An experimental model to study the effects of a senna extract on the blood constituent labeling and biodistribution of a radiopharmaceutical in rats

ABSTRACT Cassia angustifolia Vahl (senna) is a natural product that contains sennosides, which are active components that affect the intestinal tract and induce diarrhea. Authors have shown that senna produces DNA (deoxyribonucleic acid) lesions in Escherichia coli cultures and can act as an antifungal agent. Natural drugs can alter the labeling of blood constituents with technetium-99m (^99mTc) and can affect the biodistribution of radiopharmaceuticals. In this work, we have evaluated the influence of a senna extract on the radiolabeling of blood constituents and on the biodistribution of the radiopharmaceutical sodium pertechnetate (Na^99mTcO₄) in Wistar rats. Twelve animals were treated with senna extract for 7 days. Blood samples were withdrawn from the animals and the radiolabeling procedure was carried out. The senna extract did not modify the radiolabeling of the blood constituents. A biodistributional assay was performed by administering Na^99mTcO₄ and determining its activity in different organs and in blood. The senna extract altered the biodistribution of Na^99mTcO₄ in the thyroid, liver, pancreas, lungs and blood. These results are associated with properties of the chemical substances present in the aqueous senna extract. Although these assays were performed in animals, our findings suggest that caution should be exercised when nuclear medicine examinations using Na^99mTcO₄ are conducted in patients who are using senna extract.     

Passive and active hepatoma tumor targeting of new N-(2-hydroxypropyl)methacrylamide copolymer conjugates: synthesis,characterization, and evaluation in vitro and in vivo

Human hepatocellular carcinoma (HCC) is one of the major causes of death worldwide. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific sulfapyridine HPMA (HPMA: N-(2-hydroxypropyl methacrylamide)) copolymer (sulfapyridine: SPD) conjugates, nonspecific HPMA copolymer conjugates, and DTPA are described in this study. The poly(HPMA)-SPD-DTPA (DTPA: diethylenetriaminepentaacetic acid), poly(HPMA)-DTPA, and DTPA conjugates were radiolabeled with the radionuclide ^99mTc and tested for uptake by cultured H22 cells. The cellular accumulation of poly(HPMA)-SPD-DTPA-^99mTc complex was found to be time-dependent. The poly(HPMA)-SPD-DTPA-^99mTc tracer exhibited rapid uptake kinetics in cell culture with a t _1/2 of ～5?min. The uptake of poly(HPMA)-SPD-DTPA-^99mTc was significantly higher than that of poly(HPMA)-DTPA-^99mTc, indicating that the uptake of the poly(HPMA)-SPD-DTPA-^99mT was active binding. The uptake of poly(HPMA)-DTPA-^99mTc was significantly higher than that of DTPA-^99mTc, suggesting that the uptake of the poly(HPMA)-DTPA-^99mT was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p?<?0.001) tumor localization for poly(HPMA)-SPD-DTPA-^99mTc (4.98?±?0.48%ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-^99mTc (2.69?±?0.15% ID/g) and DTPA-^99mTc (0.83?±?0.03%ID/g). Moreover, higher T/B for poly(HPMA)-SPD-DTPA-^99mTc indicated reduced extravazation of the targeted polymeric conjugates in normal tissues. Specific molecular targeting and nonspecific vascular permeability are both significant in the relative tumor localization of poly(HPMA)-SPD-DTPA-^99mTc. Extravascular leak in nonspecific organs appears to be a major factor in reducing the T/B for the sulfapyridine molecules. Thus, the poly(HPMA)-SPD-DTPA is expected to be used as the potential macromolecular targeting carrier for hepatoma carcinoma in mice.     

