• Biomolecules & Therapeutics
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• 제10권1호
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• pp.37-42
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• 2002

Brain drug targeting through the blood-brain barrier (BBB) in vivo is possible with peptidornirnetic monoclonal antibodies that undergo receptor-mediated transcytosis through the BBB. Monoclonal antibody to the rat transferrin receptor, such as the OX26 was studied in rats as a transport vector through BBB on the transferrin receptor. But, OX26 is not an effective brain delivery vector in mouse. In the present studies, rat monoclonal antibody, 8D3 to the mouse transferrin receptor were evaluated for brain drug targeting vector intransgenic mouse model. Pharrnacokinetic parameters in plasma and organ uptakes were determined at varioustimes after i.v. bolus injection of [$^{}125}I$] 8D3 in Balb/c mice. Brain uptake of [$^{}125}I$] 8D3 was also studied with an internal carotid artery perfusioncapillary depletion method. After i.v. injection of [$^{}125}I$] 8D3, plasma concentrations declined biexponentially with elimination half lift of approximately 2.2 hours. Brain uptake of [$^{}125}I$] 8D3 was $0.50{\pm}0.09$ persent of injected dose per g brain after 2 hours i.v. injection. After perfusion 5 min the apparent volume of distibution of [$^{}125}I$] 8D3 in brain was $22.3 {\mu}l/g,$ which was 4.8 fold higher than the intravascular volume. These studies indicate rat monoclonal antibody to the mouse transferrin receptor, 8D3 may be used for brain drug targeting vector in mice.

• 대한약학회:학술대회논문집
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• 대한약학회 2000년도 춘계총회 및 학술대회
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• pp.142.1-142.1
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• 2000

• 약학회지
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• 제42권2호
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• pp.196-204
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• 1998

The blood-brain barrier (BBB) of rats was modificated opening reversibly by infusing a hyperosmotic solution of arabinose (1.6 molal) into the right external carotid artery. Pre vious studies demonstrated that permeability was increased maxmmally in the first 15 min and remained slightly elevated at 1 hr. As control reference, saline was used. In the present study, to evaluate the effects of osmotic BBB opening on the BBB trasport according to hydrophilic or hydrophobic characteristics of drugs. And the differences of the uptakes of these compounds to right (treated osmotic opening) and left (untreated) hemispheres in same rats were compared each other following injection of 8 mCi per rat of $^{99m}Tc$-ethylene triamine pentaacetic acid (DTPA) as hydrophilic drug or 5mg/kg of phenytoin as hydrophobic drug mto the right external carotid artery of rats between two groups (1.6 molal arabinose vs saline). The uptakes of $^{99m}Tc$-DTPA and phenytoin in the right cerebral hemispheres were increased to about thirty three times and twice rather than those in the left cerebral heimspheres, respectively. And PAs (permeability X capillary surface area) were also increased from a control mean of 2.11${\times}10^{-4}$ (Untreated) to 6.98${\times}10^{-3}\;sec^{-1}$ (treated osmotic opening for $^{99m}Tc$-DTPA and 0.29 to 0.17 $sec^{-1}$ for phenytoin, respectively. From the results of present study, it is noted that osmotic opening of BBB is more effective in the brain delivery of hydrophilic drugs rather than that of hydrophobic drugs.

• Biomolecules & Therapeutics
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• 제8권2호
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• pp.194-198
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• 2000

Taurine, 2-aminoethanesulfonic acid is widely distributed in animal tissues and has a variety of bio-logical activities. A recent worldwide study demonstrated beneficial effects of taurine on aging and age-associated disorders. In general, taurine levels in the brain decease when an animal is subjected to pathologic conditions such as ischemia-anoxia and seizure. But the taurine levles tend to increase in the brain in hypertensive state. In the present study, the blood-brain barrier (BBB) transport of [$^3$H]taurine was compared between spontaneously hypertensive rats (SHR) and normotensive Sprague-Dawley rats (SD) using intravenous injection technique in vivo. We also obtained pharmacokinetic parameters of plasma volume maker, [$^{14}$ C] sucrose and [$^3$H]taurine after inject to rats simulatenously. BBB permeability surface area product (PS) value of [$^3$H]taurine in SHR (16$\pm$2.9$\times$10$^{-3}$ ml/min/g) was significantly higher than that in SD (7.4$\pm$0.8$\times$10$^{-3}$ ml/min/g). There is also significant difference for brain uptake of [$^3$H]taurine between SHR (0.195$\pm$0.031%ID/g) and SD (0.058$\pm$0.003% ID/g). This is due to difference of area under the plasma concentration-time curve (AUC) and that of total clearance (Class) between SHR and SD. No significant difference was indicated from other organ uptakes such as lung, heart, liver SHR and SD. But also kidney uptake was much higher in SHR. In conclusion, [$^3$H]taurine in plasma was slowly eliminated in SHR than in SD and uptake of [$^3$H]taurine in SHR is much higher than that of SD. This results suggest increased taurine level in the brain in hypertension state have an any effect on the brain uptake of taurine.

