Lumbar Total Disc Replacement Leads to Increased Subsequent Facet Injections Compared to Anterolateral Lumbar Interbody Fusions.

STUDY DESIGN: Retrospective Matched Cohort. OBJECTIVE: Despite known consequences to the facet joints following lumbar total disc replacement (TDR), there is limited data on facet injection usage for persistent postoperative pain. This study uses real-world data to compare the usage of therapeutic lumbar facet injections as a measure of symptomatic facet arthrosis following single-level, stand-alone TDR vs anterolateral lumbar interbody fusion (ALIF/LLIF). METHODS: The PearlDiver database was queried for patients (2010-2021) with lumbar degenerative disc disease who received either a single-level, stand-alone TDR or ALIF/LLIF. All patients were followed for ≥2 years and excluded if they had a history of facet injections or spinal trauma, fracture, infection, or neoplasm. The two cohorts were matched 1:1 based on age, sex, insurance, year of operation, and medical comorbidities. The primary outcome was the use of therapeutic lumbar facet injections at 1-, 2-, and 5-year follow-up. Secondary outcomes included subsequent lumbar surgeries and surgical complications. RESULTS: After 1:1 matching, each cohort had 1203 patients. Lumbar facet injections occurred significantly more frequently in the TDR group at 1-year (6.07% vs 1.66%, P < .0001), 2-year (8.40% vs 3.74%%, P < .0001), and 5-year (11.47% vs 6.40%, P < .0001) follow-up. 5-year injection-free probability curves demonstrated an 87.1% injection-free rate for TDR vs 92.9% for ALIF/LLIF. There was no clinical difference in the incidence of subsequent lumbar surgeries or complications. CONCLUSION: Compared with ALIF/LLIF, patients who underwent TDR received significantly more facet injections, suggesting a greater progression of symptomatic facet arthrosis. TDR was not protective against reoperations compared to ALIF/LLIF.

Geographic Access to Pediatric Orthopedic Surgeons in the United States: An Analysis of Sociodemographic Factors.

BACKGROUND: It is unclear how pediatric orthopedic surgeons are geographically distributed relative to their patients. The purpose of this study was to evaluate the geographic distribution of pediatric orthopedic surgeons in the United States. MATERIALS AND METHODS: County-level data of actively practicing pediatric orthopedic surgeons were identified by matching several registries and membership logs. Data were used to calculate the distance between counties and nearest surgeon. Counties were categorized as "surgeon clusters" or "surgeon deserts" if the distance to the nearest surgeon was less than or greater than the national average and the average of all neighboring counties, respectively. Cohorts were then compared for differences in population characteristics using data obtained from the 2020 American Community Survey. RESULTS: A total of 1197 unique pediatric orthopedic surgeons were identified. The mean distance to the nearest pediatric orthopedic surgeon for a patient residing in a surgeon desert or a surgeon cluster was 141.9±53.8 miles and 30.9±16.0 miles, respectively. Surgeon deserts were found to have lower median household incomes (P<.001) and greater rates of children without health insurance (P<.001). Multivariate analyses showed that higher Rural-Urban Continuum codes (P<.001), Area Deprivation Index scores (P<.001), and percentage of patients without health insurance (P<.001) all independently required significantly greater travel distances to see a pediatric orthopedic surgeon. CONCLUSION: Pediatric orthopedic surgeons are not equally distributed in the United States, and many counties are not optimally served. Additional studies are needed to identify the relationship between travel distances and patient outcomes and how geographic inequalities can be minimized. [Orthopedics. 202x;4x(x):xx-xx.].

Incidental dural tears during pediatric posterior spinal fusions.

