Time Course Of Administration Research Articles

Cannabidiol: A Potential New Alternative for the Treatment of Anxiety, Depression, and Psychotic Disorders.

The potential therapeutic use of some Cannabis sativa plant compounds has been attracting great interest, especially for managing neuropsychiatric disorders due to the relative lack of efficacy of the current treatments. Numerous studies have been carried out using the main phytocannabinoids, tetrahydrocannabinol (THC) and cannabidiol (CBD). CBD displays an interesting pharmacological profile without the potential for becoming a drug of abuse, unlike THC. In this review, we focused on the anxiolytic, antidepressant, and antipsychotic effects of CBD found in animal and human studies. In rodents, results suggest that the effects of CBD depend on the dose, the strain, the administration time course (acute vs. chronic), and the route of administration. In addition, certain key targets have been related with these CBD pharmacological actions, including cannabinoid receptors (CB1r and CB2r), 5-HT1A receptor and neurogenesis factors. Preliminary clinical trials also support the efficacy of CBD as an anxiolytic, antipsychotic, and antidepressant, and more importantly, a positive risk-benefit profile. These promising results support the development of large-scale studies to further evaluate CBD as a potential new drug for the treatment of these psychiatric disorders.

The Effect of Nigella Sativa on Renal Oxidative Injury in Diabetic Rats.

Oxidative stress plays a key role in the evolution of diabetes complications. The current study looked into the potential effects of the hydroalcoholic extract of Nigella sativa on the oxidative injury of the rat kidneys in diabetic animals. The animals were placed into five study groups in a random manner as follows: (1) control, (2) diabetic, (3 and 4) treatment with two doses of N. sativa extract (200 and 400 mg/kg), and (5) treatment with metformin (300 mg/kg). The time course of administration was six weeks. The malondialdehyde (MD A) and total thiol groups, as well as the superoxide dismutase and catalase activities, were also assessed in the renal tissue and lipid profile in serum. In the diabetic groups, the level of MDA significantly increased (P < 0.01) and antioxidant levels decreased compared to the control (P < 0.05). In treated rats with N. sativa, the antioxidant status of renal tissue was improved (P < 0.05 to P < 0.001). The lipid profile also improved in the rats treated with the extract (P < 0.001). Our findings suggest that long-term administration of N. sativa in diabetic rats induced by streptozotocin can improve the status of the oxidative stress in kidney tissue.

Pharmaceutical otoprotection strategies to prevent impulse noise-induced hearing loss.

One of the ongoing challenges for hearing researchers is successful protection of the ear from noise injury. For decades, the most effective methods have been based on modifying the acoustic properties of the noise, either by reducing noise output from various sources, interfering in the acoustic exposure path with environmental controls, or altering the noise dose for the individual with personal hearing protection devices. Because of the inefficiencies of some of the acoustic modification procedures, pharmaceutical otoprotection is targeted at making the cochlea less susceptible to injury. Short-duration, high-level impulse noises, typically caused by small-scale explosions, cause different sets of injuries in the ear than long-duration, low-variance noise exposures. Therefore, the expectation is that the ears exposed to impulse noise may need different pharmaceutical interventions, both in type of compounds used and the time course of administration of the compounds. The current review discusses four different classes of compounds that have been tested as impulse noise otoprotectants. In the process of describing those experiments, particular emphasis is placed on the acoustic properties of the impulses used, with the goal of providing context for evaluating the relevance of these different models to human impulse noise-induced hearing loss.

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

Background/Aims: The onset response to a single tone as measured by electroencephalography (EEG) is diminished in power and synchrony in schizophrenia. Because neural synchrony, particularly at gamma frequencies (30-80 Hz), is hypothesized to be supported by the N-methyl-<smlcap>D</smlcap>-aspartate receptor (NMDAr) system, we tested whether phencyclidine (PCP), an NMDAr antagonist, produced similar deficits to tone stimuli in rats. Methods: Experiment 1 tested the effect of a PCP dose (1.0, 2.5, and 4.5 mg/kg) on response to single tones on intracranial EEG recorded over the auditory cortex in rats. Experiment 2 evaluated the effect of PCP after acute administration of saline or PCP (5 mg/kg), after continuous subchronic administration of saline or PCP (5 mg/kg/day), and after a week of drug cessation. In both experiments, a time-frequency analysis quantified mean power (MP) and phase locking factor (PLF) between 1 and 80 Hz. Event-related potentials (ERPs) were also measured to tones, and EEG spectral power in the absence of auditory stimuli. Results: Acute PCP increased PLF and MP between 10 and 30 Hz, while decreasing MP and PLF between approximately 50 and 70 Hz. Acute PCP produced a dose-dependent broad-band increase in EEG power that extended into gamma range frequencies. There were no consistent effects of subchronic administration on gamma range activity. Acute PCP increased ERP amplitudes for the P16 and N70 components. Conclusions: Findings suggest that acute PCP-induced NMDAr hypofunction has differential effects on neural power and synchrony which vary with dose, time course of administration and EEG frequency. EEG synchrony and power appear to be sensitive translational biomarkers for disrupted NMDAr function, which may contribute to the pathophysiology of schizophrenia and other neuropsychiatric disorders.

