Mycophenolic Acid Derivatives Research Articles

A Novel Lactam and Two Rare Mycophenolic Acid Derivatives from the Fungus Penicillium Sclerotiorum JBHL321.

A novel lactam penicillactam (1), two rare mycophenolic acid (MPA) derivatives penimycophens A and B (2 and 3), together with two known biogenetically related MPA derivatives (4 and 5) and a known alkaloid (6) were isolated from the Penicillium sclerotiorum JBHL321. The structures of these compounds were determined by comprehensive spectroscopic analyses. The absolute configuration of 1 was confirmed by electronic circular dichroism (ECD) calculations. Compound 1 represent the rare example of a oxygen bridge-linked lactam from natural products. Structurally, compounds 2 and 3 were rare MPA derivatives featuring a methoxy group at C-3. The inhibitory activity of compounds 1-6 against two phytopathogenic fungi, three phytopathogenic bacteria and four cancer cell lines were evaluated. Compounds 2-5 exhibited significant cytotoxic activity against HeLa, MCF-7, A549 and MGC-803 cells with IC50 values in the low micromolar to nanomolar. Compound 3 exhibited especially cytotoxic activity against four different cell lines with IC50 values ranging from 0.06-0.14 μM, compared to IC50 values ranging from 0.62-2.51 μM for epirubicin.

Three New Antibacterial Mycophenolic Acid Derivatives from the Marine-Derived Fungus Penicillium sp. HN-66.

Three new mycophenolic acid derivatives, penicacids L-N (1-3), together with four known analogues, were isolated from a fungus Penicillium sp. HN-66 derived from a South China Sea marine sediment. The structures of compounds 1-3 were determined on the basis of HR-ESI-MS, NMR (1H, 13C, HSQC and HMBC) data analyses, and comparison of optical rotations. Antimicrobial activities of 1-7 were tested. The results showed that compounds 1-3 and 5-7 had weak inhibitory effects against E. coli ATCC 25922 with the MIC values of 50 μg/mL.

Approaches Towards Better Immunosuppressive Agents.

Several classes of compounds are applied in clinics due to their immunosuppressive properties in transplantology and the treatment of autoimmune diseases. Derivatives of mycophenolic acid, corticosteroids and chemotherapeutics bearing heterocyclic moieties like methotrexate, azathioprine, mizoribine, and ruxolitinib are active substances with investigated mechanisms of action. However, improved synthetic approaches of known drugs and novel derivatives are still being reported to attempt better accessibility and therapeutic properties. In this review article, we present the synthesis of the designed chemical structures based on recent literature reports concerning novel compounds as promising immunosuppressive drugs. Moreover, some of the discussed derivers revealed also other types of activities with prospective medicinal potential.

Cytotoxic and antimicrobial mycophenolic acid derivatives from an endophytic fungus Penicillium sp. MNP–HS–2 associated with Macrozamia communis

Macrozamia communis and its associated endophytic fungi are untapped sources of bioactive metabolites with great potential for medicinal exploitation. Chemical investigation of the mycelial extract derived from an endophytic fungus Penicillium sp. MNP–HS–2 associated with M. communis fruit afforded four mycophenolic acid derivatives recognized as previously undescribed natural products (1–4), together with nine known metabolites (5–13). Chemical structures of isolated compounds were determined based on extensive spectroscopic analyses, including 1D/2D NMR and HRESIMS. The absolute stereochemistry of alternatain E (1) was unambiguously established by comparing its experimental and calculated time-dependent density functional theory electronic circular dichroism spectra (TDDFT-ECD). All isolated compounds were assessed for their antimicrobial and cytotoxic activities, where mycophenolic acid methyl ester (7), displayed significant cytotoxic activity against seven different cell lines with IC50 values in the low micromolar to nanomolar range. Mycophenolene A (3) exhibited significant antibacterial activity against Staphylococcus aureus (MIC = 2.1 μg/mL).

Low Incidence of Acute Antibody-Mediated Rejection after HLA Desensitization in Living Donor Kidney Transplant Recipients.

