Osteoporosis is a significant health concern to our aging population. We report here the results of a pilot placebo-controlled trial of a dietary supplement containing ipriflavone, calcium, and vitamin D on a urinary marker of bone breakdown in postmenopausal women. Seven postmenopausal women not currently receiving hormone replacement therapy received either an ipriflavone-containing supplement or placebo for 3 months. Urinary N-linked telopeptides, a marker of bone breakdown, declined by 29% in those receiving the supplement, whereas an increase in this marker was observed in the group receiving the placebo. No changes were observed in salivary hormone measurements. Although our sample size was small, to the best of our knowledge, this is the first report that demonstrates changes in N-linked telopeptide levels as a result of consuming an ipriflavone-containing product. Our findings confirm those of other researchers that demonstrate the usefulness of ipriflavone at slowing the progression of bone loss and suggest that measuring N-linked telopeptides may be a useful tool to assess therapeutic efficacy.

Objective: To study the safety of intravenously administered porcine-derived hyperimmune immunoglobulin to HIV-1, PASSHIV-1, in human's.Methods: Fourteen HIV-1-infected individuals were treated for 5-7 days with intravenous infusions of highly purified PASSHIV-1 (> 95% pure). Two of the 14 patients were retreated 3 months later with PASSHIV-1 for an additional 5 days to evaluate side-effects from retreatment with porcine immunoglobulins.Results: Ten of the patients had no side-effects from PASSHIV-1 therapy. Three patients experienced transient urticarial eruptions, which responded to antihistamine administration and did not require discontinuation of therapy. One patient, who received concomitant administration of human gammaglobulin, experienced serum sickness (type 3 hypersensitivity reaction). All patients demonstrated a significant improvement in fatigue (100% response), weight (all those with previous weight loss gained weight), fever (100% response), polyneuropathy (100% response), bronchitis (100% response), candidiasis (100% response), diarrhea (100% response), and dermatitis (100% response). One out of the five patients with Kaposi's sarcoma demonstrated > 50% improvement. Mean CD4+ cell counts in the group rose from 143 +/- 263 to 234 +/- 323 x 10(6)/l 4-6 months following completion of therapy (P = 0.013, paired Student's t-test); CD4+ counts rose > twofold in six individuals. p24 antigen, present in four patients, was negative following therapy in all patients. Other laboratory parameters that responded to therapy included: platelet counts (71% response), leukopenia (57% response), elevated lactic dehydrogenase (1000/o response), and elevated alkaline phosphatase (100% response). PASSHIV-1 was well tolerated by HIV-1-infected individuals.Conclusion: This therapy appears to be efficacious in ameliorating some of the clinical aspects and symptoms of HIV-1 infection.

Animal and human studies on aryl hydrocarbon hydroxylase (AHH) have demonstrated wide inter-individual variation. First attempts to link this variation to the susceptibility to certain cancers have been successful in mice but remained inconclusive in man. In a new approach, saliva antipyrine half-lives and metabolic clearance rates have been used to assess individual rates of benzo]a]pyrene metabolism in human subjects. Saliva antipyrine half-lives and metabolic clearance rates have been measured in 57 patients with lung cancer, 90% of whom had quit smoking more than three months prior to the test, 57 cancer-free matched controls, and 59 healthy smoking controls. The mean antipyrine half-life was significantly shorter (P less than 0.001) in lung cancer patients when compared with the cancer-free matched control group, but differed little from that of the smoking group (P less than 0.05). The data support the previous observation than lung cancer patients have increased oxidation rates which, in addition to smoking, might have predisposed them to developing lung cancer.

The plasma elimination rates of phenacetin, acetanilide and theophylline have been determined in 32 healthy subjects in an effort to find drugs resembling in their metabolism the carcinogen benzo(a)pyrene. The plasma half-lives and metabolic clearance rates of the three drugs were correlated with the inducibilities of aryl hydrocarbon hydroxylase (AHH) in mitogen-stimulated lymphocytes and the plasma half-lives and metabolic clearance rates of antipyrine determined in previous studies. Statistically significant correlations were found between the half-lives and metabolic clearance rates of phenacetin, acetanilide and theophylline and the AHH ratios except for the metabolic clearance rates of phenacetin which did not correlate. The correlations of the three drugs with the half-lives and metabolic clearance rates of antipyrine were equally good. Of all the drugs tested thus far for similarity in metabolism to benzo(a)pyrene, antipyrine showed the best association followed closely by theophylline.

