Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function

Shaw, Michael; Spector, Monroe H.; Ladman, Aaron J.

doi:10.1016/s0305-7372(79)80066-3

Cited by 52 publications

(20 citation statements)

References 44 publications

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“…These patients have important problems of drug absorption thought to be due to chemotherapy-and radiotherapyinduced damages to the intestinal epithelium. 11 With this oral itraconazole form, six out of 11 patients (54%) had reached a 'therapeutic' level of unchanged ITRA at day Ϫ1, after 7 days of itraconazole treatment, with an average of 363 Ϯ 48 ng/ml for the C min and 696 Ϯ 46 ng/ml for the C max .…”

Section: Discussionmentioning

confidence: 94%

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Michallet

Persat

Kranzhöfer

et al. 1998

Bone Marrow Transplant

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Summary:A prospective study of the pharmacokinetics of itraconazole solution was performed in 11 patients who underwent allogeneic BMT (day of BMT = day 0) after a conditioning regimen including total body irradiation (TBI). Itraconazole solution (400 mg once a day) was given 7 days before BMT and continued up to the end of neutropenia unless another antifungal treatment was necessary. Blood samples were collected before itraconazole intake (C min ) and 4 h later (C max ) every other day for assays of itraconazole (ITRA) and its active metabolite hydroxy-itraconazole (OH-ITRA). The mean values of C min ITRA and OH-ITRA, respectively, were 287 ؎ 109 ng/ml and 629 ؎ 227 ng/ml at day ؊1 and 378 ؎ 147 ng/ml and 725 ؎ 242 ng/ml at day +1. The maximum C min values were observed at day +3. Six patients at day ؊1 (54%) and 8 at day +1 (72%) had satisfactory residual plasma concentrations of at least 250 ng/ml of unchanged ITRA. From day +1 to day +9, eight patients discontinued the itraconazole treatment, five of them had satisfactory plasma residual concentrations at this time. This work shows a good bioavailability of itraconazole oral solution during the early phase after allogeneic BMT, but more data are needed for the late phases. Keywords: pharmacokinetics; itraconazole solution; BMT; TBI Prophylaxis and treatment of systemic fungal infections in patients undergoing allogeneic bone marrow transplant (BMT) remain important issues. Broad spectrum antifungals with a low toxicity and good bioavailability are being sought. Ideally, orally administered medications given to prevent invasive aspergillosis should provide a systemic effect. However several factors are likely to impair bioavailability of orally administered medications in allogeneic BMT patients: nausea and vomiting mainly during conditioning regimen period, mucositis during aplasia and acute graft-versus-host disease (GVHD) later.Itraconazole, a triazole broad spectrum antifungal 1,2 is presently marketed as capsules. Important variations in plasma itraconazole concentrations observed in patients, compared with healthy volunteers, 3 are related to individual conditions of drug absorption, thereby justifying plasma measurements. A plasma concentration of unchanged itraconazole (ITRA) у250 ng/ml is considered necessary to obtain a therapeutic effect on Aspergillus. 4 However, since hydroxy-itraconazole (OH-ITRA) has a similar antifungal effect to unchanged ITRA, 5 the active fraction is represented by the sum of unchanged ITRA and its active metabolite OH-ITRA with an effective total level of about 1000 ng equivalents/ml. This effective level could be estimated from the effective plasma levels of unchanged ITRA (Ϸ250 ng/ml) 4,6 and metabolic ratio in human plasma between ITRA and OH-ITRA ([OH-ITRA]/[ITRA] Ϸ2). 7 However the capsule formulation is of limited use in allogeneic BMT: its bioavailability is reduced when administered under fasting conditions and when coadministered with antacids. 8 Itraconazole oral solution is a new formulation where ITRA is solub...

