[New developments in the treatment of nausea and vomiting caused by chemotherapy]. / Nieuwe ontwikkelingen in de behandeling van misselijkheid en braken door chemotherapie.

With the advent of the 5HT3-receptor antagonists in the 1990s and their combination with dexamethasone, complete emesis protection during the first 24 hours after administration of an emetogenic cytostatic agent became possible in 70% of the patients. Despite acute emesis protection through the use of 5HT3-receptor antagonists and dexamethasone, 40% of the patients do have symptoms during the following days. 5HT3-receptor antagonists and dexamethasone are modestly effective in this delayed phase and the antiemetic protection decreases progressively with multiple cycles. Neurokinine(NK)-1-receptor antagonists belong to a new class of antiemetic agents that specifically target the NK-1-receptor which is involved in both the acute, and in particular, the delayed phase. Clinical studies have demonstrated that the addition of the NK-1-receptor antagonist apprepitant to a 5HT3-receptor antagonist plus dexamethasone combination improves acute emesis protection by about 20% (from approximately 60% to 80%) and by about 30-40% in the delayed phase (from approximately 30% to 60-70%). The effectiveness of this triple therapy is sustained during subsequent cycles. The chance that an individual patient will be completely protected from severe nausea and vomiting during the entire course of chemotherapy (often 6 cycles) consequently increases significantly (from 34% in the placebo group to 59% in the aprepitant group).

Dose-response studies on the spermatogonial stem cells of the rhesus monkey (Macaca mulatta) after X irradiation.

Studies of the dose response of the spermatogonial stem cells in the rhesus monkey were performed at intervals of 130 and 160 days after graded doses of X irradiation. The D0 of the spermatogonial stem cells was established using the total numbers of the type A spermatogonia that were present at 130 and 160 days after irradiation and was found to be 1.07 Gy; the 95% confidence interval was 0.90-1.34 Gy.

Protection from radiation-induced damage of spermatogenesis in the rhesus monkey (Macaca mulatta) by follicle-stimulating hormone.

In adult rhesus monkeys a two- to threefold increase in the number of spermatogonia was found at Day 75 after 1 Gy of X-irradiation when the animals were pretreated with two intramuscular injections of follicle-stimulating hormone (FSH) each day. Also the percentage of cross-sections of seminiferous tubules showing spermatogonia (repopulation index) was much higher when FSH was given before irradiation. At 75 days postirradiation the repopulation index was 39 +/- 10% after irradiation alone and 81 +/- 11% when FSH pretreatment was applied. The pretreatment with two injections of FSH each day during 16 days caused an increase in the number of proliferating A spermatogonia. In view of earlier results in the mouse, where proliferating spermatogonial stem cells appeared more radioresistant than quiescent ones, it is suggested that the protective effects of FSH treatment are caused by the increase in the proliferative activity of the A spermatogonia and consequently of the spermatogonial stem cells. The results indicate that in the rhesus monkey the maximal protective effect of FSH is reached after a period of treatment between 7 and 16 days.

Follicle-stimulating hormone stimulates spermatogenesis in the adult monkey.

A 2-fold increase in the numbers of germinal cells was observed in the seminiferous epithelium of cynomolgus monkeys treated with 15 IU FSH twice a day during 28 days. No effect was seen after 7 days of treatment. After 16 days only the numbers of Apale (Ap) spermatogonia had increased to 200% of the control level while the numbers of B spermatogonia, spermatocytes, and spermatids had increased less (160%, 129%, and 100% of the control level, respectively). In the rhesus monkey after the same dose of FSH an increase in the number of Ap spermatogonia to 152% was found after 16 days. When a dose of 25 IU FSH was administered to cynomolgus monkeys three times per week for 16 days the number of Ap spermatogonia increased to only 131% of the control level. After all treatments no effect on the number of Adark (Ad) spermatogonia was found. It was concluded that the increased levels of plasma FSH caused a specific increase in the number of Ap spermatogonia. The increased number of A spermatogonia gave rise to an increase in the number of B spermatogonia after 16 days of treatment which in turn produced more spermatocytes between 16 and 28 days of treatment. If the FSH was administered for a period of 28 days the number of round spermatids also showed a 2-fold increase. These findings indicate a correlation between plasma FSH levels and the numbers of germinal cells in the seminiferous epithelium. In monkeys treated with 450 IU human CG daily no effect on the numbers of the A spermatogonia was observed.

Effects of dopamine on intestinal vessels in anesthetized dogs.

