Drug-Induced Blood Dyscrasias

Categories of undesirable effects of drugs are described. Recent experiments on the production of hypersensitization (1) by the use of ECT solution to enhance skin sensitization to penicillin, (2) through the activity of common metabolites of different drugs, and (3) to a non-sensitizing drug by pretreatment with a sensitizing agent are reviewed. The mechanism of hemolytic anemia due to an inherited enzymatic defect and that of drug-induced purpura and the agranulocytic agents is discussed. The three groups of drugs—(1) rarely toxic, e.g. quinine; (2) always toxic in sufficient amounts, e.g. nitrogen mustard; (3) intermediate, e.g. chloramphenicol—are presented, with special consideration of chloramphenicol. It is the responsibility of the pharmacologist to develop and adopt newer methods for toxicity detection, and of the clinician to practise caution in prescribing drugs and to attempt the early recognition of any disorder they may induce. The incidence, diagnosis, prevention, treatment and prognosis of the drug-induced dyscrasias are discussed.     

Enhancing therapeutic efficacy by targeting non-oncogene addicted cells with combinations of signal transduction inhibitors and chemotherapy

The effects of inhibition of the Raf/MEK/ERK and PI3K/Akt/mTOR signaling pathways and chemotherapeutic drugs on cell cycle progression and drug sensitivity were examined in cytokine-dependent FL5.12 hematopoietic cells. We examined their effects, as these cells resemble normal hematopoietic precursor cells as they do not exhibit “oncogene-addicted” growth, while they do display “cytokine-addicted” proliferation as cytokine removal resulted in apoptosis in greater than 80% of the cells within 48 h. When cytokine-dependent FL5.12 cells were cultured in the presence of IL-3, which stimulated multiple proliferation and anti-apoptotic cascades, MEK, PI3K and mTOR inhibitors transiently suppressed but did not totally inhibit cell cycle progression or induce apoptosis while chemotherapeutic drugs such as doxorubicin and paclitaxel were more effective in inducing cell cycle arrest and apoptosis. Doxorubicin induced a G₁ block, while paclitaxel triggered a G₂/M block. Doxorubicin was more effective in inducing cell death than paclitaxel. Furthermore the effects of doxorubicin could be enhanced by addition of MEK, PI3K or mTOR inhibitors. Cytokine-dependent cells which proliferate in vitro and are not “oncogene-addicted” may represent a pre-malignant stage, more refractory to treatment with targeted therapy. However, these cells are sensitive to chemotherapeutic drugs. It is important to develop methods to inhibit the growth of such cytokine-dependent cells as they may resemble the leukemia stem cell and other cancer initiating cells. These results demonstrate the enhanced effectiveness of targeting early hematopoietic progenitor cells with combinations of chemotherapeutic drugs and signal transduction inhibitors.     

Usefulness of CV 205-502 in a case of allergy to ergot-derived drugs.

This study reports a case of allergy to ergot-derived drugs in a patient with a prolactin (PRL)-secreting microadenoma. The anamnesis revealed allergic reactions to the administration of analgesics and antibiotics. The administration of dopamine agonist drugs, such as bromocriptine (BRC; 2.5 mg) or lisuride (0.2 mg), induced after a few minutes the appearance of nausea, vomiting, postural hypotension, headache, edema of the glottis with dispnea and acroedema. The edemas disappeared a few hours after the administration of antihistaminic drugs while nausea, vomiting, postural hypotension and headache persisted for a few days. Therefore, the patient was tested with another dopamine agonist non-ergot-derived drug, quinagolide (CV 205-502), which did not cause side effects or allergic reactions. Furthermore, not only was the responsiveness to the drug optimal but it also normalized the PRL levels, and menses reappeared after more than a 5-year amenorrhea. This report suggests that ergot-derived drugs, such as lisuride and BRC, seldom induce allergic reactions apart from common side effects. Consequently, the feasibility of using a new drug with a different molecular structure (non-ergot derived) effective in the therapy of hyperprolactinemic syndromes represents a good alternative to conventional therapy.     

THE DIAGNOSIS AND TREATMENT OF MENINGITIS

Treatment of meningitis is no longer a question of the administration of antimeningococcal serum and awaiting results. Today there is at hand an ever expanding armamentarium of drugs effective on various bacteria, rickettsia and some of the larger viruses. The skillful use of these singly or in combination offers an excellent prognosis in most forms of bacterial meningitis. Tuberculous meningitis continues to present a poor outlook, but this has been improved with more intensive therapy. More effective agents are needed in the treatment of this disease.“Shotgun” therapy may be indicated in critically ill patients prior to accurate bacteriological diagnosis; it is more important that therapy should include an effective agent or combination of agents than to attempt to determine in advance the most potent form of specific therapy. Partially treated purulent meningitis may be confused with aseptic meningitis. There is at present no effective therapeutic agent for the viral meningitides, but the prognosis is favorable in most of these diseases without specific therapy.     

