Kidney Effects by Alternative Classes of Medicines in Patients and Relationship to Effects in Nonclinical Toxicity Studies.

Drug-induced kidney injury has historically been associated with renal tubule injury related to small molecule pharmaceuticals such as nonsteroidal anti-inflammatory drugs, antineoplastic agents, or antibiotics, but as a greater number of alternative classes of medicines such as biotherapeutics, molecular-targeted antineoplastic drugs, chimeric antigen receptor T-cell therapies, antibody-drug conjugates, oligonucleotide therapies, or other immunomodulatory drugs come to market, the presentation of drug-induced nephrotoxicity is changing. This review article describes the potential rare clinical events in drug-induced kidney injury that might be noted with these new therapies and their potential impact on patients. Potential pathogenic mechanisms related to immunogenicity, immune complex formation, and stimulation of downstream proinflammatory pathways with some of these alternative medicine classes have resulted in the potential for glomerulonephritis, acute interstitial nephritis, renal vasculitis, and other immune-mediated renal disorders in humans. This contrasts with nonclinical toxicity studies, where biologic therapies more often result in vasculitis and glomerulonephritis associated with antidrug antibodies and immunomodulatory pharmacology, and which are not always predictive of clinical effects. While nonclinical antidrug antibody-related renal disease is generally not clinically relevant, other immune-mediated nephrotoxicities associated with immunomodulatory drugs may be predictive of clinical adverse events. Fortunately, these conditions are still rare and account for a small percentage of serious adverse events in kidneys of patients.

The Impact of High Dose Glucocorticoids on Bone Health and Fracture Risk in Systemic Vasculitides.

Systemic vasculitides are a range of conditions characterized by inflammation of blood vessels which may manifest as single organ or life-threatening multisystem disease. The treatment of systemic vasculitis varies depending on the specific disease but historically has involved initial treatment with high dose glucocorticoids alone or in conjunction with other immunosuppressive agents. Prolonged glucocorticoid treatment is frequently required as maintenance treatment. Patients with small and large vessel vasculitis are at increased risk of fracture. Osteoporosis may occur due to intrinsic factors such as chronic inflammation, impaired renal function and to a large extent due to pharmacological therapy with high dose glucocorticoid or combination treatments. This review will outline the known mechanism of bone loss in vasculitis and will summarize factors attributing to fracture risk in different types of vasculitis. Osteoporosis treatment with specific consideration for patients with vasculitis will be discussed. The use of glucocorticoid sparing immunosuppressive agents in the treatment of systemic vasculitis is a significant area of ongoing research. Adjunctive treatments are used to reduce cumulative doses of glucocorticoids and therefore may significantly decrease the associated fracture risk in patients with vasculitis. Lastly, we will highlight the many unknowns in the relation between systemic vasculitis, its treatment and bone health and will outline key research priorities for this field.

Clinopodium chinense Attenuates Palmitic Acid-Induced Vascular Endothelial Inflammation and Insulin Resistance through TLR4-Mediated NF- κ B and MAPK Pathways.

