KAJIAN EKSPRESI TGF-ββββ1, MMP-9, KOLAGEN TIPE-1, KOLAGEN TIPE-IV, GLOMERULOSKLEROSIS, INTERSTISIAL FIBROSIS, ALBUMINURIA PADA KEJADIAN NEFROTOKSIK DOXORUBICIN DAN NEFROPROTEKTIF PENTOXIFYLLIN DENGAN HEWAN COBA MENCIT GALUR SWISS JANTAN

Pemakaian Doxorubicin (DXR) dalam pengobatan kanker semakin meningkat, dengan meningkatnya morbiditas kanker. Efek nefrotoksik dari DXR masih menjadi masalah. Pentoxify/Jin (PTX) sebagai bahan penghasil elektron dapat bersifat nefroprotektif. Sehingga kombinasi DXR dan PTX akan menurunkan efek nefrotoksik dari DXR. Penelitian ini bertujuan menjelaskan perbedaan ekspresi TGF-β1, kolagen tipe-l, kolagen tipe-IV, MMP-9, glomerulosklerosis, interstisial fibrosis, dan albuminuria pada keadaan normal, nefrotoksik dan nefroprotektif. Empat puluh delapan ekor mencit galur Swiss jantan, dibagi dalam tiga kelompok yaitu kelompok Kontrol (K) diinjeksi dengan NaCl 0,9%; Perlakuan (P) diinjeksi DXR; dan Terapi (T) diinjeksi DXR dan PTX secara i.p, masing-masing kelompok 16 ekor. Injeksi dilakukan satu kali seminggu selama tiga minggu berturut-turut. Pada minggu ke-4 dan ke-8 pasca perlakuan, masing-masing kelompok dikorbankan 8 ekor. Pemeriksaan ekspresi TGF-β1, kolagen tipe-l, kolagen tipe-IV, MMP-9 dengan teknik imunohistokimia menggunakan antibodi monoklonal. Pemeriksaan glomerulosklerosis dan interstisial fibrosis secara histopatologis, menggunakan teknik pewarnaan Verheoff van Giesen. Sedangkan pemeriksaan albuminuria dengan teknik elisa menggunakan monoklonal albumin. Analisis data menggunakan uji anova. DXR menyebabkan peningkatan ekspresi TGF-β1, kolagen tipe-l, kolagen tipe-IV, glomerulosklerosis, interstitial fibrosis, albuminuria dan penurunan MMP-9. Hal sebaliknya terlihat pada pemberian PTX yang dikombinasikan dengan DXR. Kombinasi DXR dan PTX dapat digunakan untuk menurunkan efek nefrotoksik DXR. Kata kunci: doxorubicin; pentoxyfinine; gtomerutoskterosis; interstitial fibrosi

MEPicides: Potent antimalarial prodrugs targeting isoprenoid biosynthesis

AbstractThe emergence of Plasmodium falciparum resistant to frontline therapeutics has prompted efforts to identify and validate agents with novel mechanisms of action. MEPicides represent a new class of antimalarials that inhibit enzymes of the methylerythritol phosphate (MEP) pathway of isoprenoid biosynthesis, including the clinically validated target, deoxyxylulose phosphate reductoisomerase (Dxr). Here we describe RCB-185, a lipophilic prodrug with nanomolar activity against asexual parasites. Growth of P. falciparum treated with RCB-185 was rescued by isoprenoid precursor supplementation, and treatment substantially reduced metabolite levels downstream of the Dxr enzyme. In addition, parasites that produced higher levels of the Dxr substrate were resistant to RCB-185. Notably, environmental isolates resistant to current therapies remained sensitive to RCB-185, the compound effectively treated sexually-committed parasites, and was both safe and efficacious in malaria-infected mice. Collectively, our data demonstrate that RCB-185 potently and selectively inhibits Dxr in P. falciparum, and represents a promising lead compound for further drug development.</jats:p

Synthetic fosmidomycin analogues with altered chelating moieties do not inhibit 1-deoxy-D-xylulose 5-phosphate reductoisomerase or Plasmodium falciparum growth in vitro