SPECT/CT imaging of radiolabeled cubosomes and hexosomes for potential theranostic applications

We have developed a highly efficient method for the radiolabeling of phytantriol (PHYT)/oleic acid (OA)-based hexosomes based on the surface chelation of technetium-99m (^99mTc) to preformed hexosomes using the polyamine 1, 12-diamino-3, 6, 9-triazododecane (SpmTrien) as chelating agent. We also report on the unsuccessful labeling of cubosomes using the well-known chelating agent hexamethylpropyleneamine oxime (HMPAO). The ^99mTc-labeled SpmTrien-hexosomes (^99mTc-SpmTrien-hexosomes) were synthesized with good radiolabeling (84%) and high radiochemical purity (>90%). The effect of radiolabeling on the internal nanostructure and the overall size of these aqueous dispersions was investigated by using synchrotron small angle X-ray scattering (SAXS), dynamic light scattering (DLS), and transmission electron cryo microscopy (cryo-TEM). Further, we show the utility of ^99mTc-SpmTrien-hexosomes for the in vivo imaging of healthy mice using single photon emission computed tomography (SPECT) in combination with computed tomography (CT), i.e. SPECT/CT. SPECT/CT experiments of subcutaneously administered ^99mTc-SpmTrien-hexosomes to the flank of mice showed a high stability in vivo allowing imaging of the distribution of the radiolabeled hexosomes for up to 24 h. These injected ^99mTc-SpmTrien-hexosomes formed a deposit within the subcutaneous adipose tissue, displaying a high biodistribution of ∼343% injected dose/g tissue (%ID/g), with negligible uptake in other organs and tissues. The developed ^99mTc labeling method for PHYT/OA-based hexosomes could further serve as a useful tool for investigating and imaging the in vivo performance of cubosomal and hexosomal drug nanocarriers.     

Tumor targeting HPMA-porphyrin-99mTc copolymer molecular imaging agent

Porphyrins typically show preferential uptake and retention by tumor tissues via receptor-mediated endocytosis of low-density lipoproteins. To investigate the relative importance of active and passive targeting strategies, the synthesis, characterization, in vitro uptake, and in vivo biodistribution of specific targeting porphyrin HPMA [HPMA: N-(2-hydroxypropyl)methacrylamide] copolymer tracer poly(HPMA)-porphyrin-DTPA-^99mTc (DTPA: diethylenetriaminepentaacetic acid), nonspecific targeting HPMA copolymer tracer poly(HPMA)-DTPA-^99mTc, and nontargeting tracer DTPA-^99mTc are described in this study. The results showed that the cellular accumulation of poly(HPMA)-porphyrin-DTPA-^99mTc complex was found to be time-dependent. The uptake of poly(HPMA)-porphyrin-DTPA-^99mTc was significantly higher than that of poly(HPMA)-DTPA-^99mTc, indicating that uptake of the poly(HPMA)-porphyrin-DTPA-^99mTc was active binding. The uptake of poly(HPMA)-DTPA-^99mTc was significantly higher than that of DTPA-^99mTc, suggesting that uptake of the poly(HPMA)-DTPA-^99mTc was passive binding. Twenty-four hour necropsy data in the hepatocellular carcinoma tumor model showed significantly higher (p < 0.001) tumor localization for poly(HPMA)-porphyrin-DTPA-^99mTc (5.18 ± 0.50% ID/g [percentage injected dose per gram tissue]) compared with poly(HPMA)-DTPA-^99mTc (2.69 ± 0.15% ID/g) and DTPA-^99mTc (0.83 ± 0.03% ID/g). Moreover, higher T/B for poly(HPMA)-porphyrin-DTPA-^99mTc indicated reduced extravasation of the targeted polymeric conjugates in normal tissues. Thus, the poly(HPMA)-porphyrin-DTPA-^99mTc is a potential macromolecular tumor targeting molecular agent.     

Sodium pertechnetate (Na99mTcO4) biodistribution in mice exposed to cigarette smoke

Background

The biological effects of cigarette smoke are not fully known. To improve our understanding of the action of various chemical agents, we investigated the biodistribution of sodium pertechnetate (Na^99mTcO₄) in mice exposed to cigarette smoke.

