Cucurbita Pepo.

Special issue "Curative power from nature". 1988-1989 .

Summary:
expressed by Professor Schilcher:
a requirement that any modern drug of herb origin (phytopharmacon) should meet is that its raw materials be botanically definable and their parameters be reproducible so that the quality of the product can be ensured.
Cucurbita pepo (common pumpkin) has long been used as food and a source of lamp oil and now it serves as a raw material of paramedicinal products.

Pumpkin, together with some 700 species, belongs to the family of Cucurbitaceae. Cucurbitaceae include annual as well as perennial, herbal as well as ligneous specie, usually with creeping stalks and trailers. Their diclinous flowers are generally monoecious, i.e. they are on the same plant. Both staminate and pistillate flowers have a five member synsepalous perianth (calyx, corolla); the staminates have five stamina and the pistillates have a three-carpel low-position pistil developing into the fruit characteristic of Cucurbitaceae. The family is chemically quite homogeneous generally containing tetracyclic triterpenes (cucurbitacines) responsible for the bitter taste, pentacyclic triterpenes (saponines), specific fatty acids, phytosterols, proteins and minerals (selenium, copper etc.) in the seeds. The seeds also contain chlorophyll derivatives (more exactly, protochlorophylls), which give a greenish-grey colouring to the seeds (without shell) and a greenish-brown colouring to the thick fatty oil obtained from them. Cucurbitaceae include the genera of Citrullus (e.g. C. lanatus = water melon), Cucumis (e.g. C. melo = honeydew melon, C. sativus = cucumber) and Cucurbita, consisting of species known and cultivated all over the world, which have probably developed from C. texana or C. andreana still indigenous to the American continent. According to literary sources, these plants were known and grown by natives as long as 8-9000 years ago. They appeared in Europe some time in the 16th or 17th century. From a Hungarian point of view it is worth noting that Janos Lippai in his book "Posoni kert" published in 1664 describes several pumpkin species. In Europe, Cucurbitae must have become widely grown only from the second half of the 18th century. First, even in the beginning of this century, they were grown as companion crop; since the 50's they have mostly been produced in monoculture.
The genus of Cucurbitae is divided as follows according to Terpo:
C. pepo - common pumpkin
a) convar. Microcarpina (wild forms and calabash)
b) convar. Pepo (food and oil pumpkin)
C. maxima - squash
C. moschata - cushaw
C. ficifolia
Although oil can be obtained from all these species, C. pepo convar. Pepo var. styriaca (or var. oleifara), i.e. Styrian oil pumpkin, grown in Southern Austria (on an area of 6000 hectares, according to data from the year 1980), in Wendland.
These species are characterized by creeping clinging stems, jointed and often spotty leaves, and round streaky fruit green in the beginning and gradually turning orange as the fruit is ripening.
The most valuable parts of the fruit are the greenish-grey seeds of a unique composition.
Another species is "tschermak" pumpkin, which is a dwarf plant. This favourable property does not, however, asserts itself in the seeds and, therefore, this variety is not cultivated at large scale.
As mentioned earlier, the seeds of food and oil pumpkin species - either shelled or shell-less - are raw materials of oil (the seed mass accounts for 1.6-3.0% of the fruit and the ratio of shell and core is 23:77). Earlier, shelled-seed species had been used for obtaining oil as no other species had been cultivated. Alefeld's monography published in 1866 contains the detailed description of 66 species but none of them had shell-less seeds.
By the 1950's, however, species with shell-less seeds, or with filmy skin according to Buchinger, had become wide-spread. According to literary sources, this variety of pumpkin had emerged as a result of mutation and then was successfully multiplied. It is interesting to note that both pumpkin types have multilayer skin the only difference being that in shell-less seeds these layers do not get thick and can easily be removed. In shell-less seeds the chlorenchyma layer is thicker and the chlorophyll mass is also bigger. Protochlorophylls, one of the active ingredients also responsible for the colour of the oil, are formed and stored in special plastids and membrane systems of this tissue.
Finally, a few words about oil and obtaining oil. In Europe several vegetable raw materials have been used as a source of oil for the past centuries. (since 1520). Naturally, production of oil from pumpkin seeds started later; the first manufactures were probably founded in the late 18th and early 19th century in Orseg region, Wendland and Transylvania. Interestingly, larger manufactures soon developing into factories were not interested in obtaining oil from pumpkin seeds and, therefore, production of pumpkin-seed oil has remained at a traditional manufacture level
Oil is obtained in the following way:
The shell-less (filmy skinned) seeds are separated from the fruit and dried. In the case of shelled seeds, the shell is first removed, which in old times as a social event in the village community just like the plucking of feathers. Then the seeds are ground and mixed with some hot water in a pan specially made for this purpose and then roasted on fire with careful mixing until the ground seeds become rusty brown. The roasted and hot grots are then put into oil press. Until recently the oil thus obtained was exclusively used in oil-lights or as food of the poor; now it serves as base material for healthy food products and paramedicines, such as pumpkinsedds oil capsules. The use of pumpkinseed oil for medical purposes is based on popular experience confirmed by investigators specialized in medicinal herbs as early as the 1920's (Klein in Vienna and Pater in Kolozsvar) that pumpkin seeds and the oil obtained from them have a beneficial effect on various inflammatory processes, prostatic hypertrophy and arteriosclerosis.
The author's "ars poetica" relating to paramedicinal products is very similar to that expressed by Professor Schilcher: a requirement that any modern drug of herb origin (phytopharmacon) should meet is that its raw materials be botanically definable and their parameters be reproducible so that the quality of the product can be ensured.

