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Avian influenza has been a source of worldwide concern since Hong Kong authorities detected the first outbreak in 1997. Mainly as a result of poultry-to-human transmission, more than 200 cases of infection in humans have been attributed to the A/H5, A/H7, and A/H9 viral subtypes, with a case fatality rate for A/H5N1 infections exceeding 50%. A mutant or reassortant virus capable of efficient human-to-human transmission can set off a pandemic. Increased attention to prophylaxis against viral infection has identified several potentially complementary approaches: nonpharmacologic measures (eg, travel restrictions), vaccination, chemotherapeutic agents, and herbal/natural products. All have significant limitations that point out the need for additional modalities. Herbal/natural products, particularly those based on green tea extract, offer promise as adjuncts or alternatives to current interventions and warrant further evaluation in well-controlled human trials.

Prophylaxis against influenza is difficult, and current approaches against pandemics may be ineffective because of shortages of the two proven classes of antivirals in the face of a large-scale infection. Herbal/natural products may represent an effective alternative to conventional attempts to protect against infection by avian influenza virus. QR-435, an all-natural compound of green tea extract and other agents, has been developed to provide protection against a wide range of viral infections. The antiviral activities of several QR-435 preparations as well as QR-435 (1) green tea extract were tested against A/Sydney/5/97 and A/Panama-Resvir 17 strains of avian influenza virus H3N2 by means of an assay based on Madin-Darby canine kidney cells. Toxic effects of QR-435 formulations on these cells were also evaluated as were the virucidal properties of a commercially available mask impregnated with QR-435. The efficacy of a QR-435/mask combination was compared with that of the QR control/mask combination, an untreated mask, and no mask. QR-435 had significant in vitro activity against H3N2 at concentrations that were not associated with significant cellular toxic effects. The antiviral activity of QR-435 (1) was similar to that of QR-435. Masks impregnated with QR-435 were highly effective in blocking the passage of live H3N2 virus. These preclinical results warrant further evaluation of the prophylactic use of QR-435 against viral infection in humans.

Background: Prophylaxis against influenza infection can take several forms, none of which is totally effective at preventing the spread of the disease. QR-435, an all-natural compound of green-tea extract and other agents, has been developed to protect against a range of viral infections, including the influenza subtype H3N2., Methods: Several different QR-435 formulations were tested against the two influenza A H3N2 viruses (A/Sydney/5/97 and A/Panama/2007/99) in the ferret model. Most experiments included negative (phosphate-buffered saline) and positive (oseltamivir 5 mg/kg, twice daily) controls. QR-435 and the control were administered 5 minutes after intranasal delivery of the virus as prophylaxis against infection resulting from exposure to infected but untreated ferrets and for prevention of transmission from infected and treated ferrets to untreated animals. Effects of QR-435 on seroconversion, virus shedding, and systemic sequelae of infection (weight loss, fever, reduced activity) were evaluated., Results: QR-435 prevented transmission and provided prophylaxis against influenza virus H3N2. Prophylaxis with QR-435 was significantly more than with oseltamivir in these experiments. Optimal in vivo efficacy of QR-435 requires a horseradish concentration of at least 50% of that in the original formulation, and the benefits of this preparation appear to be dose dependent., Conclusions: QR-435 is effective for both prevention of H3N2 viral transmission and prophylaxis. These preclinical results warrant further evaluation of its prophylactic properties against avian influenza virus infection in humans.

