Therapeutic Dose Range Research Articles

In vivo characterisation of the small-conductance K Ca (SK) channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) as a potential anticonvulsant

Owing to their activation by increased intracellular Ca 2+ levels following burst firing, and the resultant hyperpolarisation and dampening of neuronal excitability, the small-conductance Ca 2+-activated K + (SK Ca) channels have been proposed as a potential target for novel antiepileptic drugs. Indeed, the channel activator 1-ethyl-2-benzimidazolinone (1-EBIO) has been shown to reduce epileptiform activity in vitro. Accordingly, this study has investigated the therapeutic potential of 1-EBIO using a range of in vivo seizure models, and assessed the adverse effect liability with the rotarod and locomotor activity paradigms. To aid benchmarking of 1-EBIO's therapeutic and adverse effect potential, it was tested alongside two currently marketed antiepileptic drugs, phenytoin and levetiracetam. 1-EBIO was found to be effective at reducing seizure incidence in mice following maximal electroshock (ED 50 36.0 mg/kg) as well as increasing the threshold to electrically- and pentylenetetrazole-induced seizures (TID 10s 7.3 and 21.5 mg/kg, respectively). However, results from the mouse rotarod test revealed a strong adverse effect potential within the therapeutic dose range (ID 50 35.6 mg/kg), implying a significantly inferior therapeutic index with respect to the comparator compounds. These results, therefore, support the in vitro data detailing 1-EBIO's reduction of epileptiform activity. However, the use of in vivo models has revealed a significant adverse effect potential within the therapeutic dose range. Nevertheless, given the multiplicity of SK Ca channel subunits and that 1-EBIO has been shown to enhance additional, non-SK Ca carried currents, these findings do not preclude the possibility that more selective enhancers of SK Ca function could prove to be effective as antiepileptic medications.

Retigabine: Chemical Synthesis to Clinical Application

Retigabine [D23129; N-(2-amino-4-(4-fluorobenzylamino)-phenyl)carbamic acid ethyl ester] is an antiepileptic drug with a recently described novel mechanism of action that involves opening of neuronal K(V)7.2-7.5 (formerly KCNQ2-5) voltage-activated K(+) channels. These channels (primarily K(V)7.2/7.3) enable generation of the M-current, a subthreshold K(+) current that serves to stabilize the membrane potential and control neuronal excitability. In this regard, retigabine has been shown to have a broad-spectrum of activity in animal models of electrically-induced (amygdala-kindling, maximal electroshock) and chemically-induced (pentylenetetrazole, picrotoxin, NMDA) epileptic seizures. These encouraging results suggest that retigabine may also prove useful in the treatment of other diseases associated with neuronal hyperexcitability. Neuropathic pain conditions are characterized by pathological changes in sensory pathways, which favor action potential generation and enhanced pain transmission. Although sometimes difficult to treat with conventional analgesics, antiepileptics can relieve some symptoms of neuropathic pain. A number of recent studies have reported that retigabine can relieve pain-like behaviors (hyperalgesia and allodynia) in animal models of neuropathic pain. Neuronal activation within several key structures within the CNS can also be observed in various animal models of anxiety. Moreover, amygdala-kindled rats, which have a lowered threshold for neuronal activation, also display enhanced anxiety-like responses. Retigabine dose-dependently reduces unconditioned anxiety-like behaviors when assessed in the mouse marble burying test and zero maze. Early clinical studies have indicated that retigabine is rapidly absorbed and distributed, and is resistant to first pass metabolism. Tolerability is good in humans when titrated up to its therapeutic dose range (600-1200 mg/day). No tolerance, dependence or withdrawal potential has been reported, although adverse effects can include mild dizziness, headache, nausea and somnolence. Thus, retigabine may prove to be useful in the treatment of a diverse range of disease states in which neuronal hyperexcitability is a common underlying factor.

Evaluation of the Abuse Potential of Pagoclone, a Partial GABAA Agonist

This study assessed the abuse potential of pagoclone, a partial agonist at the gamma-aminobutyric acid type A (GABAA) benzodiazepine receptor site, in healthy recreational drug users. Twenty-three young adults, who reported past recreational use of sedative drugs or alcohol, participated in 4 sessions during which capsules containing pagoclone (doses: 1.2 mg, the higher end of the proposed therapeutic dose range, and 4.8 mg, a 4-fold higher dose), diazepam (dose, 30 mg), or placebo were randomly administered under double-blind conditions. Subjective ratings of mood, drug effects, and psychomotor tests were completed at regular intervals after ingesting the capsules. On most of the standardized measures of abuse potential, pagoclone (dose, 4.8 mg) was rated as being similar to diazepam. Both drugs increased the ratings of good effects and drug liking. However, pagoclone also produced some adverse mood effects that might limit its potential to be used recreationally, and it produced fewer sedativelike effects on some measures. In general, the results with these doses indicate that the abuse potential of pagoclone is similar to that of diazepam, although its profile as a partial agonist suggests that differences between the drugs may emerge at higher doses.

