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mydreams2005銅蟲(chóng) (小有名氣)
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[求助]
求助胸腺五肽湯姆森藥學(xué)報(bào)告
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| 求助胸腺五肽（thymopentin）湯姆森藥學(xué)報(bào)告，謝謝啦先！ |
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感謝參與，應(yīng)助指數(shù) +1
mydreams2005: 金幣+30, ★★★★★最佳答案 2013-07-17 08:54:54
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無(wú)法上傳，只能粘出來(lái)了 DRUG REPORT SUMMARY Drug name thymopentin Company Not Assigned Highest dev status Launched Therapy areas Atopic dermatitis; Hypoparathyroidism; Herpes simplex virus infection; HIV infection; Ataxia telangiectasia; Rheumatoid arthritis; Respiratory tract infection Actions Immunomodulator; Immunostimulant; Unspecified drug target Technologies Subcutaneous formulation; Intravenous formulation; Intramuscular formulation; Intra-articular formulation; Small molecule therapeutic Target Update date 05-MAR-2010 Reason for update 2 references added [744655, 769144] Top DRUG NAME Names associated with this drug Name Type thymopentin INN 69558-55-0 CAS RN Top DEVELOPMENT STATUS Detailed Status for Not Assigned Therapy Area Country Status Reference Date Ataxia telangiectasia Not assigned Launched - - Atopic dermatitis Not assigned Launched - - Herpes simplex virus infection Not assigned Launched - - HIV infection Not assigned Launched - - Hypoparathyroidism Not assigned Launched - - Respiratory tract infection Not assigned Launched - - Rheumatoid arthritis Not assigned Launched - - Top THERAPEUTIC USE United States Therapeutic uses (Source: DRUGDEX System. MICROMEDEX) Therapeutic category FDA Approvals Efficacy Summary Adult Pediatric Adult Pediatric AIDS no no Evidence is inconclusive - Preliminary data suggest the capability of subcutaneous thymopentin therapy to maintain CD4+ cell counts Further studies are needed to confirm these benefits (Hadden, 1991; Conant et al, 1992). Alopecia areata no no Evidence is inconclusive - Controlled studies of thymopentin in severe alopecia areata are needed to further evaluate its efficacy. Ataxia-telangiectasia syndrome no no Evidence is inconclusive - Approved in Germany for the treatment of DiGeorge syndrome and Louis-Bar syndrome (ataxia telangiectasia). Recommended dose is 0.5 to 1 milligram/kilogram thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. Duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996). Atopic dermatitis no no Evidence is inconclusive - Long-term therapy with thymopentin may be required for optimal effects, and studies evaluating sustained efficacy of chronic administration are needed. Chronic active hepatitis no no Evidence is inconclusive - potential beneficial effects in chronic hepatitis B may be useful as an adjunct to the hepatitis B vaccine DiGeorge sequence no no Evidence is inconclusive - Approved in Germany for the treatment of DiGeorge syndrome and Louis-Bar syndrome (ataxia telangiectasia). Recommended dose is 0.5 to 1 milligram/kilogram thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. Duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996). Febrile neutropenia no no Ineffective - No significant benefit in one small trial Malignant melanoma no no Evidence is inconclusive - Potential for monotherapy or adjunctive therapy in advanced melanoma More studies needed Nephrotic syndrome no no Ineffective - No benefit observed in patients with nephrotic syndrome Postoperative infection no no Ineffective - No significant reduction in the incidence of infection Respiratory tract infection no no Evidence is inconclusive Evidence is inconclusive Improved symptoms and reduced the incidence of recurrent respiratory tract infections in limited controlled studies Confirmation of these results in larger controlled trials is needed Rheumatoid arthritis; Adjunct no no Evidence is inconclusive Evidence is inconclusive Not consistently superior to placebo, with no alteration of immunological indices (CD8+ cells) suggestive of efficacy Potential benefit with joint swelling reduction Sézary's disease (clinical) no no Evidence is inconclusive - Potential benefit limited to one open study Top CHEMISTRY Selected compound Confidence level : 1 View Mol File thymopentin Top CAS RN Names associated with this drug Name Type 69558-55-0 CAS RN Top DRUGDEX OVERVIEW CONTRAINDICATIONS Previous hypersensitivity to thymopentin Pregnancy Do not administer subcutaneously to patients with hyper-IgE syndrome. Patients with platelet counts under 50000/mcL, leukocytes under 3500/mcL, or granulocytes under 1500/mcL Hypersensitivity to alkyl-4-hydroxybenzoates (parabens) Top DOSING INFORMATION DRUG PROPERTIES Information on specific products and dosage forms can be obtained by referring to the Tradename List (Product Index) Synonyms Thymopentin Thymopoietin Pentapeptide STORAGE AND STABILITY Thymopentin solution for injection should be stored between 4 and 6 degrees C (Prod Info Timunox(R), 1996). ADULT DOSAGE Normal Dosage Intra-articular route In rheumatoid arthritis patients, thymopentin has been given intra-articularly (knee joints) in doses of 50 milligrams once weekly for 4 weeks (Sundal & Bertelletti, 1994a). Intramuscular route Following primary chemotherapy, treatment with thymopentin 50 milligrams/day intramuscularly for 2 weeks, followed by 50 