• Journal of Veterinary Clinics
• /
• v.38 no.4
• /
• pp.204-209
• /
• 2021

A seven-month-old castrated male Chihuahua weighing 1.6 kg presented with generalized tonic-clonic seizure following ingestion of isoniazid. Emergency treatment with three doses of diazepam (total 1.5 mg/kg, intravenous [IV]) and phenobarbital (15 mg/kg IV) was administered. The seizure stopped after administration of propofol (constant rate infusion [CRI]; 0.2 mg/kg/min). Blood analyses showed mildly increased serum blood glucose concentration, hyperkalemia, and hyperphosphatemia. On suspicion of isoniazid toxicity, activated charcoal (1 g/kg, orally), lipid emulsion (CRI; 9 mL/hr), and pyridoxine hydrochloride (70 mg/kg IV) were added to the treatment regimen. Twelve hours after presentation, the dog showed increased serum liver enzyme activities, serum blood urea nitrogen, and creatinine concentrations indicating hepatic and renal failure. Twenty-two hours after presentation, blood analysis still revealed increased liver enzyme activities, blood urea nitrogen, and creatinine concentrations with low blood glucose concentration. Twenty-six hours after presentation, the dog's vital signs deteriorated and the owner elected for the dog to be euthanized. This is the first report of the clinical course of isoniazid toxicosis in a dog in South Korea. Furthermore, to our best knowledge, this is the first report where secondary multiple organ failure was observed due to isoniazid toxicosis. Clinicians should be aware of the possibility of isoniazid toxicosis in dogs. Rapid initiation of treatment after clinical recognition is warranted in such cases.

• Journal of Veterinary Science
• /
• v.23 no.4
• /
• pp.53.1-53.9
• /
• 2022

Background: Problems associated with using inhalational anaesthesia are numerous in veterinary anaesthesia practice. Decreasing the amount of used inhalational anaesthetic agents and minimising of cardiorespiratory disorders are the standard goals of anaesthetists. Objective: This experimental study was carried out to investigate the sparing effect of intravenous tramadol, lidocaine, dexmedetomidine and their combinations on the minimum alveolar concentration (MAC) of sevoflurane in healthy Beagle dogs. Methods: This study was conducted on six beagle dogs. Sevoflurane MAC was determined by the tail clamp method on five separate occasions. The dogs received no treatment (control; CONT), tramadol (TRM: 1.5 mg kg^-1 intravenously followed by 1.3 mg kg^-1 h^-1), lidocaine (LID: 2 mg kg^-1 intravenously followed by 3 mg kg^-1 h^-1), dexmedetomidine (DEX: 2 ㎍ kg^-1 intravenously followed by 2 ㎍ kg^-1 h^-1), and their combination (COMB), respectively. Cardiorespiratory variables were recorded every five minutes and immediately before the application of a noxious stimulus. Results: The COMB treatment had the greatest sevoflurane MAC-sparing effect (67.4 ± 13.9%) compared with the other treatments (5.1 ± 25.3, 12.7 ± 14.3, and 40.3 ± 15.1% for TRM, LID, and DEX treatment, respectively). The cardiopulmonary variables remained within the clinically acceptable range following COMB treatment, although the mean arterial pressure was higher and accompanied by bradycardia. Conclusions: Tramadol-lidocaine-dexmedetomidine co-infusion produced a remarkable sevoflurane MAC-sparing effect in clinically healthy beagle dogs and could result in the alleviation of cardiorespiratory depression caused by sevoflurane. Cardiorespiratory variables should be monitored carefully to avoid undesirable side effects induced by dexmedetomidine.

