Clinical Evidence Of Toxicity Research Articles

Pritchard's Regimen: The Effect of 12-Hour Versus 24-Hour Magnesium Sulphate Maintenance Regimen on the Occurrence of Seizures and Maternal Outcome in Women with Severe Features of Preeclampsia: A Triple-Blind Randomized Controlled Trial.

Magnesium sulphate (MgSO4) administered for twenty-four hours is the drug of choice for seizure prophylaxis in patients with preeclampsia with severe features. Due to its narrow therapeutic index, a reduction in the duration of MgSO4 administered in the postpartum period may not only prevent the occurrence of seizures but also reduce the adverse effects associated with this drug. This study aimed to compare the efficacy of the 12-hour and 24-hour Pritchard's MgSO4 maintenance regimen on the occurrence of seizures and maternal outcomes in patients with preeclampsia with severe features. A triple-blind randomized controlled trial was conducted among women with preeclampsia with severe features between 1st June 2022 and January 31st, 2023. The primary outcome measure was the occurrence of seizure in either arm of the study. One hundred and forty-six women were randomized into two groups, those who received a 12-hour MgSO4 regimen and placebo for the remaining twelve hours (Group I) and those who received a 24-hour MgSO4 regimen in the postpartum period (Group II). The collected data was coded and analyzed using Statistical Product and Service Solutions (SPSS) version 26 and p<0.05 was considered significant. There was no statistically significant difference between the two groups concerning the occurrence of seizures, the need to recommence MgSO4, clinical evidence of toxicity and adverse effects of MgSO4. There was also no statistically significant difference between the two groups in the total dose of MgSO4 administered, duration of urethral catheterization and duration of hospital admission. No maternal mortality was recorded in this study. The results of this study suggest that the 12-hour MgSO4 maintenance regimen is as efficacious as the traditional 24-hour regimen in preventing seizures without worsening maternal outcomes.

Assessment of the safety of intravitreal injection of metoprolol tartrate in rabbits.

To verify the safety of different doses of intravitreal metoprolol tartrate (MT) after intravitreal injection in rabbit eyes. Animals were randomly assigned into 2 groups: group I received 50µg of MT and group II 100µg of MT. A volume of 0.05mL of the drug solution was administered through an intravitreal injection, while the control eyes received an equal volume of saline solution. Safety was assessed by clinical observation, electroretinography (ERG) and histological evaluation. No evidence of clinical toxicity was observed. ERG waveforms from the MT treated eyes were similar to those recorded from the control eyes in dark-adapted state, amplitude and the implicit time are similar between the groups in light-adapted state, and their retinas had no signs of toxicity by histological evaluation 7days after intravitreal injection. The intravitreal use of metoprolol at 50 and 100µg dosages does not cause short-term retinal toxicity in rabbits.

Topical delivery of siRNA into skin using ionic liquids

Skin diseases such as lupus, cancer, psoriasis, and hyperhidrosis can potentially be treated effectively by suppressing allele-specific genes using small interfering RNA (siRNA). Injections of siRNA into skin, though effective, are painful and cover small surface areas and thus are not suitable as a long-term treatment option. Topical delivery of siRNA is an attractive alternative option to mediate RNA interference (RNAi). However, the barrier function of the epidermis impedes effective permeation of siRNA into the skin. Herein, we describe topical delivery of siRNA using ionic liquids (ILs) capable of complexing with siRNA non-covalently and delivering it effectively. Using complementary and synergistic strategies of ionic liquids, we report delivery of effective doses of siRNA into skin. The first strategy involved the use of hydrophobic cations to robe the siRNA and the second strategy involved the use of choline-geranic acid ionic liquid (CAGE) to enhance its dermal penetration. In vitro studies in porcine skin confirmed the synergistic effect of these strategies in enhancing epidermal and dermal penetration. In vivo application of siRNA formulation to SKH-1E hairless mice significantly suppressed GAPDH expression with no clinical evidence of toxicity. This is a simple, personalized, and scalable platform for effective topical delivery of siRNA for treating genetic skin diseases.

