Intramuscular injections, toxicity studies

In another clinical study, patients suffering from hemophilia B, which is a bleeding disorder caused by a deficiency of coagulation factor IX, were treated with AAV vectors expressing human factor IX (13 9). These patients participated in a Phase I trial and received intramuscular injections of AAV vectors. Although only very low levels of secreted factor IX could be detected in the plasma of one patient, the treated patients showed some clinical benefits and a reduced intake of factor IX infusions. Moreover, no vector-related toxicity and germ line transmission was observed. 

In early studies, i.v. injection of 12 mg./m was used, but this proved to be too toxic, and 6 mg./m used. Currently, intramuscular injection is being favored, because side effects are minimal. In addition to inducing the production of interferon in primates, poly(ICLC) also enhances a number of immune functions (see below). 

Two water-soluble analogs of dimercaprol have been studied as lewisite antidotes. They are meso 2,3-dimer-captosuccinic acid (DMSA) and 2,3-dimercapto-l-pro-pane sulfonic acid (DMPS). These two drugs circumvent two major disadvantages associated with treatment with BAL the need for intramuscular injection and limitation of dose by toxicity. 

Soon after DFP was discovered, it was demonstrated that it had the capacity of inhibiting AChE irreversibly. One of the earliest published reports of a systematic study of the inhibitory properties of DFP was that of Koelle and Gilman (1946). In vitro log p/50 was reported to be 6.5 for serum BuChE and 4.2, 4.5, 4.8 for AChE from rat erythrocyte, brain, and muscle, respectively, with similar values in dogs. In vivo studies after intramuscular injection in rats, dogs, and monkeys were performed and inhibition, toxic effects and AChE regenerations were evaluated. Levels in the range of 0.05-1 mg/kg showed significant inhibition of serum ChE and doses of 1-5 mg/kg caused a total inhibition of erythrocyte cholinesterase. Human exposure to a dose of 0.5-2 mg/60 kg caused marked inhibition of serum BuChE, without any inhibition of erythrocyte AChE and/or toxic symptoms. 

A peculiar neuropsychiatric reaction to intramuscular injection of procaine penicillin comprises fear of death and auditory and visual hallucinations. A widely supported theory claims that this so called Hoigne syndrome is an embolic-toxic reaction, but recent findings strongly suggest that free procaine, liberated in vivo, is responsible. In one study, 26 patients received 4.8 million units of procaine penicillin i.m. Immediately after injection the plasma procaine levels amounted to 6.6 ixglraX (3.6-11 /ug/ml) and dropped quickly to less than 1 jUg/ml in all cases within 30 minutes. One of these patients experienced auditory and visual hallucinations his zero-time level of procaine was 9.5 jug/ml. The observation that the same symptoms can be elicited by intravenous injection of procaine and also that the time sequence of the plasma procaine levels and of the symptoms coincide (since the latter too disappear in 30 minutes) clearly indicate procaine as the causative factor (13, W -). 

Primary routes of entry of toxicants to the human body are dermal, gastrointestinal, and respiratory. Methods for studying these different routes are numerous, but they are perhaps best developed for the study of dermal absorption because this route is subject to more direct methodology, whereas methods for studying respiratory or gastrointestinal absorption require more highly specialized instrumentation. Additional routes encountered in experimental studies include intraperitoneal, intramuscular, and subcutaneous routes. When direct entry into the circulatory system is desired, intravenous (IV) or intra-arterial injections can be used to bypass the absorption phase. Information from this more direct route of entry (e.g., IV) should, however, be used in addition to data from the extravascular route of interest to adequately assess the true extent of absorption of a toxicant. 

The primary toxic effect elicited by chrysene is oncogenicity. Several studies have been conducted in mice in which chrysene (diluted in a variety of agents) was applied dermally either as a single dose (followed by a tumor promoting agent) or as multiple doses. Increased incidences of dermal tumors (papillomas and carcinomas) were observed in mice administered chrysene and a tumor promoting agent. Several studies were also conducted in which mice or rats received intramuscular or subcutaneous injections of chrysene... 

The acute toxicity of palytoxin by injection has been very well evaluated, with good data available on the lethal doses of this substance to many species of animals by various routes of injection. There is no doubt that injected palytoxin, whether administered via the intraperitoneal, intravenous, intramuscular, or subcutaneous route, is an exceptionally toxic compound. There is, however, surprisingly little information available on the oral toxicity of palytoxin. The major focus of toxicological studies on food contaminants such as palytoxin shonld be risk assessment, and since such contaminants are eaten, not injected, in assessing risks to hnman health of food, oral data are of paramount importance. What data there are indicate that palytoxin is very much less toxic when given orally than when administered by injection. In a comparative stndy, more than 700 times more palytoxin was required to kill mice via gavage than by intraperitoneal injection. Similarly, a crude extract of... 

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