Relationships between the academic community and the pharmaceutical industry: the legislative background and its effect on spending on medical research and development

Patent legislation governing drugs has evolved through a series of amendments to the Patent Act. From 1923 until 1993, Canada operated a system of "compulsory licensing," allowing generic copies of patented medicines to be manufactured within Canada and, by 1969, to be imported. In 1987, the act was amended (Bill C-22) to provide patented medicines with a fixed period of market protection before a compulsory license could be issued and to create a price review board to monitor and control prices charged. In return for patent protection, brand-name drug companies promised to invest a growing percentage of sales revenue in research and development in Canada. A 1993 amendment to the Patent Act (Bill C-91) brought a fundamental change to the legislation by abolishing the system of compulsory licensing and applying general patent regulations to medicines, thereby bringing Canadian law into line with that of its trading partners. It is now illegal to sell a copy of a drug until the patent expires (20 years after the patent is filed). This means that marketed drugs are protected for 8 to 13 years, since drug development takes a large proportion of the life of the patent. Since this amendment was passed, the brand-name drug companies have made major contributions to research and development in Canada, increasing from 6.5% of sales revenue in 1987 to 11.6% in 1994. Major irritants in the legislation remain. Generic drug companies have complained about "linkage regulations" that allow brand-name drug companies to legally challenge generic drug production on the basis of alleged infringements of linked patents, delaying the marketing of the generic drug. The act also prohibits Canadian manufacturers from exporting a generic drug to a country where it is not protected if it still protected in Canada. Brand-name manufacturers want some means of patent term restoration if regulatory authorities prolong the time taken before marketing a drug. This legislation is being reviewed by parliament beginning in 1997.     

The effect of anaesthetics on the dynamic heterogeneity of lipid membranes

A randomized multicenter study was performed in order to investigate the acceptance of a low-dose OC (30 micrograms of ethinyloestradiol and 150 micrograms of desogestrel), using a 9 weeks on and 1 week off schedule (prolonged regimen, n = 198), compared to a traditional 3 weeks on, 1 week off schedule (standard regimen, n = 96). Haemoglobin and blood pressure remained the same in both groups during the study. No significant differences were found in body weight changes between the two groups. There was significantly more breakthrough bleeding and spotting in the group with prolonged regimen than in the group with standard regimen, but both breakthrough bleeding and spotting decreased during the trial. Irregular bleeding was significantly less in women who were already using OC, compared to "new starters." No serious side effects occurred. Significantly more women stopped the trial because of bleeding problems in the group with prolonged regimen, while there were significantly more women who stopped the trial because of headache in the group with standard regimen. After completing 12 months, or after premature withdrawal from the study, each women completed a questionnaire. Sixty-three per cent of the women preferred the studied alternative and twenty-six per cent preferred the traditional OC.     

Reliability of seizure classification using a semistructured interview

Methods for standardized classification of epileptic seizures are important for both clinical practice and epidemiologic research. In this study, we developed a strategy for standardized classification using a semistructured telephone interview and operational diagnostic criteria. We interviewed 1,957 adults with epilepsy ascertained from voluntary organizations. To confirm and expand the seizure history, we also interviewed a first-degree relative for 67% of subjects and obtained medical records for 59%. Three lay reviewers used all available information to classify seizures. To assess reliability, each reviewer classified a sample of subjects assigned to the others. In addition, an expert physician classified a sample of subjects assigned to two of the reviewers. Agreement was "moderate-substantial" for generalized-onset seizures, both for the comparisons between pairs of lay reviewers and for the neurologist versus lay reviewers. Agreement was "substantial-almost perfect" for partial-onset seizures, both for pairs of lay reviewers and for the neurologist versus lay reviewers. These results suggest that seizures can be reliably classified by lay reviewers, using operational criteria applied to symptoms ascertained in a semistructured telephone interview.     

Characterization of brevin, a serum protein that shortens actin filaments

We have purified a protein from rabbit serum with a molecular weight of 90,000 that inhibits the polymerization of actin measured viscometrically and that we have named "brevin" (from the Latin breviare, to shorten). From the extent of purification, we estimate that this inhibitor constitutes 0.3% of the total protein in plasma and serum. Brevin is also present in sera from humans and rats. Almost all of the activity in blood is extracellular; only 1% is present in platelets or other cellular elements. Several lines of evidence indicate that brevin is the same protein as the factor described by Fagraeus and Norberg [Fagraeus, A. & Norberg, R. (1978) Curr. Top. Microbiol. Immunol. 82, 1-13] as an actin-depolymerizing factor (ADF). If ADF and brevin are identical, then "ADF" is an inappropriate name because we find that the protein shortens actin filaments without depolymerizing them. Thus, brevin causes little change in the critical concentration of monomeric actin, even though the inhibitor binds to monomeric actin complexed to DNase I-agarose. Binding of brevin to filaments was demonstrated by sedimenting the inhibitor with F-actin. From the amounts of actin and brevin sedimented, and from the lengths of filaments measured by electron microscopy, we calculated that the stoichiometry of binding is one brevin molecule per filament over a wide range of inhibitor concentrations. This stoichiometry suggests that brevin inhibits polymerization by binding at the end of elongating actin filaments, a mechanism similar to that proposed for several intracellular actin-binding proteins and for the cytochalasins. Its abundance suggests that brevin plays an important physiological role in serum, but one not directly concerned with intracellular motility. Therefore its relationship to cytoplasmic actin-binding proteins remains to be determined.     