Desensitization allows the performance of human leukocyte antigen (HLA)-incompatible transplants. However, the incidence of acute rejection (AR) is high. This study aims to analyze the incidence of AR after transplantation with HLA-incompatible living donors in patients who underwent desensitization. Patients were immunosuppressed with tacrolimus, mycophenolic acid derivatives, and steroids after being desensitized with rituximab, plasma exchange, and/or immunoadsorption with specific cytomegalovirus immunoglobulins. A negative complement-dependent cytotoxicity or flow cytometry crossmatch and a donor-specific antibody titer < 1000 mean fluorescence intensity (MFI) were used to determine desensitization efficacy. A total of 36 patients underwent desensitization, and 27 (75%) were transplanted. After a follow-up of 58 ± 58 months (Min−Max: 0.13−169.5), five episodes of AR occurred: two antibody-mediated and three T-cell-mediated. No differences were found in baseline calculated panel-reactive antibodies (cPRA), class I or II MFI, number of antibodies, or Relative Intensity Scale (RIS) between AR and non-AR patients. Patients with antibody-mediated AR had higher cPRA (NS), MFI class I (p = 0.07) and class II (p = 0.006), and RIS (p = 0.01). The two patients with antibody-mediated AR and one patient with T-cell-mediated AR lost their grafts. In conclusion, the incidence of acute antibody-mediated rejection after desensitization was 7.4%, which occurred early post-transplantation in patients with high MFI and was associated with early graft loss.

Novel amides of mycophenolic acid and some heterocyclic derivatives as immunosuppressive agents

The group of 18 new amide derivatives of mycophenolic acid (MPA) and selected heterocyclic amines was synthesised as potential immunosuppressive agents functioning as inosine-5′-monophosphate dehydrogenase (IMPDH) uncompetitive inhibitors. The synthesis of 14 of them employed uronium-type activating system (TBTU/HOBt/DIPEA) while 4 of them concerned phosphonic acid anhydride method (T3P/Py) facilitating amides to be obtained in moderate to excellent yields without the need of phenolic group protection. Most of optimised protocols did not require complicated reaction work-ups, including chromatographic, solvent-consuming methods. The biological activity assay was performed on the T-Jurkat cell line and peripheral mononuclear blood cells (PBMCs) which are both dedicated for antiproliferative activity determination. Each of designed derivatives was characterised by reduced cytotoxicity and benzoxazole analogue (A2) revealed the most promising activity. Subsequently, an observed structure-activity relationship was discussed.

