Dipyrone Research Articles

Synthesis and Biological Activity of 1-Chloromethyl- and 1-Dichloromethyl-3,3-Dialkyl-3,4-Dihydroisoquinolinium Chlorides

1-Chloromethyl- and 1-dichloromethyl-3,3-dialkyl-3,4-dihydroisoquinolines were synthesized via cyclo-condensation of dialkylbenzylcarbinols with chloroacetonitrile or dichloroacetonitrile. Their hydrochlorides were tested for antiarrhythmic, anticonvulsant, and analgesic activity. Water-soluble 1-chloromethylisoquinoline hydrochlorides showed antiarrhythmic activity with a maximum antiarrhythmic index of 14.8. These same compounds were active against corazole-induced convulsions. 1-Dichloromethylisoquinolines had analgesic effects comparable with that of metamizole sodium.

THE CHOICE OF DRUGS FOR THE TREATMENT OF INFECTIOUS DISEASES IN CHILDREN WITH DRUG ALLERGY

The article presents the results of clinical observation of 104 children hospitalized in the infectious department and having manifestations of allergies to drugs (medicines) at the prehospital stage or in the hospital. The frequency of allergic reactions to medicines in children with infectious diseases, their characteristics, as well as approaches to the choice of drugs for treatment, as manifestations of allergies, and the underlying disease in children with drug allergies are estimated. It has been shown that antibacterial drugs are a frequent cause of skin allergic reactions in patients with lacunar angina and infectious mononucleosis. In case of allergy to beta-lactams, macrolides and lincosamides serve as an alternative in most cases. As a drug of choice for fighting fever in patients with an acute allergic reaction to drugs, ibuprofen may be recommended, possibly using paracetamol, metamizole sodium.

The pharmacoeconomic analysis of the assortment and availability indicators of combinations of spasmolithic medicines used in the symptomic treatment of irritable bowel syndrome

Irritable Bowel Syndrome (IBS) is one of the most common gastrointestinal diseases, which belongs to the group of functional gastrointestinal disorders (FGID) and is characterized by a prolonged recurrent, often lifelong course. Despite the benign nature and the absence of the threat of disability or death, IBS negatively affects the performance, the quality of life of patients and requires significant expenditure of the healthcare system on the treatment of this group of diseases. Aim. To analyze the assortment and availability indicators of the combined antispasmodic drugs (CASD) presented at the pharmaceutical market of Ukraine during 2014-2017. Materials and methods. The combined antispasmodic drugs available at the Ukrainian pharmaceutical market were analyzed according to the data of the information retrieval systems “Morion” and Compendium online. For the analysis of socioeconomic availability the solvency index Ca.s was calculated. Information on the average wage was obtained on the website of the State Statistical Service of Ukraine. Results. As of 2017, the pharmaceutical market in Ukraine consisted of 50 TN of fixed CASD. Combinations were available in a wide range of TN and, in particular, by the diversity of different combinations of active medicinal substances. The affordable price range provided an opportunity to choose CASD taking into account safety and therapeutic effectiveness. The main assortment of combined antispasmodics for the treatment of IBS at the domestic pharmaceutical market was formed mainly due to drugs of foreign manufacture compared to monopreparations with the spasmolytic effect. By the indicator of socioeconomic availability almost all CASD during the study period belonged to the group of highly available drugs. Conclusions. Within 2014-2017, there were minor changes in the range of available combinations at the pharmaceutical market of Ukraine. There were new combinations that appeared for the first time, but there were also those which manufacture was discontinued. The most numerous combination of TN from all the subgroups of drugs was the INN antispasmodic drugs in combination with analgesics by ATC code A03D A02 Pitophenone and analgesics, which in 2017 had 25 TN. The price characteristics on CASD significantly expanded socioeconomic availability for Ukrainian consumers. Most of the CASD belonged to the segment of highly available antispasmodic combinations. Among the medium available drugs some TN were noted in the number of INN by the ATC code combination A03D A02 Pitophenone and analgesics (Metamizol sodium + Pitophenone + Fentiveriene bromide) and by the ATC code combination A03A A08 ** Dicycloverin and analgesics (Dicycloverin + Paracetamol).

