Hematologic Reactions Research Articles

Major adverse reactions to yeast-derived hepatitis B vaccines—a review

Yeast-derived recombinant DNA hepatitis B vaccines usage became widely accepted since the early 1990s. Severe adverse events have been reported infrequently in adults and rarely in infants and children given hepatitis B vaccine in the ten years which have passed since the introduction of the vaccine. Some of the data were summarized in previous review articles. Our review of the literature revealed reports of serious adverse reactions which included immediate reactions (anaphylaxis and urticaria) as well as delayed reactions, including skin, rheumatic, vasculitic (including Systemic Lupus Erythematosus and glumerulonephritis), hematologic, ophthalmologic and neurologic reactions. These cases were summarized and a pathogenetic mechanism is offered.

Adverse effects of class I antiarrhythmic drugs.

Class I antiarrhythmic drugs are characterised by their ability to block the fast inward sodium current in cardiac muscle tissue. However, at the same time, they can be responsible for various effects involving other organs and systems. Although some of these effects can be helpful in specific situations, most of them, such as their pro-arrhythmic propensity, are deleterious. Some of the adverse effects of class I antiarrhythmic drugs are directly linked to sodium-channel blockade (conduction disorders haemodynamic perturbations, and digestive and neurological effects), while others are linked to other specific pharmacological properties (e.g. atropinic, or alpha- or beta-adrenergic blockade) or to nonspecific properties (idiosyncratic hypersensitivity, and haematological, dermatological or hepatic reactions). Other adverse effects are associated with complex interactions between class I antiarrhythmics and individual predisposing factors, trigger mechanisms and physiological factors (including concomitant drug treatment). These numerous variations and interactions within a specific environment and underlying disorder might be of pharmacological or/and pharmacokinetic origin, making analysis of the true liability of the class I drugs very difficult when adverse effects occur.

Blood dycrasias and hematologic reactions in ticlopidine users

Blood dycrasias and hematologic reactions in ticlopidine users

Blood Dycrasias and Hematologic Reactions in Ticlopidine Users

To the Editor. —Ticlopidine hydrochloride (Ticlid, Roche Laboratories, Nutley, NJ) is an antiplatelet drug that has been marketed in the United States since October 1991. Based on reports since then, the labeling of ticlopidine has been changed. Ticlopidine is indicated to reduce the risk of thrombotic stroke in patients who have experienced stroke precursors or had a completed stroke, and it should be reserved for patients who are intolerant of aspirin therapy indicated to prevent stroke. The product labeling as approved in 1991 included a boxed warning that states neutropenia occurred in 2.4% and severe neutropenia and/or agranulocytosis occurred in 0.8% of stroke patients who received ticlopidine in premarketing clinical trials. Reports in the medical literature suggest that ticlopidine may also be associated with aplastic anemia and thrombotic thrombocytopenic purpura. 1-3 In a preliminary worldwide search of adverse hematologic events associated with ticlopidine through 1994, a total of 645 cases

Interaction of penicillin G with the human erythrocyte membrane and models.

Penicillin G (PEN) is a widely used antibiotic whose mechanism of action is related to the interference with the synthesis of bacteria cell wall. In order to evaluate its perturbing effect upon human cell membranes PEN was made to interact with human erythrocytes, isolated resealed human erythrocyte membranes and molecular models. The latter were multibilayers of the phospholipids dimyristoylphosphatidylcholine (DMPC) and dimyristoylphosphatidylethanolamine (DMPE) as well as DMPC large unilamellar vesicles. These studies were performed by scanning electron microscopy, fluorescence spectroscopy and X-ray diffraction methods. The observed results coincide in that PEN did not exert any significant effect upon the structures of the red cell membrane neither on its molecular models. This is in agreement with its reported lack of major toxicity and hematological reactions.

