Aloe polymannose enhances anti-coxsackievirus antibody titres in mice.

Aloe polymannose (AP), a high mannose biological response modifier (BRM) purified from the Aloe barbadensis Miller plant, was tested for activity in enhancing antibody titres against coxsackievirus B3 (CVB3) and CVB3-induced myocarditis in murine models of the disease. Inoculation of mice with AP over a range of three nontoxic doses and in varying schedules did not reduce virus titres in heart tissues or ameliorate virus-induced cardiopathological alterations during acute disease. However, this BRM was found to significantly enhance titres of anti-CVB3 antibodies produced during acute infection of three strains of mice with CVB3. Simultaneous intraperitoneal inoculation of AP at a dose of 0.5 mg/kg body weight per mouse with purified CVB3 significantly increased ELISA titres of anti-CVB3 antibodies and the proportion of mice with these titres, compared with similar parameters in mice inoculated only with CVB3. The data conclusively show that AP can immunopotentiate antibody production against capsid protein epitopes of a nonenveloped picornavirus and suggest this BRM (AP) might be of benefit in enhancing antibody titres against other enteroviruses during a natural infection and poliovirus vaccine strains.

The effect of Acemannan Immunostimulant in combination with surgery and radiation therapy on spontaneous canine and feline fibrosarcomas.

Eight dogs and five cats with histopathologically confirmed fibrosarcomas were treated with Acemannan Immunostimulanta in combination with surgery and radiation therapy. These animals had recurring disease that had failed previous treatment, a poor prognosis for survival, or both. Following four to seven weekly acemannan treatments, tumor shrinkage occurred in four (greater than 50%; n = 2) of 12 animals, with tumors accessible to measurement. A notable increase in necrosis and inflammation was observed. Complete surgical excision was performed on all animals between the fourth and seventh week following initiation of acemannan therapy. Radiation therapy was instituted immediately after surgery. Acemannan treatments were continued monthly for one year. Seven of the 13 animals remain alive and tumor-free (range, 440+ to 603+ days) with a median survival time of 372 days. The data suggests that Acemannan Immunostimulant may be an effective adjunct to surgery and radiation therapy in the treatment of canine and feline fibrosarcomas.

2,3,4-Tri-O-acetyl-1,6-anhydro-beta-D-mannopyranose, an artifact produced during carbohydrate analysis. A total synthesis of 2,3,5-tri-O-acetyl-1,6-anhydro-beta-D-mannofuranose.

This study confirms that 2,3,4-tri-O-acetyl-1,6-anhydro-beta-D-mannopyranose is an artifact produced during carbohydrate analysis. A new synthesis of 2,3,5-tri-O-acetyl-1,6-anhydro-beta-D-mannofuranose is also described, and a novel dimer, 1,6':6,1'-dianhydro-2,3:2',3'-di-O-isopropylidene-5,5'-di-O-(1-methox yethyl)-di - alpha-D-mannofuranose, has been isolated. The structure of the dimer is confirmed by X-ray analysis of a derivative, 1,6':6,1'-dianhydro-2,3:2',3'-di-O-isopropylidene-di-alpha-D-mannofur anose.

Toxicologic evaluation of injectable acemannan in the mouse, rat and dog.

Acemannan, the USAN-accepted name for long-chain polydispersed beta-(1,4)-acetylated polymannose with interspersed 0-acetyl groups with a mannose monomer/acetyl ratio of approximately 1:1 and extracted from Aloe vera (barbadensis Miller), was administered as a 1.0 mg/ml solution to mice, rats and dogs, either as single dose or repeated at 4-d intervals for 8 doses by iv or ip routes. No significant signs of intoxication and no deaths occurred in animals treated with the single injection of acemannan at dosages of 80 mg/kg iv or 200 mg/kg ip in mice, 15 mg/kg iv or 50 mg/kg ip in rats, and 10 mg/kg iv or 50 mg/kg ip in dogs. On repeated injections systemic toxicity was limited to obvious transient discomfort that appeared dose related. There was accumulation of macrophages and monocytes without subsequent inflammatory reaction in lungs of the iv-treated animals, and in liver and spleen and on peritoneal surfaces of ip-treated animals. The effects were not considered adverse, but were consistent with the known immune stimulating activity of acemannan. A few deaths occurred in mice and rats that were suggestive of resulting from improper injection or sequella of necrosis of the injection site. The NOAELs for acemannan determined from these repeated injection studies were 20 mg/kg iv or ip in the mouse, 4.0 mg/kg iv and 50 mg/kg ip in the rat, and 1.0 mg/kg iv in dogs; 5.0 mg acemannan/kg ip in the dog was considered to be LOAEL, based on the emesis and abdominal discomfort induced.