Methods

Fifteen BALB/c male mice were exposed to the smoke of nine whole commercial cigarettes per day, 3 times/day, for up to 10 days to whole body exposure in a chamber. A control group of 5 BALB/c male mice was sham-smoked. One day later, the exposed and control groups of mice received (7.4 MBq/0.3 ml) of Na^99mTcO₄ before being killed at 30 min. Bones, brain, heart, intestine, kidney, liver, lungs, muscle, pancreas, spleen, stomach, testis and thyroid were weighed and these organs and blood radioactivity recorded with a gamma counter. The percentage per gram of tissue of injected dose (%ID/g) was determined for each organ.

Results

Cigarette smoke significantly decreased (p < 0.05) the %ID/g in red blood cells, bone, kidney, lung, spleen, stomach, testis and thyroid of the exposed mice.

Conclusion

The toxic effects of cigarette smoke reduced the Na^99mTcO₄ biodistribution.     

Differential radio-sensitivities of human chromosomes 1 and 2 in one donor in interphase- and metaphase-spreads after 60Co γ-irradiation

Background

Skeletal uptake of ^99mTc labelled methylene diphosphonate (^99mTc-MDP) is used for producing images of pathological bone uptake due to its incorporation to the sites of active bone turnover. This study was done to validate bone turnover markers using total skeletal uptake (TSU) of ^99mTc-MDP.

Methods

22 postmenopausal women (52–80 years) volunteered to participate. Scintigraphy was performed by injecting 520 MBq of ^99mTc-MDP and taking whole body images after 3 minutes, and 5 hours. TSU was calculated from these two images by taking into account the urinary loss and soft tissue uptake. Bone turnover markers used were bone specific alkaline phosphatase (S-Bone ALP), three different assays for serum osteocalcin (OC), tartrate resistant acid phosphatase 5b (S-TRACP5b), serum C-terminal cross-linked telopeptides of type I collagen (S-CTX-I) and three assays for urinary osteocalcin (U-OC).

Results

The median TSU of ^99mTc-MDP was 23% of the administered activity. All bone turnover markers were significantly correlated with TSU with r-values from 0.52 (p = 0.013) to 0.90 (p < 0.001). The two resorption markers had numerically higher correlations (S-TRACP5b r = 0.90, S-CTX-I r = 0.80) than the formation markers (S-Total OC r = 0.72, S-Bone ALP r = 0.66), but the difference was not statistically significant. TSU did not correlate with age, weight, body mass index or bone mineral density.

Conclusion

In conclusion, bone turnover markers are strongly correlated with total skeletal uptake of ^99mTc-MDP. There were no significant differences in correlations for bone formation and resorption markers. This should be due to the coupling between formation and resorption.     

Comparison of two peptide radiotracers for prostate carcinoma targeting

OBJECTIVES:

Scintigraphy is generally not the first choice treatment for prostate cancer, although successful studies using bombesin analog radiopeptides have been performed. Recently, a novel peptide obtained using a phage display library demonstrated an affinity for prostate tumor cells. The aim of this study was to compare the use of a bombesin analog to that of a phage display library peptide (DUP-1) radiolabeled with technetium-99m for the treatment of prostate carcinoma. The peptides were first conjugated to S-acetyl-MAG3 with a 6-carbon spacer, namely aminohexanoic acid.

METHODS:

The technetium-99m labeling required a sodium tartrate buffer. Radiochemical evaluation was performed using ITLC and was confirmed by high-performance liquid chromatography. The coefficient partition was determined, and in vitro studies were performed using human prostate tumor cells. Biodistribution was evaluated in healthy animals at various time points and also in mice bearing tumors.

RESULTS:

The radiochemical purity of both radiotracers was greater than 95%. The DUP-1 tracer was more hydrophilic (log P = -2.41) than the bombesin tracer (log P = -0.39). The biodistribution evaluation confirmed this hydrophilicity by revealing the greater kidney uptake of DUP-1. The bombesin concentration in the pancreas was greater than that of DUP-1 due to specific gastrin-releasing peptide receptors. Bombesin internalization occurred for 78.32% of the total binding in tumor cells. The DUP-1 tracer showed very low binding to tumor cells during the in vitro evaluation, although tumor uptake for both tracers was similar. The tumors were primarily blocked by DUP-1 and the bombesin radiotracer primarily targeted the pancreas.