Pharmacokinetic properties of fentanyl effervescent buccal tablets: A phase I, open-label, crossover study of single-dose 100, 200, 400, and 800 μg in healthy adult volunteers

Background: The fentanyl effervescent buccal tablet (FEBT) is designed to enhance the rate and extent of the absorption of fentanyl, an opioid, through the buccal mucosa. Objectives: The purposes of this study were to assess the dose proportionality of FEBT in healthy volunteers over the potential therapeutic dose range (100–800 μg) and characterize the pharmacokinetic (PK) profile of 4 doses (100, 200, 400, and 800 μg) of FEBT. Methods: This Phase I, randomized, open-label, 4-period crossover study was conducted at Radiant Research, Honolulu, Hawaii. Healthy adult volunteers with intolerance to opioids were randomly assigned to receive 1 of 4 single-dose sequences of FEBT: 100, 200, 400, and 800 μg (selected to encompass the anticipated therapeutic dose range), with each successive administration separated by a washout period of ≥7 days. Naltrexone hydrochloride (50-mg tablet) was administered-15 and 3 hours before and 9 hours after FEBT administration to block opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentrations were measured from venous samples obtained over 72 hours after FEBT administration. Early fentanyl exposure was assessed using AUC from time 0 to 0.75 hour (the median T max of the reference dose [100 μg]) (AUC 0-Tmax′). Adverse events (AEs) were monitored and recorded throughout the study by medically qualified personnel. Results: Thirty-two subjects (26 men, 6 women; mean [SD] age, 29.3 [7.2] years [range, 19–44 years]; mean [SD] weight, 74.7 [10.7] kg) were enrolled. Median T was between 35 and 45 minutes after FEBT administration. AUC 0−∞ and C max increased approximately linearly with increasing doses of FEBT. Mean plasma fentanyl concentrations decreased from C max in a biexponential manner at the 100- and 200-μg doses and decreased in a triexponential manner at the 800-μg dose. Despite the triexponential decrease in the mean profile observed with the 400-μg dose, a biexponential decrease was observed in approximately half of the individual profiles. AUC 0−Tmax′ ranged from 0.09 ng · h/mL with the 100-μg dose to 0.52 ng · h/mL with the 800-μg dose. The most commonly reported AEs in the 100-, 200-, 400-, and 800-μg dose groups were as follows: application-site erythema, 3, 3, 4, and 3 subjects, respectively; nausea, 3, 2, 5, and 4 subjects; somnolence, 3, 2, 3, and 2 subjects; and headache, 3, 2, 1, and 4 subjects. None of the AEs were serious. Conclusions: In this study of the dose proportionality of FEBT in healthy volunteers, the PK profile of FEBT was characterized by a high early systemic exposure of fentanyl (0.09–0.52 ng · h/mL). Dose-dependent parameters (C max and AUC) increased in an approximately dose-proportional manner from 100 to 800 μg FEBT.

Potent analgesic effects of a putative sodium channel blocker M58373 on formalin-induced and neuropathic pain in rats

M58373, 4-[2-(4-hydroxy-4-{[ N-(4-isopropoxyphenyl)- N-methylamino]methyl}piperidin-1-yl)ethyl]benzonitrile monohydrochloride, is a novel compound, which has an inhibitory activity on neurotoxin binding to the site 2 of voltage-gated sodium channels. In this study, we investigated the effects of M58373 on substance P release from sensory neurons in vitro and pain behaviors/responses in rats, compared with mexiletine. M58373 (1–10 μM) inhibited veratridine-induced release of substance P from dorsal root ganglion cells. In the formalin test, oral M58373 (0.3–10 mg/kg) reduced the time spent in nociceptive behaviors only in the late phase. In the neuropathic pain model, oral M58373 (1–10 mg/kg) attenuated mechanical allodynia and heat hyperalgesia in the nerve-injured paw without affecting normal responses in the uninjured paw. In contrast, oral mexiletine (10–100 mg/kg) had a narrow therapeutic dose range in both models because of the adverse effects on the central nervous system. These results suggest that M58373 is a favorable prototype for novel anti-neuropathic pain agents.

