Incidence Of Toxic Side Effects Research Articles

Chemotherapy combined with Shenmai injection alleviates inflammatory response and side effects in the patients with advanced colorectal cancer: A retrospective analysis

Objective: To assess the inflammatory response and side effects of chemotherapy combined with Shenmai injection (SMI) in the treatment of patients with advanced colorectal cancer (CRC). Methods: This retrospective cohort study included the clinical data of 152 patients with advanced CRC admitted to the First Affiliated Hospital of Huzhou University from April 2020 to April 2023. The patients were divided into control group (patients received chemotherapy treatment, n=75) and observation group (patients received chemotherapy combined with SMI, n=77) based on the treatment received. Tumor control rate, levels of immune function indicators before and after treatment, levels of inflammatory factor indicators, and incidence of toxic side effects in two groups were analyzed. Results: Tumor control rate in the observation group (89.61%) was higher than that in the control group (77.33%) (P<0.05). After the treatment, the levels of CD3+, CD4+, CD4+/CD8+in both groups were significantly higher than before the treatment, and significantly higher in the observation group compared to the control group (P<0.05). After the treatment, serum levels of interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-α), and interleukin-8 (IL-8) in both groups decreased compared to pretreatment levels, and was significantly lower in the observation group (P<0.05). The incidence of adverse reactions in the observation group was significantly lower than that in the control group (P<0.05). Conclusions: Compared with chemotherapy alone, chemotherapy combined with SMI better alleviates inflammatory response in patients with advanced CRC, enhance immune function, and improve tumor control rate, with a lower incidence of toxic side effects. doi: https://doi.org/10.12669/pjms.40.9.9881 How to cite this: Jin Y, Zhu W, Dai H, He X. Chemotherapy combined with Shenmai injection alleviates inflammatory response and side effects in the patients with advanced colorectal cancer: A retrospective analysis. Pak J Med Sci. 2024;40(9):---------. doi: https://doi.org/10.12669/pjms.40.9.9881 This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Delivery of SiRNA-PD-L1 by attenuated Salmonella in combination with oxaliplatin in a hepatocellular carcinoma mouse model

Oxaliplatin is currently used for chemotherapy in patients with hepatocellular carcinoma, but its increasing tolerance to tumours over time limits its clinical application. Studies have shown that high PD-L1 expression promotes the polarization of M2 macrophages. The increased infiltration of M2 macrophages, including those in HCC, is positively correlated with poor prognosis in various solid tumours. We found that oxaliplatin promoted the expression of PD-L1 in liver cancer cells, which might be attributed partly to the tolerance of tumours to oxaliplatin. Therefore, in this study, we explored the antitumour effect of attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin via Western blotting, immunohistochemistry, immunofluorescence, and flow cytometry. The results revealed that attenuated Salmonella carrying siRNA-PD-L1 combined with oxaliplatin more significantly inhibited tumour growth in tumour-bearing mice, suppressed the expression of PD-L1 in tumour tissue, increased the apoptosis of tumour cells and the expression of the tumour-related protein cleaved-caspase3, and increased the infiltration of M1 macrophages and T lymphocytes in tumour tissues. Moreover, the combination therapy increased the activation of T cells and the number of T lymphocytes and NK cells in the spleens of the mice and improved the overall antitumour immune response in the mice. Our results confirmed that attenuated Salmonella harbouring siRNA-PD-L1 combined with oxaliplatin had a significant antitumour effect and did not increase the incidence of toxic side effects, providing a theoretical reference for addressing oxaliplatin tolerance in the treatment of hepatocellular carcinoma.

Clinical Efficacy of Laparoscopic Billroth II Subtotal Gastrectomy Plus Lienal Polypeptide Injection for Gastric Cancer.