Liver transplant program at Botkin Hospital. Experience of 100 surgeries

Objective: to present an analysis of the results of 100 cadaveric liver transplants performed at Botkin Hospital from July 2018 to October 2021. Materials and methods. From July 2018 to October 2021, 100 orthotopic liver transplantation (LTx) from a deceased donor were performed at the surgical clinic of Botkin Hospital. The recipients were 58 males (58%) and 42 females (42%). The mean age of the recipients was 48.73 ± 8.56 (24–66) years, while their mean MELD was 19.54 ± 4.35 (15–33). The main indications for LTx were cirrhosis resulting from chronic viral hepatitis (CVH) C (52%), nutritional-toxic cirrhosis (20%), autoimmune liver and bile duct disease (18%), CVH B (7%), and hepatocellular carcinoma (HCC) (3%). During the period under study, 119 potential liver transplant donors were evaluated. The mean age of the donors was 44.2 ± 11.12 (21–63) years. Median levels of sodium, aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin were 141 (138–146) mmol/L, 27 (20.7–47.4) units/L, 25 (17–41.5) units/L, and 9.65 (6.42–13.7) μmol/L, respectively. The median graft hepatic steatosis was 10% (5–15). LTx was performed using the piggyback technique (99/100 cases) and classic technique with inferior vena cava resection (1/100). End-to-end porto-portal vein anastomosis was performed (99/100 cases). Anastomosis of the donor organ’s portal vein with the recipient’s left gastric vein due to occlusive thrombosis of the recipient’s portal vein was carried out (1/100). In all cases, a continuous end-to-end arterial anastomosis was formed. End-to-end choledochocholedochal anastomotic strictures (95/100) and end-to-side hepaticojejunostomy (5/100) were formed. Results. Median cold ischemia time was 312.5 minutes (280–380). Mean operative time was 488.91 ± 65.34 (95% CI: 475.9–501.9) minutes, median intraoperative blood loss was 1000 (600–1500) mL. Thirty-day mortality was 2% (Clavien–Dindo class V). Early postoperative complications (Clavien–Dindo class IIIa–IVa) developed in 12/100 patients (12%). Graft arterial thrombosis occurred in 3 cases (3%), biliary anastomotic strictures in 6 (6%), and subhepatic hematoma in 2 (2%). The average intensive care unit (ICU) bed day was 2.34 ± 1.67 (1–8). Total postoperative bed-day was 14.63 ± 5.35 (10–39). During case follow-up, a prolonged form of calcineurin inhibitor (CNI) was administered as immunosuppressive therapy in mono regimen (85 patients), in combination with mycophenolic acid derivatives (7), and in combination with everolimus (6). Of the 93 patients, 46 patients (49.46%) had the new coronavirus infection (COVID-19) before or after transplantation; in no case did COVID-19 lead to death. Six patients (13.04%) were hospitalized due to COVID-19. To date, 33/93 (25.48%) patients have been vaccinated, resulting in 75 (75%) liver transplant recipients immune to COVID-19. The overall 1-year survival rate was 95% and the 3-year survival rate was 91%. Conclusion. Introduction of LTx in multidisciplinary hospitals allows to, already at the start of the program, achieve immediate and long-term treatment outcomes (in decompensated diffuse liver disease) that are comparable to those of leading transplantation centers.

Mammalian Target of Rapamycin Inhibitors and Wound Healing Complications in Kidney Transplantation: Old Myths and New Realities.

Mammalian target of rapamycin inhibitors (mTOR-I) lacks nephrotoxicity, has antineoplastic effects, and reduces viral infections in kidney transplant recipients. Earlier studies reported a significant incidence of wound healing complications and lymphocele. This resulted in the uncomfortable willingness of transplant clinicians to use these agents in the immediate posttransplant period. As evidence and experience evolved over time, much useful information became available about the optimal use of these agents. Understandably, mTOR-I effects wound healing through their antiproliferative properties. However, there are a lot of other immunological and nonimmunological factors which can also contribute to wound healing complications. These risk factors include obesity, uremia, increasing age, diabetes, smoking, alcoholism, and protein-energy malnutrition. Except for age, the rest of all these risk factors are modifiable. At the same time, mycophenolic acid derivatives, steroids, and antithymocyte globulin (ATG) have also been implicated in wound healing complications. A lot has been learnt about the optimal dose of mTOR-I and their trough levels, its combinations with other immunosuppressive medications, and patients' profile, enabling clinicians to use these agents appropriately for maximum benefits. Recent randomized control trials have further increased the confidence of clinicians to use these agents in immediate posttransplant periods.

Synthesis and evaluation of mycophenolic acid derivatives as potential anti-Toxoplasma gondii agents

Nineteen mycophenolic acid (MPA) derivatives were designed and synthesized, and their anti-Toxoplasma activity evaluated for the first time. Among them, N-propylimidazole-modified compound E5 demonstrated the strongest activity, and the IC50 against HFF-1 (Human Foreskin Fibroblasts-1) cells following infection with T. gondii is 80.9 μM (MPA-211.5 μM) and its selectivity index is 2.2 (MPA-1.2). In vivo experiments, E5 can significantly inhibit the proliferation of tachyzoites in the abdominal cavity of mice acutely infected with T. gondii (inhibition rates 46.7%), and this inhibitory effect was greater than that of spiramycin (inhibition rates 31.3%) and MPA (inhibition rates 15.9%), this indicated that E5 had significant protective effects on the host during acute Toxoplasma infection. In addition, E5 can reduce the levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in the serum of infected mice, significantly increase the level of glutathione (GSH) in the liver, and significantly reduce the level of malondialdehyde (MDA), indicating that it has a hepatoprotective effect against T. gondii infection. Similarly, E5 can relieve hepatomegaly and splenomegaly induced by acute Toxoplasma infection. Spiramycin aggravated appetite loss in infected mice, while E5 did not. In summary, the results indicated that E5 has potential as a candidate anti-T. gondii drug.