Fourteen new fosmidomycin analogues with altered metal chelating groups were prepared and evaluated for inhibition of E. coli Dxr, M. tuberculosis Dxr and the growth of P. falciparum K1 in human erythrocytes. None of the synthesized compounds showed activity against either enzyme or the Plasmodia. This study further underlines the importance of the hydroxamate functionality and illustrates that identifying effective alternative bidentate ligands for this target enzyme is challenging

Albumin-conjugated PEG liposome enhances tumor distribution of liposomal doxorubicin in rats

To evaluate the effect of coupling of recombinant human serum albumin (rHSA) onto the surface of poly(ethylene glycol)-modified liposorne (PEG liposome) on the in vivo disposition characteristics of liposomal doxorubicin (DXR), the pharmacokinetics and tissue distribution of DXR were evaluated after intravenous administration of rHSA-modified PEG (rHSA/PEG) liposomal DXR into tumor-bearing rats. rHSA/PEG liposome prepared using a hetero-bifunctional cross-linker, N- succinimidyl 3-(2-pyridyldithio) propionate (SPDP), efficiently encapsulated DXR (over 95%). rHSA/PEG liposomal DXR showed longer blood-circulating property than PEG liposornal DXR and the hepatic and splenic clearances of rHSA/PEG liposornal DXR were significantly smaller than those of PEG liposomal DXR. It was also demonstrated that the disposition of DXR to the heart, one of the organs for DXR-related side-effects, was significantly smaller than free DXR. Furthermore, the tumor accumulation of rHSA/PEG liposomal DXR was significantly larger than that of PEG liposomal DXR. The &#34;therapeutic index&#34;, a criterion for therapeutic outcome, for rHSA/PEG fiposornal DXR was significantly higher than PEG liposomal DXR. These results clearly indicate that rHSA-conjugation onto the surface of PEG liposome would be a useful approach to increase the effectiveness and safety of PEG liposomal DXR.</p

Immunoliposome-mediated targeting of doxorubicin to human ovarian carcinoma in vitro and in vivo.

This paper deals with the utility of immunoliposomes for the delivery of doxorubicin (DXR) to human ovarian carcinoma cells in vitro and in vivo. We aimed to investigate whether immunoliposome-mediated targeting of DXR to ovarian cancer cells translates in an enhanced anti-tumour effect compared with that of non-targeted DXR liposomes (lacking the specific antibody). Target cell binding and anti-tumour activity of DXR immunoliposomes were studied in vitro and in vivo (xenograft model of ovarian carcinoma). In vitro we observed that target cell binding and cell growth inhibition of DXR immunoliposomes is superior to that of non-targeted DXR-liposomes. However, in vivo, despite the efficient target cell binding and good anti-tumour response of DXR-immunoliposomes, no difference in anti-tumour effect, compared with non-targeted DXR-liposomes, could be determined. The results indicate that premature DXR leakage from immunoliposomes occurring before the actual target cell binding and subsequent DXR association with the tumour cells, explains why no significant differences in anti-tumour activity between DXR-immunoliposomes and non-targeted DXR-liposomes were observed in vivo

REDUCED CARDIOTOXICITY AND INCREASED CYTOTOXICITY IN A NOVEL ANTHRACYCLINE ANALOG, 4'-AMINO-3'-HYDROXY-DOXORUBICIN

The acute and chronic cardiotoxicity and cytotoxicity of the novel doxorubicin (DXR) derivative 4'-amino-3'-hydroxy-DXR were compared with those of 4'-deoxy-DXR and DXR. In the acute cardiotoxicity study, the ECG and hemodynamic changes recorded in anesthetized rats that had been treated i.v. with 10 mg/kg 4'-amino-3'-hydroxy-DXR or 8.6 mg/kg 4'-deoxy-DXR were significantly less severe than those caused by 13 mg/kg DXR. In the chronic cardiotoxicity study, rats received 3 weekly i.v. injections of 3 mg/kg DXR, 3 mg/kg 4'-amino-3'-hydroxy-DXR, or 2 mg/kg 4'-deoxy-DXR during the first 14 days of the study and were observed for an additional 35-day period. DXR induced severe cardiomyopathy that was characterized by ECG changes in vivo (S-alpha-T-segment widening and T-wave flattening) and by impairment of the contractile responses (F(max), +/- dF/dt(max)) to adrenaline of hearts isolated from treated animals. 4'-Deoxy-DXR caused a progressive enlargement of the S-alpha-T segment in vivo and a significant impairment of the - dF/dt(max) value in vitro, which were less severe than those produced by DXR. The least cardiotoxic drug was 4'-amino-3'-hydroxy-DXR, which induced minor ECG changes without causing significant alterations in the contractile responses of isolated hearts to adrenaline. On the basis of the drug concentration required to inhibit 50% of the colony formation (IC50) of cell lines in vitro, 4'-amino-3'-hydroxy-DXR was less active than 4'-deoxy-DXR but at least twice as active as DXR against human cancer and murine transformed cell lines. These data indicate that 4'-amino-3'-hydroxy-DXR is significantly less cardiotoxic and more cytotoxic than DXR