Objective To evaluate the clinical efficacy of laparoscopic Billroth II subtotal gastrectomy plus lienal polypeptide injection for gastric cancer. Methods Between May 2018 and January 2021, 110 patients with gastric cancer treated in Jingzhou First People's Hospital were recruited and assigned via the random number table method to either an observation group or a control group, with 55 patients in each group. All patients received laparoscopic Billroth II subtotal gastrectomy, and the observation group additionally received lienal polypeptide injection. Outcome measures include surgical indexes, clinical efficacy, and adverse events. Results The patients in the observation group had significantly less intraoperative hemorrhage volume, smaller surgical wounds, shorter time lapse before passing gas and hospital stay, and longer operation time than those in the control group (P < 0.001). The observation group showed significantly higher efficacy than the control group (P=0.001). The observation group had a significantly lower incidence of toxic side effects and adverse events than the control group (P < 0.05). After treatment, the CD3+ and CD4+ levels were significantly elevated and the CD8+ level was decreased, with higher CD3+ and CD4+ levels and lower CD8+ levels in the observation group than in the control group (P < 0.05). Conclusion In the treatment of patients with gastric cancer, laparoscopic Billroth II subtotal gastrectomy plus lienal polypeptide injection features promising efficacy, improves the immune function of patients, effectively reduces the occurrence of toxic side effects and adverse reactions, with less trauma and rapid recovery, which shows good potential for use in clinical application.

Keratinocyte membrane-mediated nanodelivery system with dissolving microneedles for targeted therapy of skin diseases

There is a lack of actively targeting drug delivery carriers for the topical treatment of epidermal diseases, which results in drug waste and an increased incidence of toxic side effects in the clinic. We recently discovered that epidermal cells (HaCaT cells) have homologous targeting functions and developed HaCaT cell membrane-coated pH-sensitive micelles for therapeutic active targeting of skin disease. We encapsulated shikonin in these biomimetic nanocarriers and found that the nanocarriers accumulated mainly in the active epidermis when delivered with karaya gum-fabricated water-soluble microneedles. The nanocarriers were internalized by the target cells, resulting in swelling of histidine fragments with protonation and subsequent triggering of drug release, which increased the therapeutic efficacy of shikonin against imiquimod-induced psoriatic epidermal hyperplasia. This emerging biomimetic delivery strategy is a new approach for improving the treatment of skin diseases and is also very promising for use in the field of cosmetics. Additionally, we found abnormally high protein expression of Na+/K+-ATPase in diseased skin; thus, this protein may be a biomarker of psoriasis.

Insight Into the Prospects for RNAi Therapy of Cancer.

RNA interference (RNAi), also known as gene silencing, is a biological process that prevents gene expression in certain diseases such as cancer. It can be used to improve the accuracy, efficiency, and stability of treatments, particularly genetic therapies. However, challenges such as delivery of oligonucleotide drug to less accessible parts of the body and the high incidence of toxic side effects are encountered. It is therefore imperative to improve their delivery to target sites and reduce their harmful effects on noncancerous cells to harness their full potential. In this study, the role of RNAi in the treatment of COVID-19, the novel coronavirus disease plaguing many countries, has been discussed. This review aims to ascertain the mechanism and application of RNAi and explore the current challenges of RNAi therapy by identifying some of the cancer delivery systems and providing drug information for their improvement. It is worth mentioning that delivery systems such as lipid-based delivery systems and exosomes have revolutionized RNAi therapy by reducing their immunogenicity and improving their cellular affinity. A deeper understanding of the mechanism and challenges associated with RNAi in cancer therapy can provide new insights into RNAi drug development.

A Randomized Controlled Clinical Study of Irinotecan/cisplatin Regimen and Etoposide/cisplatin Regimen in the First-line Treatment of Small Cell Lung Cancer

Objectives: This paper mainly study on the effects of irinotecan/cisplatin and etoposide/cisplatin regimens in the treatment of small cell lung cancer. Methods: 50 cases of small cell lung cancer patients in our hospital were divided into control group and experimental group and administered with etoposide/cisplatin and irinotecan/cisplatin regimen, and the treatment effects of the two regimens were compared statistically. Results: After treatment, both groups achieved high treatment efficiency, and the incidence of toxic side effects was low, with no significant difference (P&gt;0.05)? serological ABCG2 and FGFBP1 level indicators were better than the control group?both showing significant differences (P&lt;0.05). Conclusions?Irinotecan has achieved better improvement in serological indicators in the first-line treatment of small cell lung cancer, with no significant difference in short-term treatment efficiency.

