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R W Howell

Publications and source records attributed to R W Howell.

At least 19 recordsLinked to original sources
PubMed1995

Generalized approach to absorbed dose calculations for dynamic tumor and organ masses.

UNLABELLED: Tumor absorbed dose calculations in radionuclide therapy are presently based on the assumption of static tumor mass. This work examines the effect of dynamic tumor mass (growth and/or shrinkage) on the absorbed dose. METHODS: Tumor mass kinetic characteristics were modeled with the Gompertz equation to simulate tumor growth and an additional exponential term to accommodate tumor shrinkage that may result as a consequence of therapy. RESULTS: Correction factors, defined as the ratio of the absorbed dose, which was calculated by considering tumor mass dynamics, to the absorbed dose, which was calculated by assuming static mass, are presented for 1- and 100-g tumors with different tumor mass kinetics. The dependence of the correction factor on the effective half-life Te of the radioactivity in the tumor and the tumor shrinkage half-time Ts was examined. The correction factors for the 1-g tumor were > 1 for short Ts and Te. In contrast, the correction factor was less than 1 for long Ts ( > 9 days). The dose correction factors for the 100-g tumor were > 1 for all Ts and Te. Finally, the dosimetric method for dynamic masses is illustrated with experimental data on Chinese hamster V79 multicellular spheroids that were treated with 3H. CONCLUSION: Correction factors as high as about 10 are likely when Te and Ts are short. As Ts increases beyond 20 days, the importance of dynamic mass diminishes because most of the activity decays before the mass changes appreciably. In some cases, mass dynamics should be taken into account when the absorbed dose to tumors is estimated.

Animals↗
PubMed1995

Kinetics and dosimetry of thallium-201 in human testes.

UNLABELLED: Thallous chloride (201Tl) is a well-known imaging agent. It has been shown to accumulate in the testes. In view of this, the testicular kinetics of 201Tl is investigated in humans and the absorbed dose to the organ calculated. METHODS: Thallous chloride 201Tl was injected intravenously into four patients for myocardial perfusion studies. After clinical evaluation, the testicular uptake and clearance of 201Tl were monitored for about 1 wk using a gamma camera. RESULTS: Testicular uptake of 201Tl was rapid with a mean biological uptake half-time of 0.67 hr and mean biological clearance half-time of 280 hr. The mean maximum testicular uptake of 201Tl was about 0.4% of the injected activity. These data were utilized to calculate the average absorbed dose to the testes. The absorbed dose to the testes was calculated to be 3.5 x 10(-4) Gy/MBq (1.3 rad/mCi) of injected activity. CONCLUSION: When the relative biological effectiveness of the Auger emitter 201Tl is taken into account, the equivalent dose to the testes is 9.5 x 10(-4) Sv/MBq (3.5 rem/mCi).

Adult↗
PubMed1995

Radioprotection against biological effects of internal radionuclides in vivo by S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET).

UNLABELLED: Radionuclides employed in diagnostic and therapeutic nuclear medicine impart radiation energy to tissue over an extended period of time, which depends on the physical half-life and the biological properties of the radiochemical employed. It is therefore important to examine the capacity of chemical radioprotectors to mitigate damage caused by chronic irradiation by incorporated radionuclides. METHODS: Spermatogenesis in mouse testis is used as the experimental model, and spermatogonial cell survival as measured by testicular spermhead count is the biological end point. The capacity of S-(2-aminoethyl)isothiouronium bromide hydrobromide (AET) to mitigate radiation damage caused by chronic irradiation by the radiochemicals 125IUdR, H125IPDM and 210Po-citrate, is investigated. RESULTS: The radioprotection provided by AET is substantial and similar for both of the radioiodinated compounds with dose modification factors (DMF) of 4.0 +/- 1.2 for 125IUdR and 3.4 +/- 0.4 for H125IPDM. In contrast, the damage caused by 210Po alpha particles is protected against to a lesser degree (DMF = 2.4 +/- 0.5). CONCLUSION: The present radioprotection data for AET, in conjunction with our earlier findings for the chemical protectors cysteamine and vitamin C in the same experimental model, suggest that such compounds may be clinically useful as mitigating agents against biological damage caused by incorporated radionuclides. The observed DMFs for AET also support our earlier premise that the mechanism by which DNA-incorporated Auger emitters impart biological damage is primarily radical mediated, and hence indirect in nature.