ARE SLOW-ACTING ANTI-RHEUMATIC DRUGS MONITORED TOO OFTEN? AN AUDIT OF CURRENT CLINICAL PRATICE

Rheumatologists usually recommend monthly blood monitoring when patients with rheumatoid arthritis (RA) are treated with slow-acting anti-rheumatic drugs (SAARDs). Is monthly monitoring needed or could its frequency be reduced? We audited the opinions of UK rheumatologists and reviewed clinical experience at three centres. To ascertain the interval at which patients are monitored and the determinants of monitoring policy we sent a questionnaire to 193 consultant rheumatologists; 143 (74%) replied. The majority use monthly monitoring for most SAARDs except sulphasalazine, chloroquine and hydroxychloroquine. There is extensive variation, which is not related to the type of rheumatology unit or whether a shared scheme with general practitioners is used. Reviewing experience in 390 patients treated with SAARDs at three adjacent rheumatology units in London showed that haematological adverse reactions were infrequent. During 1560 patient-years of treatment involving 18,720 monthly monitoring visits there were 13 haematological adverse reactions (11 thrombocytopenias and two leucopenias). Five thrombocytopenias developed after 6 months of treatment; five occurred gradually over 5 months or more and one borderline low platelet count was seen once. The two leucopenias were borderline low white cell counts occurring gradually over 3-6 months. Such frequent monitoring is expensive. The total cost of monitoring 390 patients for 1560 patient-years was 420,000 pounds. The cost of detecting each adverse reaction was 32,000 pounds. Three-monthly monitoring when therapy is established after an initial stabilizing period would have identified seven out of eight late adverse reactions. Monitoring policies are mainly based on clinical consensus with few prospective studies of their value; they need re-evaluation.

Late phase II clinical study of RP56976 (docetaxel) in patients with non-small cell lung cancer: Kudo S, Hino M, Fujita A, Igarashi T, Arita K, Niitani H et al. 4th Internal Medicine, Nippon Medical School, Tokyo. Jpn J Cancer Chemother 1994;21:2617–2623

A late phase II clinical study of RP56976 (Docetaxel) was conducted in patients with non-small cell lung cancer. Patients with non-small cell lung cancer in Stage IIIB and Stage IV not previously treated were enrolled. Docetaxel was administered at a dose of 60 mg/m2 based on the results of a phase I and an early phase II clinical study, and the efficacy and safety were examined. Of the 77 patients enrolled, 72 patients were evaluated to have completed the scheduled course of treatment by the Evaluation Committee. A partial response (PR) was seen in 18 patients, and the overall response rate was 25.0%. The response rate classified by clinical stage was 28.0% (7/25) in patients with Stage IIIB and 23.4% (11/47) in patients with Stage IV. Hematological adverse reactions included leukopenia of Grade III or more in 53.3% (40/75) and neutropenia of Grade III or more in 86.7% (65/75) as specified in the Adverse Event Reporting Form proposed by the Japan Society for Cancer Therapy. Other major adverse reactions included alopecia, asthenia, and fever, all of which were tolerable. From these results, the efficacy of docetaxel for the treatment of non-small cell lung cancer was confirmed.

Rheumatology.

The changing philosophies affecting medicine as a whole are at the forefront of rheumatology. Many of the publications of the past year have centred on improving and increasing the safety of drug treatment. There are now good grounds for hope that several newer agents to ameliorate rheumatoid arthritis are available or are in trial phase. Attitudes to chronic back pain and the chronic fatigue syndrome are more positive and treatment is more proactive. Osteoporosis is recognised as an important public health issue; the role of screening with bone densitometry has become better defined. The choice of non-steroidal anti-inflammatory drug for individual patients has until recently depended on the doctor's experience, the class of drug, and the manufacturer's recommendations. A recent publication by the Committee on Safety of Medicines has given a new perspective to selecting them.1 The committee assessed several years of reports of adverse drug reactions (yellow card) for the seven most widely used non-steroidal anti-inflammatory drugs in the United Kingdom. Ibuprofen carried the lowest risk, naproxen, indomethacin, and diclofenac intermediate risk, and azapropazone the highest risk of serious adverse upper gastrointestinal events at the doses in which these drugs are normally prescribed (fig 1). Furthermore, azapropazone had the highest number of yellow card reports for renal, liver, haematological, and hypersensitivity reactions. The report recommends that azapropazone should be used only when other non-steroidal anti-inflammatory drugs have failed, doses being restricted to a maximum of 600 mg daily in patients over 60. Drugs with low risk should generally be preferred, and these should be started in the lowest recommended dose. Only one non-steroidal anti-inflammatory drug should be used at a time. The report concludes that all members of this group are contraindicated in patients with peptic ulceration. This is controversial for patients with rheumatoid arthritis, who frequently have …

Intrapleural Chemotherapy Without Pleurodesis for Malignant Pleural Effusions: LCSG Trial 861