PII-52Rimonabant pharmacokinetics in healthy and obese subjects

BACKGROUND Rimonabant is the first selective CB1 blocker developed for the management of multiple cardiometabolic risk factors in overweight/obese patients. AIMS To assess the pharmacokinetics (PK) of rimonabant after repeated oral doses in healthy and obese subjects. METHODS PK was assessed in healthy young non-obese males in a randomized, double-blind, placebo-controlled, ascending dose study after 3, 10, 20, 40 and 60 mg once-daily doses for 21 days (N=8 active, 2 placebo/group). PK was assessed in young obese subjects (BMI≥<>30 kg/m2) in an open label study after 20 mg once-daily doses for 21 days (N=8/gender). Blood was sampled after the first and last dose for full PK profiles and at pre-dose on specified days. Plasma was analyzed for rimonabant with a validated LC-MS/MS method. RESULTS Mean (SD) non-compartmental PK parameters of rimonabant on Day 21 are: (See Table) Subjects Dose (mg) N Cmax (ng/mL) tmaxa (h) AUC0–24 (ng.h/mL) t1/2z (h) tssb (days) Healthy 3 8 57.9 (23.1) 1.51 (1.00, 2.00) 665 (323) 210 (132) Healthy 10 8 118 (42.2) 2.01 (1.50, 3.00) 1480 (446) 180 (110) 12.7 (20.2) Healthy 20 8 196 (28.1) 2.00 (1.50, 6.00) 2960 (268) 216 (96.2) Obese 20 16 188 (51.7) 2.00 (1.00, 4.00) 2480 (605) 376 (163) 25.5 (48.9) Healthy 40 8 326 (92.5) 3.00 (2.00, 5.98) 4830 (1360) 193 (73.3) 12.7 (20.2) Healthy 60 8 416 (90.6) 3.50 (1.50, 6.02) 6760 (1560) 151 (59.3) a : median (min, max) b : tss=time to reach steady-state, median (90th percentile). CONCLUSIONS Rimonabant exhibits no major deviation from dose proportionality up to 20 mg (therapeutic dose range), after which there is a less than dose-proportional increase in exposure. Obese subjects have a longer t1/2z (16 days) than non-obese subjects (6 to 9 days) due to a larger peripheral volume of distribution. Gender has no effect on rimonabant PK. Clinical Pharmacology & Therapeutics (2005) 79, P50–P50; doi: 10.1016/j.clpt.2005.12.177

Antipsychotic medication and length of stay at a psychiatric maximum-security unit in Norway (1987–2000)

The aim of this study was to evaluate psychopharmacological treatment and the length of stay (LOS) of patients with schizophrenia in a maximum-security psychiatric unit. Data were collected from the hospital files of 82 consecutively admitted patients with schizophrenia who were both admitted and discharged between the years 1987 and 2000. Psychotropic medication and LOS at the time of discharge were registered. Ninety-five per cent of the patients received antipsychotic medication. Zuclopenthixol was the most frequent medication, given to 43% of the patients. Antipsychotic polypharmacy was found in 20% of the cases. Twenty-seven per cent of the patients were medicated with doses above the recommended therapeutic dose range. During the study period, there was no change in the administration and number of psychotropics, but there was an increase in the dosage of antipsychotics. However, LOS was unchanged during the same time. This supports other findings, which suggest that there is no clinical benefit of higher antipsychotic dosage. It is suggested that an optimized medication practice could yield beneficiary effects, not only for schizophrenic symptoms, but also for violence in schizophrenic patients.

Pregabalin in neuropathic pain: A more “pharmaceutically elegant” gabapentin?

This article reviews the available information on pregabalin, a new anticonvulsant for peripheral neuropathic pain. Pregabalin was provisionally approved by the US Food and Drug Administration in December 2004 and was granted final approval after controlled substance scheduling (Schedule V) by the US Drug Enforcement Agency in August 2005. A MEDLINE search (1986-August 2005) was conducted to identify pertinent studies in the Englishlanguage. The search terms included pregabalin , PD144723, CI-1008, gabapentin , and neuropathic pain . Additional references were obtained from the bibliographies of identified articles. All studies that evaluated any aspect of pregabalin in vitro or in vivo in animals or humans were included, with a focus on data relevant to older adults. In preclinical studies, pregabalin, a structural congener of gabapentin, exhibited antinociceptive activity in animal models of neuropathic and inflammatory pain. Unlike gabapentin, pregabalin was well absorbed (>90%), and its absorption was dose independent. Like gabapentin, pregabalin was predominantly excreted unchanged in the urine (⩾98%). Dosed at SO to 200 mg TID, pregabalin was superior to placebo in relieving pain and improving sleep and health-related quality of life in patients with diabetic peripheral neuropathy and postherpetic neuralgia ( P < 0.001- P < 0.049). No active-controlled trials were available. The most problematic adverse events associated with pregabalin were dizziness and somnolence (21%26%). In the absence of active-controlled clinical trials and geriatric-specific efficacy/tolerability data, theplace of pregabalin in the analgesic armamentarium for the elderly is unclear. Because pregabalin is a Schedule V controlled substance, its utility is not compromised by substantial limitation of access or the need for extra steps in prescribing. However, abuse potential is a consideration, and utilization should be carefully monitored, particularly in patients with a past or current history of substance abuse. The improved pharmacokinetic profile of pregabalin relative to gabapentin is manifested in linear and dose-independent absorption and a narrow therapeutic dosing range. However, pregabalin still requires multiple administrations per day, and daily doses >150 mg/d require dose titration. The relatively high frequency of central nervous system adverse events, particularly dizziness and somnolence, is a concern in the elderly. Time and further experience should clarify the role of this agent.