Oil produced from the seeds of the pumpkin is rich in vitamins and minerals. PUMPKIN IS a fruit grown and eaten in North America, China, Hungary, Austria, Mexico, Yugoslavia and several Caribbean countries. The seeds of the pumpkin are a rich source of vitamins A, B and E, omega-3 and omega-6, zinc, selenium, carbohydrates and cholesterol-like molecules called phytosterols.
Countries such as Bulgaria, Turkey, Russia and Ukraine have reported that eating a handful of pumpkin seeds is beneficial for the treatment of prostatic hyperplasia. In this condition there is enlargement of the prostate, an organ found encircling the urethra of males.
Monographs produced by the German Commission E have documented the usefulness of pumpkin seed oil for the treatment of prostate enlargement and a few clinical evaluations in Europe have confirmed that it alleviates the associated urinary complications. In one clinical trial, over 2000 men suffering from prostate enlargement were treated with capsules containing pumpkin seed oil and found that there was significant improvement in urinary function.
Using an animal model of prostate enlargement, researches in the pharmacology section of the University of the West Indies have shown that pumpkin seed oil can inhibit the growth of the prostate and continue to assess the actions to elucidate the mechanism involved.
REDUCING BLOOD CHOLESTEROL
Pumpkin seed oil has also been reported in folklore to reduce blood cholesterol concentration. High levels of cholesterol in the blood are associated with chronic illnesses such as hypertension and stroke. While scientific evidence of the effect of pumpkin seed oil on cholesterol concentration in the blood is limited, it is known that including phytosterols, as well as omega-3 and omega-6 fatty acids in the diet can significantly lower blood cholesterol levels. Therefore, it is speculated that since pumpkin seed oil is rich in these compounds, then it may have clinical usefulness in reducing blood cholesterol levels. Researchers in the Pharmacology Section at the UWI are currently investigating this possible action of pumpkin seed oil on blood cholesterol concentrations.

Special issue "Curative power from nature". 1988-1989 .

Summary: No really effective drug is available at present for the treatment of prostatic hyperplasia and therefore surgery seems to be the only successful way of therapy. Authors report on their experience with the administration of Peponen capsules in patients with prostatic hyperplasia. They have found Peponen equivalent with hormone products and are of the opinion that it may be effective in younger patients with chronic prostatitis as well. They especially recommend Peponen for treatment of elderly male patients who are not considered for surgery because of their general condition, or unwilling undergo surgery.
Prostatic hyperplasia is probably the most frequent benign neoplastic growth in males. The size of the prostate in adult males does not change until about the age of 45 years. Development of benign prostatic hyperplasia (BHP) is a universal phenomenon in aging males but the pathogenesis of the disease is not yet clear. A great majority of patients over the age of 50 display histological signs of BPH and suffer from urethral compression symptoms.
Unfortunately, no really effective drug is available at present for the treatment of prostatic hyperplasia. Surgery appears to be the only successful way of therapy. The efficacy of meditation is difficult to evaluate as symptoms may remain stable for a long time in patients receiving no treatment and, furthermore, there are frequent spontaneous remissions of obstruction complaints.
PEPONEN capsules were used in 30 patients with prostatic hypertrophy. Mean age of the patients was 65.4 (53-75) years.
Patients with sterile urine only were admitted to the trial. The patients received one capsule three times daily for two months. At the commencement of treatment the patients' dysuric complaints had existed for an average of eight months. Prior to treatment urinary sediment test, rectal prostatic examination, and urine residue measurement were performed. In half of the patients uroflowmetric studies were also carried out.
The findings were as follows:
1. There was no change in the size of the prostate as determined by rectal examination.
2. The number of night urinations was reduced in two-third of the cases and remained unchanged in one-third. Eight patients reported complete disappearance of such symptoms.
3. Prior to treatment ten patients had urine residue of 34 (10-60) ml on the average and 66% of the patients had no residue. The quantity of residue was reduced in all the patients to one-third on the average and three patients became free of residue.
4. The greatest improvement was observed in subjective symptoms. Dysuric complaints were substantially reduced in 26 patients (86.7%).
5. Patients in whom uroflowmetry was performed demonstrated a 60% increase in maximum flow (from 15 ml/s to 24 ml/s).
6. No side effects were observed during treatment. Similar results were obtained by other authors using hormone products with severe side-effects. We have found PEPONEN capsules as effective as hormone products in prostatic hyperplasia. They would probably be effective in younger patients with chronic prostatitis as well. PEPONEN capsules are highly recommended for elderly male patients not considered for surgery because their general condition or unwilling to undergo surgery for some reason.

Special issue "Curative power from nature". 1988-1989 .

Summary: Authors conducted a clinical trial with Peponen capsules containing pumpkin-seed oil. Peponen was given long-term to 29 patients with prostatic hypertrophy stages I-II and favourable results were obtained: subjective symptoms were substantially reduced or disappeared and there was a reduction in prostate size as determined by ultrasound in 29% of the patients. The mechanism of urine discharge determined by uroflowmetry was not affected significantly. Adverse side-effects were not observed.
Prostatic hypertrophy (PH) frequently occurs in elderly males. The etiology of the disease is not clear; it is probably associated with hormonal dysfunction. In the old age there is a reduction in the production of male hormones leading to the growth of periurethral glands in the prostatic section of the urether, which are sensitive to female hormones and of female character evolutionary. The majority of males over 50 years, therefore, develop adenoma either with or without symptoms.
On the bases of subjective complaints and symptoms associated with the enlarged adenoma PH is divided into four stages.
In stages I and II either no or only moderate urine retention occurs. Renal functions are not yet impaired and there is no risk of urinary infection. In these stages the patients usually seek medical help because of dysuric complaints the severity of which is related to the size of the prostate but not directly proportional to the degree of urine retention. Pronounced complaints force the doctor to use conservative medication or, in some cases, resort to early surgery.
Drugs and natural products commonly used in these early stages of the disease include the following:
1. Enzyme inhibitors blocking androgenic-estrogenic metabolism at the level of the prostate (Permixon)
2. Progestogen hormones (Depostat, Hormofort)
3. Products containing animal or plant extracts (Raveron, Prostagutt, Prostazal etc.)
The wide range of products that may be considered in prostatic hypertrophy indicates that there is no "sure" drug equally effective in all patients. Since none of these drugs are surely effective and, furthermore, they are rather expensive and the hormonal products may induce severe side-effects, it is justified to use an effective, easily available and relatively in expensive product that is free of side effects.
These considerations have led us to conduct a trial with Peponen capsules containing pumpkin-seed oil.
We used Peponen in 42 patients between January 1 and October 1, 1988; no evaluable results were obtained in ten patients, who failed to cooperate; 29 of the 32 evaluable patients had prostatic hypertrophy (stages I and II) while the remaining three had chronic prostatitis.
Patients with prostatic hypertrophy stages III and IV, manifest cardiac decompensation or concomitant urolithiasis as well as those who had undergone prostatectomy were excluded from the trial.
The patients were divided into "target" and control groups according to date of birth. Patients born in odd years were given Peponen; the others (15 patients) were assigned to the control group and received Depostat injections at the dosage of one ampoule weekly for five weeks.
During treatment prostate size, changes in residual urine volume, the mechanism of urine discharge, and the subjective symptoms were checked.