Abstract 4933: Six-month oral toxicity study of endoxifen in rats

Abstract The tamoxifen metabolite, endoxifen (N-desmethyl-4-hydroxytamoxifen), is being developed for oral and local topical administration for prevention and therapy of breast cancer. As part of this development, the toxicity of oral endoxifen was evaluated in a chronic (six-month) study in rats. Groups of 25 female CD rats received daily oral (gavage) exposure to endoxifen at doses of 0 (vehicle control), 5, or 50 mg/kg/day for six months. In vivo assessments included survival; clinical and physical signs of toxicity; body weight; food consumption; ophthalmology; and clinical pathology (clinical chemistry, hematology, coagulation). Fifteen rats per group were euthanized and necropsied after six months of endoxifen exposure; remaining rats in each group were euthanized and necropsied after a four-week recovery period. All gross lesions and approximately 45 tissues per animal were evaluated microscopically. In addition, bone marrow smears collected from rats euthanized for the six month necropsy were evaluated for DNA damage (micronucleus assessment). Daily oral administration of endoxifen at 5 or 50 mg/kg/day for six months induced no treatment-related mortality, clinical evidence of toxicity, or effects on ophthalmology. Endoxifen was not genotoxic, as it had no effect on the incidence of bone marrow micronuclei. Both dose levels of endoxifen induced similar suppressions of body weight gain; food consumption was also significantly decreased in both endoxifen-treated groups. Both dose levels of endoxifen induced gross and microscopic changes in hormone-sensitive tissues. Gross pathology was identified at necropsy in the ovary (cysts) and uterus (small) in both endoxifen groups; mean relative ovarian weight was increased and mean relative uterine weight was decreased in endoxifen groups. Microscopic findings were identified in the ovaries (corpora lutea depletion, cysts), uterus (atrophy, endometrial hyperplasia), cervix (mucinous hypertrophy), mammary gland (hyperplasia), and pituitary gland (vacuolation). These changes are consistent with the activity of endoxifen as an endocrine disruptor, and suggest effects on the hypothalamic-pituitary-gonadal axis. After six months of daily oral administration, both dose levels of endoxifen induced significant reductions in body weight gain and food consumption; alterations in the weights of hormone-sensitive organs; and gross and microscopic effects, primarily in hormone-sensitive tissues. Most of the effects of endoxifen observed in this study can be ascribed to its potent antiestrogenic activity, and are interpreted as signs of its pharmacologic action. However, the gross and microscopic changes seen at both dose levels of endoxifen used in this study demonstrate that a No Observed (Adverse) Effect Level (NO[A]EL) for daily oral administration of endoxifen to female rats for six months could not be determined. [Supported by HHSN261201500024I from the NCI, DHHS.] Citation Format: Thomas L. Horn, William D. Johnson, Carol J. Detrisac, Patrick T. Curry, Elizabeth R. Glaze, David L. McCormick. Six-month oral toxicity study of endoxifen in rats [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4933.

Elevated Carboxyhaemoglobin Concentrations by Pulse CO-Oximetry is Associated with Severe Aluminium Phosphide Poisoning.

In pulse CO-oximetry of aluminium phosphide (ALP)-poisoned patients, we discovered that carboxyhaemoglobin (CO-Hb) level was elevated. We aimed to determine whether a higher CO level was detected in patients with severe ALP poisoning and if this could be used as a prognostic factor in these patients. In a prospective case-control study, 96 suspected cases of ALP poisoning were evaluated. In the ALP-poisoned group, demographic characteristics, gastric and exhalation silver nitrate test results, average CO-Hb saturation, methaemoglobin saturation, and blood pressure and blood gas analysis until death/discharge were recorded. Severely poisoned patients were defined as those with systolic blood pressure ≤80 mmHg, pH ≤7.2, or HCO3 ≤15 meq/L or those who died, while patients with minor poisoning were those without any of these signs/symptoms. A control group (37 patients) was taken from other medically ill patients to detect probable effects of hypotension and metabolic acidosis on CO-Hb and methaemoglobin saturations. Of 96 patients, 27 died and 37 fulfilled the criteria for severe poisoning. All patients with carbon monoxide saturation >18% met the criteria to be included in the severe poisoning group and all with a SpCO >25% died. Concerning all significant variables in univariate analysis of severe ALP toxicity, the only significant variable which could independently predict death was carbon monoxide saturation. Due to high mortality rate and need for intensive care support, early prediction of outcome is vital for choosing an appropriate setting (ICU or ordinary ward). CO-oximetry is a good diagnostic and prognostic factor in patients with ALP poisoning even before any clinical evidence of toxicity will develop.