• Biomolecules & Therapeutics
• /
• v.30 no.6
• /
• pp.510-519
• /
• 2022

Tofacitinib, a Janus kinase 1 and 3 inhibitor, is mainly metabolized by CYP3A1/2 and CYP2C11 in the liver. The drug has been approved for the chronic treatment of severe ulcerative colitis, a chronic inflammatory bowel disease. This study investigated the pharmacokinetics of tofacitinib in rats with dextran sulfate sodium (DSS)-induced ulcerative colitis. After 1-min of intravenous infusion of tofacitinib (10 mg/kg), the area under the plasma concentration-time curves from time zero to time infinity (AUC) of tofacitinib significantly increased by 92.3%. The time-averaged total body clearance decreased significantly by 47.7% in DSS rats compared with control rats. After the oral administration of tofacitinib (20 mg/kg), the AUC increased by 85.5% in DSS rats. These results could be due to decreased intrinsic clearance of the drug caused by the reduction of CYP3A1/2 and CYP2C11 in the liver and intestine of DSS rats. In conclusion, ulcerative colitis inhibited CYP3A1/2 and CYP2C11 in the liver and intestines of DSS rats and slowed the metabolism of tofacitinib, resulting in increased plasma concentrations of tofacitinib in DSS rats.

• Journal of The Korean Society of Clinical Toxicology
• /
• v.20 no.2
• /
• pp.39-44
• /
• 2022

N-Acetylcysteine (NAC) is the standard antidote treatment for preventing hepatotoxicity caused by acetaminophen (AAP) poisoning. This review summarizes the recent evidence for the treatment of AAP poisoning. Several alternative intravenous regimens of NAC have been suggested to improve patient safety by reducing adverse drug reactions and medication errors. A two-bag NAC infusion regimen (200 mg/kg over 4 h, followed by 100 mg/kg over 16 h) is reported to have similar efficacy with significantly reduced adverse reactions compared to the traditional 3-bag regimen. Massive AAP poisoning due to high concentrations (more than 300-lines in the nomogram) needs to be managed with an increased maintenance dose of NAC. In addition to NAC, the combination therapy of hemodialysis and fomepizole is advocated for severe AAP poisoning cases. In the case of a patient presenting with an altered mental status, metabolic acidosis, elevated lactate, and an AAP concentration greater than 900 mg/L, hemodialysis is recommended even if NAC is used. Fomepizole decreases the generation of toxic metabolites by inhibiting CYP2E1 and may be considered an off-label use by experienced clinicians. Since the nomogram cannot be applied to sustained-release AAP formulations, all potentially toxic sustained-release AAP overdoses should receive a full course of NAC regimen. In case of ingesting less than the toxic dose, the AAP concentration is tested twice at an interval of 4 h or more; NAC should be administered if either value is above the 150-line of the nomogram.

• International Journal of Stem Cells
• /
• v.16 no.4
• /
• pp.415-424
• /
• 2023

Therapeutic efficacy of mesenchymal stem cells (MSCs) is determined by biodistribution and engraftment in vivo. Compared to intravenous infusion, biodistribution of locally transplanted MSCs are partially understood. Here, we performed a pharmacokinetics (PK) study of MSCs after local transplantation. We grafted human MSCs into the brains of immune-compromised nude mice. Then we extracted genomic DNA from brains, lungs, and livers after transplantation over a month. Using quantitative polymerase chain reaction with human Alu-specific primers, we analyzed biodistribution of the transplanted cells. To evaluate the role of residual immune response in the brain, MSCs expressing a cytosine deaminase (MSCs/CD) were used to ablate resident immune cells at the injection site. The majority of the Alu signals mostly remained at the injection site and decreased over a week, finally becoming undetectable after one month. Negligible signals were transiently detected in the lung and liver during the first week. Suppression of Iba1-positive microglia in the vicinity of the injection site using MSCs/CD prolonged the presence of the Alu signals. After local transplantation in xenograft animal models, human MSCs remain predominantly near the injection site for limited time without disseminating to other organs. Transplantation of human MSCs can locally elicit an immune response in immune compromised animals, and suppressing resident immune cells can prolong the presence of transplanted cells. Our study provides valuable insights into the in vivo fate of locally transplanted stem cells and a local delivery is effective to achieve desired dosages for neurological diseases.