The Effects of Naltrexone on Subjective Response to Methamphetamine in a Clinical Sample: a Double-Blind, Placebo-Controlled Laboratory Study.

Methamphetamine (MA) use disorder is a serious psychiatric condition for which there are no FDA-approved medications. Naltrexone (NTX) is an opioid receptor antagonist with demonstrated efficacy, albeit moderate, for the treatment of alcoholism and opioid dependence. Preclinical and clinical studies suggest that NTX may be useful for the treatment of MA use disorder. To inform treatment development, we conducted a double-blind, randomized, crossover, placebo-controlled human laboratory study of NTX. Non-treatment-seeking individuals meeting DSM-IV criteria for MA abuse or dependence (n=30) completed two separate 5-day inpatient stays. During each admission, participants completed testing sessions comprised of MA cue-reactivity and intravenous MA administration (30 mg) after receiving oral NTX (50 mg) or placebo for 4 days. This study tested the hypotheses that NTX would (a) attenuate cue-induced MA craving, and (b) reduce subjective responses to MA administration. Results largely supported the study hypotheses such that (a) NTX significantly blunted cue-induced craving for MA and (b) attenuated several of the hedonic subjective effects of MA, including craving, during controlled MA administration and as compared with placebo. NTX decreased overall subjective ratings of 'crave drug,' 'stimulated,' and 'would like drug access,' decreased the the post-MA administration timecourse of 'anxious' and increased ratings of 'bad drug effects,' as compared with placebo. These findings support a potential mechanism of action by showing that NTX reduced cue-induced craving and subjective responses to MA. This is consistent with positive treatment studies of NTX for amphetamine dependence, as well as ongoing clinical trials for MA.

Does levodopa improve vision in albinism? Results of a randomized, controlled clinical trial

Dopamine is an intermediate product in the biosynthesis of melanin pigment, which is absent or reduced in albinism. Animal research has shown that supplying a precursor to dopamine, levodopa, may improve visual acuity in albinism by enhancing neural networks. This study examines the safety and effectiveness of levodopa on best-corrected visual acuity in human subjects with albinism. Prospective, randomized, placebo-controlled, double-masked clinical trial conducted at the University of Minnesota. Forty-five subjects with albinism. Subjects with albinism were randomly assigned to one of three treatment arms: levodopa 0.76 mg/kg with 25% carbidopa, levodopa 0.51 mg/kg with 25% carbidopa, or placebo and followed for 20 weeks, with best-corrected visual acuity measured at enrollment, and at weeks 5, 10, 15, and 20 after enrollment. Side-effects were recorded with a symptom survey. Blood was drawn for genotyping. Side-effects and best-corrected visual acuity 20 weeks after enrolment. All subjects had at least one mutation found in a gene known to cause albinism. Mean age was 14.5 years (range: 3.5 to 57.8 years). Follow up was 100% and compliance was good. Minor side-effects were reported; there were no serious adverse events. There was no statistically significant improvement in best-corrected visual acuity after 20 weeks with either dose of levodopa. Levodopa, in the doses used in this trial and for the time course of administration, did not improve visual acuity in subjects with albinism.

Evaluation of hepatic damage by reactive metabolites--with consideration of circadian variation of murine hepatic glutathione levels.