CONCLUSION:

Further studies with the radiolabeled DUP-1 peptide are recommended. With further structural changes, this molecule could become an efficient alternative tracer for prostate tumor diagnosis.     

Detection and quantification of experimental joint inflammation in mice by measurement of99mTc-pertechnetate uptake

We adapted the method of^99mTc-pertechnetate (^99mTc) uptake measurements to the mouse knee for detection and quantification of arthritis because clinical assessment of mouse knee-joint arthritis is not reliable. The main points to ensure reproducibility of measurements were proper fixation and positioning of the knee and careful shielding of the rest of the body from the gamma-radiation detector.^99mTc uptake was calculated as the mean of three countings. The variation coefficient of these countings ranged from 0.007 to 0.082 in non-arthritic joints and from 0.025 to 0.081 in arthritic joints. Arthritis was scored as the ratio of the^99mTc uptake in the right knee versus that in the left knee. This ratio averated 1.06 (S.D. 0.05) in non-arthritic mice 20 minutes after^99mTc administration i.p. On the second day after induction of arthritis in the right knee, this ratio ranged from 1.44 to 1.96; this was significantly higher (P<0.005) than in non-arthritic mice, and the increase remained significant during at least 20 days.^99mTc uptake measurements seem to be a useful method to detect and quantify arthritis of the knee joint in mice.     

Size Control of 99mTc-tin Colloid Using PVP and Buffer Solution for Sentinel Lymph Node Detection

Colloidal particle size is an important characteristic that allows mapping sentinel nodes in lymphoscintigraphy. This investigation aimed to introduce different ways of making a ^99mTc-tin colloid with a size of tens of nanometers. All agents, tin fluoride, sodium fluoride, poloxamer-188, and polyvinylpyrrolidone (PVP), were mixed and labeled with ^99mTc. Either phosphate or sodium bicarbonate buffers were used to adjust the pH levels. When the buffers were added, the size of the colloids increased. However, as the PVP continued to increase, the size of the colloids was controlled to within tens of nanometers. In all samples, phosphate buffer added PVP (30 mg) stabilized tin colloid (^99mTc-PPTC-30) and sodium bicarbonate solution added PVP (50 mg) stabilized tin colloid (^99mTc-BPTC-50) were chosen for in vitro and in vivo studies. ^99mTc-BPTC-50 (<20 nm) was primarily located in bone marrow and was then secreted through the kidneys, and ^99mTc-PPTC-30 (>100 nm) mainly accumulated in the liver. When a rabbit was given a toe injection, the node uptake of ^99mTc-PPTC-30 decreased over time, while ^99mTc-BPTC-50 increased. Therefore, ^99mTc-BPTC-50 could be a good candidate radiopharmaceutical for sentinel node detection. The significance of this study is that nano-sized tin colloid can be made very easily and quickly by PVP.

Graphical Abstract

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Effect of aerobic training on 99mTc-methoxy isobutyl isonitrile (99mTc-sestamibi) uptake by myocardium and skeletal muscle: implication for noninvasive assessment of muscle metabolic profile

Aim: The effect of long‐term endurance training on skeletal muscle and myocardial uptake of ^99mTc‐sestamibi, a radiopharmaceutical accumulating in the mitochondria, was investigated. Methods: Twenty‐six Wistar rats were divided into a trained (5 days week^?1 endurance running for 14 weeks) and an untrained group. On completion of training, ^99mTc‐sestamibi was administered and, 2 h post‐injection, the myocardium and the soleus, extensor digitorum longus (EDL) and medial gastrocnemius (MG) muscles were removed for the measurement of cytochrome c oxidase (CCO) activity and ^99mTc‐sestamibi uptake. Tissue ^99mTc‐sestamibi kinetics was preliminarily studied in 16 other rats for up to 2 h post‐injection. Results: Two hours post‐injection ^99mTc‐sestamibi uptake was either stable (myocardium) or still rising (skeletal muscles). Both CCO activity and ^99mTc‐sestamibi uptake decreased in the same order (myocardium, soleus, EDL, MG) in the tissues examined. The CCO activity of the EDL and MG muscles was higher (P < 0.05) in the trained compared to the untrained group. ^99mTc‐sestamibi uptake in the soleus and EDL muscles was higher (P < 0.05) in the trained compared to the untrained rats, whereas the difference in MG was marginally significant (P = 0.06) in favour of the trained group. Conclusions: Long‐term endurance training, resulting in elevated skeletal muscle CCO activity, is also associated with a similar increase in ^99mTc‐sestamibi uptake. This finding suggests that ^99mTc‐sestamibi could be used in imaging assessment of skeletal muscle metabolism with possible applications in both clinical and sports medicine settings.     