Standardized DMEK Technique: Reducing Complications Using Prestripped Tissue, Novel Glass Injector, and Sulfur Hexafluoride (SF6) Gas.

To report low complication rates in Descemet membrane endothelial keratoplasty (DMEK) using sulfur hexafluoride (SF6) gas, a novel glass injector, and donor tissue prestripped by an eye bank technician. A standardized technique of DMEK was performed in 80 consecutive Fuchs corneal dystrophy cases using technician-prestripped tissue, a novel glass injector, a modified Yoeruek tap technique, and an SF6 gas (20% concentration) bubble for prolonged tissue support. Twenty-five donors were premarked with an "S" stamp for intraoperative orientation. Surgery was performed by 2 experienced DMEK surgeons and 2 inexperienced cornea fellows. Complications were recorded, and the percent endothelial cell loss was calculated at 6 months postoperatively. There were 5 cases that received an air bubble injection postoperatively (6% rebubble rate). There were 6 grafts that immediately failed, 2 because of excessive surgical trauma, and 4 because of upside-down graft placement documented by optical coherence tomography. None of the 25 cases with an S stamp failed. Recipient corneas cleared quickly with no clinical evidence of toxicity from the SF6 gas bubble, and the grafts experienced a mean endothelial cell loss of 27% at 6 months. Tissue prestripped by an eye bank technician can be safely used for DMEK surgery. SF6 gas for prolonged tissue support may reduce the rebubble rate in DMEK, with no apparent acute toxic effect. An unrecognized upside-down graft was the primary cause of graft failure in this series. Upside-down grafts may be eliminated by the use of donor tissue premarked by the eye bank with an S orientation stamp.

Ninety-Day Oral Toxicity Assessment of an Alternative Biopolymer for Controlled Release Drug Delivery Systems Obtained from Cassava Starch Acetate.

The large consumption of biodegradable films from cassava starch acetate (FCSA) as ingredients in food and pharmaceutical products requires the assessment of the possible toxicity of these products. The aim of this study was to investigate the toxicity of biodegradable film from cassava starch acetate after oral exposure of Wistar rats for 90 days. The amount of food consumed and the body weight were weekly monitored. Blood and urine samples were obtained for the assessment of serum parameters and renal function. Histopathological analyses in target organs were also performed. No evidence of clinical toxicity in hematological, biochemical, or renal parameters in the FCSA-treated animals was found. In addition, relative organ weight and histopathological evaluations did not differ between groups treated with FCSA and control. Data obtained suggest that the subchronic exposure to FCSA does not cause obvious signs of toxicity in Wistar rats, indicating possible safety of this biofilm.

Long-term lithium treatment reduces glucose metabolism in the cerebellum and hippocampus of nondemented older adults: an [¹⁸F]FDG-PET study.

Lithium modulates several intracellular pathways related to neuroplasticity and resilience against neuronal injury. These properties have been consistently reported in experimental models, and involve the up-regulation of neurotrophic response and autophagy, and down-regulation of apoptosis, oxidative stress, and inflammation. Clinical and epidemiological studies in bipolar disorder show that acute treatment with lithium increases plasma concentrations of brain-derived neurotrophic factor, and long-term treatment lowers the risk of dementia. Neuroimaging studies indicate that lithium use is further associated with increased cortical thickness and larger hippocampal volumes. The objective of the present study was to evaluate whether these neurobiological properties of lithium reflect in increased regional brain glucose metabolism, as shown by [(18)F]FDG-PET. Participants (n = 19) were nondemented older adults recruited at the end point of a controlled trial addressing clinical and biological effects of lithium in a sample of patients with amnestic mild cognitive impairment. Twelve patients who had received low-dose lithium carbonate for 4 years were compared to seven matched controls. Chronic lithium treatment was not associated with any significant increase in brain glucose metabolism in the studied areas. Conversely, we found a significant reduction in glucose uptake in several clusters of the cerebellum and in both hippocampi. These findings were not associated with any clinical evidence of toxicity. The clinical implications of the present findings need to be clarified by future controlled studies, particularly in the light of the potential use of lithium as a disease-modifying treatment approach for certain neurodegenerative disorders, namely, Alzheimer's disease and amyotrophic lateral sclerosis.

