MD596Z - Method for treating chronic viral hepatitis C in children - Google Patents
Method for treating chronic viral hepatitis C in children Download PDFInfo
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- MD596Z MD596Z MDS20120138A MDS20120138A MD596Z MD 596 Z MD596 Z MD 596Z MD S20120138 A MDS20120138 A MD S20120138A MD S20120138 A MDS20120138 A MD S20120138A MD 596 Z MD596 Z MD 596Z
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Abstract
Description
Invenţia se referă la medicină, în particular la hepatologie, şi poate fi utilizată pentru tratamentul hepatitei virale cronice C (HVC C) la copii. The invention relates to medicine, in particular to hepatology, and can be used for the treatment of chronic viral hepatitis C (HCV C) in children.
Este cunoscută metoda de tratament al HVC C la copii, care include în caz de acutizare, spitalizarea pacientului cu respectarea regimului igieno-dietetic (regim de salon, dieta nr. 5 după Pevzner), tratamentul hepatoprotector (silimarină, fosfolipide esenţiale, legalon, acid ursodezoxiholic), terapia de dezintoxicare la indicaţii clinice (administrarea i/v a soluţiilor fiziologice, de glucoză, hepasolului etc.) şi de corecţie a proceselor metabolice (vitaminele grupelor C, B1, B6, B12) [1]. The method of treatment of HCV C in children is known, which includes, in case of exacerbation, hospitalization of the patient with observance of the hygienic-dietary regime (parlor regime, diet no. 5 according to Pevzner), hepatoprotective treatment (silymarin, essential phospholipids, legalon, ursodeoxycholic acid), detoxification therapy according to clinical indications (i/v administration of physiological solutions, glucose, hepasol, etc.) and correction of metabolic processes (vitamins of groups C, B1, B6, B12) [1].
În faza de replicare a virusului hepatitei C (VHC) se recomandă tratamentul antiviral cu administrarea interferonului alfa 2α şi β de tip standard sau pegilat cu acţiune imunomodulatoare şi antivirală în combinaţie cu ribavirin pe o durată de 12 luni. Însă o parte din aceste remedii sunt foarte costisitoare şi provoacă dezvoltarea reacţiilor adverse, ceea ce limitează aplicarea lor în practică pentru majoritatea pacienţilor, mai ales a celor de vârstă mică [Guidelines for chidren, American Association for Liver Deseases (AASLD), 2004]. In the replication phase of hepatitis C virus (HCV), antiviral treatment with standard or pegylated interferon alpha 2α and β with immunomodulatory and antiviral action in combination with ribavirin for a period of 12 months is recommended. However, some of these remedies are very expensive and cause the development of adverse reactions, which limits their application in practice for most patients, especially young ones [Guidelines for chidren, American Association for Liver Diseases (AASLD), 2004].
La fel este cunoscută metoda de tratament al HVC C care include administrarea concomitentă a interferonului, nucleinatului de sodiu şi lamivudinei [2]. The treatment method for HCV C is also known, which includes the concomitant administration of interferon, sodium nucleinate, and lamivudine [2].
O altă metodă de tratament recomandată constă în utilizarea în tratamentul hepatitei virale C a terapiei simptomatice şi a unui remediu imunomodulator şi antiviral 5α-furostan-3β,22,26-triol-3- [O-β-D-glucopiranozil(1→2)-β-D-glucopiranozil(1→4)-β-D-galactopiranozil]-26-O-β-D-glucopiranozil (pacovirină), administrat timp de 6 luni, începând cu prima zi de manifestări clinice, în doză de 50 mg, o dată pe zi, per os [3]. Another recommended treatment method consists of using symptomatic therapy and an immunomodulatory and antiviral remedy 5α-furostane-3β,22,26-triol-3- [O-β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl(1→4)-β-D-galactopyranosyl]-26-O-β-D-glucopyranosyl (pacovirin) in the treatment of viral hepatitis C, administered for 6 months, starting with the first day of clinical manifestations, at a dose of 50 mg, once a day, orally [3].
Dezavantajele acestor metode constau în eficacitatea joasă a preparatelor antivirale, care nu permit de a obţine rezultatele scontate, şi în faptul că sunt contraindicate în cazul nivelului înalt de citoliză, totodată aceste metode de tratament rezolvă parţial problemele terapeutice ce stau în faţa medicului, şi anume stoparea sau diminuarea activităţii procesului hepatic şi prevenirea evoluţiei hepatitei spre ciroză. The disadvantages of these methods are the low effectiveness of antiviral preparations, which do not allow to obtain the expected results, and the fact that they are contraindicated in case of high levels of cytolysis. At the same time, these treatment methods partially solve the therapeutic problems facing the doctor, namely stopping or reducing the activity of the liver process and preventing the evolution of hepatitis to cirrhosis.
Copiii cu HVC C care au contraindicaţii la administrarea terapiei antivirale cu remedii din clasa interferonului, recomandate de protocoalele internaţionale, sunt lipsiţi de posibilitatea efectuării unui tratament etio-patogenic antiviral. Nu întotdeauna se obţine normalizarea indicilor biochimici şi regresarea viremiei VHC. Children with HCV C who have contraindications to antiviral therapy with interferon class drugs, recommended by international protocols, are deprived of the possibility of performing an etio-pathogenic antiviral treatment. Normalization of biochemical indices and regression of HCV viremia are not always achieved.
Problema pe care o rezolvă invenţia propusă este sporirea eficacităţii tratamentului HVC C la copii, normalizarea indicilor biochimici, diminuarea nivelului viremiei VHC, prevenirea instalării fibrozei şi a cirozei hepatice, normalizarea stării generale şi ameliorarea calităţii vieţii copilului. The problem solved by the proposed invention is to increase the effectiveness of HCV C treatment in children, normalize biochemical indices, reduce the level of HCV viremia, prevent the development of fibrosis and liver cirrhosis, normalize the general condition and improve the child's quality of life.
