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THYMUS EXTRACTS:
An International Literature Review of Clinical Studies*

Continued...

Surgery

Colorectal surgery

Four hundred and twenty-five patients received thymostimulin for 7 days beginning 48 hours before surgery plus cefotetan, an antibiotic, administered at the time of anesthesia. The results showed a lower incidence of post surgical infections and abscesses compared to those who received only the antibiotic, even in patients with compromised immune responses. Respiratory tract infections were one-half as frequent compared to those who received only the antibiotic (Periti 93).

Suppurative surgical infection (SSI)

Forty-seven infants with sepsis and 34 with localized infection were given t-activin thymus extract as part of the post surgical treatment complex while 75 other infants were treated with conventional methods. Results showed that the clinical course of SSI was less severe, with more pronounced positive changes in symptoms, shortened hospital stay and decreased mortality in the treated infants. The authors confirmed that the post-operative use of thymus extracts in infants leads to an increase in the number and functional capacity of peripheral T-lymphocytes with improved bactericidal activity of circulating phagocytes in postoperative newborns with SSI (Samsygin 89).

Post-operative Sepsis

The thymus extracts thymalin and t-activin were used in a study involving post-operative sepsis. The authors reported after 14 days of treatment that thymalin stimulated T cells while acting with immunoglobulins. T-activin increased the numbers of T cells and B cells. Clinical improvement was best when the thymus extracts were used in combination with other medication (Bulava 96). After citing immunologic and clinical studies demonstrating the immunodeficiency states are the most probable causes of post-operative complications following reparative surgery of the facial bones, results were presented for 10 cases of facial surgery for congenital land acquired deformation using t-activin conjointly with surgery. This protocol normalized immune parameters and prevented development of post-operative complications (Volozhin 96).

Orthopedic implants

Teicoplanin, a thymus extract, was shown to be a useful prophylactic against infection resulting from orthopedic implant surgery. Deep prosthetic infections are very difficult to cure without removing the infected device; the outcome can be devastating, such as: total loss of joint function, amputation, and occasionally, death. Preliminary results show that teicoplanin has a role to play both in treatment of infection and as prophylaxis against hospital-acquired infection (Periti 92).

Abdominal surgery

Sixty-one patients who had been previously classified as anergic underwent elective abdominal surgery in conjunction with simultaneously receiving thymostimulin thymus extract. The authors found a notable reduction of postoperative infection in the treated group when compared with 62 controls who were anergic and underwent surgery but received no therapy (Perotti 47).

Surgery with the immunocompromised

Two hundred and twelve surgical patients at risk because they were immuno-compromised were divided into 2 homogeneous groups: the treatment group which received thymostimulin thymus extract during and after surgery, and the control group which received conventional surgical treatment. All patients were affected by severe pathologies. Positive results were obtained in the thymostimulin treated group in terms of reduced morbidity, postoperative hospitalization and mortality as compared to controls. The author’s conclusion was that treatment with thymostimulin in immuno-compromised patients is an important factor in avoiding or reducing postoperative infection rates (Lai 92).

Immunosenescence (Immune Effects of Aging)

A strong and vigorous immune system is especially important in the health of the elderly. The lifestyles of most older persons in our society compromise immunity in many ways. Several of the common causes of compromised immunity listed earlier in this paper are especially relevant to aging persons. As a group, older people tend to exercise less, consume more prescription and nonprescription drugs, and are exposed to more medical procedures. Suboptimal nutritional intake is also a common problem associated with aging. These stressors occur at a time of life in which inadequate digestion and elimination combined with decreased liver function compound their detrimental effects on immune function. Because these conditions are additive and cumulative, it is difficult to determine exactly how much of the aging in humans is due to the natural physical process and how much is incurred by lifestyle components that lead to compromised immunity. Even though the exact proportion may be difficult to assess, it is no coincidence that many of the causes of compromised immunity are also involved in aging. "The programmed decline in physiologic competence, which we know as aging, is in fact a series of concomitant changes primarily manifested in the immune system" (Weksler 81).