Malignant pleural effusions are a common and significant problem in patients with advanced malignancies. In contrast to traditional sclerosing agents, intrapleural chemotherapy has the potential advantage of treating the underlying malignancy, in addition to treating the effusion. The Lung Cancer Study Group evaluated intrapleural cisplatin and cytarabine in patients with malignant pleural effusions from a variety of solid tumors. Forty-six patients with cytologically proven symptomatic and previously untreated malignant pleural effusions were entered. Cisplatin, as a single dose of 100 mg/m2, plus cytarabine 1,200 mg, were instilled into the pleural space via a chest tube that was then immediately removed. The overall response rate, complete plus partial at 3 weeks, was 49% (18/37 patients). One patient experienced reversible grade 3 renal toxic reactions, four patients had grade 3 hematologic toxic reactions, and five patients had grade 3 cardiopulmonary toxic reactions. Median length of response was 9 months for a complete remission and 5.1 months for a partial remission. Although chemotherapy has the potential advantage of treating the underlying malignancy in addition to controlling the malignant effusion, intracavitary cisplatin and cytarabine therapy as administered in this trial appears inferior to existing sclerosing agents for the control of malignant pleural effusions. Although administration is safe, it cannot be recommended for the standard control of malignant pleural effusions, but it may have a role incorporated into combination modality therapies for diseases such as malignant pleural mesothelioma.

Toxicity of nonsteroidal anti-inflammatory drugs. An overview of the epidemiological evidence.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used throughout the world. This paper reviews the epidemiological data linking NSAID administration with gastrointestinal, hepatic, renal, haematological, and hypersensitivity reactions. Meta-analysis has demonstrated that NSAIDs are associated with serious upper gastrointestinal disorders, with a relative risk of 2.7 in patients receiving NSAIDs compared with subjects not receiving NSAIDs. An increase in the dose and duration of NSAIDs and age > 60 are associated with an increase in the risk of upper gastrointestinal toxicity. The current data strongly support a causal relationship between NSAIDs and gastrointestinal disorders. Case-control studies have demonstrated an association between some NSAIDs and neutropenia, with a relative risk of between 3 and 9 in patients treated with NSAIDs compared with nonusers of these drugs. NSAIDs have also been linked with hypersensitivity reactions, although the incidence of such reactions is very low. However, there are inconsistent data on the potential associations between NSAIDs and renal disease, and there are no epidemiological studies linking NSAIDs with acute liver disease. Overall, the incidence of serious adverse reactions associated with NSAIDs is low, and this class of drugs can be regarded as being reasonably safe.

Treatment of acute toxoplasmosis with intravenous clindamycin

The interim results are presented of an ongoing large-scale, prospective, randomized study to determine the potential role of clindamycin in the treatment of toxoplasmic encephalitis. Patients were seropositive for Toxoplasma gondii antibodies and had clinical signs compatible with toxoplasmic encephalitis. Data was available on 33 patients, 15 of whom received pyrimethamine p.o./clindamycin i.v. and then p.o., and 18 of whom received pyrimethamine p.o./sulfadiazine p.o. The interim evaluation did not reveal a remarkable difference between the two regimens in the clinical or radiologic response. Adverse reactions to both regimens were common and frequently multiple, there being more adverse gastrointestinal reactions in patients on pyrimethamine/clindamycin and more adverse hematological reactions in those on pyrimethamine/sulfadiazine.

Risk-Benefit Assessment of Carbamazepine in Children

Carbamazepine is an effective antiepileptic drug for the treatment of partial and convulsive generalised epilepsy in adults and children. The pharmacokinetic profile in children is similar to that in adults, but the half-life in long term paediatric therapy is between 6 and 12 hours, compared with 15 hours in adults. Autoinduction is present. The most common adverse effects are neurological and dose-related, and occur in up to 50% of patients treated, usually on dosage initiation or dose elevation. Most dissipate over time and require no alteration in dosage. Idiosyncratic effects include hypersensitivity, hepatic and haematological reactions. A benign leucopenia occurs in 10 to 12% of adults and children and appears to be unrelated to aplastic anaemia which occurs in approximately 1 in 575,000 treated patients per year. Carbamazepine is reported to have cognitive and behavioural advantages over other antiepileptic drugs. Overall, carbamazepine has become a major antiepileptic drug in children as well as adults.