Esenţa invenţiei constă în aceea că se administrează terapia de bază şi suplimentar, concomitent, se administrează per os 5α-furostan-3β,22,26-triol-3-[O-β-D-glucopiranozil(1→2)-β-D-glucopiranozil(1→4)-β-D-galactopiranozil]-26-O-β-D-glucopiranozil), de două ori pe zi, şi 3-O-[β-D-glucopiranozil(1→2)]-[β-D-glucopiranozil(1→3)]-[β-D-glucopiranozil(1→4)]-β-D-galactopiranozil[(25R)-5α-furostan-2α, 3β, 22α, 26-tetraol]-26-O-β-D-glucopiranozil, o dată pe zi, ambele remedii se administrează în doză de 50 mg, începând cu prima zi de manifestări clinice, cu 30 minute înainte de masă, timp de 3 luni, cu acţiune imunomodulatoare, antioxidantă, interferonogenă şi antivirală. La copiii cu HVC C şi sindrom de colestază pacovirina, capsicozida şi ribavirinul au fost administrate în combinaţie cu acid ursodezoxiholic, per os, în doze de 10 mg/kg/corp în 24 ore, timp de 3 luni. The essence of the invention consists in administering the basic therapy and additionally, concurrently, administering per os 5α-furostane-3β,22,26-triol-3-[O-β-D-glucopyranosyl(1→2)-β-D-glucopyranosyl(1→4)-β-D-galactopyranosyl]-26-O-β-D-glucopyranosyl), twice a day, and 3-O-[β-D-glucopyranosyl(1→2)]-[β-D-glucopyranosyl(1→3)]-[β-D-glucopyranosyl(1→4)]-β-D-galactopyranosyl[(25R)-5α-furostane-2α, 3β, 22α, 26-tetraol]-26-O-β-D-glucopyranosyl, once a day, both remedies are administered in a dose of 50 mg, starting with the first day of clinical manifestations, with 30 minutes before meals, for 3 months, with immunomodulatory, antioxidant, interferonogenic and antiviral action. In children with HCV C and cholestasis syndrome, pacovirin, capsicoside and ribavirin were administered in combination with ursodeoxycholic acid, per os, in doses of 10 mg/kg/body in 24 hours, for 3 months.
Rezultatul obţinut constă în elaborarea unei metode de tratament al HVC C, bazată pe preparatele: pacovirină şi capsicozidă, care pot fi aplicate, chiar şi în cazul unei citolize înalte, la copiii care au contraindicaţii la administrarea terapiei antivirale, cu ameliorarea indicilor biochimici şi micşorarea duratei de spitalizare. Pentru aprobarea metodei propuse a fost aplicată la copii cu HVC C în Clinica de Hepatologie Pediatrică a IMSP SCRC „Em. Coţaga,” au fost efectuate investigaţii clinice, paraclinice, imunologice şi virusologice cu determinarea genotipului VHC, ARN VHC cantitativ prin PCR, gradului de fibroză prin metoda de elastografie. A fost creat şi lotul martor pentru aprecierea eficacităţii metodei propuse de tratament. Studiul a fost realizat randomizat prin metoda dublu-orb. The result obtained consists in the development of a treatment method for HCV C, based on the preparations: pacovirin and capsicoside, which can be applied, even in the case of high cytolysis, to children who have contraindications to antiviral therapy, with improvement of biochemical indices and reduction of hospitalization duration. For the approval of the proposed method, it was applied to children with HCV C in the Pediatric Hepatology Clinic of IMSP SCRC "Em. Coţaga," clinical, paraclinical, immunological and virological investigations were performed with the determination of the HCV genotype, quantitative HCV RNA by PCR, the degree of fibrosis by the elastography method. The control group was also created to assess the effectiveness of the proposed treatment method. The study was conducted in a randomized double-blind manner.
Astfel, au fost selectaţi în lotul experimental 17 bolnavi cu HVC C activă, grad mediu şi înalt de activitate, cu vârstele cuprinse între 3…17 ani, care aveau contraindicaţii la tratamentul standard antiviral. Pentru aprecierea indicatorilor clinici şi biochimici aceştia au fost divizaţi în 3 subloturi a câte 6, 6 şi 5 (însumat 17 bolnavi). Acestui lot de bolnavi li s-a iniţiat tratamentul tradiţional, care include respectarea regimului igieno-dietetic (regim de salon, dieta nr. 5 după Pevzner), tratamentul hepatoprotector (silimarină, fosfolipide esenţiale, legalon, acid ursodezoxiholic), terapia de dezintoxicare la indicaţii clinice (administrarea i/v a soluţiilor fiziologice, de glucoză, hepasolului etc.) şi de corecţie a proceselor metabolice (vitamine din grupele C, B1, B6, B12), suplimentat cu pacovirină (forma medicamentoasă capsule) care a fost administrată timp de 3 luni, în doză de 50 mg, de două ori pe zi, per os, şi capsicozidă administrată timp de 3 luni, în doză de 50 mg, o dată pe zi, per os. Thus, 17 patients with active HCV C, medium and high degree of activity, aged between 3…17 years, who had contraindications to standard antiviral treatment, were selected in the experimental group. For the assessment of clinical and biochemical indicators, they were divided into 3 subgroups of 6, 6 and 5 (totaling 17 patients). This group of patients was initiated on traditional treatment, which includes compliance with the hygienic-dietary regimen (parlor regimen, diet no. 5 according to Pevzner), hepatoprotective treatment (silymarin, essential phospholipids, legalon, ursodeoxycholic acid), detoxification therapy according to clinical indications (i/v administration of physiological solutions, glucose, hepasol, etc.) and correction of metabolic processes (vitamins from groups C, B1, B6, B12), supplemented with pacovirin (capsule dosage form) which was administered for 3 months, at a dose of 50 mg, twice a day, orally, and capsicoside administered for 3 months, at a dose of 50 mg, once a day, orally.
În lotul martor (n = 17) bolnavii au fost selectaţi conform aceloraşi criterii, astfel ca loturile să fie comparabile. În cadrul acestui lot, pacovirina şi capsicozida au fost substituite cu Placebo, aplicat conform aceleiaşi scheme. În rest tratamentul a fost identic celui aplicat pacienţilor din lotul experimental. In the control group (n = 17) patients were selected according to the same criteria, so that the groups were comparable. Within this group, pacovirin and capsicoside were substituted with Placebo, applied according to the same scheme. Otherwise, the treatment was identical to that applied to the patients in the experimental group.
