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R Farinotti

Publications and source records attributed to R Farinotti.

At least 19 recordsLinked to original sources
PubMed2005

Increased expression of MDR1 mRNAs and P-glycoprotein in placentas from HIV-1 infected women.

P-glycoprotein transports several compounds including protease inhibitors, actually used in the clinical management of HIV-1 infection. Since P-glycoprotein is expressed in placental trophoblasts, its efflux activity could interfere with placental transfer of antiretrovirals. The purpose of this study was to investigate the expression of P-gp-encoding MDR1 gene and P-gp itself in full-term placentas from uninfected (n=35) and HIV-1 infected women (n=24). MDR1 transcripts were quantified by real-time PCR using relative (MDR1 normalized upon 28S levels) and absolute (copy number) determinations. P-glycoprotein localization and expression were evaluated by immunohistochemistry and western blot analysis, respectively. Relative or absolute PCR quantification showed a significant 3.3-fold (p<0.0009) or 3.7-fold (p<0.0002) mean increase in MDR1 placental transcription in HIV-infected compared to non-infected women, respectively. Ratios of individual HIV-positive values to HIV-negative mean ranged from 0.1 to 21.8. Moreover a significant 2.5-fold increased expression of immunoreactive P-glycoprotein was evidenced in placentas from HIV-infected women (p<0.0001). This MDR1 overexpression was observed in a similar extent in placentas from pregnant women treated with Zidovudine alone or in combination with Nelfinavir and/or Lamivudine. Our findings suggest that P-glycoprotein in placentas from HIV-infected women would contribute to modulate the materno-fetal transport of antiretrovirals across the placental barrier and consequently diminish fetal exposure to these compounds.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Evaluation of pharmacokinetic interaction between cetirizine and ritonavir, an HIV-1 protease inhibitor, in healthy male volunteers.

BACKGROUND: Serious adverse effects have been observed with some non-sedative H1-antihistamines (terfenadine and astemizole) when they were associated with drugs known to inhibit their metabolism. However, this is not a class effect, and this interaction should be considered on a case-by-case basis. The aim of this study was to evaluate the potential of pharmacokinetic interaction between cetirizine and ritonavir, the most potent cytochrome P450 (CYP) inhibitor. METHODS: An open-label, single-center, one-sequence crossover pharmacokinetic study was conducted in three running periods: cetirizine (CTZ) alone, ritonavir (RTV) alone and then CTZ plus RTV. For each period, steady-state pharmacokinetics were obtained. RTV and CTZ plasma concentrations were determined using validated liquid chromatography methods. The statistical method was based on a 90% confidence interval (CI) for the ratio of population geometric means (combination/drug alone) for each drug and for each parameter [area under the plasma concentration versus time curve (AUC(0-tau,ss)), value of maximum plasma concentration (C(max,ss))] and compared to bioequivalence ranges 80-125% and 70-143% for AUC(0-tau,ss) and C(max,ss), respectively. RESULTS: Among the 17 male subjects enrolled (26.4 +/- 8.6 years), 16 completed the study (1 withdrawal after the first period). The RTV pharmacokinetic parameter values were not affected by CTZ co-treatment. With RTV, a 42% increase in the CTZ AUC(0-tau,ss) (3406 versus 4840 microgh/l, 90% CI of 128-158%), a 53% increase in the CTZ elimination half-life (7.8 h versus 11.9 h, P = 0.001), a slight increase (15%) in the CTZ apparent volume of distribution (V(d,ss)/f) (34.7 l versus 39.8 l, P = 0.035), a 29% decrease in the CTZ apparent total body clearance (49.9 ml/min versus 35.3 ml/min, P < 0.001) and bioequivalent C(max,ss) (374 microg/l versus 408 microg/l) were observed. No serious drug related adverse effects were notified. CONCLUSIONS: CTZ does not significantly affect the pharmacokinetic parameters of RTV, and the association does not, thus, require a modification of the dosage of the protease inhibitor. The increased extent of exposure to CTZ in healthy subjects, in the presence of RTV administered at high doses, remained in the same range as previously observed in the elderly or in mildly renally impaired subjects.

Adolescent↗
PubMed2003

Comparison of lithium concentrations in red blood cells and plasma in samples collected for TDM, acute toxicity, or acute-on-chronic toxicity.