The size of the prostate and the volume of residual urine were determined by ultrasound; the mechanism of urine discharge was studied using uroflowmetry (maximum flow, full duration of urination, and duration of maximum flow).
These studies were complemented by laboratory tests (urinary sediment, serum urea nitrogen, creatinine). Subjective symptoms were evaluated on the bases of patients reports.
It should be noted here that prostatic hypertrophy is characterized by occasional spontaneous remissions that may last for shorter or longer periods.
Mean age of the patients was 63 (50-73) years. Mean body weight was 70.8 kg. Mean duration of treatment was 8.2 (3-10) months,
The intial dose of Peponen was two capsules three times daily for one month; the maintenance dose was one capsule three times daily for the rest of the trial.
The patients were examined after a month's treatment and then every three months.

Results:
Changes in the size of the prostate in patients receiving Peponen and in the controls are presented in Table 1.
Changes of not less than 3 mm were considered as significant. There was a reduction in transversal diameter in all eight patients in whom change was detected; change in AP diameter was observed in only one patient.
Urine flow was studied by uroflowmetry using Wolf's apparatus. At baseline, the mean urine flow rate was 24 (10-45) ml/sec; duration of maximum flow was between 3.75 and 5.0 sec while the full duration of urination was 10-95 sec. In patients with prostatic hypertrophy stages I and II the latter is more relevant and its mean value at baseline was 39.5 sec.
The uroflowmetric tests did not reveal significant differences compared with baseline (Table 2).
Peponen was primarily effective in reducing subjective symptoms. The influence of Peponen on subjective symptoms is shown in Table 3.
No significant change was observed in laboratory parameters either among those on Peponen or among the controls.

Table 1:
Changes in prostate size as determined by ultrasound

No change Decrease Increase Total
Peponen group 21 8 - 29
Control group 15 - - 15

Table 2:
Changes in urine flow

No change Improvement Deterioration Total
Peponen group 23 3 3 29
Control group 11 1 3 15

Table 3:
Changes in urination complaints

Symptom free Improvement No change Deterioration Total
Peponen group 6 21 2 29
Control group 8 4 3 15

Discussion:
Complaints associated with prostatic hypertrophy have been observed to occur less frequently in regions where the population consumes large quantities of pumpkin seed (Klein, B. Pater).
In our study Peponen was found especially effective in reducing subjective symptoms associated with prostatic hypertrophy; subjective symptoms improved in nearly all patients and disappeared in six.
Peponen reduced the size of the prostate in a surprisingly high number of the patients; this effect of Peponen may have been related to its antiedematous activity.
The mechanism of urine discharge as determined by uroflowmetry was not affected significantly.
Changes in urine retention were not evaluable as the majority of the patients had either no or minimal retention at the beginning of the trial.
Patient compliance was good. None of the patients reported side-effects and allergic reactions did not occur.
Three patients experienced improvement of sexual functions, which may be interpreted as a "beneficial" side-effect.
The low number of prostatitis cases did not allow to draw final conclusions in this indication.
The patients reported quicker reduction in subjective symptoms with the initial dose (two capsules three times daily) than with the maintenance dose, an observation which makes the study of the correlation between dose and effect worthwhile.

Int Urol Nephrol 1991;23(1):51-55

Authors report on their experience with the administration of PEPONEN capsules to 60 patients with benign prostatic hypertrophy (BPH) stages I and II. 26 patients took PEPONEN for ten months, 22 patients for at least seven months and 12 patients for at least four months at a dosage of two capsules three times daily in the first month and then one capsule three times daily. On the basis of the results of urodynamic tests and the evaluation of changes in subjective complaints, improvement was observed in more than 80% of the patients. There was an increase in urinary flow while dysuric complaints, frequent and painful urination as well as the frequency of nocturnal urination decreased.

Benign prostatic hypertrophy (BPH) is one of the best known and most frequently encountered urological diseases in males over the age of 45 years. It occurs in more than 50% of males aged over 50 and may cause complaints in 10 to 30% of them. Over the age of 64 years the incidence of BPH is as high as 90% and approximately 50% of all patients have complaints requiring treatment (1,2).
In the early stage of the disease, hypertrophy of the detrusor muscle in the bladder compensates for the increased urination resistance and therefore the patient does not usually experience any symptoms. The first symptom the patient notices is the weakening of the urine stream and, furthermore, he has difficulties in starting urination. The patient experiences a sensation of fullness even after urination. Insufficient urination leads to frequent day-time urination and nycturia. Later complete retention and overflowing incontinentia may develop. In the case of urinary tract infection, urination becomes painful and renal insufficiency may develop as a consequence of chronic retention.
BPH is diagnosed by rectal palpation, uroflometry, abdominal ultrasound examination and selective urography. BPH is divided into there stages on the basis of subjective complaints and clinical symptoms (1,2,5,8). Stage I is characterized by dysuric complaints (difficulties in starting urination), frequent day-time urination and nycturia, without residual urine. In stage II, dysuria becomes more pronounced and imperative urination impulses develop with an increase in the frequency of day-time and noctural urinations due to residual urine. In stage III, dysuria and atonic bladder lead to overflowing incontinentia and, occasionally, complete retention with uraemic symptoms may develop.
Clinical experience indicates that BPH is not necessarily of progressive character and therefore conservative therapy can successfully be used in stages I and II. The aim of conservative therapy is to relieve dysuric complaints and to reduce both the amount of residual urine and the frequency of urination.
Ruszinco was the first to report on the beneficial effects of PEPONEN capsules, an OTC product of BIOGAL Pharmaceutical Works containing pumpkin-seed oil, in BPH (10). The present study was conducted as part of a multi-centre trial organized by BIOGAL to evaluate the efficacy of PEPONEN in BPH stages I and II.