Oxycodone is safe and effective for general anesthesia.

In clinical practice, using different opioid analgesics is common during the induction and maintenance of general anesthesia and for postoperative analgesia. However, if the opioid analgesic could be limited to a single drug, we hypothesized that the risk of adverse drug interactions could be reduced, with fewer adverse effects. We examined the use of oxycodone as a single opioid in a well-defined cohort of orthopedic patients undergoing general anesthesia. In this retrolective, monocentric investigation, we reviewed data from 83 patients who underwent general anesthesia and received intravenous oxycodone as the sole analgesic (0.075 mg/kg during induction and 0.05 mg/kg during maintenance). The use of oxycodone during general anesthesia and the postoperative pain scores were recorded. Safety was evaluated by the measurement of hemodynamic changes (blood pressure, heart rate), the detection of pathologic changes in the electrocardiogram, changes of the peripheral oxygen saturation, and by the assessment of adverse effects. There was no significant change in peripheral oxygen saturation or the electrocardiogram during or while recovering from general anesthesia. Heart rate changed only slightly from reversal to recovery (73.3/min versus 78.3/min, p < 0.05) and from prior intubation to recovery (72.5/min versus 78.3/min, p < 0.05). Systolic and diastolic blood pressure did not change significantly from the time points "after intubation" to "after incision," and "during recovery." Fifty-nine percent (n = 49) of patients' records revealed pain scores with a maximum of 3 on a numeric rating scale (NRS) of 0 to10 during the postoperative period. In 45 percent of patients (n = 37), further analgesics such as acetaminophen, dipyrone, or additional doses of oxycodone were used. No severe adverse events were recorded. According to data from 93 percent of patients (n = 77), nausea scores were less than 3 on a NRS of 0 to 10. Oxycodone can be used as the sole opioid in orthopedic surgery with good intra- and postoperative efficacy and safety; ie, without clinically relevant changes in hemodynamic and respiratory parameters.

Chitosan/waste coffee-grounds composite: An efficient and eco-friendly adsorbent for removal of pharmaceutical contaminants from water

Waste coffee-grounds (WCG), a poorly explored source of biocompounds, were combined with chitosan (Cs) and poly(vinyl alcohol) (PVA) in order to obtain composites. Overall, WCG showed a good interaction with the polymeric matrix and good dispersibility up to 10 wt-%. At 5 wt-% WCG, the composite exhibited a noticeable enhancement (from 10 to 44%) of the adsorption of pharmaceuticals (metamizol (MET), acetylsalicylic acid (ASA), acetaminophen (ACE), and caffeine (CAF)) as compared to the pristine sample. The highest removal efficiency was registered at pH 6 and the removal followed the order ASA > CAF > ACE > MET. For all pharmaceuticals, the adsorption kinetics was found to follow the pseudo-second order model, while the adsorption mechanism was explained by the Freundlich isotherm. Reuse experiments indicated that the WCG-containing composite has an attractive cost-effectiveness since it presented a remarkable reusability in at least five consecutive adsorption/desorption cycles.

