Intramuscular tolerance testing

The drag is administered into the subcutis of test animals (mouse, rat, rabbit, or dog) at the latero-dorsal area of the thoracic wall. The injection volume has to be adjusted to the size of the animal. The overall evaluation of findings is done according to the scoring described for intramuscular tolerance testing (Stotzer 1989). 

In 534 individuals aged 30 years, whose mothers had participated in a double-blind, randomized, placebo-controlled trial of antenatal betamethasone (two intramuscular doses 24 hours apart) for the prevention of neonatal respiratory distress syndrome, there were no differences between those exposed to betamethasone and placebo in body size, blood lipids, blood pressure, plasma cortisol, prevalence of diabetes, or history of cardiovascular disease (397). After the oral glucose tolerance test, those who had been exposed to betamethasone had higher plasma insulin concentrations at 30 minutes (61 versus 52 mIU/1) and lower glucose concentrations at 120 minutes (4.8 versus 5.1 mmol/1) than did those exposed to placebo. Antenatal exposure to betamethasone might result in insulin resistance in adult offspring, but has no effect on cardiovascular risk factors at 30 years of age. 

Microbiological estimations of Bi in urine have limited value. Ideally the urine should be frozen and estimations of Bn should be made without delay. The least fecal contamination of urine and any bacterial prolifera tion may lead to grossly inaccurate results. After oral administration relatively little vitamin B12 appears in the urine, and serum levels are a much better indication of amounts absorbed. Vitamin Bn tolerance tests based on determinations of urinary excretion of the vitamin after intramuscular injection are described by Estrada et al. (1954). E. L. Smith (1953) found that most of the radioactive material excreted in the urine by a human subject after an oral dose of labeled vitamin B12 was not present as microbiologically active cobalamin. A urinary excretion test with radioactive vitamin B12 is discussed on page 159. 

More recent studies, 9 12 at dosages that produce behavioral changes, have shown that chronic intramuscular or Intraperltoneal administration of SNA results in development of tolerance to several test situations In several animal species. Tolerance to roughly 2-4 times as much SNA as initially given was evident in the behavioral effects of SNA In these species. Tolerance to SNA was also observed In intramuscular SNA self-administration studies In the monkey. In the development of tolerance, such pharmacologic factors as dose per injection, Injection frequency, and duration of chronic exposure were considered to play a more Important role than behavioral factors (e.g., reinforcement loss).9... 

A number of DNA vaccines have progressed into clinical trials for the prevention and/or treatment of HIV, malaria, cytomegalovirus (CMV) and hepatitis B and C [23,24], So far the DNA vaccines have been well tolerated in clinical trials [23] and have produced both humoral and cellular responses in some trials [41], but overall the potency has been disappointing [20], Although DNA is typically injected intramuscularly, alternative delivery systems have been evaluated. One such system that has been tested clinically for hepatitis B involves coating plasmid DNA onto gold beads, which are then propelled into the epidermis using a needle-free delivery system [20,42,43],... 

A 65-year-old woman, who had previously tolerated calcitonin nasal spray, developed eye and nose congestion, an itchy nose, and sneezing minutes after using intranasal salmon calcitonin (17). She was later given intramuscular salmon calcitonin and developed generalized urticaria and nasal itching within minutes. Skin testing was positive with eel and salmon calcitonins but not human calcitonin, and she was treated with human calcitonin without adverse effects. 

Another study in healthy subjects using various experimental pain models found that ketamine antagonised the respiratory depressant effect of remifentanil. Remifentanil alone produced analgesic effects with all pain tests, but ketamine only enhanced the effect of remifentanil on intramuscular electrical stimulation. Acute remifentanil-induced hyperalgesia and tolerance were detected only by the pressure pain test and were not suppressed by ketamine. The combined effects of remifentanil and ketamine probably depend on the type of pain. ... 

Most work on saponins as immunological adjuvants has been done following parenteral inoculation. Saponins are more toxic by parenteral (i.p. or i.v.) administration than by the oral route, presumably because of a more complete uptake by the former. Toxicity associated with Quil A has limited its development to veterinary vaccines. The maximum well tolerated i.p. dose in mice was estimated to be 25 ig. Significantly lower toxicity was observed by subcutaneous, intradermal, and intramuscular routes of administration. The toxicity of individual saponins varies considerably. For example, the major peak saponin QS-18 (2) was found to be toxic in mice at low doses (80% mortality within three days after i.d. injection of 125 p,g) whereas QS-7 was non toxic (100% survival with 0.5 mg, the highest dose tested). A simple analogy between hemolytic activity and toxicity is not possible since QS-21 (3), which was shown to have a slightly higher hemolytic activity than QS-18 (2), was proven to be less toxic [9]. 

Clinically, butorphanol has been evaluated in normal volunteers for safety and tolerance both orally and parenterally. Single intramuscular doses ranging from 0.1 to 20 mg were studied. There was no Indication of hallucinogenic activity even in one volunteer who received the 20 mg dose Butorphanol and nalbuphine 231 have been tested clinically for analgesia parenterally and found to be approximately 10 times morphine and equlpotent to morphine respectively. 

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