A new spectrophotometric method for the determination of methyldopa.

A new, simple and low cost spectrophotometric method for the determination of methyldopa in pharmaceutical preparations was developed. The method was based on the coupling of methyldopa with 2,6-dichloroquinone-4-chlorimide (DCQ). The absorbance maximum (λ max) of the resulted colored product was at 400 nm. Different buffers were used to determine the optimal pH for the reaction. About 1% w/v acetate buffer with pH 8.0 gave the optimal pH required for the reaction. Of the different solvents tried, water and ethanol were found to be the most suitable solvents. Beer's law was obeyed in concentration range of 4-20 µg/ml methyldopa. The correlation coefficient was found to be (r = 0.9975). The limit of detection and limit of quantification were 1.1 µg/ml and 3.21 µg/ml, respectively. The reaction ratio between methyldopa and DCQ was studied and found to be 1:3. The work included the study of the possible interference of hydrochlorothiazide found in combination with methyldopa tablets. The method was validated and results obtained for the assay of two different brands of methyldopa tablets were compared with the BP method (colorimetric). The repeatability and reproducibility of the developed method were evaluated and the obtained results quoted. The derivative formed as a result of the reaction of methyldopa with DCQ was isolated and its possible mechanistic pathway was suggested.

Stability studies on some benzocycloheptane antihistaminic agents.

The photostability of selected benzocycloheptane antihistaminic agents, namely, loratadine (I), pizotifen (II), ketotifen fumarate (III) and cyproheptatidine (IV), was investigated. Both I and II were photolabile while III and IV were photostable. To perform stability studies on the photolabile compounds (I and II), specific stability-indicating high performance liquid chromatographic (HPLC) methods were established. The accuracy, precision and reliability of the developed HPLC methods for the assay of I and II in their pharmaceutical dosage forms were reported. Assay results for both drugs were within R.S.D. values <2%. The stability-indicating power of the developed methods was validated through study of UV-degraded solutions of I and II contained in quartz cells. The photostability of both drugs was studied under UV-irradiation at 254 nm. The photodegradation kinetics of both drugs, studied in different solvents, are also reported. TLC fractionation of photodegraded solutions of both drugs, revealed two fluorescent photodegradates of drug I. The use of UV-absorbers (ascorbic acid and p-aminobenzoic acid (PABA)) enhanced the photostability of both drugs possibly through a spectral-overlay effect.

Stability studies on diloxanide furoate: effect of pH, temperature, gastric and intestinal fluids.

The degradation of the amoebicide diloxanide furoate in alkaline medium at different temperatures was investigated using both a spectrophotometric and a developed HPLC method. In solutions, the drug was found to undergo decomposition, i.e., temperature and pH dependent. The pH-rate profile at pH between 7.6 and 9.6 indicated a first-order dependence of Kobs on [-OH]. Arrhenius plot obtained at pH 8 was linear between 40 and 63 degrees C. The estimated activation energy of hydrolysis was found to be 18.25 kcal degree.mol(-1). The effect of simulated gastric and intestinal fluids on the drug was also investigated. A new thin-layer chromatographic (TLC) procedure for the fractionation of the drug and its alkaline hydrolysis products has been developed and was found to compare favorably with that of the British Pharmacopoeia. Three hydrolysis products of a basic methanolic solution of the drug, namely furoic acid, diloxanide and methylfuroate could be identified by the use of TLC, HPLC, infrared and mass spectrometry.

Effects of alkali and simulated gastric and intestinal fluids on danazol stability.

The degradation kinetics of methanolic solution of danazol (0.020% w/v) in aqueous buffers and sodium hydroxide was investigated using stability-indicating HPLC method. The drug degrades in alkaline medium through a base-catalysed proton abstraction rather than via an oxidative mechanism involving oxygen species. The degradation followed pseudo-first-order kinetics. The rates pH-profile exhibited specific base catalysis. The stability of the drug was found to be dependent on pH, buffer concentration, buffer species (acetate, borate, phosphate) and temperature. The ionic strength did not affect the stability of the drug. The energy of activation according to Arrhenius plot was estimated to be 22.62 kcal mol(-1) at pH 12 and temperatures between 30 and 60 degrees C. The effect of simulated gastric and intestinal fluids on the drug stability was also investigated. Two major hydrolytic degradation products were separated and identified by IR, NMR and mass spectrometry and the degradative pathway suggested.

