Bone turnover markers are correlated with total skeletal uptake of 99mTc-methylene diphosphonate (99mTc-MDP).

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.

Comparative renal, hepatic, and bone marrow toxicity of Cisplatin and radioactive Cisplatin (191Pt) in Wistar rats.

The aim of the study was to investigate the possibility to increase the therapeutic gain of the cytotoxic agent, cisplatin, by incorporation of radioactive platinum. In this study, we investigated how organs at risk (i.e., kidneys, bone marrow, and liver) are affected by treatment with 191Pt-cisplatin, compared to treatment with conventional cisplatin. Rats (total, n = 69) were divided into three groups and given 5 mg/kg 191Pt-cisplatin and 5 mg/kg nonradioactive cisplatin or saline. The weight of the animals and blood samples, including analysis of creatinine, bilirubin, alanine and aspartate aminotransferases and platelet count, was followed for 6 weeks after treatment. Histopathology examinations of kidney and liver tissues were performed. An initial decrease in weight gain was seen from 3 days after treatment with cisplatin and 191Pt-cisplatin and for 1 week onward; thereafter, the weight gain continued, following the same pattern as for the control group. Concentration of plasma creatinine was increased for both cisplatin groups but with no significant difference between treatment groups. No other significant differences in effect parameters were found. There was no increase in toxicity for radioactive cisplatin on liver, kidneys, and bone marrow, compared to conventional cisplatin. Further experimental and clinical studies on preparations of this type are thus warranted.

Modulation of the inflammatory response to histamine by terbutaline and sodium nitroprusside in guinea-pig skin.

We measured the microvascular response (vasodilatation and plasma exudation) to skin prick provocations with histamine, terbutaline, sodium nitroprusside (SNP) and the combinations of terbutaline and histamine as well as SNP and histamine in guinea-pig skin. The response was measured by external detection of beta radiation from transferrin labelled with (113m)In. Histamine induced a moderate microvascular response. Terbutaline alone induced a smaller response, probably reflecting vasodilatation. When added to histamine, terbutaline significantly reduced the microvascular response to histamine. The response to histamine, SNP and the combination of histamine and SNP were all similar. We conclude that the anti-inflammatory effect of terbutaline can be readily measured with this technique. We found no indication of a pro-inflammatory effect of SNP when combined with histamine. Rather, the lack of additive effect may suggest an anti-inflammatory effect of SNP on the response to histamine.

Dose delivery late in the breath can increase dry powder aerosol penetration into the lungs.

In addition to aerosol particle size and mode of inhalation, the time-point of dose delivery during inhalation may be an important factor governing the intrapulmonary distribution of aerosolized drug. To generate different intrapulmonary deposition patterns of a drug model aerosol, a device with the capability of delivering small amounts of technetium-99m-labeled lactose dry powder at pre-set time-points during inhalation was developed. A single dose of the radioaerosol was delivered after inhalation of 20% (A) or 70% (B) of the vital capacity inhaled through the device. Twelve healthy subjects were studied in a randomized crossover fashion. Planar gamma scintigraphy was carried out, and the penetration index, PI, defined as the ratio of peripheral to central lung zone deposition of radioactivity, was estimated. A significant increase in PI from 3.0 (A) to 3.7 (B) was observed with the change from early to late delivery of the dose (p < 0.01). No difference in the total amount of radioactivity within the lungs could be detected. In conclusion, independent of total pulmonary deposition, deeper dry powder aerosol penetration into the lungs was found for the dose delivered at near end instead of at the beginning of inhalation. By computational modeling of the aerosol transport and deposition, that finding was mechanistically explained by differences in airway caliber as a consequence of the level of lung inflation at the time-point of dose delivery.

Microvascular response in guinea pig skin to histamine challenge with and without application of skin window.

We measured the microvascular response to histamine in guinea pig skin. Histamine (40 mg ml(-1)) was given either as a skin prick test or applied topically onto a skin window. The skin window was prepared by applying suction and gentle warming to the skin so that a blister was formed, and by removing the top of the blister. The microvascular response was measured as the accumulation of radiolabelled transferrin in the skin in vivo, reflecting a combination plasma exudation and vasodilatation. In the control (saline) challenge, the response was slightly greater in the skin window than after skin prick challenge and the scatter was larger. Histamine challenge resulted in a significant microvascular response with respect to the control situation when measured immediately after provocation for both challenge techniques. Ten minutes after challenge, a smaller response was measured, which was still significantly greater than control for the skin prick challenge, but not for topical provocation using the skin window technique. We conclude that the microvascular response to histamine after provocation with the skin prick technique is similar to that after topical provocation using the skin window technique. The skin window technique may have a lower sensitivity than the skin prick technique owing to a higher scatter in the control situation. This difference should be considered when performing and interpreting studies of the microvascular reaction in the skin.

Planar gamma scintigraphy--points to consider when quantifying pulmonary dry powder aerosol deposition.

Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (with 95% confidence interval of 24.2-28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4-28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.

Accuracy of the quantification of organ activity from planar gamma camera images.

The accuracy in determination of organ activity of (99m)Tc was investigated, with activity estimated from gamma camera images of phantoms, using the conjugate view method. The accuracy depends on several parameters such as the choice of background correction method, the accuracy in determination of the effective attenuation coefficient and the thickness of the body and organs and on the determination of the gamma camera sensitivity. The background correction method has a major influence on the quantification of the activity. Methods which take the volume of the source organ into consideration are recommended. The discrepancy in the determined organ activity varied between an underestimation of 26% and an overestimation of 16% in the MIRD phantom, depending on which organ was studied and on the correction method used. To correct for absorption and scattering, an effective attenuation coefficient was used. A theoretical analysis showed that a change in the effective attenuation coefficient of 0.01 cm(-1) resulted in a 15% change in the calculated activity. Also the thickness of the body and the organ of interest influences the calculated activity. A 2 cm deviation in the body thickness causes a deviation of approximately 10% in the calculated activity. The quantification is improved if the attenuation coefficient is determined by transmission measurements.

Planar gamma scintigraphy--points to consider when quantifying pulmonary dry powder aerosol deposition.

Methodological aspects of planar gamma scintigraphy used to quantify pulmonary aerosol deposition were investigated using an experimental dry powder formulation. Particles of micronized salbutamol sulphate were labelled with technetium-99m and admixed to an ordered mixture of unlabelled micronized salbutamol sulphate and larger carrier particles of lactose. The radioaerosol was administered to 24 healthy subjects, 12 in each of two consecutive, similarly designed studies. Pulmonary deposition was determined using two methods: repeated planar imaging, and pharmacokinetic assessments following charcoal co-administration to prevent gastrointestinal salbutamol absorption. After due consideration had been taken to ensure appropriate radiolabelling, image acquisition and processing procedures, a scintigraphic estimate of 26.2% (24.2-28.4%) was obtained, which did not significantly differ from the pharmacokinetic estimate of 26.4% (24.4-28.7%). In summary, pre-study validation of the radiolabelling technique, quality control of radioaerosols produced during the study, correction for re-distribution of radiolabel from the lungs, selection of regions of interest, assessment of lung contours, correction for tissue attenuation of gamma rays and establishment of the actual recovery of radioactivity in the scintigraphic measurements could potentially affect the accuracy of the scintigraphic estimate of pulmonary deposition and, thus, should be carefully considered in the design or evaluation of any such study.