Piperazines toxicity

R. A. Lovell, Ivermectin and piperazine toxicity in dogs and cats. Vet. Clin. North Am. Small Anim. Pract., 1990, 20, 453-468. 

A solution of 10-(piperazin-l-yl)-10,ll-dihydrodibenzo[6,/]thiepin (2.5 g, 8.4 mmol) in 100% formic acid (20 mL) was refluxed at 150 C for 6 h. The excess acid was removed by distillation at reduced pressure and the residue was treated with 10% aq NH3 (20mL), extracted with benzene (50mL) and the benzene solution was washed with dil HC1 and evaporated to dryness to give a neutral residue yield 1.8 g (98 %) mp 88 C (EtOH) (Note benzene should be replaced by organic solvents with lower toxicity). 

The answer is b. (Katzung, p 4822) Haloperidol, a butyrophenone, is by far the most likely antipsychotic to produce extrapyramidal toxicides Other agents, such as piperazine (an aromatic phenothiazine), thiothixene (a thioxanthene), and pimozide (a diphenylbutyropiperidine) are comparitively less likely to produce extrapyramidal toxicity than haloperi-dol. The antagonism of dopamine in the nigrostriatal system might explain the Parkinson-like effects Both haloperidol and pimozide act mainly on D2 receptors, whereas thioridazine and piperazine act on ooadrenergie receptors, and have a less potent but definite effect on D2 receptors. 

Piperazine (15b) itself, often as its citrate due to its low toxicity and cheapness, is still used for the treatment of pinworm and Ascaris infections. It has been shown to block neuromuscular transmission in Ascaris by means of an anticholinergic action at the... 

Emergency treatment depends on the immediate toxic effects of BZP and TFMPP. High blood pressure, abnormal heart rate or rhythm, seizures or convulsions, fever, and abnormal movements all have specific treatments and may require hospitalization for intravenous medications and general supportive care. Coma or decreased level of consciousness, respiratory depression, difficulty breathing, and severe allergic reaction may require treatment in an intensive care unit and assisted respiration. If a user experiences any untoward effects, or if someone inadvertently takes a much larger dose of medicinal piperazines than prescribed, it is prudent to contact a doctor, emergency medical services, or poison control. 

Four simple amines in which N atoms are contained in a ring structure are shown in Figure 15.3. Of the compounds shown in Figure 15.3, the first three are liquids under ambient conditions and have the higher toxicity hazards expected of liquid toxicants. All four compounds are colorless in the pure form, but pyrrole darkens upon standing. All are considered to be toxic via the oral, dermal, and inhalation routes. There is little likelihood of inhaling piperazine, except as a dust, because of its low volatility. 

Hepatotoxicity may be as frequent with piperidine and piperazine phenothiazines as with chlorpromazine, despite previous suggestions that the toxicity of these compounds is less. 

SAFETY PROFILE Poison by ingestion and skin contact. A skin and severe eye irritant. Mutation data reported. Combustible when exposed to heat or flame. It supports combustion and decomposes to yield toxic fumes of NOx. To fight fire, use water, foam, dr) chemical. See also PIPERAZINE. 

NIOSH REL (Piperazine) TWA 5.0 mg/m SAFETY PROFILE Moderately toxic by intraperitoneal route. Mildly toxic by ingestion. When heated to decomposition it emits very toxic fumes of NO and HCl. Used in making fiber, pharmaceuticals, and insecticides. See also PIPERAZINE. 

A study has been made of anti-pinworm activity of many quaternary piperazines (1688). In general, it has been found that the presence of the piperazine nucleus in drugs makes their activity more effective and decreases their toxicity (1689). 

The mechanism of the neurotoxicity induced by piperazine in mammals is unknown. Piperazine acts as a GABA agonist in invertebrates. The mechanism of liver and kidney toxicity seen in subchronic oral studies in laboratory animals has not been determined. 

In repeated dose studies, systemic toxicity was seen at dose levels of piperazine above 50 mg kg The results of a reproductive toxicity study suggest that piperazine can impair fertility. 

In a 13 week oral study, piperazine dihydrochloride was administered to dogs (four per sex per dose) at concentrations up to 3692 ppm in the diet. Clinical chemistry changes indicative of mild liver effects were the only sign of systemic toxicity. The no-observed-adverse-effect level in the study was 1477 ppm, which is 25 mg kg of piperazine base. In another 13 week oral study, piperazine was administered to rats (10 per sex per dose) at concentrations of 50, 150, or 500 mg kg in the diet. Histopathological changes were seen in the liver and kidneys in the two higher dose groups. The no-effect level in the study was 50 mg kg... 

In a two generation reproductive toxicity study, piperazine dihydrochloride was administered in the diet of rats at doses of 250, 600, or 1250 mg kg day A dose-response effect for decreased litter size was seen in the 600 and 1250 mg kg groups suggesting that piperazine exposure at these dose levels can impair fertility. 

The quinolone class of drugs were discovered in the 1960s when Lesher et al. isolated nalidixic acid as a by-product of chloroquine synthesis (2). More than a thousand quinolones and analogs have since been synthesized and evaluated in an attempt to reduce toxicity and increase antimicrobial potency. The attachment of a fluorine to C-6 and a piperazine or methylpiperazine to C-7 has led to more active agents such as norfloxacin, ciprofloxacin, ofloxacin and lomefloxacin (3). 

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