One of the most consistent findings associated with immunosenescence in humans and animals is a decline in T cell numbers, function and proliferation as aging increases. This has been attributed to the involution of the thymus gland (Kouttab 89) and the subsequent decreased production of the thymic hormones that control T lymphocyte numbers and function (Ghanta 90). These decrease with age and are associated with a "thymic menopause" and cellular immune senescence contributing to the development of diseases in the aged (Hadden 92). The consequence of this process is an increased susceptibility to infections, auto immune diseases and cancer (Weksler 81). Liquid thymus extracts have been used to help restore cellular immunity, including the number and function of T-lymphocytes (Skotnicki 89, Kouttab 89, Hadden 89, Dabrowski 80, Segatta 86, Park 84, Poli 86, Periti 93, Harrower 32, Weksler 81). The question is whether liquid thymus extracts can do the same in the elderly person.

There is scant literature on the clinical and direct immunological effects of liquid thymus extracts in the aged. In one of the few studies, Pandolfi et al. administered thymostimulin (TP-1) to 14 randomly selected persons averaging 80 years of age who were free of neoplastic, autoimmune or infections diseases at the time of selection and had a normal lymphocyte count (Pandolfi 83). Dosage was 1 mg/kg per wk for 1 month followed by 1 mg/kg per 2 weeks for 2 months. The total treatment time was 90 days. The results were compared to a control group of 12 subjects receiving no therapy. Routine blood, urine and clinical data were evaluated before therapy, at 90 days and at 180 days. The study found no change in the absolute lymphocyte count. There was an increase in T lymphocyte resetting but it was not statistically significant due to the small N size. The only statistically significant difference in laboratory measurement between the two groups was a decrease in the sedimentation rate from a slightly elevated value of 22 before therapy began to 12 at 180 days for the treatment group, a decrease of about 50%. The clinical results of the study, however, were much more striking. Significantly fewer patients in the treated group had infections than controls (21% vs. 67%). In addition, there was only 1 episode of urinary tract infection in the treated group compared to 6 in the controls and only 2 episodes of respiratory infection in the treated group compared to 11 in the control group. No other infections in the treated group occurred, but there were 4 in the controls. No side effects or toxicities were reported.

Because no true T lymphocyte function tests were completed, we can only surmise that the cause of this improved resistance to infection may have been due to increased T cell function, as has been shown by previous studies in humans and animals (Kouttab 89, Stankiewiez 86, Dabrowski 80, Segatto 86, Park 84, Poli 86). The results of this study provide a very interesting indication that thymus extracts may not significantly increase lymphocyte numbers in relatively normal, healthy, elderly persons, but may significantly alter their clinical course, even when their lymphocyte count is normal.

Studies presented earlier in this paper demonstrated the beneficial effects of thymus extracts in treating the most common diseases associated with aging: infections, auto-immune diseases and cancer. The study presented above, however, demonstrates the possibility of benefits of liquid thymus extracts given to elderly subjects on a prophylactic basis.

Although the increased clinical response was probably due, at least in part, to the increased functional capabilities of T lymphocytes, there may also have been other factors involved. The thymus appears to be involved in decreasing some of the normal processes of aging in association with other organs and systems. In other words, they may have extra-immunological functions as well (Fabris 90, Czaplicki 89).

For example, studies have shown the beneficial effects of liquid thymus extracts on the structure and function of livers in aging animals. Typically, the hepatocyte nuclei of livers in aging animals increase in size. Mitochondria are also swollen and have deficient membrane composition with dark and electron dense internal structures. The rough endoplasmic reticulum (RER) and smooth endoplasmic reticulum (SER) also show characteristic patterns of degeneration. These characteristic changes should be taken as a criterion of aging and diminished biological activity (Weindruch 80). Fetal thymic calf extracts have been shown to induce a significant decrease in the size of hepatocyte nuclei in aging (450 day old) mice (Czapliki 90). Microscopic examination of hepatocyte mitochondria from treated mice showed the histological picture of healthy young mice. In contrast, histology of hepatocytes from the control group showed the typical patterns of degeneration associated with aging. In another study, thymus peptides (thymic factor D) extracted from swine and injected into 24-month-old rats (senescent rats) in a dosage of 2 mg/kg every other day for 3 months resulted in decreased liver content of malondialdehyde & lipofusion accompanied by increased liver glutathione peroxidase (GSH) levels. Microscopic examination revealed that hepatic mitochondrial and microsomal membranes of these aged rates had recovered to be like those of young adult rats (Chung-Kuo 93). Another finding from this study was that liver and spleen function did not deteriorate with age in the treated animals.