BACKGROUND: Lithium salts (Li+) are still one of the most appropriate treatments in manic-depressive disorders. Since Li+ has a narrow therapeutic index, plasma levels must be closely monitored to verify maintenance pharmacotherapy, to prevent side effects, to evaluate compliance and to avoid increasing rates of relapse. Although it has been reported that Li+ concentrations in red blood cells (RBC) should be a better indicator of brain levels, therapeutic drug monitoring (TDM) of Li+ is not based on its routine assessment. OBJECTIVE: The aim of this retrospective study was to compare Li+ concentrations in RBC and plasma and the calculated ratio (LiR= RBC/plasma concentrations) in the three groups of patients. METHODS: During the past 3 years, 309 Li+ measures were collected corresponding to 165 patients classified into three subgroups (TDM, acute or acute-on-chronic intoxication). Li+ plasma (Cplasma) and RBC (CRBC) concentrations were determined by atomic absorption spectrophotometry. RESULTS: Results showed that Li+ concentrations in plasma are significantly correlated to Li+ concentration in RBC (r=0.81, P<0.0001). Although a wide inter- and intra-variability was found, Cplasma, CRBC and LiR were statistically different in the three groups. Compared with TDM, Cplasma was more elevated in cases of acute intoxication whereas Li+ accumulated preferentially in RBC in cases of acute-on-chronic intoxication. CONCLUSION: This study shows the interest of determining Li+ in RBC and plasma for TDM, and that LiR could be a sensitive marker of intoxication and of Li+ impregnation.

Antimanic Agents↗
PubMed2003

[Medicinal iatrogenics in hospitals. A survey on a given day].

OBJECTIVE: Medicinal iatrogenics are responsible for hospital admissions but also occur in hospitals. In view of the lack of knowledge, prevalence and nature of the adverse drug-related events (ADE) in the Bichat-Claude Bernard hospital group in Paris, and because of the potential severity of the latter, the Local drug committee has decided to develop a policy to manage these risks. METHOD: The first stage consisted in a transversal study on a given day in the departments in which patients are hospitalised for more than 24 hours, in order to assess the prevalence, severity and preventability of ADE and to search for factors of risk. RESULTS: 107 ADE were observed in 89 patients on the day of the survey (9.9% global prevalence of ADE [CI 95%: 8.8% - 11.0%]). Among the latter, 57 patients had exhibited at least one adverse event during their hospitalisation, i.e., a prevalence of 6.3% ([CI 95%: 4.7% - 7.9%] ). Two thirds of these patients were hospitalised in medical departments. These nosocomial ADE (nosocomial adverse drug events) were serious or severe in 73% of cases and 25% could have been avoided. The only clearly identified risk factor was the number of drugs prescribed. CONCLUSION: This review has drawn the attention of the medical and paramedical community to the need to define vigilance markers, and has provided some elements of response that should be further completed by a prospective cohort study.

Adult↗
PubMed2003

Determination of the human cytochrome P450s involved in the metabolism of 2n-propylquinoline.

1 2n-Propylquinoline (2nPQ) is a newly developed drug for visceral antileishmaniasis and its activity has been previously evaluated in mice following oral administration. The study was carried out to investigate the kinetic formation of 2nPQ metabolites and to characterize the human liver CYP forms involved in its oxidative metabolism. 2. The inhibition of 2nPQ metabolite formation by specific substrates or inhibitors of CYP forms and correlation studies were performed in human liver microsomes. 2nPQ biotransformation was then studied in human lymphoblasts expressing specific CYPs and microsomal epoxide hydrolase. 3. Three major metabolites were produced by human liver microsomes and their structures were identified by ESI-LC/MS: dihydroxy-2n-propylquinoline, 3'-hydroxy-2n-propylquinoline and 1'-hydroxy-2n-propylquinoline. An intermediary metabolite, epoxy-2n-propylquinoline, formed by CYP was also biotransformed by microsomal epoxide hydrolase into dihydroxy-2n-propylquinoline. 4. 2nPQ oxidation follows Michaelis-Menten kinetics. In human liver microsomes, its metabolism was extremely inhibited by pilocarpine, coumarin and diethyldithiocarbamate. From a panel of 12 human liver microsome samples, the rate of 2nPQ oxidation was highly correlated with the activities of CYP2A6 and CYP2E1. Human lymphoblasts expressing specific CYPs showed the involvement of CYP2A6, CYP2E1 and CYP2C19. 5. The results indicate that 2nPQ metabolites are 3'- and 1'-hydroxylated by human liver microsomes and an epoxy-2n-propylquinoline is biotransformed into a dihydroxy-2n-propylquinoline by microsomal epoxide hydrolase.