Efficacy of perioperative anesthesia for patients with burns

Predictors of the severity of pain after a thermal trauma vary depending on the phase of the burn wound healing. For the analysis of a homogen eous sample of victims with a deep burn, patients with a total burn injury area of 15.4 ± 4.2%, who underwent autodermoplasty of the skin during 14 daysafter the thermal trauma.Patients were divided in to two groups: first group (n = 30), which in the perioperative period was anesthetized with Sertofen (dexketoprofen trometamol 50 mg / 2 ml 2 ml 3 times a day) in the intensive care complex. The first dose of the drug was administered intraoperatively to prevent analgesia. Fol low-up anesthesia with Sertofen was carried out at 50 mg / 2 ml 2 ml 3 time s a day for 2-3 days postoperative period. Second group (n = 28) – in the nearest postoperative period received a narcotic analgesic (promedol 2% 1 ml), as an analgesia used analgin (metamizole sodium). All patients in the first and second observation groups underwent surgical treatment of skin burns at 12.5 ± 2.8 and 10. 3 ± 2.5 days of burn disease, respectively.It was established that in patients of first group with perioperative anesthesia with Sert fen, was observed more even decrease of pain syndrome, a tendency to lower blood levels of cortisol and stable blood glucose values.It was concluded, that in perioperative period in patients with thermal trauma the use of dexketoprofen trometamol ( Sertofen ), causes effective and safe anesthesia and can be recommended in this group of patients.

Pharmacokinetic profiles of the active metamizole metabolites after four different routes of administration in healthy dogs.

Metamizole (MT), an analgesic and antipyretic drug, is rapidly hydrolyzed to the active primary metabolite 4-methylaminoantipyrine (MAA) and relatively active secondary metabolite 4-aminoantipyrine (AA). The aim of this study was to assess the pharmacokinetic profiles of MAA and AA after dose of 25mg/kg MT by intravenous (i.v.), intramuscular (i.m.), oral (p.o.), and rectal (RC) routes in dogs. Six dogs were randomly allocated to an open, single-dose, four-treatment, four-phase, unpaired, crossover study design. Blood was collected at predetermined times within 24hr, and plasma was analyzed by a validated HPLC-UV method. Plasma concentrations of MAA and AA after i.v., i.m., p.o., and RC administrations of MT were detectable from 5 (i.v. and i.m.) or 30 (p.o. and RC) min to 24hr in all dogs. The highest concentrations of MAA were found in the i.v., then i.m., p.o., and RC groups. Plasma concentrations of AA were similar for i.v., i.m., and RC, and the concentrations were approximately double those in the PO groups. The AUCEV/IV ratio for MAA was 0.75±0.11, 0.59±0.08, and 0.32±0.05, for i.m., p.o., and RC, respectively. The AUCEV/IV ratio for AA was 1.21±0.33, 2.17±0.62, and 1.08±0.19, for i.m., p.o., and RC, respectively. Although further studies are needed, rectal administration seems to be the least suitable route of administration for MT in the dog.

Course of plasma substance P concentrations during umbilical surgery in calves

The objective of this orientating study was to describe plasma concentrations of substance P in calves undergoing umbilical surgery with two different analgesic protocols. The study was conducted as a randomized controlled double blinded trial. Ten calves (aged 39 10 days) were treated with meloxicam (CON) for analgesia, and 11 calves (aged 37 8 days) with meloxicam and metamizole (MET). Umbilical surgery under general anaesthesia was performed according to a strictly standardized protocol. Blood samples were taken at the day of surgery (one hour before and 5, 15, 30, 45, 60, 90, 150 and 510 minutes after skin incision). Plasma concentrations and AUC of substance P were determined. Plasma substance P increased during umbilical surgery in both groups. In CON, there was a significant difference to plasma substance P baseline concentration 5, 30 and 90 minutes after skin incision. Plasma substance P concentrations were lower in MET compared with CON at all times, and did not differ significantly from baseline concentration. Even though there was no significant difference in the plasma substance P concentrations in-between the groups, the results show that after the administration of metamizole additionally to meloxicam, plasma substance P concentrations in MET were lower than in CON at all times. This fact could indicate that substance P might be a suitable biomarker for nociception and pain. Further studies are needed to confirm this hypothesis.