Elevated palmitic acid (PA) levels are associated with the development of inflammation, insulin resistance (IR) and endothelial dysfunction. Clinopodium chinense (Benth.) O. Kuntze has been shown to lower blood glucose and attenuate high glucose-induced vascular endothelial cells injury. In the present study we investigated the effects of ethyl acetate extract of C. chinense (CCE) on PA-induced inflammation and IR in the vascular endothelium and its molecular mechanism. We found that CCE significantly inhibited PA-induced toll-like receptor 4 (TLR4) expression in human umbilical vein endothelial cells (HUVECs). Consequently, this led to the inhibition of the following downstream adapted proteins myeloid differentiation primary response gene 88, Toll/interleukin-1 receptor domain-containing adaptor-inducing interferon- ß and TNF receptor-associated factor 6. Moreover, CCE inhibited the phosphorylation of Ikappa B kinase ß , nuclear factor kappa-B (NF- κ B), c-Jun N-terminal kinase, extracellular regulated protein kinases, p38-mitogen-activated protein kinase (MAPK) and subsequently suppressed the release of tumor necrosis factor- α , interleukin-1 ß (IL-1 ß ) and IL-6. CCE also inhibited IRS-1 serine phosphorylation and ameliorated insulin-mediated tyrosine phosphorylation of IRS-1. Moreover, CCE restored serine/threonine kinase and endothelial nitric oxide synthase (eNOS) activation and thus increased insulin-mediated nitric oxide (NO) production in PA-treated HUVECs. This led to reverse insulin mediated endothelium-dependent relaxation, eNOS phosphorylation and NO production in PA-treated rat thoracic aortas. These results suggest that CCE can significantly inhibit the inflammatory response and alleviate impaired insulin signaling in the vascular endothelium by suppressing TLR4-mediated NF- κ B and MAPK pathways. Therefore, CCE can be considered as a potential therapeutic candidate for endothelial dysfunction associated with IR and diabetes.

In vitro systems toxicology-based assessment of the potential modified risk tobacco product CHTP 1.2 for vascular inflammation- and cytotoxicity-associated mechanisms promoting adhesion of monocytic cells to human coronary arterial endothelial cells.

Cigarette smoking causes cardiovascular diseases. Heating tobacco instead of burning it reduces the amount of toxic compounds in the aerosol and may exert a reduced impact on health compared with cigarette smoke. Aqueous extract from the aerosol of a potential modified risk tobacco product, the Carbon Heated Tobacco Product (CHTP) 1.2, was compared in vitro with aqueous extract from the smoke of a 3R4F reference cigarette for its impact on the adhesion of monocytic cells to artery endothelial cells. Human coronary artery endothelial cells (HCAEC) were treated for 4 h with conditioned media from human monocytic Mono Mac 6 (MM6) cells exposed to CHTP1.2 or 3R4F extracts for 2 h or directly with those extracts freshly generated. In vitro monocyte-endothelial cell adhesion was measured concomitantly with inflammatory, oxidative stress, cytotoxicity, and death markers. Furthermore, transcriptomics analyses enabled to quantify the level of perturbation in HCAECs, and provide biological interpretation for the underlying molecular changes following exposure to 3R4F or CHTP1.2 extract. Our systems toxicology study demonstrated that approximately 10-15-fold higher concentrations of the CHTP 1.2 aerosol extract were needed to elicit similar effects as the 3R4F smoke extract on cardiovascular disease-relevant inflammation and cytotoxicity-related mechanisms and markers investigated in vitro.

Vascular sclerosing effects of bleomycin on cutaneous veins: a pharmacopathologic study on experimental animals.

BACKGROUND:: Varicose veins and the complications of venous disease are common disorders in humans. OBJECTIVE:: To study the effects of bleomycin as a potential new sclerosing agent and its adverse events in treating varicose veins. METHODS:: Bleomycin-loaded liposomes 0.1ml was injected in the dorsal ear veins of white New Zealand rabbits. Sodium tetradecyl sulfate was used as a positive control. Normal saline was used as negative control. The blood vessels of the treated ears were photographed before and at one hour and two, eight and 45 days after treatment. Biopsies from the treated areas were obtained for histological examination. Blood samples were collected to determine any possible toxicity. RESULTS:: Bleomycin by itself was ineffective; therefore, liposomes were used as a vector to deliver bleomycin to the vein lumen. Subsequently, bleomycin started showing its sclerosing effects. Toxicity monitoring showed no apparent hematologic, pulmonary, hepatic or renal toxicities. This study revealed that bleomycin induced vasculitis, which led to vascular occlusion, which was observed on day 1 and day 8. No bleomycin-related injury was noted by histopathological examination of lung sections. The calculation of the lung/body weight coefficient indicated that edema was present in the experimental groups compared with the negative and positive controls. STUDY LIMITATIONS:: Relatively small number of experimental animals used. CONCLUSIONS:: This study showed that bleomycin-loaded liposomes were able to induce vasculitis and vascular occlusion without any toxicity or complications. It might be useful, hence, to treat patients suffering from Varicose veins and other ectatic vascular diseases with this agent.