Other studies have shown decreased levels of unsaturated fatty acid peroxides in cerebral and splenic tissue of adult rodents (Czaplicki 89). Histologies of these animals revealed the preservative and antiaging effects of embryonic and early fetal calf thymus extracts. The authors’ conclusion was that the active substances produced by embryonal thymus and early fetal thymus not only affect the immunological system, but also interfere with the process of organ aging. Investigators have reported that the administration of liquid thymus extracts has been associated with the disappearance of presbyopia and climacteric changes in elderly persons (Kaliuzhnaia 89). Other investigators demonstrated that thymus extracts significantly increased the longevity of treated mice (Hadden 89, Kaliuzhnaia 89).

Taken as a group, these studies indicate that liquid thymus extracts may be useful in preserving antioxidant activity, may decrease the typical response to aging in the liver and possibly other organs, and may influence longevity in some animals.

The thymus is also fundamental to the integration and proper interaction between the immune, endocrine and central nervous systems (CNS). There is recent evidence that indicates the thymus plays an indirect but considerable role within the neuroendocrine network. A number of homeostatic processes governed by the hypothalamopituitary axis are involved, including regulation of tissue metabolism (Fabris 90, Dabraowski 90).

In summary, decreased cellular immunity is directly associated with increased aging. Liquid thymus extracts have been shown to be beneficial in some clinical conditions affecting the elderly. They have been shown to have extra-immunological benefits on other organs and systems. The use of thymus extracts may be an important, but overlooked, option in treating the possibly preventing many clinical conditions of the aging person.

Miscellaneous

Burns

Opportunistic micro-organisms causing infections in burn patients are often acquired in hospitals. These infections commonly involve Gram-positive organisms which may be resistant to several antibiotics. Teicoplanin, alone and in combination with additional antibacterial drugs, proved effective in the treatment of Gram-positive infections of various types in hospitalized burn patients (Periti 92).

In another study the thymus extract t-activin was used in combination with sodium nucleinate plus lidocaine to restore phagocytic function of peripheral blood lymphocytes and increase humoral immunity in severely burned animals. Treatment decreased colonization of pseudomonas aeruginosa and candida pathogens and decreased the death rate (Shatalova 97).

Preeclampsia and eclampsia

Progressive immune depression accompanied by a parallel drop in parathyroid hormone level to critical values has been demonstrated in patients with eclampsia. Patients with preeclampsia delivering by cesarean section were treated postoperatively with the thymus extract, t-activin. Cellular immunity was compared with patients receiving no t-activin. A marked immunostimulatory effect of the thymus extract on T-lymphocytes and especiallky on theophylline-resistant T-lymphocyte subpopulations was observed. The effect of t-activin was most marked on the 3rd to 5th day of the postoperative period (Ianiushina 92).

Male Infertility

In an unusual 2 part study, the effect of complete thymic extract on the motility and progression of sperm from men with previously confirmed asthenozoospermia was investigated. In the first part, the thymic extract was incubated in vitro with sperm obtained from men with asthenozoospermia and compared to untreated in vitro sperm from the same men. In the second part of the study, 10 men with asthenozoospermia were given injections of the thymic extract (150mg/day IM) for y days and sperm samples were compared before and after therapy. In both parts of this study results showed a significant increase in sperm motility and progression with the introduction of complete thymic extract (Arsenijevic 96).

Cardiac Function

In a 4 year study comparing treatments for men with biopsy proven myocarditis or dilated cardiomyopathy, 13 men were treated with thymomodulin plus conventional treatment, 13 with interferon-alpha plus conventional treatment, and 12 with conventional treatment alone for a period of 2 years. Results at the 2 year follow-up showed significant improvement in left ventricular ejection fraction (81% vs 66%), and maximum exercise time (5 vs 3 minutes) during exercise. At the 2 year follow-up, 88% of the men in the 2 treatment groups had normal electrocardiograms compared with 22% of the controls, and 73% had improved their functional class compared to 25% of the men in the control group (Muric 96).