milligrams 3 times a week for 3 doses, has been attempted in OVARIAN CARCINOMA patients (Heine et al, 1991). However, it was not associated with improvements in clinical course or survival time. The recommended dose for the treatment of DIGEORGE SYNDROME or LOUIS-BAR SYNDROME (ATAXIA TELANGIECTASIA) is 0.5 to 1 milligram/kilogram/day thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. The duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996a). Intravenous route For intravenous administration, 0.5 milliliter of a 100-milligram/milliliter solution of thymopentin (50 milligrams) has been diluted in normal saline to a volume of 10 milliliters and given as a slow injection over 10 minutes (Malaise et al, 1985b; Kantharia et al, 1989b). In RHEUMATOID ARTHRITIS, usual doses of thymopentin in clinical studies have been 50 milligrams intravenously three times per week. The duration of therapy has usually not exceeded 3 weeks (range, 3 to 6 weeks) (Malaise et al, 1985b; Sundal & Bertelletti, 1994a; Kantharia et al, 1989b). Thymopentin in intravenous doses of 50 milligrams three times weekly for 3 weeks has also been used in the treatment of severe ALOPECIA AREATA (Tosti et al, 1988a). Subcutaneous route Subcutaneous thymopentin 50 milligrams three times weekly for a duration of 6 weeks has been administered for the prophylaxis and treatment of recurrent RESPIRATORY TRACT INFECTION (Sundal, 1993b) and treatment of recurrent herpes labialis (Bolla et al, 1985) and HERPES ZOSTER infection (Lomuto et al, 1988a). In asymptomatic HUMAN IMMUNODEFICIENCY VIRUS INFECTION, 50 milligrams subcutaneously three times weekly for up to 52 weeks has been given in an effort to slow progression of the disease (Conant et al, 1992b). For treatment of ATOPIC DERMATITIS in adults, subcutaneous doses of 50 milligrams once daily for 6 weeks have been employed (Leung et al, 1990b). Combination therapy with chemotherapy and immunotherapy with thymopentin 50 milligrams/day for 2 weeks, followed by 50 milligrams 3 times a week, has been used in the treatment of BREAST CANCER and OVARIAN CANCER (Mallmann & Krebs, 1991; Mallmann & Krebs, 1990). It is suggested that thymopentin may reduce the immunosuppressive side effects of antineoplastic agents. In a small study, thymopentin 100 milligrams subcutaneously 1 to 3 times weekly for 11 to 289 weeks had some beneficial effects in the treatment of chronic hepatitis B (Tokus et al, 1995). The recommended dose for the treatment of DiGeorge syndrome or Louis-Bar syndrome (ataxia telangiectasia) is 0.5 to 1 milligram/kilogram/day thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. The duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996a). PEDIATRIC DOSAGE Normal Dosage Intra-articular route In children with monoarticular-onset JUVENILE CHRONIC ARTHRITIS (monoarthritis of the knee), thymopentin has been administered intraarticularly in doses of 1 milligram/kilogram weekly for 10 weeks (Bardare et al, 1990). Intravenous route Intravenous doses of thymopentin 1 milligram/kilogram three times weekly for the first 3 weeks, then once weekly for 3 subsequent weeks, have been given to children with systemic-onset juvenile chronic arthritis. In responding patients, the drug was continued as maintenance therapy in doses of 1 milligram/kilogram every 2 weeks for up to 34 months (Bardare et al, 1990). The dose of thymopentin was diluted with normal saline to a 10-milliliter volume and injected over a period of 10 minutes. Subcutaneous route Thymopentin 1 milligram/kilogram subcutaneously for 3 consecutive days, then twice weekly for 5 weeks, has been used in the treatment of recurrent RESPIRATORY TRACT INFECTIONS in children (1 to 12 years of age) (Sundal, 1993b). For treatment of ATOPIC DERMATITIS in children (over 2 years of age), subcutaneous doses of 50 milligrams once daily or three times weekly for 6 weeks have been employed (Hsieh et al, 1992a; Leung et al, 1990b). Top PHARMACOKINETICS ONSET AND DURATION Duration Multiple Dose Rheumatoid arthritis, subcutaneous: 4 to 7 weeks (Sundal & Bertelletti, 1994; Kantharia et al, 1989a; Malaise et al, 1985). Clinical benefits of thymopentin generally subside, with a tendency toward relapse 4 to 7 weeks after discontinuation of treatment (Sundal & Bertelletti, 1994; Kantharia et al, 1989a; Malaise et al, 1985). Respiratory infections, subcutaneous: 2 to 6 months (Sundal, 1993). Clinical benefit in patients with recurrent respiratory tract infection have persisted for 2 to 6 months after discontinuation of subcutaneous thymopentin therapy (three times weekly) (Sundal, 1993). Recurrent herpes labialis, subcutaneous: 17 weeks (Bolla et al, 1985a). In patients with recurrent herpes labialis, patients have remained symptom-free for an average of 17 weeks after discontinuation of thymopentin (6-week course of subcutaneous therapy), which was about three times longer than observed in a placebo group (Bolla et al, 1985a). Atopic dermatitis, subcutaneous: 4 weeks (Leung et al, 1990). A trend toward clinical relapse has been observed 4 weeks after discontinuation of subcutaneous thymopentin therapy (daily for 6 weeks) in patients with atopic dermatitis (Leung et al, 1990). ADME Absorption Bioavailability Oral, not absorbed (Friedmann, 1985a). Metabolism Metabolism Sites and Kinetics Plasma, extensive (Kantharia et al, 1989a; Lomuto et al, 1988; Malaise et al, 1985aa). Thymopentin is degraded to amino acids in plasma via the action of proteolytic enzymes, including serine protease and aminopeptidase (Kantharia et al, 1989a; Lomuto et al, 1988; Malaise et al, 1985aa). Elimination Half-life Parent Compound ELIMINATION HALF-LIFE approximately 30 seconds (Sundal & Bertelletti, 1994; Sundal, 1993; Bodini et al, 1991; Todisco et al, 1988; Malaise et al, 1985aa). Plasma elimination half-life of approximately 30 seconds; however, changes in cellular processes have persisted for several days after intravenous doses (Sundal & Bertelletti, 1994; Sundal, 1993; Bodini et al, 1991; Todisco et al, 1988; Malaise et al, 1985aa). Top CAUTIONS CONTRAINDICATIONS Previous hypersensitivity to thymopentin Pregnancy Do not administer subcutaneously to patients with hyper-IgE syndrome. Patients with platelet counts under 50000/mcL, leukocytes under 3500/mcL, or granulocytes under 1500/mcL Hypersensitivity to alkyl-4-hydroxybenzoates (parabens) PRECAUTIONS Concurrent or recent prior use of other immunomodulating agents Liver disease Diabetes mellitus (thymopentin may alter insulin requirements) ADVERSE REACTIONS Cardiovascular Effects Cardiovascular finding TACHYCARDIA and slight decreases in blood pressure have been reported occasionally after intravenous thymopentin (Bernengo et al, 1992). Data compiled by the manufacturer indicate that cardiorespiratory effects have occurred in 10 to 20% of patients treated with thymopentin (Weiss & Stocker, 1985; Friedmann, 1985); however, specific types of effects were not presented. An acute MYOCARDIAL INFARCTION occurred in one elderly patient following subcutaneous thymopentin therapy for 5 weeks (Friedmann, 1985), although a cause-effect relationship is doubtful. Dermatologic Effects Dermatological finding PRURITUS and mild RASH (primarily localized to the intravenous or subcutaneous injection site) have been observed in some patients treated with thymopentin (Fattovich et al, 1994a; Weiss & Stocker, 1985; Sundal, 1993a; Malaise et al, 1985a). URTICARIAL REACTIONS and PERIORBITAL EDEMA have occurred occasionally; they were either transient or treatable with antihistamines and/or corticosteroids (Prod Info Timunox(R), 1996). Pain and/or swelling at the subcutaneous injection site has also occurred occasionally (DeMaubeuge et al, 1985; Leung et al, 1990a; Sundal, 1993a). FLUSHING has been reported after intravenous thymopentin in some studies (Kantharia et al, 1989; Bernengo et al, 1992). Data compiled by the manufacturer indicate that dermatologic adverse effects have occurred in 13% to 19% of patients treated with thymopentin (Weiss & Stocker, 1985; Friedmann, 1985); however, specific types of effects were not presented. Gastrointestinal Effects Gastrointestinal tract finding NAUSEA, DYSPEPSIA, ABDOMINAL PAIN, and MOUTH ULCERS have been reported occasionally (usually less than 10% of patients) after parenteral thymopentin in published studies (Franchimont et al, 1985a; Malaise et al, 1985a; Kantharia et al, 1989; Giordano et al, 1991a; Fattovich et al, 1994a). VOMITING has been rare (Malaise et al, 1985a). Data compiled by the manufacturer indicate that gastrointestinal effects have occurred in 19% to 27% of patients treated with thymopentin (Weiss & Stocker, 1985; Friedmann, 1985); however, specific types of gastrointestinal effects were not presented. Hematologic Effects Hematology finding Slight reductions in neutrophil counts, red blood cell counts, hemoglobin, and hematocrit, occasionally reaching statistical significance, have been observed during thymopentin therapy (Weiss & Stocker, 1985; Franchimont et al, 1985a; Friedmann, 1985). However, these changes do not appear clinically relevant, and in many cases a relationship with thymopentin is questionable. LEUKOPENIA has been reported in a few cases (Prod Info Timunox(R), 1996). Hepatic Effects Hepatotoxicity Transient elevations in serum transaminases, bilirubin, and alkaline phosphatase have been observed after parenteral thymopentin administration (Weiss & Stocker, 1985; Friedmann, 1985). The relationship to thymopentin as well as clinical significance of these changes is questionable in most patients. Neurologic Effects Central nervous system finding HYPERSOMNIA is a prevalent adverse effect following thymopentin injections, occurring in up to 50% of patients in clinical studies (Malaise et al, 1985a; Malaise et al, 1985a; Weiss & Stocker, 1985). This effect has been persistent in some patients during the first 2 weeks of treatment. Other less frequent central nervous system effects associated with the drug are DROWSINESS, HEADACHE, ASTHENIA, giddiness, and DYSESTHESIA (Weiss & Stocker, 1985; Kantharia et al, 1989; DeMaubeuge et al, 1985; Fattovich et al, 1994a). Data compiled by the manufacturer indicate that central nervous system effects have occurred in 15 to 30% of patients treated with thymopentin (Weiss & Stocker, 1985; Friedmann, 1985); however, specific types of effects were not presented. Renal Effects Urogenital finding Heavier-than-usual menstrual flow has been reported in some women treated with parenteral thymopentin (Malaise et al, 1985a; Weiss & Stocker, 1985; Malaise et al, 1985a). Respiratory Effects Respiratory finding In one study, respiratory CONGESTION was