Vascular sclerosing effects of bleomycin on cutaneous veins: a pharmacopathologic study on experimental animals

Abstract: Background: Varicose veins and the complications of venous disease are common disorders in humans. Objective: To study the effects of bleomycin as a potential new sclerosing agent and its adverse events in treating varicose veins. Methods: Bleomycin-loaded liposomes 0.1ml was injected in the dorsal ear veins of white New Zealand rabbits. Sodium tetradecyl sulfate was used as a positive control. Normal saline was used as negative control. The blood vessels of the treated ears were photographed before and at one hour and two, eight and 45 days after treatment. Biopsies from the treated areas were obtained for histological examination. Blood samples were collected to determine any possible toxicity. Results: Bleomycin by itself was ineffective; therefore, liposomes were used as a vector to deliver bleomycin to the vein lumen. Subsequently, bleomycin started showing its sclerosing effects. Toxicity monitoring showed no apparent hematologic, pulmonary, hepatic or renal toxicities. This study revealed that bleomycin induced vasculitis, which led to vascular occlusion, which was observed on day 1 and day 8. No bleomycin-related injury was noted by histopathological examination of lung sections. The calculation of the lung/body weight coefficient indicated that edema was present in the experimental groups compared with the negative and positive controls. Study limitations: Relatively small number of experimental animals used. Conclusions: This study showed that bleomycin-loaded liposomes were able to induce vasculitis and vascular occlusion without any toxicity or complications. It might be useful, hence, to treat patients suffering from Varicose veins and other ectatic vascular diseases with this agent.

Awake without complaints: maximizing comfort during awake fiberoptic intubation.

In obese patients with unfavorable airways, awake fiberoptic intubations are sometimes performed to maintain spontaneous respiration and airway reflexes, until a secure airway is attained. Obese patients may be sensitive to the effects of sedation. Rapid oxygen desaturation may occur as a result of brief moments of apnea from even minimal amounts of sedating medications, due to poor baseline functional reserve as well as common comorbid conditions such as obstructive sleep apnea and obesity hypoventilation syndrome. To maximize the chance of success when performing an awake fiberoptic intubation in a minimally sedated patient, the upper airway should be sufficiently anesthetized. Adequate topical anesthesia minimizes airway stimulation, optimizes patient comfort and facilitates patient compliance. We report two cases of awake fiberoptic intubation in two morbidly obese patients, where a simple apparatus, made of an atomizer embedded in an oral airway, was used to effectively topicalize the airway and achieve excellent intubating condition with minimal sedation.

Acute toxicity evaluation of proliferol: a dose-escalating, placebo-controlled study in swine.

Prolotherapy is one of the many treatments available for chronic musculoskeletal disorders. A commonly used drug contains dextrose 12.5%, glycerin 12.5%, phenol 1.0%, and lidocaine hydrochloride 0.25% in aqueous solution (recently termed Proliferol). For chronic low back pain, this is injected into lumbosacral ligaments to stimulate connective tissue repair. Despite generally positive clinical results, the toxicity of this drug is not well characterized and was assessed in 48 (24 male, 24 female) Yucatan miniature swine randomly assigned to low (1x), medium (5x), or high (10x) dose or saline placebo. Outcomes included clinical observations, clinical chemistry, hematology, coagulation, urinalysis, toxicokinetics, and full gross and microscopic histopathology after 24 hours or 14 days. Findings attributable to Proliferol after 24 hours included dose-response elevations in alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, and creatine kinase, which returned to normal after 14 days. There were no remarkable findings in hematology, coagulation, or urinalysis. Urine concentrations of lidocaine and phenol both peaked after 8 hours. Histopathology findings after 24 hours included hemorrhage, inflammation, necrosis, and vascular changes in the ligaments and adjacent soft tissues at the sites of injection. After 14 days, there was evidence of repair under way, with fibrosis and skeletal muscle regeneration at the injection sites.