Patients and method

PEPONEN capsules were used in 60 male patients with bladder neck adenoma treated as ambulatory patients at the Urological Department of Semmelweis University Medical School from January to December, 1988. The diagnosis was established by rectal palpation, uroflowmetry, catheter measurement of residual urine or abdominal ultrasound examination. Ultrasound examinations were performed with SONOTRON (Toitu-CO-600) apparatus. The size of the prostrate was measured frontally and longitudinally at full bladder, the quantity of residual urine was measured according to Rutihauser and Rageth (12). The patients were divided into two groups according to the stage of their disease. The patients in stage I had no residual urine while those in stage II had residual urine. Of subjective symptoms, dysuric complaints, pain and the frequency of urination were evaluated. Pyuria, observed in some of the patients, was treated with antibiotics. The patients did not receive any other conservative medication from one month before the commencement of treatment with Peponen. In the first month, the patients took two capsules three times daily, then one capsule three times daily, independently of body weight and general condition. The patients reported for control after 4, 7, and 10 months. 26 patients for 7 months, and 12 patients for at least 4 months.

Table 1
Changes in urinary flow as a result of treatment with Peponen capsules

Tests I II (1 month) III (4 months) IV (7 months) V (10 months)
n: 36/24 36/24 25/23 14/8 18/8
Average urinary flow (ml/sec) 9.5/8.6 11.2/10.5 12.5/11.5 12.3/11.5 12.5/11.5
Maximum urinary flow (ml/sec) 15.4/13.2 17.1/15 18.2/15.1 17.8/15.6 18/15.5
Residual urine (ml) --/35-90 --/0-70 0-30/0-80 --/0-40 --/0-50
Time (sec) 4/12 5/9 4/10 5/8 5/6

Table 2
Changes in subjective complaints as a result of treatment with Peponen

I II III IV V
N: 36/24 36/24 26/23 14/8 18/8
Dysuria 16/11 8/9 7/9 7/8 5/7
Painful urination 5/6 2/4 0/3 0/4 ?+antibiotic
Frequent urination 22/18 15/15 10/12 7/5 5/4
Nycturia 18/22 12/17 10/15 6/5 8/5

Results

The changes in urinary flow during treatment are shown in Table 1. The quantity of discharged urine was 150 to 250 ml over the period of the study. As a result of treatment, there was an increase in mean urinary flow as well as maximum urinary flow in both groups. Both the mean amount of residual urine and the time required for starting urination decreased in patients of stage II, with the latter being reduced to half. In these patients there was a more pronounced increase in urine flow than in patients of stage I. The amount of residual urine was also reduced. No evaluable changes were found in 19 out of 60 patients.
As regards subjective complaints, the condition of patients of stage I showed pronounced improvement while those in stage II experienced practically no change in dysuric complaints and the frequency of nycturia (Table 2).
The patients' and investigators' judgments on the efficacy of treatment were also compared. It seems that the patients considered the changes more favourable as they actually were by the evidence of objective tests (Table 3). Only 11 (18.3%) of all patients reported no improvement; 19 patients (31.6%) reported some improvement and 32 patients (53.3%) found the treatment very effective.

Discussion

Since the pathogenesis of BPH is not known yet, treatment cannot be targeted as the actual cause of the disease. Treatment is required when the condition causes complaints. Although surgical removal of the adenoma seems to be the only way of achieving complete recovery (1, 2, 8), conservative therapy is also used in patients with BPH. In Hungary Szendro and Szelestei used hormonal therapy in BPH (8, 9). Balogh reported on the administration of Raveron to a greater number of patients (3). Romics had favourable experience with the administration of Bazoton (Kanoldt), a product containing Radix urticae extract (9). Frang et al. conducted a trial with prazosin (Minipress, Pfizer) in BPH patients (6).
The use of phytotherapeutic agents, ie. products containing medicinal plant extract, in BPH has a long history (5, 7, 11). The active substance of PEPONEN capsules used in this study is pumpkin-seed oil obtained from a pumpkin variety with shell-less seeds. The biological, biochemical, and physiological effects of pumpkin-seed oil justify its extensive usability. In BPH pumpkin-seed oil exerts a beneficial effect through the regulation of prostaglandin production by its beta-sitosterol, ergosterol, and camphosterol components. Pumpkin-seed oil increases muscular tone in the bladder hence normalizing bladder functions with a consequent reduction in inflammation and pain. Linoleic acid, sterols, vitamins E and F, and selenium in pumpkin-seed oil protect the hormones and vitamins from destruction. Thus PEPONEN may affect androgenic and prolactin activity directly in the prostate. It improves bladder function and exerts beneficial influence on the inflammatory changes of the prostate (5, 6, 10).
In the present study some improvement was observed even after one month of treatment as confirmed by the changes in clinical symptoms and urinary flow as well as the patients' judgment. Lasting improvement was achieved after four months of treatment. Later on, no further change was recorded but deterioration in the patients' condition was not observed either. Treatment with PEPONEN increased urinary flow and decreased dysuric complaints as well as the frequency of day-time and nocturnal urination in more than 80% of the patients. The improvement was more pronounced in patients with BPH of stage I. PEPONEN is regarded as equivalent with other medications in the conservative therapy of BPH.