Studies on the cardiovascular depressant effects of N-ethyl- and N-benzyl-1,2-diphenylethanolamines in the rat: elucidation of the mechanisms of action.

The influence and mechanisms of action of N-ethyl- and N-benzyl-1,2-diphenylethanolamines (compounds E and B, respectively) on the arterial blood pressure and the heart rate of the rat together with their effects on CaCl2-induced arrhythmias in the rat were investigated. Both E and B in doses of (1.5-12 micromol/kg IV) decreased the arterial blood pressure and the heart rate in a dose-dependent manner. Studies with various receptor blockers, enzyme inhibitors and CaCl2 revealed that E-induced cardiovascular depressant effects were mainly due to CaCl2 channel blocking action and activation of cyclic guanylyl cyclase or release of NO whereas the cardiovascular effects of B seemed to involve both blockade of Ca2+ channels and activation of parasympathetic ganglia. Both compounds (12-14.5 micromol/kg) completely protected the rat against CaCl2 (60 mg kg(-1))-induced tachyarrhythmias. The B compound seemed to be several times more potent than the E compound in its cardiovascular depressant actions. The results suggest the potential usefulness of both compounds in the treatment of hypertension and supraventricular arrhythmias.

Studies on the spasmolytic and uterine relaxant actions of n -ethyl and n -benzyl-1,2-diphenyl ethanolamines: elucidation of the mechanisms of action.

The influence of N -ethyl- and N -benzyl-1,2-diphenyl ethanolamines (compounds E and B, respectively) was examined on the spontaneously contracting rabbit jejunum and the rat uterus together with their influence on the contractions induced by some spasmogens in the guinea-pig ileum and oxytocics and CaCl2in the pregnant rat uterus. Both E and B inhibited the spontaneous contractions of the rabbit jejunum with ID50values of 0.13 and 0.03 micromol ml-1. Their inhibitory activities were not antagonized by alpha- or beta-adrenoceptor blockers but significantly reversed by CaCl2(0.015 micromol ml-1). The compounds also antagonized nicotine, ACh-, histamine-, 5-HT- and CaCl2-induced contractions by 44-100%. Compound E seemed to be several times more potent than B in inhibiting the spontaneous uterine contractions with an ID50of (7 nmol ml-1). Their inhibitory effects were not antagonized by beta2-adrenoceptor or H2-receptor blocking drugs. Both compounds (40 nmol ml-1) antagonized in a competitive manner CaCl2-induced contractions in the K+-depolarised uterus and PGE2and oxytocin-induced uterine contractions. The ID50values were in the range of 1.6-10.7 nmol ml-1. The results suggest that E and B compounds may be considered as putative L-Ca2+channel blockers with certain selectivities. The E compound seemed to be more selective against uterine L-Ca2+channels and the B compound against intestinal smooth muscles. Thus, the compounds may be of potential value in treatment of some colics, the irritant bowel syndrome, dysmenorrhoea and premature deliveries.

Effect of pirenzepine on the N-demethylation of D(-)ephedrine and ethylmorphine by rabbit liver microsomes.

The possible interaction of pirenzepine with the mixed-function oxidases obtained from phenobarbital-pretreated rabbit microsomes was examined in vitro. Under experimental conditions that did not lead to its own N-demethylation, the drug inhibited the microsomal oxidase systems responsible for the N-demethylation of D(-)ephedrine and ethylmorphine. Kinetic studies showed that pirenzepine inhibited the metabolism of both drugs in a competitive manner. The results indicated that the observed pirenzepine stability to the hepatic N-demethylating system is not a result of low affinity of the drug to the system.

