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Influenza: recent advancements and their clinical
applications
By F.M.M. White, MD* Dr. H. Grant Stiver, St. Boniface Gen¬ eral Hospital, Winnipeg, emphasized that influenza cannot be clinically dis¬ tinguished from many other diseases caused by respiratory viruses such as coxsackie virus, echovirus, and adenoviruses. Furthermore, diseases such as pharyngitis or pneumonia, which are often caused by other agents, may also be caused by influenza virus. In
mild, uncomplicated influenza,
productive cough
non-
is the most
frequent symptom. While most patients also have fever and sore throat, myalgia and headache occur in fewer than half of those afflicted. Physical findings are *
Laboratory
centre for disease
control, Ottawa
few, nonexudative pharyngitis being the
A number of influenza syndromes establishing a labora¬ can be identified, Dr. Stiver told the fied by hemagglutination-inhibition, symposium. Acute tracheobronchitis is neutralization or hemadsorption-inhibi- the most common, along with myalgia, tion tests using type-specific or strain- fever and chills commencing within 24 hours and lasting from 3 days to a CMA} presents a report on an interna¬ week. Secondary bacterial pneumonia tional symposium May 7, 1976 organ¬ may also occur, often appreciably after ized by the faculty of medicine, the acute phase of the disease, when University of Toronto in cooperation fever and myalgia have subsided. On¬ with Farke9 0avis asd Company Lim¬ set is usually marked by coughing of ited, Dr. Norman A. Hinton, Univer¬ sputum. Pneumococcal infec¬ sity of Toronto, was chairman, Recent purulent tion is the most common, although evidence that an influenza strain nor¬ mally found only in swine has caused staphylococcal infection may be the most severe. Primary viral pneumonia an outbreak among recruits in a US military base has focused worldwide is another important syndrome, and attention on this disease. This is the this was prevalent during the 1918-19 first evidence of person to person trans¬ pandemic. It may develop on the 2nd mission of a swine influenza virus or 3 rd day of the disease and can lead since the major pandemk of 1918-19. to profound respiratory collapse. Pa¬ During the 1975-76 season another new tients with pulmonary venous hyper¬ strain of influenza, A/Victoria/3/75 tension, particularly with mitral steno¬ has been responsible for the greatest sis, are predisposed, and mortality may impact from this disease since the exceed 90%. Mixed bacterial and viral minor pandentie of 1968-69. Advancements in our understanding of influ¬ pneumonia may be common, but it is enza in man, the development of difficult to culture the virus following efficient surveillance techniques and a secondary bacterial infection. Numer¬ vaccine technology over the past de¬ ous nonrespiratory syndromes have also cade have not been widely appreciated,
direct
means
of
tory diagnosis. Isolates may be identi¬
frequent. Palpable cervical nodes in a minority of cases. Only oc¬ casionally are rhinorrhea, conjunctiv¬ itis, exudative pharyngitis or pulmonary adventitious sounds apparent. It is important to undertake labora¬ tory diagnosis whenever possible. In¬ fluenza is most commonly diagnosed by demonstrating a fourfold or greater dif¬ The symposium, directed at providing ference in antibody titre between acute an overview of these events for the and convalescent sera. The complepractising physician, was moderated by ment-fixation technique identifies the Br, ILP. Bryce Larke, University of type of influenza virus responsible (A Alberta, Edmonton. or B); hemagglutination-inhibition tests can determine subtype or strain speci¬ specific antisera. The possibility of ficity. Other serologic tests, including more rapid diagnosis by immunofluor¬ the single radial diffusion technique, escence has been explored, but this exist but are not in common use. Cul¬ method is not widely used in diagnostic most
occur
tivation of influenza virus is the most
laboratories.
been described but are difficult to assess, as many of the reports are based on autopsy findings where organ con¬ tamination may have occurred. These include myocarditis, acute encephalitis,
polyneuritis (including Guillain-Barre syndrome), myositis, vasculitis (includ¬ ing disseminated intravascular coagula¬ tion) and immune complex diseases such as serum sickness and Goodpasture's syndrome.
Influenza in children Influenza is clinically a highly variable disease, and Dr. George M. Johnson, Fargo Clinic, Fargo, ND noted that in children with congenital heart de¬ fects with left to right shunts, congen¬ ital emphysema, asthma, cystic fibrosis, severe mental subnormality, myelomen-
Severe myositis may occur during re¬ covery from the acute phase of the disease and may persist intermittently for several weeks. This may produce Febrile convulsions have been observed very tender muscles, and children may in up to 50% of very young children refuse to walk. Finally, despite earlier (mean age, 2 years) admitted to hospital. speculation that influenza A virus may CMA JOURNAL/JUNE 5, 1976/VOL. 114 1035
ingocele, hydrocephalus, cerebral palsy, diabetes, leukemia or pneumonia (in the convalescent stage), influenza tends to affect the lower respiratory tract.
be teratogenic and may cause childhood leukemia and lymphoma, later studies do not support these hypotheses. Influenza B in children also results in a variety of clinical syndromes. In one study, abdominal pain was a prominent symptom among 28 of 68 patients admitted to hospital with confirmed influenza. Associated respiratory symptoms were minimal; pain was constant and central and associated with vomiting and fever. Such cases could well be misdiagnosed as "mesenteric adenitis" or gastrointestinal "flu". Accordingly, Dr. Johnson stressed the importance of laboratory diagnosis. Reyc-Johuson syndrome Although first described by Lord Brain in 1929, sudden infant death with findings of fatty degeneration of the viscera and encephalopathy has only
recently become known as the ReyeJohnson syndrome. Although the etiology of this entity is not well elucidated, influenza B virus has recently become strongly linked to its occurrence and is currently thought to trigger its development in susceptible children, Dr. Johnson said. An association with rural areas has been observed, but the question of individual susceptibility remains unanswered. The syndrome may reflect a difference in host response to influenza B and other viral infections. In a prospective study of influenza B and this syndrome at Kalamazoo, MI during the 1973-74 influenza B epidemic, the proportion of schoolage children with influenza B who exhibited this syndrome was calculated at 1:1750. This might indicate that under certain circumstances Reye-Johnson syndrome is more common than presupposed.
Immunology and developments in technology Dr. Gerald Blanford, Gage Research Institute, Toronto, observed that, as there are no effective antiviral preparations to treat influenza, immunologic efforts aim at enhancing natural immunity. Important viral factors are antigenic drift, which accounts for the almost continuous changes in the prevailing strain, and the virulence of the strain, which may reflect its ability to grow in the human host. Host factors include herd immunity - the way in which the incidence of any particular strain decreases as the average antibody titres in the population increase. IgG in serum and IgA in respiratory secretions are important factors in individual immunity. When IgG combines with antigen, it can fix complement and trigger immunologic and local inflammatory responses. Severity of inflammation is proportional to and determined by the quality of immune response. If IgG predominates, there will be more inflammation, bronchial basement membrane damage and pneumonia. There is little evidence that IgA can combine with an antigen, as it does not normally fix complement and therefore does not cause inflammation. In most experimental models, virus growth peaks at about the 3rd or 4th day of infection and is not detectable by the 8th day. Serum concentrations of interferon, a nonspecific virus inhibitor, rise and fall almost in parallel with the virus growth. Serum antibody concentrations increase only from the 5th day on, suggesting they do not influence the early phase of a primary infection. However, recent data do
show that antibody made at day 3 is present in the lung, complexed to antigen, and that in the absence of antibody and inflammatory responses the virus is not eradicated, even though interferon is still present. Organ response includes production of nonspecific inhibitors such as interferon and other humoral factors, stimulation of macrophage and monocyte activity and the physical attributes of inflammation that impair viral growth. Specific organ response may also occur and is considered to be antibodydependent although lymphocyte-mediated. During uncomplicated infection the virus is found mainly in mucous membranes and is associated with the arrival of immunoglobulin-secreting cells in bronchial submucosa. In alveoli, virus is found mainly in macrophages and does not seem to be infectious. Some viral activity in bronchial lymph nodes may be seen after the 3rd day, while viral antigens may persist in the spleen considerably longer and be responsible for continued levels of serum antibody. The role of cellmediated immunity remains undefined. Dr. Blanford put forward the hypothesis that bronchial response is modulated by local IgA and there is little evident effect of cell-mediated immunity. Alveolar response appears modulated mostly by IgG and cell-mediated immunity and may indeed be harmful. It appears, therefore, that the most effective response in recovery from infection is the production of local secretory IgA rather than complement-fixing IgG. Certain subclasses of IgG do not fix complement and there is some evid1036 CMA JOURNAL/JUNE 5, 1976/VOL. 114