Opportunities for rehabilitation of patients with radiation fibrosis syndrome

This review discusses the pathophysiology, evaluation, and treatment of neuromuscular, musculoskeletal, and functional disorders that can result as late effects of radiation treatment.Although radiation therapy is often an effective method of killing cancer cells, it can also damage nearby blood vessels that nourish the skin, ligaments, tendons, muscles, nerves, bones and lungs. This can result in a progressive condition called radiation fibrosis syndrome (RFS). It is generally a late complication of radiotherapy which may manifest clinically years after treatment. Radiation-induced damage can include “myelo-radiculo-plexo-neuro-myopathy,” causing muscle weakness and dysfunction and contributing to neuromuscular injury.RFS is a serious and lifelong disorder which, nevertheless, may often be decremented when identified and rehabilitated early enough. This medical treatment should be a complex procedure consisting of education, physical therapy, occupational therapy, orthotics as well as medications.     

Validity of anecdotal reports of suspected adverse drug reactions: the problem of false alarms

Suspected adverse drug reactions first reported in 1963 in the “British Medical Journal,” the “Lancet,” the “Journal of the American Medical Association,” and the “New England Journal of Medicine” were reviewed 18 years later to assess their initial validity and subsequent verification. Of 52 first reports, five were deliberate investigations into potential or predictable reactions, and in each case causality was reasonably established; the other 47 reports were essentially anecdotal. Of these 47 reports, 14 related to categories of adverse reaction where false-positive reports were unlikely: immediate reactions, local reactions, and known reactions caused by a different mode of administration or a brand previously thought or claimed to be safe. The problem of false alarms rose in the remaining types of reactions: general reactions that did not occur immediately after administration and arose for the first time with a new chemical entity. Of 33 reports of such suspected adverse reactions, validity was satisfactorily established in 14 cases on the basis of rechallenge, predictability from known pharmacology, or the unique nature of the reaction. Of the remaining 19 reports, further verification still has not been satisfactorily established in 12. Seven of these possible false alarms were haematological reactions.Although 35 of the 47 anecdotal reports were clearly correct, of the 19 reports that were not reasonably validated at the time of the report, only seven were subsequently verified. This suggests that agencies monitoring adverse drug reactions should adopt criteria for assessing the validity of first reports of suspected adverse reactions. Such criteria should include: reactions on rechallenge, a pharmacological basis for the adverse reaction, immediate acute reactions, local reactions at the site of administration, reactions with a new route of administration of a drug known to provoke such reactions by another route, and the repeated occurrence of very rare events.     

A Survey of Hemoglobin Values in Canada

A compilation of hemoglobin values has been made from submissions from laboratories in Canada using the cyanmethemoglobin standard prepared and distributed by the Canadian Communicable Disease Centre (formerly the Laboratory of Hygiene). From 84 participating laboratories 21,580 values were analyzed statistically by age and sex. “Medical referrals”, exclusive of blood dyscrasias, were included but were documented separately from “well persons”. In most age groupings no significant difference in these two categories was found.Values for boys and girls were similar up to 12 years of age. For adult women from 18 to 84 years the mean value was 13.0 g. per 100 ml. (95% confidence limits 10.8-15.2 g.); for pregnant women 19 to 44 years the mean value was 12.2 g. per 100 ml. (9.7-14.6 g.). For men aged 17 to 24 years the mean value was 15.0 g. per 100 ml. (12.8-17.3 g.); 25-49 years 14.6 g. per 100 ml. (12.4-16.9 g.); 50-69 years 14.3 g. per 100 ml. (11.8-16.8 g.). It is noteworthy that for the most part the mean values were slightly lower than those frequently quoted as “normal” and that the mean values, particularly for the male, were lower with increasing age.     