A preliminary study on molecular target identification of drugs in individualized treatment of malignant solid tumors in children

Objective: To explore the role of drug-related molecular target identification in the individualized treatment of malignant solid tumors in children. Methods: The clinical data of 40 patients diagnosed with malignant solid tumors from Beijing Tongren Hospital, Capital Medical University, between June 2017 and March 2019 were retrospectively analyzed. Immunohistochemistry, polymerase chain reaction and sequencing methods were used to determine the expression levels and mutations of tumor drug molecular targets, and to compare the efficiency as well as the incidence of toxic side effects of chemotherapy using anti-tumor drugs with various molecular targets. Results: A total of 4 tumor drug-related targets were identified in 40 tumor tissue samples, namely DNA topoisomerase-ⅡA (TOPOⅡA), β(3)-tubulin (Tubulinβ(3)), DNA topoisomerase-Ⅰ(TOPOⅠ) and dihydrofolate reductase gene polymorphisms [DHFR (C829T)]. The effective rates of platinum-based agents, methotrexate, irinotecan, vinblastine and anthracycline for malignant solid tumors in children were 90.0% (36/40), 85.0% (34/40), 70.0% (28/40), 67.5% (27/40), 62.5% (25/40), respectively. The effective rates of chemotherapy with irinotecan, methotrexate, and vinblastine in mesenchymal tumors were 68.9% (20/29), 62.1% (18/29), 68.9% (20/29), respectively, which were considerably higher than 18.2% (2/11), 36.4% (4/11) and 36.4% (4/11) in non-mesenchymal tumors, with significant differences (χ(2)=5.487, 15.345, 17.278, all P<0.05). The effective rate of chemotherapy of platinum-based drugs for non-mesenchymal tumors was 72.3% (8/11), which was significantly higher than 58.6% (17/29) in mesenchymal tumors, and the difference was statistically significant (χ(2)=11.231, P<0.05). The intensity of toxic side effects in order from high to low was anthracycline > platinum > methotrexate > vinblastine > irinotecan. Conclusion: Tumor drug-related molecular targets and the sensitivity of tumors of different origins to the same anti-tumor drug as well as side effects are predicted, which provides a theoretical and clinical basis for individualized treatment of malignant tumors in children.

Differences in efficacy between drug-eluting beads transbronchial arterial chemoembolization combined with systemic chemotherapy and systemic chemotherapy alone for unresectable lung squamous cell carcinoma

Objective: To investigate the differences in efficacy between drug-eluting beads transbronchial arterial chemoembolization (DEB-BACE) combined with systemic chemotherapy and systemic chemotherapy alone for unresectable lung squamous cell carcinoma. Methods: Totally 60 cases of unresectable lung squamous cell carcinoma undergoing systemic chemotherapy in Yancheng Third People Hospital were retrospectively selected as the research object. According to patients' wishes, they were divided into chemotherapy-only group (group A) and combined treatment group (group B). Group A received gemcitabine combined with cisplatin chemotherapy. DEB-BACE was applied in the first half, and systemic chemotherapy was administered in the second half (starting 3 d after BACE). The first half and the second half of the chemotherapy dose were 1/2 of the drug dose in the chemotherapy alone group. The short-term efficacy, incidence of toxic side effects, peripheral blood T lymphocyte subsets, serum vascular endothelial growth factor (VEGF) levels, and survival time were compared between the two groups. Results: After 2 cycles of treatment, the total effective rates of group A and group B were 50.0% (15/30) and 76.7% (23/30) (P<0.05), the incidence of nausea and vomiting (63.3% vs 20.0%), decreased appetite (76.7% vs 43.3%), hair loss (86.7% vs 40.0%), and bone marrow suppression (40.0% vs 10.0%) in group A were higher than in group B (all P<0.05). After 2 cycles of treatment, the levels of CD3(+), CD4(+)and CD4(+)/CD8(+)in the two groups were higher than before treatment (group A: 47.7%±6.6% vs 52.3%±7.7%, 31.5%±4.9% vs 34.7%±5.8%, 1.05±0.24 vs 1.18±0.32; group B: 49.2%±7.0% vs 62.0%±14.0%,29.2%±5.5% vs 42.2%±7.3%, 1.07±0.26 vs 1.39±0.42; all P<0.05), while the level of CD8(+)was lower than before treatment (group A: 30.4%±5.4% vs 24.5%±4.8%; group B: 29.5%±4.1% vs 21.1%±4.5%; all P<0.05). The CD3(+), CD4(+), and CD4(+)/CD8(+) levels in group A were lower than those in group B (P<0.05), while CD8(+)level was higher than in group B (P<0.05). After 2 cycles of treatment, the VEGF levels in the two groups were lower than before treatment (group A: (423±85) vs (352±64) ng/L; group B: (404±114) vs (296±66) ng/L; P<0.05), and the VEGF level in group A was higher than that in group B (P<0.05). The 1-year survival rates of groups A and B were 54.9% and 77.9%, and the 2-year survival rates were 17.2% and 41.7% (Log rank χ(2)=4.750, P=0.029). Conclusion: DEB-BACE combined with systemic chemotherapy is superior to systemic chemotherapy in the treatment of unresectable lung squamous cell carcinoma. It can reduce toxic and side effects, improve immune function and prolong survival time, which is worthy of clinical application.

