The 1980s through 1990s witnessed the widespread incorporation of in vitro absorption, distribution, metabolism, and excretion (ADME) approaches into drug development by drug companies. This has been exemplified by the integration of the basic science of cytochrome P450s (CYPs) into most drug metabolism departments so that information on the metabolic pathways of drugs and drug-drug interactions (DDIs) is no longer an academic exercise, but essential for regulatory submission. This has come about due to the application of a variety of new technologies and in vitro models. For example, subcellular fractions have been widely used in metabolism studies since the 1960s. The last two decades has seen the increased use of hepatocytes as the reproducibility of cell isolations improved. The 1990s saw the rejuvenation of liver slices (as new slicers were developed) and the utilization of cDNA expressed enzymes as these technologies matured. In addition, there has been considerable interest in extrapolating in vitro data to in vivo for parameters such as absorption, clearance and DDIs. The current philosophy of drug development is moving to a 'fail early--fail cheaply' paradigm. Therefore, in vitro ADME approaches are being applied to drug candidates earlier in development since they are essential for identifying compounds likely to present ADME challenges in the latter stages of drug development. These in vitro tools are also being used earlier in lead optimization biology, in parallel with approaches for optimizing target structure activity relationships, as well as identification of DDI and the involvement of metabolic pathways that demonstrate genetic polymorphisms. This would suggest that the line between discovery and development drug metabolism has blurred. In vitro approaches to ADME are increasingly being linked with high-throughput automation and analysis. Further, if we think of perhaps the fastest available way to screen for successful drugs with optimal ADME characteristics, then we arrive at predictive computational algorithms, which are only now being generated and validated in parallel with in vitro and in vivo methods. In addition, as we increase the number of ADME parameters determined early, the overall amount of data generated for both discovery and development will increase. This will present challenges for the efficient and fast interpretation of such data, as well as incorporation and communication to chemistry, biology, and clinical colleagues. This review will focus on and assess the nature of present in vitro metabolism approaches and indicate how they are likely to develop in the future.

Animals↗

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Counseling of Norplant users.

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Contraceptive Agents, Female↗

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Othello syndrome secondary to right cerebrovascular infarction.

The Othello syndrome, or delusional jealousy, occurs in idiopathic psychoses and in neurodegenerative diseases, but has rarely been described in patients with cerebrovascular infarction. A patient was observed to exhibit the delusion shortly after cerebral ischemic injury in the absence of other psychiatric symptoms. The underlying pathology was consistent with recent reports on content-specific delusions, implicating right hemisphere and frontal lobe involvement in the misinterpretation and misidentification of complex information. Psychological factors were hypothesized to shape the content of the delusional misinterpretations.

Aged↗

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Clinical and virological associations between external anogenital warts and cervical HPV infection in an STD clinic population.

To determine the significance of overt anogenital warts as indicators of human papillomavirus (HPV) infection of the cervix, 177 women attending a Sydney STD clinic were screened for evidence of cervical HPV infection using clinical criteria together with cytology and HPV DNA dot hybridization. HPV DNA probing was also performed on biopsies of 50 exophytic warts. A very high prevalence of both anogenital warts (40%), and of cervical HPV infection (58%) was indicated in this group of women. In the exophytic warts, HPV types 6/11 were most commonly detected, whereas the rates of detection of types 6/11 and 16/18 in the cervix were similar. Of the 87 women with evidence of cervical HPV infection, 57 (66%) had a history of either past or current overt exophytic anogenital warts; while the corresponding figure for the 90 women with no evidence of cervical infection was 45 (50%). Cytological evidence of dysplasia (CIN I-III) was detected in 13 (7%) of the cervical smears: of these, 4 were positive for HPV 16/18 only, 2 for 6/11 only and 4 for both 6/11 and 16/18.

Biopsy↗

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Manifestations of anogenital HPV infection in the male partners of women with anogenital warts and/or abnormal cervical smears.

The prevalence and manifestations of anogenital human papillomavirus (HPV) infection in 154 men, all of whom were the sexual partners of women with either overt anogenital warts or cervical HPV-related abnormalities, were assessed using clinical, histopathological and molecular criteria. Detailed examination of the anogenital region using a colposcope was supplemented by the use of 5% acetic acid to detect possible foci of subclinical HPV infection. Biopsies of warts and aceto-white lesions were examined histopathologically and by HPV DNA hybridization using radiolabelled HPV 6/11 and 16/18 DNA probes. More than two-thirds of the men had clinical indications of genital HPV infection: 37% had apparent macroscopic warts, almost invariably in combination with aceto-white lesions; while 34% had aceto-white lesions only. The overwhelming majority of these lesions (92%) were located on the penis only. However, only 49% of the macroscopic and 29% of the aceto-white lesions showed histological features consistent with a conclusive diagnosis of HPV infection; while the corresponding figures for HPV DNA positivity were 72% and 56% respectively. Current HPV infection was strongly associated with a past history of anogenital warts, but there was little or no correlation between the manifestations of HPV infection in the male and female sexual partners.

Adult↗