• Journal of Pharmaceutical Investigation
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• 제29권2호
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• pp.87-92
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• 1999

Drug delivery to the brain may be achieved by producing chimeric peptide, attaching the drug to protein 'vectors' which are transported into the brain from the blood by a receptor-mediated transcytosis through the blood-brain barrier (BBB). Since the BBB expresses high concentrations of transferrin receptor, and it was reported that anti-transferrin receptor mouse monoclonal antibody (OX26) undergoes transcytosis through the BBB, it is logical to assume that a drug delivery system via transferrin receptor-mediated transcytosis is a promising strategy. In the present study, therefore, we tested feasibility of several OX26 based vectors for the brain delivery of a model drug. Avidin-based delivery vectors such as OX26-streptavidin (OX26-SA), OX26-neutralite avidin (OX26-NLA) were chemically synthesized vectors and OX26 immunoglobulin G 3 type $C_{H}3$ fusion avidin $(OX26\;IgG3C_H3-AV)$ was genetically engineered. To improve the efficiency of producing chimeric peptide, we used avidin-biotin technology. Pharmacokinetics of $[^3H]biotin$ bound to OX26-SA, OX26-NLA and $OX26\;IgG3C_H3-AV$ was determined by intravenous injection technique, and their stabilities in plasma were analyzed using HPLC. The brain delivery of $[^3H]biotin$ bound to OX26-SA, OX26-NLA and OX26\;$IgG3C_{H}3-AV$ (expressed as %ID/g brain) was $0.22{\pm}0.01$, $0.18{\pm}0.01$ and $0.25{\pm}0.09$, respectively. The areas under the plasma concentration versus time curve (AUC) for OX26-SA, OX26-NLA, $OX26\;IgG3C_H3-AV$ from time zero to 60 min were $209{\pm}10$, $195{\pm}9$, $134{\pm}29\;%ID\;min/ml$ respectively and their total clearances $(CL_{tot})$ were $1.00{\pm}0.09$, $1.08{\pm}0.07$ and $1.54{\pm}0.29\;ml/min/kg$, espectively. These results showed that these vectors possess preferable pharmaceutical (e.g., resonable stability) and pharmacokinetics (e.g., significant brain uptake and enhanced AUC) for brain delivery. Therefore, these vectors may be broadly useful in the brain delivery of drugs that are not transported into the brain to a significant extent.

• 대한핵의학회지
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• 제35권1호
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• pp.69-74
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• 2001

목적: $^{99m}Tc$-HMPAO는 뇌혈류영상에 사용되는 방사성의약품으로, HMPAO (RR,SS)-4,8-diaza-3,6,6,9-tetramethylundecan-2,10-dione bisoxime)는 3개의 입체이성체(meso-, d-, l-HMPAO)가 존재한다. $^{99m}Tc$표지 meso-HMAPO와 d,l-HMPAO는 체내에서 뇌섭취에 차이를 나타낸다. 이 연구에서는 d,l-HMPAO 입체이성체 혼합물을 d-형과 l-형으로 분리하여 각각을 $^{99m}Tc$으로 표지하여 생체내분포를 비교하고자 하였다. 대상및 방법: 2,3-Butanedione monooxime과 2,2-dimethyl-1,3-propanediamine을 반응시켜 imine 형태의 중간화합물(수율: 54%)을 얻었다. 이를 환원시켜 d,l-과 meso-HMAPO 혼합물을 얻었다(수율 : 31%). 이것을 4번 분별결정하여 miso-HMPAO를 분리하였다(수율: 11%). d,l-라세미 혼합불은 (+)-타르타르 산과 (-)-타르타르 산을 이용하여 d-형과 l-형을 분리하였다(수율 25%, 5%). 합성한 각 입체이성체 HMPAO를 환원제로 $SnCI_2{\cdot}2H_2O$를 이용하여 $^{99m}Tc$으로 표지한 후, 마우스에 투여하여 1 시간 후 생체내분포를 확인하였다. 결과: 우리는 각 입체이성체 HMAPO를 합성하고 핵자기공명분광기와 선광도측정기를 이용하여 구조를 확인하였다. $^{99m}Tc$ 표피후 지용성 $^{99m}Tc$HMPAO의 방사화학적 순도는 80% 이상이었다. 각 입체이성체(d,l-, d-, l- HMPAO)의 뇌섭취율은 1.34, 1.12, 1.67% ID/g으로, l-형이 d-형보다 1.5 배 더 높았다. 결론: 우리는 각 입체이성체 HMPAO를 성공적으로 합성하였다. l-HMPAO를 분리하여 사용할 경우 보다 나은 영상을 기대할 수 있을 것으로 생각한다.