Efficacy and toxicity of abiraterone and docetaxel in octogenarians with metastatic castration-resistant prostate cancer.

To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age >80 compared to younger men. Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan-Meier method and log-rank tests. Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4months) or OS (14.0 vs 20.7months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p=0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p=0.004). Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity.

UNC569 As Novel Small Molecule Mer Receptor Tyrosine Kinase Inhibitor for Treatment of ALL

Abstract 2589 Introduction:Acute lymphoblastic leukemia (ALL) is one of the most common malignancies in children. Pediatric cure rates for ALL have dramatically increased in recent years as intensified therapeutic regimens have been developed. However, intensified therapy is associated with a significant and increased risk of short- and long-term toxicities. In addition, patients who relapse, do not reach remission, or have certain cytogenetic abnormalities have a poor prognosis and limited treatment options. Therefore, novel and less toxic therapies are needed. Tyrosine kinases are frequently abnormally regulated in cancer cells. Mer receptor tyrosine kinase is ectopically expressed in ALL cell lines and patient samples. Inhibition of Mer expression reduces pro-survival signaling, dramatically increases the sensitivity of leukemia cells to cytotoxic agents, and significantly delays development of leukemia in a mouse model. Thus, Mer tyrosine kinase inhibitors (TKIs) are excellent candidates for targeted therapies. We report here the first small molecule selective for Mer TK (UNC569) and characterization of its biochemical and anti-tumor activities in cell culture models of ALL. Methods:UNC569 is a substituted pyrazolopyrimidine that has been developed by a structure-based design and iterative medicinal chemistry from the known Mer/C52 cocrystal structure. Inhibition of Mer kinase activity by UNC569 was determined by a microfluidic capillary electrophoresis (MCE) assay in which phosphorylated and unphosphorylated substrate peptides were separated and analyzed through a LabChip EZ Reader. Western blot analysis of phosphorylated and total Mer protein was used to determine Mer inhibition by UNC569 in 697 (B-ALL) and Jurkat (T-ALL) cell lines. UNC569-mediated anti-leukemia activity was determined by detection of metabolically active cells using MTT reagent after 48 hours of exposure and by determining colony-formation in methylcellulose medium in the presence of UNC569. To investigate interactions with standard ALL therapies, apoptotic and dead cells were identified by flow cytometric analysis of cells stained with YO-PRO-1 and propidium iodide dyes after treatment with a chemotherapeutic agent alone or in combination with UNC569. Results:UNC569 is a novel small molecule Mer TKI with potent activity against Mer kinase (IC50 = 2.9 nM). In cell-based assays, UNC569 inhibited accumulation of phospho-Mer in both 697 and Jurkat ALL cells (IC50 <100 nM). Reduced proliferation and/or survival of ALL cells was also observed in 697 (IC50 = 0.91 ± 0.16 μM) and Jurkat (IC50 = 1.55 ± 0.19 μM) cultures. Treatment with UNC569 resulted in a statistically significant, dose-dependent decrease in colony-formation in Jurkat and 697 cell lines (60 ± 13.8 % (p = 0.01) and 29 ± 12.1 % (p = 0.01), respectively, relative to untreated cultures). Treatment of 697 cells with UNC569 in combination with etoposide resulted in a statistically significant increase in apoptotic and dead cells when compared with etoposide alone (43.3 ± 4.6 % vs 33.03 ± 0.73 %, p = 0.02). Treatment of Jurkat cells with a combination of UNC569 and methotrexate also resulted in a statistically significant increase in apoptotic and dead cells relative to methotrexate alone (26.9 ± 9.5 % vs 18.5 ± 5.7 %, p = 0.03). Conclusion:UNC569 is a highly effective Mer TKI that inhibits accumulation of the active phosphorylated form of Mer in B- and T-ALL cells. UNC569 mediates anti-leukemia activity against B- and T-ALL cells in culture and decreases colony-forming potential in methylcellulose. In addition, treatment with UNC569 sensitizes ALL cells to cytotoxic agents that are currently used as standard ALL therapies. Taken together, these data suggest that treatment with UNC569 may be a novel and effective ALL therapy and may be particularly effective in combination with cytotoxic therapies, thereby allowing for dose reduction and decreased incidence of toxic side effects. Disclosures:No relevant conflicts of interest to declare.

