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Abstract of papers in this issue
Lung scan
Renal tissue lymphocytes
in
Continued
lmmunohistologic studies coupled with conventional light and electron microscopic observations were made in five patients with interstitial nephritis. Most mononuclear cells making up renal interstitial infiltrates were T cells. Some chronic inflammatory cell foci within renal interstitium were characterized by clusters of la antigen-positive T cells considered to be markers for activated lymphocytes. B cells were present in very small proportions (5 percent or less). The profile of immunocompetent cells present in lesions of interstitial nephritis suggests a major role for cell-mediated immunity in this disorder. Increase in tissue lymphocytes of the Ty subclass with receptors for the Fc portion of IgG also suggests local activation of intrinsic suppressor cell mechanisms.
Husby G. Tung KSK, Williams RC Jr.: Characterization of renal tissue lymphocytes patients with interstitial nephritis. Am J Med 1981; 70: 31-38.
interstitial nephritis T ancl B lymphocytes
This is a study of 243 patients in whom 248 pulmonary angiograms were performed because of suspected pulmonary embolism. Ventilation and perfusion lung scanning in 140 of them revealed 38 to be in low and high probability groups. Of 19 patients with subsegmental and nonsegmental perfusion defects that were matched with ventilation defects, none had pulmonary embolism. Conversely, angiography was positive in 17 of 19 patients with multiple segmental or lobar perfusion defects in areas of normal ventilation. Doppler flow examinations of the veins of the legs showed normal flow in 61 of 79 (77 percent) patients with pulmonary emboli and, therefore, were insensitive indicators of embolism. There was no mortality from angiography, and serious complications occurred in 2 percent of the patients. Anticoagulation in 83 patients was associated with bleeding in 25. two of whom died. Patients who are not clearly categorized by lung scanning should undergo angiography rather than be empirically treated with long-term anticoagulation for suspected pulmonary embolism.
Cheely R, McCartney WH, Perry JR, Delany DJ, Bustad L, Wynia VH, Griggs TR: The rote of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism. Am J Med 1981; 70: 17-22.
Pulmonary embolism Pulmonary angiography Doppler flow Thrombosis Embolism Scintigraphy
Atypical mycobacteriai infection Nontubercuious mycobacterial infection
on pu8e A32
During a 10 year period, pulmonary resection in 20 patients yielded granulomas with acid-fast bacilli. Of these 20 granulomas, 12 were due to infection with Mycobacterium avium-intracellulare. M. gordonae, M. fortuitum and M. tuberculosis were cultured from one lung specimen each. In five instances acid-fast bacilli were seen but failed to grow on culture. There was no evidence of recurrence of disease for periods ranging from four months to 10 years in 14 of the 20 patients in whom follow-up was available. We conclude that solitary pulmonary “tuberculomas” are often due to nontuberculous mycobacterial infection, particularly M. avium-intracellulare. When the lesion is due to nontuberculous mycobacteria and can be resected in its entirety, drug therapy is not indicated.
Gribetz AR, Damsker 6, Bottone EJ, Kirschner PA, Teirstein AS: Solitary pulmonary nodules due to nontuberculous mycobacterial infection. Am J Med 198 1; 70: 39-43.
Pulmonary nodules Tubercuioma
Sixty-four patients were evaluated prospectively for a reflex sympathetic dystrophy syndrome (RSDS), using quantitative clinical measurements, high-resolution roentgenography and scintigraphy. Five separate groups were identified by their clinical features, allowing us to distinguish patients with definite or incomplete forms of the RSDS as well as 16 patients with other disorders. Scintigraphy was found to be a useful diagnostic study that also may provide a method of predicting therapeutic response. Systemic corticosteroid therapy proved to be a highly effective mode of treatment for up to 90 percent of the patients with the RSDS.
Kozin F, Ryan LM, Carerra GF, Soin JS, Wortmann RL: The reflex sympathetic dystrophy syndrome. Ill. Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med 1981; 70: 23-30.
Reflex sympathetic dystrophy syndrome Corticosteroid therapy
THEO-DUR Enduring Action Anhydrous Theophylline Sustained Action Tablets Description: THEO-OUR Sustained Action Tablets contain anhydroos theophyl-
line, with no color addrhves. Actions: The pharmacologic actions of theophylline are as a bronchodflator, pulmonary vasodrlator and smooth muscle relaxant since the drug directly relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels, Theophylfine also possesses other actions typical of the xanthine derivatives. coronary vasodifator, diuretic, cardiac stimulant, cerebral stimulant and skeletal muscle stimulant. The aclions of theophylline may be mediated thrw h inhibitron of phos hodiesterase and a resultant increase in intracellular cyc9IC AMP which coul 8 medrate smooth muscle relaxation. Indications: Symptomatic relief and/or prevention of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. Contraindications: THEO-OUR IS contraindicated in individuals who have shown hypersensitivity to any of its components or xanthine derivatives. Warnin s: Excessrve theophylline doses may be associated with toxicity. serum theophyl ! me levels should be monitored to assure maximum benefit with minimum risk. Incidence of toxtcny increases at serum levels greater than 20 mc /ml. High blood levels of theophylfine resulting from conventional doses are corre9ated with clinical manifestations of toxicity in: patients with lowered body plasma clearances, patients wtth liver dysfunction or chronic obstructive lung disease, and patients who are older than 55 years of age, particularly males. There are often no early srgns ot less serious theophylline toxicity such as nausea and restlessness, which may a pear in up to 50% of patients prior to onset of convulsions. Vontncular arrhyt fl mras or seizures may be the frrst signs of toxicity. Many atients who have higher theophylline serum levels exhibit a tachycardia. Theophyl Pine products may worsen pre-existing arrhythmias. Usagein Pre nancy: Safe use in pregnancy has not been established relative to possible aIfverse effects on fetal develo ment but neither have adverse .’ unfortunately, true for most effects on fetal development been established. Phis IS, anti-asthmatic medications. Therefore, use of theophylline In pregnant women should be balanced against the risk of uncontrolled asthma. Precautions: THEO-OUR TABLETS SHOULO NOT BE CHEWED OR CRUSHED. Theophyllines should not be administered concurrently with other xanthine medications It should be used with caution in patients with severe cardiac dtsease. severe hypoxemia. hypertension, hyperthyroidism, acute myocardial injury, car pulmonale. congestive heart failure, liver disease and in the elderly, particularly males, and in neonates. Great caution should be used in giving theophylline to patients in congestive heart failure since these patients show markedly prolonged theophylline blood level curves. Use theophylline Cautlousl In patlents with history of peptic ulcer. Theophylline may occasionally act as a Yocal irritant ” 10 G.I. tract although gastrointestinal symptoms are more commonly central and associated with hrgh serum concentrations above 20 mcg/ml. Adverse Rsactions: The most consistent adverse reactions are usually due to overdose and are: Gastrointestinal: Nausea, vomiting, epigastrrc pain, hematemesis. diarrhea. Central Nervous System: Headaches, irritability, restlessness, insomma. reflex hyperexcitabflity, muscle twitching, clonic and tonic generalized convulsions. Cardiovascular: Pal itation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, IiPe threatening ventricular arrhythmias. Resprratory: Tachypnea Renal. Albuminuria, increased excretion of renal tubular cells and red blood cells; potentiation of diuresis. Others: Hyperglycemia and inappropriate AOH syndrome. How Supplled: THEO-OUR100 mg, 200 mg and 300 mg Sustained Action Tablets are available in bottles of 100. 1000, and 5000, and in unit dose packages of 100 (20 x 5’s). Caution: FEDERAL LAW PROHIBITS DISPENSING WITHOUT A PRESCRIPTION. 0779 For full prescribmg information, see package insert.
ZERO-ORDER dc/dt=K’” (Constant rate absorption by GI infusion)
200 mg
100 mg
!EwwTIc*Ls INC.