Primary thyroid cancer after a first tumour in childhood (the Childhood Cancer Survivor Study): a nested case-control study

Survivors of malignant disease in childhood who have had radiotherapy to the head, neck, or upper thorax have an increased risk of subsequent primary thyroid cancer, but the magnitude of risk over the therapeutic dose range has not been well established. We aimed to quantify the long-term risk of thyroid cancer after radiotherapy and chemotherapy. In a nested case-control study, 69 cases with pathologically confirmed thyroid cancer and 265 matched controls without thyroid cancer were identified from 14,054 5-year survivors of cancer during childhood from the Childhood Cancer Survivor Study cohort. Childhood cancers were diagnosed between 1970 and 1986 with cohort follow-up to 2000. Risk of thyroid cancer increased with radiation doses up to 20-29 Gy (odds ratio 9.8 [95% CI 3.2-34.8]). At doses greater than 30 Gy, a fall in the dose-response relation was seen. Both the increased and decreased risks were more pronounced in those diagnosed with a first primary malignant disease before age 10 years than in those older than 10 years. Furthermore, the fall in risk remained when those diagnosed with Hodgkin's lymphoma were excluded. Chemotherapy for the first cancer was not associated with thyroid-cancer risk, and it did not modify the effect of radiotherapy. 29 (42%) cases had a first diagnosis of Hodgkin's lymphoma compared with 49 (19%) controls. 11 (42%) of those who had Hodgkin's lymphoma had subsequent thyroid cancers smaller than 1 cm compared with six (17%) of those who had other types of childhood cancer (p=0.07). The reduction in radiation dose-response for risk of thyroid cancer after childhood exposure to thyroid doses higher than 30 Gy is consistent with a cell-killing effect. Standard long-term follow-up of patients who have had Hodgkin's lymphoma for detection of thyroid cancer should also be undertaken for survivors of any cancer during childhood who received radiotherapy to the thorax or head and neck region.

A Comparison of Brain and Serum Pharmacokinetics of R-Fluoxetine and Racemic Fluoxetine: A 19-F MRS Study

Racemic fluoxetine consists of R- and S-fluoxetine, which are metabolized to R- and S-norfluoxetine, respectively. This study was designed to compare brain levels achieved with R-fluoxetine to those achieved with racemic fluoxetine in healthy subjects using fluorine-19 (19-F) magnetic resonance spectroscopy (MRS). In all, 13 healthy volunteers received study drug for 5 weeks using a dosing schedule designed to achieve steady state for 20 mg/day racemic fluoxetine, 80 mg/day R-fluoxetine, or 120 mg/day R-fluoxetine. The resulting brain drug levels were measured using 19-F MRS. At 5 weeks, the racemate, 80 and 120 mg/day R-fluoxetine groups had mean brain levels of 25.5, 34.9, and 41.4 microM, respectively. In the serum, R-norfluoxetine, which is thought to be an inactive metabolite, accounted for 17, 71, and 63% of the fluoxetine/norfluoxetine concentration, respectively. When the relative proportion of active to total species in serum are taken into account, the data suggest that doses of R-fluoxetine greater than 120 mg/day would be needed to achieve brain levels of active drug comparable to 20 mg/day of racemate. The 120 mg/day R-fluoxetine group experienced a mean increase in QTc interval of 44 ms, with one individual having an increase of 89 ms, which suggests that higher doses may not be tolerable. While these data support the use of MRS to aid in defining the therapeutic dose range for drug development, they also highlight the need for additional studies with concurrent animal models to establish the validity of using serum drug/metabolite ratios to interpret MRS determined brain drug levels.

Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects

Studies of novel centrally acting drugs in healthy volunteers are traditionally concerned with kinetics and tolerability, but useful information may also be obtained from biomarkers of clinical endpoints. This paper provides a systematic overview of CNS-tests used with SSRIs in healthy subjects. A useful biomarker should meet the following requirements: a consistent response across studies and drugs; a clear response of the biomarker to a therapeutic dose; a dose-response relationship; a plausible relationship between biomarker, pharmacology and pathogenesis. These criteria were applied to all individual tests found in studies of selective serotonin reuptake inhibitors (SSRIs), performed in healthy subjects since 1966, identified with a systematic MedLine search. Separate databases were created to evaluate the effects of single or multiple dose SSRI-studies, and for amitriptyline whenever the original report included this antidepressant as a positive control. Doses of the antidepressant were divided into high- and low-dose ranges, relative to a medium range of therapeutic doses. For each test, the drug effects were scored as statistically significant impairment/decrease (-), improvement/increase (+) or no change (=) relative to placebo. 56 single dose studies and 22 multiple dose studies were identified, investigating the effects of 13 different SSRIs on 171 variants of neuropsychological tests, which could be clustered into seven neuropsychological domains. Low single doses of SSRIs generally stimulated tests of attention and memory. High doses tended to impair visual/auditory and visuomotor systems and subjective performance, while showing an acceleration in motor function. The most pronounced effects were observed using tests that measure flicker discrimination (improvement at low doses: 75%, medium doses: 40%, high doses: 43% of studies); REM sleep (inconsistent decrease after medium doses, decrease in 83% of studies after high doses); and EEG recordings, predominantly in alpha (decrease in 60% and 43% of studies after low and medium doses, respectively) and in theta activity (increase in 43% and 33% of studies after medium and high doses, respectively). Amitriptyline generally impaired central nervous system (CNS) functions, which increased with doses. Multiple doses caused less pronounced effects on the reported tests. The most responsive tests to amitriptyline appeared to be EEG alpha and theta, and REM sleep duration. SSRIs in healthy subjects appear to cause slight stimulating effects after low doses, which tend to diminish with dose. The most consistent effects were observed with flicker discrimination tests, EEG (alpha and beta bands), REM sleep duration, and subjective effects at higher doses. These effects are small compared with amitriptyline and other CNS-active drugs. Multiple dosing with SSRIs caused even fewer measurable differences from placebo, probably due to adaptive processes. SSRI-effects are best detected with a test battery that is sensitive to general CNS-stimulation, but such tests only comprise a very small portion of the close to 200 different methods that were found in current review.

Table of Content 5

Topiramate (TPM) is a novel neurotherapeutic agent currently indicated for the treatment of epilepsy and undergoing development for other central nervous system indications including neuropathic pain, bipolar disorder, and migraine prophylaxis. TPM is synthesized from d-fructose and contains a sulfamate moiety that is essential for its pharmacologic activity. TPM has been observed to significantly reduce body weight in patients treated for seizure, which has prompted the realization of preclinical studies to characterize the effects of TPM in the regulation of energy balance. Studies carried out in various strains of rats have provided good evidence for the ability of TPM to blunt energy deposition. Body composition analyses from rat trials have demonstrated that TPM inhibits fat deposition while reducing the activity of lipoprotein lipase (LPL) in various white adipose tissue depots. High doses of TPM (likely above the therapeutic dose range) have also been observed to reduce protein gain without catabolic effects. Although TPM cannot be described as a potent anorectic agent, it seems to have the ability to reduce food intake; significant reductions in food intake have been observed in female obese (fa/fa) Zucker rats and in female Wistar rats. TPM can also reduce energy deposition in the absence of alterations in food intake. This effect has been clearly emphasized in female lean (Fa/?) Zucker rats. In female Sprague–Dawley rats, TPM also increased energy expenditure and it has been observed to increase LPL activity in brown adipose tissue, which could indicate that TPM has the ability to enhance regulatory thermogenesis. In addition, TPM stimulates LPL activity in skeletal muscles, further emphasizing its potential to promote substrate oxidation. The mechanisms whereby TPM affects the regulation of energy balance have yet to be understood. TPM represents an antiepileptic drug (AED) with complex biochemical/pharmacologic actions. Its negative effects on energy deposition cannot be readily predicted from these actions, as AEDs are generally expected to stimulate body weight gain. Recent data, obtained from investigations aimed at assessing the effects of TPM on neuropeptidergic systems involved in the regulation of energy balance, have failed to demonstrate any significant effects of TPM on the neuropeptide Y and proopiomelanocortin systems. In conclusion, it is clear that TPM can reduce fat deposition by either reducing food intake or stimulating energy expenditure. The mechanisms whereby an AED such as TPM controls food intake and energy expenditure remains to be delineated.©1999 ASCRS and ESCRS