A Review of Carbamazepine's Hematologic Reactions and Monitoring Recommendations

Early case reports of fatal hematologic effects attributed to carbamazepine (CBZ) resulted in extensive monitoring recommendations by the manufacturer. The rarity of blood dyscrasias led many authors to question the manufacturer's guidelines. Thus the manufacturer removed specific monitoring guidelines, allowing physicians to monitor CBZ using their clinical judgment. This article reviews case reports and studies of CBZ's hematologic effects. Due to their rapid onset, daily laboratory checks would be necessary to monitor for aplastic anemia, agranulocytosis, and thrombocytopenia. These adverse effects are best monitored by informing patients and physicians to carefully watch for signs and symptoms. Leukopenia develops more slowly, occurring in approximately 12 percent of children and 7 percent of adults. Its onset is typically within the first three months of treatment, with patients at risk having a low or low-normal pretreatment white blood cell (WBC) count. Leukopenia often reverses, even if CBZ is continued. Based upon our review of the literature, we recommend monitoring of those high-risk patients during the first three months of treatment with the frequency being determined by results of each laboratory value. WBC counts less than 3000/mm3 or neutrophil counts below 1000/mm3 warrant a decrease in dose with frequent monitoring or CBZ discontinuation, if necessary.

Kikuchi's Histiocytic Necrotizing Lymphadenitis: Report of a Case

Kikuchi's Histiocytic Necrotizing Lymphadenitis: Report of a Case

Safety of parenteral third-generation cephalosporins

Knowledge of side effects associated with different cephalosporins may be of help to prescribers. There are several side effects that are common to all cephalosporins, but overall, cefotaxime and ceftizoxime cause the fewest adverse reactions. Bleeding is probably the most common serious side effect of cephalosporins. Moxalactam causes coagulopathy and bleeding more often than do other cephalosporins, probably because it is carboxylated and has a methylthiotetrazole side chain. Cefoperazone also has a methylthiotetrazole side chain and may cause bleeding, particularly when used in doses greater than 4 g per day. Ceftriaxone has a similar side chain and there is some evidence that it can induce a coagulopathy. Coagulation tests should be monitored when any of the third-generation cephalosporins are given to patients with a high risk of bleeding. Disulfiram-like reactions are also related to the side chains associated with coagulation defects and have been reported when patients receiving cefoperazone, moxalactam, or ceftriaxone have ingested alcohol. Seizures have been reported with ceftazidime, but are uncommon. Hematologic reactions are rare with all third-generation cephalosporins. Benign diarrhea and Clostridium difficile colitis probably occur most often with moxalactam, cefoperazone, ceftazidime, and ceftriaxone, but there are few good data on this issue. Ceftriaxone has the unique ability to cause sludge (also referred to as pseudolithiasis) to form in the gallbladder, particularly in children. This may be associated with nausea, anorexia, epigastric distress, and colic, and is usually detected using ultrasonography. The sludge dissolves and symptoms subside after therapy is discontinued. None of the third-generation cephalosporins is clearly significantly nephrotoxic, even when combined with aminoglycosides. Most of the third-generation cephalosporins have surprisingly few serious side effects, which make them attractive for use in the treatment of a wide variety of serious infections.

Aplastic anaemia associated with organochlorine pesticide: case reports and review of evidence.

Three patients with aplastic anaemia had a history of substantial previous exposure to organochlorine pesticides. The temporal association between chemical exposure and the onset of first symptoms of anaemia was strongly supportive. Organochlorines have the property of lipid affinity and accumulation in adipose tissue. Objective evidence of clinically important concentrations of tissue pesticide residues may be a useful confirmation of previous exposure. In the patients studied the presence of Lindane (gamma hexachlorocyclohexane) was shown using gas chromatography/mass spectrometry with selective ion monitoring of fragments obtained from one heavily exposed patient, with concentrations about five times greater than a matched control. The presence of clinically important tissue concentrations of pentachlorophenol was also confirmed in a second patient exposed to this agent. The long term safety of organochlorine pesticides remains doubtful as they were introduced before adequate toxicological screening tests had been developed. The central registration of possible haematological adverse reactions, however, forms an important epidemiological method in the study of environmental chemical hazards and should be complied with whenever possible.

高齢者の頭頚部悪性腫ように対する化学療法

To optimize chemotherapy for head and neck malignant tumors in the elderly we compared patients older than 70 years of age with those younger than 69. Toxic reaction was comparable between the two age groups, except that hematologic and mucosal reactions in the head and neck region were more prevalent in the elderly. However, the response rate and chemosensitivities were similar between the two groups.Our findings indicate that chemotherapy for the elderly should based on a performance status under 3 grade, instead of age, and that anti-cancer drugs not affecting immunological function should be selected.

Methimazole treatment of 262 cats with hyperthyroidism.