Some Principles in the Chemotherapy of Bacterial Infections—I

The classification of antibacterial drugs into bactericidal and bacteriostatic groups is of clinical value. Bactericidal drugs are to be preferred when possible as they are more rapidly effective, may be synergistic when used in combination against bacteria difficult to eliminate, and are less likely to leave residual “persistent” organisms. Antagonism between chemotherapeutic agents is of little clinical importance.The modes of action of antibacterial drugs are reviewed. The penicillins, cephalosporins, and cycloserine interfere with bacterial cell wall synthesis. Polymyxin, colistin, and nystatin affect the bacterial cell membrane. Protein manufacture by the bacterial ribosome is interfered with by the tetracyclines, chloramphenicol, erythromycin, and lincomycin, and the initiation of protein molecules by streptomycin. Streptomycin, kanamycin, and neomycin also cause the ribosome to manufacture warped proteins. Nalidixic acid, griseofulvin, and novobiocin upset the D.N.A. replication of the bacterial chromosome.Many of the factors adverse to the success of chemotherapy are unimportant when powerful drugs are given in large doses to relatively fit patients infected with highly sensitive bacteria. But these factors become important when patients, particularly debilitated patients, are infected acutely or chronically with some of the more obstinate bacteria. Some grasp of these principles is therefore both intellectually satisfying and clinically useful.     

Strain Specific Phage Treatment for Staphylococcus aureus Infection Is Influenced by Host Immunity and Site of Infection

The response to multi-drug resistant bacterial infections must be a global priority. While mounting resistance threatens to create what the World Health Organization has termed a “post-antibiotic era”, the recent discovery that antibiotic use may adversely impact the microbiome adds further urgency to the need for new developmental approaches for anti-pathogen treatments. Methicillin-resistant Staphylococcus aureus (MRSA), in particular, has declared itself a serious threat within the United States and abroad. A potential solution to the problem of antibiotic resistance may not entail looking to the future for completely novel treatments, but instead looking into our history of bacteriophage therapy. This study aimed to test the efficacy, safety, and commercial viability of the use of phages to treat Staphylococcus aureus infections using the commercially available phage SATA-8505. We found that SATA-8505 effectively controls S. aureus growth and reduces bacterial viability both in vitro and in a skin infection mouse model. However, this killing effect was not observed when phage was cultured in the presence of human whole blood. SATA-8505 did not induce inflammatory responses in peripheral blood mononuclear cultures. However, phage did induce IFN gamma production in primary human keratinocyte cultures and induced inflammatory responses in our mouse models, particularly in a mouse model of chronic granulomatous disease. Our findings support the potential efficacy of phage therapy, although regulatory and market factors may limit its wider investigation and use.     

Predictors of normotension on withdrawal of antihypertensive drugs in elderly patients: prospective study in second Australian national blood pressure study cohort

ObjectivesTo identify simple long term predictors of maintenance of normotension after withdrawal of antihypertensive drugs in elderly patients in general practice.DesignProspective cohort study.Setting169 general practices in Victoria, Australia.Participants503 patients aged 65-84 with treated hypertension who were withdrawn from all antihypertensive drugs and remained drug free and normotensive for an initial two week period; all were followed for a further 12 months.ResultsThe likelihood of remaining normotensive at 12 months was greater among younger patients (65-74 years), patients with lower “on-treatment” systolic blood pressure, patients on single agent treatment, and patients with a greater waist:hip ratio. The likelihood of return to hypertension was greatest for patients with higher “on-treatment” systolic blood pressure.ConclusionsAge, blood pressure control, and the number of antihypertensive drugs are important factors in the clinical decision to withdraw drug treatment. Because of consistent rates of return to antihypertensive treatment, all patients from whom such treatment is withdrawn should be monitored indefinitely to detect a recurrence of hypertension.

What is already known on this topic

Systematic reviews have identified predictors of success of withdrawal of antihypertensive medicationThe reviewed studies have mainly been in a hospital or specialist clinic setting, and their recommendations may not be practical in general practice

What this paper adds

This study has identified simple predictors of success that are readily available to general practitionersOn-treatment systolic blood pressure, the number of blood pressure lowering drugs, and the age of the patient are reliable indicators of who may successfully stop taking their drugsGeneral practitioner practitioners should not be dissuaded from offering drug withdrawal to patients with greater waist:hip ratios     

Conformational Changes of Blood ACE in Chronic Uremia

Background

The pattern of binding of monoclonal antibodies (mAbs) to 16 epitopes on human angiotensin I-converting enzyme (ACE) comprise a conformational ACE fingerprint and is a sensitive marker of subtle protein conformational changes.

Hypothesis

Toxic substances in the blood of patients with uremia due to End Stage Renal Disease (ESRD) can induce local conformational changes in the ACE protein globule and alter the efficacy of ACE inhibitors.