Effect of UVB radiation emitted from the narrowband TL‐01 lamp (311 nm) on the calcitriol synthesis in organotypic cultures of keratinocytes

The skin is the only tissue yet known in which the complete UVB‐induced pathway from 7‐dehydrocholesterol (7‐DHC) to hormonally active calcitriol (1α,25‐dihydroxyvitamin D3) occurs under physiological conditions. It is well known that both calcitriol and UVB radiation exert potent antipsoriatic effects. We speculate that the therapeutic effect of UVB radiation can be attributed to UVB‐triggered cutaneous synthesis of calcitriol for which the optimum wavelength was a range of 300 ± 3 nm in vitro and in vivo. On the other hand, the narrowband Philips TL‐01 lamp which is commonly used as UVB source for therapeutical treatment of psoriasis, has a maximum spectral irradiance at around 311 nm. The aim of this study was to investigate the calcitriol‐inducing potential of the TL‐01 lamp in organotypic cultures of keratinocytes supplemented with 25 μM 7‐DHC at different radiant exposures (125–1000 mJ/cm2). We found that the maximum calcitriol‐generating capacity of the TL‐01 lamp at 500 mJ/cm2(corresponding to 2.1 SED [Standard Erythema Dose]) and 16 h after irradiation still amounts to approximately 45 percent of that of monochromatic radiation at 300 nm and 30 mJ/cm2. We conclude from our findings that irradiation with the narrowband TL‐01 lamp in therapeutic dose range can affect calcitriol synthesis in epidermal keratinocytes. Thus, the antipsoriatic effect observed after TL‐01 lamp exposures may be, at least partially, explained by the known action of newly‐synthesized calcitriol on the epidermal cell proliferation and differentiation.

Determining Triage Guidelines for Unintentional Overdoses with Calcium Channel Antagonists

Background. Calcium channel antagonists (CCAs) are known to cause significant toxicity in overdose. Determining triage guidelines for CCAs is an important but difficult task. This study was designed to determine if an unintentional overdose of a patient's CCA could result in clinically significant cardiovascular (CV) symptoms (hypotension, bradycardia, conduction disturbances). Methods. Poison center records over a 3-year period were reviewed for adults ingesting at least double their prescribed dose of CCAs and who were evaluated in an emergency department (ED). Cases were reviewed for: patient age and gender, co-ingestants, CCA involved, dosage form, dose taken, usual dose, symptoms, available vital signs, and medical outcomes. Results. 225 cases were identified; 161 cases met study criteria. There were 51 cases involving co-ingestants and 13 in which the usual dose was unknown. These were excluded. One hundred twenty-two patients (76%) were female and the mean age of all patients was 64 years. One hundred and four (65%) cases involved ingestions equal to double the usual dose (DD), 57 (35%) involved more than a DD. For DD cases, nine (9%) developed clinically significant CV signs or symptoms; while in cases with more than DD, eight (14%) did. Conclusions. This retrospective review demonstrated that the toxicity of CCAs following a therapeutic overdose can be highly variable and that the dose producing a toxic effect on the cardiovascular system may be within the maximum range of therapeutic doses. This may be the result of a number of factors, including the broad range of therapeutic doses as well as the pre-existing conditions in patients taking these medications. This variability makes home management of these cases difficult and therefore, poison centers should be conservative in their evaluation of these cases.

Dose escalation trial designs based on a molecularly targeted endpoint

Traditional phase I dose-finding studies for chemotoxic agents base dose escalation on toxicity, with escalation continuing until unacceptable toxicity is observed. Recent development of molecularly targeted agents that have little or no toxicity in the therapeutic dose range has raised questions over the best study designs for phase I studies. Two types of designs are proposed and evaluated in this paper. In these designs, escalation is based on a binary response that indicates whether or not the agent has had the desired effect on the molecular target. One design is developed to ensure that if the true target response rate is low there will be a high probability of escalating and if the true target response rate is high there will be a low probability of escalating. The other design is developed to continue to escalate as long as the true response rate is increasing and to stop escalating when the response rate plateaus or decreases. A limited simulation study is performed and the designs are compared with respect to the dose level at the end of escalation and the number of patients treated on study.