Neuromediterranee X Durres, Albanie, 8-10 Mai 2009

To assess the efficacy and toxicity of abiraterone and docetaxel in men with metastatic castration-resistant prostate cancer (mCRPC) of age > 80 compared to younger men.Retrospective chart review of 116 men treated with abiraterone and 378 men treated with docetaxel at Princess Margaret Cancer Centre. Categorical outcome measures including PSA response rate (PSA-RR) and incidence of toxic side-effects were compared using Fisher's exact test. Overall survival (OS) and biochemical progression free survival (bPFS) were analyzed using the Kaplan–Meier method and log-rank tests.Thirty-four (29%) and 50 (13%) of the men treated with abiraterone or docetaxel, respectively, were octogenarians. For abiraterone there were no significant differences in PSA-RR (42% vs. 39%), bPFS (4.7 vs. 4.4 months) or OS (14.0 vs 20.7 months) between octogenarians and younger men, respectively. Toxicity was mild with no significant differences between age groups. For men treated with docetaxel PSA-RR and OS did not differ between age groups (40% vs. 45% and 12.0 vs. 14.1 months, respectively). However, rates of febrile neutropenia were 16% and 7% for octogenarians and younger men, respectively (p = 0.048). This difference was observed despite greater use of lower dose intensity and weekly docetaxel in the elderly cohort, with 20% of them receiving lower than standard dose during their first cycle compared to 7% of younger men (p = 0.004).Treatment outcome on abiraterone and docetaxel did not differ in patients over and under the age of 80, but febrile neutropenia was more common in octogenarians treated with docetaxel despite lower dose intensity.

The effectiveness of leflunomide as a co-therapy of tumour necrosis factor inhibitors in rheumatoid arthritis: a population-based study

Background:Randomised trials have demonstrated that the efficacy of anti-tumour necrosis factor (TNF) agents is significantly increased by concomitant methotrexate (MTX) in rheumatoid arthritis (RA). In clinical routine, anti-TNF agents are...

Treatment of congestive heart failure--current status of use of digitoxin.