PURPOSE: To characterize the frequency of incidental dural tears in pediatric spine surgery, their treatment, complications, and results of long-term follow-up. METHODS: A retrospective review of all pediatric patients who underwent a posterior spinal fusion (PSF) between 2004-2019 at a tertiary children's hospital was conducted. Electronic medical records were reviewed for patient demographics, intra-operative data, presence of an incidental dural tear, repair method, and patient outcomes. RESULTS: 3043 PSFs were reviewed, with 99 dural tears identified in 94 patients (3.3% overall incidence). Mean follow-up was 35.7 months (range 0.1-142.5). When the cause of the dural tear was specified, 69% occurred during exposure, 5% during pedicle screw placement, 4% during osteotomy, 2% during removal of implants, and 2% during intra-thecal injection of morphine. The rate of dural tears during primary PSF was significantly lower than during revision PSF procedures (2.6% vs. 6.2%, p < 0.05). 86.9% of dural tears were repaired and/or sealed intraoperatively, while 13.1% had spontaneous resolution. Postoperative headaches developed in 13.1% of patients and resolved at a mean of 7.6 days. There was no difference in the incidence of headaches in patients that were ordered bedrest vs. no bedrest (p > 0.99). Postoperative infections occurred in 9.5% of patients and 24.1% patients were identified to have undergone a revision surgery. CONCLUSIONS: Incidence of intra-operative dural tears in pediatric spine surgery is 3.3%. Although complications associated with the dural tear occur, most resolve over time and there were no long-term sequelae in patients with 2 years of follow up. LEVEL OF EVIDENCE: Level IV.

Risk Factors for Reoperation Following Single-Level Cervical Disc Arthroplasty as Utilized in a Representative Sample of United States Clinical Practice: A Retrospective PearlDiver Study.

STUDY DESIGN: Retrospective Cohort. OBJECTIVES: Most data regarding cervical disc arthroplasty (CDA) outcomes are from highly controlled clinical trials with strict inclusion/exclusion criteria. This study aimed to identify risk factors for CDA reoperation, in "real world" clinical practice using a national insurance claims database. METHODS: The PearlDiver database was queried for patients (2010-2020) who underwent a subsequent cervical procedure following a single-level CDA. Patients with less than 2 years follow-up were excluded. Primary outcome was to evaluate risk factors for reoperation. Secondary outcome was to evaluate the types of reoperations. Risk factors were compared using descriptive statistics. Multivariate regression analyses were used to ascertain the association among risk factors and reoperation. RESULTS: Of 14,202 patients who met inclusion criteria, 916 (6.5%) underwent reoperation. Patients undergoing reoperation were slightly older with higher Elixhauser Comorbidity Index (ECI) scores, however both were not risk factors for reoperation. Patients with diagnoses such as smoking, myelopathy, inflammatory disorders, spinal deformity, trauma, or a history of prior cervical surgery were at greater risk for reoperation. No association was found between the year of index surgery and reoperation risk. The most common reoperation procedure was cervical fusion. CONCLUSIONS: As billed for in the United States since 2010, CDA was associated with a 6.5% reoperation rate over a mean follow-up time of 5.3 years. Smoking, myelopathy, inflammatory disorders, spinal deformity, and a history of prior cervical surgery or trauma are risk factors for reoperation following CDA. Though patients who underwent a reoperation were older, age was not found to be an independent risk factor for a subsequent procedure.

Single-Level Anterolateral and Posterior Interbody Fusion Techniques are Associated with Equivalent Long-Term Lumbar Reoperations.

