Preclinical Toxicology Studies with Acyclovir: Genetic Toxicity Tests

Preclinical Toxicology Studies with Acyclovir: Genetic ToxicityTests. Clive, D., Turner, N.T., Hozier, J., Batson, A.G. andTucker, W.E., Jr. (1983). Fundam. Appl. Toxicol 3: 587–602.Acyclovir (ACV), an antiviral drug active in the treatment oforal and genital Herpes infections, has been evaluated for mutagenicand carcinogenic potential in a battery of in vitro and in vivoshort-termassays. Negative results were obtained in the following in vitrotests: Ames Salmonella, plate incorporation and preincubationmodification assays; E. coli polA⁺/polA^– DNA repair; yeast(S. cerevisiae D4) gene conversion; Chinese hamster ovary cells(HGPRT, APRT loci and ouabain-resistance marker); L5178 Y mouselymphoma cells (HGPRT locus and ouabain-resistance marker);and C3H/10Tmouse fibroblast neo-plastic transformation assay.All except the last assay were performed in the presence andabsence of an exogenous metabolic activation system. ACV waspositive at high concentrations x exposure times in the absenceof exogenous metabolic activation in the following in vitrosystems and at the indicated concentrations: BALB/c-3T3 neoplastictransformation (50 /µg/mL, 72 h exposure); human lymphocytecytogenetics (250–500 µg/mL, 48 h exposure); andL5178Y mouse lymphoma cells (TK locus, 400–2400 µg/mL,4 h exposure; predominantly small colony mutants of chromosomalorigin produced). No effects were seen in vivo (mouse dominantlethal assay; rat and Chinese hamster bone marrow cytogenetics)at up to maximum tolerated doses (MTD). An unusual clastogeniceffect was seen in Chinese hamsters at 5 times the MTD. Overall,positive effects were seen only at either high concentrations(250 µg/mL in vitro or plasma levels) or prolonged exposure(72 hr in the BALB/ c-3T3 neoplastic transformation assay).These studies support the view that ACV is a chromosomal mutagen,i.e., one which causes multi-locus damage but not single geneeffects. The significance of these results for the genetic riskof ACV to man is discussed.     

Intramedullary Spinal Cord Metastases: A Clinical and Pathological Study of Nine Cases

The clinical and pathological findings In nine cases of intramedullaryspinal cord metastases are reported and are compared with thoseof previous studies. Intramedullary metastases are more commonthan is generally believed and the incidence is probably increasingwith the more prolonged survival of cancer patients. A widespectrum of symptoms and signs may be produced, frequently withattendant diagnostic difficulties. Most patients present withmyelopathy as the first manifestation of cancer or of its recurrence.Symptoms may be present for several months, with few clinicalsigns, despite distortion and destruction of much of the spinalcord by tumour. The extent of metastatic disease remains limitedin a significant proportion of patients. No neurological symptomsor signs differentiate intramedullary metastases clearly fromthe more common extradural deposits. However, the diagnosisshould be considered when myelopathy evolves more slowly, whereplain radiographic evidence of adjacent vertebral disease Isabsent, and particularly when myelography is normal. Early diagnosisand aggressive medical treatment may provide for a more favourableoutcome. ^* Currently Fellow in Neuropathology, The National Hospitalsfor Nervous Diseases, Queens Square, London.     

Degos disease: a new simulator of non-accidental injury

Recent high-profile cases have made paediatricians very aware of the serious implications of either missing or wrongly diagnosing non-accidental injury. Subdural fluid collections in non-mobile infants usually represent haemorrhage caused by non-accidental injury. We report a 6-month-old male who presented to the Accident and Emergency Department of Birmingham Heartlands Hospital with bilateral subdural fluid collections and skin ulcers resembling cigarette burns. Non-accidental injury was considered to be the most likely diagnosis. However, while under observation in hospital, the child's neurological condition deteriorated with progressive cerebral infarctions, and serial photographs of the skin lesions showed failure to heal. The revised diagnosis, confirmed histologically, was Degos disease, an extremely rare and often fatal occlusive vasculopathy. The child was treated palliatively and died 8 weeks after presentation. This report informs doctors of a new simulator of non-accidental injury to be considered in infants with otherwise unexplained subdural fluid collections.     