Digitalis glycosides exert a positive inotropic effect, i.e. an increase in myocardial contractility associated with a prolongation of relaxation period, and glycosides lower the heart rate (negative chronotropic), impede stimulus conduction (negative dromotropic) and promote myocardial excitability (positive bathmotropic). They seem to influence the activities of both the vagal and the sympathetic systems. Digitalis glycosides that belong to different substance classes are closely comparable concerning pharmacodynamics but differ substantially in regard to pharmacokinetics. Digoxin and its derivatives are less lipophilic, show lower protein binding and shorter half-life, are mainly eliminated via the kidney and accumulate rather rapidly in cases of insufficient kidney function. Digitoxin is highly lipophilic and extensively bound to plasma proteins, has a longer half-life, is mainly eliminated in the metabolized state via urine and faeces and does not accumulate in kidney dysfunction. As a result of a more stable pharmacokinetic profile, the incidence of toxic side effects seems to be lower with digitoxin than with digoxin. Since the beginning of the 1990s, the antagonists of the RAAS qualified as the standard treatment for congestive heart failure, often in combination with diuretics, vasodilators or beta-antagonists. However, the important role of digitalis glycosides as therapeutic comedication or alternative was never denied, especially in atrial fibrillation with tachycardia. The PROVED and RADIANCE trials proved a detrimental effect of the withdrawal of digoxin therapy on exercise capacity, left-ventricular ejection fraction and clinical symptoms. The DIG trial revealed that digoxin comedication in sinus rhythm patients with congestive heart failure was associated with a lower morbidity (as taken from death or hospitalization because of worsening heart failure) and an unchanged overall mortality--being a unique feature among the available inotropic drugs. Comparable studies for digitoxin have not yet been performed but, because of its higher pharmacological stability, it might well be associated with even more advantages in this regard than digoxin.

Clinical use, therapeutic aspects and future potential of deferiprone in thalassemia and other conditions of iron and other metal toxicity.

The therapeutic aspects and future prospects of the new iron chelating drug deferiprone are reviewed, with an emphasis on its clinical use in thalassemia and other conditions of iron overload, imbalance and toxicity, as well as its possible use in other metal toxicity conditions. Orally administered deferiprone appears to be as effective as subcutaneous deferoxamine in the removal of iron in transfused iron loaded patients, with an equivalent therapeutic index profile in both animals and humans. Only about 10% of patients requiring iron chelation therapy worldwide receive deferoxamine mainly because of its high cost, toxicity and low compliance with subcutaneous administration. Deferiprone has been used by over 6000 patients in 40 countries worldwide, in some cases daily for more than 10 years, with very promising results. Doses of 50-120 mg/kg/day are effective in bringing patients to negative iron balance. Deferiprone increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in the majority of chronically transfused iron loaded patients. All of the toxic side effects of deferiprone are considered reversible and manageable, and include agranulocytosis, musculoskeletal and joint pains, gastrointestinal complaints and zinc deficiency. In general, the incidence of toxic side effects could be reduced by using lower doses or combination therapy with deferoxamine. The suggestion that deferiprone therapy may cause liver fibrosis has not been confirmed. New therapeutic protocols for maximizing the efficacy and minimizing the toxicity of deferiprone are being considered based on new findings in relation to its metal chelation, pharmacological, toxicological and metabolic properties. (c) 2001 Prous Science. All rights reserved.

Therapeutic concentrations of cyclosporine A, but not FK506, increase P-glycoprotein expression in endothelial and renal tubule cells

The immunosuppressive drugs cyclosporine A (CsA) and tacrolimus (FK506) are extruded from cells by the multidrug resistance P-glycoprotein (P-gp), an efflux pump for drugs and xenobiotics, which may limit their therapeutic effectiveness and/or incidence of toxic side effects. In the present study, we investigated the effect of therapeutic concentrations of CsA and FK506 on the expression of P-gp in cultured endothelial and proximal tubule cells. P-gp expression in human arterial endothelial (HAEC) and rat proximal tubule cells (RPTC) was determined by immunoblotting and immunocytochemistry, and correlated with P-gp-mediated transport by measuring the intracellular accumulation of the fluorescent probe calcein. Following incubation of HAEC with therapeutic concentrations of 0.1 to 1.6 microM CsA up to seven days, P-gp expression increased in a time- and concentration-dependent manner, maximally to 291 +/- 42% of controls with 0.8 microM CsA for seven days. Similar effects of CsA were observed in RPTC. In contrast, therapeutic concentrations of FK506 (0.01 to 0.2 microM up to 7 days) did not change P-gp expression in either cell type, though at higher, supratherapeutic concentrations of FK506 (0.6 to 1.2 microM) P-gp expression was also increased. Immunocytochemistry revealed increased P-gp expression in the plasma membrane of HAEC and RPTC treated with 0.8 microM CsA, which was reflected by a decrease of P-gp-mediated accumulation of calcein in both cell types. The data suggest that the induction of P-gp expression in HAEC and RPTC at concentrations of CsA or FK506 above 0.5 microM is part of the protective answer of cells to toxic concentrations of the drugs and could therefore interfere with the therapeutic effectiveness of CsA in vivo.

