A convenient method is proposed for the synthesis of methyl 1,6-dideoxy-β-D-arabino-, 3,6-dideoxy-β-D-ribo-, and 4,6,dideoxy-β-D-xylo-hexopyranosides by the partial deoxygenation of methyl β-D-quinovopyranoside followed by liquid chromatography of the dideoxysugars.

Once-a-month injectable microspheres of leuprolide acetate prepared with copoly(DL-lactic/glycolic acid) using an in-water drying method were assessed for duration of the analogue release and pharmacological effects in rats after a single or repeated injection. The periodic challenge test revealed that a single injection of the microspheres caused a dramatic and persistent suppression of the ability of the pituitary–gonadal system to secrete gonadotropin and testosterone for over 5 weeks. The complete recovery of these functions was observed 10 weeks after the injection. The repeated injection of the microspheres at intervals of 2 or 4 weeks achieved persistent suppression of steroidogenesis after an initial transient flare-up and beneficially avoided the “acute-on-chronic response.” This depot formulation is expected to assure patient compliance and produce stronger therapeutic effects than the daily solution.

A century ago, an English psychiatrist, Henry Maudsley, wrote of the complexity of somatic and psychic connections in these terms: ‘The sorrow that has no vent in tears makes other organs weep’. Fritz Zorn, the author of a literary work, the novel Mars, published in 1977, shared this intuition: a young man from Swiss upper middle class society, Mars, develops a malignant tumour. This discovery throws his life into turmoil and he says, ‘The tumour represents hidden tears’. This brief chapter discusses four propositions: I — that psychic state is a clear component of immunological well-being; II — that stress, anxiety and depression modify cellular and humoral immunological defences; III — that neurotransmitters, neurohormones or cellular lymphokines play a major role in regulating immunological self; IV — that psychotropic drugs may modify some aspects of immunity. Scientific proof for defending these assertions differs considerably; few seem firmly verified, while many are under discussion. The expression of immunological ecology refers to biopsychosocial interactions and rules out any hypothesis of linear causality. Several thousand million cells, more than the cerebral nervous system contains, form the immunological network. Immunological cell specialization, competence and relations with other systems of the organism are numerous.

Summary

In spite of the vast amount of data generated during the new drug development process, much remains to be learned about the pharmacokinetics of a drug once it is released on the market. The ethical and logistical problems which arise during an experimental pharmacokinetic study frequently prevent the study of elderly, pediatric, or critically ill patients. The recognition of these limitations by scientists and regulators have prompted a desire to extract the maximum amount of information from data available during Phase III and Phase IV clinical trials and, in addition, to use information generated during the routine clinical care of patients. Mixed effect model analysis allows one to overcome the problems of analyzing observational data to obtain accurate and precise estimates of population pharmacokinetic parameters. Use of this approach expands the methodologies available to the data analyst and opens up a number of data sources which can now be considered for analysis.

The main objective of this study was to investigate how enzymatic lability would affect the extent of corneal and conjunctival penetration of a series of alkyl, cycloalkyl, and aryl ester prodrugs of timolol in the pigmented rabbit. Enzymatic lability of the prodrugs was studied in corneal epithelial and conjunctival homogenates, while their corneal and conjunctival penetration was determined using the isolated tissues in the modified Ussing chamber. The straight-chain alkyl and the unsubstituted cycloalkyl esters were hydrolyzed more rapidly than their corresponding branched-chain and substituted analogues as well as the aryl esters. The corneal and conjunctival penetration of all prodrugs, regardless of enzymatic lability, varied parabolically with lipophilicity. Moreover, the enzymatically more labile straight-chain alkyl esters penetrated the cornea and the conjunctiva more readily than the more stable branched-chain esters of comparable lipophilicity. Enzymatic lability is, therefore, an additional factor that should be considered in designing alkyl ester prodrugs with improved ocular drug delivery characteristics. Enzymatic lability does not, however, play as important a role as lipophilicity in the corneal and conjunctival penetration of cycloalkyl and aryl ester prodrugs.

From the work of the Kunkel (Koenig et al., 1987) and Worton groups (Burgess et al., 1987) it has been established that the protein dystrophin is absent or in some cases present in a modified form in patients with Duchenne and Becker muscular dystrophies (Xp21 myopathies). The amino acid sequence deduced from analysis of the complementary DNA indicates that dystrophin from human skeletal muscle has a molecular weight of 427,000 and consists of a polypeptide chain of 3,865 residues with a multi-domain structure (Koenig et al., 1988). The N-terminal domain of 240 residues shows homology to the N-terminal domain of the α-actinins in which region actin has been shown to bind (Mimura & Asano, 1986). The second and largest domain is formed by a succession of 25 triple helical segments (the fourth of which is truncated) with loose homology between them and which show weak similarity to similar repeats in a and β-spectrin. A third domain extending over 150 residues is cysteine-rich and is similar in sequence to the carboxy terminal domain of α-actinin that contains two calcium binding sites. The corresponding sites on dystrophin are rather rudimentary and may not be functional.