• 대한핵의학회지
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• 제29권3호
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• pp.328-331
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• 1995

$^{99m}Tc$ labeled PnAO(propylene amine oxime) derivatives have been widely studied as brain perfusion agents. We synthesized and characterized a PnAO derivative, (RR/SS/ meso)-4,8-diaza-3,9-dimethylundecane-2, 10-dione bisoxime(PRODD). Proton-NMR spectroscopy and thin layer chromatography(silica gel) were performed for its characterization. PRODD was labeled with $^{99m}Tc$ using stannous chloride as reducing agent. The labeling efficiency was determined to be about 85%. Brain uptakes of $4.16{\pm}0.42$ %ID/g and $3.24{\pm}0.13$ %ID/g were found after 10min and 30min after intravenous injection. Brain-to-blood ratios were 1.17 and 0.75 at 10 and 30 minutes, which were lower than 1.3 and 1.9 of the ratios with commercial ${\pm}$-HMPAO. Autoradiographs of rat brain sections showed the gray matter to white matter ratios of $1.13{\pm}0.10$ at 30 min after intravenous injection, which was lower than $1.94{\pm}0.19$ of commercial $^{99m}Tc$-HMPAO. With the above findings, we concluded that the lipophilic $^{99m}Tc$-PRODD complex was able to cross the blood-brain barrier, however the complex showed lower uptake than $^{99m}Tc$-HMPAO in mouse or rat brains. We could suggest possibility that PRODD could be used as another $^{99m}Tc$ chelator.

• Journal of Pharmaceutical Investigation
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• 제20권4호
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• pp.223-228
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• 1990

The contribution of endogenous transport systems to the blood-brain barrier (BBB) transport of basic and acidic drugs was studied by using a carotid injection technique in rats and an isolated bovine cerebrovascular disease state were compared between the normotensive rats (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) which have been well established as an animal model with pathogenic similarities to humans. Basic drugs such as eperisone, thiamine and scopolamine inhibited, in a concentration dependent manner the in vivo uptake of $[{^3}H]choline$ through BBB, whereas amino acids and acidic drugs such as salicylic acid and valproic acid did not inhibit the uptake. The uptake of $[^3H]choline$ by B-CAP increased with time and showed a remarkable temperature dependency. The uptake of $[^3H]choline$ by B-CAP showed the very similar inhibitory effects as observed in the in vivo brain uptake, and was competitively inhibited by a basic drug, eperisone. The in vivo BBB uptakes of $[^3H]acetic$ acid and $[^{14}C]salicylic$ acid were dependent on pH of the injectate and the concentration of drugs. Several acidic drugs such such as salicylic acid, benzoic acid and valproic acid inhibited the in vivo uptake of $[^3H]acetic$ acid, whereas amino acid, choline and a basic drug such as eperisone did not inhibit the uptake. The uptake of acetic acid by B-CAP was competitively inhibited by salicylic acid. The permeability surface area product (PS) through BBB for $[^3H]choline$ in SHRSP was significantly lower than that in WKY. The concentration of choline in the brain dialysate in SHRSP was about half of that in WKY, while no significant difference was observed in the plasma concentration of choline between SHRSP and WKY. No significant difference was observed in the transport of monocarboxylic acids, glucose and neutral amino acid through BBB between SHRSP and WKY. From these results, it was concluded that BBB transport system of choline contributes to the transport of basic drugs through BBB, that acidic drugs can be transported via a moncarboxylic acid BBB transport system and that the specific dysfuntion of the BBB choline transport in SHRSP was ascribed to the reduction of the maximum velocity of choline concentration in the brain interstitial fluids.

