PMID- 21704644
OWN - NLM
STAT- MEDLINE
DCOM- 20110929
LR  - 20110801
IS  - 1096-0333 (Electronic)
IS  - 0041-008X (Linking)
VI  - 255
IP  - 1
DP  - 2011 Aug 15
TI  - In vivo toxic and lethal cardiovascular effects of a synthetic polymeric 
      1,3-dodecylpyridinium salt in rodents.
PG  - 86-93
LID - 10.1016/j.taap.2011.06.003 [doi]
AB  - APS12-2 is one in a series of synthetic analogs of the polymeric alkylpyridinium 
      salts isolated from the marine sponge Reniera sarai. As it is a potential 
      candidate for treating non small cell lung cancer (NSCLC), we have studied its 
      possible toxic and lethal effects in vivo. The median lethal dose (LD(50)) of 
      APS12-2 in mice was determined to be 11.5mg/kg. Electrocardiograms, arterial 
      blood pressure and respiratory activity were recorded under general anesthesia in 
      untreated, pharmacologically vagotomized and artificially ventilated rats 
      injected with APS12-2. In one group, the in vivo effects of APS12-2 were studied 
      on nerve-evoked muscle contraction. Administration of APS12-2 at a dose of 8mg/kg 
      caused a progressive reduction of arterial blood pressure to a mid-circulatory 
      value, accompanied by bradycardia, myocardial ischemia, ventricular 
      extrasystoles, and second degree atrio-ventricular block. Similar 
      electrocardiogram and arterial blood pressure changes caused by APS12-2 (8mg/kg) 
      were observed in animals pretreated with atropine and in artificially ventilated 
      animals, indicating that hypoxia and cholinergic effects do not play a crucial 
      role in the toxicity of APS12-2. Application of APS12-2 at sublethal doses (4 and 
      5.5mg/kg) caused a decrease of arterial blood pressure, followed by an increase 
      slightly above control values. We found that APS12-2 causes lysis of rat 
      erythrocytes in vitro, therefore it is reasonable to expect the same effect in 
      vivo. Indeed, hyperkalemia was observed in the blood of experimental animals. 
      Hyperkalemia probably plays an important role in APS12-2 cardiotoxicity since no 
      evident changes in histopathology of the heart were found. However, acute lesions 
      were observed in the pulmonary vessels of rats after application of 8mg/kg 
      APS12-2. Predominant effects were dilation of interalveolar blood vessels and 
      lysis of aggregated erythrocytes within their lumina.
CI  - Copyright (c) 2011 Elsevier Inc. All rights reserved.
FAU - Grandic, Marjana
AU  - Grandic M
AD  - Institute of Physiology, Pharmacology and Toxicology, Veterinary Faculty, 
      University of Ljubljana, Gerbiceva 60, 1000 Ljubljana, Slovenia.
FAU - Sepcic, Kristina
AU  - Sepcic K
FAU - Turk, Tom
AU  - Turk T
FAU - Juntes, Polona
AU  - Juntes P
FAU - Frangez, Robert
AU  - Frangez R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110617
PL  - United States
TA  - Toxicol Appl Pharmacol
JT  - Toxicology and applied pharmacology
JID - 0416575
RN  - 0 (1,3-dodecylpyridinium bromide)
RN  - 0 (Pyridinium Compounds)
RN  - EC 3.1.1.7 (Acetylcholinesterase)
SB  - IM
MH  - Acetylcholinesterase/blood
MH  - Animals
MH  - Blood Pressure/drug effects
MH  - Electrocardiography/drug effects
MH  - Hemolysis/drug effects
MH  - Lethal Dose 50
MH  - Lung/drug effects/pathology
MH  - Male
MH  - Mice
MH  - Mice, Inbred BALB C
MH  - Pyridinium Compounds/*toxicity
MH  - Rats
MH  - Rats, Wistar
MH  - Respiration/drug effects
EDAT- 2011/06/28 06:00
MHDA- 2011/10/01 06:00
CRDT- 2011/06/28 06:00
PHST- 2011/02/09 00:00 [received]
PHST- 2011/05/23 00:00 [revised]
PHST- 2011/06/02 00:00 [accepted]
PHST- 2011/06/28 06:00 [entrez]
PHST- 2011/06/28 06:00 [pubmed]
PHST- 2011/10/01 06:00 [medline]
AID - S0041-008X(11)00215-8 [pii]
AID - 10.1016/j.taap.2011.06.003 [doi]
PST - ppublish
SO  - Toxicol Appl Pharmacol. 2011 Aug 15;255(1):86-93. doi: 
      10.1016/j.taap.2011.06.003. Epub 2011 Jun 17.