Edema Associated With Everolimus de Novo

The appearance of edema limits the use of everolimus de novo together with tacrolimus and steroids in kidney transplantation. We aimed to investigate the frequency and characteristics of patients with edema and compare them according to the type of immunosuppression. We studied 150 kidney transplant recipients between 2015 and 2017 based on receiving everolimus de novo (group A) or mycophenolic acid derivatives (group B). We analyzed 50 patients in group A and 100 in group B. Follow-up was 26.2 ± 10 months. Fifty-six patients presented edema (37.3%): 54% in group A and 29% in group B (P=.003). Edema was mild in 74% of patients in group A and 57.1% in group B. The probability of edema was 10.1%, 22.4%, and 41% at 3, 6, and 12 months, respectively, in group A vs 10.1%, 20.3%, and 25.4% in group B (P=.006). Patients were treated mostly with diuretics (14.3% in group A vs 27.6% in group B) and discontinuation of calcium channel blockers (46.4% in group A vs 48.3% in group B). Improvement was 70.4% in group A vs 60.7% in group B; patient worsening was 0% in group A vs 10.7% in group B; and there was no change in 29.6% in group A vs 28.6% in group B. We did not find differences in patient or graft survival in those who presented edema, regardless of the treatment group. The use of everolimus and standard doses of tacrolimus caused edema in 54% of patients, with no impact on renal function or survival compared with mycophenolic acid derivatives. The edema was mostly of low intensity and improved in most patients.

Penicacids H-J, three new mycophenolic acid derivatives from the marine-derived fungus Rhizopus oryzae.

Chemical investigation of secondary metabolites in crude methanol extract of a solid rice medium of a marine-derived fungus, Rhizopus oryzae, has enriched the metabolic profile of this genus by affording three mycophenolic acid derivatives recognized as new fungal metabolites trivially named as penicacids H–J (1–3), along with two known naphtho-γ-pyrone dimers, asperpyrone A (4) and dianhydroaurasperone C (5). Structure elucidation of isolated compounds was unambiguously determined based on extensive 1D and 2D NMR spectroscopic analyses together with comparing coupling constant and optical rotation values with those reported for related congeners in literature. All isolated compounds were assessed for their antibacterial activity against four different bacterial microorganisms and they revealed moderate to weak activities with minimum inhibitory concentration (MIC) values ranging from 62.5 to 250 μg mL−1.

Recommendations when switching therapy from immunosuppressive drugs to dupilumab in patients with atopic dermatitis

Basierend auf neuen Erkenntnissen zur molekularen Pathogenese der atopischen Dermatitis, wurde neben Glukokortikoiden und Ciclosporin mit Dupilumab nun auch eine zielgerichtete antientzündliche Systemtherapie zugelassen. Wegen ihrer Pharmakologie sind weder Glukokortikoide und Ciclosporin noch die außerhalb der Zulassung angewendeten Substanzen Methotrexat, Azathioprin und Mycophenolsäurederivate für eine Langzeittherapie geeignet. Bei der Umstellung der Therapie von den genannten niedermolekularen Substanzen auf Dupilumab sollten verschiedene Faktoren berücksichtigt werden. Hierbei sind sowohl der konkrete Anlass der Umstellung (Unwirksamkeit, unerwünschte Wirkungen oder sich einstellende Kontraindikationen) als auch die pharmakologischen Gegebenheiten zu berücksichtigen. Da es hierzu bisher keine konkreten klinischen Untersuchungen gibt, haben die Autoren auf der Grundlage einer Literaturrecherche Handlungsempfehlungen für den praktischen Alltag erarbeitet.

Penicacids E-G, three new mycophenolic acid derivatives from the marine-derived fungus Penicillium parvum HDN17-478.

