Contraception by induction of luteinized unruptured follicles with short-acting low molecular weight FSH receptor agonists in female animal models.

During recent decades minor innovative drugs have been developed for the female contraceptive market and they all contain steroidal progestagens (and estrogens) that act centrally and have side effects that can be attributed to this central action. In this study, we present an innovative tissue-specific approach for female contraception by low molecular weight (LMW) FSH receptor (FSHR) agonists, which interact with the FSHR that is dominantly expressed in the granulosa cells. The oral administration of LMW FSHR agonists with a short circulation time, induced formation of luteinized unruptured follicles (LUFs) from the Graafian follicles, thereby preventing the release of the oocyte. The short-acting LMW FSHR compounds were fully agonistic to FSHR (EC(50)=4-5 nM). In an isolated mouse follicle culture, a short incubation period (2 h) resulted in inhibition of follicular rupture, where continuous incubation induced follicle growth. Pharmacokinetics after oral administration showed a surge-like exposure in rats and monkeys. Oral administration of short-acting LMW FSHR agonists inhibited ovulation at 10 mg/kg in rats and guinea pigs by generating LUFs without affecting cyclicity. Also, inhibition of follicular rupture was shown to be reversible within one cycle. Finally, LUFs were induced without affecting the hormonal cyclicity in cynomolgus monkeys, a mono-ovulatory species. In healthy women LUF formation occurs naturally, with a LUF acting as corpus luteum that produces enough progesterone to ensure normal menstrual cyclicity. Together with the presented data this indicates that the innovative approach with short-acting LMW FSHR agonists could lead to oral contraception for females at the ovarian level.

Immunotoxicological screening of morphine and methadone in an extended 28 day study in rats.

Drug addicts are prone to infection with viruses including hepatitis-B and HIV. Besides indirect effects as a consequence of lifestyle, heroin and methadone may also enhance the risk of infections by a direct immunotoxic effect affecting resistance. In addition to general toxicological screening, we therefore performed a screening for potential immunotoxicity of morphine and methadone. Rats treated orally with different dosages of morphine or methadone for 6 weeks showed only a minor effect of overt toxicity on liver and spleen at the high dose, whereas at lower doses an increase in the relative weight of the mesenteric lymph nodes and an increase in cell density in the medullary cords were observed histopathologically, indicating a specific effect on humoral immunity. This specific immunotoxic effect was corroborated by an increased IgG concentration in serum (significant for the methadone-treated group). Further immunotoxicological research is needed aimed at revealing the potential risk of opiate use with respect to immune function. In conclusion, the present paper showed the toxicological profile of morphine and methadone in an extended 28 day subchronic study. Specific immunotoxicological effects were observed at doses where no effects were seen in routine toxicological evaluation, suggesting that the immune system is sensitive to opiates.

Subacute toxicity of Zwittergent administered intramuscularly.

In order to assess the systemic toxicity of Zwittergent 3-14, a detergent used in the protein-detergent complex vaccines for its attractive immunogenic properties, a subacute toxicity study was performed. In this 4-week toxicity experiment five female and five male rats per group were injected intramuscularly with 0.25 ml of 0, 75, 750 and 7500 micrograms Zwittergent ml-1 sterile saline solution. Body weight and food intake were recorded weekly. At day 24 urine was collected for semiquantitative (pH, protein, ketone bodies, bilirubin and occult blood) and quantitative analyses (protein, creatinine and volume). At the end of the experiment blood was sampled for haematological [haemoglobin (Hb), packed cell volume (PCV), erythrocytes, leucocytes, reticulocytes and thrombocytes and differential white blood cell count] and biochemical analyses (alanine aminotransferase and aspartate aminotransferase. At necropsy brain, heart, liver, kidneys, spleen, thymus, adrenal glands, thyroid, pituitary gland, uterus, ovaries and testes were weighed. The underlined organs and the musculus quadriceps including the injection sites were examined histopathologically. Indications for systemic toxicity were noticed in the high-dose group and included occult blood in urine, elevated protein/creatinine ratio concomitantly with an increased urine volume and increased relative kidney weight indicating a slight disturbance of the kidney function. Some changes in haematological parameters (decreased PCV and increased numbers of thrombocytes eosinophils and monocytes) and a decreased glycogen content in the liver were recorded in the high dose group. These changes may be secondary to the extensive inflammatory reaction observed in the muscle of this high-dose group.(ABSTRACT TRUNCATED AT 250 WORDS)