Adsorption Of Metamizole Sodium By Activated Carbon In Simulated Gastric And Intestinal Fluids

In vitro adsorption of metamizole sodium by activated carbon was studied at pH 1.2 and 7.5 in order to simulate gastric and intestinal fluids. In the first 5 minutes, more than eighty percent of the total adsorption occurred but the adsorption process achieved to the equilibrium in 1 hour. Time to reach equilibrium was not changed with the changing pH, concentration of the adsorbate or the adsorbent amount. The equilibrium data followed the Langmuir model and therefore fitted to L-type in accordance with the Giles classification for adsorption isotherms. The maximum removal capacities of the activated carbon for metamizole sodium were calculated using Langmuir equation and found as 185.19 mg/g and 161.29 mg/g at pH 1.2 and 7.5, respectively.

Dissolution studies of metamizole sodium and pseudoephedrine sulphate dosage forms − comparison and correlation of electronic tongue results with reference studies

This work reports a critical evaluation of the results of the release of active substances (APIs) from novel pharmaceutical formulations provided by an electronic tongue system (ET). Detailed dissolution studies of modified-release granules used in pharmacotherapy containing metamizole sodium and pseudoephedrine sulphate were carried out. The impact of the dissolution-modifying excipients (carmellose sodium and hypromellose) on the dissolution process as well as on the outcomes of the sensor array of ion-selective electrodes was investigated. The obtained dissolution profiles were compared and correlated with those registered during the reference studies performed according to the pharmacopoeial method. It was pointed out that the proper evaluation of the efficiency of the release modification requires the examination of dosage forms as well as physical mixtures of API and excipient. Moreover, the results obtained using potentiometric ET were complementary to the classical methodology. Their partial inconsistency, remarked during several experiments, should be interpreted with caution owing to simultaneous sensing of APIs and excipients by the sensors and their various performances (i.e. selectivity and sensitivity) towards these components.

Synthesis and Analgesic Activity of bis(3,4-dihydroquinoxalin-2(1H)-one) and bis(3,4-dihydro-2H-1,4-benzoxazin-2-one) Derivatives

An ester condensation between 3,5-diacetyl-2,6-dimethylpyridine and an excess of diethyl oxalate was used for the preparation of 4,4'(2,6-dimethylpyridine-3,5-diyl)bis(2-hydroxy-4-oxobut-2-enoate). The synthesized hydroxyester was shown to readily react with о-phenylenediamine and о-aminophenol with the formation of bis(3,4-dihydroquinoxalin-2(1H)-one) and bis(3,4-dihydro-2H-1,4benzoxazin-2-one) derivatives, which showed superior in vivo analgesic activity compared to the reference drug, metamizole sodium.

Metamizol: Something to think about

Metamizol: Something to think about

Synthesis and Analgesic Activity of 1-substituted 3-methyl-6-methoxy-7(n-butoxy)-3,4-dihydroisoquinolines

Cyclocondensation of O-butylated eugenol with various nitriles was used to synthesize 1-substituted derivatives of 3-methyl-6-methoxy-7-(n-butoxy)-3,4-dihydroisoquinoline. Hydrochlorides of the study compounds were tested for analgesic activity using the “hot plate” test. The experiments showed that the study compounds had analgesic effects greater than those of metamizole sodium and similar to those of ibuprofen.

Синтез и анальгетическая активность 1-замещённых 3-метил-6-метокси-7-(&lt;i&gt;н&lt;/i&gt;-бутокси)-3,4-дигидроизохинолина

Циклоконденсацией О-бутилированного эвгенола с различными нитрилами синтезированы 1-замещённые производные 3-метил-6-метокси-7-(н-бутокси)-3,4-дигидроизохинолина. Гидрохлориды полученных соединений изучены на анальгетическую активность по тесту «горячей пластинки». Опыты показали, что полученные соединения проявляют анальгетический эффект, превышающий эффекты метамизола натрия и близкий к ибупрофену.

Ultrasound-Guided Bilateral Thoracic Paravertebral Blocks as an Adjunct to General Anesthesia in Patients Undergoing Reduction Mammaplasty: A Historical Cohort Study.