Three new mycophenolic acid derivatives, penicacids E-G (1-3), together with three known analogues, mycophenolic acid (4), 4'-hydroxy-mycophenolic acid (5) and mycophenolic methyl ester (6), were isolated from a marine-derived fungus Penicillium parvum HDN17-478 from a South China Sea marine sediment sample. The structures of compounds 1-3 were elucidated by HRMS, NMR, and Mosher's method. Among them, compounds 1 and 2 were the first examples of mycophenolic acid analogs with a double bond at C-3'/C-4' position. The cytotoxicity of 1-6 was evaluated against the HCT-116, BEL-7402, MGC-803, SH-SY5Y, HO-8910 and HL-60 cell lines, and compounds 4 and 6 showed potent cytotoxicity with IC50 values ranging from 1.69 to 12.98 μmol·L-1.

P0353EFFECT OF RITUXIMAB IN PATIENTS WITH RELAPSED OR REFRACTORY PRIMARY MEMBRANOUS NEPHROPATHY

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of glomerulonephritis in non-diabetic adults. B-cell dysfunction is an important pathway involved in pathogenesis. We, therefore, investigated effects of rituximab (RTX) on the outcome of patients with relapsed or refractory primary MN. Method In this retrospective analysis, 48 patients with primary MN were evaluated. Patients, who had relapsed or refractory biopsy-proven disease, with a nephrotic-range proteinuria despite at least six months of prior immunosuppressive therapy using corticosteroids, calcineurin inhibitors or mycophenolic acid derivatives, which were used according to KDIGO guidelines. All patients received at least 2 doses of 375 mg/m2 of RTX. Proteinuria and serum albumin levels of the patients were recorded at baseline, and 3,6,12,18 and 24 months. Results Of 48 patients who participated in this study, 27(56.3%) were male. Mean age was 45.3±17.2 years. Results of serum anti-phospholipase-A2-receptor (PLA2R) were available in 31 patients, 23 of whom (74%) were positive. Proteinuria levels at 3, 6, 12, 18, and 24 months after treatment with RTX showed a significant decrease when compared to baseline (p&amp;lt;0.05) (Figure 1): From 7±3.5 g/24h at baseline to 2.6±2.4 g/24h at 12 months. Serum albumin levels at 3, 6, 12, 18, and 24 months after RTX significantly increased compared to baseline values (p&amp;lt;0.05) (Figure 2): From 2.97±0.76 g/dl at baseline to 3.88±0.67 g/dl at 12 months. Conclusion Treatment with RTXiseffective in patients suffering from relapsed or refractory primary MN.