• Radiation Oncology Journal
• /
• v.24 no.4
• /
• pp.223-229
• /
• 2006

$\underline{Purpose}$: Combined modality therapy including chemotherapy, surgery and radiotherapy is considered the standard of care for the treatment of stage III non-small cell lung cancer (NSCLC). This study was conducted to evaluate the efficacy of paclitaxel and cisplatin with induction chemotherapy followed by concurrent chemoradiotherapy for stage IIIB NSCLC. $\underline{Materials\;and\;Methods}$: Between July 2000 and October 2005, thirty-nine patients with stage IIIB NSCLC were treated with two cycles of induction chemotherapy followed by concurrent chemoradiotherapy. The induction chemotherapy included the administration of paclitaxel ($175\;mg/m^2$) by intravenous infusion on day 1 and treatment with cisplatin ($75\;mg/m^2$) by intravenous infusion on day 1 every 3 weeks. Concurrent chemoradiotherapy included the use of paclitaxel ($60\;mg/m^2$) plus cisplatin ($25\;mg/m^2$) given intravenously for 6 weeks on day 43, 50, 57, 71, 78 and 85. Thoracic radiotherapy was delivered with 1.8 Gy daily fractions to a total dose of $54{\sim}59.4\;Gy$ in $6{\sim}7$ weeks (median: 59.4 Gy). $\underline{Results}$: The follow up period was $6{\sim}63$ months (median: 21 months). After the induction of chemotherapy, 41.0% (16 patients) showed a partial response and 59.0% (23 patients) had stable disease. After concurrent chemoradiotherapy, 10.3% (4 patients) had a complete response, 41.0% (16 patients) had a partial response, and the overall response rate was 51.3% (20 patients). The 1-, 2-, 3-year overall survival rates were 66.7%, 40.6%, and 27.4% respectively, with a median survival time of 20 months. The 1-, 2-, 3-year progression free survival rates were 43.6%, 24.6%, and 24.6%, respectively, with median progression free survival time of 10.7 months. Induction chemotherapy was well tolerated. Among 39 patients who completed the entire treatment including chemoradiotherapy, 46.3% (18 patients) had esophagitis greater than grade 3 and 28.2% (11 patients) had radiation pneumonitis greater than grade 3. $\underline{Conclusion}$: Paclitaxel and cisplatin with induction chemotherapy followed by concurrent chemoradiotherapy for stage IIIB NSCLC seems to be an effective treatment. Occurrence of esophagitis and pneumonitis represents a significant morbidity and suggests a modification of the treatment regimen, either with the chemotherapy schedule or with radiotherapy treatment planning.

• Journal of Chest Surgery
• /
• v.32 no.7
• /
• pp.613-620
• /
• 1999

Background: Recently, regional or isolated organ perfusion is being studied again as a drug administration modality which is able to reduce systemic toxicity while delivering high-dose chemotherapeutic agents. This research was planned to evaluate the pharmacokinetics and long-term pathologic changes of the lung in isolated lung perfusion (ILP) with cisplatin. Material and Method: Twenty-five New Zealand white rabbits were divided into 2 groups (Group I: 10, Group II: 15). The groups were then subdivided into 2 and 3 subgroups of 5 rabbits. In group I, tissue samples of the lung and kidney, and systemic blood for platinum concentration measurement were taken 30 minutes after systemic intravenous infusion of cisplatin (5 mg/kg) and isolated lung perfusion in each 5 rabbits. In 2 subgroups of group II, lung tissues for pathologic exams were taken 30 minutes and 1 week after ILP in each 5 rabbits, which received 10% pentastarch solution only and cisplatin, respectively. In the other subgroups, lung biopsy was undertaken 4 weeks after ILP with cisplatin. Result: When cisplatin was infused via systemic vein, the platinum concentration in the lung, kidney and plasma were 1.50${\pm}$0.43 $\mu\textrm{g}$/g, 7.65${\pm}$2.49 $\mu\textrm{g}$/g, 1.19${\pm}$0.03 $\mu\textrm{g}$/ml, respectively. However, the platinum concentration in the lung was about 50 times higher (75.43${\pm}$11.47 $\mu\textrm{g}$/g) than that of intravenous infusion group, and those in the kidney and plasma were decreased (1.30${\pm}$ 0.35 $\mu\textrm{g}$/g, 0.13${\pm}$0.02 $\mu\textrm{g}$/ml) when cisplatin was introduced through ILP. Pathologic change in the treated lung with ILP was characterized by the medial hypertrophy of the pulmonary arterioles and interstitial eosinophilic infiltration, which was not dependent on cisplatin

