Pressure ulcers induced by drug administration: A new concept and report of four cases in elderly patients

Drug‐induced akinesia is a potential cause of pressure ulcers. However, pressure ulcers that are caused by drug‐induced akinesia are not considered an adverse drug reaction (ADR). We propose that drug‐induced pressure ulcers (DIPU) are pressure ulcers that are caused by an external force that is experienced after drug administration, and we considered resolution of these ulcers after drug discontinuation to be a supportive finding. In this report, we reviewed the medical records of pressure ulcer cases from a 300‐bed hospital. Among 148 patients, four patients with pressure ulcers met the criterion for DIPU. In these cases, the suspected DIPU were related to treatment with olanzapine, fluvoxamine, valproic acid, clotiazepam, triazolam and rilmazafone. These drugs were administrated to manage the patients' behavioral and psychological symptoms that accompanied dementia. The DIPU in these patients were categorized as stage IV according to the National Pressure Ulcer Advisory Panel criteria. Discontinuation of the causal drugs led to significant improvements or complete healing of the pressure ulcers, and the patients subsequently recovered their mobility. Therefore, we propose that DIPU are potential ADR that have been overlooked in clinical practice. Thus, recognition of DIPU as an ADR may be important in preventing and appropriately managing pressure ulcers among elderly patients.     

Thalidomide does not modify the ability of cells in leprosy patients to incorporate [3H]-thymidine when incubated with M. leprae antigens

The immune response in reversal reaction, (RR) and in erythema nodosum leprosum (ENL) is characterized in vitro by an enhancement in lymphocyte blast transformation against M. leprae. As thalidomide is an effective treatment for ENL, this study assessed the effect of this drug on these phenomena. Mononuclear cells from patients attending the clinic at ALERT and from healthy staff were cultured for 5 days with integral M. leprae (IMl), or a modified Dharmendra antigen (Dhar), or PPD from M. tuberculosis. In one set of cultures, thalidomide was added once at the initiation of the culture; in the other set thalidomide was added a second time (2x), 18 h prior to harvesting the cells. The mononuclear cells, in the absence of thalidomide, from healthy staff, borderline tuberculoid patients (BT) and BT patients in RR (BT/RR) incorporated [3H]-thymidine best when cultured with PPD > Dhar > M. leprae. The cells from patients with ENL did not respond well to the M. leprae antigens. Thalidomide (2x) enhanced proliferation to Dhar in the BTRR group (Wilcoxon signed rank test, P < 0.05). No significant changes occurred for the other groups. Comparing PPD-stimulated cells treated with thalidomide once to those treated with thalidomide twice, thalidomide (2x) suppressed incorporation of [H3]-thymidine by the PPD-stimulated (P < 0.05) as well as IMl-stimulated (P < 0.05) cells in the healthy staff group. In the Dhar-stimulated cells from the healthy staff thalidomide significantly suppressed TNF-alpha (P < 0.05). A mixed effect was seen within and between the other groups, but there was a trend for thalidomide to suppress TNF-alpha induced by the M. leprae, Dhar and PPD antigens.     

Transient secondary amenorrhea in women treated by thalidomide.

Compared with other side effects induced by thalidomide, amenorrhea has been relatively poorly investigated although it was first reported in 1989. The aim of this study was to determine the prevalence of amenorrhea in consecutive women treated with thalidomide in our institution from 1995 to 1999. During that period, 21 women received thalidomide associated with progestin contraception. Their clinical and biological data were retrospectively reviewed. Data concerning their genital life were systematically checked by phone with a simple questionnaire. Transient secondary amenorrhea occurred in 5 women (24%) treated for refractory cutaneous lupus erythematosus (4 cases) or complex aphthosis (1 case). The link between thalidomide and amenorrhea was suggested by the resumption of menses 2 to 3 months after drug withdrawal, recurrence of amenorrhea after reintroduction of thalidomide (1 case) and high serum levels of pituitary gonodotrophins. Amenorrhea secondary to ovarian failure is frequently observed in women treated with thalidomide. Its precise mechanism remains to be elucidated.     