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Section: Discussionmentioning

confidence: 94%

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Michallet

Persat

Kranzhöfer

et al. 1998

Bone Marrow Transplant

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“…Enteric-coated potassium chloride has been associated with small intestinal ulcerations and perforation, even with slow release forms [46][47][48] . Antineoplastic and immunosuppressive agents as well as radiation have been recognized for decades to cause small intestinal mucosal as well as colonic injury during treatment for malignant disorders [49][50][51] . Neutropenic enterocolitis is a well recognized clinical syndrome associated with disease-induced or chemotherapy-induced neutropenia and this entity may be complicated by hemorrhage and perforation [52] .…”

Section: Medication-related Causesmentioning

confidence: 99%

Spontaneous free perforation of the small intestine in adults

Freeman¹

2014

WJG

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“…29 Normally, the entire epithelium is renewed in 4-6 days, but decreased cell renewal is thought to lead to mucosal atrophy, thinning and necrosis although in rats, sublethal doses of alkylating agents mainly induced lower absorption rather than villous atrophy. 30 The ulcerative-bacteriological phase Increased redness and swelling of the mucosa and underlying tissue are usually the first signs of oral MBI, mainly due to increased vascularity and vascular permeability (inflammatory phase) and thinning of epithelium (epithelial phase). This process usually culminates in the ulcerative phase within about 14 days of starting chemotherapy.…”

Section: The Epithelial Phasementioning

confidence: 99%

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

Blijlevens¹,

Donnelly²,

Pauw³

2000

Bone Marrow Transplant

236

153

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Summary:Mucositis is an inevitable side-effect of the conditioning regimens used for haematopoietic stem cell transplantation. The condition is better referred to as mucosal barrier injury (MBI) since it is primarily the result of toxicity and is a complex and dynamic pathobiological process manifested not only in the mouth but also throughout the entire digestive tract. A model has been proposed for oral MBI and consists of four phases, namely inflammatory, epithelial, ulcerative and healing phases. A variety of factors are involved in causing and modulating MBI including the nature of the conditioning regimen, the elaboration of pro-inflammatory and other cytokines, translocation of the resident microflora and their products, for example, endotoxins across the mucosal barrier, exposure to antimicrobial agents and whether or not the haematopoietic stem cell graft is from a donor. Neutropenic typhlitis is the most severe gastrointestinal manifestation of MBI, but it also influences the occurrence of other major transplant-related complications including acute GVHD, veno-occlusive disease and systemic infections. The pathobiology, clinical counterparts and the means of measuring MBI are discussed together with potential approaches for prevention, amelioration and, perhaps, even cure. Bone Marrow Transplantation (2000) 25, 1269-1278. Keywords: mucositis; mucosal barrier injury; diagnosis; risk factors; treatment Mucositis is an inevitable side-effect of the intensive conditioning therapy used for haematopoietic stem cell transplantation 1 and usually refers to the mucosal ulceration of mouth and throat. However, it is generally accepted that oral mucositis is in reality the most obvious manifestation of damage or injury elsewhere particularly that of the gut. Hence, mucosal barrier injury (MBI) may be a more appropriate term for this biological process. There exists no clear definition of MBI which is defined by a constellation of signs and symptoms that vary in their clinical expression. Oral MBI is reported to affect 60% to 100% of transplant recipients 2,3 and is characterised by pain, oedema, erythema, lesions, pseudomembrane formation, excessive mucous production, reduced saliva and bleeding, all of which reduce the patient's ability to eat and drink. In contrast, there are no reliable data on the incidence of gut MBI although intestinal symptoms affect almost every transplant recipient to some extent and include nausea, vomiting, abdominal cramping and watery diarrhoea occasionally accompanied by macroscopic blood loss. The exact course and severity of bowel symptoms of MBI are also difficult to ascertain because many patients are in such pain due to oral MBI that they only gain relief from narcotic analgesia which induces constipation as a result of reduced gut motility. There are also a number of scoring systems for oral MBI 4 although none is universally accepted and all lack standardisation. As yet, there is no system for registering gut MBI although there are published definitions for grading toxicity o...

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Effects of cancer, radiotherapy and cytotoxic drugs on intestinal structure and function

Cited by 52 publications

References 44 publications

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Pharmacokinetics of itraconazole oral solution in allogeneic bone marrow transplant patients receiving total body irradiation

Spontaneous free perforation of the small intestine in adults

Mucosal barrier injury: biology, pathology, clinical counterparts and consequences of intensive treatment for haematological malignancy: an overview

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