The efficacy and safety of the antithyroid drug methimazole were evaluated over a 3-year period in 262 cats with hyperthyroidism. In 181 of the cats, methimazole was administered for 7 to 130 days (mean, 27.7 days) as a preoperative preparation for thyroidectomy. The remaining 81 cats were given methimazole for 30 to 1,000 days (mean, 228 days) as sole treatment for the hyperthyroid state. After 2 to 3 weeks of methimazole therapy (10 to 15 mg/d), the mean serum thyroxine (T4) concentration decreased significantly (P less than 0.001) from a pretreatment value of 12.1 micrograms/dl to 2.1 micrograms/dl. The final maintenance dose needed to maintain euthyroidism in the 81 cats that were given methimazole as sole treatment for hyperthyroidism ranged from 2.5 to 20 mg/d (mean, 11.9 mg/d). Clinical side effects developed in 48 (18.3%) cats (usually within the first month of therapy), which included anorexia, vomiting, lethargy, self-induced excoriation of the face and neck, bleeding diathesis, and icterus caused by hepatopathy. Mild hematologic abnormalities developed in 43 (16.4%) cats (usually within the first 2 months of treatment), which included eosinophilia, lymphocytosis, and slight leukopenia. In ten (3.8%) cats, more serious hematologic reactions developed including agranulocytosis and thrombocytopenia (associated with bleeding). These hematologic abnormalities resolved within 1 week after cessation of methimazole treatment. Immunologic abnormalities associated with methimazole treatment included the development of antinuclear antibodies in 52 of 238 (21.8%) cats tested and red cell autoantibodies (as evidenced by positive direct antiglobulin tests) in three of 160 (1.9%) cats tested.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of norfloxacin in the treatment of acute diarrheal disease

In studies conducted in seven countries, 392 persons with acute diarrhea were enrolled and randomly assigned to one of three regimens. In order to compare the effectiveness of various therapies for acute gastroenteritis, patients were treated for five days with either norfloxacin, 400 mg twice daily, norfloxacin, 400 mg three times a day, or trimethoprim/sulfamethoxazole, (160 mg/800 mg) twice daily. Clinical cure occurred in 89 percent (lower dose) and 91 percent (higher dose) of those treated with norfloxacin, compared with 78 percent of those receiving trimethoprim/sulfamethoxazole; cure rates in each treatment group were greater when the patient's stool contained fecal leukocytes. In 105 of 106 (99 percent) patients treated with either dose of norfloxacin and in 49 of 52 (94 percent) trimethoprim/sulfamethoxazole-treated subjects, the bacterial enteropathogen identified in the pretreatment stool was eradicated on the posttreatment specimen. Two percent (two patients) of those receiving the lower dose of norfloxacin, 3 percent (two patients) of those receiving trimethoprim/sulfamethoxazole, and 4 percent (three patients) of those receiving the higher dose of norfloxacin experienced minor and transient adverse hematologic or blood chemistry reactions. In addition, mild cutaneous reactions that were attributed to the study medications developed in two patients receiving the higher dose of norfloxacin and in three patients who received trimethoprim/sulfamethoxazole. These studies indicate that norfloxacin is safe and effective therapy for bacterial diarrhea.

HEMOLYSIS DURING SULFASALAZINE (S) THERAPY FOR PEDI-ATRIC INFLAMMATORY BOWEL DISEASE

Adverse hematologic reactions to S therapy have been well-documented in isolated IBD patients. In prior reports, hemolysis lias been noted to be infrequent, and has occurred within 2-4 weeks of initiation of therapy or coincident with an increase in dosage. Most have been receiving generally high dosages (>4g/day). These toxic manifestations are generally believed to be associated with a slow-acetylator phenotype. After diagnosing three individuals with S-induced hemolytic anemia occurring from 2 to 30 months after the initiation of therapy, we undertook to study the prevalence of S-induced hemolysis in a group of IBD patients (3-19 y.o.) without evidence of active GI blood loss. Out of 20 patients (15 U.C., 5 Crohn's), nine (45%) exhibited evidence of hemolysis by reticulocyte count (average 6.9%, range 2.4-12.8%) and haptoglobin level (average 10 mg/dl, range 0-30, nl 100-300 mg/dl). The average dosage was only 50 mg/kg/day S with a maximum of 3g/day. Upon cessation of S, hemolysis promptly resolved and the hemoglobin level increased an average of 2.1g/d. Prior observation of this hemolysis was obscured by the common occurrence of anemia and reticulocytosis in IBD, and by the laboratory variability in measurement of reticulocyte count.We conclude that in pediatric IBD patients S-induced hemolysis is common, often late in onset, and occurs with modest dosages. Patients on S-therapy should be followed with routine reticulocyte counts and haptoglobin levels as long as therapy persists.