Efalizumab‐induced thrombocytopenia: report of relapse after re‐administration

Although a reversible, sometimes severe, drug‐induced thrombocytopenia is a recognized adverse drug reaction (ADR) in patients with psoriasis treated with efalizumab, definite proof for the association of thrombocytopenia with efalizumab is still lacking (currently level II evidence for ADR). We report a patient with psoriasis who had two episodes of reversible thrombocytopenia during efalizumab; the first occurred 5 months after introduction of the medication and the second 4 months after re‐introduction of efalizumab for relapsing psoriasis. The development of a second episode of thrombocytopenia on re‐exposure to efalizumab provides, for the first time in the literature to our knowledge, definite (level I) ADR evidence for efalizumab‐induced thrombocytopenia.     

Thalidomide and thrombosis

BACKGROUND: Teratogenicity and neuropathy are the well known serious side effects induced by thalidomide. We describe 5 cases of thrombotic events occurring within a brief delay after the onset of thalidomide in a manner that suggests that thalidomide could have acted as a precipiting or as a starting factor in these events. OBSERVATIONS: Five patients including 4 patients with lupus erythematosus (1 discoid lupus, 1 subacute lupus and 2 systemic lupus erythematosus) and one patient with a severe atopic dermatitis, all without previous history of vascular events, developed an arterial thrombosis (2 cases) or a venous thrombosis (3 cases), severe in 4 cases, few days or weeks after the onset of thalidomide treatment (50 to 100 mg daily). DISCUSSION: All the patients had risk factors of thrombosis: the presence of antiphospholipids and/or anticardiolipin antibodies in lupus erythematosus patients and a trauma in the atopic case. However the absence of a previous story of thrombosis, its rapid occurrence after the onset of thalidomide and its severity are intriguing. In addition, recent studies demonstrate that thalidomide has various effects that would act, among other things, on angiogenesis. Thus, we think that a doubt exists on a negative effect of thalidomide in thrombosis risk factors patients and that this hypothesis has to be confirmed.     

Thalidomide in cutaneous lupus erythematosus

For nearly 50 years, thalidomide has struggled between success and controversy. After causing an epidemic of phocomelia and other birth defects during the 1960s, affecting thousands of neonates, thalidomide was used as a sedative in selective disorders including leprosy. The potent anti-inflammatory properties of thalidomide were serendipitously discovered while treating patients with erythema nodosum leprosum, and the drug is now approved by the US FDA for the treatment of this disease. Subsequently, the immunosuppressant effects of thalidomide, including the complex modulation of many cytokines, have been recognized. One promising application of thalidomide has been the treatment of cutaneous lupus erythematosus. Among the largest series reviewed, the drug has been found to ameliorate cutaneous lupus erythematosus in 90% of patients, on average. Remission is achieved in approximately 15-20% of patients with cutaneous lupus erythematosus at doses between 50-400 mg daily. Contraceptive concerns and the recognized neuropathic effects of thalidomide limit the use of the drug in patients with cutaneous lupus. Physicians who prescribe thalidomide in the US must be registered with the drug manufacturer. With appropriate control of drug access and close physician monitoring, thalidomide provides a needed therapeutic option for the treatment of refractory cases of cutaneous lupus erythematosus.     