.DemuIen® ethynodiol diacetate ethinyl estradiol Indication - Oral Contraception. Contraindications - Malignant tumors ot the breast or genital tract, estrogen dependent neoplasia, signiticant liver dystunction, history ot cholestatic jaundice, during breast teeding, undiagnosed vaginal bleeding, history of CVA, coronary thrombosis, classical migraine, thrombophlebitis or thromboembolic disease, ocular lesions such as partial or complete loss of vision; detect in visual fields, diplopia; suspect pregnancy. Warnings - Discontinue medication at the earliest manifestation of: thromboembolic disorders such as thrombophlebitis, cerebrovascular disease, pulmonary embolism, myocardial ischemia, retinal thrombosis; visual defects, proptosis, diplopia, undiagnosed severe headache, classical migraine, papilledema, ophthalmic vascular lesions, psychiatric disturbances. Rule Out pregnancy after two consecutive periods are missed or after the first missed period if the prescribed regimen has not been followed. Demulen may cause metabolic imbalance; observe carefully in epilepsy, asthma, cardiac and renal dysfunction. Precautions - Before use, a thorough history should be taken and a thorough physical examination performed, including the breasts and pelvic organs and a Papanicolaou smear. Follow up esamination should be within via months and at least yearly thereafter. Liver, thyroid and other endocrine function tests should not be considered accurate unless therapy has been discontinued. Withdrawal of medication for 2 to 4 months is necessary before alteration in thyroxine binding reverts to normal. Similar precautions apply to liver function studies and other tests of protein binding (e.g. plasma cortisol). Follow diabetic patients or those with a family history of diabetes closely for decrease in glucose tolerance. Persistent irregular vaginal bleeding requires investigation. In metabolic or endocrine disease and when metabolism of calcium and phosphorus is involved, careful clinical evaluation should precede medication. Possible influence of prolonged therapy on pituitary. Ovarian, adrenal, thyroid, hepatic or uterine function awaits further study. Risks of complications due to adrenocortical insufficiency appear to be minimal, but may occur. Treatment may mask the onset of the climacteric. Advise the pathologist of therapy with Demulen with relevant specimens. Uterine fibroids are subject to the same complications as may occur in pregnancy. Sudden enlargement, pain or tenderness require discontinuance of medication. Patients with a history of emotional disturbance, especially the depressive type, are prone to recurrence. If this occurs, discontinue medication. Discontinue medication in patients who develop transient aphasia, paralysis, or loss of consciousness. Give Demulen to patients with signs of essential hypertension only under close supervision. Elevation of blood pressure may occur at any time and even if asymptomatic necessitates cessation of medication. Give with great care and under close supervision to patients with a history of jaundice. Do not prescribe to those with a history of cholestatic jaundice, especially associated with pregnancy. In those patients who develop severe generalized pruritus or icterus, consider hepatic dysfunction and withdraw medication. If the jaundice is of the cholestatic type. do not resume medication. Considering the oversuppression syndrome patients may be advised to discontinue medication after approximately two years and resume only after normal ovulatory cycles have been re-established. Avoid prescribing to patients with a history of prolonged episodes of amenorrhea or infertility. Assess adolescent patients for adequate skeletal development prior to medication. Oral contraceptives may accelerate epiphyseal closure. After discontinuing Demulen. the patient should await the resumption of normal ovulating cycles before attempting to become pregnant. Use special judgment in prescribing to women with recurrent fibrocystic disease of the breast. Estrogen-progestogen combinations may increase plasma lipoproteins. Use with caution in women with pre-existent hyperlipoproteinemia. Adverse Effects - The following have been noted with varying incidence: nausea, vomiting, other GI symptoms. breakthrough bleeding, spotting. change in menstrual flow, amenorrhea, edema, suppression of lactation, migraine. cholestatic jaundice. rash (allergic), rise in blood pressure and mental depression. Disturbances in bleeding patterns are usually most pronounced during the first cycle and usually disappear after several cycles. The following have been reported. although no cause and effect relationship has been established anovulation posttreatment, premenstrual-like syndrome, changes in libido and appetite. cystitis-like syndrome, headache, nervousness. hemorrhagic eruption. and itching. Thrombophlebitis. pulmonary embolism and neuro-ocular lesions have been observed, although a cause and effect relationship has neither been established nor disproved. Various laboratory results may be altered particularly BSP. coagulation factors, tests of thyroid function. metapyrone. pregnanediol and corticosteriod determinations. Dosage - Demulen 21 - One tablet daily. Cyclic administration 3 weeks on tablets and one week off. Demulen 28 One tablet daily Continuous administration 21 active tablets followed by 7 inert tablets Availability - Each white, round tablet with Searle on one side and 71 on the other contain ethynodiol diacetate 0 mg.. and ethinyl estradiol 0.05 mg. Available in 21 and 28 day Compack dispensers (on green foil).
.. Searle Pharmaceuticals Oakvjlle, Ontano L6H 1M5
Bricanyl (terbutaline sulfate)
tablets
ACTION: Bricanyl (terbutaline sulfate) produces bronchodilation by stimulation of the . adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of muscle fibres. This action is manifested by an increase in pulmonary function as demonstrated by FEV measurementa. Bricanyl also produces a decrease in airway and pulmonary resistance. Following administration of Bricanyl tablets, a measurable change in flow rate is usually observed in 30 minutes, and improvement in pulmonary function occurs within 120-180 minutes. The maximum effect usually occurs within 120 - 180 minutes and significant bronchodilator activity has been observed to persist for 4-8 hours. INDICATIONS: Bricanyl (terbutaline sulfate) tablets are indicated as a bronchodilator for the symptomatic relief of bronchial asthma and for relief of reversible bronchospasm which may occur in association with bronchitis and emphysema. CONTRAINDICATIONS: Bricanyl® (terbutaline sulfate) tablets are contraindicated when there is known hypersensitivity to sympathomimetic amines. Bricanyl like other sympathomimetic amines, should not be used in patients with tachyarrhythmias. WARNINGS: USAGE IN PREGNANCY: The safe use of Bricanyl (terbutaline sulfate) has not been established in human pregnancy. The use of the drug in pregnancy, lactation, or women of childbearing potential requires that the expected therapeutic benefit of the drug be weighed against its possible hazards to the mother or child. Animal reproductive studies have shown no adverse effects on fetal development. USAGE IN PEDIATRICS: Bricanyl5 (terbutaline sulfate) tablets are not presently recommended for children due to IImited clinical data in pediatric patients. PRECAUTIONS: Bricanyl (terbutaline sulfate) should be used with caution in patients with diabetes, hypertenaion and hyperthyroidism. As with other sympathomimetic bronchodilator agents, Bricanyl tablets should be administered cautiously to cardiac patients, especially those with associated arrhythmias. In patients in whom the administration of Bricanyl5 tablets induces cardiac irregularities, the dose should be reduced or the administration of the drug suspended. The concomitant use of Bricanylz tablets with other sympathomimetic agents is not recommended since their combined effect on the cardiovascular system may be deleterious to the patient. However, this does not preclude the use of an aerosol bronchodilator of the adrenergic stimulant type for relief of the acute bronchospasm in patients receiving chronic oral Bricanyl therapy. ADVERSE REACTIONS: Commonly observed side effects include nervousness and tremor. Other reported reactions include headache, increased heart rate, palpitations, ectopic beats, drowsiness, nausea, vomiting, sweating and dizziness. SYMPTOMS AND TREATMENT OF OVERDOSAGE: The symptoms of overdosage are similar to those described above under ADVERSE REACTIONS, and are attributable to excessive 5 adrenergic stimulation. To antagonize the effect of excessive 13 stimulation, a 13 adrenergic blocking agent such as propranolol may be considered. DOSAGE AND ADMINISTRATION: The usual oral dose of Bricanyl (terbutaline sulfate) for adults is 5 mg administered at approximately six hour intervals three times daily, during the hours the patient is usually awake. In the event of excessive side effects in individual patients, the dose may be reduced to 2.5 mg three times daily. A total dose of 15 mg should not be exceeded ins 24 hour period. Bricanyl is not currently recommended for use in children. AVAILABILITY: Tablets containing 5 mg of Bricanyl5 are white in colour and carry a numerical inscription (i.e.5) which designates the milligram content of terbutaline sulfate. Bricanyl (terbutaline sulfate) 5 mg tablets are supplied in bottles of 100.
Astra Chemicals Ltd. j
l'toduct
1.harmac.uticaI Division ssissauga, Ontario
.iterattsre available on request.
ence of a subclass preference around the bronchi. Accordingly, there may also be a secretory IgG molecule that does not mediate inflammation at this site. The implication is that optimum immunization should be provided by nasally administered, live attenuated virus vaccines. Vaccine technology Dr. Walter Dowdle of the World Health Organization influenza center, Atlanta, GA said the ideal vaccine should be desirable (with a recognized need), acceptable (discomfort being less than disease), efficacious (potept, specific and giving long-lasting immunity) and available (obtainable when needed and at reasonable cost). In all respects, influenza vaccines have not compared favourably with most other active immunizing agents such as measles and poliovirus vaccines. The influenza virus is of medium size. It is spherical but sometimes filamentous during early growth. The coat contains two proteins, the hemagglutinin and the neuraminidase. These are embedded in a nonantigenic, hostderived lipid layer, which covers the membrane of matrix protein that shapes the virus. Beneath this lies nucleoprotein, ribonucleic acid and polymerases. The hemagglutinin attaches to cells, while the neuraminidase appears to strip sialic acid from the surface of infected cells, thereby enabling the release of virus. The hemagglutinin, neuraminidase, matrix protein and nucleoprotein are all antigenic. The matrix and nucleoprotein are not variable, and antibodies to these proteins indicate whether the virus is type A, B or C. The surface antigens are variable and provide the individual strain characteristics within each type. Antibodies against hemagglutinin and neuraminidase, particularly the former, appear to have some protective function, whereas antibodies against matrix protein and nucleoprotein are not protective. Since the virus was first isolated in
1934, four distinct types of hemagglutinin component have existed (HO from 1934 to 1947, Hi from 1947 to 1957, H2 from 1957 to 1967 and H3 to the present). There have also been two types of neuraminidase during this period, a change from Ni to N2 occurring in 1957. Subtypes A, B and C are denoted by their respective hemagglutinin and neuraminidase components. Since 1967, for example, the prevailing subtype has been H3N2. Within each subtype there is considerable strain variation, so that vaccines, to be effective, must be strain-specific and not just subtype-specific. The main problem, Dr. Dowdle explained, is to produce enough vaccine effective against a particular virus strain in time for use. The difficulty in doing this results in great variation in clinical efficacy among influenza vaccines. Potency is often a problem, and although good vaccine response relationships can be demonstrated, these must be weighed against potential toxicity, number of doses required and costs of production. Currently, highly purified vaccines are prepared by either zonal ultracentrifugation or virus-splitting techniques. These techniques produce vaccine with less than 5% foreign protein, smaller virus particles and lower toxicity, thereby allowing inoculation with a larger antigenic mass. Further major improvements in inactivated influenza vaccines are unlikely. Attenuated, nasally administered vaccines should have the advantages of producing antibody response where it is most needed, a more acceptable mode of administration, lower toxicity and more efficient production, as the vaccine strain itself will replicate in the host and thereby allow a much lower dose. Although there has been considerable experience with these vaccines in the Soviet Union and certain eastern European countries over many years, further development and evaluation is required to overcome problems of genetic stability and degree of attenuation before they are available for routine use.
