Gary L. Henderson

Shosaiko-to and other Kampo (Japanese herbal) medicines: a review of their immunomodulatory activities

The use of alternative medicine, including consumption of herbal products and dietary supplements, has been increasing substantially both in the United States and in Western Europe. One area that is garnering increased attention is the use of Oriental Medicine including Kampo, or Japanese herbal medicine. Herein, we review representative examples of research available on the most common use of Kampo medicinals, namely to improve the immune response. We also provide an extensive background on the history of Kampo. There are more than 210 different Kampo formulae used in Japan and most uses of Kampo are to modulate the immune response, i.e. to improve immunity. We have extracted data on seven common Kampo medicinals, and the data are reviewed with respect to in vitro and in vivo activities for both humans and experimental animals; the ingredients as well as the problems with classification of these materials are presented. Research suggests that Kampo herbals are biologically active and may have therapeutic potential. While it is believed that Kampo medicines have few side effects, there is a paucity of data on their toxicity as well as a relative lack of knowledge of the bioactive constituents and potential drug interactions of these agents.

Plasma l‐α‐acetylmethadol (LAAM) after acute and chronic administration

l‐α‐Acetylmethadol (LAAM) was administered orally to two groups of subjects; one group received methadone. 50 mg/day. for three months previously and the other group were heroin addicts who had no prior exposure to methadone or LAAM. Plasma elimination curves for methadone. LAAM. and its metabolites. noracetylmethadol (N‐LAAM) and dinoracetylmethadol (DN‐LAAM). were determined after acute and chronic administration. The plasma decay curve for LAAM was biexponential (t½α = 6 hr; t½β > 50 hr) following acute or chronic administration. Following chronic administration. N‐LAAM and DN‐LAAM plasma levels increased 5‐ to 10‐fold. At this time. N‐LAAM had a t½ of 31 hr and DN‐LAAM had a t½ of > 100 hr. There appear to be at least two factors which determine the long duration of action of LAAM: metabolic conversion to active metabolites and tissue or plasma binding. Both methadone and LAAM may compete for plasma protein or tissue binding sites. The clinical implications of this potential drug‐drug interaction are discussed.

Depression of Myocardial Contractile Function by Propoxyphene and Norpropoxyphene

Summary: Propoxyphene and its principal metabolite, norpropoxyphene. depressed maximum developed isometric tension (T) and its first derivative. dT/dt. in isolated cat right ventricular papillary muscles. T and dT/dt were reduced by 10 3 M concentrations of each drug (p < 0.005). and this effect was markedly intensified at 10 1 M propoxyphene, 49% reduction of T (p < 0.001): norpropoxyphene, 36% reduction of T (p < 0.001). Nonresponsiveness to electrical stimulation developed in the majority of muscles at the 10 3 M concentration of each drug and in all muscles at 10 3 M. The cardiac depressant actions of the two drugs administered simultaneously at a concentration of 10 3 M each were additive, resulting in a 15.6% decline in T. The contractile actions of propoxyphene and norpropoxyphene were not altered by the specific narcotic blocking agent, naloxone, indicating these effects were produced by a nonopiate mechanism. In contrast to propoxyphene and norpropoxyphene, morphine produced no reductions in T or dT/dt at a concentration of 10 5 M and only a slight, albeit significant (p < 0.05), depression of T (−4%) and dT/dt (−6%) at 10 4 M. The cardiac depressant effects of propoxyphene and norpropoxyphene were at least partially reversible, as indicated by substantial recovery of contractile function after drug removal (to 69–75% of control T) and by a positive inotropic response to isoproterenol. These results indicate that at high concentrations propoxyphene and norpropoxyphene have a cardiac depressant action characterized by decreased electrical excitability and reversible contractile depression, effects which are consistent with a local anesthetic action. Depression of cardiac contractile and electrophysiologic functions by propoxyphene and norpropoxyphene may play a role in the clinical toxicity associated with propoxyphene overdose.

16α-Bromo-epiandrosterone therapy modulates experimental feline immunodeficiency virus viremia: initial enhancement leading to long-term suppression