Evidence that thalidomide modifies the immune response of patients suffering from actinic prurigo

BACKGROUND: Actinic prurigo (AP) is a photodermatosis with a restricted ethnic distribution, mainly affecting Mestizo women (mixed Indian and European). The lesions are polymorphic and include macules, papules, crusts, hyperpigmentation and lichenification. Thalidomide, an effective immunomodulatory drug, was first used successfully to treat AP in 1973. In this work we describe the effect that thalidomide had on TNF-alpha sera levels and on IL-4- and IFN gamma (IFNgamma)-producing lymphocytes of actinic prurigo (AP) patients. METHODS: Actinic prurigo patients were analyzed before and after thalidomide treatment. The percentage of IL-4+ or IFNgamma+ CD3+ lymphocytes was analyzed in eight of them by flow cytometry. TNFalpha in sera was measured by ELISA in 11 patients. RESULTS: A direct correlation was observed between resolution of AP lesions and an increase in IFNgamma+ CD3+ peripheral blood mononuclear cells (P < or = 0.001) and a decrease in TNFalpha serum levels (no statistical difference). No IL-4+ CD3+ cells were detected. CONCLUSIONS: Our findings confirm that AP is a disease that has an immunological component and that thalidomide clinical efficacy is exerted not only through inhibition of TNFalpha synthesis, but also through modulation of INFgamma-producing CD3+ cells. These cells could be used as clinical markers for recovery.     

Thalidomide usage in Wales: the need to follow guidelines

BACKGROUND: Thalidomide is a potentially useful drug for several dermatological disorders. OBJECTIVES: To assess prescribing and monitoring practices for this drug in Wales. METHODS: A questionnaire was completed by 17 of 19 consultant dermatologists concerning thalidomide usage in Wales (population 2.93 million). RESULTS: Eleven of the 17 respondents had used thalidomide in 40 patients. Only two consultants gave information leaflets and only five obtained written consent. Four obtained baseline nerve conduction studies and nine obtained these during therapy. Of seven women of child-bearing age currently taking thalidomide, none had had baseline pregnancy tests. CONCLUSIONS: We describe variability in prescribing practices for thalidomide. Published guidelines are reviewed and suggestions made concerning consent forms, pregnancy testing, nerve conduction studies and patient information.     

Reacciones cutáneas adversas a medicamentos: cómo identificar el desencadenante

It is estimated that 10% to 15% of medicated patients develop adverse drug reactions (ADR). Despite the high prevalence of ADR, the identification of the trigger drugs remains a medical challenge, mainly in polymedicated patients. Our goal is to update the diagnostic tools to identify enhancer drugs of type B-ADR that compromise the skin and /or mucous membranes, in order to optimize patients’ follow-up and improve their quality of life. We develop the review in two stages: I- we review the pathophysiological mechanisms of the ADR; II- we developed the clinical approach for the identification of the triggering drug.     

Adverse reactions and alleged allergy to local anesthetics: Analysis of 331 patients

The aim of this study was to determine the prevalence of true local anesthetic (LA) allergy among patients referred for suspected hypersensitivity and to describe the main characteristics of adverse drug reactions (ADR) induced by LA in our population. We retrospectively analyzed the medical files of patients referred to the Department of Dermatovenereology, University Hospital Center Rijeka, Rijeka, Croatia, for the investigation of LA hypersensitivity in the period between January 2000 and December 2012. A total of 331 patients underwent skin testing and, in cases of negative results, subcutaneous exposition to LA. In patients with suspected delayed reaction, patch test was performed. Altogether, 331 patients reported 419 independent ADR occurring during 346 procedures. Most commonly, patients reported having only one ADR, but 41 (12.4%) of them had two reactions, 14 (4.2%) had three, five (1.5%) had four and in one patient (0.3%) five ADR to LA were observed. The majority of reactions occurred during dental procedures when most commonly lidocaine and articaine were used. Local reactions were reported in 44 patients, whereas 490 general symptoms occurred during 375 independent ADR in 287 patients. The most common symptoms were cardiovascular system reactions in 89 patients (18.2%). Allergic reaction was detected in three patients (0.91%). One patient showed immediate‐type reaction to bupivacaine and two patients had a delayed‐type reaction to lidocaine. Adverse reactions to LA are common and are mostly due to their pharmacological properties and drug combinations or psychogenic origin. Allergic accidents to LA are rare.     