Abstract P2-05-08: Combined neoadjuvant iniparib and carboplatin in locally advanced or metastatic canine mammary tumors (MT) to support human clinical studies

Abstract INTRODUCTION Among breast cancers, the triple negative subtype (negative for hormone receptors and not overexpressing HER2) has the worst prognosis and its response to Iniparib has been investigated in clinical trials. Further investigations are needed to optimize drug schedule and patient selection criteria. Iniparib antitumor mechanism is not completely understood, as well as iniparib diffusion kinetic into tumoral tissues. We address these questions in spontaneous canine invasive mammary carcinomas, which are a good model for this cancer subtype (Ibisch et al., World Veterinary Cancer Congress 2012), in a neoadjuvant setting. To our knowledge, this is the first study of iniparib administration in cancer-bearing dogs. MATERIAL AND METHODS Twenty female dogs with spontaneous MT with malignant criteria (tumor size, speed of growth, ulceration, relapse, or metastasis) were included. All tumors were described as rapidly growing. Dogs received a first infusion of iniparib at day 0 and a combination of carboplatin and iniparib at day 7. Biological materials (tumor biopsies and blood) were collected before and 5 minutes after iniparib infusion for pharmacokinetic and metabolism studies. Tumor response was evaluated by caliper measurements and histopathological analysis of mammary tumors and draining lymph nodes. A chain mastectomy was performed 3 or 4 weeks later. Histological records included the subtype of carcinoma (WHO 1999), Elston &amp; Ellis grade, presence of emboli, lymph node metastasis and IHC stainings using ER, PR, Her2 (scored according to Wolff et al.2007), CK5/6, EGF-R and Ki67. Intensity of necrosis and apoptosis was evaluated using PAS coloration and immunohistochemistry for caspase 3, at DO on tumor biopsies and at surgery. Toxicity of the protocol was evaluated and its efficiency on invasive carcinomas was compared to surgery alone (control group of 27 female dogs with invasive mammary carcinomas treated by chain mastectomy alone). RESULTS Treated and control groups shared similar features concerning animal breeds, age, neutering status and tumor location. 75% of the treated MT were malignant. Necrosis and apoptosis were significantly increased in respectively 63 and 56% of iniparib treated tumors. Clinical evidence of toxicity was minimal (15% of dogs with nausea, 60% with transient polyuria-polydipsia). Tumor stabilization was observed before surgery in all dogs but one. Median survival has not been reached. CONCLUSION Iniparib at 35mg/kg combined with carboplatin at 300 mg/m2 seemed well tolerated in this study and deserves further investigations. The degree of necrosis and apoptosis in the treated tumors can be evaluated with these techniques. Iniparib pharmacokinetic and metabolism studies in cancer-bearing dogs are ongoing. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-05-08.