Rezultatele comparării metodei propuse de tratament al HVC C la copii cu cea mai apropiată soluţie au fost analizate la finele tratamentului, după 3 luni. The results of comparing the proposed method of treating HCV C in children with the closest solution were analyzed at the end of treatment, after 3 months.
Datele comparative ale semnelor clinice de bază la copiii cu HVC C din lotul experimental şi lotul martor după tratament sunt prezentate în tab. 1. Comparative data of basic clinical signs in children with HCV C from the experimental group and the control group after treatment are presented in Table 1.
Tabelul 1 Table 1
Nr Parametrii clinici/nr. de pacienţi Lotul I (experimental) (n=17) P Lotul II (martor) (n=17) P Până la tratament După tratament Până la tratament După tratament Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) 1 Slăbiciuni generale 11 64,7±11,6 1 9,1±8,7 P<0,01 8 47,1±12,1 7 87,5±11,7 P<0,05 2 Sindromul dolor în hipocondrul drept 9 53,0±12,1 1 11,1±9,4 P<0,05 8 47,1±12,1 6 75,0±15,3 P>0,05 3 Inapetenţă 10 58,8±12,0 2 20,0±12,6 P<0,05 8 47,1±12,1 7 87,5±11,7 P<0,05No. Clinical parameters/no. of patients Group I (experimental) (n=17) P Group II (control) (n=17) P Before treatment After treatment Before treatment After treatment Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) 1 General weakness 11 64.7±11.6 1 9.1±8.7 P<0.01 8 47.1±12.1 7 87.5±11.7 P<0.05 2 Pain syndrome in the right hypochondrium 9 53.0±12.1 1 11.1±9.4 P<0.05 8 47.1±12.1 6 75.0±15.3 P>0.05 3 Loss of appetite 10 58.8±12.0 2 20.0±12.6 P<0.05 8 47.1±12.1 7 87.5±11.7 P<0.05
Notă: Abs. - cazuri absolute; Note: Abs. - absolute cases;
P. - probalitatea rezultatelor. P. - probability of results.
Analiza şi evaluarea prezumtivă a datelor prezentate în tab. 1 demonstrează că administrarea concomitentă a pacovirinei şi capsicozidei a avut acţiune benefică asupra evoluţiei principalelor semne clinice după tratament. În special merită atenţie evoluţia slăbiciunii generale, care a dispărut la 10 bolnavi din 11, sindromul dolor în hipocondrul drept, care a dispărut la 8 copii din 9 şi inapetenţa, care a dispărut la 8 bolnavi din 10. Evoluţie favorabilă au înregistrat şi astfel de semne clinice ca senzaţia de greaţă, inapetenţa, cefaleea, concomitent s-au micşorat şi dimensiunile ficatului. În lotul martor, evoluţia favorabilă a semnelor clinice s-a înregistrat la un număr mai mic de pacienţi. Evoluţia comparativă a indicilor de laborator (biochimici) la copiii cu HVC C din lotul experimental şi lotul martor după tratament este prezentată în tab. 2. The analysis and presumptive evaluation of the data presented in tab. 1 demonstrates that the concomitant administration of pacovirin and capsicoside had a beneficial effect on the evolution of the main clinical signs after treatment. Particularly noteworthy is the evolution of general weakness, which disappeared in 10 out of 11 patients, pain syndrome in the right hypochondrium, which disappeared in 8 out of 9 children and loss of appetite, which disappeared in 8 out of 10 patients. Favorable evolution was also recorded in such clinical signs as nausea, loss of appetite, headache, and at the same time the size of the liver decreased. In the control group, the favorable evolution of clinical signs was recorded in a smaller number of patients. The comparative evolution of laboratory (biochemical) indices in children with HCV C in the experimental group and the control group after treatment is presented in tab. 2.
Tabelul 2 Table 2
Indicii biochimici la pacienţii cu HVC C până şi după tratament Biochemical indices in patients with HCV C before and after treatment
Indicii biochimici Lotul I experimental (n=17) Lotul II martor (n=17) Valorile normale > norma P Valorile normale > norma P Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) ALAT (norma <mmol/l) Până la tratament 8 47,1±12,1 9 52,9±12,1 P<0,001 7 41,2±8,4 10 58,8±12,0 P>0,05 După tratament 17 100 0 0 10 58,8±12,0 7 41,2±12,0 ASAT (norma 0-37 mmol/l) Până la tratament 8 47,1±12,1 9 52,9±12,1 P<0,001 7 41,2±12,0 10 58,8±12,0 P>0,05 După tratament 17 100 0 0 10 58,8±12,0 7 41,2±12,0 γGTP (norma < 35 mmol/l) Până la tratament 10 58,8±12,0 7 41,2±12,0 P<0,001 12 70,5±11,06 5 29,5±11,06 P>0,05 După tratament 17 100 0 0 13 76,5±10,3 4 23,5±10,3Biochemical indices Experimental group I (n=17) Control group II (n=17) Normal values > norm P Normal values > norm P Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) Abs. M±m(%) ALAT (norm <mmol/l) Before treatment 8 47.1±12.1 9 52.9±12.1 P<0.001 7 41.2±8.4 10 58.8±12.0 P>0.05 After treatment 17 100 0 0 10 58.8±12.0 7 41.2±12.0 AST (norm 0-37 mmol/l) Before treatment 8 47.1±12.1 9 52.9±12.1 P<0.001 7 41.2±12.0 10 58.8±12.0 P>0.05 After treatment 17 100 0 0 10 58.8±12.0 7 41.2±12.0 γGTP (norm < 35 mmol/l) Before treatment 10 58.8±12.0 7 41.2±12.0 P<0.001 12 70.5±11.06 5 29.5±11.06 P>0.05 After treatment 17 100 0 0 13 76.5±10.3 4 23.5±10.3
Notă: Abs. - cazuri absolute; Note: Abs. - absolute cases;