Generally, reactive metabolites are detoxified by conjugation with glutathione (GSH). A GSH-depleted model was prepared by administering L-buthionine-(S,R)-sulfoximine (BSO), which can be used to detect hepatic damage by reactive metabolites. However, BSO may cause adverse effects on other organs, such as renal damage by reactive metabolites because it depletes GSH in the whole body. The present study was designed to examine whether it was possible to specifically detect hepatic damage by reactive metabolites without reducing renal GSH levels by administering BSO in a time course when hepatic GSH levels are naturally reduced. Male BALB/c mice were administered reverse osmosis (RO) water or 20 mmol/l BSO in drinking water for 4 days. Subsequently, animals in the RO water group were orally administered 500 mg/kg acetaminophen (APAP) at 9:00 or 15:00 and in the BSO group at 9:00 for 4 days. As a result, severe hepatic damage and necrosis of the renal proximal tubules were observed in the BSO/APAP administration at 9:00 group, and all animals died on 1 or 2 days after APAP administration. Hepatic damage was clearly increased in the RO water/APAP administration at 15:00 group compared with the RO water/APAP administration at 9:00 group. However, renal damage and deaths were not observed. This BSO administration model may detect renal damage induced by reactive metabolites. Using an administration time course, whereby hepatic GSH levels were naturally reduced, hepatic damage by reactive metabolites can be detected without secondary renal effects.

Repeated Intranasal Flumazenil Administration in Adult Subjects During Prolonged Benzodiazepine-induced Sedation

As part of a study exploring the use of oral diazepam to reduce carbon dioxide production and extend survival in a disabled submarine, intranasal flumazenil was used repeatedly over 48 hours to intermittently reverse benzodiazepine-induced sedation in six adult male subjects. Previous reports of intranasal flumazenil have been limited to pediatric pa-tients. Here we report the time course of administration of intranasal flumazenil and its effects on adult subjects, in whom flumazenil was given during sedation/reversal/re-sedation cycles. Sedation scores increased with flumazenil administra-tion in 24 of the 30 cycles, and in 100% of cases when subjects were at deeper levels of sedation.

Longdan Xiegan Tang has immunomodulatory effects on CD4+CD25+ T cells and attenuates pathological signs in MRL/lpr mice

Longdan Xiegan Tang (LXT) is a Chinese herbal medicine that is prescribed as an anti-inflammatory aid, a hepato-protectant, and an immunostimulant. In this study, we examined the biological effects of LXT administration in MRL/lpr mice. MRL/lpr mice provide a good model of systemic lupus erythematosus (SLE). These mice develop immunological disturbances and dysregulation in Th1 and Th2 cytokine production. Female mice were randomly separated into two groups. The experimental group received LXT (250 mg/kg/day, po) from 19 to 21 weeks of age. Splenic CD3+CD4+, CD3+CD8+, and CD4+CD25+ T cells were increased in the LXT-administered mice compared to MRL/lpr controls, and this was associated with splenomegaly. There was a marked reduction in IFN-gamma, TNF-alpha, anti-dsDNA antibody, and there were reduced IgG immune complex deposits in the glomeruli. LXT also restored kidney glutathione levels, thereby limiting the toxic effects of the inflammatory mediators iNOS and COX-2, which are overproduced in MRL/lpr mice. Two-dimensional gel electrophoresis was used to analyze proteome changes. LXT protected MRL/lpr mice against developing the lupus syndrome through up-regulation of phosphoglycerate kinase 1 and down-regulation of ferritin light chain 1, selenium-binding protein 2, and alpha-enolase. This study indicates that LXT at this dose and time course of administration was effective in reducing oxidative stress associated with disease progression in MRL/lpr mice. LXT could be useful as adjunctive therapy for reducing distress in SLE.

Examination of a long-term clozapine administration by high resolution segmental hair analysis

The long-term administration of clozapine could be verified by fine segmentation and analysis of single hairs of one person to examine the history of a multiple poisoning case.Segments of 1–2.5mm length were extracted by ultrasonification in 30μl of the mobile phase (mixture of methanol+water, 50+50). By application of isocratic liquid chromatography and using narrow bore columns (Synergy Polar-RP, Phenomenex), an acceleration and miniaturization of the HPLC–MS–MS assay could be achieved.Total amounts of clozapine down to 30fg (on column) and its desmethyl metabolite could be analysed in multiple reaction monitoring mode. According to typical sample amounts of ∼16μg, relevant hair concentrations higher than 1pg/mg were detected.Significant and reproducible concentration profiles along the hair fibres revealed characteristic administration cycles. The administration time course -in particular the time of its termination—could be verified with a precision of a few days. The accuracy and reproducibility of the concentration profile was proven based on multiple investigations of single hairs. An individual hair growth rate of 0.55mm/day was determined with a relative standard deviation of 8% by comparison of concentration profiles in hairs collected after a time span of 165 days.