STUDY DESIGN: Retrospective Cohort Study. OBJECTIVE: This study compares reoperation rates and complications following single-level ALIF/LLIF and TLIF/PLIF. SUMMARY OF BACKGROUND DATA: Anterior lumbar interbody fusion (ALIF), lateral lumbar interbody fusion (LLIF), transforaminal lumbar interbody fusion (TLIF), and posterior lumbar interbody fusion (PLIF) are widely used for degenerative disc disease. Lumbar interbody fusions have high rates of reoperation primarily related to adjacent segment pathology and pseudarthrosis. METHODS: The PearlDiver database was queried for patients (2010-2021) who had single-level ALIF/LLIF or TLIF/PLIF with same-day, single-level posterior instrumentation. ALIF/LLIF were combined and similarly, TLIF/PLIF were combined, given how these operations are indistinguishable with Current Procedural Terminology (CPT) coding. All patients were followed for ≥2 years and excluded if they had spinal traumas, fractures, infections, or neoplasms prior to surgery. The two cohorts, ALIF/LLIF and TLIF/PLIF, were matched 1:1 based on age, sex, Elixhauser-Comorbidity Index (ECI), smoking status, and diabetes. The primary outcome was the incidence of all-cause subsequent lumbar operations. Secondary outcomes included 90-day surgical complications. RESULTS: After 1:1 matching, each cohort contained 14,070 patients. All-cause subsequent lumbar operations were nearly identical at 5-year follow-up (9.4% ALIF/LLIF vs. 9.5% TLIF/PLIF, P=0.91) (Table 2). Survival analysis using all-cause subsequent lumbar operations as the endpoint showed an equivalent 10-year survival rate of 86.0% (95%CI: 85.2-86.8) (Figure 1). Within 90 days, TLIF/PLIF had more infections (1.3% vs. 1.7%, P=0.007) and dural injuries (0.2% vs. 0.4%, P=0.001). There was no difference in wound dehiscence, hardware complications, or medical complications (Table 3). CONCLUSION: As utilized in real-world clinical practice, single-level anterolateral versus posterior approaches for interbody fusion have no effect on long term reoperation rates.

Vertebral Artery Dissection in the Setting of Unstable Os Odontoideum: A Case Report.

CASE: A healthy 5-year-old boy presented with a gradual onset of headaches and acute global right-sided weakness over 10 days. The work-up revealed unstable os odontoideum leading to multiple posterior circulation infarcts with vertebral artery dissection. He underwent antiplatelet therapy, cervical collar immobilization, and delayed occiput to C2 posterior spinal fusion and instrumentation with iliac crest autograft. At 2-year follow-up, the patient had a solid fusion mass, appropriate cervical alignment, and was without neurologic sequelae. CONCLUSION: This case adds to a sparse body of literature in the management of vertebral artery dissection with vertebrobasilar insufficiency secondary to unstable os odontoideum.

New technique and case report: Robot-assisted intralaminar screw fixation of spondylolysis in an adolescent.

Introduction: Management of spondylolysis in adolescents is generally successful with conservative management. Uncommonly, surgical fixation is necessary for refractory cases. Direct repair with intralaminar screws is one commonly utilized technique. Recently, less invasive spinal procedures are becoming viable with the enabling of technologies, including robotics. Case description: A 14-year-old baseball player and surfer presented with low back pain, diagnosed by MRI as bony edema and stress fractures of the posterior spinal elements. After 18 months, the pain was unresponsive to rest, physical therapy, and bracing. There was no radicular pain or neurologic symptoms. Computed tomography (CT) revealed bilateral, chronic nonhealing pars defects at L5. He underwent outpatient, robot-assisted percutaneous intralaminar fixation with hydroxyapatite-coated screws through a 2 cm skin incision. Outcome: On postoperative day 1, the patient reported relief of his preoperative pain and he was ambulating without difficulty. At 2 weeks follow-up, the patient was completely pain free and surfing. At 2 months follow-up, low-dose CT demonstrated partial incorporation of the hydroxyapatite-coated screws, and the patient returned to sports. At 6 months follow-up, the patient had no pain and was swinging his baseball bat with full force. Low-dose CT revealed complete healing of the defects with full incorporation of the hydroxyapatite-coated screws. Conclusions: A novel minimally invasive robotic percutaneous approach for direct spondylolysis repair using hydroxyapatite-coated screws is a potential surgical treatment option for non-healing pars defects in adolescent patients.

Influence of demographic change on the demand for radiotherapy using forecasted predictions for prostate cancer in Germany.