Medicines and psychoactive agents in traffic users—the medico-legal problem in Poland

The increasing number of traffic accidents connected with rapid development of motorization makes us think of their causes. Regulations by law binding in Poland demand traffic users to be checked up on the presence of agents similar ethyl alcohol. Commonly abused medicines, especially sedative and psychotropic but also hypnotic and analgesic are a great traffic problem. Up to the present analytical procedures and a model medico-legal opinion on the influence of medicines on psychophysical efficiency have not been standardised. In the paper the authors have presented the results of their research on agents negatively influencing the human psychophysical efficiency carried out in the Forensic Medicine Department, Silesian University of Medicine, Katowice. The research comprised individuals involved in both traffic crashes and accidents who (as checked) either where not under the influence of ethyl alcohol or the concentration of ethanol was low (1‰). Positive cases most often showed only one sort of medicines (barbiturates, benzodiazepines or opiates). In other cases barbiturates and benzodiazepines, benzodiazepines and opiates as well as derivatives of benzodiazepine and tricyclic antidepressants were determined. Blood concentrations of all these substances were in a wide range of therapeutic doses.

Pharmacokinetics of Proton Pump Inhibitors in Children

The use of proton pump inhibitors (PPIs) has become widespread in children and infants for the management of paediatric acid-related disease. Pharmacokinetic profiles of only omeprazole and lansoprazole have been well characterised in children over 2 years of age with acid-related diseases. Few data have been recently published regarding the pharmacokinetics of pantoprazole in children, and none are available for rabeprazole or esomeprazole. The metabolism of PPI enantiomers has never been studied in the paediatric population. A one-compartment model best describes the pharmacokinetic behaviour of omeprazole, lansoprazole and pantoprazole in children, with important interindividual variability for each pharmacokinetic parameter. Like adults, PPIs are rapidly absorbed in children following oral administration; the mean time to reach maximum plasma concentration varies from 1 to 3 hours. Since these agents are acid labile, their oral formulations consist of capsules containing enteric-coated granules. No liquid formulation is available for any of the PPIs. Thus, for those patients unable to swallow capsules, extemporaneous liquid preparations for omeprazole and lansoprazole have been reported; however, neither the absolute nor the relative bioavailabilities of these oral formulations have been studied in children. Intravenous formulations are available for omeprazole (in Europe), lansoprazole and pantoprazole. PPIs are rapidly metabolised in children, with short elimination half-lives of around 1 hour, similar to that reported for adults. All PPIs are extensively metabolised by the liver, primarily by cytochrome P450 (CYP) isoforms CYP2C19 and CYP3A4, to inactive metabolites, with little unchanged drug excreted in the urine. Similar to that seen in adults, the absolute bioavailability of omeprazole increases with repeated dosing in children; this phenomenon is thought to be due to a combination of decreased first-pass elimination and reduced systemic clearance. The apparent clearance (CL/F) of omeprazole, lansoprazole and pantoprazole appears to be faster for children than for adults. A higher metabolic capacity in children as well as differences in the extent of PPI bioavailability are most likely responsible for this finding. This may partly account for the need in children for variable and sometimes considerably greater doses of PPIs, on a per kilogram basis, than for adults to achieve similar plasma concentrations. Furthermore, no studies have been able to demonstrate a statistically significant correlation between age and pharmacokinetic parameters among children. Despite the small number of very young infants studied, there is some evidence for reduced PPI metabolism in newborns. The limited paediatric data regarding the impact of CYP2C19 genetic polymorphism on PPI metabolism are similar to those reported for adults, with poor metabolisers having 6- to 10-fold higher area under the concentration-time curve values compared with extensive metabolisers. Finally, because a pharmacokinetic/pharmacodynamic relationship exists for PPIs, the significant interindividual variability in their disposition may partly explain the wide range of therapeutic doses used in children. Further studies are needed to better define the pharmacokinetics of PPIs in children <2 years of age.

Pharmacokinetics and Dose Proportionality of Fentanyl Effervescent Buccal Tablets in Healthy Volunteers

Fentanyl effervescent buccal tablets (FEBT) are designed to enhance the rate and efficiency of fentanyl absorption through the buccal mucosa. This study was undertaken to characterise the pharmacokinetics and assess the dose proportionality of FEBT in healthy volunteers within the potential therapeutic dose range. Twenty-five healthy adults (mean age 33 years) completed a single-dose, randomised, open-label, four-dose, four-period, crossover study of FEBT. They were administered FEBT 200, 500, 810 or 1080microg. The subjects in this study were not opioid tolerant; therefore, naltrexone was administered to block any opioid receptor-mediated effects of fentanyl. Venous blood samples for measurement of serum fentanyl concentrations were obtained over 36 hours following dosing. Adverse events were recorded throughout the study. The pharmacokinetics of FEBT were characterised by an absorption phase with a median time to reach maximum serum concentration (tmax) of 0.75-0.99 hours that was consistent irrespective of dose. Mean serum fentanyl concentrations exhibited a biexponential decline from peak after FEBT 200 and 500microg doses and a triexponential decline after FEBT 810 and 1080microg doses. The maximum serum concentration (Cmax) of fentanyl was proportional up to and including the 810microg dose. The increase in Cmax was 20% less than proportional at the 1080microg dose. Systemic exposure to fentanyl, as measured by the area under the serum concentration-time curve from time zero to infinity (AUCinfinity), increased proportionally with increasing doses of FEBT (200-1080microg). No serious adverse events were reported during the study. The pharmacokinetics of FEBT were characterised by a high early fentanyl concentration as a result of absorption across the buccal mucosa of the oral cavity, which results in bypassing first-pass metabolism. This high early tmax contributed to enhanced early systemic fentanyl exposure. Maximum concentration and AUCinfinity of FEBT increased in a dose-proportional manner from 200 to 810microg. This study provides preliminary pharmacokinetic data for FEBT across the potential therapeutic dose range.