Subchronic oral administration of acemannan in the rat and dog.

Acemannan is the USAN-accepted name for long-chain polydispersed beta-(1,4)-acetylated polymannose with interspersed O-acetyl groups, with a mannose monomer/acetyl ratio of approximately 1:1. This complex polysaccharide is extracted from Aloe vera (barbadensis Miller); the technical material contains approximately 78% acemannan. Technical grade acemannan was administered po to rats for 14 d at 5% of the diet and for 6 mo at up to 2,000 mg/kg/d, and to beagle dogs for 90 d at up to 1,500 mg/kg/d without significant effect on any parameter measured in either species.

In vitro evaluation of the synergistic antiviral effects of acemannan in combination with azidothymidine and acyclovir.

The antiviral effects of selected combinations between acemannan (ACE-M), a long-chained, polydispersed, beta-(1,4)-acetylated mannan, were tested in combination with azidothymidine (AZT) and acyclovir (ACY) in vitro. The rationale for such combinations was based on the antiviral and immunomodulatory properties exhibited by ACE-M. In addition, the observed antiviral effects of ACE-M against human immunodeficiency virus type 1 (HIV-1) and other enveloped viruses appear to be related to modification of the glycosylation of viral glycoproteins. Therefore, the inhibitory effect of ACE-M does not overlap with that of AZT or ACY. The studies presented herein show that ACE-M combined with suboptimal noncytotoxic concentrations of AZT or ACY act synergistically to inhibit the replication of HIV-1 and herpes simplex virus type 1 (HSV-1), respectively. The median effect method was not applicable for analysis because the test compounds show mutually nonexclusive drug effects. For a meaningful evaluation and interpretation of the effects of drug combinations, the biological significance of combinations must be considered, that is, the protective effect of the combination, the noncytotoxicity of the combination, the mechanism(s) of action of the individual compounds comprising the combination, and so forth. With respect to effects on U1 cells latently infected with HIV-1, treatment with combinations of AZT and ACE-M does not potentiate virus replication.

Inhibition of AIDS virus replication by acemannan in vitro.

Acemannan (ACE-M), a beta-(1,4)-linked acetylated mannan, was evaluated for in vitro activity against human immunodeficiency virus type 1 (HIV-1). Castanospermine (CAS), deoxymannojirimycin (DMN), swainsonine (SWS), azidothymidine (AZT), and dideoxythymidine (DDC) were tested in parallel as control compounds. In vitro antiviral efficacy of ACE-M was evaluated in a variety of cell lines including human peripheral mononuclear, CEM-SS1 and MT-2(2) cells. The virus strain, number of infectious units per cell, and target cell line were important factors in determining the degree of inhibition of viral cytopathic effect in the presence of ACE-M and other control compounds tested. Maximum inhibitory effect was observed in CEM-SS cells infected with the RFII strain of HIV-1. This inhibitory effect was determined to be concentration-dependent. Assay design included primary screening to measure cell viabilities of infected target cells in the presence and absence of test compounds. When tested on HIV-1/RFII-infected CEM-SS cells, the 50% inhibitory effect of CAS (IC50 = 28), an inhibitor of alpha-glucosidase I, was determined to be similar to that observed for ACE-M (IC50 = 45). However, DMN and SWS, inhibitors of mannosidase I and II, tested in parallel to CAS and ACE-M, exhibited no IC50 values. Antiviral potential of ACE-M as an inhibitor of syncytia formation was also explored using CEM-SS cells. Suppression of syncytia formation was observed at an ACE-M concentration of 31.25 micrograms/ml, and complete inhibition was observed at 62.5 micrograms/ml. In addition, HIV-1 RNA levels were studied to establish the antiviral potential of ACE-M in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

The biological activities of mannans and related complex carbohydrates.