Licensing requirements Dr. John Furesz, bureau of biologics, Ottawa, reviewed development of influenza vaccines over the past 4 decades and showed how this has contributed greatly to our understanding of the disease itself. At present, only inactivated influenza vaccines are licensed for use in Canada and the United States. The decision not to license live vaccines has been based pri-
manly on lack of genetic markers and data for the incidence of possible reversion. Since protection with inactivated vaccines varies greatly, the possible use of adjuvants to promote higher antibody titres and induce a broader antibody response has received some attention. Although data from clinical trials are impressive, adjuvant vaccines are difficult to produce and require
CMA JOURNAL/JUNE 5, 1976/VOL. 114 1039
particular care in administration. In man. Benefit/cost considerations cur¬ addition, adjuvants have been shown to rently favour the continued use of modify the humoral and cellular re¬ zonally purified, inactivated, aqueous sponse in animals. In man, their ad¬ vaccines. With production of any vaccine it is ministration could result in an Arthus reaction or a delayed hypersensitivity important to have stringent quality con¬ reaction on subsequent vaccination. trol to ensure it is safe and potent More recently, the principle of recom- enough. Before production, evidence is bination has been used to prepare vac¬ required that eggs are supplied by a cines in time for new epidemics since certified source. Tests for safety include most new isolates from man grow poor¬ assessment of sterility, pyrogenicity and ly in eggs. These recombinants repre¬ general safety in guinea pigs and swine. sent a virus with the antigenic character Additional tests are done to detect live of the most recent variant and the im¬ virus and check the identity of vaccine proved growth capacity in eggs of a strains. Protein content is also impor¬ second strain already attenuated for tant, as it can indicate potential toxi¬
city. Use of recombinant vaccines also requires an adequate history for the attenuated donor parent virus. At pres¬ ent, potency is assessed by measuring hemagglutinin activity, which is then expressed in chick cell agglutinin (CCA) or international units. Finally, before a
vaccine is licensed, data from studies into immune response and reactogenicity in man are reviewed. Although some correlation exists between anti¬ body level and immunity, the antibody level itself is not an indication of the vaccine's efficacy, which can only be determined by the challenge of an
epidemic.
Swine influenza Dr. Walter Dowdle described the emergence of swine influenza at Fort Dix military recruit base in New Jersey. Increased incidence of febrile respira¬ tory tract disease was noted during the last 2 weeks of January 1976. Throat cultures Feb. 3 revealed A/Victoria/3/75 virus as well as four unusual viruses. The center for disease control (CDC), Atlanta, GA was immediately notified. The next day, two similar isolates were identified, one obtained from a recruit who collapsed on a march and died shortly thereafter from hemorrhagic pneumonitis. By Feb. 12 these viruses had been identified by the CDC as influenza A viruses, and they were finally identified as swine influenza virus Feb. 14. Reisolation of the virus and serologic evidence provided fur¬ ther confirmation by Feb. 19, and the World Health Organization was officially notified of this evidence of person-to-person transmission. Within the next few weeks further infection among several hundred recruits at Fort
Dix
revealed. The first cases prob¬ Caution is urged, however, in inter¬ occurred in early January. pretation of serologic prevalence data, The clinical features were similar to as 3% of persons not previously ex¬ those of A/Victoria infections except posed will have a heterotypic increase for the one death. The United King¬ in titre of antibodies to other strains dom in the meantime demonstrated a of influenza virus. The Fort Dix outbreak may be ecorange of clinical features, from asymp¬ tomatic infection to moderately severe logically unique and might or might illness, among six volunteers. Earlier not lead to pandemic spread. However, swine strains failed to infect most in¬ there has never been a new major dividuals and did not cause illness in variant of influenza A virus that did those in whom infection did occur. To not cause global epidemics, although date there has been no evidence of neither has there been so little initial spread to the community. Although evidence of spread under such cir¬ sporadic cases of A/swine infections cumstances. The basis for deciding now have been previously documented, in to vaccinate is that if vaccines are to almost all cases there has been a history be available and in use by the onset of contact with pigs. The first isolation of the next influenza season, one can¬ in humans was made in 1974 at autop¬ not afford to wait. Furthermore, in sy from a man in Minnesota who had view of the typically rapid onset of died from Hodgkin's disease. In addi¬ influenza activity, the time necessary tion, almost 90% of those over age to vaccinate large numbers of people 50 have serologic evidence of ex¬ and the appreciable delay in achieving posure to a closely related virus strain protective antibody titres following in¬ presumed to be the cause of the 1918- dividual vaccination, it would not be 19 pandemic and thought to have cir- realistic to stockpile vaccine and await culated for several years thereafter. further evidence of spread. was
ably
Vaccine recommendations for United States and Canada mortality is the single most mented repeatedly since first described important consequence of epidemic in¬ by William Farr in 1847. For example, fluenza, said Dr. Michael B. Gregg, in the 1957-58 pandemic, over two center for disease control, Atlanta. A thirds of the excess number of deaths reduction in the incidence of disease, was accounted for by those over age achieved by immunizing those at great¬ 65, and 85% by persons with pneu¬ est risk, should result in decreased mor¬ monia, influenza or cardiovascular or tality. The impact of influenza epidem¬ renal disease. ics upon mortality, particularly amongst There are also vaccine considera¬ the aged and infirm, has beeen docu¬ tions. Factors such as the variable ef¬
Excess
1040 CMA JOURNAL/JUNE
5, 1976/VOL. 114
ficacy, the short-term immunity, the requirement for repeated administration and the occurrence of side effects, par¬ ticularly in the young, support the con¬ cept of immunizing only high-risk groups. The periodicity of epidemics is not generally predictable; the constant mutation of the virus, which can make vaccine-induced immunity quickly obsolete, also militates against immu-
nization of persons who cannot be considered at high risk. US policy, therefore, routinely recommends annual immunization of persons aged 65 and over and those with chronic diseases (cardiac, bronchopulmonary and renal diseases, and diabetes mellitus and other metabolic disorders). Final recommendations for the coming winter have not yet been made. Field trials with the A/New Jersey (swine) strain are currently in progress, and sufficient information on dosage and administration should be available in June. However, it is clear that bivalent vaccine will be recommended for the usual high-risk groups and will consist of A/Victoria and A/New Jersey (swine) strains. A monovalent
vaccine containing the swine strain will be recommended for the rest of the population, with the possible exception of infants because of the very high adverse reaction rate among this group. Canada Dr. R.P. Bryce Larke, University of Alberta, Edmonton, commented that during the 1918-19 pandemic an unusually high excess mortality occurred among persons 20 to 50 years old, as well as among those over 65 and per¬ sons with chronic diseases. Accordingly the Canadian recommendations are: (1) that monovalent A/New Jersey (swine) influenza vaccine be made available for persons between ages 20 and 50 (high¬ est
risk, 20 to 40), priority being given
those responsible for maintenance of essential services; (2) that bivalent A/swine and A/Victoria influenza vaccino be made available to those of all ages with the chronic conditions described above and to everyone over 65; and (3) that A/swine influenza vaccine not be routinely administered to infants and children under 16 because of their greater susceptibility to severe adverse reactions. This third recommendation was made under the initial impression that the vaccine would be relatively crude, a situation that now appears less likely. Also, despite the considerable incidence of influenza, excess mortality does not occur in this group. Canadian recommendations are subject to the availability of vaccine.