Effect of Benincasa hispida Cogniaux on high glucose-induced vascular inflammation of human umbilical vein endothelial cells.

Vascular inflammation is an important factor which can promote diabetic complications. Preliminary investigations of several crude plant extracts including aqueous extract of Benincasa hispida Cogniaux exhibit anti-inflammatory properties. This study investigates the mechanism of anti-vascular inflammatory activity of an aqueous extract of B. hispida Cogniaux (ABH) in human umbilical vein endothelial cells (HUVECs). The study was performed on HUVECs that were pretreated with various concentrations (1-20 microg/ml) of ABH before exposure with high glucose (25 mM) for 48 h. Cell ELISA and Western blot analysis showed that ABH inhibited high glucose-induced cell adhesion molecules (CAMs) surface and protein expression, resulting in reduced adhesion of U937 monocytes. ABH also inhibited the mRNA expression level of monocyte chemoattractant protein-1 (MCP-1) and interleukin-8 (IL-8). High glucose-induced ROS production was inhibited by treatment of ABH. We observed that pretreatment with HUVECs with ABH blocks NF-kappaB activation via blocking phosphorylation and degradation of its inhibitory protein, IkappaB-alpha. ABH also reduced NF-kB promoter activity. These results suggest that ABH reduces high glucose-induced CAMs activation by inhibiting monocyte adhesion, ROS, and NF-kappaB in HUVECs.

Nitric oxide involvement in lipid emulsion-induced vascular pain in anesthetized rats.

We examined the vascular pain induced by arterial infusion of 20% lipid emulsion by using a flexor reflex model in anesthetized rats. Arterial infusion of 20% lipid emulsion at doses of 0.6 to 2 ml/2 min induced flexor reflexes that were late in onset, persistent, and intense compared with those induced by 2.7% amino acid and 7.5% glucose solution, 5% sodium chloride solution, 1% propofol, and capsaicin. The flexor reflex induced by 20% lipid emulsion was significantly inhibited by preinjected procaine hydrochloride (4 mg/rat, i.a.) but not by the critical dose of indomethacin (10 mg/kg, i.p.). These results suggest that the flexor reflex might reflect a 20% lipid emulsion-induced vascular pain response and that the site of action of noxious agents involved in this event might be a vascular bed, but the production of prostanoids through cyclooxygenase might not be involved in the action mechanisms. The 20% lipid emulsion-induced vascular pain was significantly inhibited by preinjection of 10 mg/kg N(G)-nitro-l-arginine methyl ester hydrochloride (l-NAME), a nitric oxide (NO) synthase inhibitor, and the inhibition by l-NAME was recovered by the addition of sodium nitroprusside (30 microg/kg/min), which is an endothelium-independent NO donor to 20% lipid emulsion. These results indicate that increased NO production is responsible for 20% lipid emulsion-induced vascular pain. In summary, the arterial infusion of 20% lipid emulsion induced a delayed, persistent and intense flexor reflex, presumably indicating vascular pain in rats that might be induced by NO production through the activation of NO synthase.

Musculoskeletal manifestations and autoimmune diseases related to new biologic agents.

PURPOSE OF REVIEW: The anti-tumor necrosis factor agents are now widely used in the management of patients with rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis and juvenile inflammatory arthritis. One of the most common observations made during their use is the development of autoantibodies. The purpose of this paper is to review this phenomenon and its clinical implications. RECENT FINDINGS: While the development of different autoantibodies is a common encounter, rare cases of lupus-like syndromes have been reported. On the other hand, a variety of immune-mediated clinical manifestations have been described, including vasculitis and demyelinating syndromes. Rare cases of cytopenia and non-specific lung injuries have also been reported. SUMMARY: While these clinical complications are rare and isolated events, clinicians must be aware of their occurrence. The experience with the anti-tumor necrosis factor agents is rather short and new, unusual immune-mediated complications may still appear. Clinicians should be prepared to recognize them.

