Reproduction inhibitors

Berger, P. J., Sanders, E. H., Gardner, P. D., and Negus, N. C. (1977). Phenolic plant compounds functioning as reproductive inhibitors in Microtus montanus. Science 195,575-577. 

Because of their ability to induce sterility in insects, hydrazine-derived compounds have long been of interest to us in our search for new reproduction inhibitors (1.-.4) In this context, we recently evalu = ated compound, ll-(2,4-dif luoropheny 1)-2-( 2-f luoro phenyl)-hydrazinecarboxamide (Figure 1), and found that it inhibited oviposition in house flies (Musca domestlea L.) when administered orally to adults. However, since infertility was accompanied by excessive adult mortality, failure to lay eggs was probably symptomatic of nonspecific toxic effects rather than effects directed at the reproduction pathway. 

The weak activity of 52 (chlordimeform) and 104 (amitraz) as reproduction inhibitors in individual mites was surprising. Of the 109 compounds examined, the rank order for inhibition of reproductive potential at 500 ppm at 72 hours was 50 for formamidine 52 (chlordimeform) it yielded 11.7%, 5.6% and 16.6% reduction of... 

To explore this further, a demographic study was conducted with chlordimeform, amitraz, and compound 17, which was the most active mite reproduction inhibitor among the nonlethal formamidines (20). Each of the three formamidines caused a reduction in survivorship and fecundity which resulted in a significant decrease in the intrinsic rate of increase of the mite population. In these experiments, amitraz was most potent, chlordimeform was intermediate, and compound 17 was least potent (20). This apparent disparity between the strong activity of chlordimeform and amitraz on mite reproduction at the population level and their weak activity at the individual level can be explained as follows. The effects of amitraz on population growth were due mainly to its lethal activity to the various life stages, and the effects of chlordimeform were due to its lethality to life stages as well as its reduction of fecundity. The activity of compound T7 resulted only from its reduction of fecundity (20). 

USE Experimental insect reproduction inhibitor, Kenaga, J. Econ. Entomol 62, 1006 (1969). 

In the three examples presented, the conditioned aversion response played the leading role. In the first, It was recognized that the response is probably the most effective at manipulating the food habits of a wild carnivore. In the second, the problem associated with this response ("bait shyness") In getting adequate acceptance of a treated bait when using a reproductive Inhibitor led to Its use as a repellent. In the third, extensive screening efforts for a bird repellent Identified one material, methlocarb,... 

Up until 1986 the major use for 2-j -butylphenol was in the production of the herbicide, 2-j -butyl-4,6-dinitrophenol [88-85-7] which was used as a pre- and postemergent herbicide and as a defoHant for potatoes (30). The EPA banned its use in October 1986 based on a European study which showed that workers who came in contact with 2-j -butyl-4,6-dinitrophenol experienced an abnormally high rate of reproduction problems. Erance and the Netherlands followed with a ban in 1991. A significant volume of 2-j -butyl-4,6-dinitrophenol is used worldwide as a polymerization inhibitor in the production of styrene where it is added to the reboiler of the styrene distillation tower to prevent the formation of polystyrene (31). OSBP is used in the Par East as the carbamate derivative, 2-j -butylphenyl-Ai-methylcarbamate [3766-81-2] (BPMC) (32). BPMC is an insecticide used against leaf hoppers which affect the rice fields. 

Many pesticides cause endocrine disruption in vertebrate and invertebrate species at concentrations that are not overtly metabolically toxic. The insect growth inhibitor diflubenzuron can affect the reproduction, development and behaviour of estuarine crustaceans at concentrations of just lOmgP (reviewed... 

The most recent advance in treating HIV infections has been to simultaneously attack the virus on a second front using a protease inhibitor. Recall from Section 27.10 that proteases are enzymes that catalyze the hydrolysis of proteins at specific points. When HIV uses a cell s DNA to synthesize its own proteins, the initial product is a long polypeptide that contains several different proteins joined together. To be useful, the individual proteins must be separated from the aggregate by protease-catalyzed hydrolysis of peptide bonds. Protease inhibitors prevent this hydrolysis and, in combination with reverse transcriptase inhibitors, slow the reproduction of HIV. Dramatic reductions in the viral load in HIV-infected patients have been achieved with this approach. 

Based on the predicted effects on HIV-1 and T cell dynamics, antiviral genes have been grouped into three classes (Fig. 1) (von Laer et al. 2006b). Early inhibitors are classified as class 1, inhibitors of intracellular reproduction of the viral genome and production of viral gene product are class II, and late inhibitors are considered class 111. A comprehensive list of types of antiviral genes reported to date for each class is found in Table 1 (von Laer et al. 2006a). 

No animal or human data were available for inhalation exposure. There are no data regarding effects in humans after oral exposure. Information is available in animals regarding health effects following acute, intermediate, and chronic oral ingestion of diisopropyl methylphosphonate. The animal data obtained after oral exposure indicate that diisopropyl methylphosphonate is moderately toxic after acute bolus exposure but has a lower order of toxicity after intermediate and chronic exposures in food. No data were found on the toxicity of diisopropyl methylphosphonate after exposure in drinking water. Further, diisopropyl methylphosphonate is rapidly metabolized and excreted and does not accumulate. It does not appear to have reproductive or developmental effects. At the doses tested, it does not appear to be an acetylcholinesterase inhibitor, although this issue has not been resolved yet. Limited data are available for dermal exposure in humans and animals. Diisopropyl methylphosphonate does not appear to be a... 

Substances known as intercalators, such as rifamycin and actinomycin D (bottom) are deposited in the DNA double helix and thereby interfere with replication and transcription (B). As DNA is the same in all cells, intercalating antibiotics are also toxic for eukaryotes, however. They are therefore only used as cytostatic agents (see p. 402). Synthetic inhibitors of DNA topoisomerase II (see p. 240), known as gyrase inhibitors (center), restrict replication and thus bacterial reproduction. 

Protease Inhibitors (Pis) interrupt the HIV reproduction cycle and prevent the virus from being assembled by interfering with the HIV protease enzyme. As a result, copies of HIV are not able to infect new cells. 

Single agents are seldom used to treat HIV infection. Instead, multidrug therapy is used to counteract the rapid mutation rate of HIV and to minimize drug toxicity. Highly active antiretroviral therapy (HAART) uses combinations of reverse transcriptase inhibitors and protease inhibitors (Table 51.1). In this system, drugs working by different mechanisms produce a sequential blockade of steps required for viral reproduction. It is... 

For early clinical trials, where it is unlikely there will be full reproductive toxicology data, any application should include a discussion of whether any effects on reproduction can be anticipated from the primary pharmacodynamics. The nature of the target receptor binding and any potential for binding to receptors involved in reproduction should be considered. For compounds in classes already known to be teratogenic such as cytotoxic anticancer products, retinoids, or histone deacetylase inhibitors, it can be reasonably expected that... 

---