P0406ASSOCIATION OF MICROHEMATURIA WITH OUTCOMES IN ADULT PATIENTS WITH IGA NEPHROPATHY

Abstract Background and Aims Although hematuria is the cardinal symptom of IgA nephropathy (IgAN), its effects on the outcome have not been studied extensively. We, therefore, aimed to analyze the association between microhematuria and clinicopathological features as well as outcome parameters in adult patients with IgAN. Method 129 adults with IgAN, diagnosed by kidney biopsy, and followed up for a median duration of 54.5 (IQR: 24.25-92.75) months, were included in this retrospective study. Urinary sediment analyses during the bouts of macrohematuria were not taken into consideration. For the purpose of this analysis, microhematuria was described as ≥5 red blood cells per high-power field (RBCs/hpf) and classified as mild (5-9 RBCs/hpf), moderate (10-19 RBCs/hpf), or severe (≥20 RBCs/hpf). Study outcome (event) was defined as at least a 50% reduction in baseline eGFR or development of stage 5 chronic kidney disease (eGFR &amp;lt;15 ml/min/1.73 m2). eGFRs of the patients were calculated by using CKD-EPI formula. Results Demographic, clinical, laboratory and histopathological features of patients at the time of diagnosis are summarized in the table. Usage of ACEi/ARBs [75/81 (92.5%) vs 45/48 (93.75%), p=0.803], fish oil [30/81 (37%) vs 19/48 (39.5%), p=0.773], azathioprine [16/81 (19.7%) vs 10/48 (20.8%), p=0.882] and mycophenolic acid derivatives [14/81 (17.2%) vs 11/48 (22.9%), p=0.434] were comparable among the patients with and without microhematuria. Corticosteroids were more frequently used in patients with microhematuria [41/81 (50.6%) vs 17/48 (35.4%)], although this difference was not statistically significant (p=0.093). Overall 30 patients (23.2%) reached the study outcome, and there were no differences between patients with (19, 23.4%) and without (11, 22.9%) microhematuria (p=0.944). Kaplan-Meier analysis revealed that event free survival rates were similar across study groups: 77.1% for patients without microhematuria; while 80% for mild, 77.3% for moderate, and 72.7% for severe microhematuria (p=0.436) (Figure). Microhematuria did not predict the study outcome when multivariable Cox regression analyses were performed [HR: 1.847 (95% CI: 0.696-4.904), p=0.218]. Throughout the follow-up, microhematuria disappeared (dropped below 5 RBCs/hpf) in 43 patients (53%), 8 of whom (18.6%) reached the study outcome as compared to 11 patients (28.9%) with persistent microhematuria (p=0.273). Disappearance of microhematuria was not a predictor of study outcome, as well [HR: 0.386 (95% CI: 0.068-2.180), p=0.281]. Conclusion Microhematuria is not associated with renal outcomes of adult patients with IgAN.

Anticancer Properties of Amino Acid and Peptide Derivatives of Mycophenolic Acid.

Although Mycophenolic Acid (MPA) is applied as prodrugs in clinic as an immunosuppressant, it also possesses anticancer activity. MPA acts as Inosine-5'-Monophosphate Dehydrogenase (IMPDH) inhibitor, where the carboxylic group at the end of the side chain interacts with Ser 276 of the enzyme via hydrogen bonds. Therefore, MPA derivatives with other polar groups indicated high inhibition too. On the other hand, potent anticancer agents like dacarbazine and cisplatin give numerous side-effects. Based on the literature data, MPA derivatives should be explored towards anticancer properties. Conversion of the carboxylic group of MPA to amide could maintain antiproliferative activity. Therefore, we decided to investigate several amino acid and peptide derivatives of MPA against chosen cancer cell lines in vitro. Amides of MPA hold threonine and arginine amino acid unit. These amino acid derivatives were tested as L and D enantiomers and both in free acid and methyl esters forms. Additionally, MPA was modified with tuftsin or retro-tuftsin as biologically active peptides, which could act as a drug carrier. Amino acid and peptide derivatives of MPA were investigated in vitro as potential anticancer agents on cell lines: Ab melanoma, A375 melanoma and SHSY5Y neuroblastoma. The activity of the tested compounds was compared to parent MPA and known chemotherapeutics: dacarbazine and cisplatin. Amino acid moiety and the sequence of amino acids in the peptide part influenced observed activity. The most active amino acid MPA analogues occurred to be D and L-threonine derivatives as methyl esters, probably due to better cell membrane penetration.

Immunosuppressive properties of amino acid and peptide derivatives of mycophenolic acid

Mycophenolic acid (MPA) was coupled with amino acids and biologically active peptides including derivatives of tuftsin to modify its immunosuppressive properties. Both amino acid unit in the case of simple MPA amides and modifications within peptide moiety of MPA - tuftsin conjugates influenced the observed activity. Antiproliferative potential of the obtained conjugates was investigated in vitro and MPA amides with threonine methyl ester and conjugate of MPA with retro-tuftisin occurred to be more selective against PBMC in comparison to parent MPA. Both amino acid and peptide derivatives of MPA acted as inosine-5′-monophosphate dehydrogenaze (IMPDH) inhibitors.