The effects of dopamine administered in graded intravenous bolus injections (0.1 to 51.2 micrograms.kg-1) were studied simultaneously in a number of splanchnic vessels at organ level in anesthetized dogs with and without preceding administration of phenoxybenzamine. Hemodynamic data are presented for each artery as conductance, which were obtained by dividing mean flow by mean arterial pressure. The data were analyzed by two different means: 1) the response to 12.8 micrograms of dopamine during one minute, and 2) by dose-response curves. Early and late effects during the one minute post injection measurement time could be distinguished after the administration of dopamine. In the superior pancreaticoduodenal, the superior mesenteric, the inferior mesenteric, the left gastric, and the hepatic arteries an early reduction in conductance was seen, while in the femoral artery an increase in conductance was observed. Early reduction was often followed by an increase in conductance above the preinjection level. This early reduction in conductance was absent when dopamine was administered after phenoxybenzamine, while a more pronounced increase was observed during the late phase. There was a slight reduction in renal artery flow, probably caused by a slight reduction in arterial pressure. Because there was no increase in the conductance of the hepatic artery--both with and without phenoxybenzamine--it may be concluded that no specific dopamine receptors are present in this vascular bed in dogs.

Depletion of the spermatogonia from the seminiferous epithelium of the rhesus monkey after X irradiation.

In unirradiated testes large differences were found in the total number of spermatogonia among different monkeys, but the number of spermatogonia in the right and the left testes of the same monkey appeared to be rather similar. During the first 11 days after irradiation with 0.5 to 4.0 Gy of X rays the number of Apale spermatogonia (Ap) decreased to about 13% of the control level, while the number of Adark spermatogonia (Ad) did not change significantly. A significant decrease in the number of Ad spermatogonia was seen at Day 14 together with a significant increase in the number of Ap spermatogonia. It was concluded that the resting Ad spermatogonia are activated into proliferating Ap spermatogonia. After Day 16 the number of both Ap and Ad spermatogonia decreased to low levels. Apparently the new Ap spermatogonia were formed by lethally irradiated Ad spermatogonia and degenerated while attempting to divide. The activation of the Ad spermatogonia was found to take place throughout the cycle of the seminiferous epithelium. Serum FSH, LH, and testosterone levels were measured before and after irradiation. Serum FSH levels already had increased during the first week after irradiation to 160% of the control level. Serum LH levels increased between 18 and 25 days after irradiation. Serum testosterone levels did not change at all. The results found in the rhesus monkey are in line with those found in humans, but due to the presence of Ad spermatogonia they differ from those obtained in non-primates.

Repopulation of the seminiferous epithelium of the rhesus monkey after X irradiation.

Repopulation of the seminiferous epithelium became evident from Day 75 postirradiation onward after doses of 0.5, 1.0, and 2.0 Gy of X rays. Cell counts in cross sections of seminiferous tubules revealed that during this repopulation the numbers of Apale (Ap) spermatogonia, Adark (Ad) spermatogonia, and B spermatogonia increased simultaneously. After 0.5 Gy the number of spermatogonia increased from approximately 10% of the control level at Day 44 to 90% at Day 200. After 1.0 and 2.0 Gy the numbers of spermatogonia increased from less than 5% at Day 44 to 70% at Days 200 and 370. The number of Ad and B spermatogonia, which are considered to be resting and differentiating spermatogonia, respectively, already had increased when the number of proliferating Ap spermatogonia was still very low. This early inactivation and differentiation of a large part of the population of Ap spermatogonia slows down repopulation of the seminiferous epithelium of the primates. By studying repopulating colonies in whole mounts of seminiferous tubules various types of colonies were found. In colonies consisting of only A spermatogonia, 40% of the A spermatogonia were found to be of the Ad type, which indicates that even before the colony had differentiated, 40% of the A spermatogonia were inactivated into Ad. Differentiating colonies were also found in which one or two generations of germ cells were missing. In some of those colonies it was found that the Ap spermatogonia did not form any B spermatogonia during one or two cycles of the seminiferous epithelium, while in other colonies all Ap spermatogonia present had differentiated into B spermatogonia. This indicates that the differentiation of Ap into B spermatogonia is a stochastic process. When after irradiation the density of the spermatogonia in the epithelium was very low, it could be seen that the populations of Ap and Ad spermatogonia are composed of clones of single, paired, and aligned spermatogonia, which are very similar to the clones of undifferentiated spermatogonia in non-primates.

Duration of the cycle of the seminiferous epithelium and its stages in the rhesus monkey (Macaca mulatta).

Doses of 1 Gy or more of X-irradiation killed all B spermatogonia present in the testis, and during the first 3 weeks after irradiation, virtually no new B spermatogonia were formed. The number of Apale spermatogonia decreased during the first cycle of the seminiferous epithelium while the number of Adark spermatogonia only began to decrease during the second cycle after irradiation. In this study, the duration of the cycle of the seminiferous epithelium in the rhesus monkey was estimated to be 10.5 days (SE = 0.2 days). This was determined following the depletion of germinal cells in the seminiferous epithelium during the first 3 weeks after irradiation. The duration of each of the 12 stages of the cycle was also determined. Our observations of the progress of germinal cell depletion revealed that after a dose of X-irradiation sufficient to kill all B spermatogonia, all spermatocytes disappeared from the testis within about 17 days, and all spermatids within about 31 days.