Miami, Florida 33169 &AI A32
Aldactone” (spironolactone)
WARNING Spiraaolactone has been shown to be a tumorigen in chronic toxicity studies in rats (sea Warnings). Aldactone shoald be used only in those conditions described under Indica_ tions. Unnecessary use of this drug should be avoided. Indications: Lkgnosis and treatment of primary hypecaldosteronrsm Essential hypertension, edema of congestive heart failure and the nephrotrc syndrome, when other measures are consrdered inappropriate.. Cirrhosis of the liver accompamed by edema and/or ascites Hypokalemla Contraindications: Amma, acute renal msuffrcienc! slgnihcant lmparrment of renal function. or hyperkalem/a. Warninns: Excessive ootasslum Intake mav cause hyperka/emTa. Potassium sipplements should not be given mth Aldactone Do not admmlster concurrently mth other potassium-spanng duetics Splronolactone has been shown to be a tumongen in chrome toxtnty stud/es m rats In one study usmg 25. 75, and 250 times the usual daiiy human dose (2 mg /kg j there was a statist/Cal/y srgnificant dose-related mcrease in benrgn adenomas of the thyrotd and testes In female rats there was a statisticaily srgnrhcant increase in mabgnant mammary tumors at the mid-dose only In male rats there was a dose-related increase m proiiferabve changes in the liver. At the highest dosage /eve/ /XXI mg /kg) the range of effects included hepatocyiomegalx hyperplastrc nodules and hepatocellular carcinoma; the last was not stat&a//y significant. Precautions: Pattents should be carefully evaluated for possible disturbances of fluid and electrolyte balance. Hyperkalemia may occur in patients with impaired renal function or excessrve potassium intake and can cause cardrac Irregularities wh/ch may be fatal Hyponatremra may be caused or aggravated, especially when Aldactone is administered m combination with other diuretics i?ansient elevation of BUN and/or m/Id andosis may occur Aldactone potentiates the effect of other duretrcs or antihypertensive agents, particularly ganghonic biocking agents,’ therefore the dosage of such drugs should be reduced by at least 50 percent when adding Aldactone Gynecomastia may develop and in rare instances some breast enlarge ment may persist L4scular responsiveness to norep,nephrine may be reduced Spironolactone may cross the placenta/ barrier Use in pregnant women requres that the anticpared benefit be weIghed against posstble hazard to the fetus. Breast feedmg should be discontinued when Aldactone is being used Adverse Reactions: Gynecomasba IS observed not mfrequently Gastrointestmal symptoms including crampmg and drarrhea, drowsiness, IetharqK headache, maculopapular or erythematous cutaneous ‘eruptions, orticaria, mental confusron. druo fever ataxia. inab&v to achieve or majntain erect&n, irregular ‘menses’ or amenorrhea, postmenopausal bleeding, hrrsutism and deepening of the vorce Carcinoma of the breast has been reported but a cause-and-effect relationshrp has not been established Adverse reactrons are usually reversible upon discontinuation of the drug. Dosage and Administration For primary hyperaldosteronism: 400 mg da//y for three to four weeks (long test). or for four davs (short test). For preparation for suriery or for long-term maintenance therap)! 100 to $XJ rn$ daily for edeme m adu s: /rubal dally dosage IS 100 mg. in dlnded doses but may range from 25 to 200 mg. dai/y If after five days an adequate diuretic response has not occurred a second duet/c which acts more proximally in the renal tubule mav be added The dosaoe of Aldactone should remam unchanged when other d~uretlc therapy IS added For edema bt children: Inma/ daily dosage should provide approximately 15 mg per pound of body werght (3 3 mg /kg.) in divided doses. For esseatfa/ hyperteasioa: Initial adult daily dosage of 50 to l&J mg. in divided doses, alone or with dioret‘its tiich act mme proximally m the renal tubule. or with other antihypertenslve age& Continue treatment for at least two weeks since maximal resoonse mav not occur before this time. Adjust subsequeni dosage &co&g to pabent response. Far hvpabalamia: 25 to 1lWmg. da//y in divided doses.
Address medical inquiries toG. 0. Sear/e & Co. Madtwl Commumcations Department Bar 5110, Chrcago. Illinois 60680
A34
(disopyramide phosphate) Jxtracts
f papers in this issue
&fore prescrtbmg /vorpace /drsopymmrde phosphate/, please consult current compIHe prescnbrng informatron a summar) of whfch foilows Indicadms: For suppress/on and prevention of recufrence of the follomng cardtac arrhythmias when they occur singly or m combmaoon unrhcal premature (ectopfci ventncular contractions. premature fectoprcl ventrricular coniractrons of multdocal ortg~n. parrad premature ventricular contracti~s (couplets/. and episodes of ventrxular tachycardia (persister8 ver;trtcular tachycardla IS ordmarily rreated wrth 0 C cardioversmn) Norpace is equaily effecfrve m both drgrtalued and nondrgrtabed patients It IS also equally effect!ve m treatmg pnmary cardiac arrhythmias and those whrch occur in assocratmn with organ/c heart disease mciudrng coronary artery %sease Orai Norpace nas not been adeuuately studted m pattents with acute myocardial mfarc~ tion or with persrstent venlricular tachycardla or atrral arrhythmtas and rs nor mdt cated for arrhythmras due to drgMs mtoxrcatmn The v&e of anbarrhythmcc drugs in preventmy sudden dea!h rn patrents wth serrws ventucular sctopic act/vrty has not been e.stabr!shefi Contraindicatimm: Cardragemc shock, preexistmg seconds or thrrd-degree AV biock iif no pacemaker IS present], or know hypersen.w:y’to the drug Werninas:Norpace may caese or worsencoogestive haart fagore ICHfi or produce severe hypoteasim as a conseqaance of its negative iaotropicproperties. Hypotaasion has been observed primaf#y with primary card~moyopathy or inadequately compensated CM Norpace shoald not be used ie patients with uncompensated or mergMly corn pensated CM or hypetensimi unless the condition is secondary to cardiac arrhythmia. Patients with a history of heart faLre may be treated with Norpece. but w&d attention mast be given to mainteiaiag cardiac fanc tion, inchdingoptimaldigita#zetion. ff hypotensiw OCWIS or CHF womeas, Norpece shoakl be discoatinuedand, if necessary. restarted at a lower dosage only after adequate cerdiec compensation has been estemshed Norpece sboakl be discontinued if significant widenby lgraeter thanW/o/ of the (u1S complax occurs. Prdoegatien of the QT interval /cerrected/ and wetsanieg of the arrhythmia may occur. Patients who have evidenced prden ation of the &7 interval in response to qainidine may he at particalar n2 If 47prdengation greater than 25% is observed and if ectapy coatbmes, the patient should be monitored cfosely. and discontineatim of Nerpace considered In rare instances eignifieant hypoglycemia has been reporteddaring Norpace therapy. 7be concomitant use of Norpace with other Type 1 antierrhythmic agents should be reserved for patients with &threatening arrhythmias who are demonstrably unrespoasive to single agent antiarrhytbmic tharapr Such use may produce serious negative inotropic effects, or may exceeeivdy prdong conduction. Patients receiving more than one antiarrhythmic drug must be carefaSy monitored. if firstdegree heart block devefeps, the dosegeof Norpace should be reduced If the block parsists, contineetieo of Norpace mast dependuponan assessment of benefit versastish. Developmentof second- or tbird-dogreeAV blochor uni, bi- or trifescicalarblock requires discontinuation of Norpece, an/ass the ventricular rate is adequately coatreM by a pacemaker Becaase of its antichognergic activiw Norpece sbouM not be usedin pa tients with gfeucoma, myasthenia gratis or urinary retention, unless adeqaate overriding maesaras are teken. Precautions: Patients wfth atria/ flutter or hboliabon should bc drg,tahzed poor to Norpace admmrstratrcn to ensure ihaf drug-Induced enhancement ofAV conduction does not allow a ventricular rate beyond physto/og/ca//y acceptable kmits Jhe effec! of Norpace 1spresently onceriam :n patients wtth srck smus syndrome, WolitParkmson- White syndrome, or bundle branch block i’affents wrrh myoardrts (K other cardromyopathy may devptnn - -r sign,f,car;t hypotensior; n response to the usual dosage of Norpace Norpace dosage should be reduced m pat/ants wrth m?pa#redrenal or hepasc function and the slectrocardmgram careful/y monitored ior s,gns of overdosage Antfarrhylhmlc drugs may be meffectrve in patients wrth hypokaiemra. Therefore, ary potassium dehcrt should be corrected before mstMrny Norpace therapy Safe use m pregnancy has not been established ilisoovramrde has been found m human retal blood Nmpece has been rep&d to stimulatecootractimsof the pregnant uterus.Useof Norpace m pregnant women requires that the potentral benefit be werghed agamst posnble hazards fo fhe fetus Followmg oral admmistration, d/so