Dose Escalation Phase I Study in Healthy Volunteers to Evaluate the Safety of a Natural Product PM701

MATERIALS AND METHODS

This study has been conducted after extensive experimental work and during the period between January 2008-2010.

Tested Agent
PM701, is a natural product; which in our earlier studies have shown to be clean, sterile and free of toxicity in a wide variety of experiments (Khorshid, 2008).

The natural product from PM701, has been formulated in the form of hard vegetation gelatin capsule. Each capsule contained 300 mg. Only clinically fit volunteers received 3 capsules day^-1 in the first week and 5 capsules day^-1 for the second week and/or 8 capsules day^-1 for third weeks and 10 capsules day^-1 for four months. Clinical examinations and other investigations were performed on day 0, 14 and 21 from the start of drug therapy and finally on the day of termination of drug (four months later).

Volunteers and Trials
Limited clinical trials on 14 individuals were conducted in this study.

The nature of the drug was explained and written consent was signed by each volunteer. All volunteers were subjected to medical history and clinical examination. Those having the history of allergic condition such as: asthma, urticaria, psychiatric disorders were excluded from the study. Likewise people with dyspepsia, gastric ulcer or duodenal ulcer; pregnancy or breast feeding were also not considered for the present trials. It was assured that all participating in this study meet inclusion and exclusion criteria. All 14 people were carefully selected for the trials.

Dose of PM 701
After clinical examinations and investigations, volunteers received PM701 in capsule form according to the following schedule:

Biochemical Evaluations
All volunteers were exposed to biochemical analysis before and after PM701 treatment These assessments included, complete differential blood count, serum analysis for albumin, total bilirubin, alkaline phosphates, alanine transaminase (ALT), aspartate transaminase (AST), creatinine, electrolytes and sugar.

Other examinations were done if required such as abdominal sonography and serum pregnancy test of a child bearing potentials was done as when required.

The therapy continued to a maximum of 16 weeks and all laboratory investigations were recorded.

Prophylactic Measure
The following measures are strongly suggested to reduce the change of renal complication with treatment: Patients should drink plenty amount of water with camel milk

RESULTS AND DISCUSSION

The study was approved by the Institutional Review Board of the King Abdulaziz University (298-09 at 1/16/2008) and was conducted in our hospital under contact medical supervision. All patients provided written informed consent.

PM701 Production
Formulation of Powder Mixture

The active ingredient is mixed with appropriate amount of the diluents and lubricant in various portions, the formula that gives the optimal flow properties and highest active ingredient content is selected. The active ingredient powder and excipients are mixed by light tribulation (geometric dilution). The blend is transferred to the mixer, mixing for 3-5 h. Random samples are taken for analysis of uniformity of content.

Filling of the Powder into the Hard Gelatin Capsules
The capsules are prepared using hand-operated capsules machine operated as specified by the manufacturer operation manual. The weight required to fill the specified number of capsule is determined and amount of powder exceed the required weight by 5% is used.

The finished capsules are cleaned by shaking with powdered NaCl, rolled on sterilized cloth covered surface, then subjected to a stream of lightly compressed air.

The capsules (10-20 capsules) are baked into the sterilized clean glass container (with moisture adsorption packets).

Safety
The PM701 in a capsule form was well tolerated by all patients. There were no serious adverse events observed during the study and no patient withdrew from the study due to an adverse event caused by the product PM701 (Table 3).

Table 1:	General characteristics of the volunteers

Table 2:	Clinical laboratory findings of normal volunteers at zero time (control group)

Four patients have been suddenly withdrawn from the study before starting the analysis due to their travel during the period of continuous investigation.

Table 1 summarized the biochemical investigations of the healthy volunteers before entering the actual study and treated as control. The same tests were repeated just after receiving the PM701 on day 14 and 21 and finally after four months at the termination of experiments. The results have been summarized in Table 3. A separate Table 4 shows a comparative study of control and treated individuals. This study reports the effect of oral administration of natural product PM701 in humans. Although, the group sizes in the study do not allow good statistical evaluation, the high percentage of safety of this product suggests its possible applicability in large scale study. Most of the observations fall within the normal range of each test.

The drug was safe in the normal volunteers and it could be applicable for phase II studies. No undesired change or reaction in the body chemistry was detected as shown in Table 2. All the vital organs studied such as liver, kidney and bone marrow showed normal functions before (Table 2) and after PM701 administration (Table 3). However, one case reported initial slight increase in liver enzymes which came to normal range shortly after treatment without further complication till the end. A comparison between normal and treated volunteers showed insignificant difference. Clinical trials are conducted to allow safety and efficacy data to be collected for new drugs. Our trials were conducted on normal volunteers, since a satisfactory information has been gathered on the efficacy and quality of non-clinical safety of PM701 (Korshid, 2008).Although, people taking part in phase I trials often have advanced cancer and have usually had all the treatment available to them, we conducted our study using healthy volunteers as camel urine (PM701) is traditionally used in our country safely as folk remedy for many disease (Al-Rawais, 2002).

Table 3:	Clinical laboratory findings of normal volunteers after treatment with PM701 (at 0, 14 and 28 days)

Table 4:	Comparative study of control and treated volunteers after 28 days of treatment

Although, this study on healthy volunteers was limited (14 patients),all volunteers showed safety and tolerability of the MP701. Few individuals showed some gastrointestinal disturbance, especially hyperacidity and increase in sleeping tendency after initiation of the therapy. No significant change in liver and kidney functions or abnormal profile of complete blood count have been observed.

As we expect, for any new drug, the possibility of severe anaphylactic or idiosyncratic reactions have not been ignored, no such adverse effects were observed.

The pharmacological and toxicological studies of the product PM701 in animal models showed no any toxic or harmful effect on different vital organs (Khorshid, 2008). So, we may conclude that PM701 is clean sterile product which has the ability to inhibit the proliferation of cancer cells both in vitro and in vivo (Khorshid and Moshref, 2006) and has no adverse effect either on animals species and or human health volunteers. So, moving to phase II trial on advanced cancer patients might be advisable to explore the efficacy of PM701 as anticancer agent.

ACKNOWLEDGMENTS

The authors gratefully acknowledged financial support of El-Zamel's scientific chair NO.MBK/3/429, Research and Consultation Institute and King Fahd Medical Research King Abdulaziz University.