Complex polymers containing mannose (mannans) possess significant biological activity when administered to mammals. When given orally, they inhibit cholesterol absorption and induce hypocholesterolemia. If administered by other routes, they bind to mannose-binding proteins and induce macrophage activation and interleukin-1 release, inhibit viral replication, stimulate bone marrow activity, promote wound healing and inhibit tumor growth. This range of activities makes the mannans, potentially important biological-response modifiers and therapeutic agents.

Metabolism of acetone to isopropyl alcohol in rats and humans.

Isopropyl alcohol and acetone have been detected in autopsy blood samples of individuals not previously exposed to these compounds. Since some of these individuals had a history of diabetes mellitus, it has been suggested that in these cases, reduction of acetone to isopropyl alcohol might be a metabolic pathway for its production. This hypothesis was investigated in a study of normal and diabetic rats. Acute administration of acetone resulted in measureable levels of isopropyl alcohol in blood. Metabolism of acetone to isopropyl alcohol was different in normal and diabetic animals. Blood levels of isopropanol reached a maximum at the second highest dose in normal rats, but there was a two-phase response in diabetic rats. In a second series of experiments, acetone was administered on alternate days for a week. In spite of this chronic administration (and persistence of high blood acetone), there was no enhancement of acetone metabolism to isopropyl alcohol. These experiments indicate that high levels of blood acetone could result in transformation to isopropyl alcohol.

Uptake and release of 14C-morphine by pulmonary endothelium and cultured pulmonary endothelial cells.

1. Isolated perfused rabbit lungs and cultured pulmonary endothelial cells take up radiolabeled [14C]morphine in proportion to the amount of labeled drug in the medium. 2. The accumulated label is readily released from the isolated lungs by perfusion with unlabeled morphine or naloxone, but not by perfusion with Krebs-Ringer solution, sucrose or thiopental. 3. Thiourea also enhances efflux of radioactivity, suggesting that the release is not related to interaction with specific opiate receptors. 4. Uptake of [14C]morphine by cultured rabbit or human endothelial cells is unaffected by morphine or naloxone, and the release of radioactivity is not enhanced by these agents. 5. None of the drugs used caused pulmonary edema in the isolated lung preparation, and they did not cause the release of lactic dehydrogenase from cultured endothelial cells. 6. It is concluded that morphine can be taken up by pulmonary endothelium, but it is probably not bound to specific receptors, and it does not injure the endothelial cells.

Isopropyl alcohol metabolism after acute intoxication in humans.

Two cases of acute overdose with isopropyl alcohol are reported. Blood concentrations of the alcohol and its major metabolite, acetone, were measured during the metabolism phase of the alcohol, and acetone was elevated thirty-seven hours later in one case. Isopropyl alcohol disappeared from the blood at a rate following first-order kinetics in both cases. Blood half-live were estimated at 155 and 187 minutes in the two patients, respectively.

Pharmacokinetics of amantadine hydrochloride in subjects with normal and impaired renal function.

Amantadine is useful for the prevention and treatment of influenza A and for the treatment of Parkinson's disease and drug-induced extrapyramidal disorders. We have compared the pharmacokinetics of amantadine in patients with impaired or negligible renal function to that in normal subjects. The half-life of elimination in subjects with normal renal function was 11.8 +/- 2.1 hours (range, 9.7 to 14.5 h). Eight patients with various degrees of renal insufficiency (creatinine clearance from 43.1 to 5.9 mL/min . 1.73 m2) had half-lives of elimination from 18.5 h to 33.8 days. We also studied 10 patients on thrice-weekly hemodialysis. Assuming complete bioavailability of the drug, less than 5% of the dose was removed by each 4-hour hemodialysis. The mean half-life of elimination during chronic hemodialysis was 8.3 days (range, 7.0 to 10.3). We present guidelines for use of amantadine in patients with impaired renal function, including those on maintenance hemodialysis.

Cyanide concentrations in blood after amygdalin (laetrile) administration in rats.

Toxic amounts of cyanide are released into the blood of rats following the oral administration of amygdalin (laetrile); cyanide blood concentrations and toxicity are markedly less when amygdalin is given intravenously. Analysis of the time course of cyanogenesis suggests that cyanide could accumulate in blood after repeated oral doses of amygdalin.