Adult↗
PubMed2003

A 6-month prospective survey of cutaneous drug reactions in a hospital setting.

BACKGROUND: Few prospective studies are available on the incidence and analysis of the characteristics of adverse cutaneous drug reactions in hospital settings. OBJECTIVES: A 6-month prospective study was managed in our hospital among hospitalized patients to: (i) evaluate the incidence of cutaneous allergic reactions from systemic drugs; (ii) study characteristics of patients with cutaneous drug reactions; (iii) describe the adverse cutaneous reactions; and (iv) evaluate drug reaction imputability and preventability. METHODS: All suspected allergic cutaneous reactions to systemic drugs were collected during a 6-month period (November 2000 to May 2001). Exhaustivity of recording was ensured by regular dissemination of information about this study to the practitioners; a simple method for inclusion by fax was established. Inclusion criteria were suspected cutaneous allergic reactions induced by systemic drugs responsible for hospitalization or developed during hospitalization. A physical examination was done by a dermatologist who completed a standardized questionnaire. Requested information included patient characteristics (associated disorders, severity score), drug intake (list and chronology of the drug intake during the 3 weeks preceding the adverse reaction) and characteristics of the skin reaction (type, course). A group comprising dermatologists and pharmacologists evaluated the drug imputability and preventability. RESULTS: Forty-eight cases were collected. A prevalence of 3.6/1000 among hospitalized patients was estimated. The prevalence rate was higher in patients hospitalized in medical departments (0.5%) than in surgical departments (0.01%) (P < 0.001). The cases were mostly recruited in departments of infectious diseases and dermatology. The most frequent associated disorders were: human immunodeficiency virus (HIV) infection (19%), connective tissue disease (10%) and viral or autoimmune hepatitis (12%). Of these patients, 31% had had a previous immunological drug reaction. Adverse cutaneous drug reactions were principally exanthematous (56%). Reactions were considered severe in 34% of cases because they were responsible for hospitalization (18%), increased the duration of hospitalization (14%) or were life threatening (2%). Principal imputable drugs were antibiotics, mainly penicillins. An imputability score was likely in 56% of cases, but it was only possible to conclude definitively in 44% of patients. In 15% of the cases, the side-effect was considered to be preventable. CONCLUSIONS: This study finds a lower incidence than other studies that reported an incidence of 2% of cutaneous drug reactions in hospitalized patients, but only allergic adverse cutaneous reactions induced by systemic drugs were collected in this study. The previous studies were principally done in selected patients hospitalized only in general internal medicine or medical divisions. Our results confirm some data already known about skin drug reactions: HIV infection as a risk factor (P < 0.0001), high prevalence of adverse cutaneous reactions due to antibiotics, and difficulty in ascertaining the imputability of a drug. A high proportion (34%) of these reactions was severe and 15% were avoidable; these two facts justify the development of an intensive programme of clinical pharmacology.

Adult↗
PubMed2002

Chronic administration of verapamil, ketoconazole and carbamazepine: impact on immunological parameters.

Inhibitors of P-glycoprotein (P-gp) (verapamil) or cytochrome P-450 (ketoconazole) may reduce IL2 production and T lymphocyte proliferation in vitro. We have examined the effects of chronic oral administration of these drugs and of the cytochrome P450 inductor, carbamazepine, on the hematological and immunological parameters of mice. We found no changes after giving the mice 0.12 mg verapamil, 0.85 mg ketoconazole, or 0.514 mg carbamazepine per mouse for 4 weeks (5 days/week). But giving the drugs for an additional 7 weeks at 0.6 mg (verapamil), 4.25 mg (ketoconazole) or 2.57 mg/mouse (carbamazepine), resulted in significant decreases in monocytes in the verapamil treated group (-51%) and in CD4+ cells in the carbamazepine group (-35%). Chronic oral administration of these drugs reduced the lymphocyte counts of mice by 10-18% and their NK counts by 10-16%. These changes could be due to changes in P-gp function in the transport of IL2, with decreases caused by verapamil and ketoconazole.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2001

Determination of N-acetylation phenotype using caffeine as a metabolic probe and high-performance liquid chromatography with either ultraviolet detection or electrospray mass spectrometry.