• The Korean Journal of Nuclear Medicine
• /
• v.28 no.2
• /
• pp.177-185
• /
• 1994

Pharmacologic coronary vasodilation in conjunction with myocardial perfusion scintigraphy has become an alternative to dynamic exercise test for the diagnosis and risk stratification of coronary artery disease, especially in patients who are unable to perform adequate exercise. Dipyridamole and adenosine have been used for pharmacologic stress testing with myocardial perfusion imaging. Adenosine is a potent coronary vasodilator with rapid onset of action, short half-life, near maximal coronary vasodilation and less serious side effects. ST segment depression has been reported in about 7-15% of patients with coronary artery disease receiving dipyridamole in conjunction with myocardial perfusion imaging. The exact cause and clinical significance are not known. In order to evaluate the relationship between adenosine-induced ST segment depression during $^{99m}Tc$-MIBI myocardial perfusion scintigraphy and the severity of coronary artery disease, we performed $^{99m}Tc$-MIBI imaging after intravenous Infusion of adenosine In 120 patients with suspected coronary artery disease. Of the 120 patients, 28 also performed coronary angiography. There were 24 patients with ST segment depression during $^{99m}Tc$-MIBI scintigraphy and 96 patients without ST segment depression. Adenosine was infused Intravenously at a dose of 0.14mg/kg per minute lot 6minutes and $^{99m}Tc$-MIBI was injected at 3 minute. We then com-pared the hemodynamic changes, side effects, scintigraphic and angiographic findings. Heart rate increased $90{\pm}19$ beats/minute in the group with ST depression compared with $80{\pm}16$ beats/minute in the group without ST depression(p<0.05). Baseline systolic blood pressure was significantly higher in the group with ST depression($152{\pm}27$ mmHg) than in the group without 57 depression($140{\pm}21$mmHg, p<0.05). Double product at baseline($10.90{\pm}2.77$ versus $9.55{\pm}2.34\;beats/minute{\times}mmHg$) and during adenosine infusion($12.72{\pm}3.89$ versus $10.83{\pm}2.98\;beats/minute{\times}mmHg$) were significantly higher in the group with ST depression(p<0.05). The incidence of anginal chest pain was also significantly higher in the group with ST depression(ST versus 29%, p<0.0001). The $^{99m}Tc$-MIBI images were abnormal in 23(96%) patients with ST segment depression and 66(69%) patients without ST segment depression(p<0.05). In patients with ST segment depression, there were more reversible perfusion defects than in patients without ST segment depression(83 versus 55%, p<0.05). The number of abnormal segments were significantly higher in the group with ST depression($3.05{\pm}2.01$ versus $1.51{\pm}1.45$, p<0.005). In patients with ST segment depression, there were more segments of reversible perfusion defects than in patients without segment depression($2.15{\pm}2.11$ versus $0.89{\pm}1.24$, p<0.05). There were no differences in the angiographic severity by vessel(p ; NS). We concluded that ST segment depression during $^{99m}Tc$-MIBI myocardial perfusion scintigraphy with Intravenous adenosine is related to the severity of coronary artery disease.