significantly more frequent with thymopentin than with placebo in asymptomatic patients with human immunodeficiency virus infection (Conant et al, 1992a). Other Adverse reaction to drug, General Two reports from the manufacturers of thymopentin (based upon data from unpublished or published clinical trials) indicate that the most frequent adverse effects of this agent are cardiorespiratory in nature (10% to 20% of patients) or involve the central nervous system (15% to 30% of patients), gastrointestinal tract (19% to 27%), or skin (13% to 19%) (Weiss & Stocker, 1985; Friedmann, 1985). Similar incidences with placebo were cited by one team of investigators (Weiss & Stocker, 1985). However, details of specific studies were not presented. Top CLINICAL APPLICATIONS MONITORING PARAMETERS Therapeutic Laboratory Parameters Immunologic parameters for selected patients and/or those specific and appropriate to a particular condition (eg, lymphocyte phenotypes (CD3, CD4, CD8), immunoglobulins, immune complexes, skin tests for delayed-type hypersensitivity). Changes in immune parameters have not correlated consistently or at all with clinical efficacy in adult patients with rheumatoid arthritis (Malaise et al, 1985a; Kantharia et al, 1989) or recurrent respiratory infections (Sundal, 1993a). In children with systemic-onset juvenile chronic arthritis, a decrease in the CD4+/CD8+ ratio paralleled clinical effects in one study (Bardare et al, 1990a). In asymptomatic patients with human immunodeficiency virus (HIV) infection, percentages of CD4+ cells have been higher in those treated with thymopentin compared to placebo. A tendency for decreases in CD8+ cells was seen with thymopentin. These effects were not evident in symptomatic patients (Conant et al, 1992a). Other laboratory tests appropriate for condition being treated (eg, complete blood count with differential and p24 antigen in asymptomatic HIV-infected patients). Physical Findings Clinical improvement of condition being treated Toxic Laboratory Parameters Complete blood counts periodically during therapy Routine blood chemistry periodically during therapy (including blood glucose) Thymopentin has reduced insulin requirements in insulin-dependent diabetes (DeMaubeuge et al, 1985) Physical Findings Temperature, blood pressure, and pulse after each intravenous injection Evidence of thymopentin-related toxicity (eg, prolonged episodes of sleep, persistent nausea) PLACE IN THERAPY SUMMARY Thymopentin has shown efficacy in several conditions associated with altered immune function, although additional studies confirming its usefulness are needed. The role of the drug will most likely be adjunctive, or as an alternative in refractory patients. Studies designed to optimize dose and dose scheduling of thymopentin are needed. Thymopentin has demonstrated a variable degree of clinical usefulness in several disorders associated with altered immune function, including asymptomatic human immunodeficiency virus (HIV) infection, severe atopic dermatitis, recurrent respiratory tract infection (elderly), rheumatoid arthritis, herpes simplex infection, Sezary syndrome, progressive systemic sclerosis, and myelodysplastic syndromes. However, evaluation of the true efficacy of this agent in these indications and others is limited. In hemodialysis patients, evidence suggests that the ability of thymopentin to augment responses to hepatitis B vaccine may be related to proper sequencing of administration. The relationship between timing of these agents and efficacy requires further study. The place in therapy of thymopentin will likely be as an adjunct to other regimens and as an alternative treatment in patients unresponsive to, or intolerant of, other modalities. However, it cannot be recommended for formularies until additional efficacy studies are completed. Cost will be a factor governing the use of thymopentin for all indications, especially with a dose regimen of three times weekly and if clear-cut benefits on morbidity and mortality in certain conditions are not realized. Thymopentin is approved for the treatment of DiGeorge Syndrome and Louis-Bar Syndrome (ataxia telangiectasia) in Germany. MECHANISM OF ACTION / PHARMACOLOGY PHARMACOLOGY Immunoregulatory actions of thymopentin on peripheral T-lymphocytes appear to be mediated by elevations in intracellular cyclic guanosine-3',5'-monophosphate (cyclic GMP) (Faist et al, 1988; Sundal & Bertelletti, 1994). Thymopentin is the active pentapeptide moiety of thymopoietin, a thymic hormone secreted by thymic epithelial cells with immunomodulatory activity (Leung et al, 1990; Hsieh et al, 1992; Hadden, 1991). Structurally, thymopentin consists of 5 amino acid residues--L-arginine, L-lysine, L-asparagine, L-valine, and L-tyrosine--corresponding to amino acids 32 to 36 of the 49-amino acid sequence of natural thymopoietin; the biological activity of thymopoietin resides in this amino acid segment, and the activity of thymopentin has mimicked that of the parent molecule in numerous in vitro systems (Hsieh et al, 1992; Sundal & Bertelletti, 1994; Sundal, 1993; Giordano et al, 1991). Similar to thymopoietin, thymopentin has been demonstrated in vitro and in animal models to promote differentiation of thymocytes; inhibit differentiation of B-lymphocytes (by blocking plasma-cell surface