Table 3
Effect of Peponen treatment

Patient's judgment Doctor's judgment
Very good 32 patients 25 patients
Good 12 patients 8 patients
Slight improvement 5 patients 8 patients
No change 11 patients 19 patients
n: 60 patients 60 patients

REFERENCES

1. Altwein I.E., Jacobi, C.G.: Urologie. Enke Verlag, Stuttgart, 1986.
2. Balogh F., ed: Urologia (Urology) Medicina, Budapest, 1986.
3. Balogh F.: A Raveron erteke egyes urologiai megbetegedesek kezeleseben. (The Use of Raveron in Treatment of certain urological diseases) Urol. Nephrol. Szle, 1987, 14, 195.
4. Bartsch G. et al: Light microscopic stereological analysis of normal human prostate and of benign prostatic hyperplasia. J. Urol. 1979, 122, 487.
5. Eggerhart G., Gallyas, F: Klinische Erfahrungen mit Harzol-Kapseln in der Behandlung des Prostate-Adenoms. Urologe (B). 1987, 27, 227.
6. Frang D., Hamvas, A., Nagy F: Az alfa-adrenoceptor blokkolo prazosin (Minipress) helye a holyagnyak-adenomas begetek kezeleseben. [The role of alpha-adrenoceptor blocking prazosin (Minipress) in treatment of patients with bladder-neck adenoma] (Submitted for publication)
7. May P., Sokeland P: Phytopherapie in der Urologie-Editorial - Ruologe (B) 1987, 27, 213.
8. Pinter J., ed: Prostata hyperplasia (Prostate hyperplasia) Magyar Urologiai Tarsasag V. Kongresszusa, Debrecen, 1979.
9. Romics I: Observations with Bazoton in the management of prostatic hyperplasia. Int. Urol. Nephrol., 1987, 19, 293.
10. Ruszinko B. et al: Peponen kapszula alkalmazasaval szerzett tapasztalataink (Experience with administration of PEPONEN capsules) Gyogyszereink. 1986. 1.
11. Sonneschein R.: Untersuchung der Wirksamkeit eines prostatotropen Phytotherapeutikums (Urtica plus) bei Benigner Hyperplasie und Prostatitis-eine multizentrische Studie. Urologe (B) 1987. 27. 232.
12. Khoury S., ed: Ultrasound in Urology, Int. Scient. 1985, 309.

Horvath S, Bedo Z.
2nd Department of Surgery (1), 3rd Department of Internal Medicine (2), Debrecen University Medical School, Debrecen, Hungary
According to popular experience, the incident of hypertension, atherosclerosis and prostatic hypertrophy is lower in people regularly consuming pumpkin-seed oil. Authors report on their experience with the administration of Peponen capsules (Biogal) containing pumpkin-seed oil to hyperlipidaemic patients and conclude that Peponen reduces the level of serum total cholesterol, triglyceride, and LDL-cholesterol while increasing the concentration of protective HDL-cholesterol. These beneficial effects of Peponen are primarily observed in patients with Fredrickson IIa and IIb hyperlipidaemia.