Impact of Venlafaxine on Gene Expression Profile in Lymphocytes of the Elderly with Major Depression – Evolution of Antidepressants and the Role of the “Neuro-Immune” System

Antidepressive drugs offer considerable symptomatic relief in mood disorders and, although commonly discovered by screening with single biological targets, most interact with multiple receptors and signaling pathways. Antidepressants require a treatment regimen of several weeks before clinical efficacy is achieved in patient populations. While the biochemical mechanisms underlying the delayed temporal profile remain unclear, molecular adaptations over time are likely involved. The selective serotonin and noradrenaline reuptake inhibitor, venlafaxine, offers a dual antidepressive action. Its pharmacological behavior, however, is unknown at the genetic level, and it is difficult to monitor in human brain samples. Because the hypothalamic-pituitary-adrenal axis is often severely disrupted in mood disorders, lymphocytes may serve as models of neuropsychiatric conditions. As such, we examined the role of venlafaxine on the gene expression profile of human lymphocytes. DNA microarray was used to measure the expression patterns of multiple genes in human lymphocytes from depressed patients treated with this mood stabilizer. In this self-controlled study, RNAs of control and treated samples were purified, converted into cDNA and labeled with either Cy3 or Cy5, mixed and hybridized to DNA microarrays containing human oligonucleotides corresponding to more than 8,000 genes. Genes that were differentially regulated in response to treatment were selected for follow up on the basis on novelty, gene identity, and level of over-expression/repression, and selected transcripts were profiled by real-time PCR (data have been normalized to beta-actin). Using software analysis of the microarray data, a number of transcripts were differentially expressed between control and treated samples, of which only 57 were found to significantly vary with the "P" value of 0.05 or lower as a result of exposure to venlafaxine. Of these, 31 genes were more highly expressed and 26 transcripts were found to be significantly less abundant. Most selected genes were verified with QRT-PCR to alter. As such, independent verification using QRT-PCR demonstrated the reliability of the method. Genes implicated in ionic homeostasis were differentially expressed, as were genes associated with cell survival, neural plasticity, signal transduction, and metabolism. Understanding how gene expression is altered over a clinically relevant time course of administration of venlafaxine may provide insight into the development of antidepressant efficacy as well as the underlying pathology of mood disorders. These changes in lymphocytes are thought to occur in the brain, and a "neuro-immune system" is proposed by this study.

Aging, peripheral nerve injury and nociception: Effects of the antioxidant 16-desmethyltirilazad

Peripheral neuropathies increase with aging, and reactive oxygen species contribute to the symptomatology of neuropathic pain disorders. In this study, we examined age-related differences in the therapeutic efficacy of pre- or post-treatments of the amino-steroidal antioxidant 16-desmethyltirilazad in delaying the onset and/or limiting the duration of tactile-evoked allodynia following the induction of peripheral mononeuropathies in rats. Two different models of nerve injury were utilized to induce allodynia in young and aged rats: (1) the chronic constriction injury (CCI) model of Bennett and Xie [Bennett GJ, Xie Y-K. A peripheral mononeuropathy in rat that produces disorders of pain sensation like those seen in man. Pain 1988;33:87–107]; (2) the partial sciatic nerve ligation (PSNL) model of Seltzer et al. [Seltzer Z, Dubner R, Shir YA. Novel behavioral model of neuropathic pain disorders produced in rats by partial sciatic nerve injury. Pain 1990;43:205–18]. Calibrated von Frey filaments were used to examine changes in paw withdrawal threshold values. The results demonstrated that pre-treating young and aged rats with 16-desmethyltirilazad prior to the induction of peripheral mononeuropathies prevented the onset of neuropathic pain. However, once post-operative tactile allodynia was established, post-treatment therapy was ineffective at reversing the symptoms. These findings support the mediatory role of reactive oxygen species in neuropathic pain disorders, and suggest that the antiallodynic efficacy of antioxidant intervention is dependent on the time course of administration.