antigen acquisition); stimulate multiplication, maturation, and differentiation of T-lymphocytes; and promote reconstitution of immune defects (Faist et al, 1988; Lomuto et al, 1988; Fattovich et al, 1994; Beyer et al, 1990; Thivolet et al, 1983; Salvati & Riario-Sforza, 1990). Suppression of interleukin-4 production and enhanced production of interleukin-2 and gamma-interferon have been reported (Hsieh et al, 1992; Dumann et al, 1990; Lomuto et al, 1988; Leung et al, 1990). Studies in patients with respiratory tract infections have indicated the ability of thymopentin to increase CD4+ cells, decrease CD8+ cells, and produce slight improvement of the CD4/CD8 ratio (Sundal et al, 1993)(Todisco et al, 1988). In asymptomatic patients with human immunodeficiency virus (HIV) infection, chronic therapy with subcutaneous thymopentin has maintained CD4+ cells compared to placebo (Conant et al, 1992). Uremic patients have responded to thymopentin with significant increases in the T-helper fraction, erythrocyte and hemoglobin levels, and platelet counts (Salvati & Riario-Sforza, 1990). Although thymopentin has a plasma half-life of less than one minute, it tends to induce relatively long-lasting changes in cellular processes, particularly T-cells, up to 5 days after intravenous doses (Franchimont et al, 1985; Sundal & Bertelletti, 1994). Clinical benefit after discontinuation of therapy has persisted for weeks or months in several conditions (Sundal, 1993; Malaise et al, 1985; Leung et al, 1990; Sundal & Bertelletti, 1994). This effect appears to be related to activation of a poorly-defined biological sequence which does not require persistent high levels of the drug; an influence on immature lymphocytes has been suggested to play a role. The ability of thymopentin to elicit persistent effects after withdrawal of therapy has been labeled (and attributed to) "immunoreconstruction" (Sundal, 1993). There is evidence that T4 cells are more sensitive to stimulation by thymopentin than are T8 cells, with higher concentrations of the hormone being required to stimulate suppressor cells also. The subcutaneous route (with low bioavailability) appears to preferentially stimulate T-cell helper mechanisms, and has been advocated for patients with defective T-helper mechanisms (eg, primary immune deficiencies, chronic herpes simplex); the intravenous route has been shown to additionally stimulate the T-suppressor subpopulation and is recommended by some investigators in diseases which may be related to insufficient T-suppressor activity (eg, rheumatoid arthritis, progressive systemic sclerosis) (Giordano et al, 1991; Sundal & Bertelletti, 1994; Sundal, 1993; Tosti et al, 1988). However, further confirmatory studies are needed to support the significance of these differences. REVIEW ARTICLES A review of studies evaluating the efficacy of thymopentin in rheumatoid arthritis is presented (Sundal & Bertelletti, 1994). THERAPEUTIC USES AIDS Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Preliminary data suggest the capability of subcutaneous thymopentin therapy to maintain CD4+ cell counts Further studies are needed to confirm these benefits (Hadden, 1991; Conant et al, 1992). Adult: In one double-blind study (n=91), subcutaneous thymopentin 50 milligrams three times weekly for 24 weeks maintained percentages of CD4+ cells at a significantly higher level than with placebo in asymptomatic HIV-infected patients; a shorter median time to a 20% increase in the percentage of CD4+ cells was also observed with thymopentin during this time. These trends favoring thymopentin were similar during treatment for 52 weeks, although statistical significance was not achieved. A trend toward improvement of the CD4/CD8 ratio was also reported with thymopentin, and this reached significance at 24 weeks. Constitutional symptoms developed in several asymptomatic patients treated with placebo but in none receiving thymopentin in the 52-week study (not a significant difference); however, numbers of initially asymptomatic patients developing candidiasis, oral hairy leukoplakia, or herpes zoster were similar in each group. In the subset of symptomatic patients in this study (n=39), disease progression and levels of CD4+ cells remained similar in the placebo and thymopentin groups throughout 52 weeks of treatment; two patients in each group progressed to acquired immunodeficiency syndrome (AIDS) during the study (Conant et al, 1992b). Although these data suggest potential benefits of thymopentin in asymptomatic patients with HIV, a larger trial is needed. The combination of thymopentin plus zidovudine in asymptomatic patients and those with AIDS deserves investigation. Alopecia areata Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Controlled studies of thymopentin in severe alopecia areata are needed to further evaluate its efficacy. Adult: Intravenous thymopentin was ineffective in promoting hair regrowth in patients with alopecia totalis or universalis who were unresponsive to previous sensitizing therapy (squaric acid dibutylester or diphencyprone). Topical cyclosporine 10% and photochemotherapy (PUVA) also failed to benefit these patients (Tosti et al, 1991). One uncontrolled trial (n=20) suggested the efficacy of intravenous thymopentin (50 milligrams three times weekly for 3 weeks) in