to
World Health Organization: surveillance of influenza Dr. Walter Dowdle stated that the World Health Organization program now includes 95 designated national in¬ fluenza centres and approximately 250 collaborating laboratories in 62 coun¬ tries, with two international centres in Atlanta and London. The program aims, first, to provide for the detection and isolation of new antigenic variants of influenza virus, thereby enabling an early alert of a possible pandemic, and, second, to do¬ cument globally the epidemic behaviour and antigenic nature of prevailing virus strains. The success of this program depends primarily upon continuous, ef¬ fective surveillance of the strains in circulation. Information about influenza is forwarded directly by national centres to one of the two international centres, where the antigenic characteristics of the isolates are compared with those of other viruses prevalent throughout the world. Based on findings by both centres, recommendations regarding vaccine formulation are made by WHO, and candidate vaccine strains are dispatched. This entire operation usually
requires
less than
a
month. It has
en-
rough categories: isolated cases, isolated
abled, for example, the incorporation of outbreaks, regional involvement and the recent A/England and A/Port widespread involvement. Over the past Chalmers strains into vaccines prior to 3 years a system of monitoring ab-
their disease impact in North America. United States Dr. Michael B. Gregg pointed out that without active influenza surveil¬ lance, the Fort Dix outbreak might not have been identified. However, assess¬ ment of extent and impact remain primitive. The program relies more on mortality data than notification by phy¬ sicians because of a lack of sensitivity and specificity in clinical diagnosis. In the mid 1930s approximately 50 large cities in the United States began report¬ ing deaths from pneumonia and influ¬ enza to the Public Health Service. Since then the number of cities of 100 000 population or more that report by postcard each week has increased to 121. Weekly monitoring of viral diag¬ noses from 70 to 80 collaborating labo¬ ratories in the US is a specific indicator. In the mid-1960s an additional system was introduced. State epidemiologists were asked to report influenza in four
Occupational health considerations
senteeism from schools and factories each week has been introduced. A further technique of monitoring visits to physicians or emergency rooms proved sensitive, particularly in pedia¬ tric populations, but requires further evaluation. The National Center for Health Statistics each week surveys by telephone a representative sample of US families to determine the prevalence of respiratory disease. Comparison with mortality data shows this system is a rapid indicator of influenza activity. Canada Roy West, laboratory centre for dis¬ ease control, Ottawa, explained the six aims of influenza surveillance in Can¬ ada: to measure the impact on the community, to characterize the pre¬ vailing strain, to evaluate future vac¬ cination programs, to participate fully in WHO influenza programs, to further the knowledge of influenza etiology and rapidly to generate and disseminate information to those concerned with control. In addition, in order to gauge the impact of influenza in a given population in any given season, it is desirable to know as soon as possible the current antigenic strain in the com¬ munity, the level of population immu¬ nity to current and previous strains, the relation of these strains to the cross protection afforded, the incidence and mortality of clinical influenza in the population, and the prevalence of sub¬ clinical or inapparent infection. These criteria could be met by a weekly viral
Dr. Donald C. Bews, MDS Health Care women are more greatly affected by Services, Montreal, described the prob¬ epidemics than men and their overall lem of increased absence due to sick¬ rate of absence due to sickness is high¬ er. A 3-year study of voluntary influ¬ ness in industry during winter. In a enza among this population study of Bell Canada employees from duringvaccination the 1960s did not support rou¬ 1959 to 1974, in which absences of 8 tine annual vaccination influ¬ days or more (all of which require a enza in industrial groups.against This does medical certificate) were analysed, not, however, preclude the use of diseases of the respiratory system strain-specific vaccines if available in diagnostic reporting system, weekly ex¬ accounted for between 25 and 30% of sufficient time to avert an expected cess mortality statistics, continuous cross-sectional serologic surveys to give total absences. The study suggested epidemic. CMA JOURNAL/JUNE 5, 1976/VOL. 114 1049
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to 'starting SINEMET*; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucome; in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS
When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chores. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon mey appear earlierwith combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored conti nuously during period of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not begivento nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptometgc postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Meet Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be earlysigns of excessive dosage. Other Serleus Reseilene: Oscillations in performance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
Other adverse reactions that may occur: Psychiatric: incroasod libido with serious antisocial bohavior, ouphoria, iothargy, sedation, stimuiation, fatigue and maiaise, confusion, insomnia, nightmares, hailucinations and delusions, agitation and anxioty. Nourologic: ataxia, faintness, impairment of gait, headache, increased hand tromor, akinetic opisodos, akinesia paradoxica', incroase in tho froquency and duration of the osculations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, siaiorrhea; difficuity in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific EGG changes, flushing, phlebitis. Hornatologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskoletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, poetnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpocialSenses:blurredvision diplopia, dilated pupils, activation of latent Homer's syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SiNEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombe tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare.
DOSAGE SUMMARY In order to reduce the Incidence of adverse reactions and achieve maximal benefit. therapy with SINEMET* must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Coinlined therapy with SINEMET* hes a narrower
therapeutic range then with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of Involuntary movements should be regarded as a sign of levodope toxicity and an Indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinealas. Therapy In Patients not receiving Levedopa: Initially 1/2 tablet once or twice a day, increase by 1/2 tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy In Patients receiving Levodopa: Discontinue levodopa for at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804.TabietsSlNEMET* 250, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100. I MERCK 'Trademark
O SHARP
I & DOHME CANADA LIMITED
Pointe Claire, Quebec
1052 CMA JOURNAL/JUNE 5, 1976/VOL. 114
(MC973a)
a continuing picture of population immunity levels, family telephone surveys to provide good clinical morbidity data and a "virus watch" program using sentinel groups. A weekly system of telephoning laboratories across Canada for viral diagnoses has been in operation now for 2 years. Supplemented by clinical and epidemiologic information, these data form the basis of weekly surveillance reports sent to all participating laboratories and epidemiologists. In addition, a system of obtaining weekly excess mortality data has come into effect over the past few months. Furthermore, a continuous serologic survey based on sera collected routinely across Canada is scheduled for commencement within the next few weeks. The possibilities of a family telephone survey and a virus watch program are currently under assessment.
Family practice Dr. Michael Tarrant, a Calgary family physician, described his study of influenza in a group practice during the 1975-76 season. Throat swabs of persons with acute respiratory tract illness revealed influenza virus in approximately 30% of cases. Influenza B infections appeared earlier in this season than did A and were more highly concentrated in children. A survey revealed a 65% attack rate among families of index cases, suggesting influenza may be considered a family disease. Influenza A demonstrated greater clinical severity than influenza B, as reflected in time lost from usual activities due to illness. Symptoms were what one might expect, although the occurrence of anterior chest pain in 43 % of influenza A patients was observed and thought to reflect the onset of tracheitis. Self treatment with vitamins, cough medicines, acetylsalicylic acid, increased amounts of fluid or heating pads did not affect the severity or duration of illness. Antibiotics were prescribed for some patients, who were advised the medicine should not be taken unless fever persisted for more than 4 days or subsided and then recurred, or sputum changed colour. Compliance was poor; most of these patients took the medication regardless of instructions. Furthermore, the untreated group was observed to suffer shorter and less severe illness. Treatment with antibiotics should be reserved for patients in whom there is clear evidence of bacterial infection. A review of clinic records over recent years revealed a close relationship between bronchitis, pneumonia and incidence of influenza. U
Influenza: recent advancements and their clinical
applications
By F.M.M. White, MD* Dr. H. Grant Stiver, St. Boniface Gen¬ eral Hospital, Winnipeg, emphasized that influenza cannot be clinically dis¬ tinguished from many other diseases caused by respiratory viruses such as coxsackie virus, echovirus, and adenoviruses. Furthermore, diseases such as pharyngitis or pneumonia, which are often caused by other agents, may also be caused by influenza virus. In
mild, uncomplicated influenza,
productive cough
non-
is the most
frequent symptom. While most patients also have fever and sore throat, myalgia and headache occur in fewer than half of those afflicted. Physical findings are *
Laboratory
centre for disease
control, Ottawa
few, nonexudative pharyngitis being the
A number of influenza syndromes establishing a labora¬ can be identified, Dr. Stiver told the fied by hemagglutination-inhibition, symposium. Acute tracheobronchitis is neutralization or hemadsorption-inhibi- the most common, along with myalgia, tion tests using type-specific or strain- fever and chills commencing within 24 hours and lasting from 3 days to a CMA} presents a report on an interna¬ week. Secondary bacterial pneumonia tional symposium May 7, 1976 organ¬ may also occur, often appreciably after ized by the faculty of medicine, the acute phase of the disease, when University of Toronto in cooperation fever and myalgia have subsided. On¬ with Farke9 0avis asd Company Lim¬ set is usually marked by coughing of ited, Dr. Norman A. Hinton, Univer¬ sputum. Pneumococcal infec¬ sity of Toronto, was chairman, Recent purulent tion is the most common, although evidence that an influenza strain nor¬ mally found only in swine has caused staphylococcal infection may be the most severe. Primary viral pneumonia an outbreak among recruits in a US military base has focused worldwide is another important syndrome, and attention on this disease. This is the this was prevalent during the 1918-19 first evidence of person to person trans¬ pandemic. It may develop on the 2nd mission of a swine influenza virus or 3 rd day of the disease and can lead since the major pandemk of 1918-19. to profound respiratory collapse. Pa¬ During the 1975-76 season another new tients with pulmonary venous hyper¬ strain of influenza, A/Victoria/3/75 tension, particularly with mitral steno¬ has been responsible for the greatest sis, are predisposed, and mortality may impact from this disease since the exceed 90%. Mixed bacterial and viral minor pandentie of 1968-69. Advancements in our understanding of influ¬ pneumonia may be common, but it is enza in man, the development of difficult to culture the virus following efficient surveillance techniques and a secondary bacterial infection. Numer¬ vaccine technology over the past de¬ ous nonrespiratory syndromes have also cade have not been widely appreciated,
direct
means
of
tory diagnosis. Isolates may be identi¬
frequent. Palpable cervical nodes in a minority of cases. Only oc¬ casionally are rhinorrhea, conjunctiv¬ itis, exudative pharyngitis or pulmonary adventitious sounds apparent. It is important to undertake labora¬ tory diagnosis whenever possible. In¬ fluenza is most commonly diagnosed by demonstrating a fourfold or greater dif¬ The symposium, directed at providing ference in antibody titre between acute an overview of these events for the and convalescent sera. The complepractising physician, was moderated by ment-fixation technique identifies the Br, ILP. Bryce Larke, University of type of influenza virus responsible (A Alberta, Edmonton. or B); hemagglutination-inhibition tests can determine subtype or strain speci¬ specific antisera. The possibility of ficity. Other serologic tests, including more rapid diagnosis by immunofluor¬ the single radial diffusion technique, escence has been explored, but this exist but are not in common use. Cul¬ method is not widely used in diagnostic most
occur
tivation of influenza virus is the most
laboratories.