New drug therapies and their effect on the skin

New therapeutic agents – mainly those applied in treatment of cancer and in immunologically mediated diseases – can elicit previously unknown cutaneous adverse drug reactions (ADR) and each dermatologist should be familiar with these clinical pictures. Established classification systems fail to adequately represent ADR to these new therapeutics, which often belong to the group of biological immune response modifiers. Thus, a new classification system was recently proposed for ADR to these new drugs and this paper gives an overview of typical clinical entities. The emphasis is put on ADR elicited by EGFR inhibitors and by TNF antagonists. Current strategies for management of these ADR, as well as for selected other new therapeutics and their typical ADR, are discussed.The fast development of new drugs and their wider application will undoubtedly continue to be a challenge for dermatologists.     

Thalidomide therapy for cutaneous lupus erythematosus: historical and practical considerations

ABSTRACT: Connective tissue diseases are notoriously difficult to treat and the cutaneous manifestations of lupus erythematosus (LE) can be severe, leading to significant and progressive disfigurement. Fortunately several modalities exist for the treatment of this condition. However, oftentimes patients manifest severe disease and are refractory to conventional treatment. Second- and third-line agents used to treat cutaneous LE (CLE) can also exhibit many intolerable side effects. Thalidomide, a drug with a notorious past, has been found to be efficacious in the treatment of most of these patients. Response can be dramatic and patients are often maintained on thalidomide as a monotherapy. We review thalidomide's past, with a focus on its use in the treatment of CLE. We also discuss the practical issues involved in safely administering this drug, using three case histories. In conclusion, thalidomide is very effective in the treatment of CLE, however, prolonged use is often needed to maintain long-term remission. Properly used, thalidomide is very safe, with minimal and mild side effects. However, proper implementation and monitoring is imperative to guard against known serious side effects of teratogenicity and neuropathy.     

光滑假丝酵母菌耐药基因CDR1、CDR2、SNQ2表达的研究

目的:探讨光滑假丝酵母菌耐三唑类抗真菌药物临床株耐药基因表达情况.方法:34株复发性外阴阴道假丝酵母菌病的临床分离株,通过265 rDNA D1/D2区分子鉴定为光滑假丝酵母菌,应用法国生物梅里埃酵母菌药敏试剂盒ATBTM FUNGUS3,进行体外药物敏感性试验.实时荧光定量PCR方法检测34株菌株耐药基因CDR1、CDR2、SNQ2表达量.结果:34株光滑假丝酵母菌中,有2株为敏感株,2株对ITR剂量依赖敏感,30株为耐药株,且呈现交叉耐药现象.对氟康唑(FCA)、伊曲康唑(ITR)、伏立康唑(VRC)抗真菌药物的耐药率分别为26.32％、86.84％、34.21％.耐药株CDR1、SNQ2基因表达明显高于敏感株(P＜0.0005),CDR2表达量无差别(P＞0.05).结论:光滑假丝酵母菌对三唑类药物MIC值高,其药物敏感性低与耐药基因CDR1、SNQ2的过度表达有关.     

Safety and efficacy of nivolumab in Japanese patients with malignant melanoma: An interim analysis of a postmarketing surveillance