P. - probalitatea rezultatelor. P. - probability of results.
Conform rezultatelor înregistrate, în lotul experimental s-a depistat o evoluţie pozitivă a indicilor biochimici ALAT, ASAT, γGTP, care după tratament au fost în limitele normei la toţi pacienţii incluşi în studiu. ALAT s-a normalizat la 9 din 9 pacienţi, ASAT la 9 din 9 pacienţi, γGTP la 7 pacienţi din 7. În lotul martor, o evoluţie favorabilă a indicilor biochimici s-a înregistrat la un număr mai mic de pacienţi. Deşi diferenţa la sfârşitul tratamentului cu pacovirină şi capsicozidă este statistic veridică, se observă clar tendinţa de normalizare a indicilor biochimici de bază ALAT, ASAT, γGTP, caracteristici pentru contingentul de bolnavi cu HVC C. According to the recorded results, in the experimental group a positive evolution of the biochemical indices ALAT, ASAT, γGTP was detected, which after treatment were within the normal limits in all patients included in the study. ALAT normalized in 9 out of 9 patients, ASAT in 9 out of 9 patients, γGTP in 7 out of 7 patients. In the control group, a favorable evolution of the biochemical indices was recorded in a smaller number of patients. Although the difference at the end of the treatment with pacovirin and capsicoside is statistically significant, the trend of normalization of the basic biochemical indices ALAT, ASAT, γGTP, characteristic for the contingent of patients with HCV C, is clearly observed.
Ponderea copiilor cu HVC C care au răspuns la tratamentul cu pacovirină şi capsicozidă este prezentată în tab. 3. The proportion of children with HCV C who responded to treatment with pacovirin and capsicoside is presented in Table 3.
Tabelul 3 Table 3
Ponderea pacienţilor cu HVC C care au răspuns la tratamentul cu pacovirină şi capsicozidă Proportion of HCV C patients who responded to treatment with pacovirin and capsicoside
Pacienţii Ponderea, % ARN VHC Cazuri absolute M±m(%) Pacienţi: total 17 100 Pacienţi cu diminuarea nivelului de viremie 16 94,1±5,7 Pacienţi fără diminuarea nivelului de viremie 1 5,9±5,7Patients Share, % HCV RNA Absolute cases M±m(%) Patients: total 17 100 Patients with decreased viremia level 16 94.1±5.7 Patients without decreased viremia level 1 5.9±5.7
Analiza şi evaluarea prezumtivă a datelor prezentate în tab. 3 demonstrează că administrarea pacovirinei împreună cu capsicozida a avut o acţiune benefică asupra nivelului de viremie la 16 pacienţi din 17. Se observă clar tendinţa de diminuare a nivelului de viremie la copiii cu HVC C. Ponderea reducerii încărcăturii virale la pacienţii cu HVC C în urma tratamentului cu pacovirină şi capsicozidă este prezentată în tab.4 The analysis and presumptive evaluation of the data presented in Table 3 demonstrates that the administration of pacovirin together with capsicoside had a beneficial effect on the level of viremia in 16 out of 17 patients. The trend of decreasing the level of viremia in children with HCV C is clearly observed. The proportion of viral load reduction in patients with HCV C following treatment with pacovirin and capsicoside is presented in Table 4.
Tabelul 4 Table 4
Reducerea încărcăturii virale la pacienţii cu hepatită HVC C în urma tratamentului cu pacovirină şi capsicozidă (copii ARN/ml) Reduction of viral load in patients with hepatitis C HCV following treatment with pacovirin and capsicoside (RNA copies/ml)
Nivelul mediu de viremie înainte de tratament 7891452,7 Nivelul mediu de viremie după tratament 4181705 Ponderea diminuării nivelului de viremie 47%Average viremia level before treatment 7891452.7 Average viremia level after treatment 4181705 Percentage of viremia level reduction 47%
Analiza şi evaluarea datelor prezentate în tab. 4 demonstrează că administrarea concomitentă a preparatelor pacovirină şi capsicozidă are o acţiune benefică asupra indicelui viral, manifestată prin reducerea nivelului de ARN/ml la copii. Astfel nivelul mediu de viremie înainte de tratament a constituit 7891452,7, iar după tratament este de 4181705 - cu o diminuare până la 47%. Rezultatele prezentate denotă o acţiune benefică a preparatelor asupra evoluţiei principalelor semne clinice la copiii cu HVC C, confirmată prin rezultatele investigaţiilor de laborator. The analysis and evaluation of the data presented in tab. 4 demonstrates that the concomitant administration of pacovirin and capsicoside preparations has a beneficial effect on the viral index, manifested by the reduction of the RNA/ml level in children. Thus, the average level of viremia before treatment was 7891452.7, and after treatment it is 4181705 - with a decrease of up to 47%. The presented results denote a beneficial effect of the preparations on the evolution of the main clinical signs in children with HCV C, confirmed by the results of laboratory investigations.
Toţi bolnavii au suportat bine administrarea preparatelor pacovirină şi capsicozidă, nesemnalându-se reacţii adverse. Nici într-un caz nu a fost necesară sistarea tratamentului, astfel demonstrându-se că pacovirina şi capsicozida pot fi administrate copiilor cu HVC C şi în cazul unei citolize înalte. All patients tolerated the administration of pacovirin and capsicoside preparations well, with no adverse reactions reported. In no case was it necessary to discontinue treatment, thus demonstrating that pacovirin and capsicoside can be administered to children with HCV C even in cases of high cytolysis.
În calitate de exemple prezentăm următoarele cazuri clinice. As examples, we present the following clinical cases.
Exemplul 1 Example 1
Pacientul Z.A., 16 ani, a fost internat în Spitalul Clinic Republican pentru Copii „Em. Coţaga” secţia hepatologie pediatrică la 16.08.2010 cu acuze la dureri şi senzaţie de greutate în hipocondrul drept, greţuri, slăbiciuni generale, fatigabilitate, xerostomie. Patient Z.A., 16 years old, was admitted to the Republican Clinical Hospital for Children "Em. Coţaga" pediatric hepatology department on 16.08.2010 with complaints of pain and heaviness in the right hypochondrium, nausea, general weakness, fatigue, xerostomia.