Lentinan is a beta 1-->3 glucan isolated from Lentinus edodes (Shiitake mushroom) which has immune modulating properties. We have conducted two phase I/II placebo-controlled trials on a total of 98 patients. In one study at the San Francisco General Hospital (SFGH), ten patients each were administered 2, 5, or 10 mg of lentinan or placebo i.v. once a week for eight weeks. In the second study at the Community Research Initiative in New York (CRI), two groups of 20 patients each were administered 1 or 5 mg of lentinan i.v. twice a week for 12 weeks, and ten patients were administered placebo (vehicle containing mannitol plus dextran 40) i.v. twice a week. Entry criteria were an HIV positive test, CD4 levels of 200-500 cells, age 18-60 years, and without current opportunistic infections. This study confirms, in Caucasian subjects also, the good tolerability of lentinan observed in Japanese cancer patients. Side effects were mainly mild, especially when infusion was carried out over a 30-minute period. In the SFGH study, where administration was over a ten minute period, there were nine side effects severe enough to be reported to the FDA (one case each of anaphylactoid reaction, back pain, leg pain, depression, rigor, fever, chills, granulocytopenia and elevated liver enzymes) and there were four patients who discontinued therapy because of side effects. In the CRI study, where infusion was over a 30-minute period, there were no side effects reportable to the FDA and there were four dropouts due to side effects or personal preference. Most side effects resolved promptly after the discontinuation of medication, and all of them were relieved within 24 hours. Patients in the study have shown a trend toward increases in CD4 cells and in some patients neutrophil activity. Because of the small numbers, these values do not have statistical significance. Inasmuch as no side effects such as anemia, leukopenia, pancreatitis or neuropathy were seen, and in view of the positive effects of lentinan on certain surrogate markers (recognizing that these were small studies), we recommended a long-term clinical trial of lentinan in combination with didanosine (ddI) or zidovudine in HIV positive patients. Most patients in these trials did not have measurable p24 levels. In the CRI trials of ten patients with elevated p24 levels, eight on lentinan and two on placebo had decreased p24 levels. Of these decreases, those with lentinan and one with placebo were marked. These results were provocative and needed confirmation. Subsequent to this study, a trial of lentinan in combination with didanosine (ddI) showed a mean increase of 142 CD4 cells/mm3 over a twelve month period, in contrast to a decrease in CD4 cells in patients on ddI alone (Gordon et al. 1995).

This study evaluated tolerance (and possible efficacy) for 21 days of i.v. administration at three dose levels of curdlan sulfate (CRDS) (a semisynthetic sulfated polysaccharide), administered over 30 minutes, in HIV and CMV (in some cases) infected individuals with CD4 levels < 500 cells/mm3. Half of the subjects were previously treated with reverse transcriptase inhibitors (RTI) (which were continued during the CRDS administration) and half the patients had no prior RTI treatment. Evaluation of other sulfated polysaccharides in HIV had been discontinued due to side effects and lack of activity. Three groups of HIV patients (also including subsets with CMV infection) were treated separately with 50 mg/70 Kg, 100 mg/70 Kg and 200 mg/70 Kg of CRDS infused i.v. over thirty minutes daily for 21 days. In each dose group, half of the patients selected were being treated with a RTI and half were on no RTI. Patients were monitored for CD4 cell levels, viral load in some cases, and safety parameters in blood. Samples of urine and semen were additionally taken for CMV by culture and for PCR assay in subsets of participants. CRDS in this 21 day study was well-tolerated and produced few reportable side effects. Systematic decreases in platelets and increases in p24 antigen previously seen with dextran sulfate were not observed in this study with CRDS. In the 21 patients testing positive for CMV at the start of the study, 12 were CMV negative at the end of 21 days. In an untreated historical control group, 0/36 went from CMV positive to negative over a period of 13-15 years. The anti-CMV activity of CRDS in this study, therefore, had a p value < 0.001, based on these historical controls. The marked temporary increases in CD4 levels seen in the single dose and the seven-day CRDS studies on HIV patients were also seen for 21 days in the current study (p = 0.0001). Treatment with CRDS seems promising against CMV in HIV infected patients, even with once daily dosing of this two-hour half-life drug. CRDS was well tolerated and its lack of toxicity makes it an attractive candidate for CMV-infected HIV patients. Multiple daily dosing, or the continuous infusion of CRDS, could lead to increased effectiveness against both HIV and CMV, especially in combination with other agents. Given the toxicity of existing anti-CMV agents, and considering the emerging importance of CMV in atherosclerotic disease, further studies on CRDS are warranted.

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which inhibits the attachment of HIV to T-cells, and also has intracellular anti-HIV activity. In Phase I clinical trials, CRDS was found in 4 hr i.v. infusions, to be well tolerated up to 200 mg/70 kg and unexpectedly to produce marked, dose-related increases in CD4 lymphocytes in HIV-infected patients. Prolongation of bleeding time is expected to be the dose limiting toxicity, but no episodes of bleeding were seen. In one of the studies in this report, CRDS was administered i.v. daily for 7 days to HIV patients at doses of 40, 100, 140 and 180 mg/70 kg/day. At the higher doses, marked increases in CD4 and CD8 lymphocytes were observed. These increases mainly returned to baseline after 24 hr. To further delineate the pharmacokinetics of these changes in CD4 and CD8 lymphocytes, another Phase I study was done in which CRDS was infused i.v. over a 30 min period in HIV patients at single doses of 25, 50, 75, 100, 125, 150, 175 and 200 mg/70 kg/day. The drug was well tolerated in all cases and marked increases in CD4 lymphocytes were again seen at the higher doses, in some cases amounting to increases of 500 cells/mm3 after a single dose. The half-life of CRDS in man was found to be about two hours, as measured by activated partial thromboplastin time (APTT) and by plasma assays.