pyramrde has beerr found m human mdk at a concentraoon not exceedmg that m plasma Muse of rhe drug 1s deemed essenttal, an alternate msrhod of infant few’,ng should be mst:tuted Effects of Norpace on the feius dunng deirvery or on the Course of labor and dehverf are unknown Safety and effectiveness of Norpace m chrldren have not been establrshed Adverse Reactions: Dry mouth. unnary hesftancy constrpahon, biorred nsron. dry nose/eyes/throat, urinary retention. umary frequency and urgent): impotence, nausea, pam/bioatmg@as. anorexfa. d/a&a. vomtting nervousness, c+zzmess genera/ fatigue/muscle weakness. __ __ headache. malarse. achesloams, hvootensmn, conqesttve heart fariure, cardiar cnn~ ductron dtsturbances, edema/werght yam, short& of breath, syncope. chest pam oenerahzed rash/dermatos~s, itchmq, hypokalerma, elevated cholesterol/ ;nglyclycendes. depressron. msomnra, aysurla, numbness /tmyling, elevated liver enzymes. AV block, eievated BUN, elevated creafmme, decreased hemoglobm/ hematocrrt, and hypoglycemra Acute psychos& cholestatrc jaundice, and agraanuIocytrxts, all ihree revers!ble. have neen reporteo Dosageand Admimistratfm: Dosage must be md/vrduahzed on the basrs of response and tolerance The usual adult dosage IS 400 to 800 rng per day grver! m dfnded dose.7four times da//y The recommended dosage schedule for most adults IS HI mg every SIX ho& For pabents less than 1Ill pounds (50 kg) the recommended dosage IS 100 mg every SIX hours If raprd control of arrhythmia IS essenfidl an rmtlal loadmg dose of 300 mg of Norpace (200 mg for pabents less than 110pwndsl IS recommended For patrents with cardiomyopathy or possrble wrdrac decompensabon. a loadmg dose should not be g,ven and the mitral dose hmtted to 100 my every SIX hours, wrth subsequent dzage adfustments made gradual/y wrth close momtormg See GUIrant campleteprescr&ng infmmatim fer deeege recemmandetiws. How SuppEcd: Capsules contammg 100 mg or 150 mg of disopyramrde base SE;~~E
A40
Sear/e Laboratories Dwston of Sear/e PharmaceutKals Box 5170, Chicago, lllinois 60680
Inc
Insulin-dependent
Diabetes mellitus
Islet-cell antibodies
mellitus. Am J
autoimmunlty
Continued
The possible role of autoimmunity in the pathogenesis of insulindependent diabetes mellitus is critically reviewed. Autoimmune phenomena (antipancreatic cell-mediated autoimmunity and islet cell antibodies) are demonstrable in most patients with insulin-dependent diabetes mellitus at the time of diagnosis. No direct cytotoxic effect on human beta-cells of specifically reactive lymphoid cells and/or antibodies from such patients has been demonstrated. Furthermore, the nature of the beta-cell specific antigens invoked is unknown, making methods for detectii of islet-cell antibodies unsatllfactory-also because of lack of stanftardi2ation between laboratories. Atthough thsre is no experimental evidence to show thatautoimmune mechanisms are directly invofved in beta-cell doskuction in insulin-dependent dftes mellitus. it is concluded that the existing knowledge is very suggestive and should be explored futher by improved technology.
diabetes
Cell-mediated
Nerup J, Lernmark A: Autoimmunity in insulindependent Med 1981; 70: 135-141.
Insulin-dependent,
Autoimmunity
Genetic heterogeneity, the concept that diabetes can have many different causes, was first suggested by the existence of rare genetic synckcmes with diabetes, ethnic differences in clinical features and genetic heterogeneity of animal models. Genetic heterogeneity is now considered to be firmly established by family, twin, metabolic, immunologic and HLA disease association studies that separate idiopathic diabetes into insulin-dependent types (juvenile-onset type) and noninsulindependent types (maturityonset type). Further heterogeneity is being demonstrated within each of these broad groups of disorders-within insulin-dependent diabetes using the HLA antigens and immunologic studies, and within noninsulindependent diabetes using such criteria as obesity, insulin response, age of onset and chlorpropamide-primed alcohol-induced f!ushing. This heterogeneity has major implications for the research and care of our diabetic patients since the precise etiology, risk of complications and genetic counseling are likely to vary among those different disorders that result in diabetes.
disorders. Am J Med
mellltus
Glucose intolerance
Nonlnsulln-dependent
Rotter JI, Rimoin DL: The genetics of the glucose intolerance 1981; 70: 116-126.
Diabetes mellitus
mellltus
Genetics Juvenile-onset
animals.
diabetes
Am J Med
Transmembrane
signaling
Receptor
subunit structures
on page A45
Our understanding of the molecular basis of insulin action remains incomplete, but important new insights have recently been achieved. All avallable evidence to date indicates that intracellular signalling by the hormone results from its initial interaction with specific cell surface receptors. Insulin receptors from all tissues studied to date appear to be minimally composed of two M, 125,000 subunits denoted as (Y and two M, 90.000 subunits denoted as p. The four subunits are linked together by disulfide bonds to give a symmetrical configuration with a stoichiometry of (o-s-s-fl)-s-s-(a-s-s-b). Another area of recent progress involves the successful generation of a soluble factor (or factors) by insulin capable of modulating the activity of insulin-sensitive enzymes in cell-free systems. The data available are consistent with the hypothesis that insulin-receptor interaction leads to the activation of a membrane protease that catalyzes the release of a peptide mediator or mediators of insulin action.
Czech MP: Insulin action. Am J Med 1981; 70:142-150.
Insulin
The importance of environmental factors in the pathogenesis of juvenile-onset diabetes mellitus is suggested by genetic and epidemiologic observations. Group B Coxsackie viruses and mumps virus have been implicated, and several other agents also could play a role in the disease. A picornavirus similar to the Coxsackie viruses exhibits specific tropism for the beta cells of the islets of Langerhans, causing a disease in mice that is similar to juvenile-onset diabetes. In these animals, genetic and metabolic factors appear to influence the severity of beta cell injury. Immunopathologic considerations also may be important. Viewed in concert, ‘the evidence supports the notion that certain “wild” viruses may possess specific tropism for beta cells and destroy them during the course of a systemic infection. Host factors clearly play a role, but their relative importance in the pathogenesis of the disease remains to be defined.
mellitus in man and experimental
lmmunopathology
Craighead JE: Viral diabetes 1981; 70: 127-134.
Viruses
insulin resistance Obesity
Nocturnal hypoglycemia Pregnancy
of con-
Continued
The compelling evidence that blood glucose control will slow or prevent microvascular complications has stimulated research to find better ways of managing insulin-dependent diabetes. Reviewed here are some of the approaches being utilized as well as the advances that have been made in conventional insulin treatment, which is likely to remain the mainstay of treatment in the coming decade. These investigators conclude that the practical problems of improving diabetic control are essentially those of logistics and that these problems apply even more forcefully to doctors for whom the new technology will bring radical changes in the management of diabetes, not least in terms of increased time and involvement.
Tattersall R, Gale E: Patient self-monitoring of blood glucose and refinements ventional insulin treatment. Am J Med 1981; 70: 177-182.
Self-monitoring of blood glucose Diabetes “Open loop” systems
)nSUlin resistance is a characteristic feature of both obesity and noninsulindependent diabetes mellitus, and the cause of this insulin resistance resides at the level of the target tissue. The specific mechanisms underlying these insulin-resistant states are heterogeneous, and a continuum of defects exists. In patients with mild insulin resistance, the impairment in insulin action is due to decreased numbers of insulin receptors leading to decreased insulin sensitivity. In patients with severe insulin resistance, decreased numbers of insulin receptors and a postreceptor defect in insulin action coexist, but the postreceptor defect is the predominant abnormality. Between these extremes, the relative roles of receptor defects and postreceptor defects vary, but the general trend is that as the insulin resistance worsens, the postreceptor defect becomes more prominent.
in obesity and noninsu-
insulin receptors
Olefsky JM. Kolterman OG: Mechanisms of insulin resistance lin-dependent (type Ii) diabetes. Am J Med 1981; 70: 151-168.
Diabetes Glucose clamp insulin sensitivity insulin action Insulin-receptor binding
JS: Treatment
of diabetes
mellitus
by devices.