Effect of Ursodeoxycholic Acid on the Biodistribution and Excretion of Technetium-99m Radiopharmaceuticals in Rat: A Potential Image Quality Enhancer

PurposeThis study aimed to investigate the effect of ursodeoxycholic acid (UDCA) on the biodistribution and excretion of technetium-99m (Tc-99m)-labeled radiopharmaceuticals.Materials and MethodsTc-99m hydroxy-methylene-diphosphonate (HDP), Tc-99m pertechnetate, and Tc-99m dimercaptosuccinic acid (DMSA) were injected via the tail vein of rats. After 30 min, the control group was administered saline, and the UDCA group was given UDCA orally. Scintigraphy images were acquired after 30 min and 1, 2, 3, and 4 h. Radioactivity and rate of change were compared. Tc-99m mercaptoacetyltriglycine (MAG₃) imaging was also performed.ResultsIn image analysis of Tc-99m HDP, radioactivity of the buttock was lower in the UDCA group at 4 h. Rates of change in the buttock were significantly different at 3 h–30 min and 4 h–30 min, and buttock radioactivity in the UDCA group had decreased more. In analysis of Tc-99m pertechnetate, radioactivity of the buttock was higher in the control group. Rates of change in the thyroid gland and buttock were different at 1 h–30 min, 3 h–30 min, and 4 h–30 min, with radioactivity in the UDCA group decreasing more. In the analysis of Tc-99m DMSA, while the radioactivity of the kidneys in the control group showed little decrease at 1 h–30 min, that in the UDCA group increased. In the analysis of Tc-99m MAG₃ images, radioactivity and radioactivity/total body radioactivity (TBA) values for the kidneys were higher in the UDCA group at 2 min. At 5 and 10 min, radioactivity/TBA values for soft tissue in the UDCA group were lower than those in the control group.ConclusionThis study demonstrated that administration of UDCA increases renal excretion and soft tissue clearance of radiopharmaceuticals. This investigation could contribute to the broadening of applications of UDCA.     

Drug‐induced cardiomyopathy: Characterization of a rat model by [18F]FDG/PET and [99mTc]MIBI/SPECT

BackgroundDrug‐induced cardiomyopathy is a significant medical problem. Clinical diagnosis of myocardial injury is based on initial electrocardiogram, levels of circulating biomarkers, and perfusion imaging with single photon emission computed tomography (SPECT). Positron emission tomography (PET) is an alternative imaging modality that provides better resolution and sensitivity than SPECT, improves diagnostic accuracy, and allows therapeutic monitoring. The objective of this study was to assess the detection of drug‐induced cardiomyopathy by PET using 2‐deoxy‐2‐[¹⁸F]fluoro‐D‐glucose (FDG) and compare it with the conventional SPECT technique with [^99mTc]‐Sestamibi (MIBI).MethodsCardiomyopathy was induced in Sprague Dawley rats using high‐dose isoproterenol. Nuclear [¹⁸F]FDG/PET and [^99mTc]MIBI/SPECT were performed before and after isoproterenol administration. [¹⁸F]FDG (0.1 mCi, 200‐400 µL) and [^99mTc]MIBI (2 mCi, 200‐600 µL) were administered via the tail vein and imaging was performed 1 hour postinjection. Isoproterenol‐induced injury was confirmed by the plasma level of cardiac troponin and triphenyltetrazolium chloride (TTC) staining.ResultsIsoproterenol administration resulted in an increase in circulating cardiac troponin I and showed histologic damage in the myocardium. Visually, preisoproterenol and postisoproterenol images showed alterations in cardiac accumulation of [¹⁸F]FDG, but not of [^99mTc]MIBI. Image analysis revealed that myocardial uptake of [¹⁸F]FDG reduced by 60% after isoproterenol treatment, whereas that of [^99mTc]MIBI decreased by 45%.ConclusionWe conclude that [¹⁸F]FDG is a more sensitive radiotracer than [^99mTc]MIBI for imaging of drug‐induced cardiomyopathy. We theorize that isoproterenol‐induced cardiomyopathy impacts cellular metabolism more than perfusion, which results in more substantial changes in [¹⁸F]FDG uptake than in [^99mTc]MIBI accumulation in cardiac tissue.     