PURPOSE: Demographic change will lead to an increase in age-associated cancers. The demand for primary treatment, especially oncologic therapies, is difficult to predict. This work is an attempt to project the demand for radiation therapy (RT) in 2030, taking into account demographic changes using prostate cancer (PC) as an example. MATERIALS AND METHODS: Using the GENESIS database of the Federal Statistical Office, we retrieved demographic population projections for 2030 and retrospective demographic surveys from 1999 to 2019. Additionally, we queried incidence rates for PC in the respective age groups of 50-54, 55-59, 60-64, 65-69, 70-74, 75-79, 80-84, and +85 years from 1999-2019 via the Federal Cancer Registry of the Robert Koch Institute. We used a regression method to determine the age-dependent correlation between the incidence of PC and the population size of the respective age group by combining the data from 1999 to 2019. This information was used to calculate the incidence rates in the age groups of the expected population for 2030 and the expected new cases of PC in 2030. Finally, we extrapolated the indications for the demand for RT based on data from the Report on Cancer Incidence in Germany from 2016. RESULTS: Considering a population-dependent incidence rate, an increase in new cases of PC is expected. This increase is particularly evident in the age groups of 70-74 and 80-84 years. With regards to RT, the estimate indicates an overall increase of 27.4% in demand. There is also a shift in RT demands towards older patients, especially in the 80- to 84-year-old age group. CONCLUSION: We observe an age-associated increase in primary cases of PC. This is likely to result in an increased demand for RT. The exact demand cannot be predicted. However, trends can be estimated to plan for the demand. This, though, requires a good database from cancer registries.

Medical Encounters and Treatment Outcomes in Ironman-Distance Triathlon.

PURPOSE: This study aimed to examine the injury and illness characteristics, treatments, and outcomes at elite ultraendurance triathlon events. METHODS: We quantified participant demographics, injury types, treatments, and disposition for medical encounters at 27 Ironman-distance triathlon championships from 1989 to 2019. We then calculated the likelihood of concurrent medical complaints in each encounter. RESULTS: We analyzed 10,533 medical encounters among 49,530 race participants for a cumulative incidence of 221.9/1000 participants (95% confidence interval [CI] = 217.7-226.2). Younger (<35 yr; 259.3/1000, 95% CI = 251.6-267.2) and older athletes (70+ yr; 254.0/1000, 95% CI = 217.8-294.4) presented to the medical tent at higher rates than middle-age adults (36-69 yr; 180.1/1000, 95% CI = 175.4-185.0). Female athletes also presented at higher rates when compared with males (243.9/1000, 95% CI = 234.9-253.2 vs 198.0/1000, 95% CI = 193.4-202.6). The most common complaints were dehydration (438.7/1000, 95% CI = 426.2-451.6) and nausea (400.4/1000, 95% CI = 388.4-412.6). Intravenous fluid was the most common treatment (483/1000; 95% CI = 469.8-496.4). Of the athletes who received medical care, 116.7/1000 (95% CI = 110.1-123.4) did not finish the race, and 17.1/1000 (95% CI = 14.7-19.8) required hospital transport. Athletes rarely presented with an isolated medical condition unless their injury was dermatologic or musculoskeletal in nature. CONCLUSIONS: Ultraendurance triathlon events have high rates of medical encounters among female athletes, as well as both younger and older age categories. Gastrointestinal and exertional-related symptoms are among the most common complaints. Intravenous infusions were the most common treatment after basic medical care. Most athletes entering the medical tent finished the race, and a small percentage were dispatched to the hospital. A more thorough understanding of common medical occurrences, including concurrent presentations and treatments, will allow for improved care and optimal race management.

High affinity binding of paclitaxel to human serum albumin.