The chief carcinogens of tobacco smoke--the polycyclic aromatic hydrocarbons--must be activated in the cells to exert their carcinogenic effect. This activation is carried out by the enzyme system aryl hydrocarbon hydroxylase (AHH). Mitogen-stimulated, human lymphocyte studies of AHH activity indicate wide individual variation, which is under strict genetic control. The venous blood samples from 90 patients with a laryngeal carcinoma were assayed, and a significant overrepresentation of patients with genetically high AHH inducibility was demonstrated. Our results suggest the possibility of identifying those tobacco users at higher genetic risk for developing carcinoma of the larynx.

Lung cancer is one of the leading causes of cancer deaths in most Western countries. In the United States it accounts for 33% of the cancer deaths in males and 11% of the cancer deaths in females. More males die from lung cancer than from the four next common cancer sites combined, i. e., colon, prostate, pancreas, and stomach cancer. In females, lung cancer holds third place in cancer deaths, preceded only by breast and colon cancer (Silverberg, 1977). Of all the common cancers it is the one most clearly associated with environmental agents, the most notable of which is cigarette smoking.

Phenobarbital and antipyrine half-lives were measured in 31 subjects. A high correlation ( r = 0.87) was found for the plasma elimination rates of the two drugs, suggesting the same or a similar route or a common regulatory control of their metabolism. The half-lives of phenobarbital and antipyrine also correlated highly with the aryl hydrocarbon hydroxylase (AHH) inducibilities in mitogen-stimulated lymphocytes of the same individuals. In the second part of the study, plasma antipyrine half-lives were measured in 22 subjects after a single oral dose of 18 mg/kg, and the AHH inducibilities were determined in their cultured lymphocytes. After 7 days on phenobarbital at aryl hydrocarbon hydroxylase inducibilityadjusted doses ranging between 1.0 and 2.0 mg/kg daily, the antipyrine half-lives were measured again and the percentage of decrease between the initial and second antipyrine half-lives was determined. Shortening of the plasma half-lives occurred in all subjects to various degrees, ranging between 13.3 and 30.6%. However, under our experimental conditions in which the dose of phenobarbital was adjusted to the individual rates of metabolism of the inducing agent, no relationship could be found between the initial antipyrine half-life and the percentage of shortening of its plasma half-life, such as had been reported by several authors.

A strong correlation was found in a carefully selected homogenous population (n = 57) between antipyrine plasma half-life and the percent induction of aryl hydrocarbon hydroxylase by 3-methylcholanthrene in mitogen-stimulated lymphocytes from the same individual. The correlation coefficient of r = 0.923 indicates that antipyrine and benzo[a]pyrene share one or several common determinants that are responsible for the observed interindividual variation in the oxidation rates of the two compounds. When a heterogenous population (n = 80) was studied, the above correlation was not found (r = 0.425).

A high correlation was observed between the aryl hydrocarbon hydroxylase activities in short-term lymphocyte cultures of 23 individuals and their plasma half-lives of antipyrine and phenylbutazone. Individuals with low inducibility of aryl hydrocarbon hydroxylase activities had very long plasma half-lives of antipyrine and phenylbutazone, whereas subjects with high inducibility of aryl hydrocarbon hydroxylase activites had relatively short plasma half-lives. Individuals with intermediate aryl hydrocarbon hydroxylase activities displayed intermediate half-lives for both drugs. The observed correlation indicates determinants which are common to the elimination of antipyrine or phenylbutazone, and aryl hydrocarbon hydroxylase metabolism of hydrocarbons. The differences in rates of drug elimination are probably due to genetic differences and may have pharmacological and therapeutic significance.

Summary Induction of aryl hydrocarbon hydroxylase in cultured human lymphocytes by 3-methylcholanthrene was determined for 103 healthy unrelated adults. The ratio of 3-methylcholanthrene-treated to control cells, a measure of induction, ranged from 1.4 to 5.6 among this population, and the value for each individual was constant under different culture conditions and was highly reproducible. At least two groups can be identified with respect to extent of induction. The results suggest that the capacity for aryl hydrocarbon hydroxylase induction in man is genetically determined. Implications for susceptibility to chemical carcinogenesis are discussed.

Epoxide hydrase (EH), a microsomal enzyme, is present and inducible in cultured human leukocytes. Its base levels ranged between 0.05 and 0.20 nmoles of diol among 12 individuals tested. It is inhibited by trichloropropene oxide (TCPO) and cyclohexene oxide (CHO). EH was inducible up to 1.6 times resting levels by 3-methylcholanthrene and up to 2.0 times by phenobarbital in a 24 hr period. Other hydrocarbons—dibenz(a,h)anthracene, benz(a)anthracene and benzo(a)pyrene—gave either weak or no measurable induction. The magnitudes of induction of aryl hydrocarbon hydroxylase (AHH) and EH by the same inducing agent showed a high correlation, suggesting that the mechanism for the induction of the two enzymes is the same.