• Journal of Korean Neurosurgical Society
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• 제63권5호
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• pp.649-656
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• 2020

Objective : Unclear mental state is one of the major factors contributing to diagnostic failure of occult skeletal trauma in patients with traumatic brain injury (TBI). The aim of this study was to evaluate the overlooked co-occurring skeletal trauma through whole body bone scan (WBBS) in TBI. Methods : A retrospective study of 547 TBI patients admitted between 2015 and 2017 was performed to investigate their cooccurring skeletal injuries detected by WBBS. The patients were divided into three groups based on the timing of suspecting skeletal trauma confirmed : 1) before WBBS (pre-WBBS); 2) after the routine WBBS (post-WBBS) with good mental state and no initial musculoskeletal complaints; and 3) after the routine WBBS with poor mental state (poor MS). The skeletal trauma detected by WBBS was classified into six skeletal categories : spine, upper and lower extremities, pelvis, chest wall, and clavicles. The skeletal injuries identified by WBBS were confirmed to be simple contusion or fractures by other imaging modalities such as X-ray or computed tomography (CT) scans. Of the six categorizations of skeletal trauma detected as hot uptake lesions in WBBS, the lesions of spine, upper and lower extremities were further statistically analyzed to calculate the incidence rates of actual fractures (AF) and actual surgery (AS) cases over the total number of hot uptake lesions in WBBS. Results : Of 547 patients with TBI, 112 patients (20.4 %) were presented with TBI alone. Four hundred and thirty-five patients with TBI had co-occurring skeletal injuries confirmed by WBBS. The incidences were as follows : chest wall (27.4%), spine (22.9%), lower extremities (20.2%), upper extremities (13.5%), pelvis (9.4%), and clavicles (6.3%). It is notable that relatively larger number of positive hot uptakes were observed in the groups of post-WBBS and poor MS. The percentage of post-WBBS group over the total hot uptake lesions in upper and lower extremities, and spines were 51.0%, 43.8%, and 41.7%, respectively, while their percentages of AS were 2.73%, 1.1%, and 0%, respectively. The percentages of poor MS group in the upper and lower extremities, and spines were 10.4%, 17.4%, and 7.8%, respectively, while their percentages of AS were 26.7%, 14.2%, and 11.1%, respectively. There was a statistical difference in the percentage of AS between the groups of post-WBBS and poor MS (p=0.000). Conclusion : WBBS is a potential diagnostic tool in understanding the skeletal conditions of patients with head injuries which may be undetected during the initial assessment.

• 대한핵의학회지
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• 제29권1호
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• pp.22-30
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• 1995

저자들은 두개 기저나 경부종괴 또는 내경동맥의 동맥류등으로 인하여 내경동맥의 결찰이 필요한 환자에 있어서 객관적인 관점에서 수술전에 영구적인 내경동맥의 결찰의 안전성에 관하여 $^{99m}Tc$-HMPAO 뇌 SPECT를 이용하여 보고자 하였다. 내경동맥의 결찰이 고려되는 24명의 두개기저나 경부종괴 환자를 대상으로 하였다. 저자들은 풍선 시험 결찰술 시행전과 시행중의 양측 중대뇌동맥 영역의 섭취정도를 $^{99m}Tc$-HMPAO 뇌 SPECT를 이용하여 비교해보았고 이러한 결과를 신경학적 검사, 경동맥 스텀프압 고리고 뇌전도검사등과 비교해 보았다. 대상환자중 19명의 환자에서는 풍선 시험 결찰술 동안 신경학적 이상등의 문제들을 경험하지 않았고 이들에 있어 중대뇌동맥영역의 섭취정도는 결찰술 시행전에 비교하여 95-101%에 해당하였다. 나머지 5명의 환자에서는 일과성 반신마비와 의식소실등의 심한 신경학적 증상을 보였고 이들에 있어 중대뇌동맥 영역의 섭취정도는 시행전에 비하여 77-85%에 해당하였으며 다른 검사결과와도 잘 부합되었다. 결론적으로 풍선시험결찰술 시행전과 시행중의 $^{99m}Tc$-HMPAO 뇌 SPECT는 중대뇌동맥영역의 섭취가 시행전에 비교하여 85%이하인 경우 영구적인 신경학적 결손을 예측할 수 있는 간단하고 객관적인 방법이 될 수 있을 것으로 생각한다.