A rapid, sensitive method using liquid chromatography-electrospray mass spectrometry (LC-ES-MS) was developed and evaluated for the simultaneous quantitative determination of caffeine metabolites 1U, 1X and AAMU in human urine. This method involved a simple dilution of urine samples. The chromatographic separation was achieved on a C18 reversed-phase column using a gradient of acetonitrile in 2 mM, pH 3.0 ammonium formate as mobile phase. After ionisation in an electrospray source, mass spectrometric detection was performed in the negative ion, selected ion monitoring mode. This method yielded acceptable accuracy and precision within the range 0.25-50 microg/ml. This analytical method was applied to investigate the N-acetylator phenotype of HIV-infected patients and compared with high-performance liquid chromatography with UV detection. Its specificity was better, which appeared to be absolutely necessary to prevent errors in metabolic ratios and phenotype interpretation.

Acetylation↗
PubMed2001

Intestinal absorption and metabolism of chlorpheniramine enantiomers in rat.

Chlorpheniramine (CPAM) is a chiral antihistaminic drug commercialized as a racemic mixture. The intestinal absorption and metabolism of CPAM have been investigated in rat using in vivo (oral and IV administration), in situ (intestinal loop model), and in vitro (everted sac model) experiments. Oral and IV administrations of 20 mg/kg of the racemic mixture show that the pharmacokinetics of CPAM are stereoselective, with higher AUCs for the (+)-S-enantiomer compared to its antipode. The monodesmethyl metabolite (DCPM) was quantifiable in blood and its pharmacokinetics are stereoselective after oral but not after IV administration. Experiments using intestinal loops and everted sacs showed that the absorption is not stereoselective and that in vivo stereoselective formation of DCPM is presumably due to stereoselective hepatic metabolism. Moreover, the in vitro and in situ absorption of CPAM are not modified by modulators of P-glycoprotein and cytochromes P450 (cyclosporin A, ketoconazole).

Animals↗
PubMed2001

Maternal-fetal transfer and amniotic fluid accumulation of lamivudine in human immunodeficiency virus-infected pregnant women.

OBJECTIVE: The purpose of this study was to investigate placental transfer and amniotic fluid concentrations of lamivudine in human immunodeficiency virus-infected women who received the agent during pregnancy. STUDY DESIGN: Mothers in the study were receiving antiretroviral therapy that included lamivudine in a clinical setting. Maternal blood, cord blood, and amniotic fluid samples were obtained simultaneously at the time of delivery from 57 mother-infant pairs. RESULTS: At a median of 8.5 hours after the last maternal oral 150-mg dose of lamivudine, median maternal and fetal plasma concentrations were 302 and 240 ng/mL, respectively. Individual maternal and fetal concentrations were strongly correlated (r2 = 0.36; P < 10(-4)), and their median ratio was about 1. The median concentration in the amniotic fluid was 5 times higher than that in maternal plasma (upper range of ratio, 133). CONCLUSION: Lamivudine appeared to cross the placenta by simple diffusion and is concentrated in the amniotic fluid. High amniotic fluid levels of lamivudine may carry both benefits and risks for the child.

Acquired Immunodeficiency Syndrome↗
PubMed2001

Maternal-fetal transfer of saquinavir studied in the ex vivo placental perfusion model.

OBJECTIVE: This study was undertaken to determine the placental transfer of the human immunodeficiency virus protease inhibitor saquinavir. STUDY DESIGN: An ex vivo perfused human placental cotyledon model was used. Ten placental perfusion studies were performed, with concentrations of saquinavir in the maternal compartment ranging from 322 to 2197 ng/mL (within reference therapeutic ranges). Drug concentrations were determined by high-performance liquid chromatography. RESULTS: The mean (+/- SD) fetal transfer rate of saquinavir was 1.8% +/- 1.6%, and the mean (+/- SD) clearance index was 0.05 +/- 0.05. A mean (+/- SD) of 1.6% +/- 3.1% of the perfused saquinavir was retained by the cotyledon. The small amount of saquinavir that crossed the placenta corresponded to the fraction not bound to human serum albumin. CONCLUSION: The low rate of placental transfer of saquinavir suggests that use of this antiretroviral drug by pregnant women may not lead to significant exposure of the fetus.

