A drug fatality involving Kratom.

A 17-year-old white man who showed no obvious signs of trauma was found unresponsive in bed and was pronounced dead at the scene. The decedent had a documented history of heroin abuse and chronic back pain and reportedly self-medicated with Kratom (mitragynine). The autopsy was remarkable only for pulmonary congestion and edema and a distended bladder, both of which are consistent with, though not diagnostic of, opiate use. A laboratory work-up revealed therapeutic levels of over-the-counter cold medications and benzodiazepines. However, of interest was a level of mitragynine at 0.60 mg/L. Given the facts of the case, the Medical Examiner certified the cause of death as "possible Kratom toxicity" and the manner of death was classified as "accident."

Postmortem atropine concentrations in resuscitation cases.

The medications used during resuscitation are often in and of themselves toxic. Several reports have been published regarding toxicities of these drugs, including lidocaine, procainamide, and atropine. But how does a forensic pathologist or toxicologist differentiate a possible intoxication from therapeutic or resuscitory use especially given that the concentrations of such drugs, when used in the setting of resuscitation, have not been studied? Concentrations of a well-known resuscitation medication, atropine, were assessed in cases where it was administered before death during attempted resuscitation in an effort to address this deficiency. A review of deaths occurring in 2009 was undertaken to identify cases where drugs known to be used during resuscitation were present on toxicological analysis. Autopsy reports and medical records were examined to determine how much atropine was administered, the timing and route of administration, the time the sample was drawn (antemortem and postmortem), the source of the sample, and the ultimate cause of death. Eighty-nine cases were identified in which atropine was given before death during attempted resuscitation and was detected in the blood on postmortem toxicological screening; 11 cases were identified in which atropine was administered before death yet was not detected on the postmortem toxicological screening. Mean age was 41 years, and there were 65 males and 35 females. The overall median dose of atropine given was 3 mg, the median difference between the time of last administration of the atropine to the time of death (or draw for antemortem samples) was 15 minutes, and the median atropine concentration was 0.1 mg/L. Analysis failed to reveal significant differences in the atropine concentration based on the route of administration (intravenous or intraosseus), the cause of death, or the time since administration (within the first 2 hours). Analysis did reveal a difference between the atropine concentrations in peripheral versus central blood sources and with prolonged postmortem interval (>24 hours) suggesting postmortem redistribution.

In vitro and in vivo evaluation of a melamine dendrimer as a vehicle for drug delivery.

Cell-based and acute and subchronic in vivo toxicity profiles of a dendrimer based on melamine reveal that this class of molecules warrants additional study as vehicles for drug delivery. In cell culture, a substantial decrease in viability was observed at 0.1 mg/mL. For the acute studies, mice were administered 2.5, 10, 40 and 160 mg/kg of dendrimer via i.p. injection. At 160 mg/kg, 100% mortality was seen 6-12 h after injection. For the other cohorts, blood chemistry work revealed no renal damage was taking place at 48 h. Liver enzyme activity nearly doubled for the mice treated at 40 mg/kg suggesting hepatotoxicity. For the subchronic studies, three i.p. injections of 2.5-40 mg/kg of dendrimers were administered at 3-week intervals. No mortality was observed. Forty-eight hours following the last administration, blood chemistry revealed no renal damage, but liver damage was indicated by elevated serum enzyme activity at the highest dose. Histopathological data further confirms that doses up to 10 mg/kg show no hepatic damage at subchronic doses. However, subchronic doses at 40 mg/kg lead to extensive liver necrosis.

Cytotoxicity, hemolysis, and acute in vivo toxicity of dendrimers based on melamine, candidate vehicles for drug delivery.

A small library of dendrimers was prepared from a common precursor that is available in 5 g scale in five linear steps at 56% overall yield. The precursor is a generation three dendrimer that displays 48 peripheral sites by incorporating AB4 surface groups. Manipulation of these sites provided six dendrimers that vary in the chemistry of the surface group (amine, guanidine, carboxylate, sulfonate, phosphonate, and PEGylated) that were evaluated for hemolytic potential and cytotoxicity. Cationic dendrimers were found to be more cytotoxic and hemolytic than anionic or PEGylated dendrimers. The PEGylated dendrimer was evaluated for acute toxicity in vivo. No toxicity--neither mortality nor abnormal blood chemistry based on blood urea nitrogen levels or alanine transaminase activity--was observed in doses up to 2.56 g/kg i.p. and 1.28 g/kg i.v.

Reduction of drug toxicity using dendrimers based on melamine.

Dendrimers based on melamine can reduce the organ toxicity of solubilized cancer drugs administered by intraperitoneal injection. Methotrexate and 6-mercaptopurine, both FDA approved anticancer drugs, are known hepatotoxins. The solubility of these molecules can be increased by mixing them with a dendrimer based on melamine. C3H mice were administered subchronic doses of methotrexate or 6-mercaptopurine with and without a solubilizing dendrimer. Forty-eight hours after dosing, the mice were sacrificed and serum was collected for biochemical analyses. The levels of alanine transaminase, ALT, were used to probe liver damage. When the drugs are encapsulated by the dendrimer, a significant reduction in hepatotoxicity is observed: ALT levels from the rescued groups (drug + dendrimer) were 27% (methotrexate) and 36% (6-mercaptopurine) lower than those of animals treated with the drug alone.