Effects of N-methyl- and N-isobutyl-1,2-diphenyl ethanol amines on the spontaneous and evoked contractions in the rat isolated uterus.

1. The effects of N-methyl- and N-isobutyl-1,2-diphenyl ethanol amine (compounds M & E), respectively and diltiazem (D) were examined on the spontaneous and evoked uterine contractions of pregnant rats in vitro. 2. Addition of compound M (75-300 microM), compound E (15-60 microM) or D (100-400 nM) to the uterine tissues, inhibited the spontaneous contractions in a dose-dependent manner. The potency order was D greater than E greater than M. 3. The inhibitions were reversed by elevating the extracellular Ca2+ concentration by 20 mM. The compounds also antagonised CaCl2-evoked contractions. 4. Treatment of rats with either compound during pregnancy days (1-16) did not affect the implantation process and did not induce any teratogenicity. 5. The uterine inhibitory effects of the compounds may be due to blockade of uterine Ca2+ channels.

Cardiovascular depressant effects of N-methyl- and N-isobutyl-1,2-diphenyl ethanolamines: elucidation of the mechanisms of action.

The cardiovascular effects of N-methyl-1,2-diphenyl ethanolamine (compound M) and N-isobutyl-1,2-diphenyl ethanolamine (compound E) were examined in anaesthetized rats and their effects were compared with those of verapamil and diltiazem. Administration of compound M (10-80 mumole/kg), compound E (2-16 mumole/kg), diltiazem (1.5-24 mumole/kg) or verapamil (1.25-10 mumole/kg) induced dose-dependent decreases in arterial blood pressure and heart rate. The induced cardiovascular changes were not antagonized by chlorpheniramine, cimetidine or imidazole. Indomethacin antagonized the diltiazem-induced hypotension without any effect on that of compounds M and E. The effects of all compounds tested were antagonized by pretreatment of the rats with CaCl2 (1.2-2.4 mmole/kg). Furthermore, methylene blue significantly antagonized the compound E- and diltiazem-induced hypotension. Treatment of the animals with propranolol enhanced the compound M- and E-induced hypotension. Compounds M and E antagonized the NA-induced increase in arterial blood pressure in a competitive manner. Compounds M and E seem to exert their cardiovascular effects via interference with the influx of extracellular Ca2+. Furthermore, compound E and diltiazem may act partially via activation of guanylyl cyclase.

Synthesis and antinociceptive activity of ring substituted N-[(2-phenyl-2-hydroxy)ethyl]-4-phenyl-4-carboethoxypiperidines.

A series of phenyl substituted N-[(2-phenyl-2-hydroxy)ethyl]-4-phenyl-4-carboethoxylpiperidine were synthesized and their antinociceptive activity tested in mice and compared with morphine sulphate. All compounds demonstrated antinociceptive activity in both the hot plate and the writhing tests. The studies showed that the antinociceptive activity is dependable on both the nature and the position of the substituent on the phenyl ring. Antagonism study with naloxone suggests possible interaction of the new compounds with the opioid receptors.

Antiaggregatory activity of N-methyl- and N-isobutyl-1,2-diphenyl ethanolamines in rat platelets.

The ability of N-methyl-1,2-diphenyl ethanolamine (compound M), N-isobutyl-1,2-diphenyl ethanolamine (compound E), diltiazem and verapamil to inhibit in vitro ADP-induced platelet aggregation was examined in rat platelet-rich plasma. Pretreatment of the platelets with the compounds (0.1-3 mM) for 3 min at 37 degrees C, inhibited an ADP-induced aggregation in a concentration-dependent manner. The maximum percentage inhibitions induced by compounds M, E, diltiazem and verapamil were: 95.5 +/- 6.5, 98.4 +/- 7.5, 100 and 95.9 +/- 8.3% at concentrations of 3, 0.64, 0.96 and 0.4 mM, respectively (n = 8 - 12). The inhibitory dose 50 (ID50) values for compounds M, E, diltiazem and verapamil were 1.3 +/- 0.13, 0.29 +/- 0.01, 0.44 +/- 0.03 and 0.2 +/- 0.01 mM, respectively. The antiaggregatory effects were not antagonized by methylene blue (50-200 microM), but were completely antagonized (greater than 95%) by elevation of the Ca2+ level in the platelet-rich plasma by 0.2-0.7 mM. Co-administration of (-)propranolol (17 microM) with anyone of the compounds enhanced the antiaggregatory effects. The compounds (0.1-0.2 mM) enhanced the prostacyclin (0.01 nM)-induced antiaggregatory activity. The antiaggregatory effects of the compounds are likely to be due to an inhibition of influx of Ca2+ into the platelets.