Amiodarone induced lipidosis similar to Niemann-Pick C disease. Biochemical and morphological study

Amiodarone is effective in the treatment of supraventricular and ventricular cardiac arrhythmia, however a high incidence of toxic side effects has been observed in various organs and tissues during chronic treatment. Ultrastructural observation of affected tissues reveals myelinoid inclusion bodies. The exact pathogenetic mechanism of these changes is still unknown. In this study we investigated the biochemical effects of this drug on lysosomal hydrolases and the alterations induced in subcellular organelles of fibroblasts cultured for 24 h with different concentrations of amiodarone in the medium. Of the enzyme activities assayed, we only observed a significant reduction in sphingomyelinase. Ultrastructural observation of fibroblasts showed swollen lysosomes and a few onionoid inclusion bodies at lower concentrations of the drug; at higher concentrations the lysosomal system was severely impaired. Cytochemical staining of unesterified cholesterol with filipin showed accumulation of cholesterol. We conclude that chronic amiodarone treatment in experimental conditions induces inhibition in sphingomyelinase activity through interaction with membrane lipids and modification of bilayer structure. Higher concentrations of the drug impair cholesterol transport and induce lipid accumulation. These results may be useful for understanding the pathogenesis of induced lipidosis in patients in chronic treatment with amiodarone.

Fungal Infections Of The Larynx

Some generalizations regarding fungal infections of the larynx can be made. The reader is cautioned to refer to discussions of the individual infections for exceptions to these generalizations. For the most part, the mycoses are organisms of low pathogenicity emerging as opportunistic organisms thriving in a compromised host. The isolated fungal infections of the larynx reported are exceptions to the rule. Involvement of the larynx and other body sites outside the lung generally indicates a widely disseminated form of the disease. Fungal infections most commonly occur in the immunocompromised patient, including those afflicted with AIDS, cancer, leukemia, and other lymphoreticular neoplasms, patients on long-term corticosteroid therapy, patients with chronic systemic diseases, including diabetes mellitus and severe pulmonary disease, and patients who have undergone successful organ transplantation, which depends on immunologic suppression. Although specific fungi are characteristically found in designated endemic areas, the diseases may surface in remote areas in persons who have recently traveled through the endemic sites. The pathologic picture can be confusing, and pseudoepitheliomatous changes at times resemble malignancy. When atypical features occur in a patient with a suspicious history, special stains and cultures as well as skin tests and serologic studies may be helpful in establishing the diagnosis. For the most part, amphotericin B has been the mainstay of therapy, although the introduction of the newer azole drugs (ketoconazole, itraconazole and fluconazole) may present a breakthrough in the future therapy of these lesions. Ketoconazole has been proven efficacious in certain fungal infections. Itraconazole has recently been released for clinical use. Because of its lower incidence of toxic side effects, it may replace ketoconazole in the therapy of these diseases. Finally, fluconazole, taken orally, effectively crosses the blood-brain barrier; appropriate clinical trials may prove it to be an acceptable agent for those fungi commonly affecting the central nervous system.

Present status and future prospects of oral iron chelation therapy in thalassaemia and other diseases.