Insulin administration
Am J Med 1981;
70:183-
on page A56
A very important aspect of diabetes mellitus is whether or not normalization or near-normalization of blood glucose and/or other metabolites and hormones may reduce or eliminate the chronic complications of this disease. To answer this question and to provide a more “physiologic” approach to insulin administration, a constellation of devices have reached the stage of clinical investigation. These include small portable pump systems that can provide variable rates of insulin infusion via the subcutaneous, intravenous or intraperitoneal routes. In addition, bedside artificial “beta cells” having the capability of providing insulin infusions, with the rate varying as a function of continuous glucose measurements, are available for short-term studies. Under development are implantable continuous infusion devices and implantable glucose sensors that could in the future lead to a miniaturized implantable glucose-controlled insulin administration system.
Soeldner 194.
Diabetes meliitus
Devices, pumps-sensors
During the past few years, it has become increasingly apparent that insulin resistance may be a more frequent cause or contributing factor for carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness) or both. Alterations in sensitivity and responsiveness to insulin can only be distinguished by evaluating insulin dose-response curves. When used in conjunction with the measurement of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism(s) responsible for insulin resistance.
Rizza RA, Mandarin0 LJ. Gerich JE: Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding. Am J Med 1981; 70: 169-176.
insulin resistance Dose-response curve
NEW KLOTRIX@
lPOMsslUM CHLDRIDQ SLOW-RELEASE WBLETB 10 mEq BESCRlPTfON KLOTRIX ISafilm-coated (not enlent-coated)
tablet contarmng 750 mg potassrum chlorrde fepurvalent to 10 mEq) in a wax matrrx Thrs formulation IS Intended to provide a controlled release of potassrum from the matrrx to minimrze the likelihood of producrng hrgh locahzed concentrations of potassrum wrthrn fhegastrorntestrnal tract. INOICAlIONS- BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEOING WITH SLOW-RELEASE POFASSIUM CHLORIOE PREPARATIONS. THESE URUGS SHOULD BE RESERVED FOR WfOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TUFAKE LIPUIO OR EFFERVESCENT POlASSlUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WllH 1HESE PREPARATIONS. 1 For therapeutic use rn patients with hypokalemia wdh or wrthout metabolrc alkalosrs; rn digitalis rntoxrcation and m patrents wtth hypokalemic famrlral periodic paralysis 2. For prevention of potassium depletron when the dretary intake of potassrum IS Inadequate In the followrng conditions: Patrents recerving digrtalrs and drwetics for congestive heart failure; hepahc crrrhosrs with ascrtes; states of aldosterone excess wrth normal renal functron; potassium-losing nephropathy, and certarn drarrheal states. 3. The use of potassrum salts In pattents receiving diuretics for uncomphcated essential hypertension IS often unnecessary when such patients have a normal dietary pattern Serum potassium should be checked periodrcally, however, and, rf hypokalemra occurs, dietary supplementation with potassium-contarnmgfoods may be adequate to control milder cases. In more severe cases supplementation with potassmm salts may be indicated. CONTRAlNUlCAllONS In patients with hyperkalemra. since a further Increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemra may complicate any of the followrngcondrtions~ chronic renal farlure. systemicacrdosrs such as drabetrc acidosis, acute dehydration, extensrve trssue breakdown as in sevwe burns, adrenal nrsufficrency, or the admrmstration of a potassium-sparmg dutretrc (eg, sprronolactone, triamterene). Wax-matrix potassium chloride preparations have produced esophageal ulceratron in certain cardiac patrents with esophageal compression due to enlarged left atrmm. All solid dosage fwms of potassium supplements are contraindicated in any patient rn whom there IS cause for arrest or delay in tablet passage through the G.I. tract. In these Instances, potassium supplementation should be wrth a hqurd preparahon. WARNINBS, Hypsrkalamil: In patients with impaired mechantsms for excreting potassrum, admrmstratron of potassium salts can produce hyperkalemra and cardiac arrest. This occurs most commonly in patients given potassium Intravenously but may also occur when given orally. Potentially fatal hyperkalemra can develop raprdly and be asymptomatlc. Use of potassium salts in patrents with chronic renal disease, or any other conditron which impairs potassium excretion requrres partrcularly careful monitorrng of the serum potassium concentration and appropriate dosage adjustment. Interaction with potassium-sparing diuretics: Hypokalemra should not be treated by the concomttant administration of potassium salts and a potassurm-sparing diuretic leg, spironolactone or trramterene), since the srmuttaneous admrmstratron of these agents can produce severe hyperkalemia. Gastrointestinal lesions: Potassium chloride tablets have produced stenotrc and/or ulcerative lesions of the small bowel and deaths. These lesions are caused by a high localized concentrahon of potassium ion rn the region of a rapidly drssblving tablet, which Injures the bowel wall and thereby produces obstruction, hemorrhage, or perforation KLOTAIX IS a wax-matrix tablet fwmulatec to provrde a conbqlled rate of release of potassium chloride and thus to mrnrmrze the possibrlrty of a high local concentratron of potasstum ion near the bowel wall Whrle the reported frequency of small-bowel lesions is much less with wax-matrrx tablets (less than one per 100,000 patrent-years1 than wrth enter&coated potassium chloride tablets (40-50 per 100,000 patient-years) cases associated wrth wax-matrix tablets have been reported both in foreign cwntries and In the United States. In addrtron, perhaps because the wax-matrix preparations are not enterrc-coated and release potassrum rn the stomach, there have been reports of upper gastrointestinal bleedrrg associated with these products. The total number of gastrointestrnal lesions remains less than one per 100,000 patrent-years. KLOTRIX should be discontrnued rmmedrately and the possibility of bowel obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleedrng occurs. Metabolic acidosis: Hypokalemra in patrents with metabolic acidosis should be treated with an alkalinizing potassnrm salt such as potassrum bicarbonate, potassrum citrate. or potassium acetate PRECAUTIONS Potassium depletron IS ordinarrly diagnosed by demonstratrng hypokalemra rn a patient wrth a climcal history suggestrng some cause for potassrum depletron. In interpreting the serum potassium level, the physrclan should bear tn mind that acute alkalosm per se can produce hypokalemia In the absence of a defrcrt rn total body potassium, while acute acidosrs perse can increase the serum potassrum concentratron into the normal range even in the presence of a reduced total body potassmm. Treatment of potassmm depletron particularly rn presence of cardiac disease, renal disease, or acidosis, requires careful attention to acid-base balance and appropriate momtorrng of serum electrolytes, electrocardiogram and cluucal status of patient. ADVERSE REACTIONS Most common to oral potassium salts, nausea, ,vomiting, abdominal drscomfort, and diarrhea. These symptoms are due to uritatron of the gastrointestinal tract and are best managed by dilutrng the preparation further, taking the dose with meals, or reducing the dose. One of the most severe adverse effects IS hyperkalemra (see Contraindrcations and Warnmgs). There also have been reports of upper and lower gastrorntestinal conditions rncludrng obstruction, bleeding, ulceratron and perforation (see Contrarndications and Warnings); other factors known to be assocrated with such condrtrons were present rn many of ihese patients. Skin rash has been reported rarely. UOSAGE Usual dretary intake potassium by the average adult is 40 to 80 mEq per day. Potassium depletion suffrcrent to cause hypokalemra usually requires loss of 200 or more mEq of potassrum from the total body store. Dosage must be adlusted to the rndrvidual needs of each patient but IS typically rn the range of 20 mEq per day for prevention of hypokalemia to 40-100 mEq per day or more for treatment of potassium depletron. Nota: KLOTRIX slow-release tablets must be swallowed whale and never crushed or chewed. HOW SUPPLIED Bottles of 100. PHARMACEUTICAL DIVISION
A56
Renal tissue lymphocytes
in
Continued
lmmunohistologic studies coupled with conventional light and electron microscopic observations were made in five patients with interstitial nephritis. Most mononuclear cells making up renal interstitial infiltrates were T cells. Some chronic inflammatory cell foci within renal interstitium were characterized by clusters of la antigen-positive T cells considered to be markers for activated lymphocytes. B cells were present in very small proportions (5 percent or less). The profile of immunocompetent cells present in lesions of interstitial nephritis suggests a major role for cell-mediated immunity in this disorder. Increase in tissue lymphocytes of the Ty subclass with receptors for the Fc portion of IgG also suggests local activation of intrinsic suppressor cell mechanisms.