The antiarrhythmic activity of N-alkyl-1,2-diphenylethanolamines.

The activity of N-alkyl-1,2-diphenylethanolamines against CaCl2-induced cardiac arrhythmia was evaluated in the rat. The potencies of the compounds were compared with that of the established calcium ion-channel blocker, verapamil. The N-methyl, N-ethyl, and N-isobutyl derivatives as well as verapamil at doses of 2-8 mumols kg-1 protected the animals against the induced arrhythmia. The potency order was verapamil greater than N methyl greater than N-ethyl greater than N-isobutyl derivatives. The N-isopropyl and N-butyl derivatives were inactive. The antiarrhythmic activity of the compounds was not due to local anesthetic activity but may be caused by calcium-channel inhibition.

Antipsychotic properties of new N-(4-substituted-1-piperazinylethyl)- and N-(4-substituted-1-piperidinylethyl)-phthalimides.

A series of N-(4-phenyl- and 4-pyridyl-1-piperazinylethyl)- and N-(4-phenyl-1-piperidinylethyl)-phthalmides were synthesized and tested for antipsychotic activity. All compounds suppressed the spontaneous motor activity and the apomorphine-induced climbing in mice and pergolide-induced locomotor activity in rats, demonstrating psychotropic properties equal to the corresponding properties of sulpiride. Although the compounds, like sulpiride, were less potent than haloperidol in blocking the locomotor activities, they caused no catalepsy, a major side effect following treatment with conventional antipsychotic agents. It is likely that the new compounds produce their neuroleptic activities through inhibition of limbic dopamine receptors.

Synthesis and pharmacological activity of N-alkyl-1,2-diphenylethanolamines.

A series of N-alkyl-1,2-diphenylethanolamines were synthesized and their pharmacological activities evaluated on various mammalian organs and systems. All compounds produced a generalized inhibitory effect on smooth and cardiac muscles and an increase in coronary flow as well as a brief reduction in rabbit blood pressure. The latter effect was not prevented by pretreatment of the animals with atropine, propranolol, or metoprolol. The compounds were devoid of local anesthetic activity and their inhibitions of the contraction of the isolated rabbit intestine and perfused heart were reversed by exogenous calcium ions. It is proposed that the compounds produce their effects through calcium-channel blockade. The inhibitory effects of some of these compounds were comparable to those of a known calcium-channel blocker.

Acute reversible pulmonary ischemia. A cause of the acute chest syndrome in sickle cell disease.

A 6-year-old girl with sickle cell disease was admitted to the hospital with the diagnosis of the acute chest syndrome. The laboratory findings and the radionuclear lung scan supported a diagnosis of pulmonary infarction rather than pneumonia. She improved with intravenous fluids, oxygen, penicillin, and theophylline. The most likely explanation for the rapid resolution of the clinical syndrome, the chest x-ray, and lung scan abnormalities is that masses of sickled cells caused transient pulmonary vascular occlusion leading to perfusion defects and ischemia, and that the sickled cell thrombi were dislodged before the infarction occurred. To our knowledge, this phenomenon has not been described as a cause of the acute chest syndrome in sickle cell disease in children.

Synthesis and antimicrobial activity of new furan derivatives.

5-Nitrofuran derivatives were synthesized and their antibacterial activity was investigated using standard bacterial strains and clinical isolates. The compounds showed inhibitory effects on both Gram-positive and Gram-negative organisms.