Female↗
PubMed2001

Effect of chronic renal failure on the expression and function of rat intestinal P-glycoprotein in drug excretion.

BACKGROUND: In chronic renal failure, the renal excretion of certain drugs is dramatically reduced. To determine whether other routes of drug elimination, such as secretion through the intestinal barrier by intestinal P-glycoprotein can be altered, we compared P-glycoprotein activity, P-glycoprotein protein content, and P-glycoprotein mRNA levels in intestine of control and chronic renal failure rats. METHODS: Chronic renal failure was surgically induced in rats by partial (7/8) nephrectomy. After 5 weeks, intestinal transport of rhodamine 123, a P-glycoprotein substrate, was carried out using an in vitro model of everted gut sacs. P-glycoprotein protein content was quantified by enzyme-linked immunosorbent assay and P-glycoprotein mRNA expression was evaluated by semi-quantitative reverse transcriptase polymerase chain reaction. RESULTS: A decrease of intestinal rhodamine 123 transport was observed in chronic renal failure rats, pointing to an inhibition of P-glycoprotein activity. Transport was inhibited in both sham-operated rats and rats with chronic renal failure by verapamil and cyclosporin A, but relative inhibition vs baseline was less marked in chronic renal failure than in sham-operated rats. In contrast, no significant differences in levels of P-glycoprotein protein or mRNA were observed between the two groups. CONCLUSIONS: Intestinal secretion of rhodamine 123 is mainly mediated by P-glycoprotein. It was reduced in rats with chronic renal failure, reflecting reduced intestinal drug elimination via a decrease in P-glycoprotein transport activity rather than via protein underexpression.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed2000

Interactions of racemic mefloquine and its enantiomers with P-glycoprotein in an immortalised rat brain capillary endothelial cell line, GPNT.

The brain distribution of the enantiomers of the antimalarial drug mefloquine is stereoselective according to the species. This stereoselectivity may be related to species-specific differences in the properties of some membrane-bound transport proteins, such as P-glycoprotein (P-gp). The interactions of racemic mefloquine and its individual enantiomers with the P-glycoprotein efflux transport system have been analysed in immortalised rat brain capillary endothelial GPNT cells. Parallel studies were carried out for comparison in human colon carcinoma Caco-2 cells. The cellular accumulation of the P-glycoprotein substrate, [(3)H]vinblastine, was significantly increased both in GPNT cells and in Caco-2 cells when treated with racemic mefloquine and the individual enantiomers. In GPNT cells, the (+)-stereoisomer of mefloquine was up to 8-fold more effective than its antipode in increasing cellular accumulation of [(3)H]vinblastine, while in Caco-2 cells, both enantiomers were equally effective. These results suggest that racemic mefloquine and its enantiomers are effective inhibitors of P-gp. Furthermore, a stereoselective P-glycoprotein inhibition is observed in rat cells but not in human cells. The efflux of [(14)C]mefloquine from GPNT cells was decreased when the cells were incubated with the P-gp modulators, verapamil, cyclosporin A or chlorpromazine, suggesting that MQ could be a P-gp substrate.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2000

Stereospecific versus nonstereospecific assessments for the bioequivalence of two formulations of racemic chlorpheniramine.