Animals↗
PubMed1994

Dosimetry of Auger-electron-emitting radionuclides: report no. 3 of AAPM Nuclear Medicine Task Group No. 6.

The biological effects of Auger-electron-emitting radionuclides can be as severe as those of alpha particles of high linear energy transfer. A great deal of effort has been expended in exploring the biological effects of Auger electron emitters. Much of this effort has been devoted to improving theoretical and experimental techniques required to calculate absorbed doses and correlate them with the observed biological effects. Given that the main purpose of dosimetry is to obtain a physical descriptor with which to correlate radiation toxicity, then nowhere is this challenge greater than when biological specimens are subject to Auger electron cascades. The dense shower of short-range Auger electrons released by radionuclides, which decay by electron capture or internal conversion, results in biological damage that is highly dependent on the location of the decay site within the cell. In this report, different approaches to Auger electron dosimetry are described and compared. Methods to calculate the absorbed dose from Auger electron emitters at the DNA, cellular, multicellular, and organ levels are described as they relate to the biological effects. The concept of a radiation weighting factor for Auger electrons to be used in the calculation of equivalent dose is reviewed. The importance of subcellular distribution of Auger emitters in determining the biological effects of these radionuclides is emphasized and incorporated into the equivalent dose formalism. The Task Group recommends that a preliminary radiation weighting factor of 10 be used for deterministic effects of Auger electrons, and a value of 20 for stochastic effects.

Biophysical Phenomena↗
PubMed1994

Relative biological effectiveness of 99mTc radiopharmaceuticals.

The radiotoxicity of three 99mTc-labeled compounds is investigated using spermatogenesis in mouse testis as the experimental model, and spermatogonial cell survival as the biological end point. The radiopharmaceuticals studied are pertechnetate (99mTcO4-), pyrophosphate (99mTc-PYP), and hydroxyethylene diphosphate (99mTc-HDP). The mean lethal doses at 37% survival (D37) are 0.70 +/- 0.06, 0.84 +/- 0.13, and 0.59 +/- 0.08 Gy for 99mTcO4-, 99mTc-PYP, and 99mTc-HDP, respectively. When these results are compared with the D37 value obtained with external x rays or internal gamma rays, the relative biological effectiveness (RBE) of these compounds are 0.94 +/- 0.09, 0.79 +/- 0.13, and 1.1 +/- 0.16, respectively. These results show that the radiotoxicity of 99mTc in mouse testis is essentially similar to that of low-LET radiations (i.e., RBE approximately 1). To understand these results, the distribution of these radiocompounds in the testis is determined and correlated with the observed RBE values. The expected range of RBE values for 99mTc radiopharmaceuticals in organs is 0.95 to 1.5, depending on the fraction of organ activity that is bound to DNA. This suggests that the Auger electrons emitted in the decay of 99mTc are not capable of causing extreme toxicity in vivo. These results provide further support for 99mTc as the radionuclide of choice for imaging in nuclear medicine.

Animals↗
PubMed1992

Radiotoxicity of some iodine-123, iodine-125 and iodine-131-labeled compounds in mouse testes: implications for radiopharmaceutical design.

In this work, spermhead survival in mouse testis was used to investigate the radiotoxicity of several intratesticularly localized radioiodinated pharmaceuticals. Radioiodines that decay by electron capture and/or internal conversion (123I, 125I) as well as by beta- decay (131I) were coupled to pharmaceuticals that selectively localize in different cell compartments. Dose response curves yield D37 values of 62 cGy, 75 cGy, 61 cGy and 7.7 cGy for 123IMP (N-isopropyl-p-iodoamphetamine), 131IdU (iododeoxyuridine), H131IPDM (N,N,N'-trimethyl-N'-(2-hydroxyl-3-methyl-5-iodobenzyl)-1,3-propanediami ne) and 125IdC (iododeoxycytidine), respectively. At 37% survival, the relative biological effectiveness (RBE) of these radiochemicals, when compared to the pure gamma-emitting radiochemical 7Be-chloride (D37 = 65 cGy), are 1.0, 0.89, 1.1 and 8.4, respectively. Intratesticular 7Be, with an effective half-life of 430 hr in the organ, was used as the source of reference radiation to determine the RBE values because it solely emits 477 keV gamma rays, and the dose to the testis is delivered chronically, as in the case of the other radiocompounds. Subcellular distribution studies show that all of the cellular activity is localized in the cytoplasm in the cases of 123IMP and H131IPDM, while virtually all of 131IdU and 125IdC were bound to DNA in the cell nucleus. In agreement with our earlier in vivo studies, these data show that subcellular distribution plays a key role in the radiotoxicity of Auger electron emitters such as 123I and 125I, and has no role for beta emitters such as 131I. These findings may have implications in the design of radiopharmaceuticals for both diagnosis (localize Auger emitter in cytoplasm of cell) and therapy (localize Auger emitter in cell nucleus).