A search for an animal model of the Spanish toxic oil syndrome.

To date, pathology characteristics of toxic oil syndrome (TOS), a disease associated with consumption of a contaminated cooking oil in Spain in 1981, have not been reproduced in an animal model. As vasculitis, eosinophilia, and a rise in circulating IgE levels were features of the acute phase of TOS, leading to an autoimmune outcome, a review of predisposition to these aspects across species was conducted. The intent was to determine predisposed strains or species that potentially might be effective in testing the toxic oils and thus defining the precise identity of the toxic contaminant(s). A number of potential candidates emerge from this review. Among mice, these include the NZB mouse hybrids, the MRL/lpr and SJL/J strains, and a transgenic mouse model of eosinophilia. The Brown Norway may be the most appropriate rat strain, while beagle dogs inbred to be genetically predisposed to immune complex disease and vasculitis are also a candidate species. Of the more exotic species, the mink and ferret have characteristics that might make them suitable candidates for testing oil samples.

Evaluation of antineutrophil cytoplasmic antibody seroconversion induced by minocycline, sulfasalazine, or penicillamine.

OBJECTIVE: Case reports have suggested that minocycline, sulfasalazine, and penicillamine are associated with antineutrophil cytoplasmic antibody (ANCA)-positive vasculitis. This study evaluated ANCA seroconversion due to these agents in serum samples prospectively collected in randomized, double-blind, controlled trials. METHODS: The sources of study sera were 3 clinical trials: 1) a 48-week trial of minocycline for early rheumatoid arthritis, with 64 patients receiving minocycline compared with 68 receiving placebo; 2) a 37-week trial of sulfasalazine for rheumatoid arthritis, with 51 receiving sulfasalazine compared with 38 receiving placebo; and 3) a 104-week trial of penicillamine for early systemic sclerosis, with 15 undergoing high-dose penicillamine treatment versus 12 receiving low-dose penicillamine. ANCA were measured in the baseline and study-end serum samples by indirect immunofluorescence (IIF) for perinuclear ANCA (pANCA) and cytoplasmic ANCA (cANCA) patterns, and by antigen-specific enzyme-linked immunosorbent assay (ELISA) for antibodies to myeloperoxidase (anti-MPO) and proteinase 3 (anti-PR3). Laboratory personnel were blinded to the group identity of the samples. ANCA results were interpreted using an ANCA scoring system that combines the results of IIF and ELISA testing. RESULTS: No patient in any of the active study drug groups demonstrated ANCA seroconversion according to the final interpretation of the combined IIF and ELISA results. Twelve of the 248 patients (5%) were positive for anti-MPO with pANCA at baseline. No subject was positive for anti-PR3 with cANCA. There were no findings suggestive of vasculitis in any of these patients. CONCLUSION: From our study results, there was no suggestion of ANCA seroconversion induced by minocycline, sulfasalazine, or penicillamine. However, these findings do not rule out the possibility of rare, sporadic cases of either ANCA seroconversion or true drug-induced vasculitis with these drugs.

Antioxidants may contribute in the fight against ageing: an in vitro model.