• Radiation Oncology Journal
• /
• v.16 no.1
• /
• pp.7-16
• /
• 1998

Purpose : To evaluate survival rate and prognostic factors affecting survival of patients with esophageal cancer treated with concurrent chemoradiation. Materials and Methods : Eligibility included biopsy proven invasive carcinoma of the cervical or thoracic esophagus, confined to esophagus and mediastinum with or without regional lymph node and supraclavicular lymph node, and ECOG Performance status $H_0-H_2$. Patients received radiation therapy with 5940cGy over 7 weeks and chemotherapy, consisted of 5-FU(1000 $mg/m^2/day$ in continuous infusion for 5 days, days 1 to 5 and days 29 to 33) and mitomycin C($8mg/m^2$ intravenous bolus at day 1). After concurrent chemoradiation, maintenance chemotherapy was followed with 5-FU(1000 $mg/m^2/day$ in continuous infusion for 5 days at 9th, 13th, and 17th weeks) and cisplatin($80mg/m^2$ intravenous bolus at the first day of each cycle). Results : From November 1989 to November 1995, 44 patients were entered in this study. After treatment, complete response rate and partial response rate were $59\%$ and $41\%$. Overall 1, 2, and 5-year survivals were $59\%$, $38\%$, and $9.6\%$(median 17 months), Prognostic factors affecting survival were response to treatment and T-stage. Among 26 complete responders, there were 6 local recurrences, 3 distant recurrences, 1 local and distant recurrence, and 2 unknown site recurrences Acute and chronic complication rates with grade 3 or more were $20\%$ and $13.0\%$ and there was no treatment-related mortality. Conclusion : Concurrent chemoradiation, compared with historical control groups that treated with radiation alone, improved median survival and did not significantly increase treatment-related complications. Complete responders had longer survival duration than partial responders. Predominant failure pattern was local failure. So, efforts to improve local control should be proposed.

• Tuberculosis and Respiratory Diseases
• /
• v.40 no.1
• /
• pp.16-22
• /
• 1993

Background: The Microbicidal and cytotoxic activities of neutrophils are to a large extent dependent on a burst of oxidative metabolism which generates superoxide anion, hydrogen peroxide, and other reactive products of oxygen. The respiratory burst of PMN is initiated by intracellular calcium mobilization that follows immune or particular stimulation and is very sensitive to modulation by c-AMP or adenosine. Despite its antagonism against adenosine, earlier study has demonstrated potent theophylline inhibition of the PMN respiratory burst at variable ranges of blood concentrations of theophylline in the healthy normal volunteers and in the septic animals pretreated or early post-treated with aminophylline (AMPH) or pentoxifylline. However it is unclear whether theophylline inhibits the superoxide generation or not in the established human sepsis caused by acute pneumonia, as taking into consideration of the fact that full activation of neutrophils have occurred within minutes after the septic insult in the animal experiments. Methods: We measured the $O_2$ generation of peripheral arterial neutrophils obtained from 11 human septic subjects caused by acute pneumonia before and 1 hour after completion of continuous AMPH infusion. Patients were identified and studied within 48 hour of admission. All subjects were administered an intravenous loading and maintenance dose of AMPH. The generation of $O_2$ was measured at a discrete time point (60 min) by the reduction of ferricytochrome c.PMA (10 ${\mu}g/ml$) was used as a stimulating agent. PMNs were isolated at a concentration of $2{\times}10^6$ cells/ml. The arterial oxygen tension, blood pressure and heart rates were also checked to evaluate the systemic effects of AMPH in the acute pneumonia. Results: The mean serum concentration of AMPH at 60 minutes was $8.8{\pm}0.6{\mu}g/ml$. Sixty minutes after AMPH infusion the generatition of $O_2$ was decreased from $0.076{\pm}0.034$ to $0.013{\pm}0.004$(OD) (p<0.05) and from $0.177{\pm}0.044$ to $0.095{\pm}0.042$(OD) (p<0.01) in the resting and stimulated PMNs respectively. $PaO_2$ was not changed after AMPH infusion. Conclusion: AMPH may compromise host defense by significant inhibition of neutrophil release of superoxide anion and it had no effect on improving $PaO_2$ in the acute pneumonia.