Chlorpheniramine (chlorphenamine, CPAM) is a racemic antihistaminic H1 drug containing two enantiomers. The aim of this study was to assess the bioequivalence of two formulations (reference and Vietnamese-tested formulation) of racemic chlorpheniramine combined with phenylpropanolamine in an open-labeled, randomized, crossover two-period study, after administration of 8 mg of racemic chlorpheniramine in 12 healthy Vietnamese subjects. First, dissolution of both formulations was tested in vitro according to USP requirements. Then the 12 subjects received both formulations after an overnight fast and a 7-day wash-out period. Plasma samples were collected up to 168 h. Plasma concentrations of total chlorpheniramine and its individual enantiomers were determined with a validated chiral HPLC method and pharmacokinetic parameters were estimated using model-independent analysis. For the reference formulation, Cmax and AUC values were higher for (+)S-chlorpheniramine ((+)S-CPAM) compared to (-)R-chlorpheniramine ((-)R-CPAM) (13.3 vs. 6.8 ng/ml and 409 vs. 222 ng/ml/h, respectively) while Clt/F and Vd/F were lower (9.8 vs. 17.6 l/h and 321 vs. 627 l, respectively). No difference was observed for Tmax, t(1/2), and MRT. Pharmacokinetic parameters were similar for the reference and the Vietnamese-tested formulation. Bioequivalence was assessed by Schuirmann test, as recommended by the current FDA and European Community criteria. Dissolution tests showed that both formulations were equivalent. A nonstereospecific, but not a stereospecific, approach indicated bioequivalence between the formulations.

Adult↗
PubMed2000

In vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia.

We evaluated the in vivo activity of levofloxacin alone or in combination with imipenem or amikacin in a mouse model of Acinetobacter baumannii pneumonia using a susceptible strain and one with low-level resistance (MIC/MBC of levofloxacin: 0.06/0.06 and 4/4 mg/L, respectively). As demonstrated previously with other pathogens, the AUC/MIC ratio predicted the efficacy of fluoroquinolones against A. baumannii. This parameter correlated with bactericidal effect and survival. Combination therapy did not enhance the efficacy of levofloxacin.

Acinetobacter Infections↗
PubMed2000

Placental transfer of pyrimethamine studied in an ex vivo placental perfusion model.

Pyrimethamine is used as and anti-infectious agent because of its antifolate properties. Its action is synergistic with that of dapsone and sulfamides on Toxoplasma gondii. The goal of the present study was to evaluate the placental transfer of pyrimethamine in an ex vivo model of perfused human placental cotyledon at term. Human placentas were perfused according to the slightly modified method of Schneider. The pyrimethamine fetal transfer rate was approximately 30%, while cotyledon clearance was about 1.8 ml/min. The placental transfer of pyrimethamine seems to be independent of the maternal concentrations of pyrimethamine, suggesting passive diffusion mechanisms or a nonsaturable active transport at the tested concentrations.

Female↗
PubMed2000

alpha(2)-adrenergic receptors stimulate oligopeptide transport in a human intestinal cell line.

Di- and tripeptides, as well as peptidomimetic drugs such as cephalexin (CFX), are absorbed by enterocytes via the oligopeptide transporter PepT1. We recently showed that the alpha(2)-adrenergic agonist clonidine increases CFX absorption in anaesthetized rats. Herein, we investigated whether alpha(2)-adrenergic receptors can directly affect PepT1 activity in a clone of the differentiated human intestinal cell line Caco-2 (Caco-2 3B) engineered to stably express alpha(2A)-adrenergic receptors at a density similar to that found in normal mucosa. Measurement of CFX fluxes across cell monolayers cultured on transwell filters demonstrated that the alpha(2)-agonists clonidine and UK14304 caused a 2-fold increase of CFX transport in Caco-2 3B cells, but not in Caco-2 (expressing PepT1 but not alpha(2)-adrenergic receptors) or in the HT29 19A clone (expressing alpha(2)-adrenergic receptors but not PepT1). The stimulatory effect of clonidine was abolished by glycyl-sarcosine (a competitor for the transporter) and blocked by yohimbine or RX821002 (alpha(2)-antagonists). Analysis of the kinetics of CFX transport in control and clonidine-treated Caco-2 3B cells showed that clonidine increased V(max) of CFX transport without changing K(m). Clonidine action was abolished by colchicine but not altered by amiloride, demonstrating that microtubule integrity but not Na(+)/H(+) exchanger activity is necessary for the effect of alpha(2)-agonists to occur. In conclusion, clonidine can directly activate alpha(2)-adrenergic receptors located on epithelial cells. The precise molecular mechanisms whereby these receptors modulate PepT1 activity remain to be elucidated but an increased translocation to the apical membrane of preformed cytoplasmic transporter molecules is likely to be involved.

Adrenergic alpha-2 Receptor Agonists↗