Synthesis in vitro of intrinsic membrane proteins by free, membrane-bound, and Golgi apparatus-associated polyribosomes from rat liver

A fraction of intrinsic membrane proteins was prepared from the major membranous cell components of rat liver by extraction of the membranes with KCl and deoxycholate. Analysis by sodium dodecyl sulfate-polyacrylamide gel electrophoresis revealed that the compositions of the intrinsic protein fractions from rough and endoplasmic reticulum, smooth endoplasmic reticulum. Golgi apparatus, plasma membrane, and nuclear envelope were similar to each other but distinct from that of mitochondria. Among endomembranes, differences were in the ratios of protein constituents plus a few protein bands of Golgi apparatus and plasma membranes not found in endoplasmic reticulum or nuclear envelope. The abilities of total rough endoplasmic reticulum, polysomes released from rough endoplasmic reticulum, and free polysomes to incorporate amino acids into the intrinsic protein fraction were tested in vitro. Polysomes bound to endoplasmic reticulum has the greatest capacity to synthesize proteins of this fraction as shown by co-purification of radioactive products and by immunoprecipitation. Although the majority of the radioactive products synthesized by bound polysomes were distinct from those synthesized by free polysomes, certain radioactive products synthesized by free polysomes also co-purified with intrinsic membrane proteins. The results show no absolute segregation between free and bound polysomes in the synthesis of intrinsic membrane proteins. However, the majority of these proteins appear to be synthesized by polysomes bound to the endoplasmic reticulum. Several intrinsic proteins found in plasma membranes do not appear in rough endoplasmic reticulum. To determine where these proteins were synthesized, the ability of other endomembrane components to support in vitro incorporation of [14C]leucine into protein was examined. In contrast to plasma membranes, isolated Golgi apparatus fractions did incorporate [14C]leucine to an extent greater than could be explained by contamination with rough endoplasmic reticulum. Golgi apparatus in situ and isolated from rat liver have polyribosomes associated with a zone of cytoplasm at the Golgi apparatus periphery occupied by tubules and vesicles. The polysomes are not directly attached to membranes as with rough endoplasmic reticulum and may represent a special class of "Golgi apparatus-associated" polysomes. The polysomes, when associated with Golgi apparatus membranes, incorporated amino acids in vitro. The products synthesized in vitro were analyzed by treatment with KCl and deoxycholate and separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Certain proteins synthesized by the Golgi apparatus-associated polysomes remained insoluble after the treatment with KCl and deoxycholate. The proteins synthesized by the Golgi apparatus fraction had mobilities similar to proteins in plasma membranes which were absent from endoplasmic reticulum, and which were relatively minor components of Golgi apparatus...     

Sodium nitroprusside: pharmacology, toxicology and therapeutics

Sodium nitroprusside is a potent, effective, and readily reversible direct vasodilating agent. It is broken down by hemoglobin into cyanide, which is in part detoxified by liver and kidney to thiocyanate. Some cyanide, especially in nitroprusside- "resistant" individuals who need large amounts of the drug, appears to remain free to cause cyanide poisoning. Patients requiring inordinate amounts probably should not continue to receive the drug, although maximum dosage limits for long-term therapy are not established. Blood thiocyanate levels do not indicate the extent to which free cyanide is limiting oxygen utilization in essential tissue, nor do blood cyanide levels. Metabolic acidosis, elevated lactate levels, elevated lactate/pyruvate ratios, and elevated mixed venous blood oxygen content are at present the best indications of the presence of cyanide poisoning during nitroprusside administration. Nitroprusside appears useful for induction of hypotension during surgery, and for treatment of hypertensive emergencies from all causes, although continuance for more than a few days is probably unwise. The reductions of cardiac afterload and ventricular filling pressure by nitroprusside appear useful in treatment of severe myocardial failure or infarction, but studies of myocardial cyanide toxicity are needed before complete acceptance of this therapy is warranted. Initial dose rates between 0.5 and 1.5 mug/kg/min are recommended only as starting points for very careful titration. Total projected intra-operative dosage should be calculated as quickly as possible and should not exceed 3-3.5 mg/kg. It is hoped that future studies will reveal the maximum dose of nitroprusside that can safely be metabolized in a 24-hour period, and may indicate that cofactors of rhodanase such as thiosulfate, or cobalamins such as hydroxocobalamin, can be administered with nitroprusside to prevent cyanide poisoning.     