Methodology/Principal Findings

The recognition of ACE by 16 mAbs to the epitopes on the N and C domains of ACE was estimated using an immune-capture enzymatic plate precipitation assay. The precipitation pattern of blood ACE by a set of mAbs was substantially influenced by the presence of ACE inhibitors with the most dramatic local conformational change noted in the N-domain region recognized by mAb 1G12. The “short” ACE inhibitor enalaprilat (tripeptide analog) and “long” inhibitor teprotide (nonapeptide) produced strikingly different mAb 1G12 binding with enalaprilat strongly increasing mAb 1G12 binding and teprotide decreasing binding. Reduction in S-S bonds via glutathione and dithiothreitol treatment increased 1G12 binding to blood ACE in a manner comparable to enalaprilat. Some patients with uremia due to ESRD exhibited significantly increased mAb 1G12 binding to blood ACE and increased ACE activity towards angiotensin I accompanied by reduced ACE inhibition by inhibitory mAbs and ACE inhibitors.

Conclusions/Significance

The estimation of relative mAb 1G12 binding to blood ACE detects a subpopulation of ESRD patients with conformationally changed ACE, which activity is less suppressible by ACE inhibitors. This parameter may potentially serve as a biomarker for those patients who may need higher concentrations of ACE inhibitors upon anti-hypertensive therapy.     

Fetal Endoxins and Complications of Pregnancy

Maternal endoxin (digoxinlike substance) is proposed as arising in the fetal area of the fetal adrenal cortex. Its function may be to sensitize the uterus for labor, much as does cortisol in the sheep fetus. Because endoxin is a sodium-potassium-adenosine triphosphatase inhibitor, however, it may also induce maternal vasoconstriction. On our service, normal pregnant women have detectable endoxin after 35 weeks with increasing amounts at term. Specimens of cord blood often have “digoxin” in the therapeutic range. We find that about 40% of women in premature labor and 65% of pregnant women with hypertension have elevated levels of serum endoxin. Postdate gravid women sometimes have very low endoxin levels. Pregnant women with complications and elevated digoxin (endoxin) levels could have specific antidigoxin therapy if endoxin proves to be a modulator of their symptoms. Digoxinlike substances are also sometimes elevated in ill nonpregnant persons, such as those with renal, liver, or heart failure, or hypertension.     

Filamentous Bacterial Viruses VII. Inhibition of fd Deoxyribonucleic Acid Synthesis After a Temperature Jump into Protein-Synthesis Inhibitors

Synthesis of fd deoxyribonucleic acid (DNA) was stopped by transferring infected bacteria from 32 C into chloramphenicol or serine hydroxamate at 42 C, but not by addition of these antibiotics at 32 C, and not by a temperature change in the absence of antibiotics. The inhibition of fd DNA synthesis by serine hydroxamate at 42 C was reversed by excess serine. The ability to synthesize fd DNA at 42 C in chloramphenicol was rescued by delaying the addition of chloramphenicol for a few minutes after the transfer from 32 to 42 C. The colony-forming ability of abortively infected bacteria was also rescued from “killing” by delaying the addition of chloramphenicol after a transfer from 32 to 42 C.     

Thyroid Nodules and Thyroid Cancer

A review of clinical and laboratory features of thyroid cancer, designed to help in a more precise selection of patients for operation, showed that factors contributing to a high index of suspicion of cancer include previous exposure to low doses of radiation, the presence of a firm, solitary thyroid nodule clearly different from the rest of the gland, a young patient, nodules that are “cold” on scan with radioiodine, and nodules that fail to regress after an adequate trial of thyroxine therapy. Factors contributing to a low index of suspicion of thyroid cancer include soft or cystic lesions, multinodular goiters, nodules that are “hot” on ¹³¹ I scan, and those that regress during thyroxine treatment.When these factors are used to select patients for surgical operation, about 30 percent are found to have thyroid cancer.Until more precise methods for preoperative diagnosis are established, it is suggested that this type of clinical selection may be very helpful in the management of patients with thyroid nodules or nontoxic goiter.     

Individual Normal Laboratory Values—Preliminary Observations

A brief and preliminary outline is given describing a consecutive and continuing study of laboratory blood values of only 12 of 48 “normal healthy” subjects with only a few values given. The major emphasis is that of obtaining blood from each subject over a 12-week period to be repeated annually in order to determine individual values and in obtaining a chemical identification of each subject with the anticipation that more information will be available concerning the meaning and limiting parameters of “normal” biologic values. Such a study is made available through the application of modern advances in automation and the wide use of computers. It seems likely that some disorders can be discovered before clinically apparent, with the hope that consequent preventive measures and therapy may be more effective.The few values presented represent only a small part of those yet to be obtained. Much more work is needed in this study of normal values whose parameters must be further defined.     