Efek Protektif Andrografolid terhadap Kejadian Kardiotoksisitas Pasca Aplikasi Doksorubisin pada Tikus

Cardiotoxicity is one of the important side effects of doxorubicin, an anthracycline antibiotic and chemotherapeutic drug. The aim of this study was to explore the potential protective effect of andrographolide (Andro), an anti-inflammatory and anti-oxidant agents, against cardiotoxicity induced by doxorubicin (DXR). Thirty Sprague Dawley rats (80-100 g) were divided into four groups: (a) Control (b) DXR (4 mg/kg intraperitoneally (IP) were made weekly for 4 weeks), (c) DXR+Andro20 (low dose andro; 20 mg/kg IP weremade daily for 4 weeks, 24 h after DXR), (d) DXR+Andro100 (high dose andro; 100 mg/kg IP were made daily for 4 weeks, 24 h after DXR). Furthermore, at the end of experimental period, all rats were euthanized and hearts were removed for hispatological analyses. Hematoxylin-eosin (HE) and Masson Trichrome (MT) staining were used to observe the histomorphological alterations and fibrosis of hearts, respectively. Our results showed that andrographolide treatment (20 mg/kg) augmented the detrimental effects of DXR such as decreased body weight and heart weight, as compared with those in DXR-treated rats. Histopathologically, heart tissue from control group showed compact myocardial architecture without any noticeable lesions. Histopathological analysis fromDXR group showed severe inflammation and fibrosis, whereas DXR+Andro20 group showed almost normal heart morphology. Andrographolide at a dosage of 100 mg/kg did not show protective effects against doxorubicin,and even aggravated myocardial inflammation, as compared with DXR-treated rats. These results indicate that low dose of andrographolide compromised doxorubicin-induced decreased body weight, heart inflammation, andfibrosis

Bone mineral density by digital X-ray radiogrammetry is strongly decreased and associated with joint destruction in long-standing Rheumatoid Arthritis: a cross-sectional study

<p>Abstract</p> <p>Background</p> <p>The aims were to explore bone mineral density (BMD) by digital X-ray radiogrammetry (DXR) in postmenopausal women with long-lasting rheumatoid arthritis (RA) in relation to dual x-ray absorptiometry (DXA)-BMD, joint destruction by conventional radiographs and disease related variables in a cross-sectional study.</p> <p>Methods</p> <p>Seventy-five postmenopausal women with RA were examined by DXA measuring DXA-BMD of the forearm, total hip and lumbar spine, by scoring joint destruction on plain radiographs by the method of Larsen and by DXR-BMD in metacarpals two to four. The DXR-BMD results of the RA women were compared with an age and sex-matched reference database. A function of DXR-BMD in relation to age and disease duration was created. Associations were investigated by bivariate and multiple linear regression analyses.</p> <p>Results</p> <p>DXR-BMD was strongly decreased in RA patients compared to the reference database (p < 0.001). Calculations showed that DXR-BMD was not markedly influenced the first years after diagnosis of RA, but between approximately 5-10 years of disease there was a steep decline in DXR-BMD which subsequently levelled off. In multiple regression analyses disease duration, CRP and DXR-BMD were independent variables associated with Larsen score (R²= 0.64). Larsen score and BMD forearm were independent determinants of DXR-BMD (R²= 0.79).</p> <p>Conclusions</p> <p>DXR-BMD was strongly reduced and associated with both Larsen score and DXA-BMD forearm in these postmenopausal women with RA implying that DXR-BMD is a technique that reflects both the erosive process and bone loss adjacent to affected joints.</p