been described but are difficult to assess, as many of the reports are based on autopsy findings where organ con¬ tamination may have occurred. These include myocarditis, acute encephalitis,
polyneuritis (including Guillain-Barre syndrome), myositis, vasculitis (includ¬ ing disseminated intravascular coagula¬ tion) and immune complex diseases such as serum sickness and Goodpasture's syndrome.
Influenza in children Influenza is clinically a highly variable disease, and Dr. George M. Johnson, Fargo Clinic, Fargo, ND noted that in children with congenital heart de¬ fects with left to right shunts, congen¬ ital emphysema, asthma, cystic fibrosis, severe mental subnormality, myelomen-
Severe myositis may occur during re¬ covery from the acute phase of the disease and may persist intermittently for several weeks. This may produce Febrile convulsions have been observed very tender muscles, and children may in up to 50% of very young children refuse to walk. Finally, despite earlier (mean age, 2 years) admitted to hospital. speculation that influenza A virus may CMA JOURNAL/JUNE 5, 1976/VOL. 114 1035
ingocele, hydrocephalus, cerebral palsy, diabetes, leukemia or pneumonia (in the convalescent stage), influenza tends to affect the lower respiratory tract.
be teratogenic and may cause childhood leukemia and lymphoma, later studies do not support these hypotheses. Influenza B in children also results in a variety of clinical syndromes. In one study, abdominal pain was a prominent symptom among 28 of 68 patients admitted to hospital with confirmed influenza. Associated respiratory symptoms were minimal; pain was constant and central and associated with vomiting and fever. Such cases could well be misdiagnosed as "mesenteric adenitis" or gastrointestinal "flu". Accordingly, Dr. Johnson stressed the importance of laboratory diagnosis. Reyc-Johuson syndrome Although first described by Lord Brain in 1929, sudden infant death with findings of fatty degeneration of the viscera and encephalopathy has only
recently become known as the ReyeJohnson syndrome. Although the etiology of this entity is not well elucidated, influenza B virus has recently become strongly linked to its occurrence and is currently thought to trigger its development in susceptible children, Dr. Johnson said. An association with rural areas has been observed, but the question of individual susceptibility remains unanswered. The syndrome may reflect a difference in host response to influenza B and other viral infections. In a prospective study of influenza B and this syndrome at Kalamazoo, MI during the 1973-74 influenza B epidemic, the proportion of schoolage children with influenza B who exhibited this syndrome was calculated at 1:1750. This might indicate that under certain circumstances Reye-Johnson syndrome is more common than presupposed.
Immunology and developments in technology Dr. Gerald Blanford, Gage Research Institute, Toronto, observed that, as there are no effective antiviral preparations to treat influenza, immunologic efforts aim at enhancing natural immunity. Important viral factors are antigenic drift, which accounts for the almost continuous changes in the prevailing strain, and the virulence of the strain, which may reflect its ability to grow in the human host. Host factors include herd immunity - the way in which the incidence of any particular strain decreases as the average antibody titres in the population increase. IgG in serum and IgA in respiratory secretions are important factors in individual immunity. When IgG combines with antigen, it can fix complement and trigger immunologic and local inflammatory responses. Severity of inflammation is proportional to and determined by the quality of immune response. If IgG predominates, there will be more inflammation, bronchial basement membrane damage and pneumonia. There is little evidence that IgA can combine with an antigen, as it does not normally fix complement and therefore does not cause inflammation. In most experimental models, virus growth peaks at about the 3rd or 4th day of infection and is not detectable by the 8th day. Serum concentrations of interferon, a nonspecific virus inhibitor, rise and fall almost in parallel with the virus growth. Serum antibody concentrations increase only from the 5th day on, suggesting they do not influence the early phase of a primary infection. However, recent data do
show that antibody made at day 3 is present in the lung, complexed to antigen, and that in the absence of antibody and inflammatory responses the virus is not eradicated, even though interferon is still present. Organ response includes production of nonspecific inhibitors such as interferon and other humoral factors, stimulation of macrophage and monocyte activity and the physical attributes of inflammation that impair viral growth. Specific organ response may also occur and is considered to be antibodydependent although lymphocyte-mediated. During uncomplicated infection the virus is found mainly in mucous membranes and is associated with the arrival of immunoglobulin-secreting cells in bronchial submucosa. In alveoli, virus is found mainly in macrophages and does not seem to be infectious. Some viral activity in bronchial lymph nodes may be seen after the 3rd day, while viral antigens may persist in the spleen considerably longer and be responsible for continued levels of serum antibody. The role of cellmediated immunity remains undefined. Dr. Blanford put forward the hypothesis that bronchial response is modulated by local IgA and there is little evident effect of cell-mediated immunity. Alveolar response appears modulated mostly by IgG and cell-mediated immunity and may indeed be harmful. It appears, therefore, that the most effective response in recovery from infection is the production of local secretory IgA rather than complement-fixing IgG. Certain subclasses of IgG do not fix complement and there is some evid1036 CMA JOURNAL/JUNE 5, 1976/VOL. 114
.DemuIen® ethynodiol diacetate ethinyl estradiol Indication - Oral Contraception. Contraindications - Malignant tumors ot the breast or genital tract, estrogen dependent neoplasia, signiticant liver dystunction, history ot cholestatic jaundice, during breast teeding, undiagnosed vaginal bleeding, history of CVA, coronary thrombosis, classical migraine, thrombophlebitis or thromboembolic disease, ocular lesions such as partial or complete loss of vision; detect in visual fields, diplopia; suspect pregnancy. Warnings - Discontinue medication at the earliest manifestation of: thromboembolic disorders such as thrombophlebitis, cerebrovascular disease, pulmonary embolism, myocardial ischemia, retinal thrombosis; visual defects, proptosis, diplopia, undiagnosed severe headache, classical migraine, papilledema, ophthalmic vascular lesions, psychiatric disturbances. Rule Out pregnancy after two consecutive periods are missed or after the first missed period if the prescribed regimen has not been followed. Demulen may cause metabolic imbalance; observe carefully in epilepsy, asthma, cardiac and renal dysfunction. Precautions - Before use, a thorough history should be taken and a thorough physical examination performed, including the breasts and pelvic organs and a Papanicolaou smear. Follow up esamination should be within via months and at least yearly thereafter. Liver, thyroid and other endocrine function tests should not be considered accurate unless therapy has been discontinued. Withdrawal of medication for 2 to 4 months is necessary before alteration in thyroxine binding reverts to normal. Similar precautions apply to liver function studies and other tests of protein binding (e.g. plasma cortisol). Follow diabetic patients or those with a family history of diabetes closely for decrease in glucose tolerance. Persistent irregular vaginal bleeding requires investigation. In metabolic or endocrine disease and when metabolism of calcium and phosphorus is involved, careful clinical evaluation should precede medication. Possible influence of prolonged therapy on pituitary. Ovarian, adrenal, thyroid, hepatic or uterine function awaits further study. Risks of complications due to adrenocortical insufficiency appear to be minimal, but may occur. Treatment may mask the onset of the climacteric. Advise the pathologist of therapy with Demulen with relevant specimens. Uterine fibroids are subject to the same complications as may occur in pregnancy. Sudden enlargement, pain or tenderness require discontinuance of medication. Patients with a history of emotional disturbance, especially the depressive type, are prone to recurrence. If this occurs, discontinue medication. Discontinue medication in patients who develop transient aphasia, paralysis, or loss of consciousness. Give Demulen to patients with signs of essential hypertension only under close supervision. Elevation of blood pressure may occur at any time and even if asymptomatic necessitates cessation of medication. Give with great care and under close supervision to patients with a history of jaundice. Do not prescribe to those with a history of cholestatic jaundice, especially associated with pregnancy. In those patients who develop severe generalized pruritus or icterus, consider hepatic dysfunction and withdraw medication. If the jaundice is of the cholestatic type. do not resume medication. Considering the oversuppression syndrome patients may be advised to discontinue medication after approximately two years and resume only after normal ovulatory cycles have been re-established. Avoid prescribing to patients with a history of prolonged episodes of amenorrhea or infertility. Assess adolescent patients for adequate skeletal development prior to medication. Oral contraceptives may accelerate epiphyseal closure. After discontinuing Demulen. the patient should await the resumption of normal ovulating cycles before attempting to become pregnant. Use special judgment in prescribing to women with recurrent fibrocystic disease of the breast. Estrogen-progestogen combinations may increase plasma lipoproteins. Use with caution in women with pre-existent hyperlipoproteinemia. Adverse Effects - The following have been noted with varying incidence: nausea, vomiting, other GI symptoms. breakthrough bleeding, spotting. change in menstrual flow, amenorrhea, edema, suppression of lactation, migraine. cholestatic jaundice. rash (allergic), rise in blood pressure and mental depression. Disturbances in bleeding patterns are usually most pronounced during the first cycle and usually disappear after several cycles. The following have been reported. although no cause and effect relationship has been established anovulation posttreatment, premenstrual-like syndrome, changes in libido and appetite. cystitis-like syndrome, headache, nervousness. hemorrhagic eruption. and itching. Thrombophlebitis. pulmonary embolism and neuro-ocular lesions have been observed, although a cause and effect relationship has neither been established nor disproved. Various laboratory results may be altered particularly BSP. coagulation factors, tests of thyroid function. metapyrone. pregnanediol and corticosteriod determinations. Dosage - Demulen 21 - One tablet daily. Cyclic administration 3 weeks on tablets and one week off. Demulen 28 One tablet daily Continuous administration 21 active tablets followed by 7 inert tablets Availability - Each white, round tablet with Searle on one side and 71 on the other contain ethynodiol diacetate 0 mg.. and ethinyl estradiol 0.05 mg. Available in 21 and 28 day Compack dispensers (on green foil).