This study investigates whether ultrasound-guided thoracic paravertebral blocks would improve postoperative analgesia in patients undergoing bilateral reduction mammaplasty. After obtaining ethics committee approval, data of 70 patients who underwent bilateral reduction mammaplasty were reviewed. Sixty-four patients' data were evaluable; 30 were in the general anesthesia group and 34 were in the thoracic paravertebral block group. Data such as time to first pain, intraoperative fentanyl requirement, postoperative numeric rating scale scores, number of patients who required tramadol in the postoperative care unit, and rescue analgesic consumption through the first 2 postoperative days were analyzed. Time to first pain was 311 minutes (range, 0 to 1605 minutes) and 20 minutes (range, 0 to 120 minutes) in the thoracic paravertebral block and general anesthesia groups, respectively (p < 0.001). Fentanyl requirement was 52.94 ± 11.94 µg and 115 ± 29.79 µg in the thoracic paravertebral block and general anesthesia groups, respectively (p < 0.001). Numeric rating scale scores were lower in the thoracic paravertebral block group through the first 2 postoperative hours (p < 0.001), and only two of 34 patients required tramadol in the postoperative care unit (p < 0.001). On postoperative day 1, both metamizole sodium (p < 0.001) and paracetamol (p = 0.018), and on day 2, only metamizole sodium (p < 0.001) consumption was lower in the thoracic paravertebral block group. Adding ultrasound-guided thoracic paravertebral blocks to general anesthesia postponed time to first pain and reduced analgesic consumption in patients undergoing bilateral reduction mammaplasty. Therapeutic, III.

Growth and characterization of organic layers deposited on porous-patterned Si surface

The organic layers with the thickness from a few nanometers up to few micrometers have been deposited from the chemical solution at room temperature on porous patterned Si surfaces using two medical solutions: thiamine diphosphide (pH=1÷2) and metamizole sodium (pH=6÷7). Based on evolution of morphology, structural and compositional features obtained by scanning electron microscopy, X-ray analysis, reflectance high energy electron diffraction the grown mechanisms in thin organic layers are discussed in the terms of terrace-step-kink model whereas self-organized assemblies evaluated more thick layers. Transport mechanism features and possible photovoltaic properties are discussed on the base of differential current-voltage characteristics.

Antinociceptive effect of systemically administered dipyrone (metamizol), magnesium chloride or both in a murine model of cancer

Opioid effectiveness to treat cancer pain is often compromised by the development of tolerance and the occurrence of undesirable side effects, particularly during long-term treatment. Hence, the search for more efficient analgesics remains a necessity. The main goal of this study was to relieve neuropathic symptoms associated with tumour growth by administering the non-opioid analgesic dipyrone (DIP) alone or in combination with magnesium chloride (MgCl2 ), an adjuvant that blocks the NMDA receptor channel. Mice were inoculated with a melanoma cell line (B16-BL6) in the left thigh and two protocols were used to evaluate the effect of DIP (270mg/kg), MgCl2 (200mg/kg), or the combination DIP-MgCl2 . In the therapeutic protocol the drugs, alone or combined, were administered once tumour had promoted increased nociception. In the preventive protocol, drugs were administered prior to the appearance of the primary tumour. Tumour growth was assessed with a caliper and nociception was determined using behavioural tests. DIP promoted antinociception only at the beginning of both protocols due to the development of tolerance. The combination DIP-MgCl2 improved the antinociceptive effect, avoiding tolerance and reducing tumour growth in the preventive treatment, more efficiently than each compound alone. These results suggest that DIP-MgCl2 may represent a safe, affordable and accessible option to reduce tumour growth and to treat cancer pain avoiding the risk of tolerance, without the typical complications of opioids agents, particularly when long-term treatment is required. This study shows a non-opioid analgesic combined with an adjuvant as a therapeutic option to treat cancer pain. The avoidance of antinociceptive tolerance when repeated administration is required, as well as tumor growth reduction, are additional advantages to be considered.