treatment of severe alopecia areata. Complete hair regrowth was observed in 42% of patients with alopecia areata involving greater than 50% of the scalp and in 25% of those with ALOPECIA TOTALIS or universalis; regrowth was not evident until 1 to 5 months after initiation of therapy (Tosti et al, 1988a). Ataxia-telangiectasia syndrome Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Approved in Germany for the treatment of DiGeorge syndrome and Louis-Bar syndrome (ataxia telangiectasia). Recommended dose is 0.5 to 1 milligram/kilogram thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. Duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996). Atopic dermatitis Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Long-term therapy with thymopentin may be required for optimal effects, and studies evaluating sustained efficacy of chronic administration are needed. Adult: Administration of subcutaneous thymopentin for durations of at least 6 weeks may provide clinical benefit to patients with atopic dermatitis. Elevated T-lymphocyte activation, B-cell immunoglobulin E overproduction, hyperstimulatory Langerhans cells, and defective cell- mediated immunity appear to be involved in the pathogenesis of atopic dermatitis, and treatment of these patients with thymopentin has been investigated as a means of normalizing imbalanced immune responsiveness (Cooper, 1994). One 6-week, double-blind study (n=100) reported the modest superiority of thymopentin 50 milligrams subcutaneously once daily over placebo in adults and children with moderate-to-severe atopic dermatitis. Both placebo and thymopentin significantly reduced total severity scores throughout the study, with reductions being significantly greater with thymopentin only at week 6; at this time, thymopentin was superior to placebo with regard to reductions in pruritus and erythema but not edema/papulations, scaling, dryness, or excoriations. Patients tended to relapse 4 weeks after discontinuance of thymopentin (Leung et al, 1990b). A smaller open study (n=16) of 12 weeks' duration also suggested the superiority of subcutaneous thymopentin (50 milligrams 3 times weekly) over placebo in children with severe atopic dermatitis. In vitro studies indicated the tendency of thymopentin to suppress production of interleukin-4 and to increase production of interferon-gamma (Hsieh et al, 1992a). Chronic active hepatitis Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: potential beneficial effects in chronic hepatitis B may be useful as an adjunct to the hepatitis B vaccine Adult: A 6-month course of subcutaneous thymopentin (50 milligrams daily for 1 month, then every other day for 5 months) was ineffective in the treatment of chronic HEPATITIS B in one controlled study (n=30) (Fattovich et al, 1994b). In a small study (n=8), thymopentin 100 milligrams subcutaneously 1 to 3 times weekly for 11 to 289 weeks had some beneficial effects in the treatment of chronic HEPATITIS B (Tokus et al, 1995). AST (aspartate transaminase) normalized in 7 patients within 8 to 22 weeks, while ALT (alanine transaminase), GGT (gamma-glutamyl transpeptidase), and alkaline phosphatase improved significantly, and the viral replication markers, HBe-Ag and HBV-DNA, seroconverted. Liver biopsies demonstrated reversal of inflammation and cell necrosis. Hepatitis reactivated in 4 patients after discontinuation or dose reduction, but transaminases improved and the viral replication markers seroconverted within 7 to 19 weeks. Uremic patients are highly susceptible to hepatitis B virus infection. Hepatitis B vaccination is frequently ineffective in producing seroconversion in these patients, which may be due to uremia- associated impairment of the immune system (eg, decrease in T- lymphocytes and natural killer cells; altered T-helper/T-suppressor ratio). Although 95% of healthy subjects develop hepatitis B surface antigen antibodies after hepatitis B vaccine, this occurs in only 60 to 70% of dialysis patients (Dumann et al, 1990a; Donati & Gastaldi, 1988; Melappioni et al, 1992). Due to its immunostimulatory potential, subcutaneous thymopentin has been investigated as an adjuvant to hepatitis B vaccine and influenza vaccine in hemodialysis patients who were either previous nonresponders to the vaccine or had not been vaccinated previously. This has achieved mixed results, due to timing or dose of thymopentin administration. Improved seroconversion rates were observed when thymopentin was administered for at least 2 weeks following vaccination (with or without pretherapy prior to vaccination); whereas schedules involving pretreatment for 1 to 3 weeks prior to vaccination and two or three doses postvaccination (over one week), with or without inclusion of a thymopentin dose simultaneously with the vaccine, have not produced beneficial results. Administration of only one adjuvant dose of thymopentin simultaneously with the vaccine has been shown to actually inhibit the antibody response (Melappioni et al, 1992; Dumann et al, 1990a; Donati & Gastaldi, 1988; Grob et al, 1985). Specific regimens that have been successful are the following: (a) thymopentin 50 milligrams subcutaneously 3 times weekly for 3 consecutive weeks, with hepatitis B vaccine administered after one week of pretreatment (concurrently with the fourth thymopentin injection) (Grob