.. Searle Pharmaceuticals Oakvjlle, Ontano L6H 1M5
Bricanyl (terbutaline sulfate)
tablets
ACTION: Bricanyl (terbutaline sulfate) produces bronchodilation by stimulation of the . adrenergic receptors in bronchial smooth muscle, thereby causing relaxation of muscle fibres. This action is manifested by an increase in pulmonary function as demonstrated by FEV measurementa. Bricanyl also produces a decrease in airway and pulmonary resistance. Following administration of Bricanyl tablets, a measurable change in flow rate is usually observed in 30 minutes, and improvement in pulmonary function occurs within 120-180 minutes. The maximum effect usually occurs within 120 - 180 minutes and significant bronchodilator activity has been observed to persist for 4-8 hours. INDICATIONS: Bricanyl (terbutaline sulfate) tablets are indicated as a bronchodilator for the symptomatic relief of bronchial asthma and for relief of reversible bronchospasm which may occur in association with bronchitis and emphysema. CONTRAINDICATIONS: Bricanyl® (terbutaline sulfate) tablets are contraindicated when there is known hypersensitivity to sympathomimetic amines. Bricanyl like other sympathomimetic amines, should not be used in patients with tachyarrhythmias. WARNINGS: USAGE IN PREGNANCY: The safe use of Bricanyl (terbutaline sulfate) has not been established in human pregnancy. The use of the drug in pregnancy, lactation, or women of childbearing potential requires that the expected therapeutic benefit of the drug be weighed against its possible hazards to the mother or child. Animal reproductive studies have shown no adverse effects on fetal development. USAGE IN PEDIATRICS: Bricanyl5 (terbutaline sulfate) tablets are not presently recommended for children due to IImited clinical data in pediatric patients. PRECAUTIONS: Bricanyl (terbutaline sulfate) should be used with caution in patients with diabetes, hypertenaion and hyperthyroidism. As with other sympathomimetic bronchodilator agents, Bricanyl tablets should be administered cautiously to cardiac patients, especially those with associated arrhythmias. In patients in whom the administration of Bricanyl5 tablets induces cardiac irregularities, the dose should be reduced or the administration of the drug suspended. The concomitant use of Bricanylz tablets with other sympathomimetic agents is not recommended since their combined effect on the cardiovascular system may be deleterious to the patient. However, this does not preclude the use of an aerosol bronchodilator of the adrenergic stimulant type for relief of the acute bronchospasm in patients receiving chronic oral Bricanyl therapy. ADVERSE REACTIONS: Commonly observed side effects include nervousness and tremor. Other reported reactions include headache, increased heart rate, palpitations, ectopic beats, drowsiness, nausea, vomiting, sweating and dizziness. SYMPTOMS AND TREATMENT OF OVERDOSAGE: The symptoms of overdosage are similar to those described above under ADVERSE REACTIONS, and are attributable to excessive 5 adrenergic stimulation. To antagonize the effect of excessive 13 stimulation, a 13 adrenergic blocking agent such as propranolol may be considered. DOSAGE AND ADMINISTRATION: The usual oral dose of Bricanyl (terbutaline sulfate) for adults is 5 mg administered at approximately six hour intervals three times daily, during the hours the patient is usually awake. In the event of excessive side effects in individual patients, the dose may be reduced to 2.5 mg three times daily. A total dose of 15 mg should not be exceeded ins 24 hour period. Bricanyl is not currently recommended for use in children. AVAILABILITY: Tablets containing 5 mg of Bricanyl5 are white in colour and carry a numerical inscription (i.e.5) which designates the milligram content of terbutaline sulfate. Bricanyl (terbutaline sulfate) 5 mg tablets are supplied in bottles of 100.
Astra Chemicals Ltd. j
l'toduct
1.harmac.uticaI Division ssissauga, Ontario
.iterattsre available on request.
ence of a subclass preference around the bronchi. Accordingly, there may also be a secretory IgG molecule that does not mediate inflammation at this site. The implication is that optimum immunization should be provided by nasally administered, live attenuated virus vaccines. Vaccine technology Dr. Walter Dowdle of the World Health Organization influenza center, Atlanta, GA said the ideal vaccine should be desirable (with a recognized need), acceptable (discomfort being less than disease), efficacious (potept, specific and giving long-lasting immunity) and available (obtainable when needed and at reasonable cost). In all respects, influenza vaccines have not compared favourably with most other active immunizing agents such as measles and poliovirus vaccines. The influenza virus is of medium size. It is spherical but sometimes filamentous during early growth. The coat contains two proteins, the hemagglutinin and the neuraminidase. These are embedded in a nonantigenic, hostderived lipid layer, which covers the membrane of matrix protein that shapes the virus. Beneath this lies nucleoprotein, ribonucleic acid and polymerases. The hemagglutinin attaches to cells, while the neuraminidase appears to strip sialic acid from the surface of infected cells, thereby enabling the release of virus. The hemagglutinin, neuraminidase, matrix protein and nucleoprotein are all antigenic. The matrix and nucleoprotein are not variable, and antibodies to these proteins indicate whether the virus is type A, B or C. The surface antigens are variable and provide the individual strain characteristics within each type. Antibodies against hemagglutinin and neuraminidase, particularly the former, appear to have some protective function, whereas antibodies against matrix protein and nucleoprotein are not protective. Since the virus was first isolated in
1934, four distinct types of hemagglutinin component have existed (HO from 1934 to 1947, Hi from 1947 to 1957, H2 from 1957 to 1967 and H3 to the present). There have also been two types of neuraminidase during this period, a change from Ni to N2 occurring in 1957. Subtypes A, B and C are denoted by their respective hemagglutinin and neuraminidase components. Since 1967, for example, the prevailing subtype has been H3N2. Within each subtype there is considerable strain variation, so that vaccines, to be effective, must be strain-specific and not just subtype-specific. The main problem, Dr. Dowdle explained, is to produce enough vaccine effective against a particular virus strain in time for use. The difficulty in doing this results in great variation in clinical efficacy among influenza vaccines. Potency is often a problem, and although good vaccine response relationships can be demonstrated, these must be weighed against potential toxicity, number of doses required and costs of production. Currently, highly purified vaccines are prepared by either zonal ultracentrifugation or virus-splitting techniques. These techniques produce vaccine with less than 5% foreign protein, smaller virus particles and lower toxicity, thereby allowing inoculation with a larger antigenic mass. Further major improvements in inactivated influenza vaccines are unlikely. Attenuated, nasally administered vaccines should have the advantages of producing antibody response where it is most needed, a more acceptable mode of administration, lower toxicity and more efficient production, as the vaccine strain itself will replicate in the host and thereby allow a much lower dose. Although there has been considerable experience with these vaccines in the Soviet Union and certain eastern European countries over many years, further development and evaluation is required to overcome problems of genetic stability and degree of attenuation before they are available for routine use.