Husby G. Tung KSK, Williams RC Jr.: Characterization of renal tissue lymphocytes patients with interstitial nephritis. Am J Med 1981; 70: 31-38.
interstitial nephritis T ancl B lymphocytes
This is a study of 243 patients in whom 248 pulmonary angiograms were performed because of suspected pulmonary embolism. Ventilation and perfusion lung scanning in 140 of them revealed 38 to be in low and high probability groups. Of 19 patients with subsegmental and nonsegmental perfusion defects that were matched with ventilation defects, none had pulmonary embolism. Conversely, angiography was positive in 17 of 19 patients with multiple segmental or lobar perfusion defects in areas of normal ventilation. Doppler flow examinations of the veins of the legs showed normal flow in 61 of 79 (77 percent) patients with pulmonary emboli and, therefore, were insensitive indicators of embolism. There was no mortality from angiography, and serious complications occurred in 2 percent of the patients. Anticoagulation in 83 patients was associated with bleeding in 25. two of whom died. Patients who are not clearly categorized by lung scanning should undergo angiography rather than be empirically treated with long-term anticoagulation for suspected pulmonary embolism.
Cheely R, McCartney WH, Perry JR, Delany DJ, Bustad L, Wynia VH, Griggs TR: The rote of noninvasive tests versus pulmonary angiography in the diagnosis of pulmonary embolism. Am J Med 1981; 70: 17-22.
Pulmonary embolism Pulmonary angiography Doppler flow Thrombosis Embolism Scintigraphy
Atypical mycobacteriai infection Nontubercuious mycobacterial infection
on pu8e A32
During a 10 year period, pulmonary resection in 20 patients yielded granulomas with acid-fast bacilli. Of these 20 granulomas, 12 were due to infection with Mycobacterium avium-intracellulare. M. gordonae, M. fortuitum and M. tuberculosis were cultured from one lung specimen each. In five instances acid-fast bacilli were seen but failed to grow on culture. There was no evidence of recurrence of disease for periods ranging from four months to 10 years in 14 of the 20 patients in whom follow-up was available. We conclude that solitary pulmonary “tuberculomas” are often due to nontuberculous mycobacterial infection, particularly M. avium-intracellulare. When the lesion is due to nontuberculous mycobacteria and can be resected in its entirety, drug therapy is not indicated.
Gribetz AR, Damsker 6, Bottone EJ, Kirschner PA, Teirstein AS: Solitary pulmonary nodules due to nontuberculous mycobacterial infection. Am J Med 198 1; 70: 39-43.
Pulmonary nodules Tubercuioma
Sixty-four patients were evaluated prospectively for a reflex sympathetic dystrophy syndrome (RSDS), using quantitative clinical measurements, high-resolution roentgenography and scintigraphy. Five separate groups were identified by their clinical features, allowing us to distinguish patients with definite or incomplete forms of the RSDS as well as 16 patients with other disorders. Scintigraphy was found to be a useful diagnostic study that also may provide a method of predicting therapeutic response. Systemic corticosteroid therapy proved to be a highly effective mode of treatment for up to 90 percent of the patients with the RSDS.
Kozin F, Ryan LM, Carerra GF, Soin JS, Wortmann RL: The reflex sympathetic dystrophy syndrome. Ill. Scintigraphic studies, further evidence for the therapeutic efficacy of systemic corticosteroids, and proposed diagnostic criteria. Am J Med 1981; 70: 23-30.
Reflex sympathetic dystrophy syndrome Corticosteroid therapy
THEO-DUR Enduring Action Anhydrous Theophylline Sustained Action Tablets Description: THEO-OUR Sustained Action Tablets contain anhydroos theophyl-
line, with no color addrhves. Actions: The pharmacologic actions of theophylline are as a bronchodflator, pulmonary vasodrlator and smooth muscle relaxant since the drug directly relaxes the smooth muscle of the bronchial airways and pulmonary blood vessels, Theophylfine also possesses other actions typical of the xanthine derivatives. coronary vasodifator, diuretic, cardiac stimulant, cerebral stimulant and skeletal muscle stimulant. The aclions of theophylline may be mediated thrw h inhibitron of phos hodiesterase and a resultant increase in intracellular cyc9IC AMP which coul 8 medrate smooth muscle relaxation. Indications: Symptomatic relief and/or prevention of asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. Contraindications: THEO-OUR IS contraindicated in individuals who have shown hypersensitivity to any of its components or xanthine derivatives. Warnin s: Excessrve theophylline doses may be associated with toxicity. serum theophyl ! me levels should be monitored to assure maximum benefit with minimum risk. Incidence of toxtcny increases at serum levels greater than 20 mc /ml. High blood levels of theophylfine resulting from conventional doses are corre9ated with clinical manifestations of toxicity in: patients with lowered body plasma clearances, patients wtth liver dysfunction or chronic obstructive lung disease, and patients who are older than 55 years of age, particularly males. There are often no early srgns ot less serious theophylline toxicity such as nausea and restlessness, which may a pear in up to 50% of patients prior to onset of convulsions. Vontncular arrhyt fl mras or seizures may be the frrst signs of toxicity. Many atients who have higher theophylline serum levels exhibit a tachycardia. Theophyl Pine products may worsen pre-existing arrhythmias. Usagein Pre nancy: Safe use in pregnancy has not been established relative to possible aIfverse effects on fetal develo ment but neither have adverse .’ unfortunately, true for most effects on fetal development been established. Phis IS, anti-asthmatic medications. Therefore, use of theophylline In pregnant women should be balanced against the risk of uncontrolled asthma. Precautions: THEO-OUR TABLETS SHOULO NOT BE CHEWED OR CRUSHED. Theophyllines should not be administered concurrently with other xanthine medications It should be used with caution in patients with severe cardiac dtsease. severe hypoxemia. hypertension, hyperthyroidism, acute myocardial injury, car pulmonale. congestive heart failure, liver disease and in the elderly, particularly males, and in neonates. Great caution should be used in giving theophylline to patients in congestive heart failure since these patients show markedly prolonged theophylline blood level curves. Use theophylline Cautlousl In patlents with history of peptic ulcer. Theophylline may occasionally act as a Yocal irritant ” 10 G.I. tract although gastrointestinal symptoms are more commonly central and associated with hrgh serum concentrations above 20 mcg/ml. Adverse Rsactions: The most consistent adverse reactions are usually due to overdose and are: Gastrointestinal: Nausea, vomiting, epigastrrc pain, hematemesis. diarrhea. Central Nervous System: Headaches, irritability, restlessness, insomma. reflex hyperexcitabflity, muscle twitching, clonic and tonic generalized convulsions. Cardiovascular: Pal itation, tachycardia, extrasystoles, flushing, hypotension, circulatory failure, IiPe threatening ventricular arrhythmias. Resprratory: Tachypnea Renal. Albuminuria, increased excretion of renal tubular cells and red blood cells; potentiation of diuresis. Others: Hyperglycemia and inappropriate AOH syndrome. How Supplled: THEO-OUR100 mg, 200 mg and 300 mg Sustained Action Tablets are available in bottles of 100. 1000, and 5000, and in unit dose packages of 100 (20 x 5’s). Caution: FEDERAL LAW PROHIBITS DISPENSING WITHOUT A PRESCRIPTION. 0779 For full prescribmg information, see package insert.
ZERO-ORDER dc/dt=K’” (Constant rate absorption by GI infusion)
200 mg
100 mg
!EwwTIc*Ls INC.