16alpha-Bromo-epiandrosterone (epiBr), a synthetic derivative of the natural hormone dehyroepiandrosterone (DHEA), was evaluated for its effects on feline immunodeficiency virus (FIV) infection in experimental cats. The rationale for this study was based on the ability of DHEA to significantly reduce the mortality to viral infections in mice. DHEA and epiBr also have demonstrable in vitro anti-viral activity for both HIV-1 and FIV. Preliminary pharmacokinetic studies in cats demonstrated that subcutaneously injected epiBr was rapidly absorbed, completely metabolized, and nontoxic. Metabolites were excreted in both urine and feces, with the latter having the most complex pattern of breakdown products. Cats were then divided into four groups; two groups were infected with FIV and two uninfected. Two groups, one infected and one uninfected were treated on 5 consecutive days of weeks 0, 4, 8, 12 and 16 with epiBr. The remaining two groups were mock treated with the drug vehicle alone. Treatment started 1 week prior to infection and extended for 4 weeks after infection. Cats were observed for 20 weeks post-FIV infection. Infected cats had identical decreases in blood neutrophil and lymphocyte counts following, regardless of whether they were treated with epiBr or vehicle alone. The CD4/CD8 T-cell ratio was decreased following FIV exposure, but was significantly more decreased for the epiBr treated animals from week 2 post-infection onward. CD4+ T cells were decreased in FIV-infected cats treated with epiBr compared to their untreated cohort, while CD8+ T cells tended to be higher in treated animals. FIV infected cats that were treated with epiBr had over one-log higher virus loads at week 2 post-infection than non-epiBr treated cohorts. In spite of this enhanced initial viremia, the subsequent levels of virus in the blood were significantly lower in epiBr treated versus untreated animals. EpiBr treated cats had significantly higher FIV-p24 antibody responses than control cats receiving vehicle alone, although primary and secondary antibody responses to a T-cell dependent non-FIV antigen, keyhole limpet hemocyanin (KLH), were unaffected. EpiBr treatment significantly decreased the expected FIV-induced suppression of IL-12 p40 mRNA levels in peripheral blood mononuclear cells (PBMCs) observed at weeks 4, 5, 8, 9 and 16 post-infection, but had no influence on FIV-induced changes in IL-4, IL-6, IL-10, IFN-gamma, MIP-1alpha and RANTES.

Comparative study on the derivatization of l-α-acetylmethadol metabolites for electron capture gas-liquid chromatography

Six reagents-trichloroacetyl chloride, trichloroacetic anhydride, pentafluorobenzoyl chloride, heptafluorobutyryl chloride, heptafluorobutyric anhydride, and trifluoroacetic anhydride- were evaluated as potential derivatizing reagents for quantitating the metabolites of l-alpha-acetylmethadol (LAAM) -noracetylmethadol, dinoracetylmethadol, methadol, and normethadol-by electron capture gas-liquid chromatography. All of the reagents studied reacted quantitatively with all of the metabolites except methadol; however, trichloroacetyl chloride was found to be the most satisfactory general reagent for analyzing these metabolites in biological fluids. A gas-liquid chromatographic method is presented which combines both flame ionization and electron capture detection for quantitating plasma and urine levels of methadone, l-alpha-acetylmethadol and its metabolites.

Tocainide suppression of immune-complex-mediated dermal inflammation: Comparison with prostaglandin E1

Local anesthetic agents have been shown to alter a variety of polymorphonuclear leukocyte (PMN) functions and may be useful as anti-inflammatory agents. We compared the anti-inflammatory effects of therapeutic doses of the recently released local anesthetic-antiarrythmic drug tocainide to pharmacologic doses of prostaglandin E1 (PGE1) on immune-complex-mediated dermal inflammation in female Sprague-Dawley rats. Intense dermal inflammation was produced using a classic reverse passive Arthus reaction, and the inhibition of PMN accumulation in the subdermis was quantitated in biopsy samples taken 2.5 hr after the reaction was initiated and the drug was given. Using a light microscope with a counting grid, biopsy sections were randomly sampled in a blinded fashion and an inflammation index equal to the ratio of PMNs to fibroblasts was determined for each animal. The mean inflammation index in 10 animals given 25 mg of tocainide (mean serum level = 14.6 micrograms/ml) was 9.3 +/- 1.2 (+/- SEM), which was significantly less than the index of 17.7 +/- 2.5 in 10 control animals (P less than 0.025). Similarly, the five animals that received either 500 or 250 micrograms of PGE1 had a significantly reduced index, with the effect of 250 micrograms PGE1 comparable to the effect of the tocainide. These findings suggest that therapeutic levels of tocainide reduce the accumulation of PMNs in immune-complex-mediated dermal inflammation; thus, local anesthetic agents may be useful in the treatment of certain inflammatory disorders.

Extraction method and thin-layer chromatographic system for the determination of α-l-acetylmethadol and metabolites in biological fluids

An extraction method and thin-layer chromatographic (TLC) system for the determination of alpha-l-acetylmethadol and its known metabolites (methadol, noracetylmethadol, dinoracetylmethadol, normethadol, 6-acetamide-4,4-diphenyl-3-heptanol, and N-methyl-6-acetamido-4,4-diphenyl-3-heptanol) are described. The parent drug and metabolites are extracted from biological fluids with ethyl acetate and separated by TLC using silica gel plates and a developing system of ethyl acetate-methanol-water-ammonia (85:10:1:1). This system may be used to quantitatively determine levels of radiolabeled drug and metabolites by scraping the TLC plates into 3-mm zonal fractions and measuring the amount of radioactivity by scintillation counting. A representative radiochromatogram obtained from an extract of monkey urine is shown.