Elderly humans have altered cellular redox levels and dysregulated immune responses, both of which are key events underlying the progression of chronic degenerative diseases of ageing, such as atherosclerosis and Alzeimer's disease. Poorly maintained cellular redox levels lead to elevated activation of nuclear transcription factors such as NFkB and AP-1. These factors are co-ordinately responsible for a huge range of extracellular signalling molecules responsible for inflammation, tissue remodelling, oncogenesis and apoptosis, progessess that orchestrate many of the degenerative processess associated with ageing. It is now clear that levels of endogenous anti-oxidants such as GSH decrease with age. This study aimed to investigate the potential of exogenous anti-oxidants to influence inflammatory responses and the ageing process itself. We investigated the potential of the dietary antioxidant, quercetin, to reverse the age related influences of GSH depletion and oxidative stress using in vitro human umbilical vein endothelial cells (HUVEC) and human skin fibroblast (HSF) cell models. Oxidative stress-induced inflammatory responses were investigated in a GSH depletion and a Phorbol 12-myristate 13-acetate (PMA)-induced stress model. As measured with a sensitive HPLC fluorescence method, GSH in HUVEC was depleted by the addition of L-buthionine-[S,R]-sulfoxiniine (BSO), a gamma-glutamylcysteine synthetase inhibitor, to the culture medium at a concentration of 0.25 mM. Time course studies revealed that the GSH half-life was 4.6 h in HUVEC. GSH depletion by BSO for 24 h led to a slight increase in intracellular adhesion molecule - 1 (ICAM1) expression and prostaglandin E2 (PGE2) secretion in both types of cells. However, GSH depletion markedly enhanced PMA-induced ICAM and PGE2 production in HUVEC. Responses were progressively elevated following prolonged BSO treatment. Inhibition studies showed that 1-(5-Isoquinolinylsulfonyl)-2-methylpiperazine (H7), a protein kinase C (PKC) inhibitor, not only abolished most of PMA-induced ICAM-1 expression and PGE2, production, but also eliminated GSH depletion-enhanced PMA stimulation. This enhancement was also inhibited by supplementation with quercetin. The results clearly demonstrate that GSH depletion increased the susceptibility of vascular endothelial cells and fibroblasts to oxidative stress associated inflammatory stimuli. This increased in vitro susceptibility may be extrapolated to the in vivo situation of ageing, providing a useful model to study the influence of micronutrients on the ageing process. In conclusion, these data suggest that dietary antioxidants could play a significant role in the reduction of inflammatory responses.

[The inhibitory effect of selenite and other antioxidants on the complement mediated experimental pulmonary alveolitis].

OBJECTIVE: To test the regulatory effect of selenite and other antioxidants on complement PMN activation feedback mechanism mediated inflammatory response in experimantal pulmonary vasculitis. METHODS: Mouse model of pulmonary Arthus reaction vasculitis developed with BSA sensitization and antigen inhalation was used for tests of inhibitory effect of oral administration of sodium selenite, glycyrrhizin flavonoids and/or vitamin E on the incidence of developing vasculitis, which could reflect the modulation of inflammatory response and tissue injury. RESULTS: A remarkable inhibitory effect of selenite or combined flavonoid and vitamin E on the induction of pulmonary vasculitis were observed as the incidence of vasculitis could drop from 100% of the untreated group down to 25% of the antioxidants treated groups, revealing modulation of inflammatory response. CONCLUSIONS: It indicated a newer insight into mechanism of the inflammatory response could give a novel approach to the modulation of inflammatory response. An adjuvant therapy of selenium and antioxidants to the interventions of inflammatory disorders has been expected.

Potential complications associated with normothermic lonidamine infusion and with systemic acidosis in dogs receiving lonidamine during whole body hyperthermia (WBH).

The vascular toxicosis of lonidamine (40 mg/h) or vehicle infusion was investigated in six dogs. Vasculitis and thrombosis were observed in veins infused with lonidamine but not in veins infused with vehicle. This finding suggests that it may not be possible to use lonidamine infusion to circumvent therapeutic limitations associated with the oral lonidamine formulation currently used in patients. We also investigated the systemic toxicosis of lonidamine (400 mg/m2; rapid intravenous bolus) or vehicle in six other dogs that developed systemic acidosis (pH < or = 7.0) during whole body hyperthermia (42 degrees C x 90 min). Gross and histologic haemorrhage was observed in all dogs; however, haemorrhagic lesions in acidotic dogs receiving lonidamine + WBH were more severe than changes observed in acidotic dogs receiving vehicle + WBH. These observations confirm the results of in vitro studies which suggest that the combined effect of lonidamine and hyperthermia is enhanced under acidic conditions. Furthermore, these findings indicate that acid-base status of patients receiving lonidamine during WBH must be monitored carefully to avoid serious complications.