et al, 1985); (b) three doses of hepatitis B vaccine at monthly intervals, with 12 doses of subcutaneous thymopentin on alternate days between the first and second vaccination (Donati & Gastaldi, 1988). In the latter study, 86% of thymopentin-treated patients were seropositive at both one and six months of follow-up, compared to 30% to 50% of those receiving hepatitis B vaccine alone. DiGeorge sequence Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Approved in Germany for the treatment of DiGeorge syndrome and Louis-Bar syndrome (ataxia telangiectasia). Recommended dose is 0.5 to 1 milligram/kilogram thymopentin intramuscularly or subcutaneously for 2 weeks, followed by 0.5 to 1 milligram/kilogram 2 to 3 times weekly. Duration of therapy should be based on the patient's clinical status and response (Prod Info Timunox(R), 1996). Febrile neutropenia Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Ineffective Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: No significant benefit in one small trial Adult: The addition of thymopentin to granulocyte-colony stimulating factor (G-CSF) in the treatment of chemotherapy-related febrile leukopenia has not demonstrated a notable benefit. In a placebo-controlled trial of 100 patients, G-CSF plus thymopentin was given to 22 patients. The incidence of febrile episodes decreased from 22% to 18% with the addition of thymopentin, but this was not statistically significant. Of patients receiving G-CSF alone, 22% had a febrile event, compared with 52% of patients receiving thymopentin alone, and 64% receiving placebo (Gebbia et al, 1994). Malignant melanoma Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Potential for monotherapy or adjunctive therapy in advanced melanoma More studies needed Adult: High-dose intravenous therapy with thymopentin (TP5) in a small group of 16 patients with cutaneous or subcutaneous melanoma metastases brought a response rate of 37.5% after the first of two courses with no side effects (Cascinelli et al, 1998). Lymphoid infiltrates showed a prevalence of CD45RO+, CD4+, and CD8+ lymphocytes after treatment. Patients responding to intravenous TP5 1 gram every other day for 7 weeks were given a second course of TP5 2 grams every other day for 5 weeks. Two of the 6 responders had prior chemotherapy. After the second course at 2 grams, one patient achieved a complete response and the other five remained in partial response. The median duration of response after the second course was 7.5 months, and all responding patients remained alive after a median 9 months of follow-up from start of treatment. All non-responding patients died. Nephrotic syndrome Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Ineffective Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: No benefit observed in patients with nephrotic syndrome Adult: A preliminary study reported no benefit of subcutaneous thymopentin (50 milligrams three times weekly for 3 weeks) on relapse rates in adult patients with relapsing minimal-change nephrotic syndrome. Thymopentin also did not appear to influence lymphocyte subsets or function in these patients (Cheng & Jones, 1993). Postoperative infection Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Ineffective Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: No significant reduction in the incidence of infection Adult: Perioperative thymopentin was not associated with a significant decrease in postoperative infection in a placebo-controlled study of 206 patients with gastric or colorectal cancer. However, notable postoperative decreases in CD3- and CD4-positive T cells were observed in elderly patients. Differences in postoperative T cell subpopulations were not observed among young patients in receiving either active or placebo treatment (Braga et al, 1994). Respiratory tract infection Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive Recommendation: Adult, Class III; Pediatric, Class III Strength of Evidence: Adult, Category B; Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Improved symptoms and reduced the incidence of recurrent respiratory tract infections in limited controlled studies Confirmation of these results in larger controlled trials is needed Adult: Several studies, mostly uncontrolled, have reported the efficacy of subcutaneous thymopentin (usual doses of 50 milligrams 3 times weekly for 6 weeks) in the prophylaxis and treatment of respiratory tract infections, predominantly CHRONIC BRONCHITIS in elderly patients. In placebo-controlled studies, thymopentin has produced significant improvement in overall "general clinical condition" and trends toward or significant reductions in bronchial secretions, number of recurrences of infection, and reduction in cough; these clinical benefits were maintained for prolonged periods (2 to 6 months) after discontinuation of treatment. However, no significant effect of the drug on blood-gas exchange or spirometry were observed (Sundal, 1993b). Some studies have reported trends toward beneficial immunologic changes during thymopentin therapy (ie, increases in CD4+ cells, decreases in CD8+ cells, slight improvement of the CD4/CD8 ratio), whereas no changes in these parameters were seen in others (Sundal, 1993b; Todisco et al, 1988a). Pediatric: Thymopentin 1 milligram/kilogram subcutaneously for 