Licensing requirements Dr. John Furesz, bureau of biologics, Ottawa, reviewed development of influenza vaccines over the past 4 decades and showed how this has contributed greatly to our understanding of the disease itself. At present, only inactivated influenza vaccines are licensed for use in Canada and the United States. The decision not to license live vaccines has been based pri-
manly on lack of genetic markers and data for the incidence of possible reversion. Since protection with inactivated vaccines varies greatly, the possible use of adjuvants to promote higher antibody titres and induce a broader antibody response has received some attention. Although data from clinical trials are impressive, adjuvant vaccines are difficult to produce and require
CMA JOURNAL/JUNE 5, 1976/VOL. 114 1039
particular care in administration. In man. Benefit/cost considerations cur¬ addition, adjuvants have been shown to rently favour the continued use of modify the humoral and cellular re¬ zonally purified, inactivated, aqueous sponse in animals. In man, their ad¬ vaccines. With production of any vaccine it is ministration could result in an Arthus reaction or a delayed hypersensitivity important to have stringent quality con¬ reaction on subsequent vaccination. trol to ensure it is safe and potent More recently, the principle of recom- enough. Before production, evidence is bination has been used to prepare vac¬ required that eggs are supplied by a cines in time for new epidemics since certified source. Tests for safety include most new isolates from man grow poor¬ assessment of sterility, pyrogenicity and ly in eggs. These recombinants repre¬ general safety in guinea pigs and swine. sent a virus with the antigenic character Additional tests are done to detect live of the most recent variant and the im¬ virus and check the identity of vaccine proved growth capacity in eggs of a strains. Protein content is also impor¬ second strain already attenuated for tant, as it can indicate potential toxi¬
city. Use of recombinant vaccines also requires an adequate history for the attenuated donor parent virus. At pres¬ ent, potency is assessed by measuring hemagglutinin activity, which is then expressed in chick cell agglutinin (CCA) or international units. Finally, before a
vaccine is licensed, data from studies into immune response and reactogenicity in man are reviewed. Although some correlation exists between anti¬ body level and immunity, the antibody level itself is not an indication of the vaccine's efficacy, which can only be determined by the challenge of an
epidemic.
Swine influenza Dr. Walter Dowdle described the emergence of swine influenza at Fort Dix military recruit base in New Jersey. Increased incidence of febrile respira¬ tory tract disease was noted during the last 2 weeks of January 1976. Throat cultures Feb. 3 revealed A/Victoria/3/75 virus as well as four unusual viruses. The center for disease control (CDC), Atlanta, GA was immediately notified. The next day, two similar isolates were identified, one obtained from a recruit who collapsed on a march and died shortly thereafter from hemorrhagic pneumonitis. By Feb. 12 these viruses had been identified by the CDC as influenza A viruses, and they were finally identified as swine influenza virus Feb. 14. Reisolation of the virus and serologic evidence provided fur¬ ther confirmation by Feb. 19, and the World Health Organization was officially notified of this evidence of person-to-person transmission. Within the next few weeks further infection among several hundred recruits at Fort
Dix
revealed. The first cases prob¬ Caution is urged, however, in inter¬ occurred in early January. pretation of serologic prevalence data, The clinical features were similar to as 3% of persons not previously ex¬ those of A/Victoria infections except posed will have a heterotypic increase for the one death. The United King¬ in titre of antibodies to other strains dom in the meantime demonstrated a of influenza virus. The Fort Dix outbreak may be ecorange of clinical features, from asymp¬ tomatic infection to moderately severe logically unique and might or might illness, among six volunteers. Earlier not lead to pandemic spread. However, swine strains failed to infect most in¬ there has never been a new major dividuals and did not cause illness in variant of influenza A virus that did those in whom infection did occur. To not cause global epidemics, although date there has been no evidence of neither has there been so little initial spread to the community. Although evidence of spread under such cir¬ sporadic cases of A/swine infections cumstances. The basis for deciding now have been previously documented, in to vaccinate is that if vaccines are to almost all cases there has been a history be available and in use by the onset of contact with pigs. The first isolation of the next influenza season, one can¬ in humans was made in 1974 at autop¬ not afford to wait. Furthermore, in sy from a man in Minnesota who had view of the typically rapid onset of died from Hodgkin's disease. In addi¬ influenza activity, the time necessary tion, almost 90% of those over age to vaccinate large numbers of people 50 have serologic evidence of ex¬ and the appreciable delay in achieving posure to a closely related virus strain protective antibody titres following in¬ presumed to be the cause of the 1918- dividual vaccination, it would not be 19 pandemic and thought to have cir- realistic to stockpile vaccine and await culated for several years thereafter. further evidence of spread. was
ably
Vaccine recommendations for United States and Canada mortality is the single most mented repeatedly since first described important consequence of epidemic in¬ by William Farr in 1847. For example, fluenza, said Dr. Michael B. Gregg, in the 1957-58 pandemic, over two center for disease control, Atlanta. A thirds of the excess number of deaths reduction in the incidence of disease, was accounted for by those over age achieved by immunizing those at great¬ 65, and 85% by persons with pneu¬ est risk, should result in decreased mor¬ monia, influenza or cardiovascular or tality. The impact of influenza epidem¬ renal disease. ics upon mortality, particularly amongst There are also vaccine considera¬ the aged and infirm, has beeen docu¬ tions. Factors such as the variable ef¬
Excess
1040 CMA JOURNAL/JUNE
5, 1976/VOL. 114
ficacy, the short-term immunity, the requirement for repeated administration and the occurrence of side effects, par¬ ticularly in the young, support the con¬ cept of immunizing only high-risk groups. The periodicity of epidemics is not generally predictable; the constant mutation of the virus, which can make vaccine-induced immunity quickly obsolete, also militates against immu-
nization of persons who cannot be considered at high risk. US policy, therefore, routinely recommends annual immunization of persons aged 65 and over and those with chronic diseases (cardiac, bronchopulmonary and renal diseases, and diabetes mellitus and other metabolic disorders). Final recommendations for the coming winter have not yet been made. Field trials with the A/New Jersey (swine) strain are currently in progress, and sufficient information on dosage and administration should be available in June. However, it is clear that bivalent vaccine will be recommended for the usual high-risk groups and will consist of A/Victoria and A/New Jersey (swine) strains. A monovalent
vaccine containing the swine strain will be recommended for the rest of the population, with the possible exception of infants because of the very high adverse reaction rate among this group. Canada Dr. R.P. Bryce Larke, University of Alberta, Edmonton, commented that during the 1918-19 pandemic an unusually high excess mortality occurred among persons 20 to 50 years old, as well as among those over 65 and per¬ sons with chronic diseases. Accordingly the Canadian recommendations are: (1) that monovalent A/New Jersey (swine) influenza vaccine be made available for persons between ages 20 and 50 (high¬ est
risk, 20 to 40), priority being given
those responsible for maintenance of essential services; (2) that bivalent A/swine and A/Victoria influenza vaccino be made available to those of all ages with the chronic conditions described above and to everyone over 65; and (3) that A/swine influenza vaccine not be routinely administered to infants and children under 16 because of their greater susceptibility to severe adverse reactions. This third recommendation was made under the initial impression that the vaccine would be relatively crude, a situation that now appears less likely. Also, despite the considerable incidence of influenza, excess mortality does not occur in this group. Canadian recommendations are subject to the availability of vaccine.
to
World Health Organization: surveillance of influenza Dr. Walter Dowdle stated that the World Health Organization program now includes 95 designated national in¬ fluenza centres and approximately 250 collaborating laboratories in 62 coun¬ tries, with two international centres in Atlanta and London. The program aims, first, to provide for the detection and isolation of new antigenic variants of influenza virus, thereby enabling an early alert of a possible pandemic, and, second, to do¬ cument globally the epidemic behaviour and antigenic nature of prevailing virus strains. The success of this program depends primarily upon continuous, ef¬ fective surveillance of the strains in circulation. Information about influenza is forwarded directly by national centres to one of the two international centres, where the antigenic characteristics of the isolates are compared with those of other viruses prevalent throughout the world. Based on findings by both centres, recommendations regarding vaccine formulation are made by WHO, and candidate vaccine strains are dispatched. This entire operation usually
requires
less than
a
month. It has
en-
rough categories: isolated cases, isolated
abled, for example, the incorporation of outbreaks, regional involvement and the recent A/England and A/Port widespread involvement. Over the past Chalmers strains into vaccines prior to 3 years a system of monitoring ab-
their disease impact in North America. United States Dr. Michael B. Gregg pointed out that without active influenza surveil¬ lance, the Fort Dix outbreak might not have been identified. However, assess¬ ment of extent and impact remain primitive. The program relies more on mortality data than notification by phy¬ sicians because of a lack of sensitivity and specificity in clinical diagnosis. In the mid 1930s approximately 50 large cities in the United States began report¬ ing deaths from pneumonia and influ¬ enza to the Public Health Service. Since then the number of cities of 100 000 population or more that report by postcard each week has increased to 121. Weekly monitoring of viral diag¬ noses from 70 to 80 collaborating labo¬ ratories in the US is a specific indicator. In the mid-1960s an additional system was introduced. State epidemiologists were asked to report influenza in four
Occupational health considerations
senteeism from schools and factories each week has been introduced. A further technique of monitoring visits to physicians or emergency rooms proved sensitive, particularly in pedia¬ tric populations, but requires further evaluation. The National Center for Health Statistics each week surveys by telephone a representative sample of US families to determine the prevalence of respiratory disease. Comparison with mortality data shows this system is a rapid indicator of influenza activity. Canada Roy West, laboratory centre for dis¬ ease control, Ottawa, explained the six aims of influenza surveillance in Can¬ ada: to measure the impact on the community, to characterize the pre¬ vailing strain, to evaluate future vac¬ cination programs, to participate fully in WHO influenza programs, to further the knowledge of influenza etiology and rapidly to generate and disseminate information to those concerned with control. In addition, in order to gauge the impact of influenza in a given population in any given season, it is desirable to know as soon as possible the current antigenic strain in the com¬ munity, the level of population immu¬ nity to current and previous strains, the relation of these strains to the cross protection afforded, the incidence and mortality of clinical influenza in the population, and the prevalence of sub¬ clinical or inapparent infection. These criteria could be met by a weekly viral
Dr. Donald C. Bews, MDS Health Care women are more greatly affected by Services, Montreal, described the prob¬ epidemics than men and their overall lem of increased absence due to sick¬ rate of absence due to sickness is high¬ er. A 3-year study of voluntary influ¬ ness in industry during winter. In a enza among this population study of Bell Canada employees from duringvaccination the 1960s did not support rou¬ 1959 to 1974, in which absences of 8 tine annual vaccination influ¬ days or more (all of which require a enza in industrial groups.against This does medical certificate) were analysed, not, however, preclude the use of diseases of the respiratory system strain-specific vaccines if available in diagnostic reporting system, weekly ex¬ accounted for between 25 and 30% of sufficient time to avert an expected cess mortality statistics, continuous cross-sectional serologic surveys to give total absences. The study suggested epidemic. CMA JOURNAL/JUNE 5, 1976/VOL. 114 1049
(levodopa and carbidopa combination) INDICATIONS Treatment of Parkinson's syndrome with exception of drug induced parkinsonism. CONTRAINDICATIONS When a sympathomimetic amine is contraindicated; with monoamine oxidase inhibitors, which should be discontinued two weeks prior to 'starting SINEMET*; in uncompensated cardiovascular, endocrine, hematologic, hepatic, pulmonary or renal disease; in narrowangle glaucome; in patients with suspicious, undiagnosed skin lesions or a history of melanoma.