Din anamnestic: se consideră bolnav din 2009, când a fost primar diagnosticat cu HVC C, genotip 1b. Copilul se află în evidenţa endocrinologului din 2004 cu diabet zaharat tip 1 insulinodependent, dezechilibrat. S-a tratat staţionar şi ambulatoriu, ultima dată în 2009. Starea copilului s-a înrăutăţit în 02.2010 când a suportat un episod de chetoacidoză care a fost cupat. Examenul clinic constată hiperpigmentare la nivelul plicilor cutanate cubitale, palmare, în regiunea ombilicală, ţesut adipos subcutanat slab dezvoltat, greutatea 43 kg, talia 151 cm. Abdomenul moderat mărit în volum, sensibil la palpare. Ficatul proemină sub rebordul costal drept +6,0+6,0+7,0 cm, dur la palpare. Splina +4,0 cm de consistenţă dură la palpare. Ascită şi edeme ale membrelor inferioare absente. From the anamnesis: he is considered sick since 2009, when he was first diagnosed with HCV C, genotype 1b. The child has been in the endocrinologist's records since 2004 with insulin-dependent, unbalanced type 1 diabetes. He was treated inpatient and outpatient, the last time in 2009. The child's condition worsened in 02.2010 when he suffered an episode of ketoacidosis that was treated. The clinical examination found hyperpigmentation in the cubital and palmar skin folds, in the umbilical region, poorly developed subcutaneous adipose tissue, weight 43 kg, waist 151 cm. The abdomen was moderately enlarged in volume, sensitive to palpation. The liver protrudes under the right costal margin +6.0+6.0+7.0 cm, hard to palpation. The spleen +4.0 cm, hard to palpation. Ascites and edema of the lower limbs absent.
A fost examinat paraclinic: 17.08.2010: Hb - 128 g/l; eritrocite - 4,2 · 1012/l; trombocite - 256 · 109/l; leucocite - 7,0 109/l, nesegmentate - 1%, segmentate - 48%; limfocite - 37%; monocite - 11%; VSH - 25 mm/h. Bilirubina - 8,4 µmol/L; ALAT - 180 U/L; ASAT - 62 U/L; ureea - 7,0 mmol/l; anti-HCV - pozitiv; HBsAg - negativ; anti-HBcor negativ. Profilul glicemic: glicemia 23,1…8,5…7,4…6,7…10,1…12,7 mmol/L. Glucozurie pozitivă: ARN VHC (din 16.08.2010) cantitativ - 12 824 841 copii/ml (3 206 210 UI/ml); a fost determinat genotipul 1b. Ecografia abdomenului: hepatomegalie moderată cu modificări difuze în parenchim; semne de colecistită cronică calculoasă, colesteroză a vezicii biliare. He was examined clinically: 17.08.2010: Hb - 128 g/l; erythrocytes - 4.2 1012/l; platelets - 256 109/l; leukocytes - 7.0 109/l, unsegmented - 1%, segmented - 48%; lymphocytes - 37%; monocytes - 11%; ESR - 25 mm/h. Bilirubin - 8.4 µmol/L; ALAT - 180 U/L; ASAT - 62 U/L; urea - 7.0 mmol/l; anti-HCV - positive; HBsAg - negative; anti-HBcor negative. Glycemic profile: blood glucose 23.1…8.5…7.4…6.7…10.1…12.7 mmol/L. Positive glucosuria: HCV RNA (as of 16.08.2010) quantitative - 12 824 841 copies/ml (3 206 210 IU/ml); genotype 1b was determined. Abdominal ultrasound: moderate hepatomegaly with diffuse changes in the parenchyma; signs of chronic calculous cholecystitis, gallbladder cholesterosis.
S-a stabilit diagnosticul clinic de: HVC C, genotip 1b, gradul III activitate biochimică, faza de viremie înaltă. Colesteroză a vezicii biliare cu Sludge biliar şi dischinezie hipomotorie. Diabet zaharat tip I dezechilibrat, formă gravă. S-a instituit tratamentul simptomatic, inclusiv regimul igieno-dietetic nr. 9 după Pevzner, insulinoterapia - insulina se administrează la orele (800…1300…1830…2130); hepatoprotectori - ursofalc, heptal. La tratamentul de bază suplimentar The clinical diagnosis was established: HCV C, genotype 1b, biochemical activity level III, high viremia phase. Cholesterosis of the gallbladder with biliary sludge and hypomotor dyskinesia. Unbalanced type I diabetes mellitus, severe form. Symptomatic treatment was instituted, including hygienic-dietary regimen No. 9 according to Pevzner, insulin therapy - insulin is administered at (800…1300…1830…2130); hepatoprotectors - ursofalc, heptal. Additional to the basic treatment
s-a administrat pacovirină, per os, în doză de 50 mg, de două ori pe zi, pentru o perioadă de 3 luni şi capsicozidă, per os, în doză de 50 mg, o dată pe zi, pentru o perioadă de 3 luni. În urma tratamentului efectuat, starea generală a pacientului s-a ameliorat, valorile glicemiei în descreştere 3,6…9,1…8,4…3,5…9,9…9,4 mmol/L. Ulterior copilul a fost externat din spital urmând să primească ambulatoriu tratamentul cu pacovirină 50 mg, de două ori pe zi, timp de 3 luni şi capsicozidă în doză de 50 mg, o dată pe zi, timp de 3 luni, sub supravegherea hepatologului şi endocrinologului pediatru. Pe parcursul tratamentului reacţii adverse la pacovirină şi capsicozidă nu au fost constatate. Peste 3 luni de tratament dimensiunile ficatului s-au diminuat cu 2 cm la palpare depăşind rebordul costal cu + 4,0 cm; dimensiunile splinei s-au diminuat până la 2,5 cm. Valorile aminotransferazelor s-au normalizat: ALAT - 32,6 U/L; ASAT - 38,2 U/L. Bilirubina se menţinea la valori normale - 18 µmol/L; glicemia - 6,9 mmol/L. Pacovirin was administered orally at a dose of 50 mg twice daily for a period of 3 months and capsicoside at a dose of 50 mg once daily for a period of 3 months. Following the treatment, the patient's general condition improved, with blood glucose levels decreasing from 3.6 to 9.1 to 8.4 to 3.5 to 9.9 to 9.4 mmol/L. The child was subsequently discharged from the hospital and was to receive outpatient treatment with Pacovirin 50 mg twice daily for 3 months and Capsicum 50 mg once daily for 3 months, under the supervision of a pediatric hepatologist and endocrinologist. No adverse reactions to Pacovirin and Capsicum were observed during the treatment. After 3 months of treatment, the liver dimensions decreased by 2 cm on palpation, exceeding the costal margin by + 4.0 cm; the spleen dimensions decreased to 2.5 cm. The aminotransferase values normalized: ALAT - 32.6 U/L; ASAT - 38.2 U/L. Bilirubin was maintained at normal values - 18 µmol/L; blood glucose - 6.9 mmol/L.