Topotecan vitreous and plasma levels and retinal toxicity after transcorneal intravitreal delivery in healthy albino rabbits: Alternative retinoblastoma treatment

To determine intravitreal and plasma concentrations and retinal toxicity after transcorneal intravitreal injection of 1 μg and 2 μg of topotecan (Hycamtin). Twelve healthy albino rabbits were included in this in vivo experiment. Six anesthetized albino rabbits received a single transcorneal intravitreal injection of 1 μg (group A) or 2 μg (group B) of topotecan. Vitreous and blood samples were collected until 168 h. Left eyes were treated with the same volume of saline. Plasma and vitreous levels of topotecan were determined by high-performance liquid chromatography. Area under the plasma concentration time curve (AUC) was calculated using trapezoidal rule. Clinical evidence of toxicity was classified into four grades according to anatomical structures. Electroretinograms (ERGs) were recorded. Time to maximum concentration was observed up to 2 h after drug injection in group A whereas up to 1 h in group B. Low levels of topotecan were detected in plasma in both groups and in the vitreous humor of the contralateral eye in group B. Topotecan levels (mean vitreous AUC in group A 2.55 μg/mL.h and in group B 5.338 μg/mL.h) were detectable up to 6 h in both groups. We observed following structural changes in rabbit eyes: corneal vascularization, cataract, hemophthalmus, choroidal edema and focal retinal atrophy. Abnormal ERGs were obtained. Our findings proved that transcorneal intravitreal administration of 1 μg and 2 μg of topotecan results in potentially cytotoxic intraocular concentrations. More studies are needed to establish the safety of topotecan for retinoblastoma in children.

Topical antiseptics in wound care: time for reflection

Topical antiseptics in wound care: time for reflection

Abstract 1672: The plasma and cerebrospinal fluid pharmacokinetics of sorafenib after intravenous administration in non-human primates

Abstract Background: Sorafenib is an oral multikinase inhibitor that targets intracellular and receptor protein kinases thought to be crucial in the pathogenesis and growth of many tumors including brain tumors. Sorafenib is FDA approved for advanced renal cell and hepatocellular carcinoma. Clinical trials in primary and metastatic brain tumors are ongoing. We evaluated the plasma and cerebrospinal fluid (CSF) pharmacokinetics (PK) of sorafenib after an intravenous (IV) dose in a non-human primate (NHP) model. Methods: Sorafenib 7.3 mg free base equivalent/kg was administered as a 1h IV infusion in 20% cyclodextrin and normal saline to 3 NHP with IV catheters and Ommaya reservoirs. Serial paired plasma and CSF samples were drawn over 24h for PK analysis. Sorafenib was quantified with a validated liquid chromatography/tandem mass spectrometry assay. The lower limit of quantification for plasma and CSF was 5 ng/mL and 0.025 ng/mL, respectively. PK parameters were estimated using non-compartmental methods. CSF penetration was calculated from the AUC CSF : AUC plasma. Plasma free drug exposures (AUC) were calculated from published values for human plasma protein binding (99.5%). Results: IV administration of sorafenib was well tolerated in the NHP without evidence of clinical toxicity. The PK parameters of sorafenib in NHP for plasma and CSF are described in the table below. The mean CSF penetration of sorafenib was 0.02%. When corrected for plasma protein binding, the mean CSF penetration was 3.4%. Conclusions: Sorafenib is well tolerated in NHP and measureable in CSF after an IV dose. The CSF penetration of sorafenib is limited relative to total and free drug exposure in plasma.Plasma and CSF PK of sorafenib in NHPAnimalCmax plasma [µg/mL]Clearance [mL/min/kg]AUC 0-24h plasma [µg•h/mL]Cmax CSF [µg/mL]AUC 0-24h CSF [µg•h/mL]CSF penetration [%]17.62.231.20.000450.00420.01326.42.029.60.000580.00660.02233.41.323.20.000460.00340.015Mean5.81.728.00.000500.00480.02SD2.10.54.30.000070.00160.005 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1672.

The haemotoxicity of azathioprine in repeat dose studies in the female CD-1 mouse.