Side Effects

Over 200 articles were reviewed in the preparation of this paper. One of the most striking consistencies throughout the many articles was the absence of harmful side effects produced by thymus extracts. Except for two incidents of toxicity (see "Toxicities" section), no hazardous side effects were listed, even in the studies involving injections. A few authors noted the lack of harmful side effects. This is unusual in medical literature, especially in new or experimental therapies. One review article found "a complete lack of detrimental side effects" in over 50 studies it reviewed (Kouttab 89). Beneficial side effects are not usually measured or reported in clinical experiments, however, one study reported a decreased sensitivity to viral and bacterial infections and an improvement in the general clinical state and overall well-being of subjects taking a thymus extract (Skotnicki 89).

Some studies used thymus extracts to decrease the iatrogenic side effects and toxicity of radiotherapy, chemotherapy and surgery (Vuckovic 92, Alba 91, Negri 92).

Toxicities

Only 2 toxicities were reported in all of the papers referenced here or in any of the other papers reviewed. This is an important finding, particularly when compared to the side effects and toxicities of some of the drugs used to treat the same conditions that thymus extracts have successfully treated, especially in the frail or chronically ill patient.

One study, however, showed a severe anaphylactic reaction to thymostimulin. This was a report of a single 36-year-old male receiving thymostimulin as part of the treatment for a neck tumor. In this unusual case, the man showed an anaphylactic response on the first injection. Subsequent tests showed no skin response to bovine material but a response specific to the thymostimulin (Marcos 91). In light of this we would suggest routine skin tests before injection of any thymus extracts as a precautionary measure.

Contraindications

Although none have been reported, all patients with an organ transplant or other forms of allografts (same species, different genetic strain) or xenografts (different species) must be cautious of any agent capable of stimulating a cellular immune response as there is the potential risk of increasing the graft-versus-host response rejection rate of implants. Orthopedic implants, however, may be an exception as the study noted above successfully used a thymus extract to prevent complications of orthopedic implant surgery and reported no increase of implant rejection (Periti 92).

Summary

Thymus extracts have been shown to be of significant therapeutic value using both clinical and laboratory indices. It is important to note that the improvements taking place in several of these experiments were not just palliative improvements. In some studies there were indications of an actual reconstitution of the cellular immune system as indicated by the increase in the numbers of T lymphocytes (Skotnicki 89, Kouttab 89, Hadden 89, Stankiewiez 86), macrophages (Andolina 87) and suppressor cells (Kouttab 89) and a restoration of function of these and other cells as shown by: increased conversion of immature thymocytes to non-dedicated T cells in human bone marrow (Kouttab 89); enhanced proliferation response to concanavalin A (Con A) (Dabrowski 80) and phytohemagglutinin (PHA) (Segatto 86, Poli 86, Vuckovic 92, Marjanska 75); increased E-rosette formation (Macchiarini 89); increased phagocytosis and bactericidal activity of circulating phagocytes (Kartasheva 91, Samsygin 89, Alba 91), increased numbers of macrophages and monocytes (Kouttab 89, Tas 90); decreased carcino-embryonic antigen (CEA) levels in cancer patients (Reinke 85); and a restoration of skin test responsiveness (DTH response) in previously unresponsive patients (Kouttab 89, Lasisz 90, Periti 93, Marjanska 75). Laboratory tests have also confirmed the favorable effects of thymus extracts on humoral immunity as shown by: an increase in the B lymphocytes (Twomey 82) and serum immunoglobulins to normal (Kouttab 89); an increase in depressed salivary IgA levels (Fiocchi 86); and a down regulation of elevated IgE (Kouttab 89, Fiocchi 87, Bagnato 89, Cavagni 89) and eosinophil counts (Kouttab 89, Fiocchi 87).

The positive effects of thymus extracts have even been demonstrated in laboratory tests for autoimmune reactions by reducing rheumatoid factor alpha 2 and serum G globulin levels (Skotnicki 89, Skotnick 86, Lasisz 90) with an accompanying rise in the depressed hemoglobin and serum iron levels as the autoimmune factors decreased (Skotnicki 86). The ability to affect these multifactor autoimmune reactions provides further indications that the regulatory mechanisms modified by thymic extracts are systemic. Their effects do not come from just focal inhibition or stimulation of a single mechanism.