Miami, Florida 33169 &AI A32
Aldactone” (spironolactone)
WARNING Spiraaolactone has been shown to be a tumorigen in chronic toxicity studies in rats (sea Warnings). Aldactone shoald be used only in those conditions described under Indica_ tions. Unnecessary use of this drug should be avoided. Indications: Lkgnosis and treatment of primary hypecaldosteronrsm Essential hypertension, edema of congestive heart failure and the nephrotrc syndrome, when other measures are consrdered inappropriate.. Cirrhosis of the liver accompamed by edema and/or ascites Hypokalemla Contraindications: Amma, acute renal msuffrcienc! slgnihcant lmparrment of renal function. or hyperkalem/a. Warninns: Excessive ootasslum Intake mav cause hyperka/emTa. Potassium sipplements should not be given mth Aldactone Do not admmlster concurrently mth other potassium-spanng duetics Splronolactone has been shown to be a tumongen in chrome toxtnty stud/es m rats In one study usmg 25. 75, and 250 times the usual daiiy human dose (2 mg /kg j there was a statist/Cal/y srgnificant dose-related mcrease in benrgn adenomas of the thyrotd and testes In female rats there was a statisticaily srgnrhcant increase in mabgnant mammary tumors at the mid-dose only In male rats there was a dose-related increase m proiiferabve changes in the liver. At the highest dosage /eve/ /XXI mg /kg) the range of effects included hepatocyiomegalx hyperplastrc nodules and hepatocellular carcinoma; the last was not stat&a//y significant. Precautions: Pattents should be carefully evaluated for possible disturbances of fluid and electrolyte balance. Hyperkalemia may occur in patients with impaired renal function or excessrve potassium intake and can cause cardrac Irregularities wh/ch may be fatal Hyponatremra may be caused or aggravated, especially when Aldactone is administered m combination with other diuretics i?ansient elevation of BUN and/or m/Id andosis may occur Aldactone potentiates the effect of other duretrcs or antihypertensive agents, particularly ganghonic biocking agents,’ therefore the dosage of such drugs should be reduced by at least 50 percent when adding Aldactone Gynecomastia may develop and in rare instances some breast enlarge ment may persist L4scular responsiveness to norep,nephrine may be reduced Spironolactone may cross the placenta/ barrier Use in pregnant women requres that the anticpared benefit be weIghed against posstble hazard to the fetus. Breast feedmg should be discontinued when Aldactone is being used Adverse Reactions: Gynecomasba IS observed not mfrequently Gastrointestmal symptoms including crampmg and drarrhea, drowsiness, IetharqK headache, maculopapular or erythematous cutaneous ‘eruptions, orticaria, mental confusron. druo fever ataxia. inab&v to achieve or majntain erect&n, irregular ‘menses’ or amenorrhea, postmenopausal bleeding, hrrsutism and deepening of the vorce Carcinoma of the breast has been reported but a cause-and-effect relationshrp has not been established Adverse reactrons are usually reversible upon discontinuation of the drug. Dosage and Administration For primary hyperaldosteronism: 400 mg da//y for three to four weeks (long test). or for four davs (short test). For preparation for suriery or for long-term maintenance therap)! 100 to $XJ rn$ daily for edeme m adu s: /rubal dally dosage IS 100 mg. in dlnded doses but may range from 25 to 200 mg. dai/y If after five days an adequate diuretic response has not occurred a second duet/c which acts more proximally in the renal tubule mav be added The dosaoe of Aldactone should remam unchanged when other d~uretlc therapy IS added For edema bt children: Inma/ daily dosage should provide approximately 15 mg per pound of body werght (3 3 mg /kg.) in divided doses. For esseatfa/ hyperteasioa: Initial adult daily dosage of 50 to l&J mg. in divided doses, alone or with dioret‘its tiich act mme proximally m the renal tubule. or with other antihypertenslve age& Continue treatment for at least two weeks since maximal resoonse mav not occur before this time. Adjust subsequeni dosage &co&g to pabent response. Far hvpabalamia: 25 to 1lWmg. da//y in divided doses.
Address medical inquiries toG. 0. Sear/e & Co. Madtwl Commumcations Department Bar 5110, Chrcago. Illinois 60680
A34
(disopyramide phosphate) Jxtracts
f papers in this issue
&fore prescrtbmg /vorpace /drsopymmrde phosphate/, please consult current compIHe prescnbrng informatron a summar) of whfch foilows Indicadms: For suppress/on and prevention of recufrence of the follomng cardtac arrhythmias when they occur singly or m combmaoon unrhcal premature (ectopfci ventncular contractions. premature fectoprcl ventrricular coniractrons of multdocal ortg~n. parrad premature ventricular contracti~s (couplets/. and episodes of ventrxular tachycardia (persister8 ver;trtcular tachycardla IS ordmarily rreated wrth 0 C cardioversmn) Norpace is equaily effecfrve m both drgrtalued and nondrgrtabed patients It IS also equally effect!ve m treatmg pnmary cardiac arrhythmias and those whrch occur in assocratmn with organ/c heart disease mciudrng coronary artery %sease Orai Norpace nas not been adeuuately studted m pattents with acute myocardial mfarc~ tion or with persrstent venlricular tachycardla or atrral arrhythmtas and rs nor mdt cated for arrhythmras due to drgMs mtoxrcatmn The v&e of anbarrhythmcc drugs in preventmy sudden dea!h rn patrents wth serrws ventucular sctopic act/vrty has not been e.stabr!shefi Contraindicatimm: Cardragemc shock, preexistmg seconds or thrrd-degree AV biock iif no pacemaker IS present], or know hypersen.w:y’to the drug Werninas:Norpace may caese or worsencoogestive haart fagore ICHfi or produce severe hypoteasim as a conseqaance of its negative iaotropicproperties. Hypotaasion has been observed primaf#y with primary card~moyopathy or inadequately compensated CM Norpace shoald not be used ie patients with uncompensated or mergMly corn pensated CM or hypetensimi unless the condition is secondary to cardiac arrhythmia. Patients with a history of heart faLre may be treated with Norpece. but w&d attention mast be given to mainteiaiag cardiac fanc tion, inchdingoptimaldigita#zetion. ff hypotensiw OCWIS or CHF womeas, Norpece shoakl be discoatinuedand, if necessary. restarted at a lower dosage only after adequate cerdiec compensation has been estemshed Norpece sboakl be discontinued if significant widenby lgraeter thanW/o/ of the (u1S complax occurs. Prdoegatien of the QT interval /cerrected/ and wetsanieg of the arrhythmia may occur. Patients who have evidenced prden ation of the &7 interval in response to qainidine may he at particalar n2 If 47prdengation greater than 25% is observed and if ectapy coatbmes, the patient should be monitored cfosely. and discontineatim of Nerpace considered In rare instances eignifieant hypoglycemia has been reporteddaring Norpace therapy. 7be concomitant use of Norpace with other Type 1 antierrhythmic agents should be reserved for patients with &threatening arrhythmias who are demonstrably unrespoasive to single agent antiarrhytbmic tharapr Such use may produce serious negative inotropic effects, or may exceeeivdy prdong conduction. Patients receiving more than one antiarrhythmic drug must be carefaSy monitored. if firstdegree heart block devefeps, the dosegeof Norpace should be reduced If the block parsists, contineetieo of Norpace mast dependuponan assessment of benefit versastish. Developmentof second- or tbird-dogreeAV blochor uni, bi- or trifescicalarblock requires discontinuation of Norpece, an/ass the ventricular rate is adequately coatreM by a pacemaker Becaase of its antichognergic activiw Norpece sbouM not be usedin pa tients with gfeucoma, myasthenia gratis or urinary retention, unless adeqaate overriding maesaras are teken. Precautions: Patients wfth atria/ flutter or hboliabon should bc drg,tahzed poor to Norpace admmrstratrcn to ensure ihaf drug-Induced enhancement ofAV conduction does not allow a ventricular rate beyond physto/og/ca//y acceptable kmits Jhe effec! of Norpace 1spresently onceriam :n patients wtth srck smus syndrome, WolitParkmson- White syndrome, or bundle branch block i’affents wrrh myoardrts (K other cardromyopathy may devptnn - -r sign,f,car;t hypotensior; n response to the usual dosage of Norpace Norpace dosage should be reduced m pat/ants wrth m?pa#redrenal or hepasc function and the slectrocardmgram careful/y monitored ior s,gns of overdosage Antfarrhylhmlc drugs may be meffectrve in patients wrth hypokaiemra. Therefore, ary potassium dehcrt should be corrected before mstMrny Norpace therapy Safe use m pregnancy has not been established ilisoovramrde has been found m human retal blood Nmpece has been rep&d to stimulatecootractimsof the pregnant uterus.Useof Norpace m pregnant women requires that the potentral benefit be werghed agamst posnble hazards fo fhe fetus Followmg oral admmistration, d/so