Azathioprine (AZA) is a cytotoxic immunosuppressive drug used in the prevention of rejection in organ transplants and the treatment of auto-immune diseases. However, AZA is haemotoxic causing significant bone marrow depression. The present studies were to characterize the haemotoxicity of AZA in the female CD-1 mouse. In Experiment 1, a dose-ranging study, with AZA gavaged daily for 10 days, clinical evidence of toxicity was evident at 125 mg/kg and above. Experiment 2 was a dose-response study with AZA gavaged daily for 10 days at 40-120 mg/kg. At day 1 after the final dose, AZA induced a dose-related pancytopaenia, reduced femoral marrow cellularity, increases in serum levels of the cytokine fms-like tyrosine kinase 3 ligand, reduction in granulocyte-monocyte colony-forming units and erythroid colonies, and increased bone marrow apoptosis. Histology demonstrated hepatocyte hypertrophy, thymic atrophy, reduced splenic extramedullary haemopoiesis, and reduced cellularity of sternal bone marrow. In Experiment 3, AZA was dosed for 10 days at 100 mg/kg with autopsies at 1, 3, 9, 22, 29, 43 and 57 days postdosing. At 1, 3 and 9 days, haematological parameters reflected changes in Experiment 2. At 22/29 days, many blood parameters were returning towards normal; at 43/57 days, most parameters compared with controls. However, there was some evidence of a persistent (i.e. residual/late-stage) mild reduction in RBC and erythroid progenitor cell counts at day 43/57. We conclude that the CD-1 mouse provides an acceptable model for the haemotoxicity of AZA in man.

Safety of High Dose Lidocaine in Flexible Bronchoscopy

Background The maximum safe dose for topical lidocaine during flexible bronchoscopy (FB) without toxicity is not established; recent guidelines advocate a dose <8.2 mg/kg. Noting our routine use of lidocaine above 12 mg/kg, we prospectively evaluated the safety of high dose topical lidocaine. Methods The standard institution FB preparation included 4% nebulized lidocaine, 2% nasal viscous lidocaine, 2% aqueous lidocaine for the vocal cords, and 1% aqueous lidocaine for the tracheobronchial tree. Procedure data were collected to include FB indication and duration, lidocaine use, and postprocedure symptoms. Serum lidocaine and blood methemoglobin levels were obtained 45 minutes postlidocaine administration. Results Consecutive data were collected for 154 patients with a mean age of 64.7 years. The most common FB indication (60%) was evaluation of a lung mass or mediastinal adenopathy. No arrhythmias or seizures were noted. Symptoms of euphoria or dizziness were reported in 84 patients (62.2%). Mean lidocaine usage was 15.4±4.5 mg/kg (1.17±0.20 gm). Lidocaine dose for females was significantly higher than males (16.9±4.9 mg/kg vs. 14.3±3.8 mg/kg, P=0.0003). There was no significant difference in dose on the basis of age, indication for FB, or presence of symptoms. Mean serum lidocaine level was 1.6±0.7 μg/mL and mean blood methemoglobin level was 0.7±0.3%. There were no significant differences shown. Conclusions Our routine use of lidocaine in FB is higher than recommended. There were not significantly elevated serum lidocaine or blood methemoglobin levels, or clinical evidence of toxicity.

Serum and Wound Drain Ropivacaine Concentrations After Wound Infiltration in Joint Arthroplasty

Ropivacaine blood and drain levels were measured in 20 hip and 15 total knee arthroplasties after intraoperative wound infiltration with 150 to 200 mL (360-400 mg) of ropivacaine, followed by a 48-hour intra-articular pain pump infusion of 1000 mg (knees) and 300 mg (hips) commencing 12 hours postoperatively. Concentrations were below 2 μg/mL over the first 12 hours before the pain pump increased levels. Peak total ropivacaine concentration ranged from 0.65 to 4.36 μg/mL with the pain pump. The high infiltration doses produced levels below or within the safe threshold of 1 to 3 μg/mL. Pain pump infusion produced some C max levels above 3.0 μg/mL, but there was no clinical evidence of toxicity. Wound drain amounts (0.53-26.69 mg) indicate reinfusion should be safe, although further study is needed to confirm this.