This study was carried out to assess the safety and efficacy of a combination of lentinan, an immune modulator, and didanosine (ddI) in a controlled study in HIV positive patients with CD4 levels of 200-500 cells/mm3. Didanosine was administered to HIV patients at doses of 400 mg/day (po) for six weeks (bid), then 2 mg of lentinan i.v. was added per week for 24-80 weeks. A control group (20%) received ddI only. A total of 107 patients were enrolled at three sites, and 88 patients started the ddI/lentinan phase. The combination caused significant increases in CD4 levels up to 38 weeks, whereas ddI alone was significant at the 5% level at 14 weeks. Based on these data, lentinan qualifies as a participant in future multi-drug studies in HIV.

Curdlan sulfate (CRDS) is a semi-synthetic sulfated polysaccharide which has anti-HIV activity in vitro, and inhibits attachment of the virus to T-cells. After two weeks of exposure of virus and cells to CRDS, there is complete inhibition of virus replication. CRDS is also active against cytomegalovirus. The favorable toxicological profile of CRDS in animals suggested clinical trials. In this study, doses of 0.014, 0.14, 0.42, 1.42, 2.84 and 4.26 mg/Kg (hereinafter referred to as 1, 10, 30, 100, 200 and 300 mg/body, respectively, for convenience) were administered to three HIV-positive patients at each dose level for four hours intravenously. Activated partial thromboplastin times (APTT) were measured hourly. Unexpectedly, single doses of CRDS produced marked, dose-related, increases in CD4 lymphocytes in HIV-infected patients. There were no clinical side effects seen at any dose tested. All laboratory parameters were normal except for prolongation of APTT in the 200 and 300 mg dose group. Two patients in the 300 mg dose group had a doubling of the APTT during the four hour infusion, which was the termination point of the trial according to the protocol. The half-life of CRDS was estimated to be 2 to 3 hours from the APTT data and from the blood level assays (not shown). CRDS was well tolerated in the study with the APTT levels being a convenient monitoring basis for dosing. Marked increases in CD4 levels were seen at higher doses, which, if confirmed and extended, may have therapeutic implications. CRDS is considered safe for multiple dosing with monitoring of APTT.

The need for improved controlled delivery of testosterone to hypogonadal men stimulated the development of a self-adherent transscrotal testosterone system to provide programmed testosterone delivery through the uniquely permeable scrotal skin. In this short- and long-term efficacy trial, the responses of testosterone and its metabolites to the application of transscrotal testosterone systems of varying testosterone content were compared with the response to 200 mg of testosterone enanthate. Daily transscrotal testosterone system administration resulted in a rapid increase of testosterone and bioavailable, non-sex hormone binding globulin-bound testosterone levels to normal, peaking at two hours, followed by a slow decline over 23 hours, resembling the diurnal variation of endogenous testosterone. One year of daily transscrotal testosterone system therapy demonstrated continued reliable absorption of testosterone and suppression to normal of the luteinizing hormone in two of three patients. There was a greatly disproportionate increase of serum dihydrotestosterone over testosterone, suggesting 5-alpha reduction at the scrotal site. The subjects reported marked subjective improvement. Thus, the transscrotal testosterone system is a novel, effective, and well-tolerated method of delivering testosterone to hypogonadal patients.

Careful evaluation was carried out in 93 men older than 50 with erectile dysfunction. Their mean age was 61 years and the disorder had been present for a mean of 4.5 years. While 14 men (15%) had psychosocial factors that may have been pertinent, only 2 scored poorly on an Affect Balance Scale and 3 were receiving psychoactive medications. Results of nocturnal penile tumescence were abnormal in 91%. In 39% penile-brachial pressure indices were suggestive of pelvic vascular disease and in 9% were consistent with a pelvic "steal syndrome." Pelvic or peripheral nerve conduction disorders were also commonly seen in 54%. Endocrinopathy may have contributed to the dysfunction in 35%. Twenty-one men had diabetes mellitus, two new cases of hypothyroidism were discovered and hypogonadism was diagnosed definitely in four and considered likely in five others. Coexisting medical conditions were found in more than 90% of the men, especially hypertension, use of antihypertensive medications and atherosclerotic disease. Previous prostatectomies (19%) and vasectomies (30%) were common in the surgical histories. Given the wide range of disorders uncovered in older men complaining of impotence, diagnostic study of potential causes may lead to a more rational approach for the evaluation and management of these men.