Paclitaxel, a very potent antitumor agent is a hydrophobic molecule with low aqueous solubility. Its currently used formula (Taxol) contains the drug in a 1 : 1 (v/v) mixture of ethanol and Cremophor EL. To minimize vehicle-related toxicity, we developed a novel, water-soluble formulation in which paclitaxel is bound noncovalently to human serum albumin. For this purpose, studies of the paclitaxel-albumin binding equilibrium were performed. Paclitaxel dissolved in ethanol was added to the aqueous solution of human serum albumin. Precipitated paclitaxel was removed and unbound drug was separated by ultrafiltration. Paclitaxel concentration was measured by RP-HPLC. Binding data were evaluated based both on the Scatchard plot and the general binding equation describing binding equilibria with the stepwise stoichiometric binding constants. The Scatchard plot was found to be curvilinear with a slight positive slope of the final part. Parameters of high affinity specific binding were determined from the initial part of the curve (nsp = 1.3 and Ksp = 1.7 x 10(6) M(-1)). Stoichiometric binding constants were estimated by fitting the general binding equation to the experimental data (K1 = 2.4 x 10(6) M(-1) and K2 = 1.0 x 10(5) M(-1)). Saturation of the protein with paclitaxel, similarly to other ligands of albumin, could not be reached. The greatest observed value of r (number of paclitaxel molecules bound to one albumin molecule) was 6.6.

Specific reverse transcription-PCR quantification of vascular endothelial growth factor (VEGF) splice variants by LightCycler technology.

BACKGROUND: Overexpression of vascular endothelial growth factor (VEGF) is associated with increased angiogenesis, growth and invasion in solid tumors, and hematologic malignancies. The expression of isoforms of VEGF, which mediate different effects, can be discriminated by splice-variant-specific quantitative reverse transcription-PCR (RT-PCR), but current methods have only modest sensitivity and precision and suffer from heteroduplex formation. METHODS: We used a real-time RT-PCR assay on the LightCycler system. Applicability for detection of different VEGF mRNAs and total VEGF message was tested on seven healthy tissues (each pooled from healthy donors) and seven correlated malignant tissues. Results were normalized to beta(2)-microglobulin mRNA. Amplification of VEGF splice variants was performed exclusively with variant-specific reverse primers, whereas forward primer and fluorescent probe were common to obtain similar RT-PCR kinetics. RESULTS: Highly specific detection of VEGF splice variants was achieved with minor intra- and interassay variation (<0.22 threshold cycle). Total VEGF expression was higher in malignant tissues. In healthy tissues, the mRNA encoding diffusible variants VEGF(121) and VEGF(165) constituted on average 78% (SD = 9.3%) of the total VEGF message, and the cell-adherent variant VEGF(189) constituted on average 22% (SD = 5.4%). In contrast, in malignant tissues VEGF(121) and VEGF(165) accounted for 94% (SD = 7.6%) and VEGF(189) only 6% (SD = 3.7%). CONCLUSIONS: Because of the ability for quantification of VEGF splice variants with high specificity, sensitivity, and reproducibility, this new LightCycler assay is superior to conventional semiquantitative competitive RT-PCR and immunological assays and may contribute to better understanding of VEGF-mediated angiogenesis.

Multistep mechanism of substrate binding determines chaperone activity of Hsp70.

The 70 kDa heat shock proteins (the Hsp70 family) assist refolding of their substrates through ATP-controlled binding. We have analyzed mutants of DnaK, an Hsp70 homolog, altered in key residues of its substrate binding domain. Substrate binding occurs by a dynamic mechanism involving: a hydrophobic pocket for a single residue that is crucial for affinity, a two-layered closing device involving independent action of an alpha-helical lid and an arch, and a superimposed allosteric mechanism of ATP-controlled opening of the substrate binding cavity that operates largely through a beta-structured subdomain. Correlative evidence from mutational analysis suggests that the ADP and ATP states of DnaK differ in the frequency of the conformational changes in the alpha-helical lid and beta-domain that cause opening of the substrate binding cavity. The affinity for substrates, as defined by this mechanism, determines the efficiency of DnaJ-mediated and ATP hydrolysis mediated locking-in of substrates and chaperone activity of DnaK.

Investigation of the interaction between DnaK and DnaJ by surface plasmon resonance spectroscopy.