In the last few years we have witnessed the emergence of oral chelation which is a new form of therapy for transfusional iron-loaded patients in thalassaemia and other refractory anaemias. The need for a cheap, non-toxic, orally effective iron chelator is paramount because it could potentially save the lives of many thousands of patients. At present, less than 10% of the patients requiring iron chelation therapy worldwide receive the widely used chelating drug desferrioxamine (DF) because of its high cost, oral inactivity and toxicity. The most promising oral iron chelator is 1, 2-dimethyl-3-hydroxypyrid-4-one (L1 or INN: Deferiprone), which has so far been taken by over 450 patients in 15 countries, and in some cases daily for over 4 years with very promising results. L1 was shown at 50-100 mg/kg/day to be effective in bringing patients to negative iron balance. It increases urinary iron excretion, decreases serum ferritin levels and reduces liver iron in multi-transfused iron-loaded patients. Toxic side effects were mainly encountered at high doses (80-100 mg/kg/day) and include transient agranulocytosis (5 cases), transient musculoskeletal and joint pains (10-20%), gastric intolerance (2-6%) and zinc deficiency (1%). The incidence of these toxic side effects was reduced by using lower doses of 50-75 mg/kg/day. The overall efficacy and toxicity of L1 is comparable to that of DF in animals and humans. Further work is required for identifying susceptible individuals to L1 toxicity, and also optimum dose protocols of L1 which can maximise iron excretion and minimise the incidence of toxic side effects.

Plasma protein binding of bupivacaine in pregnant women at term

The increased toxicity of bupivacaine in parturients is a well-known phenomenon. The reduced plasma protein binding of bupivacaine is one of the possible reasons. Therefore, we measured the free fraction of bupivacaine in plasma samples of parturients and non-pregnant volunteers. The free fraction was significantly higher in parturients (8.2% vs 5.4%) associated with a lower concentration of the alpha-1-acid glycoprotein (0.42 vs 1.01 g/l) and a higher concentration of progesterone (156 vs 0.4 ng/ml). The addition of progesterone to plasma samples of non-pregnant volunteers did not influence the free fraction of bupivacaine, whereas the addition of alpha-1-acid glycoprotein to the plasma of parturients decreased the free fraction significantly. Therefore, the lower concentration of this protein is the principal reason for the higher free fraction of bupivacaine in pregnancy and possibly one of the causes of the higher incidence of toxic side effects of bupivacaine in obstetric use.

Phase II study of oral 4-demethoxydaunorubicin in previously treated (except anthracyclines) metastatic breast cancer patients.

Forty-eight patients with metastatic breast cancer previously treated with cytostatics (except anthracyclines) underwent peroral treatment with 4-demethoxydaunorubicin (4-DMDR), a new daunorubicin analogue. Forty-three patients received greater than or equal to 2 cycles and have been evaluated. The mean age was 54 years, with 10 premenopausal and 33 postmenopausal patients. All the patients showed progressive disease. Performance status 0-2 (ECOG score) was recorded in 34, and 3 in 7 patients. Soft tissue metastases were recorded in 23, visceral in 10 and bone in 10 patients. 4-DMDR was administered in the dose of 15 mg/m2 perorally daily, on day 1, 2 and 3 (45 mg/m2 per cycle). Since there was no severe toxicity, after 2 cycles the dosage was increased to 60 mg/m2 per cycle. The patients received 2-6 cycles (median 3) and the total cumulative dose ranged from 90 to 300 mg/m2 (median 140 mg/m2). Objective response was observed in 10 patients (1 complete remission, 9 partial remissions) with a response rate of 23% (10/43). Soft tissue metastases were most responsive (8/23-35%). Two responses were observed in visceral organs. Response lasted 2-6+ months (median 4 months). Toxic side effects have been mild with myelotoxicity (grade I-II) observed in 23% of patients. Alopecia (grade 1-15 patients, grade II and III = 4 patients) was moderate. Nausea and vomiting (grade I-II) was present in 60% of patients. In all the patients MUGA scans (left ventricular ejection fraction) were in normal range, however, reversible ECG changes have been recorded in 4 patients (grade I = 3, grade II = 1). All the changes appeared on the 3rd day of the cycle but became normal before starting a new cycle. In conclusion, it should be emphasized that 4-DMDR administered perorally (45 mg/m2 per cycle) in previously treated (except anthracycline) metastatic breast cancer patients showed antitumor efficacy with a low incidence of toxic side effects. Further clinical studies, possibly with the dose escalation in the schedule we have used, will be needed in previously untreated breast cancer patients to determine exact antitumor activity of this new daunorubicin analogue.