Single- and Multiple-Dose Pharmacokinetic and Dose-Proportionality Study of??Oxymorphone Immediate-Release Tablets

Oxymorphone hydrochloride (referred to as oxymorphone), a semisynthetic mu-opioid agonist, is known to produce a more rapid onset of action and greater analgesic potency compared with its parent compound, morphine. Until recently, oxymorphone has been available only in suppository and intravenous formulations. This study examined the pharmacokinetics and dose proportionality of a new immediate-release (IR) tablet formulation of oxymorphone and its metabolites (6-OH-oxymorphone and oxymorphone-3-glucuronide) following single- and multiple-dose administration in healthy volunteers. A randomised, three-way crossover design was employed, with a target sample size of 24 healthy men and women. A single dose of oxymorphone IR (5, 10 and 20mg) was administered on day 1. After drug washout on day 2, study participants then received the same dose every 6 hours (22 total doses) on days 3 to 8. Treatment periods were separated by a 7-day washout. Naltrexone hydrochloride was coadministered to prevent opioid-related adverse events. Blood was collected up to 48 hours after day 1 to determine single-dose pharmacokinetics and up to 6 hours after the last dose for determination of pharmacokinetics at steady state. Twenty-three of 24 enrolled subjects (12 men, 11 women) completed the study. Following a single dose of 5, 10 or 20mg, the oxymorphone IR mean area under the plasma concentration versus time curve from time zero to infinity ([AUC(infinity)] 4.5, 9.1 and 20.1 microg . h/L, respectively) and maximum plasma concentration ([C(max)] 1.1, 1.9 and 4.4 microg/L, respectively) confirmed dose proportionality. 6-OH-oxymorphone and oxymorphone-3-glucuronide also increased in an approximate 2-fold fashion. Similar results were observed for AUC and C(max) of oxymorphone and its metabolites at steady state. Steady state was achieved within 3 days of 6-hourly administration. The median t(max) (time to reach C(max)) was 0.5 hours for all single doses of oxymorphone and at steady state, and the terminal elimination half-life (t(1/2)) was approximately 7.3-9.4 hours. Adverse events were generally mild, and no clinically significant changes in laboratory or other safety variables were noted. Because successful pain management often requires careful drug titration across a wide therapeutic dose range, it is important that opioid formulations provide predictable increases in drug concentration with increasing dose. The single-dose and steady-state pharmacokinetic profiles of oxymorphone IR tablets were linear and dose proportional across the dose range from 5 to 20mg.

Imatinib inhibits the functional capacity of cultured human monocytes

Imatinib is a tyrosine kinase inhibitor that has been reported to specifically inhibit the growth of bcr-abl expressing chronic myeloid leukaemia progenitors. This drug functions by blocking the ATP-binding site of the kinase domain of bcr-abl, and has also been found to inhibit the c-abl, platelet-derived growth factor receptor, ARG and stem cell factor receptor tyrosine kinases. Reports have recently emerged demonstrating that imatinib also inhibits the growth of non-malignant haemopoietic cells. Here, we demonstrate that concentrations of imatinib within the therapeutic dose range inhibit the function of cultured monocytes (CM) from normal donors. A decrease in the response of CM to LPS was observed morphologically and functionally, with CM grown in the presence of imatinib showing decreased pseudopodia formation and inhibition of IL-6 and TNF-alpha production following LPS stimulation. Imatinib also reduced the ability of M-CSF and GM-CSF stimulated CM to phagocytose zymosan particles, with uptake of non-opsonized zymosan by M-CSF stimulated CM (M-CM) being most affected. M-CM that had been cultured in the presence of imatinib were also impaired in their ability to stimulate responder cells in a mixed lymphocyte reaction. These results demonstrate that human monocytes cultured in the presence of imatinib are functionally impaired, and suggest that imatinib displays inhibitory activity against other kinase(s) that play a role in monocyte/macrophage development.