Vegetable oils are widely used as articles of food and some of them are typical foodstuff in ethnic groups. Pumpkin-seed oil is extensively used in Hungary and the neighboring countries (e.g. Yugoslavia and Syria). In these areas, the incidence of prostate hyperplasia, hypertension, and arterioslcerotic diseases is lower, a phenomenon which has been connected with regular pumpkin-seed consumption.
The composition of pumpkin-seed oil has not yet been fully elucidated; linoleic acid, linolenic acid, beta-carotene, lutein, beta- and gamma-tocopherol, chlorophyll, and selenium have so far been identified as components. Due to its special composition, pumpkin-seed oil may indeed be able to delay arteriosclerotic processes, presumably through a favourable influence on abnormal lipid metabolism. It seemed obvious, therefore, to conduct clinical trials with pumpkin-seed oil in patients with diagnosed hyperlipidaemia, including those with coronary heart disease.
According to experimental studies in rats, pumpkin-seed oil is able to reduce serum cholesterol levels thus reducing the lipid content of vessel walls and tissues. It inhibits platelet aggregation, i.e. it can delay the process of arteriosclerosis. Certain essential fatty acids and prostaglandin precursors can reduce vascular reactivity to rennin and angiotensin II so they may have an antihypertensive effect.
Earlier, we had conducted a clinical trial with Peponen capsules, a paramedicinal product of Biogal, containing 300 mg of pumpkin-seed oil extract per capsule. The study was performed in 37 patients with diagnosed coronary sclerosis who also suffered from hyperlipidaemia of Fredrickson types II or IV.*
It can be seen that peponen reduces serum cholesterol levels as well as triglyceride levels and increases HDL-cholesterol levels. More precisely, it increases low HDL-cholesterol levels toward the physiological range and does not affect normal HDL-levels. Its effect on total serum cholesterol and triglyceride levels proved to be significant.
The favourable results had encouraged us and Biogal to study the effect of Peponen in a greater number of patients. In 1988, a clinical study was conducted in the 2nd Department of Surgery and the 3rd Department of Internal Medicine, Debrecen University Medical School, as part of a multicentre trial designed to evaluate the effect of Peponen in hyperlipidaemic patients.
The patients at the 2nd Department of Surgery were selected from those who had undergone coronary bypass surgery. Surgery had taken place at least half a year before treatment with Peponen was started. 30 patients were selected; distribution of the patients according to the type of hyperlipidaemia is shown in figure 3.24 of the 30 patients had hyperlipdaemia of Fredrickson types IIa and IIb; type had type I, two had type III, and two had type IV hyperlipidaemia.
The patients at the 3rd Department of Internal Medicine ere selected at screening. The 38 hyperlipdaemic patients thus selected had no complaints and took no medication; 14 patients belonged to Fredrickson type IIa and 11 to type IIb; six patients had type I, six patients had type III, and one had type IV hyperlipidaemia*.
The results are presented*.
Of patients who had undergone coronary bypass surgery, favourable changes were found only those with Fredrickson types IIa and IIb hyperlipidaemia but not in types I, III, and IV. In 8 of 14 patients with type II hyperlipidaemia, serum cholesterol levels decreased from 9.27 mmol/l to 8.02 mmol/l; the triglyceride levels were reduced from 2.35 mmol/l to 1.68 mmol/l, LDL-levels from 6.93 mmol/l to 5.29 mmol/l, and VLDL-levels from 0.91 mmol/l to 0.43 mmol/l while HDL-cholesterol levels increased from 0.93 mmol/l to 1.23 mmol/l. These changes occurred in only about one-third of the patients. The numbers below the columns in figure 4 indicate the number of patients with favourable changes. The overall evaluation did not reveal significant improvement; nevertheless, the changes observed in some of the cases were important although not significant.
Data of patients having undergone coronary bypass surgery
Out of 30 patients
24 patients: Fredrickson type IIa
2 patients: Fredrickson type I
2 patients: Fredrickson type III
2 patients: Fredrickson type IV
The patients were on Colfarit and Betaloc.
Data of patients with symptom-free hyperlipidaemia
Out of 38 patients
14 patients: Fredrickson type IIa
11 patients: Fredrickson type IIb
6 patients: Fredrickson type I
6 patients: Fredrickson type III
1 patient: Fredrickson type IV
The results of patients with symptom-free hyperlipidaemia are shown in figure 5*. It can be seen that favourable effects of Peponen were observed in patients with hyperlipidaemia of Friedrickson type II, but not in those with other types; no deterioration, however, was observed in any of the tested parameters. In 14 patients with hyperlipidaemia of type IIa, triglyceride decreased from 1.67±0.64 mmol/l to 1.51±0.1 mmol/l, total cholesterol levels from 7.55±0.82 mmol/l to 6.67±1.15 mmol/l, LDL cholesterol levels from 5.53±0.72 mmol/l to 4.86±1.15 mmol/l and VLDL from 0.50±0.16 mmol/l to 0.31±0.17 mmol/l after two months' treatment. There was practically no change in HDL-cholesterol levels, they moved from 1.57±0.37 mmol/l to 1.58±0.43 mmol/l. Interestingly, while significant changes (remarkable increase in HDL-cholesterol) had been found in the lipid levels of patients taking part in the 1987 study, in this study, the lipid lowering effect of Peponen was not so pronounced although favourable changes were undoubtedly observed in one-third of the patients, especially in those with hyperlipidaemia of Fredrickson type II. All patients in the coronary bypass group took Betaloc andColfarit and these might have exerted an antilipaemic effect. The favourable changes were not universal in the group of symptom-free patients either although they did not take any other drug besides Peponen. The changes were similar in both groups, except for HDL-levels. In the coronary bypass group, 8 patients demonstrated an increase in HDL-levels. Certain drugs may indeed influence the effect of Peponen but we cannot exclude the possibility of differences in raw material used for the production of Peponen capsules. Since the raw material of Peponen is a natural substance, its composition may be influenced by conditions such as the site of pumpkin production. These conditions should be taken into account in the future.
On the basis of these findings, the conclusion can be drawn that Peponen, a product of natural active substance, is a valuable contribution to the range of therapeutic agents used in hyperlipdaemia. Several drugs are available for the treatment of hyperlipidaemia but only a few of them are of confirmed efficacy. The effects of Peponen are remarkable and although it is not the drug of first choice, it is worth trying in hyperlipdaemia of Fredrickson type II. Peponen has no side effects; it improves the patients' general condition and appetite without affecting the body weight. According to earlier experience, it improves the symptoms of prostate hyperplasia and it can even enhance sexual potency in males. Pepnone has also been reported to potentiate the effect of lipid lowering drugs (lipathyl, Bezalip).

Corradi G, Hegedus M, and Frang D.
Department of Urology, Semmelweis University Medical School, Budapest
Effect of Peponen capsules was evaluated in 27 patients with andrological disorders. Ten patients receiving low doses of testosterone served as control. Peponen was of beneficial effect in fertility disorders associated with prostatic dysfunction. Efficacy of Peponen in the treatment of infertility of unknown origin was similar to that achieved among the controls on conventional therapy. Further studies are required to establish the therapeutic role of Peponen capsules.

Pumpkin-seed oil contains several of the hormones and other substances that play an important role in the maintenance of testicular functions. These substances include vitamin E, prostaglandin precursor unsaturated fatty acids and, furthermore, sterolons and squalens serving as intermediaries in the production of compounds of sterane structure (1).
Prostatic secretion accounts for one-third of semen. Normal proteolytic enzyme functions are indispensable for the liquefaction of semen. Normal functioning of the prostate plays an important role in the maintenance of fertility. The beneficial effects of pumpkin-seed oil on prostate function, partly through the above biochemical pathways and partly due to its anti-inflammatory activity, may also contribute to the maintenance of fertility. These considerations have led us to evaluate Peponen capsules (Biogal Pharamceutical Works) in andrology.

Material and method
Forty patients with fertility disorders visiting our andrological consultations were given Peponen capsules (one capsule three times daily for three months).
Twenty-seven patients completed the study. Prior to and on completion of the three-month treatment andrological-spermatological tests were performed according to WHO recommendations (3). Patients with fertility disorders of unknown origins were selected for the study; disorders of known etiology (variocele, hypogondism, etc.) were excluded. Our results are summarized in Table 1.
In Table 2 the results are presented by groups established according to cell count.

A group of ten patients receiving low doses of testosterone as conventional andrological treatment served as control. The criteria of selection were the same as for the Peponen group.
The results of controls are presented in Table 3.

Four of the control patients and ten of those on Peponen showed improvement. Five of the latters had the highest degree of improvement. These patients had a history of prostatic complaints and slow liquefaction of semen was observed in them.
Their data are presented in Table 4.