Chronic treatment with the thiazolidinedione, MCC-555, is associated with reductions in nitric oxide synthase activity and beta-cell apoptosis in the pancreas of the Zucker Diabetic Fatty rat.

The Zucker Diabetic Fatty (ZDF) rat is a model of impaired insulin sensitivity arising from hyperphagia owing to a mutation in the leptin receptor. In time, young ZDF rats, which are not initially diabetic, develop impaired pancreatic beta-cell function leading to apoptotic cell death. This results in an inability to fully compensate for the reduction in insulin sensitivity with hypersecretion of insulin. Young, pre-diabetic ZDF rats were treated, over a 4-week period, with the thiazolidinedione compound MCC-555, and the islet morphology studied in comparison to ZDF rats not given MCC-555. In particular, changes in the apoptotic incidence, as measured using TUNEL staining to localize apoptotic cells, were studied over the 4-week period. Changes in the induction of nitric oxide synthase and in the accumulation of nitrate/nitrite within the pancreas were also studied during the time course of administration of MCC-555. The study has demonstrated that the administration of MCC-555 significantly decreases the apoptotic incidence in the islets of Langerhans of pre-diabetic ZDF rats given the compound, as compared to those not given MCC-555, as well as decreasing the accumulation of nitrate/nitrite within the pancreas.

Effect of nicotine and nicotinic receptors on anxiety and depression.

Nicotine has been shown to have effects on anxiety and depression in both human and animal studies. These studies suggest that nicotinic acetylcholine receptors (nAChRs) can modulate the function of pathways involved in stress response, anxiety and depression in the normal brain, and that smoking can result in alterations of anxiety level and mood. The effects of nicotine are complex however, and nicotine treatment can be either anxiolytic or anxiogenic depending on the anxiety model tested, the route of nicotine administration and the time course of administration. The paradoxical effects of nicotine on emotionality are likely due to the broad expression of nAChRs throughout the brain, the large number of nAChR subtypes that have been identified and the ability of nicotine treatment to both activate and desensitize nAChRs. Activation of nAChRs has been shown to modulate many systems associated with stress response including stress hormone pathways, monoaminergic transmission and release of classical neurotransmitters throughout the brain. Local administration studies in animals have identified brain areas that may be involved in the anxiogenic and anxiolytic actions of nicotine including the lateral septum, the dorsal raphe nuclei, the mesolimbic dopamine system and the hippocampus. The ensemble of studies to date suggest that under certain conditions nicotine can act as an anxiolytic and an antidepressant, but that following chronic use, adaptations to nicotine can occur resulting in increased anxiety and depression following withdrawal.

Convulsions Induced by Ropivacaine During Interscalene Brachial Plexus Block

Convulsions Induced by Ropivacaine During Interscalene Brachial Plexus Block

Effects of Tetrabenazine on Methamphetamine-Induced Hyperactivity in Mice are Dependent on Order and Time-Course of Administration

The ambulation-increasing effect of methamphetamine (MAP: 2 mg/kg SC) in mice persisted for about 3 h. Tetrabenazine (TBZ: 4 mg/kg SC), a depleter of monoamines from the cytoplasmic pool did not increase ambulation on its own. Pretreatment with TBZ at 1.5 h before administration of MAP inhibited the stimulant effect of MAP. In contrast, combined administration of two drugs resulted in a transient but considerable enhancement of MAPs stimulant effect. Post-MAP treatment with TBZ at 0.5–2 h hardly modified MAPs behavioral effects. In contrast, 3–6 h post-MAP treatment with TBZ induced a transient increase in activity, although the stimulant effect of MAP had already disappeared. The maximum increase in ambulatory stimulation was produced by 4-h post-MAP treatment with TBZ. The inhibitory effect of TBZ pretreatment on MAP-induced hyperactivity, as well as the transient hyperactivity elicited by TBZ when administered along with MAP, or 4 h after MAP, was dose-dependent. Preliminary studies revealed that transient hyperactivity was never produced by combination of GBR-12909 (a selective dopamine reuptake inhibitor) with TBZ or MAP with oxypertine (a selective norepinephrine releaser/depleter), but produced by combination of nialamide (a monoamine oxidase inhibitor) with TBZ. Inhibition of MAPs effects by TBZ pretreatment suggests that enhancement of dopamine release from cytoplasmic pool, and inhibition of dopamine reuptake by MAP, are involved in MAPs acute behavioral effects. Further, the fact that neither TBZ administration following GBR-12909 pretreatment, nor oxypertine treatment following MAP pretreatment, elicited transient hyperactivity suggests that dopamine is involved in hyperactivity elicited by post-MAP treatment with TBZ. It is also suggested that inhibition of monoamine oxidase (MAO) by MAP and dopamine displacement by TBZ may be responsible for the transient stimulation produced by 3–6 h post-MAP treatment with TBZ. It is hypothesized that the MAO inhibitory action of MAP persists after cessation of its acute stimulant effect, possibly up to 6 h after administration.