Identification of α-Glucosidase Inhibitors from Cyperus articulatus L. Rhizome Extract Using HRLC-MS/MS and Molecular Docking

Cyperus articulatus is widely distributed in Indian subcontinent and its rhizome has been used as folk medicine in different geographical regions for treatment of diseases like malaria, epilepsy and dysentery. In present study the rhizome extracts were studied to identify the natural inhibitor compounds for α-amylase and α-glucosidase. Among six different solvent extracts of the rhizome, the acetone extract which showed to have highest phenolics and flavonoids exhibited α-glucosidase inhibition (IC50 9.1 μg/mL). Different fractions were collected using column chromatography and flash chromatography to analyze the active fractions. Two major fractions significantly showed high enzyme inhibitory activity. In HRLC-MS/MS phenolic as well as non-phenolic class of compounds were identified such as quercetrin, dihydroquercetin, mycophenolic acid, koparin-2-methylether, C16-sphinganine, embelin, phytosphingosine, colforsin, 7,8-dihydroxystearic acid and palmitic acid derivative. The two active fractions having IC50 8.38 and 7.65 μg/mL, were shown to exhibit competitive and mixed type inhibition, respectively. Molecular docking analysis of the compounds with the α-glucosidase active site showed that the phenolic class of compounds have efficient binding with one of the aspartate (Asp66, Asp349 and Asp212) residues whereas there was non-polar contacts with other residues in case of non-phenolic compounds such as long chain hydroxyl acids. The results suggest that Cyperus articulatus rhizome is a potential source of drug ingredients for the management of type-II diabetes.

Immunosuppressives and enteral feeding tubes: An integrative review.

Immunosuppression is the main goal in the treatment of autoimmune diseases, chronic inflammatory diseases, and solid organ and tissue transplantation. However, due to a lack of liquid-form medications, it is challenging to achieve adequate immunosuppression when the patient is using enteral feeding tubes. It is necessary to transform solid oral medications into other forms for administration. Besides that, the occupational risk should be considered, and safety-handling measures should be taken. This review aimed to investigate the available evidence regarding the use of immunosuppressive drugs through enteral feeding tubes, focusing on the administration technique, efficacy and treatment safety. We performed an integrative review using the databases PubMed, LILACS, SciELO, Cochrane and Google Scholar, including papers published between 1997 and 2017 in Portuguese, English and Spanish. We excluded editorials, theoretical reflections, abstracts presented at events, dissertations, theses, monographs and studies with extemporaneous formulations administered only by the oral route. In addition, we investigated the references of the included papers, as well as pharmaceutical guides, books and package inserts of selected drugs for additional evidence. Information and recommendations found were analysed and classified according to the GRADE system. Fifty papers were identified, and 14 met the selection criteria. Among the assessed immunosuppressive drugs, we observed that tacrolimus, mycophenolic acid derivatives and azathioprine were the most studied, and they have more guided recommendations regarding their use through enteral feeding tubes. We noted the need for personal protective equipment for the conversion of the solid oral dosage forms, along with special caution during administration, due to occupational hazard. Other important factors identified were the position of the tube and interactions with the enteral nutrition, because they may compromise absorption, bioavailability and serum blood levels of immunosuppressive agents. However, the studies found have methodological limitations and poor quality, and this was taken into consideration during the classification of the evidence. The lack of information about the administration of immunosuppressive drugs through enteral feeding tubes should not be a limiting factor, considering the need for treatment of patients in these circumstances. Risks and benefits must be carefully analysed, and factors regarding compounding and administration through the enteral tube must be considered before beginning treatment. Hence, more primary studies are necessary for better fundamental clinical management.

A mycophenolic acid derivative from the fungus Penicillium sp. SCSIO sof101

Mycophenolic acid (MPA) is a group of metabolite derived from several species of Penicillium, which shows potent bioactivity. In this study, a new derivative of MPA compound named penicacid D (1), was isolated from the marine derived fungus Penicillium sp. SCSIO sof101, along with seven known compounds (2-8). Their structures were elucidated based on the HR-ESI-MS and NMR data. Moreover, the 1H and 13C NMR data of compound 2 and the 13C NMR data of compound 3 are reported. Compounds 1, 4 and 6 exhibited weak activities against Escherichia coli (clinical isolation number 100385570) and Acinetobacter baumannii (clinical isolation number 100069).