Hsp70 chaperones assist protein folding through ATP-regulated transient association with substrates. Substrate binding by Hsp70 is controlled by DnaJ co-chaperones which stimulate Hsp70 to hydrolyze ATP and, consequently, to close its substrate binding cavity allowing trapping of substrates. We analyzed the interaction of the Escherichia coli Hsp70 homologue, DnaK, with DnaJ using surface plasmon resonance (SPR) spectroscopy. Resonance signals of complex kinetic characteristics were detected when DnaK was passed over a sensor chip with coupled DnaJ. This interaction was specific as it was not detected with a functionally defective DnaJ mutant protein, DnaJ259, that carries a mutation in the HPD signature motif of the conserved J-domain. Detectable DnaK-DnaJ interaction required ATP hydrolysis by DnaK and was competitively inhibited by chaperone substrates of DnaK. For DnaK mutant proteins with amino acid substitutions in the substrate binding cavity that affect substrate binding, the strength of detected interaction with DnaJ decreased proportionally with increased strength of the substrate binding defects. These findings indicate that the detected response signals resulted from DnaJ and ATP hydrolysis-dependent association of DnaJ as substrate for DnaK. Although not considered as physiologically relevant, this association allowed us to experimentally unravel the mechanism of DnaJ action. Accordingly, DnaJ stimulates ATP hydrolysis only after association of a substrate with the substrate binding cavity of DnaK. Further analysis revealed that this coupling mechanism required the J-domain of DnaJ and was also functional for natural DnaK substrates, and thus is central to the mechanism of action of the DnaK chaperone system.

Effect of etoposide on the pharmacokinetics of methotrexate in vivo.

The effect of etoposide on the pharmakokinetics of methotrexate (MTX) was examined in vivo. High-dose (5g/m2/24 h) MTX therapy was combined with two etoposide (100mg/m2/ 1 h) infusions as a part of the medulloblastoma protocol developed in our department. Vepesid therapy was administered in two different schedules. The first group of patients received etoposide immediately before and at the end (24 h) of MTX treatment. The second group was treated with etoposide at 24 and at 48 h after starting MTX infusion. In this latter group both treatment-related grade III and grade IV toxicity developed more frequently than in the first group (58.6 versus 29.2%, for grade 3 toxicity p=0.019, for grade 4 toxic signs p=0.040, respectively). We observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum MTX levels (determined by high-performance liquid chromatography) were elevated by 53-109 and 26-65%, respectively, by the third hour after completion of Vepesid infusion. This effect was detectable for 6 h. All the liver and kidney functions of the patients were within the normal range. These results suggest the possibility of partial recirculation of extra/intracellular MTX into the blood after etoposide administration. Based on these results, the therapeutic protocol has been modified, and Vepesid is given prior to and at the end (24 h) of high-dose MTX treatment. Under these conditions only a slight decrease of MTX elimination has been detected between 25 and 28 h. These results emphasize the role of possible schedule-dependent interactions of cytostatic drugs.

Basal transcription factors TBP and TFIIB and the viral coactivator E1A 13S bind with distinct affinities and kinetics to the transactivation domain of NF-kappaB p65.

Transactivation domains (TADs) are able to contact several components of the basal transcription apparatus and co-activator molecules. In order to study these interactions in biophysical detail, binding of the well-characterized TAD from the human transcription factor NF-kappaB p65 (RelA) to the basal transcription factors TBP and TFIIB and the viral co-activator protein E1A 13S was chosen as a model system to investigate the kinetics and affinities of such protein-protein interactions by surface plasmon resonance analysis. The TAD of NF-kappaB p65 showed remarkably different affinities and kinetics in binding to the various proteins. The real-time kinetic measurements revealed an association rate constant (kass) of 2.3 x 10(6)/M/s for the interaction between the p65 TAD and TBP. The association rate constants of the p65 TAD were much weaker for TFIIB (6.8 x 10(4)/M/s) and for the E1A 13S protein (4.9 x 10(4)/M/s). The dissociation rate constants (kdiss) were determined to be 7.9 x 10(-4)/s for TBP, 1.6 x 10(-3)/s for TFIIB and 1.3 x 10(-3)/s for the E1A protein. Accordingly, the calculated dissociation constants (Kd) differed between 3.4 x 10(-10)M for the strongly binding TBP protein and 2.3 x 10(-8)M and 2.6 x 10(-8)M for the weaker binding TFIIB and E1A 13S proteins respectively. Non-linear analysis of the appropriate part of the sensorgrams revealed monophasic association and dissociation kinetics for binding between the p65 TAD and all three interaction partners. The remarkable differences in protein affinities add another aspect to a more detailed understanding of formation of the transcription preinitiation complex. The co-transfection of TBP and E1A 13S stimulated NF-kappaB p65-dependent gene expression, showing the biological significance of these interactions.