pyramrde has beerr found m human mdk at a concentraoon not exceedmg that m plasma Muse of rhe drug 1s deemed essenttal, an alternate msrhod of infant few’,ng should be mst:tuted Effects of Norpace on the feius dunng deirvery or on the Course of labor and dehverf are unknown Safety and effectiveness of Norpace m chrldren have not been establrshed Adverse Reactions: Dry mouth. unnary hesftancy constrpahon, biorred nsron. dry nose/eyes/throat, urinary retention. umary frequency and urgent): impotence, nausea, pam/bioatmg@as. anorexfa. d/a&a. vomtting nervousness, c+zzmess genera/ fatigue/muscle weakness. __ __ headache. malarse. achesloams, hvootensmn, conqesttve heart fariure, cardiar cnn~ ductron dtsturbances, edema/werght yam, short& of breath, syncope. chest pam oenerahzed rash/dermatos~s, itchmq, hypokalerma, elevated cholesterol/ ;nglyclycendes. depressron. msomnra, aysurla, numbness /tmyling, elevated liver enzymes. AV block, eievated BUN, elevated creafmme, decreased hemoglobm/ hematocrrt, and hypoglycemra Acute psychos& cholestatrc jaundice, and agraanuIocytrxts, all ihree revers!ble. have neen reporteo Dosageand Admimistratfm: Dosage must be md/vrduahzed on the basrs of response and tolerance The usual adult dosage IS 400 to 800 rng per day grver! m dfnded dose.7four times da//y The recommended dosage schedule for most adults IS HI mg every SIX ho& For pabents less than 1Ill pounds (50 kg) the recommended dosage IS 100 mg every SIX hours If raprd control of arrhythmia IS essenfidl an rmtlal loadmg dose of 300 mg of Norpace (200 mg for pabents less than 110pwndsl IS recommended For patrents with cardiomyopathy or possrble wrdrac decompensabon. a loadmg dose should not be g,ven and the mitral dose hmtted to 100 my every SIX hours, wrth subsequent dzage adfustments made gradual/y wrth close momtormg See GUIrant campleteprescr&ng infmmatim fer deeege recemmandetiws. How SuppEcd: Capsules contammg 100 mg or 150 mg of disopyramrde base SE;~~E
A40
Sear/e Laboratories Dwston of Sear/e PharmaceutKals Box 5170, Chicago, lllinois 60680
Inc
Insulin-dependent
Diabetes mellitus
Islet-cell antibodies
mellitus. Am J
autoimmunlty
Continued
The possible role of autoimmunity in the pathogenesis of insulindependent diabetes mellitus is critically reviewed. Autoimmune phenomena (antipancreatic cell-mediated autoimmunity and islet cell antibodies) are demonstrable in most patients with insulin-dependent diabetes mellitus at the time of diagnosis. No direct cytotoxic effect on human beta-cells of specifically reactive lymphoid cells and/or antibodies from such patients has been demonstrated. Furthermore, the nature of the beta-cell specific antigens invoked is unknown, making methods for detectii of islet-cell antibodies unsatllfactory-also because of lack of stanftardi2ation between laboratories. Atthough thsre is no experimental evidence to show thatautoimmune mechanisms are directly invofved in beta-cell doskuction in insulin-dependent dftes mellitus. it is concluded that the existing knowledge is very suggestive and should be explored futher by improved technology.
diabetes
Cell-mediated
Nerup J, Lernmark A: Autoimmunity in insulindependent Med 1981; 70: 135-141.
Insulin-dependent,
Autoimmunity
Genetic heterogeneity, the concept that diabetes can have many different causes, was first suggested by the existence of rare genetic synckcmes with diabetes, ethnic differences in clinical features and genetic heterogeneity of animal models. Genetic heterogeneity is now considered to be firmly established by family, twin, metabolic, immunologic and HLA disease association studies that separate idiopathic diabetes into insulin-dependent types (juvenile-onset type) and noninsulindependent types (maturityonset type). Further heterogeneity is being demonstrated within each of these broad groups of disorders-within insulin-dependent diabetes using the HLA antigens and immunologic studies, and within noninsulindependent diabetes using such criteria as obesity, insulin response, age of onset and chlorpropamide-primed alcohol-induced f!ushing. This heterogeneity has major implications for the research and care of our diabetic patients since the precise etiology, risk of complications and genetic counseling are likely to vary among those different disorders that result in diabetes.
disorders. Am J Med
mellltus
Glucose intolerance
Nonlnsulln-dependent
Rotter JI, Rimoin DL: The genetics of the glucose intolerance 1981; 70: 116-126.
Diabetes mellitus
mellltus
Genetics Juvenile-onset
animals.
diabetes
Am J Med
Transmembrane
signaling
Receptor
subunit structures
on page A45
Our understanding of the molecular basis of insulin action remains incomplete, but important new insights have recently been achieved. All avallable evidence to date indicates that intracellular signalling by the hormone results from its initial interaction with specific cell surface receptors. Insulin receptors from all tissues studied to date appear to be minimally composed of two M, 125,000 subunits denoted as (Y and two M, 90.000 subunits denoted as p. The four subunits are linked together by disulfide bonds to give a symmetrical configuration with a stoichiometry of (o-s-s-fl)-s-s-(a-s-s-b). Another area of recent progress involves the successful generation of a soluble factor (or factors) by insulin capable of modulating the activity of insulin-sensitive enzymes in cell-free systems. The data available are consistent with the hypothesis that insulin-receptor interaction leads to the activation of a membrane protease that catalyzes the release of a peptide mediator or mediators of insulin action.
Czech MP: Insulin action. Am J Med 1981; 70:142-150.
Insulin
The importance of environmental factors in the pathogenesis of juvenile-onset diabetes mellitus is suggested by genetic and epidemiologic observations. Group B Coxsackie viruses and mumps virus have been implicated, and several other agents also could play a role in the disease. A picornavirus similar to the Coxsackie viruses exhibits specific tropism for the beta cells of the islets of Langerhans, causing a disease in mice that is similar to juvenile-onset diabetes. In these animals, genetic and metabolic factors appear to influence the severity of beta cell injury. Immunopathologic considerations also may be important. Viewed in concert, ‘the evidence supports the notion that certain “wild” viruses may possess specific tropism for beta cells and destroy them during the course of a systemic infection. Host factors clearly play a role, but their relative importance in the pathogenesis of the disease remains to be defined.
mellitus in man and experimental
lmmunopathology
Craighead JE: Viral diabetes 1981; 70: 127-134.
Viruses
insulin resistance Obesity
Nocturnal hypoglycemia Pregnancy
of con-
Continued
The compelling evidence that blood glucose control will slow or prevent microvascular complications has stimulated research to find better ways of managing insulin-dependent diabetes. Reviewed here are some of the approaches being utilized as well as the advances that have been made in conventional insulin treatment, which is likely to remain the mainstay of treatment in the coming decade. These investigators conclude that the practical problems of improving diabetic control are essentially those of logistics and that these problems apply even more forcefully to doctors for whom the new technology will bring radical changes in the management of diabetes, not least in terms of increased time and involvement.
Tattersall R, Gale E: Patient self-monitoring of blood glucose and refinements ventional insulin treatment. Am J Med 1981; 70: 177-182.
Self-monitoring of blood glucose Diabetes “Open loop” systems
)nSUlin resistance is a characteristic feature of both obesity and noninsulindependent diabetes mellitus, and the cause of this insulin resistance resides at the level of the target tissue. The specific mechanisms underlying these insulin-resistant states are heterogeneous, and a continuum of defects exists. In patients with mild insulin resistance, the impairment in insulin action is due to decreased numbers of insulin receptors leading to decreased insulin sensitivity. In patients with severe insulin resistance, decreased numbers of insulin receptors and a postreceptor defect in insulin action coexist, but the postreceptor defect is the predominant abnormality. Between these extremes, the relative roles of receptor defects and postreceptor defects vary, but the general trend is that as the insulin resistance worsens, the postreceptor defect becomes more prominent.
in obesity and noninsu-
insulin receptors
Olefsky JM. Kolterman OG: Mechanisms of insulin resistance lin-dependent (type Ii) diabetes. Am J Med 1981; 70: 151-168.
Diabetes Glucose clamp insulin sensitivity insulin action Insulin-receptor binding
JS: Treatment
of diabetes
mellitus
by devices.