Influence of dissolution-modifying excipients in various pharmaceutical formulations on electronic tongue results

The overall performance of a potentiometric electronic tongue (ET) as well as the sensitivity and selectivity pattern of particular ion-selective electrodes forming the array towards exemplary APIs (metamizole sodium, pseudoephedrine sulphate) and excipients (hypromellose, carmellose, Eudragit E) was determined. Simultaneous sensing of both API and the encapsulating excipient in their physical mixture was noticed using potentiometric sensors. Usually, such altering of chemical image is treated as an evidence of taste masking/modified release effect (linked with chemical entrapment of API in polymer matrix), while the observed “mixture effect” can also take place which may complicate the interpretation of ET results. Moreover, the influence of the same excipients on chemical images of various APIs was compared and related to sensor array performance. The presented considerations should be taken into account in the case of ET assessment of drug dissolution profiles and detection of modified release effect, especially when novel drug delivery systems are considered.

Influence of different excipients on the properties of hard gelatin capsules with metamizole sodium

Abstract Metamizole is an effective non-opioid analgesic drug used in the treatment of acute and chronic pain. Due to induced potentially life-threatening blood disorders, metamizole was withdrawn from market in many parts of the world, however, it is one of the most popular analgesics in Poland that is available as an over the counter drug. Patients tend to prefer capsules over tablets, as they are easier to swallow and taste better. The powder-filled capsules also have greater bioavailability and require less excipients, as compared to tablets. Polymic excipients are mainly used in capsule filling, and have influence upon the physico-chemical properties of the hard gelatin capsules and the powder formulation. The aim of the study was to determine whether various combinations of polymers impact the disintegration time and pharmaceutical availability of hard gelatin capsules with metamizole sodium. The results of our work demonstrated that the 80% of all active substance was released in all tested formulations within 15 minutes. Herein, the capsule containing lactose monohydrate had the longest release (4% after 2 min.), while capsules containing mannitol had the fastest release (81.2% after 2 min.). Moreover, the addition of HPMC to capsules with lactose brought about a slight increase in the metamizole release rate, while the addition of PVP 30 to capsules with microcrystalline cellulose slightly accelerated release. This data suggests that the use of different polymers in capsules formulation brings about changes in the physical properties of powders and modifies the release profile of metamizole. In our study, the most preferred formulation was one containing microcrystalline cellulose (good powder properties and fairly fast release).

Pharmacokinetic Assessment of the Marker Active Metabolites 4-Methyl-amino-antipyrine and 4-Acetyl-amino-antipyrine After Intravenous and Intramuscular Injection of Metamizole (Dipyrone) in Healthy Donkeys

Metamizole (MT) is an analgesic and antipyretic drug labelled for use in humans, horses, cattle, swine, and dogs in some countries. Metamizole is rapidly hydrolyzed to the active primary metabolite 4-methyl-amino-antipyrine (MAA). MAA is formed in much larger amounts compared to other minor metabolites. Among the other secondary metabolites, 4-amino-antipyrine (AA) is also relatively active. The aim of this research was to evaluate the pharmacokinetic profiles of MAA and AA after administration of 25 mg/kg MT by intravenous (IV) and intramuscular (IM) routes in healthy donkeys. Six jennies were randomly allocated to two equally sized treatment groups according to a 2 × 2 crossover study. Blood was collected at predetermined times within 24 hours, and plasma was analyzed by a validated HPLC UV method. Plasma concentrations of MAA after IV and IM administrations of MT were detectable from 5 minutes to 10 hours in all the donkeys. Plasma concentrations of AA were detectable from 5 minutes to 8 hours, but in smaller amounts. Cmax (P < .01), AUC0-last, AUC0-∞, AUMC0-last, and MRT (P < .05) were statistically different between the IV and IM groups. The AUCIM/AUCIV ratio of MAA was 1.37. The AA concentrations were lower than those found for MAA. The AA plasma versus time curves profiles after the two routes of administration of MT were variable (within the groups) and different (between the groups). Tmax, λz, and AUC0-last were found to be statistically different between the groups (P < .05). The AUCIM AA/AUCIV AA ratio was 2.26.