Table 1
No. of patients N=27 Before Peponen After Peponen Difference
Cell count million/ml 12.7 16.3 3.6
Motility % 43.4 55.5 12.1
Intensive movement % 25.4 37.3 11.9
Structure % 42.3 54.3 12.0

Table 2
Cell count million/ml No. of patients No improvement Improvement Percentage improvement
1-5 4 4 -- 0%
5-10 7 5 2 28.5%
10-15 9 4 5 55.5%
15-20 7 4 3 42.8%
Total 27 17 10 37.0%

Table 3
No. of patients N=10 Before treatment After treatment Difference
Cell count million/ml 12.5 17.6 5.1
Motility % 62.5 65.5 3.0
Intensive movement % 33.6 46.5 12.9
Structure % 54.7 57.1 2.4

Table 4
No. of patients N=5 Before treatment After treatment Difference
Cell count million/ml 12.6 19.4 6.8
Motility % 51.2 68.5 17.3
Intensive movement % 23.5 51.2 27.7
Structure % 44.6 65.2 20.6

Discussion
Drug treatment of fertility disorders of idiopathic origin poses serious problem. The number of andrological drugs presently available is limited; there are not more than ten drugs that are currently used with more or less success. Andrologists, therefore, look forward with great interest to new drugs launched on the market.
The aim of our study was to evaluate Peponen capsules in andrological patients. Patients receiving low doses of testosterone were used as controls. After three months' treatment one-third of the patients improved; improvement was manifested inc ell count, motility as well as structure. In some cases the degree of improvement reached that of the controls although these changes were not significant. With drugs generally considered effective (2) a 20 to 40% improvement can be expected; such percentage of improvement can be achieved with Peponen.
In view of spontaneous fluctuations in sperm count (2), the results of this study should be confirmed in a higher number of patienets followed up over a longer period of time. The results of the five patients whose data are presented in Table 4 were found especially promising. In this group of patients there was a definite and outstanding improvement. These patients had a history of prostatic dysfunction and prolongation of semen liquefaction was detected in them.
On the basis of our experience Peponen capsules seem to b useful in the andrological practice. Favourable results may be expected in one-sixth of the patients. Natural origin and the lack of side-effects constitute a special advantage of the product.

REFERENCES
1. Jancso S., A tokmagolaj biokemiai hatasai (Biochemical Effects of Pumpkin-Seed Oil) Manuscript on file at BIOGAL Medical Division, 1988
2. Bain, J., Schill, W.B., Schwartzstein, L., eds., Treatment of Male Infertility, Springer Verlag, Berlin, Beidelberg, New York, 1982
3. Belsey, M.A., Eliasson, R., Gallagos, A.J. et al, World Health Organization Laboratory Manual for the Examination of Human and Cervical Mucus Interaction. Singapore Press Concern, 1980.

Kakuk, G.
Nephrological Unit, 1st Department of Internal Medicine, Debrecen University Medical School, Debrecen, Hungary

Summary: Peponen capsules were used in 22 patients with chronic renal insufficiency, eight of whom received conservative therapy while 14 were on haemodialysis. Peponen was administered in a dose of two capsules three times daily over a period of four months. The patients' general condition, physical status, and laboratory parameters were regularly checked and changes in appetite were recorded. The majority of the patients reported beneficial effects with Peponen and there were favourable changes in some laboratory parameters (thrombocyte count, haemoglobin, haematocrit, serum total protein, albumin, serum uric acid, BUN alkaline phosphatase), primarily in patients in stage II chronic renal insufficiency. In view of the findings, author considersraising the dose of Peponen to 3-4 capsules three times daily in future studies.

Clinical experience of the past few years has clearly demonstrated that arteriosclerotic vascular diseases, including accelerated coronary sclerosis, constitute an important cause of morbidity and mortality in patients with impaired renal function and those on dialysis (4,10).
In renal insufficiency, lipid metabolic disorders and the severity of arteriosclerosis are closely correlated (1,4). In patients with renal insufficiency erythrocyte deformity induces unfavourable haemorrheological changes, which--when combined with lipid metabolic disorders-accelerate the progression of renal disease (8).
Regular administration of polyunsaturated fatty acids of vegetable and animal origin can, however, favourably affect these unwanted changes (2,3,6,7,8,9). These observations have led us to use PEPONEN capsules (BIOGAL, Debrecen/Hungary) containing essential fatty acids and vitamin E (7) in patients with stage II renal insufficiency receiving conservative therapy and those in stage III on dialysis, with the purpose of improving the patients' general condition as well as their renal function and metabolism.

Patients and methods
The most important clinical data of the eight patients on conservative therapy (group A) are presented in Table 1. Mean age of the eight patients was 49 (20-80) years. Most of the patients suffered from glomerulonephritis. Their daily diet contained 0.4-0.8 g/kg body weight of protein rich in essential amino acids and provided a calorie intake of 35-40 cal/kg body weight. The patients were given antihypertensive drugs when necessary but did not receive either vitamins or serum cholesterol lowering drugs.
Clinical data of the 14 patients on haemodialysis (group B) are shown in Table 2. Most of the patients had glomerulonephritis. Mean age of the five female and nine male patients was 37 (24-60) years and they had been on dialysis for an average of 43 (5-136) months. The patients' diet supplied 40-45 cal/kg body weight daily and contained 1.2-1.5 g/kg body weight of protein rich in essential amino acids. The patients were given antihypertensives when necessary. No serum cholesterol lowering agents were administered to the patients during the study. The patients were dialysed three times weekly for four hours each using capillary dialysers with a surface of 1.25-1.3 m2.
Clinical data of the 14 patients on haemodialysis (group B) are shown inTable 2. Most of the patients had glomerulonephritis. Mean age of the first five female and nine male patients was 37 (24-60) years and they had been on dialysis for an average of 43 (5-136) months. The patients' diet supplied 40-45 cal/kg body weight daily and contained 1.2-1.5 g/kg body weight of protein rich in essential amino acids. The patients were given antihypertensives when necessary. No serum cholesterol lowering agents were administered to the patients during the study. The patients were dialysed three times weekly for four hours each using capillary dialysers with a surface of 1.25-1.3 m2.
Patients in both group A and group B received two PEPONEN capsules three times daily before meals. The patients took PEPONEN continuously for four months. Patients with diffuse parenchymal liver disease or taking drugs directly affecting serum lipid levels were excluded from the study. Prior to commencement of the study, written consent was obtained from each patient in accordance with relevant principles of the Helsinki Declaration (1965).
Before the studies and at the end months 1, 2, and 4, the laboratory parameters listed in Table 3 were checked.
The patients were regularly supervised; they reported for control at the Nephrological Unit once a month or at the Dialysis Department three times a week and were asked about their general condition, sthenia, and appetite.
The laboratory results were statistically evaluated (student's one-sample t-test).