Insulin administration
Am J Med 1981;
70:183-
on page A56
A very important aspect of diabetes mellitus is whether or not normalization or near-normalization of blood glucose and/or other metabolites and hormones may reduce or eliminate the chronic complications of this disease. To answer this question and to provide a more “physiologic” approach to insulin administration, a constellation of devices have reached the stage of clinical investigation. These include small portable pump systems that can provide variable rates of insulin infusion via the subcutaneous, intravenous or intraperitoneal routes. In addition, bedside artificial “beta cells” having the capability of providing insulin infusions, with the rate varying as a function of continuous glucose measurements, are available for short-term studies. Under development are implantable continuous infusion devices and implantable glucose sensors that could in the future lead to a miniaturized implantable glucose-controlled insulin administration system.
Soeldner 194.
Diabetes meliitus
Devices, pumps-sensors
During the past few years, it has become increasingly apparent that insulin resistance may be a more frequent cause or contributing factor for carbohydrate intolerance than was hitherto appreciated. Abnormal insulin action may result from prereceptor, receptor or postreceptor defects. These may be manifested by an increase in the concentration of insulin necessary for a half-maximal effect (decreased sensitivity) or a decrease in the maximal response to insulin (decreased responsiveness) or both. Alterations in sensitivity and responsiveness to insulin can only be distinguished by evaluating insulin dose-response curves. When used in conjunction with the measurement of insulin binding to its receptor, the characteristics of these curves can provide insight into the mechanism(s) responsible for insulin resistance.
Rizza RA, Mandarin0 LJ. Gerich JE: Mechanisms of insulin resistance in man. Assessment using the insulin dose-response curve in conjunction with insulin-receptor binding. Am J Med 1981; 70: 169-176.
insulin resistance Dose-response curve
NEW KLOTRIX@
lPOMsslUM CHLDRIDQ SLOW-RELEASE WBLETB 10 mEq BESCRlPTfON KLOTRIX ISafilm-coated (not enlent-coated)
tablet contarmng 750 mg potassrum chlorrde fepurvalent to 10 mEq) in a wax matrrx Thrs formulation IS Intended to provide a controlled release of potassrum from the matrrx to minimrze the likelihood of producrng hrgh locahzed concentrations of potassrum wrthrn fhegastrorntestrnal tract. INOICAlIONS- BECAUSE OF REPORTS OF INTESTINAL AND GASTRIC ULCERATION AND BLEEOING WITH SLOW-RELEASE POFASSIUM CHLORIOE PREPARATIONS. THESE URUGS SHOULD BE RESERVED FOR WfOSE PATIENTS WHO CANNOT TOLERATE OR REFUSE TUFAKE LIPUIO OR EFFERVESCENT POlASSlUM PREPARATIONS OR FOR PATIENTS IN WHOM THERE IS A PROBLEM OF COMPLIANCE WllH 1HESE PREPARATIONS. 1 For therapeutic use rn patients with hypokalemia wdh or wrthout metabolrc alkalosrs; rn digitalis rntoxrcation and m patrents wtth hypokalemic famrlral periodic paralysis 2. For prevention of potassium depletron when the dretary intake of potassrum IS Inadequate In the followrng conditions: Patrents recerving digrtalrs and drwetics for congestive heart failure; hepahc crrrhosrs with ascrtes; states of aldosterone excess wrth normal renal functron; potassium-losing nephropathy, and certarn drarrheal states. 3. The use of potassrum salts In pattents receiving diuretics for uncomphcated essential hypertension IS often unnecessary when such patients have a normal dietary pattern Serum potassium should be checked periodrcally, however, and, rf hypokalemra occurs, dietary supplementation with potassium-contarnmgfoods may be adequate to control milder cases. In more severe cases supplementation with potassmm salts may be indicated. CONTRAlNUlCAllONS In patients with hyperkalemra. since a further Increase in serum potassium concentration in such patients can produce cardiac arrest. Hyperkalemra may complicate any of the followrngcondrtions~ chronic renal farlure. systemicacrdosrs such as drabetrc acidosis, acute dehydration, extensrve trssue breakdown as in sevwe burns, adrenal nrsufficrency, or the admrmstration of a potassium-sparmg dutretrc (eg, sprronolactone, triamterene). Wax-matrix potassium chloride preparations have produced esophageal ulceratron in certain cardiac patrents with esophageal compression due to enlarged left atrmm. All solid dosage fwms of potassium supplements are contraindicated in any patient rn whom there IS cause for arrest or delay in tablet passage through the G.I. tract. In these Instances, potassium supplementation should be wrth a hqurd preparahon. WARNINBS, Hypsrkalamil: In patients with impaired mechantsms for excreting potassrum, admrmstratron of potassium salts can produce hyperkalemra and cardiac arrest. This occurs most commonly in patients given potassium Intravenously but may also occur when given orally. Potentially fatal hyperkalemra can develop raprdly and be asymptomatlc. Use of potassium salts in patrents with chronic renal disease, or any other conditron which impairs potassium excretion requrres partrcularly careful monitorrng of the serum potassium concentration and appropriate dosage adjustment. Interaction with potassium-sparing diuretics: Hypokalemra should not be treated by the concomttant administration of potassium salts and a potassurm-sparing diuretic leg, spironolactone or trramterene), since the srmuttaneous admrmstratron of these agents can produce severe hyperkalemia. Gastrointestinal lesions: Potassium chloride tablets have produced stenotrc and/or ulcerative lesions of the small bowel and deaths. These lesions are caused by a high localized concentrahon of potassium ion rn the region of a rapidly drssblving tablet, which Injures the bowel wall and thereby produces obstruction, hemorrhage, or perforation KLOTAIX IS a wax-matrix tablet fwmulatec to provrde a conbqlled rate of release of potassium chloride and thus to mrnrmrze the possibrlrty of a high local concentratron of potasstum ion near the bowel wall Whrle the reported frequency of small-bowel lesions is much less with wax-matrrx tablets (less than one per 100,000 patrent-years1 than wrth enter&coated potassium chloride tablets (40-50 per 100,000 patient-years) cases associated wrth wax-matrix tablets have been reported both in foreign cwntries and In the United States. In addrtron, perhaps because the wax-matrix preparations are not enterrc-coated and release potassrum rn the stomach, there have been reports of upper gastrointestinal bleedrrg associated with these products. The total number of gastrointestrnal lesions remains less than one per 100,000 patrent-years. KLOTRIX should be discontrnued rmmedrately and the possibility of bowel obstruction or perforation considered if severe vomiting, abdominal pain, distention, or gastrointestinal bleedrng occurs. Metabolic acidosis: Hypokalemra in patrents with metabolic acidosis should be treated with an alkalinizing potassnrm salt such as potassrum bicarbonate, potassrum citrate. or potassium acetate PRECAUTIONS Potassium depletron IS ordinarrly diagnosed by demonstratrng hypokalemra rn a patient wrth a climcal history suggestrng some cause for potassrum depletron. In interpreting the serum potassium level, the physrclan should bear tn mind that acute alkalosm per se can produce hypokalemia In the absence of a defrcrt rn total body potassium, while acute acidosrs perse can increase the serum potassrum concentratron into the normal range even in the presence of a reduced total body potassmm. Treatment of potassmm depletron particularly rn presence of cardiac disease, renal disease, or acidosis, requires careful attention to acid-base balance and appropriate momtorrng of serum electrolytes, electrocardiogram and cluucal status of patient. ADVERSE REACTIONS Most common to oral potassium salts, nausea, ,vomiting, abdominal drscomfort, and diarrhea. These symptoms are due to uritatron of the gastrointestinal tract and are best managed by dilutrng the preparation further, taking the dose with meals, or reducing the dose. One of the most severe adverse effects IS hyperkalemra (see Contraindrcations and Warnmgs). There also have been reports of upper and lower gastrorntestinal conditions rncludrng obstruction, bleeding, ulceratron and perforation (see Contrarndications and Warnings); other factors known to be assocrated with such condrtrons were present rn many of ihese patients. Skin rash has been reported rarely. UOSAGE Usual dretary intake potassium by the average adult is 40 to 80 mEq per day. Potassium depletion suffrcrent to cause hypokalemra usually requires loss of 200 or more mEq of potassrum from the total body store. Dosage must be adlusted to the rndrvidual needs of each patient but IS typically rn the range of 20 mEq per day for prevention of hypokalemia to 40-100 mEq per day or more for treatment of potassium depletron. Nota: KLOTRIX slow-release tablets must be swallowed whale and never crushed or chewed. HOW SUPPLIED Bottles of 100. PHARMACEUTICAL DIVISION
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