Importance of Administration Method in High-Dose Anticancer Chemotherapy from Toxicological Standpoint in Rats

We examined death rates in Fisher rats when chemotherapeutic drugs were administered in a prescribed amount by either a single or divided dose. Lower death rates were observed when nimustine hydrochloride (ACNU) was given in a divided dose, or when cyclophosphamide (CY), vindesine sulfate (VDS) or vincristine (VCR) was administered as a single dose. Lower hematological toxicity was observed when ACNU was administered in 2 doses and CY in a single dose. With etoposide, we did not observe any significant difference between the two administration methods. In a combination study with ACNU and VDS, we observed lower toxic death rates when the dose of ACNU was split and VDS was given as a single dose. ACNU-induced death was substantially reduced by syngeneic bone marrow support or granulocyte colony-stimulating factor treatment. Our experiments indicate that the toxicity of the administration of chemotherapeutic agents may be significantly modified by altering the time course of administration. This would hopefully result in reducing the chemotherapy-related mortality associated with high-dose anticancer chemotherapy.

The oxidation of leucine in tumour-bearing rats

Rats bearing the Walker-256 carcinosarcoma showed significant changes in leucine metabolism compared with their non-tumour-bearing controls. After a single intravenous tracer dose of L-[1-14C]leucine in vivo, 14CO2 release by tumour-bearing rats was significantly elevated throughout the time course of administration. In addition, both the clearance and turnover rates of the tracer were significantly enhanced in these animals. Incubation of soleus muscles from control and tumour-bearing rats in the presence of L-[1-14C]leucine revealed an enhanced oxidation of the amino acid in the tumour-bearing group. Tumour tissue slices were also able to oxidize the tracer at a similar rate to that found in soleus muscles from control animals.

Effects of morphine on net water absorption, mucosal adenylate cyclase activity and PGE 2 metabolism in rat intestine

Morphine (10 mg/kg s.c.) was shown to increase net basal water and electrolyte absorption in rat ileum and colon perfused in vivo. These effects were significantly greater in the ileum. Under the same conditions of dosage and time course of administration the activities of relevant mucosal enzymes were studied. Ileal mucosal adenylate cyclase stimulated by prostaglandin E 2 (PGE 2) in vitro was inhibited by morphine pretreatment. Colonic stimulated cyclase activity was unaffected as were basal activities in both regions. Morphine did not alter the activities of enzymes involved in PGE 2 metabolism and is unlikely to act by modulating endogenous PG levels. Transport ATPase activities, were also unchanged in morphine treated animals. These results are discussed in relation to the mechanism of action of morphine on intestinal mucosa.

Cumulative radiation effect part IV. Normalisation of fractionated and continuous therapy — Area and volume correction factors

In three previous papers, a scale of accumulated sub-tolerance radiation damage, the Cumulative Radiation Effect (CRE), was described for fractionated treatment regimes and continuous radiation therapy from both long-lived and short-lived sources. This scale provides a means of assessing and comparing the biological effects of various treatments. In this paper, it is intended to further the scope of application of the CRE-system by describing in detail the normalisation between the assessments of fractionated and continuous therapy. To do this, it is necessary to consider area and volume correction factors, whose roles are to modify the values of uncorrected CREs so that a specific biological effect, regardless of the area or volume treated, is described by a unique value of the corrected CRE. The problem arising when the CRE achieved by a treatment regime is not constant over a volume is briefly discussed and a simple hypothesis is proposed which may stimulate interest in this problem. The establishment of a normalisation procedure between fractionated treatment regimes and continuous radiation therapy, which is the primary aim of this paper, serves to integrate the concept of the CRE into a unified system of assessment of biological damage, so that a unique value of the CRE describes a specific level of biological damage regardless of the area or volume treated, or the time course of administration of the radiation employed.