SURFACE APPEARANCES OF THE ECCRINE SWEAT DUCT BY SCANNING ELECTRON MICROSCOPY

SUMMARY.– Impressions of the skin surface were taken with silicone rubber and secondary positive replicas were made with Araldite. After coating with gold they were examined with the scanning electron microscope. The openings of the sweat ducts were easily seen on the palms and soles, and each of their orifices was patent. The terminal ducts have also been identified on the surface of skin on the limbs and trunk, and the appearances of these ducts is described. By oblique rotation a patent orifice was identified for each sweat duct, and by sequential cellophane tape stripping it was shown that all the sweat ducts were patent throughout their spiral course in the horny layer.     

THE MEASUREMENT OF TRANSEPIDERMAL WATER LOSS

SUMMARY.— Transepidermal water loss has been measured at the equilibrium state, i.e. when it reached a constant value at a particular flow rate of dry gas passing over the skin. Measured in this way, transepidermal water loss from the skin is dependent on the rate of flow of the dry gas and the surface area of skin exposed to the flow. Increases in flow rate of dry gas and reduction in the surface area of skin exposed produce corresponding increases in skin water loss. These changes in skin water loss are believed to be due to changes in ambient water vapour pressure within the measuring system. The results are discussed in relation to the possibility of expressing the transepidermal water loss in absolute terms and of measuring the water content of keratin.     

Temazepam misuse in a group of injecting drug users

It is well recognized that many injecting drug users are poly-drug users. The intravenous use of Temazepam has become popular recently. In response to the ease of misuse, the pharmaceutical industry produced a formulation that would be as ‘resistant’ as possible to injecting. The preparation is a gel-fitted formulation, one proprietary name being Temazepam Gelthix. General Practitioners have been encouraged to prescribe gel-filled capsules to potential drug misusers in order to reduce the harm Temasepam can cause by its misuse. This study of 23 Temazepam injectors shows that the group still find the gel-filled preparation readily injectable. It appears to be more problematic in causing medical complications including superficial thrombophlebitis, abscesses and deep venous thrombosis. Temazepam misuse can cause drug users to become more chaotic. The study group recognize this and suggest there should be stricter control on the supply of Temasepam to drug dependents. General Practitioners, who are the main source of Temazepam prescribing, require additional training in prescribing to drug users.     

Assessment of bleomycin, adriamycin and mitomycin-C in the treatment of recurrent cervical cancer

Summary. Twenty women with recurrent squamous cell carcinoma of the cervix were treated with bleomycin followed by adriamycin and mitomycin-C. Treatment was repeated every 28 days. In 18 patients who could be assessed there was one complete response and five partial responses (response rate 33%). Two partial responses were seen in 13 lesions arising from previously irradiated sites of disease (response rate 23%). Three complete responses and three partial responses were observed in 10 lesions arising from non-previously irradiated sites of disease (response rate 60%). In all responding cases tumour regression was noted before the end of the third cycle of treatment. Toxicity was predictable and manageable. These results suggest that chemotherapy may be used as a cytoreductive procedure before radical local treatment.     

Acidosis Impairs the Protective Role of hERG K+ Channels Against Premature Stimulation

Acidosis and the hERG K⁺ Channel . Introduction: Potassium channels encoded by human ether‐à‐go‐go‐related gene (hERG) underlie the cardiac rapid delayed rectifier K⁺ channel current (I_Kr). Acidosis occurs in a number of pathological situations and modulates a range of ionic currents including I_Kr. The aim of this study was to characterize effects of extracellular acidosis on hERG current (I_hERG), with particular reference to quantifying effects on I_hERG elicited by physiological waveforms and upon the protective role afforded by hERG against premature depolarizing stimuli. Methods and Results: I_hERG recordings were made from hERG‐expressing Chinese Hamster Ovary cells using whole‐cell patch‐clamp at 37°C. I_hERG during action potential (AP) waveforms was rapidly suppressed by reducing external pH from 7.4 to 6.3. Peak repolarizing current and steady state I_hERG activation were shifted by ～+6 mV; maximal I_hERG conductance was reduced. The voltage‐dependence of I_hERG inactivation was little‐altered. Fast and slow time‐constants of I_hERG deactivation were smaller across a range of voltages at pH 6.3 than at pH 7.4, and the contribution of fast deactivation increased. A modest acceleration of the time‐course of recovery of I_hERG from inactivation was observed, but time‐course of activation was unaffected. The amplitude of outward I_hERG transients elicited by premature stimuli following an AP command was significantly decreased at lower pH. Computer simulations showed that after AP repolarization a subthreshold stimulus at pH 7.4 could evoke an AP at pH 6.3. Conclusion: During acidosis the contribution of I_hERG to action potential repolarization is reduced and hERG may be less effective in counteracting proarrhythmogenic depolarizing stimuli. (J Cardiovasc Electrophysiol, Vol. 21, pp. 1160‐1169)