WARNINGS
When given to patients receiving levodopa alone, discontinue levodopa at least 12 hours before initiating SINEMET* at a dosage that provides approximately 20% of previous levodopa. Not recommended in drug-induced extrapyramidal reactions; contraindicated in management of intention tremor and Huntington's chores. Levodopa related central effects such as involuntary movements may occur at lower dosages and sooner, and the 'on and off' phenomenon mey appear earlierwith combination therapy. Monitor carefully all patients for the development of mental changes, depression with suicidal tendencies, or other serious antisocial behaviour. Cardiac function should be monitored conti nuously during period of initial dosage adjustment in patients with arrhythmias. Safety of SINEMET* in patients under 18 years of age not established. Pregnancy and lactation: In women of childbearing potential, weigh benefits against risks. Should not begivento nursing mothers. Effects on human pregnancy and lactation unknown. PRECAUTIONS General: Periodic evaluations of hepatic, hematopoietic, cardiovascular and renal function recommended in extended therapy. Treat patients with history of convulsions cautiously. Physical Activity: Advise patients improved on SINEMET* to increase physical activities gradually, with caution consistent with other medical considerations. In Glaucoma: May be given cautiously to patients with wide angle glaucoma, provided intraocular pressure is well controlled and can be carefully monitored during therapy. With Antihypertensive Therapy:Assymptometgc postural hypotension has been reported occasionally, give cautiously to patients on antihypertensive drugs, checking carefully for changes in pulse rate and blood pressure. Dosage adjustment of antihypertensive drug may be required. With Psychoactive Drugs: If concomitant administration is necessary, administer psychoactive drugs with great caution and observe patients for unusual adverse reactions. With Anesthetics: Discontinue SINEMET* the night before general anesthesia and reinstitute as soon as patient can take medication orally. ADVERSE REACTIONS Meet Cemmen: Abnormal Involuntary Movements-usually diminished by dosage reduction-choreiform, dystonic and other involuntary movements. Muscle twitching and blepharospasm may be earlysigns of excessive dosage. Other Serleus Reseilene: Oscillations in performance: diurnal variations, independent oscillations in akinesia with stereotyped dyskinesias, sudden akinetic crises related to dyskinesias, akinesia paradoxica (hypotonic freezing) and 'on and off' phenomenon. Psychiatric: paranoid ideation, psychotic episodes, depression with or without development of suicidal tendencies and dementia. Rarely convulsions (causal relationship not established). Cardiac irregularities and/or palpitations, orthostatic hypotensive episodes, anorexia, nausea, vomiting and dizziness.
Other adverse reactions that may occur: Psychiatric: incroasod libido with serious antisocial bohavior, ouphoria, iothargy, sedation, stimuiation, fatigue and maiaise, confusion, insomnia, nightmares, hailucinations and delusions, agitation and anxioty. Nourologic: ataxia, faintness, impairment of gait, headache, increased hand tromor, akinetic opisodos, akinesia paradoxica', incroase in tho froquency and duration of the osculations in performance, torticollis, trismus, tightness of the mouth, lips or tongue, oculogyric crisis, weakness, numbness, bruxism, priapism. Gastrointestinal: constipation, diarrhea, epigastric and abdominal distress and pain, flatulence; eructation, hiccups, siaiorrhea; difficuity in swallowing, bitter taste, dry mouth; duodenal ulcer; gastrointestinal bleeding; burning sensation of the tongue. Cardiovascular: arrhythmias, hypotension, nonspecific EGG changes, flushing, phlebitis. Hornatologic: hemolytic anemia, leukopenia, agranulocytosis. Dermatologic: sweating, edema, hair loss, pallor, rash, bad odor, dark sweat. Musculoskoletal: low back pain, muscle spasm and twitching, musculoskeletal pain. Respiratory: feeling of pressure in the chest, cough, hoarseness, bizarre breathing pattern, poetnasal drip. Urogenital: urinary frequency, retention, incontinence, hematuria, dark urine, nocturia, and one report of interstitial nephritis. SpocialSenses:blurredvision diplopia, dilated pupils, activation of latent Homer's syndrome. Miscellaneous: hot flashes, weight gain or loss. Abnormalities in laboratory tests reported with levodopa alone, which may occur with SiNEMET*: Elevations of blood urea nitrogen, SGOT, SGPT, LDH, bilirubin, alkaline phosphatase or protein bound iodine. Occasional reduction in WBC, hemoglobin and hematocrit. Elevations of uric acid with colorimetric method. Positive Coombe tests reported both with SINEMET* and with levodopa alone, but hemolytic anemia extremely rare.
DOSAGE SUMMARY In order to reduce the Incidence of adverse reactions and achieve maximal benefit. therapy with SINEMET* must be individualized and drug administration continuously matched to the needs and tolerance of the patient. Coinlined therapy with SINEMET* hes a narrower
therapeutic range then with levodopa alone because of its greater milligram potency. Therefore, titration and adjustment of dosage should be made in small steps and recommended dosage ranges not be exceeded. Appearance of Involuntary movements should be regarded as a sign of levodope toxicity and an Indication of overdosage, requiring dose reduction. Treatment should, therefore, aim at maximal benefit without dyskinealas. Therapy In Patients not receiving Levedopa: Initially 1/2 tablet once or twice a day, increase by 1/2 tablet every three days if desirable. An optimum dose of 3 to 5 tablets a day divided into 4 to 6 doses. Therapy In Patients receiving Levodopa: Discontinue levodopa for at least 12 hours, then give approximately 20% of the previous levodopa dose in 4 to 6 divided doses. FOR COMPLETE PRESCRIBING INFORMATION, PARTICULARLY DETAILS OF DOSAGE AND ADMINISTRATION, PLEASE CONSULT PRODUCT MONOGRAPH WHICH IS AVAILABLE ON REQUEST. HOW SUPPLIED Ca8804.TabietsSlNEMET* 250, dapple-blue, oval, biconvex, scored, compressed tablets coded MSD 654, each containing 25 mg of carbidopa and 250 mg of levodopa. Available in bottles of 100. I MERCK 'Trademark
O SHARP
I & DOHME CANADA LIMITED
Pointe Claire, Quebec
1052 CMA JOURNAL/JUNE 5, 1976/VOL. 114
(MC973a)
a continuing picture of population immunity levels, family telephone surveys to provide good clinical morbidity data and a "virus watch" program using sentinel groups. A weekly system of telephoning laboratories across Canada for viral diagnoses has been in operation now for 2 years. Supplemented by clinical and epidemiologic information, these data form the basis of weekly surveillance reports sent to all participating laboratories and epidemiologists. In addition, a system of obtaining weekly excess mortality data has come into effect over the past few months. Furthermore, a continuous serologic survey based on sera collected routinely across Canada is scheduled for commencement within the next few weeks. The possibilities of a family telephone survey and a virus watch program are currently under assessment.
Family practice Dr. Michael Tarrant, a Calgary family physician, described his study of influenza in a group practice during the 1975-76 season. Throat swabs of persons with acute respiratory tract illness revealed influenza virus in approximately 30% of cases. Influenza B infections appeared earlier in this season than did A and were more highly concentrated in children. A survey revealed a 65% attack rate among families of index cases, suggesting influenza may be considered a family disease. Influenza A demonstrated greater clinical severity than influenza B, as reflected in time lost from usual activities due to illness. Symptoms were what one might expect, although the occurrence of anterior chest pain in 43 % of influenza A patients was observed and thought to reflect the onset of tracheitis. Self treatment with vitamins, cough medicines, acetylsalicylic acid, increased amounts of fluid or heating pads did not affect the severity or duration of illness. Antibiotics were prescribed for some patients, who were advised the medicine should not be taken unless fever persisted for more than 4 days or subsided and then recurred, or sputum changed colour. Compliance was poor; most of these patients took the medication regardless of instructions. Furthermore, the untreated group was observed to suffer shorter and less severe illness. Treatment with antibiotics should be reserved for patients in whom there is clear evidence of bacterial infection. A review of clinic records over recent years revealed a close relationship between bronchitis, pneumonia and incidence of influenza. U