Amphetamines↗
PubMed1992

Absorbed dose calculations for rapidly growing tumors.

One of the most promising areas for cancer therapy with administered radiopharmaceuticals is the treatment of very small tumors and micrometastases. Small tumors and micrometastases, however, may be rapidly growing at the time of treatment, resulting in a substantial change in mass during the period of irradiation. In this work, the formalism required to calculate the average absorbed dose to rapidly growing tumors is developed and applied to an in vitro tumor model. Further application to in vivo human myeloma tumors reveals that tumor growth may have a significant effect on the average dose delivered to the tumor from incorporated radionuclides. These considerations may assist in establishing dose-response relationships necessary for radiopharmaceutical cancer therapy.

Cell Division↗
PubMed1991

Radiotoxicity of 125I-iododeoxyuridine in pre-implantation mouse embryos.

The radiotoxicity of DNA incorporated 125I in cultured pre-implantation two-cell mouse embryos was investigated and compared with external gamma-irradiation. The uptake of 125IdU in the two-cell stage embryos was determined as a function of incubation time and concentration of radioactivity (MBq/ml) in the medium. The absorbed dose to the embryos was calculated using conventional procedures. The embryo survival curves show that the dose at 37% survival is only about 15 cGy for 125IdU, whereas for 137Cs-photons it is 175 cGy. The extreme toxicity observed is thought to be due to the localized energy deposition of the numerous low energy Auger electrons emitted in the decay of 125I. These results are consistent with earlier observations in mouse testis and cultured cells and point to the need for assessing the radiation risk from incorporated Auger electron emitting radionuclides based on their subcellular distribution.

Animals↗
PubMed1991

The question of relative biological effectiveness and quality factor for auger emitters incorporated into proliferating mammalian cells.

The problem of determining RBE values for Auger emitters incorporated into proliferating mammalian cells is examined. In general, the reference radiation plays a key role in obtaining experimental RBE values. Using survival of cultured Chinese hamster V79 cells as the experimental model, new data are provided regarding selection of a reference radiation for internal Auger emitters. These data show that gamma rays delivered acutely (137Cs) are more than twice as lethal as gamma rays delivered chronically with an exponentially decreasing dose rate (99mTc). The results confirm that the reference radiation should be delivered chronically in a manner consistent with the extended exposure received by the cells in the case of incorporated radionuclides. Through a direct comparison of the radiotoxicity of Auger emitters and alpha emitters, the high RBE values reported for DNA-bound Auger emitters are confirmed. These studies reveal that the DNA binding compound [125I]iododeoxyuridine (125IdU) is about 1.6 times more effective in killing V79 cells than 5.3 MeV alpha particles from intracellularly localized 210Po-citrate. In addition, toxicity studies with the radiochemicals 125IdU and [125]-iododeoxycytidine (125IdC) establish the equivalence of the radiosensitivity of thymine and cytosine base sites in the DNA. In view of these results, and information already available, the question of establishing quality factors for Auger emitters is considered. Finally, a method for calculation of the dose equivalent for internal Auger emitters is advanced.

Animals↗
PubMed1991

Induction of sperm head abnormalities by incorporated radionuclides: dependence on subcellular distribution, type of radiation, dose rate, and presence of radioprotectors.