This broad range of laboratory indices taken as a whole indicates that thymus extracts are capable of affecting the immune response at a fundamental level.

One of the most striking features of therapy using thymus extracts is the wide variety of conditions in which these extracts have been successfully employed. They have been used orally and as injectables; by themselves and in combination with other therapeutics. In some instances, they have been the only effective treatment. These extracts have been successfully used clinically to prevent and treat primary and secondary infections (Kartasheva 91, Periti 92), prevent relapses (Kouttab 89) and secondary complications of infections (Kartasheva 91), and to reduce postoperative infection rates(Lai 92). They have also been used to: modulate the deleterious effects of radiotherapy, chemotherapy and surgery (Vuckovic 92, Alba 91, Negri 92); accelerate the rate of wound healing (Skotnicki 89); decrease some of the effects of aging (Czapliki 90, Chung-Kuo 93); improve the efficacy of other treatments (Grigor’ev 89); and as an adjuvant in surgery (Periti 93, Samsygin 89, Periti 92, Lai 92) and treatments using antifungal, antibiotic and antiviral agents (Skotnicki 89, Radomska 87, Czaplicki 89, Ianiushina 92, Gilman 87, Drews 84).

Few medicines can boast effectiveness in treating conditions so diverse as: infections [deep disseminated (Dworniak 91), or focalized (Grismondi 91) of bacterial (Guliamov 91) and viral (Kicka 86, Dworniak 91, Zeman 91, Skotnicki 84) origins]; respiratory diseases [infections (Kouttab 89, Fiocchi 86), non-infections (Stankiewiez 86, Matusiewicz 87, Gieldanowski 81, Smogorzewska 84), acute (Stankiewiez 86) and chronic (Gieldanowski 81, Smogorzewska 84, Frolov 92, Tortorella 92)]; diseases of immunodeficiency (Davies 82, Valesini 87); autoimmunity (Skotnicki 84, Kartasheva 91, Suchkova 90); allergies (Chachoua 89); degenerative skin diseases (Skotnicki 89, Kouttab 89, Pecora 91, Cavagni 89, Kaliuzhnaia 89); as well as neoplasias of the lung (Capelli 92), larynx (Mantovani 92), leukocytes (Skotnicki 89, Martelli 82, Makhonova 91, Drozdova 90, Marjanska 75), breast (Alba 91, Negri 92, Reinke 85, Griffith 88) and of colorectal and gastric origin (Ciconi 92, Urban 77, Cybulski 87). They have also been shown to be of benefit in increasing the survival time of patients with severe or terminal illnesses (Kartasheva 91, Cybulski 87, Samsygin 89, Periti 92).

In some cases these results persisted long after the treatment was discontinued. This indicates that it was effective in changing the natural course of the disease by working at the causative level, i.e. the faulty immune process rather than at the combative (antibiotics) or symptomatic (bronchodilators, etc.) levels. In other cases, the change was seen only while the extracts were being administered, indicating that even though these extracts were not effective at the causal level, they were still able to play a significant role in the therapeutic regimen and, at the least, provide an improvement in the clinical state land general well-being of the patient (Skotnicki 89). The combined results of the many studies on the various thymus extracts, taken as a group, is very encouraging and appears to offer a possible new alternative and/or adjunct to present therapies.

Individually, many of the studies showed design weaknesses. Small N-size plagued most of these studies with as few as 4 subjects in some. In several studies there was no randomization of groups and in a few, no control groups. Only a few of the studies used double-blind trials. Although there is a need for better designed studies, the combined results and the variety of health conditions reported to respond to the thymus extracts tested provide enough material to consider thymus extracts as a potentially promising and useful new area of treatment and research.

In summary, thymus extracts have been shown to be extremely versatile in treating a wide variety of illnesses and clinical conditions ranging from mild to life threatening. They appear to primarily affect the cellular branch of immunity but other areas of influence are probable. Some of the most severe clinical conditions showed the most profound recovery.

Thymus extracts were beneficial in nearly all studies with a degree of efficiency varying from symptomatic relief to curative. The overall clinical impact was extremely positive with no reports of undesirable side effects and only 2 toxicities. The favorable clinical response combined with the lack of side effects or toxicity makes the use of thymus extracts a potential treatment and research option that has yet to be recognized on this continent.

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