Hydrophilic and lipophilic radiopharmaceuticals as tracers in pharmaceutical development: In vitro – In vivo studies

Background

Scintigraphic studies have been performed to assess the release, both in vitro and in vivo, of radiotracers from tablet formulations. Four different tracers with differing physicochemical characteristics have been evaluated to assess their suitability as models for drug delivery.

Methods

In-vitro disintegration and dissolution studies have been performed at pH 1, 4 and 7. In-vivo studies have been performed by scintigraphic imaging in healthy volunteers. Two hydrophilic tracers, (^99mTc-DTPA) and (^99mTc-MDP), and two lipophilic tracers, (^99mTc-ECD) and (^99mTc-MIBI), were used as drug models.

Results

Dissolution and disintegration profiles, differed depending on the drug model chosen. In vitro dissolution velocity constants indicated a probable retention of the radiotracer in the formulation. In vivo disintegration velocity constants showed important variability for each radiopharmaceutical. Pearson statistical test showed no correlation between in vitro drug release, and in vivo behaviour, for ^99mTc-DTPA, ^99mTc-ECD and ^99mTc-MIBI. High correlation coefficients were found for ^99mTc-MDP not only for in vitro dissolution and disintegration studies but also for in vivo scintigraphic studies.

Conclusion

Scintigraphic studies have made a significant contribution to the development of drug delivery systems. It is essential, however, to choose the appropriate radiotracers as models of drug behaviour. This study has demonstrated significant differences in release patterns, depending on the model chosen. It is likely that each formulation would require the development of a specific model, rather than being able to use a generic drug model on the basis of its physicochemical characteristics.     

Evaluation of 99mTc-HYNIC-βAla-Bombesin(7-14) as an agent for pancreas tumor detection in mice

Pancreatic adenocarcinoma is important in oncology because of its high mortality rate. Deaths may be avoided if an early diagnosis could be achieved. Several types of tumors overexpress gastrin-releasing peptide receptors (GRPr), including pancreatic cancer cells. Thus, a radiolabeled peptide derivative of gastrin-releasing peptide (GRP) may be useful as a specific imaging probe. The purpose of the present study was to evaluate the feasibility of using^99mTc-HYNIC-βAla-Bombesin_(7-14)as an imaging probe for Capan-1 pancreatic adenocarcinoma. Xenographic pancreatic tumor was developed in nude mice and characterized by histopathological analysis. Biodistribution studies and scintigraphic images were carried out in tumor-bearing nude mice. The two methods showed higher uptake by pancreatic tumor when compared to muscle (used as control), and the tumor-to-muscle ratio indicated that^99mTc-HYNIC-βAla-Bombesin_(7-14)uptake was four-fold higher in tumor cells than in other tissues. Scintigraphic images also showed a clear signal at the tumor site. The present data indicate that^99mTc-HYNIC-βAla-Bombesin_(7-14)may be useful for the detection of pancreatic adenocarcinoma.     

Does 99mTc-MDP bone scintigraphy add to the investigation of patients with symptomatic unicompartmental knee replacement?