A postmarketing surveillance study is ongoing to evaluate nivolumab treatment for Japanese patients with malignant melanoma and accumulate data on all adverse events (AE) and efficacy. In this interim analysis, we evaluated data from approximately 100 Japanese medical institutions obtained from the nivolumab approval date in Japan (4 July 2014) through 3 July 2016. Patients were monitored during the first 12 months of treatment. Nivolumab was administrated by i.v. infusion (2 mg/kg every 3 weeks). A total of 680 and 610 patients were evaluated for safety and efficacy, respectively. The incidences of adverse drug reactions (ADR) and grade 3 or higher ADR were 53.53% and 12.35%, respectively. Predominant ADR included hypothyroidism (11.32%) and abnormal enzyme activity, such as increase of aspartate aminotransferase (7.79%), alanine aminotransferase (6.76%), alkaline phosphatase (6.18%) and γ‐glutamyltransferase (5.44%). Grade 3 or higher ADR of special interest with an incidence of 1% or higher were hepatic function disorder (2.50%), colitis/diarrhea (2.06%) and infusion reaction (1.32%). No cases of encephalitis or venous thromboembolism, other AE of special interest, were observed. The estimated median overall survival was 379 days (95% confidence interval [CI], 290–not reached [NR]) in the overall population, NR (95% CI, 305–NR) for cutaneous melanoma and 340 days (95% CI, 275–NR) for mucosal melanoma. The improvement rate based on the antitumor response at the last evaluation was 22.2% (131/590 patients). No new safety concerns were raised, and serious ADR of special interest were infrequent. Nivolumab showed equivalent efficacy in patients with mucosal melanoma and those with cutaneous melanoma.     

HLA-A31 strongly associates with carbamazepine-induced adverse drug reactions but not with carbamazepine-induced lymphocyte proliferation in a Japanese population

Carbamazepine (CBZ) is the most frequent culprit drug for severe cutaneous adverse drug reactions (ADR), such as Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and drug-induced hypersensitivity syndrome (DIHS). A strong association between human leukocyte antigen (HLA)-B*1502 and CBZ-induced SJS/TEN has been reported in Han Chinese, Thai, Malaysian and Indian populations, but not in Caucasian or Japanese populations. Recent studies showed an association between HLA-A*3101 and CBZ-induced ADR in Caucasian and Japanese populations. We conducted a case-control study to determine HLA genotyping of patients with CBZ-induced ADR in a Japanese population. Fifteen patients with CBZ-induced ADR and 33 subjects who had taken CBZ for more than 3 months without evidence of any ADR as a control were enrolled. In addition, the results of a CBZ-induced lymphocyte stimulation test were compared between the groups. A strong association was found between HLA-A31 and CBZ-induced ADR (P < 0.001), and a weak association was found between HLA-A11 and HLA-B51 with CBZ-induced ADR. No HLA-B*1502 was found in either patients or control subjects. The mean CBZ-induced lymphocyte stimulation index was significantly high in patients with CBZ-induced ADR compared with CBZ-tolerant patients (P < 0.001); however, no significant difference was seen between HLA-A31-positive subjects and HLA-A31-negative subjects in either group. These findings suggest that HLA-A31 is strongly associated with CBZ-induced ADR in the Japanese, but does not determine CBZ-induced lymphocyte proliferation.     

Thalidomide in the treatment of sixty cases of chronic discoid lupus erythematosus

The therapeutic effect of thalidomide in chronic discoid lupus erythematosus (CDLE) was studied in sixty patients who were followed up for 2 years. In fifty-four patients (90%) a complete or marked regression of the disease was observed, but when the thalidomide was stopped, thirty out of forty-one (71%) patients relapsed. Patients undergoing a second course of thalidomide treatment again responded well. Nine of the patients in whom the disease recurred after successful treatment with thalidomide and who had been unresponsive to intermittent treatment with antimalarials, showed a good response to a second or third course with thalidomide. Mild side-effects were common and 25% of patients complained of slight to moderate polyneuritic symptoms. Since electroneurological examinations had not been performed before the thalidomide therapy, the frequency of neurological side-effects cannot be accurately calculated but we recommend neurological examinations before and periodically during thalidomide treatment. Thalidomide is a very effective drug in CDLE, but in most cases it exerts its effect only whilst treatment is continued. Its use should be restricted to patients resistant to topical steroids and systemic antimalarials.     