Nivelul viremiei ARN VHC s-a diminuat cu 63%, de la 12 824 841 copii/ml (3 206 210 UI/ml) până la 4 726 911 copii/ml (1 181 727 UI/ml). The level of HCV RNA viremia decreased by 63%, from 12,824,841 copies/ml (3,206,210 IU/ml) to 4,726,911 copies/ml (1,181,727 IU/ml).
Exemplul 2 Example 2
Pacientul C.A., 5 ani, a fost internat în Spitalul Clinic Republican pentru Copii „Em. Coţaga” , secţia hepatologie pediatrică la 08.06.2009 cu acuze la dureri periodice în hipocondrul drept şi stâng, oboseală la efort fizic, inapetenţă, sindrom astenic pronunţat, nervozitate, labilitate emoţională. Patient C.A., 5 years old, was admitted to the Republican Clinical Hospital for Children "Em. Coţaga", pediatric hepatology department on 08.06.2009 with complaints of periodic pain in the right and left hypochondrium, fatigue during physical exertion, loss of appetite, pronounced asthenic syndrome, nervousness, emotional lability.
Conform anamnesticului: copilul a fost născut din prima sarcină cu semne clinice de eminenţă de avort în a II jumătate a sarcinii, greutatea ponderală la naştere 2560 g, icter a n/născutului fiziologic. La vârsta de 4 săptămâni a fost sonografic determinată MCC - defect septal ventricular, cordaj fals, insuficienţă mitrală I-II, insuficienţă tricuspidală, insuficienţă pulmonară. A fost operat la vârsta de 6 luni cu instalarea cardiostimulatorului. Este depistat primar cu ASAT sporit şi anti CMV la vârsta de 4 luni, tratat ambulatoriu de hepatită toxică până în iunie 2009. According to the anamnesis: the child was born from the first pregnancy with clinical signs of imminent miscarriage in the second half of pregnancy, birth weight 2560 g, physiological neonatal jaundice. At the age of 4 weeks, MCC was determined sonographically - ventricular septal defect, false chordae, mitral insufficiency I-II, tricuspid insufficiency, pulmonary insufficiency. He was operated on at the age of 6 months with the installation of a pacemaker. He was initially diagnosed with increased AST and anti-CMV at the age of 4 months, treated as an outpatient for toxic hepatitis until June 2009.
La internare starea generală a copilului de gravitate medie, greutatea ponderală la internare 19 kg, cu semne de astenie pronunţată, cardiostimulator. Examenul clinic constată hepatomegalie 3,0+3,0+3,5 cm, splenomegalie +2,5 cm de consistenţă dură la palpare, fără semne de ascită. Upon admission, the child's general condition was of average severity, weight at admission 19 kg, with signs of pronounced asthenia, pacemaker. Clinical examination revealed hepatomegaly 3.0+3.0+3.5 cm, splenomegaly +2.5 cm of hard consistency on palpation, without signs of ascites.
A fost examinat paraclinic: 09.06.09: Hb - 136 g/l; eritrocite - 4,31 · 1012/l; trombocite 361 · 109/l; leucocite - 9,0 · 109/l, nesegmentate - 1%, segmentate - 56%; limfocite - 38%; monocite 4%; VSH - 20 mm/h. 09.06.09: Bilirubina - 19,2…6,1…13,2 µmol/L; ALAT - 18 U/L; ASAT - 21 U/L; GTT - 22 mmol/l; fosfataza alcalină - 483 mmol/l; anti-HCV - pozitiv; AgHBs - negativ; anti-HBs - negativ, ARN VHC (din 15.06.09) cantitativ -312 619 copii/ml (78 154 UI/ml). Ecografia abdomenului a determinat hepatosplenomegalie moderată cu modificări difuze în parenchim; vezica biliară hipotonică. ECG - pe fon de cardiostimulator - fără dereglări de ritm. He was examined paraclinically: 09.06.09: Hb - 136 g/l; erythrocytes - 4.31 · 1012/l; platelets 361 · 109/l; leukocytes - 9.0 · 109/l, unsegmented - 1%, segmented - 56%; lymphocytes - 38%; monocytes 4%; ESR - 20 mm/h. 09.06.09: Bilirubin - 19.2…6.1…13.2 µmol/L; ALAT - 18 U/L; ASAT - 21 U/L; GTT - 22 mmol/l; alkaline phosphatase - 483 mmol/l; anti-HCV - positive; HBsAg - negative; anti-HBs - negative, HCV RNA (as of 15.06.09) quantitative -312 619 copies/ml (78 154 IU/ml). Abdominal ultrasound determined moderate hepatosplenomegaly with diffuse changes in the parenchyma; hypotonic gallbladder. ECG - on the background of a pacemaker - without rhythm disturbances.
S-a stabilit diagnosticul clinic de HVC C în faza de viremie, fără activitate biochimică. Stare după intervenţie chirurgicală pe cord cu instalarea cardiostimulatorului. S-a instituit tratamentul simptomatic, inclusiv regimul igieno-dietetic, terapia de susţinere cu captopril, veroşpiron, riboxină. S-a administrat pacovorină şi capsicozidă, per os, 50 mg o dată pe zi. Ulterior copilul a fost externat la domiciliu pentru continuarea tratamentului în condiţii de ambulatoriu cu pacovirină per os, în doză de 50 mg, de două ori pe zi, cu 30 min înainte de masă, timp de 3 luni, iar capsicozidă timp de 3 luni, începând cu prima zi de manifestări clinice, în doză de 50 mg, o dată pe zi, cu 30 min înainte de masă, per os, sub supravegherea hepatologului pediatru. The clinical diagnosis of HCV C in the viremia phase was established, without biochemical activity. Condition after cardiac surgery with pacemaker installation. Symptomatic treatment was instituted, including a hygienic-dietary regimen, supportive therapy with captopril, verospiron, riboxin. Pacovorin and capsicoside were administered, orally, 50 mg once a day. Subsequently, the child was discharged home for continued treatment in outpatient conditions with pacovorin orally, at a dose of 50 mg, twice a day, 30 min before meals, for 3 months, and capsicoside for 3 months, starting with the first day of clinical manifestations, at a dose of 50 mg, once a day, 30 min before meals, orally, under the supervision of a pediatric hepatologist.