INTRAVITREAL BEVACIZUMAB (AVASTIN) FOR CENTRAL AND HEMICENTRAL RETINAL VEIN OCCLUSIONS

To evaluate the safety, visual acuity changes, and morphologic effects associated with intravitreal bevacizumab injections for the management of macular edema due to ischemic central or hemicentral retinal vein occlusion (RVO). In this prospective, open-label study, 7 consecutive patients (7 eyes) with macular edema associated with ischemic central or hemicentral RVO were treated with intravitreal injections of 2.0 mg (0.08 mL) of bevacizumab at 12-week intervals. Standardized ophthalmic evaluation was performed at baseline and at weeks 1, 6, and 12 after each injection. Clinical evidence of toxicity and complications as well as changes in logarithm of minimum angle of resolution Early Treatment Diabetic Retinopathy Study best-corrected visual acuity (BCVA), central macular thickness (CMT) and total macular volume (TMV) shown by optical coherence tomography (OCT), and dye leakage shown by fluorescein angiography were evaluated. The median age of the 7 patients was 65 years (range, 58-74 years), and the median duration of symptoms before injection was 7 months (range, 2.5-16 months). At baseline, mean BCVA was 1.21 (Snellen equivalent, approximately 20/320) in the affected eye. Mean baseline CMT and TMV were 730.1 microm and 17.1 mm(3), respectively. Fluorescein leakage was observed in the macula and affected retinal quadrants in all seven eyes. Six patients completed the 25-week follow-up examination with reinjections performed at weeks 12 and 24. The most common adverse events were conjunctival hyperemia and subconjunctival hemorrhage at the injection site. At the last follow-up, mean BCVA in the affected eye was 0.68 (Snellen equivalent, 20/100(+1). No patient had a decrease in BCVA. Mean CMT and TMV at the 25-week follow-up were 260.3 microm and 9.0 mm(3), respectively; fluorescein leakage within the macula and affected retinal quadrants as compared with baseline was markedly reduced in all patients. Coupled with fluorescein angiographic findings, OCT data suggest a trend of macular edema recurrence between 6 weeks and 12 weeks after injection. Intravitreal bevacizumab injections of 2.0 mg at 12-week intervals were well tolerated and were associated with short-term BCVA stabilization or improvement and favorable macular changes in all patients with ischemic RVO and associated macular edema.

Serial injection of botulinum toxin for muscle imbalance due to regional spasticity in the upper limb

Background and purpose. Three-dimensional movement in the upper limb presents a challenge for functional management of regional spasticity. Potential toxicity of botulinum toxin limits the number of muscles which may be injected in any one session. Serial injection may offer a solution, but carries theoretical risk of development of resistance due to antibody formation. This article reviews a small case series, gathered in a post-acute neuro-rehabilitation setting, to evaluate the use of serial botulinum toxin injection in terms of goal achievement and clinical evidence for toxicity or resistance.Methods. Nine patients with regional spasticity following acute stroke or brain injury had serial injection of botulinum toxin to muscle groups around the shoulder, elbow and/or wrist. Injection was followed by splinting/physiotherapy as appropriate. Goal attainment scaling was used to assess outcome.Results. Functional goals achieved were reduction of pain (n = 6/7) associated reaction (n = 4/5) or care needs (n = 5/6), improved gait (n = 2/3) or independence in self-care (n = 2/5). Two ‘golden responder’ cases are presented in detail to demonstrate resolution of symptoms with up to four serial injections of botulinum toxin over a period of up to 6 months. No clinical evidence of toxicity or resistance was seen in any case.Conclusion. These preliminary findings suggest that serial botulinum toxin injection followed by appropriate physiotherapy/splinting may provide effective treatment for regional spasticity. Resistance has not presented a problem in this post-acute situation, where treatment has not been required beyond a few months. Ongoing evaluation is underway.

Clinical Evaluation of Gemcitabine in Dogs with Spontaneously Occurring Malignancies

We conducted a clinical evaluation of gemcitabine in 19 dogs with spontaneously occurring malignancies. The principal objectives of this study were to characterize toxicity and seek preliminary evidence of antitumor activity of gemcitabine administered every 2 weeks (biweekly) as a 30-minute IV infusion. A total of 64 doses, ranging from 300 mg/m2 to 675 mg/m2, were administered during the initial 8-week evaluation period, and an additional 131 doses were administered during the extended evaluation period. The total cumulative dose for the 10 dogs receiving gemcitabine in the extended evaluation period ranged from 1,500 mg/m2 to 24,300 mg/m2. Clinical evidence of toxicity was minimal. Cumulative myelosuppression was not apparent. Unexplained retinal hemorrhages occurred in 1 dog. No complete or partial remissions were observed during the initial evaluation period; however, objective responses were observed in 2 dogs during the extended evaluation period. Gemcitabine is a promising new chemotherapeutic agent that can be used safely in dogs with cancer. Biweekly administration of doses of 675 mg/m2 IV results in minimal and acceptable toxicity.