Wiederentdeckung von Thalidomid Erfolgreiche Behandlung des chronisch diskoiden Lupus erythematodes

Thalidomide, an oral drug introduced in Germany in 1953 as a mild sedative, was withdrawn from the world market when its teratogenic effect was discovered some years later. It has since been selectively reintroduced to treat a variety of autoimmune or inflammatory diseases such as erythema nodosum leprosum, prurigo nodularis, graft-versus-host disease, and discoid lupus erythematosus (DLE). We report on three patients with long-standing, severe DLE showing no response to systemic first-, second- and third-line treatments. After four weeks of therapy with thalidomide the skin lesions had improved dramatically and after three to six months all three patients responded with an almost complete remission. The side effects of thalidomide, especially somnolence and paresthesias, were minor and well tolerated by the patients. Our data confirm that thalidomide provides one of the most useful therapeutic alternatives for chronic refractory DLE, despite the risks of teratogenicity and polyneuropathy.     

Thalidomide in dermatology

Thalidomide is an effective agent to treat over 25 seemingly unrelated dermatological conditions that have an inflammatory or autoimmune basis. The main side-effects of teratogenesis and peripheral neuropathy limit its use. Currently, in Australia no assurance is given as to the quality, safety and efficacy of thalidomide. The use of thalidomide for toxic epidermal necrolysis can lead to an increase in mortality, and its use as a prophylactic agent for the prevention of chronic graft-versus-host disease following bone marrow transplantation has raised more speculations as to the safety of this notorious drug. A review of the therapeutic indications for thalidomide in dermatology as well as the mechanisms of action and side-effects of this drug are presented. The current suggested guidelines for its use in clinical practice in Australia are discussed.     

Photoprotection by thalidomide in patients with chronic cutaneous and systemic lupus erythematosus: discordant effects on minimal erythema dose and sunburn cell formation

BACKGROUND: Thalidomide is an anti-inflammatory and immunomodulatory agent with proven efficacy in several refractory inflammatory skin conditions including photoexacerbated skin diseases. The effects of thalidomide on ultraviolet (UV)-induced cutaneous damage in humans have not been extensively studied. We describe the results of minimal erythema dose (MED) testing in nonlesional skin of three patients with chronic cutaneous lupus erythematosus (CCLE) before and after treatment with thalidomide. OBJECTIVES: To determine whether thalidomide treatment provides clinical and histological evidence of photoprotection from acute UV injury. METHODS: MED testing was performed in nonlesional skin of three patients with CCLE before and after treatment with thalidomide. Skin biopsy specimens were taken from MED sites for in situ immunochemistry. RESULTS: In each patient, the MED to UVB irradiation was significantly higher while the patient was receiving thalidomide treatment than in the absence of thalidomide, suggesting a systemic photoprotective effect. Thalidomide treatment had no significant effect on markers of apoptosis including sunburn cell formation and terminal deoxynucleotidyl transferase-mediated biotinylated deoxyuridine triphosphate nick end labelling, which identifies single-strand breaks in DNA. CONCLUSIONS: Thalidomide inhibits acute UVB erythema at 24 h after exposure, as a 100-mg daily dose of this drug for 4 weeks conveyed a sun protection factor of 1.56 to > 4.0. We conclude that inhibition of UVB-induced inflammation may, in part, explain the therapeutic benefits of this agent on photosensitive diseases.     

Arzneimittelallergien

Cutaneous adverse drug reactions (ADR) are common and encompass a broad clinical spectrum. Since the skin acts as a signaling organ for ADR, the dermatologist plays a key role in their diagnosis. Only a minor part of cutaneous ADR are due to underlying allergic mechanisms. Among these, delayed-type reactions such as maculopapular exanthems and immediate-type reactions such as urticaria and angioedema predominate. Risk factors for the development of cutaneous allergic ADR may be related to the patient (e.g. certain HLA-types), the drug (e.g. its reactivity), and underlying conditions (e.g. viral infections). Antibiotics, non-steroidal anti-inflammatory agents and anticonvulsive medications are most often reported to be causally related.