AimThe purpose of this study was to determine whether nuclear medicine ^99mTc-Methyl diphosphonate bone scintigraphy (^99mTc-MDP bone scintigraphy) added information over plain radiographs loosening infection in symptomatic unicompartmental knee replacements (UKRs).Methods and materialsA cohort of 39 patients who presented with knee pain following UKR was retrospectively reviewed. All had undergone nuclear medicine bone scans for possible loosening or infection of the prosthesis. The findings of the bone scintigraphy were compared to subsequent operative findings during diagnostic arthroscopic investigation or revision surgery for those patients who had undergone these procedures.ResultsOf the 39 patients with painful knees following UKR, surgical findings confirmed that 11 had either loose (n = 9) or infected (n = 2) implants. Logistic regression analysis demonstrated no statistically significant combination of features on nuclear medicine or radiographs associated with failure of the prosthesis due to infection or loosening (p > 0.05).Classification of a satisfactory position of the UKR on plain radiography exhibited a high negative predictive value (96% for infections, and 80% for loosening). However, plain radiograph was not sensitive for loosening (50%) or infection (37%) of the UKR with very low positive predictive values (9.1% for infection and 27.3% for loosening).ConclusionThis study provides no evidence to support the routine use of ^99mTc-MDP bone scintigraphy in the clinical decision-making for patients with a painful UKR.Level of evidence: level 4.     

Perfusion scanning using 99mTc-HMPAO detects early cerebrovascular changes in the diabetic rat

Background

^99mTc-HMPAO is a well-established isotope useful in the detection of regional cerebral blood flow. Diabetes gives rise to arterial atherosclerotic changes that can lead to significant end organ dysfunction, prominently affecting perfusion to the heart, kidneys, eyes and brain. In the current study, we investigated the role of ^99mTc-HMPAO cerebral perfusion scans in detecting early vascular changes in the diabetic brain.

Methods

Cerebral perfusion studies were performed on both control and streptozotocin-(STZ) induced diabetic male Wistar rats. Rat brain imaging using a gamma camera was performed for each group 0.5, 2, 4, and 24 hours post ^99mTc-HMPAO injection. Data processing for each cerebral perfusion scan was performed by drawing a region of interest (ROI) circumferentially around the brain (B). Background (BKG) due to signal from the soft tissue of each rat was subtracted. Brain ^99mTc-HMPAO uptake minus background counts (net brain counts; NBC) were then compared between the two groups.

Results

The NBC (mean ± SD) for the STZ group were statistically significantly higher (p = 0.0004) than those of the control group at each of the time points studied.

Conclusion

^99mTc-HMPAO brain scan may be useful in the detection of early atherosclerotic changes in the diabetic rat brain.     

Toxicity of methimazole on femoral bone in suckling rats: Alleviation by selenium

AimsSelenium has a pharmacological properties and it is well considered as an antioxidant. The present study investigated the potential ability of selenium, used as a nutritional supplement, to alleviate bone impairments in suckling rats whose mothers were treated with methimazole, an antithyroid drug.Main methodsFemale Wistar rats were randomly divided into four groups of six each: group I served as control which received standard diet; group II were rendered hypothyroid by administration of methimazole (250 mg L^?1 in their drinking water); group III received both methimazole (250 mg L^?1 in their drinking water) and selenium (0.5 mg kg^?1 of diet); group IV received 0.5 Na₂SeO₃ mg kg^?1 of diet. Treatments were started from the 14th day of pregnancy until day 14 after delivery.Key findingsMethimazole treatment decreased femur length and weight in 14-day-old rats, when compared to controls. Femur antioxidant enzyme activities, superoxide dismutase, catalase and glutathione peroxidase decreased. Lipid peroxidation recorded an increase revealed by high femur malondialdehyde levels. Methimazole also caused a significant decrease in calcium and phosphorus levels in bone. Yet, in plasma and urine, they increased and decreased inversely. Besides, plasma total tartrate-resistant acid phosphatase was enhanced, while total alkaline phosphatase was reduced. Co-administration of selenium through diet improved the biochemical parameters cited above. Nevertheless, distorted histoarchitecture revealed in hypothyroid rat femur was alleviated by Se treatment.SignificanceThe present study suggests that selenium is an important protective element that may be used as a dietary supplement protecting against bone impairments.     