3 consecutive days then twice weekly for 5 weeks was efficacious in reducing the frequency of recurrent respiratory tract infections in children (1 to 12 years of age) in one open study (Sundal, 1993b). Rheumatoid arthritis; Adjunct Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive; Pediatric, Evidence is inconclusive Recommendation: Adult, Class III; Pediatric, Class III Strength of Evidence: Adult, Category B; Pediatric, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Not consistently superior to placebo, with no alteration of immunological indices (CD8+ cells) suggestive of efficacy Potential benefit with joint swelling reduction Adult: Open (Bodini et al, 1991a; Franchimont et al, 1985b) and controlled (Malaise et al, 1985b; Sundal & Bertelletti, 1994a; Kantharia et al, 1989b) studies have provided evidence of the short-term efficacy of intravenous thymopentin (50 milligrams three times weekly) in the treatment of adult rheumatoid arthritis. In controlled studies, improvement during thymopentin therapy was not always statistically significant in comparison with placebo; consistently better responses have been observed with thymopentin for swollen joint scores, whereas improvements in joint pain on motion, joint pain at rest, grip strength, overall pain, and morning stiffness were variable. One placebo-controlled study (Kantharia et al, 1989b) reported no effect whatsoever of thymopentin relative to placebo on morning stiffness, grip strength, patient assessment of pain, or overall disease activity. In patients showing improvement on thymopentin, clinical benefits generally subside, with a tendency toward relapse 4 to 7 weeks after discontinuation of treatment (Malaise et al, 1985b; Kantharia et al, 1989b). No significant correlation between clinical effects and changes in hematological or immunological indices (CD4+ and CD8+ cells, immunoglobulins) have been reported in uncontrolled or controlled studies of intravenous thymopentin in adult patients (Bodini et al, 1991a; Franchimont et al, 1985b; Malaise et al, 1985b; Sundal & Bertelletti, 1994a; Kantharia et al, 1989b). The duration of thymopentin therapy in most studies has been three weeks (range, 3 to 6 weeks), and patient populations have been small. Larger controlled studies of longer duration are needed to confirm the efficacy of this agent in rheumatoid arthritis. A more practical alternative to multiple weekly intravenous doses of thymopentin will be required if the drug is ultimately to gain acceptance in this disorder. The use of high subcutaneous doses once weekly should be evaluated. Further exploration of "maintenance" doses is also needed; intravenous dosing every 2 weeks was beneficial in juvenile chronic arthritis in one study (Bardare et al, 1990), although this requires confirmation in a controlled study. One small uncontrolled study has suggested the efficacy of INTRAARTICULAR thymopentin (50 milligrams once weekly) in the treatment of adult rheumatoid arthritis; increases in CD8+ cells (mainly T- suppressor cells) and total CD4+ counts were observed in responding patients (Sundal & Bertelletti, 1994a). Further investigation of this route of administration is needed. Pediatric: Prolonged therapy with intravenous thymopentin was reported to improve morning stiffness and systemic features of systemic-onset juvenile chronic arthritis significantly in a small open study (Bardare et al, 1990). Thymopentin was given in doses of 1 milligram/kilogram one to three times weekly for the first 6 weeks, followed by maintenance therapy with the same dose every 2 weeks for up to 34 weeks. A reduction in fever, lymph node/liver/spleen size, and erythrocyte sedimentation rate was observed during long-term treatment; the CD4+/CD8+ ratio also decreased progressively from the third week onward, related to an increase in CD8+ cells. In three other children with monoarticular-onset juvenile chronic arthritis (monarthritis of the knee) in this study, intra-articular thymopentin 1 milligram/kilogram weekly was associated with a decrease in synovial CD4+ cells and a slight decrease in synovial CD8+ cells; peripheral blood lymphocyte populations were unaltered. In both systemic-onset patients and those with monarthritis, thymopentin had no significant effect on joint disability. Sézary's disease (clinical) Overview FDA Approval: Adult, no; Pediatric, no Efficacy: Adult, Evidence is inconclusive Recommendation: Adult, Class III Strength of Evidence: Adult, Category B See Drug Consult reference: RECOMMENDATION AND EVIDENCE RATINGS Summary: Potential benefit limited to one open study Adult: Thymopentin 50 milligrams subcutaneously three times weekly (mean, 16 months) was associated with complete or partial remission in 75% of patients with Sezary syndrome (a cutaneous T-cell lymphoma) in a preliminary open study; median response duration was 22 months, and the 4-year survival probability was 54%. Clinical benefit was accompanied by significant increases in CD8+ cells and a reduction in CD4+ cells; natural killer cells increased progressively during treatment, and this increase was related to longer survival (Bernengo et al, 1992a). A controlled study is required to confirm the efficacy of thymopentin in Sezary syndrome. |
2樓2013-07-17 08:35:00
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