The prevalence of hepatitis B surface antigen in commercially prepared plasma products

Commercially available lots of plasma derivatives prepared between 1957 and 1975 were tested for hepatitis B surface antigen (HBsAg) by radioimmunoassay. In all, 69 per cent of lots of plasma protein fraction, 40 per cent of factor IX concentrate, 20 per cent of normal serum albumin, 13 per cent of antihemophilic factor, 3 per cent of fibrinogen, and 0.7 per cent of immune serum globulin lots tested were HBsAg-positive. There was great variation in the prevalence of HBsAg-positive lots of each product among the different manufacturers, reflecting not only differences in methods of processing plasma, but also differences in donor populations. Those manufacturers relying upon volunteer donor plasma or placental source material demonstrated lower rates of HBsAg-positive lots of final products than those relying upon commercial donor plasma. There was a marked decrease in the prevalence of positive lots during the period 1971 to 1973, coincident with the onset of routine plasma donor screening for HBsAg. However, current requirements for plasma screening have not resulted in totally HBsAg-free plasma products. Use of more sensitive and more reliable tests for HBsAg will probably reduce contamination of plasma pools with HBsAg to undetectable levels. Despite HBsAg-status, however, the "high-risk" plasma products (fibrinogen, antihemophilic factor, factor IX concentrate) must still be considered capable of transmitting hepatitis and used only with the strictest indications.     

Outpatient chemotherapy of advanced breast cancer in a community setting: a five-drug regimen

Forty-two (37 evaluable) unselected women with advanced breast carcinoma were treated with a modified "Cooper regimen" in a community setting. After 12 weeks of induction therapy, the patients were evaluated for response and toxicity. The 74% overall response rate (78% in the evaluable group) compares favorably with that of other series. The median duration of remission was 13.7 months. The median survival was 17 months for the evaluable patients and 14 months for the entire group. Twenty-two percent of the patients required hospitalization during the induction phase, and 35% were treated exclusively as outpatients during all phases of therapy. There was only one drug-related death. It is concluded that a complex chemotherapeutic regimen can be managed adequately by physicians experienced in chemotherapy in a community setting with results comparable to those from cancer centers.     

Thyroid cancer after exposure to external radiation: a pooled analysis of seven studies

The thyroid gland of children is especially vulnerable to the carcinogenic action of ionizing radiation. To provide insights into various modifying influences on risk, seven major studies with organ doses to individual subjects were evaluated. Five cohort studies (atomic bomb survivors, children treated for tinea capitis, two studies of children irradiated for enlarged tonsils, and infants irradiated for an enlarged thymus gland) and two case-control studies (patients with cervical cancer and childhood cancer) were studied. The combined studies include almost 120,000 people (approximately 58,000 exposed to a wide range of doses and 61,000 nonexposed subjects), nearly 700 thyroid cancers and 3,000,000 person years of follow-up. For persons exposed to radiation before age 15 years, linearity best described the dose response, even down to 0.10 Gy. At the highest doses (> 10 Gy), associated with cancer therapy, there appeared to be a decrease or leveling of risk. For childhood exposures, the pooled excess relative risk per Gy (ERR/Gy) was 7.7 (95% CI = 2.1, 28.7) and the excess absolute risk per 10(4) PY Gy (EAR/10(4) PY Gy) was 4.4 (95% CI = 1.9, 10.1). The attributable risk percent (AR%) at 1 Gy was 88%. However, these summary estimates were affected strongly by age at exposure even within this limited age range. The ERR was greater (P = 0.07) for females than males, but the findings from the individual studies were not consistent. The EAR was higher among women, reflecting their higher rate of naturally occurring thyroid cancer. The distribution of ERR over time followed neither a simple multiplicative nor an additive pattern in relation to background occurrence. Only two cases were seen within 5 years of exposure. The ERR began to decline about 30 years after exposure but was still elevated at 40 years. Risk also decreased significantly with increasing age at exposure, with little risk apparent after age 20 years. Based on limited data, there was a suggestion that spreading dose over time (from a few days to > 1 year) may lower risk, possibly due to the opportunity for cellular repair mechanisms to operate. The thyroid gland in children has one of the highest risk coefficients of any organ and is the only tissue with convincing evidence for risk about 1.10 Gy.