Alternative chromatographic system for the quality control of lipophilic technetium-99m radiopharmaceuticals such as [99mTc(MIBI)6]+

Knowledge of the radiochemical purity of radiopharmaceuticals is mandatory and can be evaluated by several methods and techniques. Planar chromatography is the technique normally employed in nuclear medicine since it is simple, rapid and usually of low cost. There is no standard system for the chromatographic technique, but price, separation efficiency and short time for execution must be considered. We have studied an alternative system using common chromatographic stationary phase and alcohol or alcohol:chloroform mixtures as the mobile phase, using the lipophilic radiopharmaceutical [^99mTc(MIBI)₆]⁺ as a model. Whatman 1 modified phase paper and absolute ethanol, Whatman 1 paper and methanol:chloroform (25:75), Whatman 3MM paper and ethanol:chloroform (25:75), and the more expensive ITLC-SG and 1-propanol:chloroform (10:90) were suitable systems for the direct determination of radiochemical purity of [^99mTc(MIBI)₆]⁺ since impurities such as^99mTc-reduced-hydrolyzed (RH),^99mTcO₄ ^- and [^99mTc(cysteine)₂]^-complex were completely separated from the radiopharmaceutical, which moved toward the front of chromatographic systems while impurities were retained at the origin. The time required for analysis was 4 to 15 min, which is appropriate for nuclear medicine routines.     

Quantitation of arthritis by99mTc-uptake measurements in the mouse knee-joint: correlation with histological joint inflammation scores

A method is described to detect and to quantitate inflammation in knee-joints of mice. Approximately 10 Ci^99mTechnetium pertechnetate (^99mTc) is injected subcutaneously in the neck region and the accumulation of the short-lived isotope in the knee-joint is detected by external gamma counting.^99mTc-uptake values correlate well with histological grading of joint inflammation at various intervals after induction of the inflammation. The method can be used to detect changes in activity of unilateral as well as bilateral joint inflammation using either the ratio of^99mTc uptake in the right knee versus that in the left knee or absolute^99mTc-uptake values.     

Pharmacokinetics/pharmacodynamics of antipseudomonal bacteriophage therapy in rats: a proof-of-concept study

ObjectivesPan-drug-resistant (PDR) Pseudomonas aeruginosa is one of the three top-priority pathogens identified by the WHO, and bacteriophages have been investigated as an alternative therapy. However, knowledge on the pharmacokinetics/pharmacodynamics (PK/PD) of phage therapy is sparse, limiting its clinical applications. This study aimed to evaluate the PK/PD of the antipseudomonal phage øPEV20 in vivo following intravenous administration.MethodsHealthy Sprague-Dawley rats were given øPEV20 as a single intravenous bolus of ~6, 9 and 11-log₁₀PFU/rat. Arterial blood was sampled over 72 h. At 72 h, the animals were killed and multiple tissues were harvested for biodistribution studies. A PK model was developed using the importance sampling algorithm and deterministic simulations with a PD model were performed.ResultsA three-compartment model with non-linear clearance described the exposure of øPEV20 in blood. Model evaluation indicated that the model was robust and parameter estimates were accurate. The median (standard error) values of model-predicted PK parameters for V_C, V_P1, V_P2, Q₁, Q₂, V_m and K_m were 111 mL/rat (8.5%), 128 mL/rat (4.97%), 180 mL/rat (4.59%), 30.4 mL/h/rat (19.2%), 538 mL/h/rat (4.97%), 4.39 × 10¹⁰ PFU/h/rat (10.2%) and 1.64 × 10⁷ PFU/mL/rat (3.6%), respectively. The distribution of øPEV20 was not homogeneous; there was preferential accumulation in the liver and spleen. Deterministic simulations with a PD model confirmed the importance of the host immune system in facilitating phage-mediated bacterial elimination.ConclusionsWe developed a robust PK model to describe the disposition of phages in healthy rats. This model may have significant potential in facilitating future preclinical and clinical PK/PD investigations.