting point for further innovation. Historical analysis shows that in several instances research in the field of angiotensin-converting enzyme inhibitors has been triggered by ADRs. The model presented here might be applicable to other areas of innovative drug research.     

Demonstration of synergistic effects of hyperthermia and photodynamic therapy using the chick chorioallantoic membrane model.

The chick chorioallantoic membrane (CAM) model was used to study vascular effects of photodynamic therapy (PDT) and hyperthermia (HPT) and the synergism of these modalities. The CAM is a convenient medium for monitoring the modifications of the vasculature. It is possible to view the CAM and to examine structural changes of individual blood vessels in real time. Moreover, the CAM is a closed system which lends itself to mathematical modeling of the temporal and spatial temperature profile and in which HPT can be performed quantitatively and to a selected depth, using different lasers. A porphyrin-type photosensitizer solution was applied to areas of the CAM, defined by teflon O-rings placed on the surface. Uptake dynamics of the sensitizer into the CAM was determined by analyzing its fluorescence in vivo. The CAM area was irradiated with a dual-wavelength laser system composed of a dye laser at 644 nm (to induce PDT) and a CO2 laser at 10.6 microns (to bring about HPT). Damage to the CAM vasculature, due to combined PDT+HPT, was compared to the outcome of the separate modalities, and a synergistic effect of about 40% was observed.     

Pulmonary Function in Survivors of Wilms' Tumor

The respiratory status of 47 patients surviving childhood Wilms' tumor was studied. The group that had receivedflnnk irradiation (which impinges on the lower lung) (n - 17) had a sisnijGantly lower mean percent predicted for forced expiratory volume in one second, residual volume, and total lung capaci(v when compared to those who had received no irradiation (n - 23). Those patients who had received whole-lung irradiation (n - 3) had sisnijicantly lower transfn. foctor for carbon monoxide and gas transfer per unit lung volume whm compared to the nonirradiated group (n - 23). There was no sipiftiant dimue in the prevalence of respiratory symptoms between the three groups. Patients receiving any form of radiotherapy for Wilms' tumor may have abnormulities o f pulmonary function and should have pulmonary function tests performed as part o f their long-tmn follow-up.     

Neurobehavioral effects among subjects exposed to high static and gradient magnetic fields from a 1.5 Tesla magnetic resonance imaging system--a case-crossover pilot study.

The interactive use of magnetic resonance imaging (MRI) techniques is increasing in operating theaters. A study was performed on 17 male company volunteers to assess the neurobehavioral effects of exposure to magnetic fields from a 1.5 Tesla MRI system. The subjects' neurobehavioral performances on a neurobehavioral test battery were compared in four 1-hr sessions with and without exposure to magnetic fields, and with and without additional movements. Adverse effects were found for hand coordination (-4%, P < 0.05; Pursuit Aiming II) and near visual contrast sensitivity (-16% and -15%, P < 0.10; Vistech 6000). The results from the remaining tests were inconclusive due to a strong learning effect. No additional effect from gradient fields was detected. The results indicate that working near a 1.5 Tesla MRI system may lead to neurobehavioral effects. Further research is recommended, especially in members of operating teams using interactive MRI systems.     

Cough and converting enzyme inhibitors

Persisting cough developed in three children treated with converting enzyme inhibitors. The symptoms disappeared within 3–7 days after withdrawing medication. These observations in children complement previous reports in adults and indicate that cough may be induced by treatment with these agents.     

Quantitation of T2′ anisotropic effects on magnetic resonance bone mineral density measurement

In this paper, the authors quantitate the anisotropy of susceptibility effects in an uniaxial trabecular bone model and show its relevance to clinical MR bone mineral density measurements. A physical model is described that quantitates the anisotropic MR behavior of uniaxial trabecular bone. To test the model, a phantom of parallel polyethylene filaments was scanned every 15° between 0° and 90° with respect to the system's main magnetic field (B₀). The distal radial metaphysis of a healthy female volunteer was scanned in orthogonal projections. The signal from each phantom image and each radial image was separated in a pixel-wise fashion into R₂ and R₂′ maps. As predicted, R₂′ relaxation showed anisotropic behavior and changed according to sin² (?), confirming that columnar structures parallel with B₀ will cause no MR susceptibility effects. Scans of the distal radius showed that R₂′ relaxation was twice as great with the forearm perpendicular to B₀ as when it was parallel to it, demonstrating different contributions from struts and columns. For both phantom and radial bone scans, R₂ relaxation was isotropic and did not change with object orientation.     

Controlling for occasion-specific effects when assessing the test–retest reliability of self-report health questionnaires

OBJECTIVE: This study proposes a method for self-report health questionnaires to adjust test-retest reliability for changes during the test-retest interval based on an external measure, and to distinguish such changes from random response errors. METHODS: In our application, eighty participants completed the Symptoms of Illness Checklist (SIC) on two occasions, two weeks apart, immediately before interviews given on each occasion by one of two physicians in a crossover design. The physician interview scores served as external measures, and structural equation modeling was used to estimate the parameters of a model that corrected for the occasion-specific effect of participants' responses using information from the interviews. RESULTS: Correcting for changes in symptoms during the test-retest interval increased SIC test-retest reliability from .744 to .804 and significantly improved model fit (chi2(diff)(1) = 30.78, p < .001). CONCLUSIONS: The results suggest methods that can improve the evaluation of self-report health questionnaire test-retest reliability by identifying changes using an external measure, and distinguishing these from random response errors; these increased the estimated SIC test-retest reliability and indicated that the SIC was indeed able to measure changes over the studied time interval. This method can be applied across a broad range of questionnaires.     

Eye movement quantitative evaluation before and after high-dose 6-methylprednisolone in multiple sclerosis

We studied saccadic and smooth pursuit eye movements in 24 patients suffering from multiple sclerosis during disease worsening, before and after high-dose 6-methylprednisolone infusions. Quantitative evaluation of saccades was based on amplitude/duration and amplitude/peak velocity relationships, precision (i.e. the ratio of actual to desired saccade amplitude) and the latency, whereas smooth pursuit eye movements were studied using target velocity/performance index relationship. At basal recordings, 22/24 (91.7%) of the patients showed at lest one abnormality. Eleven of the 24 patients (45.8%) showed modification of one or several parameters: improvement in 6 patients, worsening in 2, coexistence of both trends in 3. Latency improvement was the only significant modification when patients were considered as a group. Neurophysiological modifications did not correspond to clinical changes.     

The Testes in Cadmium Intoxication: Morphological and vascular aspects

Cadmium toxicity was tested on young male Wistar rats by injecting 1 mg/ml of cadmium chloride (CdCl2) intra-peritoneally. Post-mortem examination was done 4 hours, 24 hours and 14 days after cadmium administration to observe time-sequence cadmium-induced alterations in vascular permeability of the mesothelium in the pleura, peritoneum and tunica vaginals. This paper mainly reports the alterations observed in the testes. Vascular permeability was assessed by the colloidal carbon technique. Vascular labelling was evidenced as early as 4 hours after CdCl2, injection; 24 hours later severe oedema with leakage of particles to the interstitium and also into the tubules was patent. Fourteen days after CdCl2 administration atrophy of the testes with necrosis of the tubules, fibrosis of the interstitium and vascular thrombosis was found, compatible with chemical castration.