Human growth hormone produced with recombinant DNA technology: development and production.

The molecular basis of recombinant DNA technology is described, and the principles of genetically engineered proteins developed. The production of hGH by such methods utilizes a strain of Escherichia coli as host and a vector plasmid containing the appropriate information. Fermentation and purification of the hGH produced gives a preparation of high purity, containing only 1-2 ppm of E. coli polypeptide (ECP). This somatrem (Somatonorm) is identical to pituitary hGH except for an additional methionine residue at the N-terminal. Monoclonal antibodies fail to distinguish between pituitary hGH and somatrem. Preclinical studies of a variety of pharmacological and toxicological parameters indicate that the two hGH preparations have identical biological effects; no toxicological or mutagenic effects of somatrem have been detected.

Clinical experience with somatrem in growth hormone deficiency.

Three studies of human growth hormone (hGH) in hGH deficiency were initiated. In the first of these, adolescent patients were switched from pituitary hGH to somatrem (SI preparation) for 1 month. No significant differences were noted in any of the clinical parameters measured during treatment with either preparation. In the second study, nine patients (six of them naïve) were treated with somatrem (SII preparation) for 9-12 months. The naïve patients exhibited catch-up growth, and bone age developed in parallel to chronological age during the study period. Somatomedin activity increased and correlated positively with growth. Antibodies to hGH and Escherichia coli polypeptide (ECP) developed in some patients, but titres and binding capacities were low. In the third study, 21 patients are currently being treated with Somatonorm; the first 3-6 months are evaluable. Growth velocities increased to normal values. Antibodies to hGH and ECP were present in several patients, but again the titres and binding capacities were low, and Somatonorm was less antigenic than the SI and SII preparations.

Drug use during pregnancy and breast-feeding. A classification system for drug information.

Since 1978 the Swedish catalogue of registered pharmaceutical specialties (FASS) has carried a special section entitled "Pregnancy and breast-feeding" in each product presentation, intended to form an aid for the prescription of drugs to women during childbearing and lactation. After a brief review of transplacental transport and milk secretion, reproduction-toxicology studies in animals, and methods for clinical evaluation of drugs for use during pregnancy, the classification system is presented. On the basis of available data with regard to effects on early and late stages of pregnancy and labour, all the pharmaceutical specialties concerned are assigned to one of the following pregnancy categories: A, B 1, B 2, B 3, C or D. The letters refer to information based on findings in man, and the figures to information based on animal data. For drugs in categories B 3, C or D any harmful effects observed or likely to occur in man or animals are to be specified. The pregnancy categories are defined as follows: Category A. Drugs which may be assumed to have been used by a large number of pregnant women and women of child-bearing age, without any form of definite disturbance in the reproductive process having been noted so far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category B. Drugs which may be assumed to have been used by only a limited number of pregnant women and women of child-bearing age, without any form of definite disturbance in the reproduction process having been noted so far, e.g. an increased incidence of malformations or other direct or indirect harmful effects on the fetus. Category C. Drugs which by their pharmacological effects have caused, or must be suspected of causing disturbances in the reproduction process that may involve risk to the fetus without being directly teratogenic. Category D. Drugs which have caused an increased incidence of fetal malformations or other permanent damage in man or which on the basis of e.g. reproduction-toxicology studies must be suspected of doing so. This category comprises drugs with primary teratogenic effects. If the drug also has pharmacological effects that may directly or indirectly have a harmful effect on the fetus, this must also be stated. As experience of effects of drugs in Category B is limited, results of reproduction-toxicology studies in animals are indicated by allocation to one of three subgroups according to the following definitions: Category B 1.(ABSTRACT TRUNCATED AT 400 WORDS)

PIP: Since 1978, the Swedish catalogue of registered pharmaceutical preparations (FASS) has classified drugs in terms of their effects on reproduction and breastfeeding. On the basis of available data concerning effects on pregnancy and labor, pharmaceutical specialties are asigned to 1 of the following pregnancy categories: A--drugs that have been used by large numbers of pregnant women and women of childbearing age with no evidence of any disturbance in the reproductive process; B--drugs that have been used by only a limited number of pregnant and reproductive age women, yet have not been noted to cause any harmful effects on fetal development; C--drugs whose pharmacological effects are suspected to cause disturbances in the reproductive process that may involve risk to the fetus without being directly teratogenic; and D--drugs that, on the basis of reproduction-toxicology studies, are suspected to have caused an increased incidence of fetal malformations. Of the 675 active substances identified in the drugs included in FASS 1984, 205 have been allocated to Category A, 183 to Category A, 183 to Category B, 118 to Category C, and 70 to Category D. Category C includes beta-adrenoceptor blocking agents, benzothiadiazines and related diuretics, dicoumarl, sufonamides, rifampicin, chloramphenicol, glucocorticoids, antithyroid substances, benzodiazepines, narcotic analgetics, ergotamine, and inhibitors of prostglandin synthesis; Category D includes ethanol, quinine and quinidine, chloroquine and hydroxycloroquine, warfarin, cytostatic drugs, tetracyclines, aminoglycosides, androgens and other anabolic steriods, gestagens, diethylstilbestrol, penicillamine, phenobarbital, and anticonvulsants. With respect to use during breastfeeding, drugs are allocated to the following 4 groups: Group I--does not enter breast milk; Group II--enters breast milk but is unlikely to affect the infant; Group III--enters breast milk in such quantities that there is risk of affecting the infant; and Group IV--not known whether it enters breast milk. Group IV comprises over 50% of the drugs listed.

Medication during pregnancy and breast-feeding--a new Swedish system for classifying drugs.

As an aid for the prescription of drugs for women during pregnancy and lactation, a special section entitled "Pregnancy and breast-feeding" has been added to the description of most of the products in the Swedish catalogue of registered pharmaceutical specialties (FASS) since 1978. This article describes the system and also presents examples of the general texts proposed for certain groups of drugs.

Oncological study in rats of Ferastral, an iron-poly-(sorbitol-gluconic acid) complex, after intramuscular administration.

Four groups of Sprague-Dawley rats were given Ferastral, an iron-poly(sorbitol-gluconic acid) complex (IPSG) or Imferon, an iron-dextran complex, intramuscularly twice a week for 17 weeks. The experiment lasted for 95 weeks. Each compound was given to two groups, one low dose group and one high dose group. Depending on the body mass, the dose levels varied between 2.5 and 10 mg (25-50 mg/kg body mass) and between 5 and 20 mg (50-100 mg/kg body mass) of iron per rat, respectively. The mean total dose of iron per rat was calculated to be 235 and 495 mg, respectively. Another group of animals served as a control. From about the 30th experimental week onwards tumours developed at the intramuscular injection sites in the groups given Ferastral and Imferon. The tumours appeared to be sarcomas. In almost all the treated animals that lived longer than 30 weeks after the start of the experiment, sarcomas were present at the intramuscular injection sites. The sarcomas appeared earlier in the high dose groups than in the low dose groups and slightly earlier in the rats given Ferastral than in those given Imferon. No other pathological changes, including neoplasms, were considered to be related to the treatment.