In contrast to the biological effects caused by exposure to external beams of radiation, the effects of tissue-incorporated radionuclides are highly dependent on the type of radiation emitted and on their distribution at the macroscopic, microscopic, and subcellular levels, which are in turn determined by the chemical nature of the radionuclides administered. Induction of abnormalities of sperm heads in mice is investigated in this work after the injection of a variety of radiochemicals including alpha emitters. When the initial slopes of the dose-response curves are used to compare the relative biological effectiveness (RBE) of different radiocompounds, the alpha particles emitted in the decay of 210Po are more effective than Auger electrons emitted by 125I incorporated in the DNA of the spermatogonial cells, and both emissions are more effective than X rays. It is also shown that the Auger emitters (125I, 111In) distributed in the cell nucleus are more efficient in producing abnormalities than the same radionuclides localized in the cytoplasm. These findings are consistent with our earlier observations, where spermatogonial cell survival is assayed as a function of the testicular absorbed dose. Further, chronic irradiation of testis with gamma rays from intratesticularly administered 7Be is about three times more effective in causing abnormalities than a single acute exposure to 120-kVp X rays. The resulting RBE values correlate well with our data on sperm head survival with the same radiocompounds. Finally, the radioprotector cysteamine, when administered in small, nontoxic amounts, significantly reduces the incidence of sperm abnormalities from alpha-particle radiation as well as emissions from 125I incorporated into DNA, the dose reduction factors being 10 and 14, respectively.

Alpha Particles↗
PubMed1990

Biological consequence of nuclear versus cytoplasmic decays of 125I: cysteamine as a radioprotector against Auger cascades in vivo.

When the radionuclide 125I is localized in mouse testis as 125I-iododeoxyuridine (an analogue of thymidine) and incorporated into the DNA of spermatogonial cells, the cytocidal effects are as severe as those due to densely ionizing alpha particles. In contrast, 125I confined to the cytoplasm of these cells is much less radiotoxic, the efficacy being the same as for selective irradiation of the testis with sparsely ionizing external X rays. The biological effects, in both cases, are strongly mitigated upon pretreatment of the testes with very small amounts (0.75 microgram) of cysteamine, a radioprotector. These findings suggest an important role for such chemical agents in radiation protection and in understanding the mechanisms of radiation damage involving radionuclides incorporated in tissue.

Animals↗
PubMed1989

In-vivo radiotoxicity of DNA-incorporated 125I compared with that of densely ionising alpha-particles.

When the atomic nucleus of 125I decays by orbital electron capture followed by internal conversion, numerous very-low-energy electrons (Auger electrons) are emitted, so that the energy density in the immediate vicinity of the decay site is extremely high. 125I incorporated into DNA was as effective as densely ionising 5.3 MeV alpha-particles from 210Po in reducing the sperm-head population in mice. Hence the biological risks of Auger-electron emitting radionuclides widely used in biology and medicine ought to be reassessed.

Animals↗
PubMed1988

Cytotoxicity of some indium radiopharmaceuticals in mouse testes.

The biological effects of [111In]oxine, [111In]citrate, and [114mIn]citrate localized in mouse testes as well as the effects of external x-rays are investigated. The in vivo radiotoxicity of [111In] oxine is far greater than the chemotoxicity of oxine. Of these radiolabeled compounds, [111In] oxine is the most effective in reducing the sperm-head population, the mean lethal dose (D37) to the organ being about 0.16 Gy at 37% survival of the sperm heads. The corresponding values of D37 for [111In]citrate, [114mIn]citrate and x-rays are approximately 0.34, 0.57, and 0.67 Gy, respectively. The present results affirm our earlier finding of the inadequacy of conventional dosimetry in estimating the biologic consequences of Auger-electron emitters in vivo. The very different radiotoxicities of [111In]oxine and [111In]citrate draw attention to the role of the chemical nature of the radiolabeled compounds in the expression of biologic effects in vivo, an aspect that is not considered explicitly in the formulation of conventional dosimetry.

Animals↗
PubMed1979

The comparative antidepressant value of lofepramine and amitriptyline. Results of a controlled trial with comments on the scales used.

A double-blind controlled trial comparing the antidepressant activity of amitriptyline with lofepramine is reported. Forty-six patients entered the 4-week trial. Analysis of the Hamilton Depression Rating Scale scores at the beginning and end of the trial showed no significant difference between the therapeutic efficacy of lofepramine and amitriptyline. However, patients with endogenous depression responded significantly more rapidly to lofepramine as measured by Visual Analogue Scales and showed a significantly greater degree of clinical improvement after 4 weeks' treatment, as measured by Global Assessment. Adverse effects were similar in the two treatment groups. The use of rating scales in trials of depressive illnesses is discussed. The Visual Analogue Scale for depression was found to be a simple, useful and valid measure.

Aged↗