Peste o lună de la iniţierea tratamentului cu pacovirină şi capsicozidă (12.07.09): valorile aminotransferazelor se menţin la valori normale: ALAT- 15 U/L; ASAT -19 U/L; nivelul viremiei ARN VHC s-a diminuat cu 74% - de la 312 619 (78 154 UI/ml) până la 81 772 copii/ml (20 443 UI/ml). Pe parcursul tratamentului reacţii adverse la administrarea preparatului nu au fost depistate. Peste 3 luni de tratament dimensiunile ficatului s-au diminuat cu 1 cm, la palpare depăşind rebordul costal cu 2,0+2,5 cm; dimensiunile splinei s-au diminuat până la 1,0 cm. Nivelul viremiei ARN VHC s-a diminuat cu 83% - de la 312 619 (78 154 UI/ml) până la 53 385 copii/ml (13 346 UI/ml). One month after the initiation of treatment with pacovirin and capsicoside (12.07.09): aminotransferase values remain normal: ALAT - 15 U/L; ASAT -19 U/L; HCV RNA viremia level decreased by 74% - from 312,619 (78,154 IU/ml) to 81,772 copies/ml (20,443 IU/ml). During the treatment, no adverse reactions to the administration of the preparation were detected. After 3 months of treatment, the liver dimensions decreased by 1 cm, on palpation exceeding the costal margin by 2.0+2.5 cm; the spleen dimensions decreased to 1.0 cm. The level of HCV RNA viremia decreased by 83% - from 312,619 (78,154 IU/ml) to 53,385 copies/ml (13,346 IU/ml).
Exemplul 3 Example 3
Pacientul R.D., 9 ani, a fost internat în Spitalul Clinic Republican pentru Copii „Em. Coţaga”, secţia hepatologie pediatrică la 14.02.2010 cu acuze la dureri în hipocondrul drept, inapetenţă, oboseală la efort fizic, astenie moderată, nervozitate, irascibilitate, cefalee periodică. Patient R.D., 9 years old, was admitted to the Republican Clinical Hospital for Children "Em. Coţaga", pediatric hepatology department on 14.02.2010 with complaints of pain in the right hypochondrium, loss of appetite, fatigue during physical exertion, moderate asthenia, nervousness, irascibility, periodic headache.
Din anamnestic: se consideră bolnav din 2009 când primar a fost diagnosticat cu HVC C, genotip 1b. Copilul se află în evidenţa neurologului de la vârsta de 2 ani cu stare după comoţie cerebrală şi sindrom convulsiv, primind tratament neurologic periodic. Conform anamnezei din 2008 mama copilului suferă de HVC C, genotip 1b. From the anamnesis: he is considered sick since 2009 when the primary was diagnosed with HCV C, genotype 1b. The child has been in the neurologist's records since the age of 2 with a condition after a cerebral concussion and convulsive syndrome, receiving periodic neurological treatment. According to the anamnesis from 2008, the child's mother suffers from HCV C, genotype 1b.
La internare starea generală a copilului de gravitate medie, greutatea ponderală 24 kg. Examenul clinic constată tegumentele palide, curate, cianoză periorbitală. Abdomenul moale, uşor sensibil la palpare în hipocondrul drept. Ficatul proemină cu 2,0…2,5 cm sub rebordul costal drept, la palpare este semidur. Splina sub rebordul costal stâng. Upon admission, the child's general condition was of average severity, weight 24 kg. Clinical examination revealed pale, clean skin, periorbital cyanosis. The abdomen was soft, slightly sensitive to palpation in the right hypochondrium. The liver protruded 2.0…2.5 cm below the right costal margin, semi-hard to palpation. The spleen was below the left costal margin.
A fost examinat paraclinic: 14.02.10: Hb - 116 g/l; eritrocite - 3,93 · 1012/l; trombocite 345 · 109/l; leucocite - 4,0 · 109, nesegmentate - 3%, segmentate - 51%; limfocite - 39%; monocite 6%; VSH - 12 mm/h. 14.02.10: Bilirubina - 14 µmol/L; ALAT - 56 U/L; ASAT - 51 U/L; GTT - 36 mmol/l; fosfataza alcalină - 478 mmol/l; anti HCV - pozitiv; HBsAg - negativ. ARN VHC (din 17.02.2010) cantitativ 75 769 copii/ml (18 942 UI/ml); a fost determinat genotipul 1b. He was examined paraclinically: 14.02.10: Hb - 116 g/l; erythrocytes - 3.93 1012/l; platelets 345 109/l; leukocytes - 4.0 109, non-segmented - 3%, segmented - 51%; lymphocytes - 39%; monocytes 6%; ESR - 12 mm/h. 14.02.10: Bilirubin - 14 µmol/L; ALAT - 56 U/L; ASAT - 51 U/L; GTT - 36 mmol/l; alkaline phosphatase - 478 mmol/l; anti HCV - positive; HBsAg - negative. HCV RNA (as of 17.02.2010) quantitative 75 769 copies/ml (18 942 IU/ml); genotype 1b was determined.
Ecografia abdomenului a determinat hepatomegalie moderată cu modificări difuze în parenchim; anomalie de dezvoltare a formei vezicii biliare (forma „S”) cu semne de colecistită acalculoasă şi dischinezie hipomotorie. Abdominal ultrasound determined moderate hepatomegaly with diffuse changes in the parenchyma; abnormal development of the gallbladder shape ("S" shape) with signs of acalculous cholecystitis and hypomotor dyskinesia.
S-a stabilit diagnosticul clinic de HVC C, genotip 1b, gr. minimal de activitate biochimică, fază de viremie înaltă. Stare după comoţie cerebrală cu sindrom convulsiv. The clinical diagnosis of HCV C, genotype 1b, minimal biochemical activity level, high viremia phase was established. Post-concussion condition with convulsive syndrome.