Adefovir dipivoxil for the treatment of HBeAg-positive chronic hepatitis B: a review of the major clinical studies

Adefovir dipivoxil (ADF) is an orally bioavailable prodrug of adefovir, a phosphonate nucleotide analog of adenosine monophosphate [1]. Adefovir has potent in vitro activity against hepadnaviruses, retroviruses and herpesviruses [2–5]. The intracellular compound, adefovir diphosphate, acts as a competitive inhibitor and chain-terminator of hepatitis B virus (HBV) replication mediated by HBV DNA polymerase [6]. Ten mg daily of adefovir has recently been licensed for the treatment of chronic hepatitis B in adults with evidence of HBV replication. The efficacy of ADF was investigated in patients with compensated liver disease and evidence of HBV replication; in patients failing lamivudine therapy, including posttransplantation patients, patients with compensated and decompensated liver failure and patients co-infected with human immunodeficiency virus (HIV). Several of these studies have been published. The data in HBeAg-positive patients is reviewed in this manuscript.

American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning.

Almost all cases of acute methanol toxicity result from ingestion, though rarely cases of poisoning have followed inhalation or dermal absorption. The absorption of methanol following oral administration is rapid and peak methanol concentrations occur within 30-60minutes. Methanol has a relatively low toxicity and metabolism is responsible for the transformation of methanol to its toxic metabolites. Methanol is oxidized by alcohol dehydrogenase to formaldehyde. The oxidation of formaldehyde to formic acid is facilitated by formaldehyde dehydrogenase. Formic acid is converted by 10-formyl tetrahydrofolate synthetase to carbon dioxide and water. In cases of methanol poisoning, formic acid accumulates and there is a direct correlation between the formic acid concentration and increased morbidity and mortality. The acidosis observed in methanol poisoning appears to be caused directly or indirectly by formic acid production. Formic acid has also been shown to inhibit cytochrome oxidase and is the prime cause of ocular toxicity, though acidosis can increase toxicity further by enabling greater diffusion of formic acid into cells. Methanol poisoning typically induces nausea, vomiting, abdominal pain, and mild central nervous system depression. There is then a latent period lasting approximately 12-24 hours, depending, in part, on the methanol dose ingested, following which an uncompensated metabolic acidosis develops and visualfunction becomes impaired, ranging from blurred vision and altered visual fields to complete blindness. For the patient presenting with ophthalmologic abnormalities or significant acidosis, the acidosis should be corrected with intravenous sodium bicarbonate, the further generation of toxic metabolite should be blocked by the administration of fomepizole or ethanol and formic acid metabolism should be enhanced by the administration of intravenous folinic acid. Hemodialysis may also be required to correct severe metabolic abnormalities and to enhance methanol and formate elimination. For the methanol poisoned patient without evidence of clinical toxicity, the first priority is to inhibit methanol metabolism with intravenous ethanol orfomepizole. Although there are no clinical outcome data confirming the superiority of either of these antidotes over the other, there are significant disadvantages associated with ethanol. These include complex dosing, difficulties with maintaining therapeutic concentrations, the need for more comprehensive clinical and laboratory monitoring, and more adverse effects. Thus fomepizole is very attractive, however, it has a relatively high acquisition cost. The management of methanol poisoning includes standard supportive care, the correction of metabolic acidosis, the administration of folinic acid, the provision of an antidote to inhibit the metabolism of methanol to formate, and selective hemodialysis to correct severe metabolic abnormalities and to enhance methanol and formate elimination. Although both ethanol and fomepizole are effective, fomepizole is the preferred antidote for methanol poisoning.