[In vivo effect of etoposide on the pharmacokinetics of methotrexate]. / Az etoposid hatása a metotrexát farmakokinetikájára in vivo.

High dose (5 g/m2/24 h) methotrexate therapy was combined two times with etoposide (100 mg/m2/1h) infusions as a part of the Medulloblastoma protocol developed in our Department Vepesid therapy was administered in two different schedules. The first group of the patients have received etoposide immediately before and at the end (24th h) of methotrexate treatment. The second group was treated with etoposide at 24 h and at 48 hour after starting methotrexate infusion. In this latter group treatment related grade 3-4 toxicity developed more frequently than in the first group (58.6% vs 33.3%). The authors observed that after the second dose of etoposide given at 48 h (second group) both total and unbound serum methotrexate levels (determined by high performance liquid chromatography) were elevated by 53.14-109.19%, and 25.86-64.95%, respectively by the third hour after completion of Vepesid infusion. This effect was detectable for 6 hours. All the liver and kidney functions of the patients were in the normal range. These results suggest the possibility of partial recirculation of extra/intracellular methotrexate into the blood after etoposide administration. Based on these results the therapeutic protocol has been modified and Vepesid is given prior to and at the end (24 h) of high dose methotrexate treatment. Under these conditions only a slight decrease of methotrexate elimination has been detected between the 25-28th h. These results emphasize the role of possible schedule dependent interactions of cytostatic drugs.

[Pharmacokinetic study of dibromodulcitol in children with brain tumors]. / A dibrómdulcit farmakokinetikai vizsgálata agytumoros gyermekekben.

Systemic pharmacokinetics of high-dose (500 mg/m2), orally administered dibromodulcitol (Elobromol) were studied in 16 chemotherapeutic courses administered to 5 patients. Cerebrospinal fluid dibromodulcitol levels were also analysed in two patients. Bromoepoxydulcitol, dianhydrodulcitol are cytotoxic, whereas bromoanhydrodulcitol, andhydroepoxydulcitol are inactive metabolites detectable during the biotransformation of dibromodulcitol. The HPLC method, developed by our team, is suitable for the determination of both dibromodulcitol and its main metabolites (dianhydrodulcitol and bromoanhydrodulcitol). Our publication is the first in the literature to describe the pharmacokinetic properties of these three hexite-derivatives in pediatric patients. With the exception of one patient, concentration-time curves were analysed by the one-compartment model. From the 30th minute following administration, dibromodulcitol was detectable in all plasma samples for at least 12 hours, its concentration however was usually undetectable by the 24th hour. Though highly variable in value, dianhydrodulcitol concentrations were detectable during all but one therapeutic courses. The following peak concentrations were observed: dibromodulcitol: 3.46-30.63 microM; dianhydroldulcitol: 1.70-6.17 microM; bromoanhydrodulcitol: 0-5.63 microM. The correlation of area under the curve for bromoanhydrodulcitol and dibromodulcitol was exponential up to 200 microMxh with no additional increase detectable above this limit; the distribution of dianhydrodulcitol values were described by a maximum-curve. The possibility of enterohepatic recirculation could not be excluded for any of the compounds studied. Each of the three hexitol derivatives were detectable in the cerebrospinal fluid even if the concentration of the individual metabolite remained undetectable in plasma. The cerebrospinal fluid concentrations of dibromodulcitol were almost constant in the period from 2.5 to 8 hours following administration.(ABSTRACT TRUNCATED AT 250 WORDS)