S-a instituit tratamentul simptomatic, inclusiv regimul igieno-dietetic nr. 5 după Pevzner, hepatoprotectori - silimarină, acid lipoic. La tratamentul de bază s-a administrat suplimentar pacovirină, per os, 50 mg, de două ori pe zi, pentru o perioadă de 3 luni şi capsicozidă, per os, 50 mg, o dată pe zi, pentru o perioadă de 3 luni. Ulterior copilul a fost externat la domiciliu pentru tratament ambulatoriu cu pacovirină, per os, 50 mg, de două ori pe zi, timp de 3 luni şi capsicozidă, per os, 50 mg, o dată pe zi, pentru o perioadă de 3 luni, sub supravegherea hepatologului pediatru. Pe parcursul tratamentului reacţii adverse la pacovirină şi capsicozidă nu au fost constatate. Peste 3 luni de tratament dimensiunile ficatului s-au diminuat cu 1 cm, la palpare depăşind rebordul costal cu +1,0…+1,5 cm, splina sub rebordul costal stâng. Valorile aminotransferazelor s-au normalizat: ALAT - 34 U/L ; ASAT - 24 U/L. Nivelul viremiei ARN VHC s-a diminuat cu 30% - de la 75 769 copii/ml (18 942 UI/ml) până la 53 068 copii/ml (13 267 UI/ml). Symptomatic treatment was instituted, including the hygienic-dietary regimen No. 5 according to Pevzner, hepatoprotectors - silymarin, lipoic acid. In addition to the basic treatment, pacovirin, per os, 50 mg, twice a day, for a period of 3 months, and capsicoside, per os, 50 mg, once a day, for a period of 3 months, was additionally administered. Subsequently, the child was discharged home for outpatient treatment with pacovirin, per os, 50 mg, twice a day, for 3 months and capsicoside, per os, 50 mg, once a day, for a period of 3 months, under the supervision of a pediatric hepatologist. During the treatment, no adverse reactions to pacovirin and capsicoside were observed. After 3 months of treatment, the liver size decreased by 1 cm, on palpation exceeding the costal margin by +1.0…+1.5 cm, the spleen below the left costal margin. Aminotransferase values normalized: ALAT - 34 U/L; ASAT - 24 U/L. The level of HCV RNA viremia decreased by 30% - from 75,769 copies/ml (18,942 IU/ml) to 53,068 copies/ml (13,267 IU/ml).
Astfel aprecierea eficacităţii clinice a pacovirinei (forma medicamentoasă capsule) şi a capsicozidei (forma medicamentoasă comprimate) pe un lot de 17 bolnavi ne permite să afirmăm că administrarea acestor preparate a avut o acţiune pozitivă asupra manifestării principalelor semne clinice ale sindroamelor asteno-vegetativ şi dispeptic, care au dispărut la un număr semnificativ de bolnavi. La majoritatea absolută a pacienţilor aflaţi în studiu s-a observat micşorarea dimensiunilor ficatului, apreciate la palpare, totodată la pacienţii din lotul experimental dinamica pozitivă a indicilor paraclinici (ALAT, ASAT şi γGTP) a fost şi mai pronunţată. Thus, the assessment of the clinical efficacy of pacovirine (capsule dosage form) and capsicoside (tablet dosage form) on a group of 17 patients allows us to state that the administration of these preparations had a positive effect on the manifestation of the main clinical signs of astheno-vegetative and dyspeptic syndromes, which disappeared in a significant number of patients. In the absolute majority of patients in the study, a decrease in liver size was observed, assessed on palpation, while in patients from the experimental group the positive dynamics of paraclinical indices (ALAT, ASAT and γGTP) was even more pronounced.
Administrarea pacovirinei şi a capsicozidei în calitate de remedii medicamentoase suplimentare la tratamentul tradiţional, în conformitate cu metoda propusă în invenţie, a dus la o normalizare mai rapidă şi mai intensivă a indicilor clinici şi paraclinici comparativ cu cea mai apropiată soluţie - metoda de tratament tradiţională, datorită faptului că pacovirina şi capsicozida pot fi administrate şi în cazul unei citolize înalte, ceea ce a condiţionat o evoluţie mai favorabilă a procesului patologic şi o recuperare mai rapidă a bolnavilor, o normalizare mai intensivă a indicilor biochimici cu reducerea semnificativă a duratei de manifestare a principalelor semne clinice în lotul experimental, comparativ cu lotul martor. The administration of pacovirin and capsicoside as additional medicinal remedies to traditional treatment, in accordance with the method proposed in the invention, led to a faster and more intensive normalization of clinical and paraclinical indices compared to the closest solution - the traditional treatment method, due to the fact that pacovirin and capsicoside can be administered even in the case of high cytolysis, which conditioned a more favorable evolution of the pathological process and a faster recovery of the patients, a more intensive normalization of biochemical indices with a significant reduction in the duration of manifestation of the main clinical signs in the experimental group, compared to the control group.
Astfel, algoritmul propus în tratamentul copiilor cu HVC C, contraindicaţi tratamentului standard antiviral, include suplimentarea terapiei de bază cu pacovirină, care se administrează per os cu 30 min înainte de masă, capsule în doză de 50 mg, de două ori pe zi, timp de 3 luni şi capsicozidă, care se administrează per os cu 30 min înainte de masă în comprimate, în doză de 50 mg, o dată pe zi, pentru o perioadă de 3 luni. Thus, the proposed algorithm for the treatment of children with HCV C, contraindicated for standard antiviral treatment, includes supplementing basic therapy with pacovirin, which is administered orally 30 min before meals, capsules at a dose of 50 mg, twice a day, for 3 months, and capsicoside, which is administered orally 30 min before meals in tablets, at a dose of 50 mg, once a day, for a period of 3 months.
1. American Gastroenterological Association ,, Medical Position Stateman on the Management of Hepatitis C for children, " 2006 1. American Gastroenterological Association, Medical Position Statesman on the Management of Hepatitis C for children, 2006
2. Guidelines However, American Association for the Study of Liver Diseases (AASLD), 2007. 2. Guidelines However, American Association for the Study of Liver Diseases (AASLD), 2007.
3. MD 2549 G2 2004.09.30 3. MD 2549 G2 2004.09.30
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