The founder of the PNC has worked at the VA Greater Los Angeles Healthcare System as a research scientist since March 1974. He initially studied pancreatic disease and found that zinc metabolism is deficient in patients with pancreatitis.  Thus, he and his colleagues initiated elucidation of intestinal zinc absorption mechanisms and were the first to demonstrate that prostaglandins (PGs) regulate intestinal zinc absorption. Subsequently, they demonstrated that arachidonic acid (AA), steroid hormones, L-histidine, and CHP are involved in the regulation of intestinal zinc absorption and muscle tissue zinc uptake. Others reported that citric acid chelates zinc and stimulates intestinal zinc absorption. Although a vast number of papers on zinc metabolism are published annually, the intestinal zinc absorption mechanisms are still not clearly understood. It has been reported that relatively high amounts of zinc, citric acid, testosterone, and CHP are found in mammalian prostate. Thus, they hypothesized that all of these constituents synergistically regulate cellular zinc metabolism. Since diabetic animals and humans are zinc deficient, they examined the effects of prostate extract (PE) from rabbit on intestinal zinc absorption in streptozotocin-induced diabetic rats. Administration of PE significantly increased intestinal zinc absorption and decreased blood glucose levels in these rats. Subsequently, they determined the effects of freeze dried bovine prostate powder plus zinc (Pro-Z) on patients with diabetes. Three month treatment with 2-4 Pro-Z gel capsules containing 200 mg dry prostate powder plus 20 mg zinc/capsule each day very significantly improved three hour above average glucose concentration (TAFGC), which is the measurement of insulin sensitivity, and decreased HbA1c and urine glucose levels (Table 2). Since CHP is also found in relatively high amounts in prostate and histidyl-proline glycoprotein is the zinc transporter in plasma, they determined the effect of CHP on glucose control in streptozotocin-induced diabetic rats, and found that CHP was as effective as PE. These findings led them to study the effects of Cyclo-Z on the treatment of Type 2 diabetes in animals and in humans.

Previous studies have suggested that diabetes is associated with defective IDE production and stimulation of IDE may improve blood sugar control. Cyclo-Z may be a potent stimulator of IDE activity. We have examined anti-diabetic activities of Cyclo-Z in five different animal models: 1) streptozotocin-induced diabetic rats (Type 1 model); 2) ob/ob mice (Type 2 diabetes with obesity); 3) Goto-Kakizaki (G-K) rats (Type 2 diabetes without obesity); 4) aging Sprague-Dawley rats (naturally induced human insulin resistance-like or mild-Type 2 diabetes); and 5) high carbohydrate fed mice (over eating induced diabetes). Our colleague at the VA Greater Los Angeles Healthcare System demonstrated that Cyclo-Z treatment increased IDE synthesis in human amyloid protein transgenic mice and stimulated degradation of Amyloid b protein and insulin. We have also performed a clinical trial with Pro-Z in diabetic subjects and a formal Phase 1 clinical trial with Cyclo-Z in healthy human volunteers. In addition, our colleague in China recently performed a pilot clinical trial with 18 moderate to serious diabetic subjects for 6 months. Aside from one patient, the entire diabetic subject who received Cyclo-Z treatment noted significant improvement in their glycemic control. These studies with Pro-Z containing CHP and zinc, Cyclo-Z and zinc plus CHP in drinking water in various animal models and in humans demonstrated that Cyclo-Z is an excellent anti-diabetes agent. These data suggests Cyclo-Z may be an effective anti-diabetes agent in humans.

Phase 1 clinical trial with Cyclo-Z (3 mg CHP plus 20 mg zinc) gel capsule: In order to obtain final approval of FDA for commercialization of Cyclo-Z, we performed a formal phase 1 clinical trial with Cyclo-Z on 49 healthy volunteers who signed consent to participate in the study and finished the study. The double-blinded study showed no adverse side effects in subjects taking one time oral intake of 0, 2, 4, or 8 capsules of Cyclo-Z. All subjects had normal blood chemistry data and cell numbers at the start of the trial (0 hours) and no changes of these data from the baseline were exhibited during 24 hours (0, 2, 4, 8, and 24 hours). However, subjects (n = 12) who took 8 capsules of Cyclo-Z before breakfast showed significantly reduced blood glucose levels at 8 hours, but their plasma glucose levels were within normal range. Twenty-four hours later, the blood glucose levels returned to the similar levels prior to Cyclo-Z intake. In our animal studies, the optimal acute dose of Cyclo-Z is five fold of the daily dose required for long term diabetes treatment. Thus, this dose was only 70-80% of the optimal dose of Cyclo-Z for acute treatment of diabetic animals to improve TAFGC and blood glucose levels. Since Cyclo-Z is still effective on these non-diabetic subjects who may or may not have insulin resistance, we expect that the presently proposed phase 2a clinical trial with diabetic subjects will be fully successful in generating data of “proof of concept”.

Pilot study with 18 diabetic subjects: Our colleagues in China performed a pilot clinical trial with Cyclo-Z in moderate to severe diabetic subjects, and obtained favorable results. During 6 month Cyclo-Z treatment period, 18 diabetic subjects experienced significantly improved diabetic conditions with Cyclo-Z treatment. The decreases of fasting blood glucose levels were not statistically significant, however the decreases of postprandial blood glucose levels two hours after breakfast, lunch and dinner were all extremely significant (p<0..0001, <0.0001 and 0.0003 respectively) during the first 120 days. After 120 days, postprandial blood glucose levels started to increase. This is likely due to the premature withdrawal of insulin injection and/or drug treatment before the improvement of insulin sensitivity. In contrast, HbA1c levels were significantly lower during 90-180 day treatment period (p<0.01 vs. 30 day mean values) than the first 30-90 day treatment period (p<0.05). More interestingly, the decreases of insulin doses before breakfast, lunch and dinner were all extremely significant (p<0.0001). Essentially all the study subjects either totally stopped daily insulin injection or used very low doses of insulin at the end of 6 month study. The doses of metformin were lowered in three subjects by 2.688 ± 0.805 mg/day. Neither incidence of hypoglycemia nor adverse side effect was reported during this study period.