Table 1

Patients in Group A (n=8)

Patient No. Diagnosis Age (years) Sex
1 Glomerulonephr. chr. 20 Male
2 Hypertonia ess. Nephroscler. 80 Male
3 Glomerulonephr. chr. 46 Male
4 Glomerulonephr. chr. 66 Male
5 St. p. transp. renis 38 Male
6 Pyelonophr. chr. 57 Male
7 Diabetes nephrop. 56 Male
8 Glomerulonephr. chr. 31 Male

49 (20-80) male = 8
GNC = 4
PNC = 1
Other = 3

Table 2

Patients in Group B (n = 14)

Patient No. Diagnosis Age (Years) Duration of
haemodialysis treatment (months) Sex
1 Glomerulonephr. chr. 29 55 Female
2 Glomerulonephr. chr. 38 12 Male
3 Glomerulonephr. chr. 34 18 Female
4 Glomerulonephr. chr. 36 46 Female
5 Hereditaer nephr. 33 66 Female
6 Pyelonephr. chr. 43 33 Male
7 Glomerulonephr. chr. 54 47 Male
8 Pyelonephr. chr. 43 33 Male
9 Ren polycst 37 136 Male
10 Glomerulonephr. chr. 27 18 Male
11 Glomerulonephr. chr. 26 82 Male
12 Glomerulonephr. chr. 49 5 Female
13 Pyelonephr. chr. 33 26 Male
14 Glomerulonephr. chr. 24 35 Male

37 (24-60) 43 (5-136) female = 5
male = 9

GNC = 9
PNC = 3
Other = 2

Results

Table 4 shows changes in the subjective parameters including general condition, appetite, and physical activity. As seen in the table, most patients reported favourable changes.
No statistically significant changes, either positive or negative, were found in any of the laboratory parameters in group A or group B. It should be noted, however, that some of the parameters in patients with chronic renal insufficiency on conservative therapy tended to improve during the study period; these parameters include haemoglobin, haematrocrit, se. total protein, and albumin showing a moderate increase, while se. uric acid, Bun, and alkaline phrosphatase demonstrating a tendency of decrease (Fi. 1-8).
A slight increase in serum total protein and albumin and a decrease in serum bilirubin represented positive changes in haemodialysed patients (Fig. 9-11).
No adverse effects were observed during the four-month PEPONEN treatment.

Table 3

Laboratory tests

Haematological tests:
WBC, haemoglobin (Hgb), haematocrit (Htcrt), thrombocyte count (Thrc)

Serum total protein, albumin, uric acid, BUN, creatinine, Na, K, Ca, P

Serum lipids: serum cholesterol, triglyceride, HDL-C, C/HDL-C

Liver function enzyme assays: gamma GT, SGOT, alkaline phosphatase, serum bilirubin, blood glucose

Table 4
Group A
Subjective Judgment General condition Appetite Physical activity Total
Improved 6 5 5 17
No change 2 2 3 7

Group B
Subjective Judgment General condition Appetite Physical activity Total
Improved 10 10 10 30
No change 4 4 4 12

Discussion

Our study covering a total of 22 patients is regarded as a preliminary investigation from which the following are concluded:

1. The majority of the patients, especially those with stage II renal insufficiency, reported an improvement in general condition, appetite, and physical activity. In uremic patients, these changes alone deserve attention. It is still a question, however, what mechanism underlies these positive subjective changes. Unsaturated fatty acids also contained in PEPONEN capsules have been suggested to favourably affect prostaglandin metabolism and haemorheological changes (3,5,7,10).
2. Laboratory parameters did not show a significant change, either positive or negative, but some of the parameters demonstrated a favourable tendency, especially in group A. In view of the fact that 3,000 mg of fish oil was used in similar studies (3), the applied PEPONEN dosage (two capsules three times daily, corresponding to 1,800 mg daily intake of fish oil containing omega-3 polyunsaturated fatty acids produced significant changes in lipid metabolism. On the basis of these findings, in future studies we are going to use PEPONEN in a dose of 10 capsules/day.
3. Use of PEPONEN is safe and without any unwanted side-effects. It is especially recommended as a supplement to diet.

REFERENCES

1. Bagdade J.P., Porte D., Burman J.R.: New Engl, J. med. 279:181-185. 1968.
2. Barcelli U., Pollak V.E.: Nephron, 41:209-212. 1985.
3. Bilo H. J. G., Rustemeier C., Pop-Snijders C., Donker A. J. M.: 12. Nephrologisches Seminar, Heidelberg, 4-5. Febr. 1988 Eds. E. Ritz and K. Andrassy.
4. Degoulet P., Legrain M., Reach J. et al: Nephron, 31:103-105. 1982.
5. Kikuchi Y., Koyama T., Tozawa S. et al: Nephron, 30:8-14, 1982.
6. Kromhout D., Bosschieter E.B., Coulander L.: New Engl. J. Med. 19:1205-1209. 1985.
7. "Peponen Capsules" (Oleum Cucurbitae Pepo). Ed. S. Jancso. Biogal Pharmaceutical Works, Medical Division, Debrecen, 1987.
8. Rylance P.B., Gordge M.P., Saymor R. et al: Nephron, 43:196-202. 1986.
9. Simpson L.O.: Nephron, 44:256-258. 1986.
10. Tomohito H. Nakazawa R., Tateno S. et al: Kidney Int. 26:81-84, 1984.