Substrate-induced Changes in Protease Active Site Conformation Impact on Subsequent Reactions with Substrates

Enzymatic catalysis of biochemical reactions is essential to all living systems. The “lock and key” and “induced fit” models were early contributions to our understanding of the mechanisms involved in the reaction between an enzyme and its substrate. However, whether a given substrate-induced conformation is rigid or remains flexible has not yet been determined. By measuring the enzyme activity and intrinsic fluorescence of a nonspecific Eisenia fetida protease-I with different chromogenic substrates, we show that in subsequent reactions of protease with substrates, both the “lock and key” and “induced fit” mechanisms are used depending on the degree of conformational change required. Chromozym-Th- or chromosym-Ch-induced protease conformations were unable to bind chromozym-U. The chromosym-U-induced protease conformation remained flexible and could be further induced by chromozym-Th and chromozym-Ch. When low concentrations of guanidine HCl were used to disturb the conformation of the enzyme, only small changes in intrinsic fluorescence of the chromozym-Th-induced protease were detected, in contrast to the native enzyme whose intrinsic fluorescence markedly increased. This indicates that the substrate-induced enzyme was relatively rigid compared with the native protease. Utilizing a lock and key mechanism for secondary substrate reactions may have adaptive value in that it facilitates high efficiency in enzymatic reactions.     

PROTHROMBIN TIME—Determination by a Whole Blood Micro-Method for Control of Anticoagulant Therapy

A micro technique that is here described for “prothrombin time” determinations, employing capillary whole blood, provides a range of values which is closely correlated with the Quick one-stage plasma method, thus providing inter-changeability of results both in normal persons and in patients who have been treated with anticoagulant drugs.Avoidance of the use of a water bath and centrifuge permit this technique to yield immediate results at the bedside, in the office or in the patient''s home.The use of a whole blood instead of a plasma technique lends additional safety to control of anticoagulant medication, since it may reflect depression of clotting factors not apparent by the usual plasma methods.     

The Metabolism of the Volatile Amines: VII. The Clinical Significance of Two Components of the Blood Ammonia Level

Blood ammonia levels consist of two components: ammonia present in blood at the time of shedding, termed “free” ammonia, and ammonia produced by the deamidating action of the alkali reagents. Blood of healthy people contained little or no “free” ammonia while blood of patients with chronic liver disease occasionally showed levels up to 1.2 μg./ml. Patients with hepatic encephalopathy had significantly elevated levels which usually fell to zero following therapy. Levels of “free” ammonia above 0.6 μg./ml. were diagnostic of hepatic encephalopathy in patients suffering from unexplained neurological disorders.The rate of formation of ammonia by the alkali reagents was increased in patients with hepatic necrosis and was depressed in those with chronic hepatitis. The ammonia appeared to arise from the deamidation of glutamine and asparagine, present in blood in both the free and peptide forms.     

The Female Post-Mating Response Requires Genes Expressed in the Secondary Cells of the Male Accessory Gland in Drosophila melanogaster

Seminal proteins from the Drosophila male accessory gland induce post-mating responses (PMR) in females. The PMR comprise behavioral and physiological changes that include increased egg laying, decreased receptivity to courting males, and changes in the storage and use of sperm. Many of these changes are induced by a “sex peptide” (SP) and are maintained by SP’s binding to, and slow release from, sperm. The accessory gland contains two secretory cell types with distinct morphological and developmental characteristics. Products of these “main” and “secondary” cells work interdependently to induce and maintain the PMR. To identify individual genes needed for the morphology and function of secondary cells, we studied iab-6^cocu males, whose secondary cells have abnormal morphology and fail to provide products to maintain the PMR. By RNA-seq, we identified 77 genes that are downregulated by a factor of >5× in iab-6^cocu males. By functional assays and microscopy, we tested 20 candidate genes and found that at least 9 are required for normal storage and release of SP in mated females. Knockdown of each of these 9 genes consequently leads to a reduction in egg laying and an increase in receptivity over time, confirming a role for the secondary cells in maintaining the long-term PMR. Interestingly, only 1 of the 9 genes, CG3349, encodes a previously reported seminal fluid protein (Sfp), suggesting that secondary cells may perform essential functions beyond the production and modification of known Sfps. At least 3 of the 9 genes also regulate the size and/or abundance of secondary cell vacuoles, suggesting that the vacuoles’ contents may be important for the machinery used to maintain the PMR.